Mayo Clinic Myeloma Amyloidosis Dysproteinemia Group
Transcript of Mayo Clinic Myeloma Amyloidosis Dysproteinemia Group
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Mayo Clinic Myeloma Amyloidosis Dysproteinemia Group
Scottsdale Arizona Rochester Minnesota Jacksonville Florida
Vision Statement
To Advance Individualized Care Have a
Global Impact and Cure
Myeloma and Related Disorders
copy2014 MFMER | 3357202-3
Strength of Our Practice Mayo Clinic 1960-2014
Strengths
bull Largest Myeloma and Related Disorders Groups in the World
bull Multidisciplinary Group
bull Hematologists
bull 20 at Mayo Clinic Rochester MN
bull 6 at Mayo Clinic Arizona
bull 4 at Mayo Clinic Florida
bull 14 hematologists are at Professor Level
bull Specialists in Divisions other than HemOnc
bull 7 across the 3 sites
bull Complete Integration across the 3 Mayo Clinic sites
bull Myeloma SPORE (PI Leif Bergsagel)
Strengths
bull International Leadership in research education and practice
bull Molecular Classification of MGUS SMM and Myeloma
bull Risk-adapted therapy of Myeloma and Related Disorders
bull Epidemiology of Plasma Cell Disorders
bull Related Plasma Cell Disorders
bull MGRS
bull Amyloidosis
bull POEMS
bull Castlemanrsquos disease
bull WM
bull Mayo Led Clinical Trials
bull Leadership in ECOG
bull Extensive Clinical and Laboratory Databases
Unique Programs
bull Epidemiology Biomarkers (Rajkumar Kyle Kumar Dispenzieri)
bull Virotherapy (Russell Dingli Peng)
bull Center for Individualized Medicine (Stewart)
bull Vaccine and Adoptive Cell Therapy (Lin)
bull Novel Imaging for Myeloma (Drake)
bull Novel Laboratory Evaluation (Ketterling Morice)
bull Mass Spec (Murray Bergen Barnidge Kurtin)
bull Genomics (Stewart Bergsagel Fonseca)
bull Novel Therapeutics (Stewart Bergsagel Kumar)
bull Immunotherapy (Lin Chanan-Khan)
bull Hematology-Oncology Outcomes Research-Oriented Group (Go Hashmi)
International Leadership
bull NCI Multiple Myeloma Steering Committee
bull Shaji Kumar Chair Vincent Rajkumar- member
bull ECOG Myeloma Committee
bull Vincent Rajkumar Chair
bull Journals (Editors of Myeloma Section)- Leukemia European Journal of Haematology American Journal of Hematology Blood Cancer Journal Mayo Clin Proc Clin Lymphoma and Myeloma Amyloid
International Leadership
bull International Myeloma Working Group (IMWG)
bull Vincent Rajkumar co-chair
bull International Myeloma Foundation (IMF)
bull Robert Kyle and Vincent Rajkumar Board Members Robert Kyle Chair of the Scientific Advisory Board
bull International Waldenstroumlms Macroglobulinemia Foundation (IWMF)
bull Robert Kyle and Steve Ansell Board of Trustees Robert Kyle chair Scientific Advisory Committee
bull International Society of Amyloidosis (ISA)
bull Angela Dispenzieri President
bull International Myeloma Society (IMS)
bull Angela Dispenzieri Treasurer
bull International Kidney and Monoclonal Gammopathy Research Group (IKMG)
bull Nelson Leung President Angela Dispenzieri Treasurer
Clinical Trial Leadership
bull Principal Investigator (PI) Role on many prominent NationalInternational Phase III Trials
bull Pomalidomide trials (Martha Lacy)
bull E1A06 MPT vs MPR (Keith Stewart)
bull MM 020 Rd vs MPT (Angela Dispenzieri)
bull S0777 Rd vs VRd (Angela Dispenzieri)
bull ASPIRE Rd vs KRd (Keith Stewart)
bull E1A11 VRD vs KRd (Shaji Kumar)
bull Ixazomib Rd vs IRd (Vincent Rajkumar)
bull Ixazomib Phase III AL (Angela Dispenzieri)
bull S1304 Highstd dose carfilzomib (Sikander Ailawadhi)
bull S1211 RVd vs RVd-Elo (Sikander Ailawadhi)
Publications
bull ~80-100 per year excluding abstracts and book chapters
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Vision Statement
To Advance Individualized Care Have a
Global Impact and Cure
Myeloma and Related Disorders
copy2014 MFMER | 3357202-3
Strength of Our Practice Mayo Clinic 1960-2014
Strengths
bull Largest Myeloma and Related Disorders Groups in the World
bull Multidisciplinary Group
bull Hematologists
bull 20 at Mayo Clinic Rochester MN
bull 6 at Mayo Clinic Arizona
bull 4 at Mayo Clinic Florida
bull 14 hematologists are at Professor Level
bull Specialists in Divisions other than HemOnc
bull 7 across the 3 sites
bull Complete Integration across the 3 Mayo Clinic sites
bull Myeloma SPORE (PI Leif Bergsagel)
Strengths
bull International Leadership in research education and practice
bull Molecular Classification of MGUS SMM and Myeloma
bull Risk-adapted therapy of Myeloma and Related Disorders
bull Epidemiology of Plasma Cell Disorders
bull Related Plasma Cell Disorders
bull MGRS
bull Amyloidosis
bull POEMS
bull Castlemanrsquos disease
bull WM
bull Mayo Led Clinical Trials
bull Leadership in ECOG
bull Extensive Clinical and Laboratory Databases
Unique Programs
bull Epidemiology Biomarkers (Rajkumar Kyle Kumar Dispenzieri)
bull Virotherapy (Russell Dingli Peng)
bull Center for Individualized Medicine (Stewart)
bull Vaccine and Adoptive Cell Therapy (Lin)
bull Novel Imaging for Myeloma (Drake)
bull Novel Laboratory Evaluation (Ketterling Morice)
bull Mass Spec (Murray Bergen Barnidge Kurtin)
bull Genomics (Stewart Bergsagel Fonseca)
bull Novel Therapeutics (Stewart Bergsagel Kumar)
bull Immunotherapy (Lin Chanan-Khan)
bull Hematology-Oncology Outcomes Research-Oriented Group (Go Hashmi)
International Leadership
bull NCI Multiple Myeloma Steering Committee
bull Shaji Kumar Chair Vincent Rajkumar- member
bull ECOG Myeloma Committee
bull Vincent Rajkumar Chair
bull Journals (Editors of Myeloma Section)- Leukemia European Journal of Haematology American Journal of Hematology Blood Cancer Journal Mayo Clin Proc Clin Lymphoma and Myeloma Amyloid
International Leadership
bull International Myeloma Working Group (IMWG)
bull Vincent Rajkumar co-chair
bull International Myeloma Foundation (IMF)
bull Robert Kyle and Vincent Rajkumar Board Members Robert Kyle Chair of the Scientific Advisory Board
bull International Waldenstroumlms Macroglobulinemia Foundation (IWMF)
bull Robert Kyle and Steve Ansell Board of Trustees Robert Kyle chair Scientific Advisory Committee
bull International Society of Amyloidosis (ISA)
bull Angela Dispenzieri President
bull International Myeloma Society (IMS)
bull Angela Dispenzieri Treasurer
bull International Kidney and Monoclonal Gammopathy Research Group (IKMG)
bull Nelson Leung President Angela Dispenzieri Treasurer
Clinical Trial Leadership
bull Principal Investigator (PI) Role on many prominent NationalInternational Phase III Trials
bull Pomalidomide trials (Martha Lacy)
bull E1A06 MPT vs MPR (Keith Stewart)
bull MM 020 Rd vs MPT (Angela Dispenzieri)
bull S0777 Rd vs VRd (Angela Dispenzieri)
bull ASPIRE Rd vs KRd (Keith Stewart)
bull E1A11 VRD vs KRd (Shaji Kumar)
bull Ixazomib Rd vs IRd (Vincent Rajkumar)
bull Ixazomib Phase III AL (Angela Dispenzieri)
bull S1304 Highstd dose carfilzomib (Sikander Ailawadhi)
bull S1211 RVd vs RVd-Elo (Sikander Ailawadhi)
Publications
bull ~80-100 per year excluding abstracts and book chapters
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
copy2014 MFMER | 3357202-3
Strength of Our Practice Mayo Clinic 1960-2014
Strengths
bull Largest Myeloma and Related Disorders Groups in the World
bull Multidisciplinary Group
bull Hematologists
bull 20 at Mayo Clinic Rochester MN
bull 6 at Mayo Clinic Arizona
bull 4 at Mayo Clinic Florida
bull 14 hematologists are at Professor Level
bull Specialists in Divisions other than HemOnc
bull 7 across the 3 sites
bull Complete Integration across the 3 Mayo Clinic sites
bull Myeloma SPORE (PI Leif Bergsagel)
Strengths
bull International Leadership in research education and practice
bull Molecular Classification of MGUS SMM and Myeloma
bull Risk-adapted therapy of Myeloma and Related Disorders
bull Epidemiology of Plasma Cell Disorders
bull Related Plasma Cell Disorders
bull MGRS
bull Amyloidosis
bull POEMS
bull Castlemanrsquos disease
bull WM
bull Mayo Led Clinical Trials
bull Leadership in ECOG
bull Extensive Clinical and Laboratory Databases
Unique Programs
bull Epidemiology Biomarkers (Rajkumar Kyle Kumar Dispenzieri)
bull Virotherapy (Russell Dingli Peng)
bull Center for Individualized Medicine (Stewart)
bull Vaccine and Adoptive Cell Therapy (Lin)
bull Novel Imaging for Myeloma (Drake)
bull Novel Laboratory Evaluation (Ketterling Morice)
bull Mass Spec (Murray Bergen Barnidge Kurtin)
bull Genomics (Stewart Bergsagel Fonseca)
bull Novel Therapeutics (Stewart Bergsagel Kumar)
bull Immunotherapy (Lin Chanan-Khan)
bull Hematology-Oncology Outcomes Research-Oriented Group (Go Hashmi)
International Leadership
bull NCI Multiple Myeloma Steering Committee
bull Shaji Kumar Chair Vincent Rajkumar- member
bull ECOG Myeloma Committee
bull Vincent Rajkumar Chair
bull Journals (Editors of Myeloma Section)- Leukemia European Journal of Haematology American Journal of Hematology Blood Cancer Journal Mayo Clin Proc Clin Lymphoma and Myeloma Amyloid
International Leadership
bull International Myeloma Working Group (IMWG)
bull Vincent Rajkumar co-chair
bull International Myeloma Foundation (IMF)
bull Robert Kyle and Vincent Rajkumar Board Members Robert Kyle Chair of the Scientific Advisory Board
bull International Waldenstroumlms Macroglobulinemia Foundation (IWMF)
bull Robert Kyle and Steve Ansell Board of Trustees Robert Kyle chair Scientific Advisory Committee
bull International Society of Amyloidosis (ISA)
bull Angela Dispenzieri President
bull International Myeloma Society (IMS)
bull Angela Dispenzieri Treasurer
bull International Kidney and Monoclonal Gammopathy Research Group (IKMG)
bull Nelson Leung President Angela Dispenzieri Treasurer
Clinical Trial Leadership
bull Principal Investigator (PI) Role on many prominent NationalInternational Phase III Trials
bull Pomalidomide trials (Martha Lacy)
bull E1A06 MPT vs MPR (Keith Stewart)
bull MM 020 Rd vs MPT (Angela Dispenzieri)
bull S0777 Rd vs VRd (Angela Dispenzieri)
bull ASPIRE Rd vs KRd (Keith Stewart)
bull E1A11 VRD vs KRd (Shaji Kumar)
bull Ixazomib Rd vs IRd (Vincent Rajkumar)
bull Ixazomib Phase III AL (Angela Dispenzieri)
bull S1304 Highstd dose carfilzomib (Sikander Ailawadhi)
bull S1211 RVd vs RVd-Elo (Sikander Ailawadhi)
Publications
bull ~80-100 per year excluding abstracts and book chapters
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Strengths
bull Largest Myeloma and Related Disorders Groups in the World
bull Multidisciplinary Group
bull Hematologists
bull 20 at Mayo Clinic Rochester MN
bull 6 at Mayo Clinic Arizona
bull 4 at Mayo Clinic Florida
bull 14 hematologists are at Professor Level
bull Specialists in Divisions other than HemOnc
bull 7 across the 3 sites
bull Complete Integration across the 3 Mayo Clinic sites
bull Myeloma SPORE (PI Leif Bergsagel)
Strengths
bull International Leadership in research education and practice
bull Molecular Classification of MGUS SMM and Myeloma
bull Risk-adapted therapy of Myeloma and Related Disorders
bull Epidemiology of Plasma Cell Disorders
bull Related Plasma Cell Disorders
bull MGRS
bull Amyloidosis
bull POEMS
bull Castlemanrsquos disease
bull WM
bull Mayo Led Clinical Trials
bull Leadership in ECOG
bull Extensive Clinical and Laboratory Databases
Unique Programs
bull Epidemiology Biomarkers (Rajkumar Kyle Kumar Dispenzieri)
bull Virotherapy (Russell Dingli Peng)
bull Center for Individualized Medicine (Stewart)
bull Vaccine and Adoptive Cell Therapy (Lin)
bull Novel Imaging for Myeloma (Drake)
bull Novel Laboratory Evaluation (Ketterling Morice)
bull Mass Spec (Murray Bergen Barnidge Kurtin)
bull Genomics (Stewart Bergsagel Fonseca)
bull Novel Therapeutics (Stewart Bergsagel Kumar)
bull Immunotherapy (Lin Chanan-Khan)
bull Hematology-Oncology Outcomes Research-Oriented Group (Go Hashmi)
International Leadership
bull NCI Multiple Myeloma Steering Committee
bull Shaji Kumar Chair Vincent Rajkumar- member
bull ECOG Myeloma Committee
bull Vincent Rajkumar Chair
bull Journals (Editors of Myeloma Section)- Leukemia European Journal of Haematology American Journal of Hematology Blood Cancer Journal Mayo Clin Proc Clin Lymphoma and Myeloma Amyloid
International Leadership
bull International Myeloma Working Group (IMWG)
bull Vincent Rajkumar co-chair
bull International Myeloma Foundation (IMF)
bull Robert Kyle and Vincent Rajkumar Board Members Robert Kyle Chair of the Scientific Advisory Board
bull International Waldenstroumlms Macroglobulinemia Foundation (IWMF)
bull Robert Kyle and Steve Ansell Board of Trustees Robert Kyle chair Scientific Advisory Committee
bull International Society of Amyloidosis (ISA)
bull Angela Dispenzieri President
bull International Myeloma Society (IMS)
bull Angela Dispenzieri Treasurer
bull International Kidney and Monoclonal Gammopathy Research Group (IKMG)
bull Nelson Leung President Angela Dispenzieri Treasurer
Clinical Trial Leadership
bull Principal Investigator (PI) Role on many prominent NationalInternational Phase III Trials
bull Pomalidomide trials (Martha Lacy)
bull E1A06 MPT vs MPR (Keith Stewart)
bull MM 020 Rd vs MPT (Angela Dispenzieri)
bull S0777 Rd vs VRd (Angela Dispenzieri)
bull ASPIRE Rd vs KRd (Keith Stewart)
bull E1A11 VRD vs KRd (Shaji Kumar)
bull Ixazomib Rd vs IRd (Vincent Rajkumar)
bull Ixazomib Phase III AL (Angela Dispenzieri)
bull S1304 Highstd dose carfilzomib (Sikander Ailawadhi)
bull S1211 RVd vs RVd-Elo (Sikander Ailawadhi)
Publications
bull ~80-100 per year excluding abstracts and book chapters
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Strengths
bull International Leadership in research education and practice
bull Molecular Classification of MGUS SMM and Myeloma
bull Risk-adapted therapy of Myeloma and Related Disorders
bull Epidemiology of Plasma Cell Disorders
bull Related Plasma Cell Disorders
bull MGRS
bull Amyloidosis
bull POEMS
bull Castlemanrsquos disease
bull WM
bull Mayo Led Clinical Trials
bull Leadership in ECOG
bull Extensive Clinical and Laboratory Databases
Unique Programs
bull Epidemiology Biomarkers (Rajkumar Kyle Kumar Dispenzieri)
bull Virotherapy (Russell Dingli Peng)
bull Center for Individualized Medicine (Stewart)
bull Vaccine and Adoptive Cell Therapy (Lin)
bull Novel Imaging for Myeloma (Drake)
bull Novel Laboratory Evaluation (Ketterling Morice)
bull Mass Spec (Murray Bergen Barnidge Kurtin)
bull Genomics (Stewart Bergsagel Fonseca)
bull Novel Therapeutics (Stewart Bergsagel Kumar)
bull Immunotherapy (Lin Chanan-Khan)
bull Hematology-Oncology Outcomes Research-Oriented Group (Go Hashmi)
International Leadership
bull NCI Multiple Myeloma Steering Committee
bull Shaji Kumar Chair Vincent Rajkumar- member
bull ECOG Myeloma Committee
bull Vincent Rajkumar Chair
bull Journals (Editors of Myeloma Section)- Leukemia European Journal of Haematology American Journal of Hematology Blood Cancer Journal Mayo Clin Proc Clin Lymphoma and Myeloma Amyloid
International Leadership
bull International Myeloma Working Group (IMWG)
bull Vincent Rajkumar co-chair
bull International Myeloma Foundation (IMF)
bull Robert Kyle and Vincent Rajkumar Board Members Robert Kyle Chair of the Scientific Advisory Board
bull International Waldenstroumlms Macroglobulinemia Foundation (IWMF)
bull Robert Kyle and Steve Ansell Board of Trustees Robert Kyle chair Scientific Advisory Committee
bull International Society of Amyloidosis (ISA)
bull Angela Dispenzieri President
bull International Myeloma Society (IMS)
bull Angela Dispenzieri Treasurer
bull International Kidney and Monoclonal Gammopathy Research Group (IKMG)
bull Nelson Leung President Angela Dispenzieri Treasurer
Clinical Trial Leadership
bull Principal Investigator (PI) Role on many prominent NationalInternational Phase III Trials
bull Pomalidomide trials (Martha Lacy)
bull E1A06 MPT vs MPR (Keith Stewart)
bull MM 020 Rd vs MPT (Angela Dispenzieri)
bull S0777 Rd vs VRd (Angela Dispenzieri)
bull ASPIRE Rd vs KRd (Keith Stewart)
bull E1A11 VRD vs KRd (Shaji Kumar)
bull Ixazomib Rd vs IRd (Vincent Rajkumar)
bull Ixazomib Phase III AL (Angela Dispenzieri)
bull S1304 Highstd dose carfilzomib (Sikander Ailawadhi)
bull S1211 RVd vs RVd-Elo (Sikander Ailawadhi)
Publications
bull ~80-100 per year excluding abstracts and book chapters
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Unique Programs
bull Epidemiology Biomarkers (Rajkumar Kyle Kumar Dispenzieri)
bull Virotherapy (Russell Dingli Peng)
bull Center for Individualized Medicine (Stewart)
bull Vaccine and Adoptive Cell Therapy (Lin)
bull Novel Imaging for Myeloma (Drake)
bull Novel Laboratory Evaluation (Ketterling Morice)
bull Mass Spec (Murray Bergen Barnidge Kurtin)
bull Genomics (Stewart Bergsagel Fonseca)
bull Novel Therapeutics (Stewart Bergsagel Kumar)
bull Immunotherapy (Lin Chanan-Khan)
bull Hematology-Oncology Outcomes Research-Oriented Group (Go Hashmi)
International Leadership
bull NCI Multiple Myeloma Steering Committee
bull Shaji Kumar Chair Vincent Rajkumar- member
bull ECOG Myeloma Committee
bull Vincent Rajkumar Chair
bull Journals (Editors of Myeloma Section)- Leukemia European Journal of Haematology American Journal of Hematology Blood Cancer Journal Mayo Clin Proc Clin Lymphoma and Myeloma Amyloid
International Leadership
bull International Myeloma Working Group (IMWG)
bull Vincent Rajkumar co-chair
bull International Myeloma Foundation (IMF)
bull Robert Kyle and Vincent Rajkumar Board Members Robert Kyle Chair of the Scientific Advisory Board
bull International Waldenstroumlms Macroglobulinemia Foundation (IWMF)
bull Robert Kyle and Steve Ansell Board of Trustees Robert Kyle chair Scientific Advisory Committee
bull International Society of Amyloidosis (ISA)
bull Angela Dispenzieri President
bull International Myeloma Society (IMS)
bull Angela Dispenzieri Treasurer
bull International Kidney and Monoclonal Gammopathy Research Group (IKMG)
bull Nelson Leung President Angela Dispenzieri Treasurer
Clinical Trial Leadership
bull Principal Investigator (PI) Role on many prominent NationalInternational Phase III Trials
bull Pomalidomide trials (Martha Lacy)
bull E1A06 MPT vs MPR (Keith Stewart)
bull MM 020 Rd vs MPT (Angela Dispenzieri)
bull S0777 Rd vs VRd (Angela Dispenzieri)
bull ASPIRE Rd vs KRd (Keith Stewart)
bull E1A11 VRD vs KRd (Shaji Kumar)
bull Ixazomib Rd vs IRd (Vincent Rajkumar)
bull Ixazomib Phase III AL (Angela Dispenzieri)
bull S1304 Highstd dose carfilzomib (Sikander Ailawadhi)
bull S1211 RVd vs RVd-Elo (Sikander Ailawadhi)
Publications
bull ~80-100 per year excluding abstracts and book chapters
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
International Leadership
bull NCI Multiple Myeloma Steering Committee
bull Shaji Kumar Chair Vincent Rajkumar- member
bull ECOG Myeloma Committee
bull Vincent Rajkumar Chair
bull Journals (Editors of Myeloma Section)- Leukemia European Journal of Haematology American Journal of Hematology Blood Cancer Journal Mayo Clin Proc Clin Lymphoma and Myeloma Amyloid
International Leadership
bull International Myeloma Working Group (IMWG)
bull Vincent Rajkumar co-chair
bull International Myeloma Foundation (IMF)
bull Robert Kyle and Vincent Rajkumar Board Members Robert Kyle Chair of the Scientific Advisory Board
bull International Waldenstroumlms Macroglobulinemia Foundation (IWMF)
bull Robert Kyle and Steve Ansell Board of Trustees Robert Kyle chair Scientific Advisory Committee
bull International Society of Amyloidosis (ISA)
bull Angela Dispenzieri President
bull International Myeloma Society (IMS)
bull Angela Dispenzieri Treasurer
bull International Kidney and Monoclonal Gammopathy Research Group (IKMG)
bull Nelson Leung President Angela Dispenzieri Treasurer
Clinical Trial Leadership
bull Principal Investigator (PI) Role on many prominent NationalInternational Phase III Trials
bull Pomalidomide trials (Martha Lacy)
bull E1A06 MPT vs MPR (Keith Stewart)
bull MM 020 Rd vs MPT (Angela Dispenzieri)
bull S0777 Rd vs VRd (Angela Dispenzieri)
bull ASPIRE Rd vs KRd (Keith Stewart)
bull E1A11 VRD vs KRd (Shaji Kumar)
bull Ixazomib Rd vs IRd (Vincent Rajkumar)
bull Ixazomib Phase III AL (Angela Dispenzieri)
bull S1304 Highstd dose carfilzomib (Sikander Ailawadhi)
bull S1211 RVd vs RVd-Elo (Sikander Ailawadhi)
Publications
bull ~80-100 per year excluding abstracts and book chapters
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
International Leadership
bull International Myeloma Working Group (IMWG)
bull Vincent Rajkumar co-chair
bull International Myeloma Foundation (IMF)
bull Robert Kyle and Vincent Rajkumar Board Members Robert Kyle Chair of the Scientific Advisory Board
bull International Waldenstroumlms Macroglobulinemia Foundation (IWMF)
bull Robert Kyle and Steve Ansell Board of Trustees Robert Kyle chair Scientific Advisory Committee
bull International Society of Amyloidosis (ISA)
bull Angela Dispenzieri President
bull International Myeloma Society (IMS)
bull Angela Dispenzieri Treasurer
bull International Kidney and Monoclonal Gammopathy Research Group (IKMG)
bull Nelson Leung President Angela Dispenzieri Treasurer
Clinical Trial Leadership
bull Principal Investigator (PI) Role on many prominent NationalInternational Phase III Trials
bull Pomalidomide trials (Martha Lacy)
bull E1A06 MPT vs MPR (Keith Stewart)
bull MM 020 Rd vs MPT (Angela Dispenzieri)
bull S0777 Rd vs VRd (Angela Dispenzieri)
bull ASPIRE Rd vs KRd (Keith Stewart)
bull E1A11 VRD vs KRd (Shaji Kumar)
bull Ixazomib Rd vs IRd (Vincent Rajkumar)
bull Ixazomib Phase III AL (Angela Dispenzieri)
bull S1304 Highstd dose carfilzomib (Sikander Ailawadhi)
bull S1211 RVd vs RVd-Elo (Sikander Ailawadhi)
Publications
bull ~80-100 per year excluding abstracts and book chapters
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Clinical Trial Leadership
bull Principal Investigator (PI) Role on many prominent NationalInternational Phase III Trials
bull Pomalidomide trials (Martha Lacy)
bull E1A06 MPT vs MPR (Keith Stewart)
bull MM 020 Rd vs MPT (Angela Dispenzieri)
bull S0777 Rd vs VRd (Angela Dispenzieri)
bull ASPIRE Rd vs KRd (Keith Stewart)
bull E1A11 VRD vs KRd (Shaji Kumar)
bull Ixazomib Rd vs IRd (Vincent Rajkumar)
bull Ixazomib Phase III AL (Angela Dispenzieri)
bull S1304 Highstd dose carfilzomib (Sikander Ailawadhi)
bull S1211 RVd vs RVd-Elo (Sikander Ailawadhi)
Publications
bull ~80-100 per year excluding abstracts and book chapters
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Publications
bull ~80-100 per year excluding abstracts and book chapters
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Education
bull httpwwwmsmartorg Practice Guidelines
bull wwwtwittercommayomyeloma
bull Myeloma Fellowship
bull Kurtz Myeloma Research Fellowship
bull Myeloma Book - Fully Mayo authored (Springer 2013)
bull Amyloidosis Book (Springer 2010)
bull UpToDate (All chapters related to myeloma and related disorders)
bull Wintrobe Clinical Hematology
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
MGUS and SMM
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
MGUS SMM MM
Asymptomatic
No end-organ damage
Asymptomatic
No MDEs
MDEs
Observation only Observation only Therapy required
Clinical
Picture
Therapy
Bone
Marrow M
Protein
lt10 plasma cells
AND lt3gmdL M
protein
10-60 plasma
cells OR ge3 gmdL
M protein
ge10 plasma
cells
MDEs Hypercalcemia anemia renal failure or lytic bone lesions attributable to plasma cell disorder
gt=60 clonal PCs gt=100 FLC ratio gt1 focal lesion on MRI
Kyle RA N Engl J Med June 21 2007 Rajkumar SV Lancet Oncology 2014
Developed Definition and Classification of MGUS SMM MM
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Kyle R et al N Engl J Med 20063541362-1369
Determined the Prevalence of MGUS in USA
Kyle RA et al N Engl J Med 2006 Volume 3541362-1369
bull MGUS present in 3 of general population gt50 years
bull 17 in 50-59
bull gt5 in over 70
bull Men gt Women
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Dispenzieri A et al Lancet 2010 3751721 - 1728
Defined and Determined Prevalence of Light Chain MGUS
bull LC-MGUS is present in 08 of general population gt50 years
LC-MGUS LC-MGUS
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Landgren OhellipRajkumar SV Leukemia 2014
n-=12482
Blacks
Whites
Hispanics
Determined 2-fold Increased Prevalence of MGUS among African Americans in USA
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Kyle R et al N Engl J Med 20073562582-2590
Defined Risk of Progression of MGUS and SMM
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Kyle R et al N Engl J Med 20063541362-1369
Estimated MGUS Annual Health Care Costs in USA
Go RS et al Leukemia 2016 In Press
bull About 540000 individuals living with a diagnosis of MGUS
bull At least $110 million annual cost to health care
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Copyright copy2009 American Society of Hematology Copyright restrictions may apply
Landgren OhelliphellipRajkumar SV Blood 20091135412-5417
Demonstrated MGUS always precedes MM
100 had
preceding
MGUS
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed Cytogenetic Classification of SMM
Del 17p t(414) Gain(1q)
No
cytogenetic abnormalities
All other
High-Risk Low-Intermediate Low-Risk
Rajkumar SV Leukemia 2013271738-1744 Neben et al J Clin Oncol 2013
Trisomies
High-Intermediate
Median TTP ~2 years Median TTP ~3 years Median TTP ~5 years Median TTP ~10 years
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Myeloma Biology
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Led Many Studies on Pathogenesis of MGUS and its progression to myeloma
Bergsagel PL et al Proc Natl Acad Sci U S A 19969313931-6 Bergsagel PL et al Blood 2005106296-303 Fonseca R et al Blood 20021001417-24 Fonseca R et al Cancer Res 2004641546-58 Rajkumar S V Clin Cancer Res 2009155606-5608
copy2009 by American Association for Cancer Research
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
First determined two major subtypes of Myeloma Hyperdiploid and Non-Hyperdiploid
Gene expression
Primary
IgH
TRXs
Non
Hyperdiploid
No
IgH
TRX
Hyperdiploid
Secondary
IgH
TRX
Ploidy
variable
Gene expression
Fonseca Blood 10225622003
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed genetic classification of hyperdiploid myeloma
Chng W J et al et al (2007) Cancer Research 67(7) 2982ndash2989
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
First to show inverse relationship between IgH Translocations and trisomies
Fonseca R et al (2003) Blood 102(7) 2562ndash2567
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
First comprehensive genetic description of MGUS and AL MGUS similar to MM and AL 50 t(1114)
Hayman S R et al Blood 98(7) 2266ndash2268
Fonseca R et al Blood 100(4) 1417ndash1424
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed VkMYC mouse model of Myeloma
Chesi et al Cancer Cell 2008
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
28
Affer et al Leukemia 2014
Method MYC
rearrangements
FISH 15
aCGH 44
Either 49
13 Ig enhancers - distributed equally across genetic subtypes
23 non-Ig enhancers - more common in hyperdiploid
Juxtaposition of super enhancers adjacent to MYC
Identified MYC rearrangements in ~50 of MM patients
Condition MYC
rearrangements
Untreated 47
Relapsed 52
t(1114) 25
Hyperdiploid 66
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Identified that mutations of NFkB are frequent in Myeloma
Keats Cancer Cell 2008
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Described Clonal Tides in Myeloma
Keats J J et al Blood 20121201067-1076
copy2012 by American Society of Hematology
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Myeloma Clinical Studies
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Healthcare Disparities in Myeloma
bull First to show that Hispanics have the worst outcome of all racialethnic subgroups in myeloma
bull First to explore the benefit of NCINCCN centers on outcomes in myeloma
bull Benefit of NCI centers within SEER registry seen only in Whites
bull Benefit of NCCN centers within SEER registry seen in Whites and African-Americans not in other minorities
Ailawadhi S et al Br J Haematol 2012158(1)91-8
Ailawadhi S et al Cancer 2016 122(4) 618-25
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
1961-70
1971-80
1981-90
1991-2000
2001-2010
Kumar S Blood 2008111 2516 ndash 2520 Kumar S Leukemia (2014) 28 1122ndash1128
Demonstrated Improved Survival in Myeloma
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Led Development of New Diagnostic Criteria for Myeloma
Rajkumar SV Lancet Oncology 2014
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Led Development of International Staging System for Myeloma
Greipp PR J Clin Oncol 2005233412-3420
Stage Survival in Months
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed Cytogenetic Classification of Myeloma
t(1416) (C-MAF)
t(1420) (MAF-B)
t(1114) (CCND1)
t(614) (CCND3)
Trisomies
t(414) (FGFR3 MMSET)
~10 have both trisomies and IgH translocations
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed Cytogenetic Myeloma Risk-Stratification
t(1416) t(1420) Del 17p
t(1114)
t(614)
t(414)
High-Risk Intermediate-Risk Standard-Risk
msmartorg
Presence of trisomies ameliorates high risk
Median survival lt3 years Median survival 6-7 years
Trisomies
Gain (1q)
Fonseca R et al Leukemia 2009232210-21 Kumar S et al Blood 20121192100-5
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Durie et al Leukemia 2006201467-73
Leadership Role in Development of IMWG Response Criteria for Myeloma
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Su
rviv
al
pro
bab
ilit
y
Months
Plt0001
t(414)
t(1416)
-17p13
D13
All others including
t(1114)
Poor 247 mos
Intermediate 423 mos
Good 510 mos
Fonseca et al Blood 1014569 2003
First Developed Global Genetic Prognostic Model for
Myeloma
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Demonstrated that Clinical Activity of a New Myeloma Drug can be
predicted by drug response in de novo VkMYC mice
Updated from Chesi et al Blood 2012
Response rate gt20
as a single agent in
patients
Response rate lt20
as a single agent in
patients
Response is gt50
reduction in
paraprotein
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Pioneered out patient transplant for myeloma with lowest complication rate reported
Gertz et al Mayo Clin Proc 2008 Oct83(10)1131-8
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Development of New Drugs in Multiple Myeloma
Led first phase III
of isatuximab
First published phase II of dinaciclib
Led pivotal trial that led
to full approval of carfilzomib
First published phase II of ixazomib
First published phase II of pomalidomide
2011-2015 2016-
Co-investigator in
Summit Trial that led to approval of bortezomib
Led trials that led to approval of thalidomide
First published phase II of lenalidomide
1999-2010
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Best Response within 4 Cycles using ECOG criteria
198 of 202 eligible pts
bull ThalDex 63
bull Dex 41
1-sided
p-value=0002
Rajkumar et al J Clin Oncol 200624431-436
Led trial that led to approval of thalidomide in myeloma ECOGCTSU Randomized Phase III Trial (E1A00)
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Number at risk RD 223 179 103 37 0 Rd 221 192 103 37 0
00
02
04
06
08
10
0 6 12 18 24
Surv
ival pro
bab
ility
Months
0
02
04
06
08
1
0 6 12 18 24
Treatment ON 1 year OS rate RD 35223 87 Rd 10222 96
Rajkumar SV et al Lancet Oncology 2009
Led trial that showed low-dose Dex improves survival
Established the Rd regimen that is now backbone for many myeloma regimens
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Copyright copy American Society of Clinical Oncology
Lacy M Q et al J Clin Oncol 275008-5014 2009
Led first published phase II of Pomalidomide in Myeloma
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Progression-free Survival
Stewart AK et al N Engl J Med 2015372142-152
Led trial that led to full approval of carfilzomib in myeloma KRd vs Rd Aspire Trial
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52
response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the
response-evaluable populati
Kumar et al The Lancet Oncology Volume 15 Issue 13 2014 1503 - 1512
Led first published phase II of ixazomib in Myeloma
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
First phase 1 trial of Venetoclax in Myeloma Demonstration of single agent activity
Kumar S et al ASH 2015
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
First described association of myeloma with reversible pulmonary hypertension
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
eastern cooperative oncology group
Leading Current National Trial for Newly Diagnosed Myeloma
Actively Accruing
E4A03 Phase III ndash Newly Diagnosed Myeloma PI Shaji Kumar
VRd x 12
cycles
KRd x 12
cycles
Revlimid
X 2years
Revlimid
Until prog
Continue therapy
till prog or toxicity
Continue therapy
till prog or toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
AMYLOIDOSIS
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Vrana JA Gamez JD Madden BJ Theis JD Bergen HR 3rd Dogan A Blood 2009114(24)4957-4959
Developed Classification of amyloidosis by laser microdissection and mass spectrometry based
proteomic analysis in clinical biopsy specimens
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed Amyloid Proteome Signature
Vrana JA et al Clinical diagnosis and typing of systemic amyloidosis in subcutaneous
fat aspirates by mass spectrometry-based proteomics Haematologica 201499(7)1239-1247
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Troponin T TnT lt0035 mcgL
NT-proBNP lt332 ngL
Troponin I TnI lt01 mcgL
NT-proBNP lt332 ngL
Developed Staging for AL amyloidosis
Mayo AL Staging v20
Dispenzieri et al Journal of Clinical Oncology 20041223751-7
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed Staging System for AL Amyloidosis
Mayo AL Staging v 30 (n=758)
Kumar S et al Journal of Clinical Oncology 201230989-995
Risk factors 1 point each for
score 0-3 Stage 1-4
bull FLC-diff ge 180 mgL
bull cTnT ge 0025 mcgL
bull NT-ProBNP ge1800 ngL
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
No at risk 1247 601 352 202 95 30 7
N Median OS
AL-only (le 10 BMPC) 679 42 m
AL-PCMM (gt 10 BMPC) 476 16 m
AL-CRAB 100 11 m
Developed definition of MM in patients with AL Amyloidosis
Overall survival in patients with gt10 BMPC similar to patients with end-organ damage (CRAB)
P lt0001
Follow up from diagnosis months
Kourelis et al JCO 201331(34)4319-4324
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
First published study of CyBorD in AL Amyloidosis The current standard frontline treatment
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Defined Role of transplantation in AL amyloidosis
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed Transplant Eligibility Criteria for AL Amyloidosis
10 month mortality 25 P=00003
Troponin T lt006 mcgL
Troponin T ge006 mcgL
NT-proBNP lt5000 pgL
NT-proBNP ge 5000 pgL
100 day mortality 25 Plt00001
Gertz et al Bone Marrow Transplantation 201348(4)557-61
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Pioneered Treatment of AL Amyloidosis with Sequential Heart and Stem Cell Transplantation
Lacy MQ Dispenzieri A Hayman SR et al The Journal of heart and lung transplantation
the official publication of the International Society for Heart Transplantation 200827(8)823-829
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Leung N Griffin MD Dispenzieri A et al American journal of transplantation 20055(7)1660-1670
Pioneered treatment of AL Amyloidosis with Sequential Kidney and Stem Cell Transplantation
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed Len-Dex in AL Amyloidosis
Dispenzieri et al Blood 2007 Jan 15109(2)465-70
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed CRD for AL Amyloidosis
Kumar SK Hayman SR Buadi FK et al Blood 2012119(21)4860-4867
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed Pomalidomide-Dex for AL Amyloidosis
Dispenzieri A Buadi F Laumann K et al Blood 2012119(23)5397-5404
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Led first antibody trial for AL amyloidosis
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Developed Response Criteria for AL amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
po
rtio
n s
urv
ivin
g
CR (97 patients 36 deaths100 py)
VGPR (233 patients 96 deaths100 py)
PR (140 patients 237 deaths100 py)
NR (179 patients 472 deaths100 py)
p=001
plt0001
plt0001
Survival of 649 patients based
on hematologic response at 6 months
Led validation of response criteria for AL
amyloidosis
0 12 24 36 48
Time (months)
00
01
02
03
04
05
06
07
08
09
10
Pro
port
ion s
urv
ivin
g
NT-proBNP progression (at least 300 ngL and 30 increase) 169 patients
NT-proBNP stable 108 patients
NT-proBNP response (at least 300 ngL and 30 decrease) 100 patients
plt0001
plt0001
Survival of 377 patients with
baseline NT-proBNP ge650 ngL according
to NT-proBNP response and progression
at 6 months
Palladini G Dispenzieri et al Journal of clinical oncology 2012 30 4541-9
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Largest US experience with familial amyloidosis
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
POEMS SYNDROME
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Major Contributions in Patients with POEMS Syndrome
1 Largest single institution series mdash presentationoutcomes
2 Diagnosis
bull Unique bone marrow findings
bull Platelet count to differentiate from CIDP
bull VEGF to differentiate POEMS from other diseases
3 Treatment
bull Expectations with radiation therapy
bull Expectations with ASCT
bull First report of lenalidomide
bull First report of cyclophosphamide-bortezomib-dex
4 Prognosis
bull High platelets risk for stroke
bull Low albumin risk for relapse
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Demonstrated that Overall Survival in POEMS Syndrome Better than Previously Reported
Overa
ll s
urv
iva
l (
)
Months
0
20
40
60
80
100
0 50 100 150 200 250 300 350
Median 138 years
Dispenzieri A Kyle RA Lacy MQ et al Blood 2003101(7)2496-2506
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Demonstrated unique BM Findings in POEMS lymphoid aggregates rimmed by PC amp
megakaryocyte atypia
Dao et al Blood 2011 117(24)6438-44
HampE 200x CD138
l k
33 of 67 cases
had lymphoid
aggregates
32 of these had
clonal PC
5967 had mega
rimming or clonal
PC
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Defined Role of Primary Radiation therapy for POEMS Syndrome (n=38)
bull 4 year OS 97
bull 4 year failure free survival 52
bull Risk factors for failure bull DLCOlt70
bull Elevated urine protein
Failure defined as receiving a new treatment
Median follow-up 43 months
Humeniuk Blood 2013122(1)68-73
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Demonstrated Role of Stem Cell Transplant for POEMS
00
02
04
06
08
10
0 12 24 36 48 60 72 84 96
Months post-ASCT
Perc
en
t su
rviv
al
Between 31999-102011 59 patients had ASCT
Median follow-up of 40 months (0-147 months)
OS
PFS
DSouza A et al Blood Jul 5 2012120(1)56-62
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Demonstrated Improvement in Peripheral Neuropathy with ASCT in POEMS
Karam C Klein CJ Dispenzieri A et al Neurology 201584(19)1981-1987
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Waldenstrom Macroglobulinemia (WM)
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Chng W J et al Blood 20061082755-2763
First genetic and genomic studies in WM Lack of IgH translocations and 6q deletions in 50
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Described flare of Waldenstrom after Rituximab
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Largest US experience with CAD
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
Rare Plasma Cell Disorders
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
1 4 820 18
33
83 92
0
10
20
30
40
50
60
70
80
90
100
Clinical and Genetic Description of Plasma Cell Leukemia
MGUS
SMM
newly diagnosed MM
first relapse MM
second relapse MM
PCL
HMCLs
FISH (MGUS n=184 SMM n=116 relapsed MM n=62 and PCL n=26)
aCGH (newly diagnosed MM n=224 relapsed MM n=158 and HMCLs n=48)
p 53 mutational status was evaluated in relapsed MM (n=84) and HMCLs (n=48)
Tiedemann et al Leukemia 2008 22 1044-1052
Studied 8 patients with 17p deletions at RR 7 did not have deletion at diagnosis
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema
First published report of stem cell transplant for TEMPI syndrome
First to publish stem cell transplat for scleromyexedema