Multiple Myeloma in 2014:

What Advanced Practice Providers Should Know

November 2014

Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida

Joseph Mikhael, MD, MEd, FRCPCStaff Hematologist, Mayo Clinic Arizona

Objectives

1. Provide an overview of the types and spectrum of multiple myeloma

2. Discuss the “significance” of MGUS and its practical management

3. Review the diagnosis and staging of myeloma

4. Discuss the approach to therapy, including stem cell transplantation

5. Highlight the improvement in prognosis for patients with myeloma

Myeloma case

68 yo male

• 9 month history of low back pain

• Treated by FP, PT, Chiropractor – no improvement

• FP did plain x-rays, revealed multiple lytic lesions

• Gradual increasing fatigue, SOBOE

Case cont.

• Hb 7.8, WBC 5.6, Plts 132

• Ca 10.8, Creat 1.6

• IgG Level 5800 (A and M depressed)

• No Bence Jones proteinuria

• Bone Marrow: 60% plasmacytosis

• CRP normal, Albumin 3.4

• B2M elevated

Case contd.

• Does he have Myeloma?

• What is your first step?

• What to do about his hypercalcemia?

• What to do about his anemia?

• What to do about his bony disease?

Epidemiology

• 1% of malignancies

• 10% of Heme cancers

• 21000 Americans annually

Epidemiology

• Men > Women

• Blacks > Whites

• Median age of diagnosis is 66• 10% < 50, 2% <40

M-proteinNormal

+ - + -

Pathophysiology

• Malignant plasma cell dyscrasia

• Accumulation of plasma cells in the bone marrow

• These produce a single immunoglobulin (Ig) – monoclonal protein

• Sequelae relate to presence of plasma cells or interactions they induce via cytokines in microenvironment

The Plasma Cell

Carr and Rodak: Clin Hematol Atlas

The malignant clone

Bone Marrow

Lymph node

IgG,A,D,E plasma cell

IgM

hypermutationlymphoblastplasmablast

pre-B cell

somatic

Plasma cell

How do plasma cells become “evil”?

Immunoglobulins

Kyle, R. A. et al. N Engl J Med 2004;351:1860-1873

Mechanisms of Disease Progression in the Monoclonal Gammopathies

Molecular progression

Normal plasma

cell

Asymp-tomatic

Myeloma

Aggressive Myeloma

Active Myeloma

Del 13Secondary translocations

TranslocationsInfection

Inflammation

ras & p53 mutationc-myc dysregulation

Bone resorptionAngiogenesis

MGUS

The Spectrum of Myeloma

MGUS Asymptomatic MM (smouldering)

“True” MM PC Leukemia

Organ damage

none none yes yes

Marrow Disease

<10% plasma cells

≥ 10% plasma cells

≥ 10% plasma cells

Plasma cells in blood

Management Monitor 1-2 times/yr

Close follow up (q 3 mts)

therapy Highdose combo chemo

Transforma-tion rate

1% /yr 10-20%/yr n/a n/a

MGUS

Monoclonal Gammopathy of Unknown Significance

• Presence of a serum monoclonal protein (concentration ≤ 3g/dL)

• Less than 10% plasmacytosis in marrow

• No evidence of End-Organ damage (CRAB)• Calcium elevation, Renal Insufficiency,

Anemia, Bony disease

• Asymptomatic

• No co-existing plasma cell dyscrasia or lymphoproliferative disease (table)

Diseases associated with a monoclonal gammopathy

• Plasma cell disorders• Monoclonal gammopathy of undetermined significance

(MGUS)• Biclonal gammopathy of undetermined significance• Idiopathic Bence Jones proteinuria• POEMS syndrome, Osteosclerotic myeloma• Castleman's disease• AL (light chain) amyloidosis• Solitary plasmacytoma• Multiple myeloma, Smoldering multiple myeloma

• B-cell lymphoproliferative disorders• Non-Hodgkin's lymphoma• Chronic lymphocytic leukemia• Lymphoplasmacytic lymphoma (Waldenstrom

macroglobulinemia)• Post-transplant monoclonal gammopathies

Epidemiology

• Prevalence is approximately 1-3% in adults in the USA, Sweden, France and Japan1

• Higher as we age:• ≥ 50: 3.2%• ≥ 70: 5.3%• ≥ 85: 7.5%2

• 2-3 fold higher incidence in Africans and African American population3

• Annual risk of transformation to MM or related diseases of 1%4

1 Kyle Blood 1972, Axelsson Acta Med Scan 1986, Saleun J Clin Path 1982, Iwanaga Mayo Clin Proc 2007; 2 Kyle NEJM 2006; 3 Singh J Lab Clin Med 1990, Cohen AM J Med 1998, Landgren Blood 2006; 4 Kyle et al NEJM 2002

Kyle R et al. N Engl J Med 2002;346:564-569

Risk of Progression among 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy of Undetermined Significance was Diagnosed in 1960 through 1994

MGUS Progression

• Potential Predictive Factors of Progression

• M protein size1

• IG class: IgA>IgM>IgG2

• Bone marrow plasmacytosis3,4

• Presence of urinary Bence Jones proteinuria3

• Free Light Chain Assay5

1 Kyle NEJM 2002, 2 Kyle Blood 2003, 3 Cesana JCO 2002, 4 Perez-Persona Blood 2007 5 Rajkumar BJH 2004

Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

Rajkumar, S. V. et al. Blood 2005;106:812-817

Figure 3. Risk of progression of MGUS to myeloma or related disorder using a risk-stratification model that incorporates the FLC ratio and the size and type of the serum

monoclonal protein

20 year

58%

37%

21%

5%

Monitoring

• No absolute consensus

• Algorithm:• Make accurate diagnosis• Obtain baseline bloodwork (incl total Igs and

FLC), 24 hr urine and skeletal survey• Repeat testing (history, physical, blood work

only) at 6 months• If lower risk, can be seen annually (assuming

asymptomatic)• If higher risk, I prefer every 6 months

Bone Marrow

Diagnosis of Myeloma

The diagnosis of Myeloma is made as a result of several tests:1. Blood Counts (CBC – white, red, platelets)2. Blood and urine tests for immune proteins

– IgG, IgA, IgM – total number (combination of normal protein and abnormal or “M” protein)

– May also be “light chains” which are component of abnormal protein

– May require 24 hour urine collections

Diagnosis of Myeloma contd.3. Bone Marrow tests (aspirate and biopsy)

– This looks for the % of plasma cells in the marrow

– Also looks for abnormal cytogenetics of the plasma cells and FISH analysis

4. X-rays

looking for osteopenia, lytic lesions and fractures (NOT a bone scan)

possibly MRI of the spine

5. Other blood tests

creatinine, calcium, albumin beta-2-microglobulin

Multiple Myeloma - Types

• Subtypes of MM are determined based on the kind of abnormal protein

IgG – 55%IgA – 25%IgD – 1-2%IgM – 1%Light Chain Disease only – 20%Non Secretors 1-2 %

M spike in gamma region

Multiple Myeloma

• Unfortunately, MM is not a curable disease (yet!!)

• Historically most people did not live for much more than 2 years…

• However, the average survival is now at least 8 years

• This has been a result of two key developments:1. Autologous Stem Cell Transplant2. Novel Drugs (thalidomide, bortezomib,

lenalidomide, carfilzomib, pomalidomide)

Myeloma Staging

• Older system of Salmon-Durie staging• Not as useful anymore

• Newer system of using 2 factors:• Albumin and Beta-2-microglobulin• It is “prognostic” for survival

• Practically, there are 2 stages1. Can wait and watch2. Requires treatment

Cytogenetics

• These are the genes of the plasma cells (not the patient)

• May indicate more about the biology of the disease

• Most can be found at diagnosis, but others may be “acquired” later

• Could well be the most “prognostic” tool in myeloma as it may separate “high risk” myeloma from standard risk

0.0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150

Su

rviv

al p

rob

abil

ity

Su

rviv

al p

rob

abil

ity

MonthsMonths

P<0.001P<0.001

t(4;14)t(14;16)-17p13

t(4;14)t(14;16)-17p13

1313

All others includingt(11;14)All others includingt(11;14)

Poor 24.7 mosIntermediate 42.3 mosGood 51.0 mos

Poor 24.7 mosIntermediate 42.3 mosGood 51.0 mos

Fonseca et al Blood 101:4569, 2003

Molecular Prognostic ModelMolecular Prognostic Model

Myeloma Treatment

Principles of therapy

1. Stop the production of the abnormal plasma cells (chemo)

2. Strengthen the bone and prevent fractures

3. Increase the hemoglobin count and reduce fatigue

4. Reduce risk of infections

5. Promote well being and quality of life

Treatment with Chemotherapy

• Goal is to reduce the number of plasma cells and the proteins they produce

• Timing is important as it may be possible to wait & watch

• It is not “curative” but may put the disease into remission

• Must be tailored to individual based on disease factors (type, severity, organs involved) and patient factors (age, general health…)

Managing myeloma: the components

Supportive Care

Initial Therapy

Consolidation Maintenance

Treatment of Relapsed

disease

Transplant EligiblePatients

Transplant Ineligiblepatients

Consolidation/ Maintenance/ Continued therapy

Mayo Stratification for Myeloma And Risk-adapted Therapy

Newly Diagnosed Myeloma

Website: www.msmart.org

mSMART

mSMART 2.0: Classification of Active MM

FISH Del 17p t(14;16) t(14;20)

GEP High risk

signature

All others including: Hyperdiploid t(11;14)** t(6;14)

FISH t(4;14)‡

Cytogenetic Deletion 13 or hypodiploidy

PCLI >3%

High-Risk Intermediate-Risk* Standard-Risk*†

Mikhael et al Mayo Clinic Proceedings April 2013

mSMART 2.0: Classification of Active MM

FISH Del 17p t(14;16) t(14;20)

GEP High risk

signature

All others including: Hyperdiploid t(11;14) t(6;14)

FISH t(4;14)*

Cytogenetic Deletion 13 or hypodiploidy

PCLI >3%

High-Risk 20% Intermediate-Risk 20% Standard-Risk 60%

3 years 4-5 years 8-10 years

mSMART – Off-StudyTransplant Eligible

a Bortezomib containing regimens preferred in renal failure or if rapid response neededb If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixaforc Continue Rd for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year* Consider risks and benefits; consider limited duration 12-24 months

Standard Risk

Autologous stem cell transplant

4 cycles of Rda or CyBorD

Collect Stem Cellsb

Continue Rd;

c or

CyBorD for ~12 months

High Risk

4 cycles of VRd

Intermediate Risk

Autologous stem cell transplant

Bortezomib based therapy for minimum of 1 year

4 cycles of CyBorD

Autologous stem cell transplant, especially if

not in CR

V or VCd for minimum of 1 year

2 cycles of Rd consolidation; Then Len maintenance if not in VGPR and Len responsive*

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v11 //last reviewed Dec 2013

mSMART – Off-StudyTransplant Ineligible

a Dex is usually discontinued after first yearb Bortezomib containing regimens preferred in renal failure or if rapid response needed*Clinical trials strongly recommended as the first option

Intermediate Risk Standard Risk*

MP + weekly Bortezomib or weekly CyBorD for

~12 months

Bortezomib based therapy for minimum of 1 year

High Risk

VRd* for ~12 months, Rda, b

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v11 //last reviewed Dec 2013

Continue VRd as maintenance for minimum

of 1 year

Initial Response

• Please note that the ultimate goal is both DEPTH and LENGTH of response

• Deepest response is “Complete” Remission (=CR) vs partial remission or minimal remission

• It appears that a deeper response (esp CR) may predict a longer remission and even survival

• HOWEVER, trends do not predict any individual patient

• We treat the patient not the disease

Treatment sequence

Induction Consolidation

Front line treatment

Maintenance

Maintenance

Rescue

Relapsed

VADDEX

SCTNothing

PrednisoneThalidomide

Few options

Treatment sequence

Induction Consolidation

Front line treatment

Post consolidation

Maintenance

Rescue

Relapsed

OLD VADDEX

SCTNothing

PrednisoneThalidomide

Few options

NEW

Thal/Dex VD

Rev/DexCyBorD

VTDVRD

SCTVD/VRD

NothingThalidomide?Bortezomib?

Lenalidomide?

BortezomibLenalidomideThalidomideCarfilzomib

PomalidomideElotuzumab

HDACBendamustine

Monoclonal Antibodies

2006-2010 73% 56%

2001-2005 63% 31%

IMPACT OF NOVEL THERAPY 2012/2013

Median 7.3 years

5 YEAR SURVIVAL BY AGE

AGE≤ 65 YRS

AGE> 65 YRS

2012 ASH Abstract #3972 Kumar et al

Long-Term Survival With CyBorD Induction Therapy In Newly Diagnosed

Multiple Myeloma

Craig B. Reeder, MD, Donna E. Reece, MD, Vishal Kukreti, MD, FRCPC, Joseph Mikhael, MD, Christine I. Chen, MD, Suzanne Trudel, MD, Kristina Laumann, Joseph Hentz, Giovani Piza, Rafael Fonseca, MD, P. Leif Bergsagel, MD, Jose F Leis, MD, PhD, Rodger E. Tiedemann, MBChB, PhD, FRACP, FRCPA, Jacy

Spong, BS, RN, BSN, Angela Mayo, PA/NP and Keith Stewart, MD

Reeder C. et al.; ASH 2013: abstract 3192

Results - Response

ITT Cohort 1 Cohort 2 All (n=63)

ORR 88% (29/33) 90% (27/30) 89% (56/63)

CR / nCR 36% (12/33) 47% (14/30) 41% (26/63)

>VGPR 61% (20/33) 63% (19/33) 62% (39/63)

After 4 cycles

Cohort 1 Cohort 2 All (n=55)

ORR 96% (27/28) 93% (24/27) 93% (51/55)

CR / nCR 46% (13/28) 48% (13/27) 47% (26/55)

>VGPR 71% (20/28) 63% (17/27) 67% (37/55)Reeder C. et al.; ASH 2013: abstract 3192

Results - Survival

Progression Free Survival (5 yr)

Overall Survival (5 yr)

ALL(n=63)

42%(95% CI:31-57)

70%(95% CI: 59-82)

Standard Risk (n=39)

48%(95% CI: 33-69)

81%(95% CI: 69-95)

High Risk(n=24)

33%(95% CI: 19-59)

54% (95% CI: 37-78)

Most patients underwent auto stem cell transplant after completing the induction trial and most did not utilize maintenance therapy post SCT.

Reeder C. et al.; ASH 2013: abstract 3192

LONG-TERM SURVIVAL WITH CYBORD: ASH 20131

1 ASH Abstract #3192 Reeder et al

OS: All PatientsOS 81% at 5 years for

standard risk

OS by Risk Status

The “NEW” CyBorD

• All three drugs given weekly• Cyclophosphamide 300mg/m2 PO• Bortezomib 1.5 mg/m2 IV or SQ• Dexamethasone 40mg PO

• We consider one cycle a 4 week course

• No “week off”

• Less neuropathy, more convenience, equal efficacy

• Always give viral prophylaxis

Retrospective, observational study: VCD and VRD as initial treatment for MM

VCD(n= 101)

VRD(n= 75)

Median ageMean treatment durationPts undergoing ASCT

62.7 years5.1

months50%

60.9 years5.4 months

59%

Best response after 4 cycles2-year PFS2-year OS

89%66.6%90.8%

81%63.2%87.4%

Common AEs reported in at least 3 treatment cycles

FatiguePeripheral NeuropathyAnemiaGI

18%11%11%9%

9%16%16%8%

Conclusion: Comparable outcomes with VCD and VRD in terms of response, PFS, OS and similar safety profiles

Kumar et al. ASH 2013: Abstract 3178, poster presentation

ASH 2012-3: Induction RegimensResponse Rates (%) & Survival

Trial N nCR/sCR >=VGPR >=PR PFS OS

CarCyDex 58 68 76 95 1-yr 86% 1 yr 85%

CarLenDex 41 68 88 96 1 yr ≤ 83 NA

CarThalDex1 50 18 60 92 1 yr 88% NA

MLN9708-Len-Dex

65 23 58 90 1 yr 93% NA

MLN9708-Len-Dex

64 24 67 96 NA NA

CyCarThalDex 54 18 76 91 1 yr 90% 1 yr 98%

R2V2 30 40 73 97 1 yr 97% 1 yr 100%

Blood 120(21) 2012: Sonneveld Abs 333 Kumar Abs 332 Kaufman Abs 336: Len, Bortezomib, Dex, and Vorinostat

Blood 122(21) 2013:Bringhen, Abs 685 Korde, Abs 538 Mikhael, Abs 3179 Richardson Abs 535

1 Induction portion of CTD x 4 followed by HDM and consolidation with CTD x 4

How Deep a Response Required before ASCT?

MM06-04-12_6.ppt

Autologous Autologous TransplantTransplant

Diagnosis and Initial Diagnosis and Initial InductionInduction

Autologous Autologous TransplantTransplant

12 months from diagnosis to ASCT12 months from diagnosis to ASCT

Salvage CohortSalvage Cohort

No Salvage CohortNo Salvage Cohort

ASCTDiagnosis

Effect of Pre-transplant Salvage Therapy Prior to Autologous Transplant (ASCT) in Patients Not

Responding to Initial Induction for MM

Salvage Salvage ChemotherapyChemotherapy

< PR to induction< PR to induction

Vij Blood 120(21) 2012, abstract 597

Outcomes with/without Pre-ASCT Salvage

(Source: Txz12_23 & _24) MM06-04-12_15.ppt

P = NS P = NS

Vij Blood 120(21) 2012, abstract 597

Median follow-up Salvage No Salvage Months 68 (110-180) 61 (9-181)

Stem Cell Transplant

• Concept: eliminate any remaining abnormal plasma cells in the bone marrow with HIGH dose chemotherapy (ie what may be left after initial chemotherapy)

• Process1. Use initial chemotherapy to reduce plasma cells2. Collect stem cells from bone marrow

a. Mobilization with neupogen (G-CSF) +/- chemob. Collection by pheresis in stem cell unitc. Storage of stem cells (frozen)

3. Admit and give high dose treatment (wipe out current marrow)4. Re-Infuse stem cells previously collected and wait for them to

“grow”

Patient

Priming Therapy

FreezeCollect PBSCs

High-dose Chemotherapy

Reinfuse PBSCs

+/- Post-ASCT therapy

ASCT

Autologous Stem Cell Transplantation: Timing

• Most trials incorporate SCT as consolidation therapy after initial treatment

• Trials comparing timing of transplant, as part of initial treatment or after relapse, show better disease free survival with initial SCT but equivalent overall survival

• Currently there is some debate about the role of SCT when novel drugs are used for initial treatment

Autologous Transplant Improves Responsesafter Traditional or Novel Induction

Sonneveld

JCO 12

Harrouseau

JCO 10

Cavo

Lancet 10

VAD BtzAD VAD BtzD ThalD BtzThalD

Induction

≥nCR

5% 11% 7% 15% 11% 31%

Transplant

≥nCR

15% 31% 18% 35% 31% 52%

Transplant Ineligible

FIRST Design: Lenalidomide and Low-dose Dexamethasone (Rd/Rd18) vs. MPT

ARM A

Arm BRd18

Arm CMPT

N = 535

Arm ARd

LEN + Lo-DEX until Progressive DiseaseLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN 0.25mg/kg D1-4/42PREDNISONE 2mg/kg D1-4/42THALIDOMIDE 200mg D1-42/42

Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 100 mg D1-42/42, Melphalan2 0.2 mg/kg D1–4

• Stratification: age, country and ISS stage

1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.

International Staging System; LT, long-term; PD, progressive disease; OS, overall survival

n= 1,623 - 18 countries from North America, Asia-Pacific, and Europe represented from 246 Centers

n=535

n=541

n=547

Facon T. et._ASH 2013: Abstract 2

FIRST Trial: Final PFSContinuous Rd the risk of PFS events (PD or death) by 28% vs. MPT

mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone.

Median PFS

Rd (n= 535) 25.5 mos

Rd18 (n= 541) 20.7 mos

MPT (n= 547) 21.2 mos

Rd 535 400 319 265 218 168 105 55 19 2 0

Rd18 541 391 319 265 167 108 56 30 7 2 0

MPT 547 380 304 244 170 116 58 28 6 1 0

Hazard ratio

Rd vs. MPT: 0.72; P = 0.00006

Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349

Time (months)

Pat

ien

ts (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

72 w

ks

Facon T. et._ASH 2013: Abstract 2

FIRST Trial: Overall Survival Interim Analysis574 deaths (35% of ITT)

Pat

ien

ts (

%)

RdRd18MPT

535541547

488505484

457465448

433425418

403393375

338324312

224209205

121124106

434430

563

000

4-year OS

Rd (n= 535) 59.4%

Rd18 (n= 541) 55.7%

MPT (n= 547) 51.4%

Overall survival (months)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

Hazard ratio Rd vs. MPT: 0.78; P = 0.0168 ( 22% risk of death with Rd)

Rd vs. Rd18: 0.90; P = 0.307 Rd18 vs. MPT: 0.88; P = 0.184

The pre-specified boundary (p<0.0096) was not crossed for Rd_continuous vs MPT_18 months

Facon T. et._ASH 2013: Abstract 2

Relapsed Disease

Treatment sequence

Induction Consolidation

Front line treatment

Post consolidation

Maintenance

Rescue

Relapsed

OLD VADDEX

SCTNothing

PrednisoneThalidomide

Few options

NEW

Thal/Dex VD

Rev/DexCyBorD

VTDVRD

SCTVD/VRD

NothingThalidomide?Bortezomib?

Lenalidomide?

BortezomibLenalidomideThalidomideCarfilzomib

PomalidomideElotuzumab

HDACBendamustine

Monoclonal Antibodies

Carfilzomib: A Novel Agent Designed to Promote Selective and Sustained Proteasome Inhibition

• Carfilzomib is a next-generation, selective proteasome inhibitor• Potent and sustained target suppression• Improved antitumor activity• Minimal off-target activity with low neurotoxicity

69

HN

NH

O HN

O

O

NHO

NO O

O

EpoxyketoneTetrapeptide

Adapted from: Kuhn DJ, et al. Blood. 2007;110:3281-3290.

Neuropathy Was Infrequent and Not Dose LimitingPooled data from single-agent studies (003 / 004 / 005)

• Peripheral neuropathy occurred infrequently across all single-agent studies*

• Only 6 patients (1.2%) experienced a Grade 3 PN event

• No Grade 4 PN events

• Only 1 patient had drug discontinued for PN (study 004; BTZ-treated arm)

70Adapted from: Singhal S, et al. ASH 2010. Abstract 1954 (poster presentation).*Includes the terms peripheral neuropathy, neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy

N=505

Did not experience peripheral neuropathy

Grade 3 PN (1.2%)

Grade 1/2 PN (13.4%)

Carfilzomib - Practical

• Highly effective and very well tolerated

• Beware of tumor lysis hence dosing schedule

• Cardiac issue present but mostly mitigated by fluid management

• Issues of weekly dosing being explored

• Lack of neuropathy very attractive

• Upfront uses increasing

Molecular Structure of Thalidomide, Lenalidomide and Pomalidomide

Molecular Structure of Thalidomide, Lenalidomide and Pomalidomide

Structurally similar, but functionally different both qualitatively and

quantitatively

Myeloma Pomalidomide Summary

73

Lacy Pom/Dex1-3 reg

Lacy Pom/DexLen ref

RichardsonPom+/- dex

MM-002

PR 63% 32% 28%

MR 82%* 47% 52%

Median 3 prior regimens

Median 4-6 prior regimens

Pomalidomide - Practical

• Similar to lenalidomide with slightly less myelotoxicity and fatigue

• Dosing range 2-4mg

• Thromboprophylaxis necessary

• Feasible in combination

NEWER THERAPIES: ASH 2013

TOP 8

Anti-CD 38 monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284)

MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983) ARRY 520 (abstracts #285 and #1982) ACY-1215 (abstracts #759 and #3190) Selinexor (also known as KPT-330, abstract #279) Anti-CD 138 monoclonal antibody (BT062, indatuximab

ravatansine, abstract #758) Panabinostat (abstract #1970) Bendamustine (abstract #1971)

Anti-CD 38 monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284)

MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983) ARRY 520 (abstracts #285 and #1982) ACY-1215 (abstracts #759 and #3190) Selinexor (also known as KPT-330, abstract #279) Anti-CD 138 monoclonal antibody (BT062, indatuximab

ravatansine, abstract #758) Panabinostat (abstract #1970) Bendamustine (abstract #1971)

Conclusions

• MGUS is a common condition that must be appropriately managed, including risk stratifying patients

• Multiple Myeloma is an uncommon condition but has improved survival with use of novel agents and stem cell transplant

• Newer agents are showing outstanding results with the recent additions of carfilzomib and pomalidomide

• Although the mainstay of treatment is directed at the cancer itself, considerations must be given to supportive care and quality of life