Post on 26-Dec-2015
MYELOMA 2015: WHERE HAVE WE BEEN..WHERE ARE WE GOING?
clinicaloptions.com/oncologyBest Practices in Multiple Myeloma
Multiple Myeloma
Plasma cell disorder: calcium elevation, renal dysfunction, anemia, and bone destruction
Estimated 24,050 cases and 11,090 deaths in 2014[1]
Median age at diagnosis: 69 yrs[2]
5-yr survival has improved substantially (45% in 2004-2010 vs 28% in 1987-1989[2]) due to novel agents
Sensitive to treatment, but not curable
– Progression inevitable
The future: risk-adapted therapy, individualized treatment
1. American Cancer Society. Cancer facts & figures. 2014. 2. SEER stat fact sheet: myeloma. 2013.
• NEW DEFINITIONS
NEW PARADIGMSUPFRONT TREATMENTMAINTENANCENEW AGENTSAUTO TRANSPLANT (CONSOLIDATION)
TYPICAL CASE
65 year old woman
Hb 108
Albumin 32
Total protein 102
Increased gammaglobulins May be polyclonal eg HCV,
rheumatoid
May be monoclonal product of clonal plasma cells in marrow
Antibody production by plasma cells
Kappa Lambda
BONE MARROW
MYELOMA: STAGING
CBC CMP FREE LIGHT CHAINS BETA MICROGLOBULIN SPEP, IMMUNOFIXATION., ?URINE STUDIES
BONE IMAGING (PLAIN XRAY PET OR MRI)
BONE MARROW EXAM, TO INCLUDE GENETIC STUDIES (CYTOGENETICS, FISH)
clinicaloptions.com/oncologyBest Practices in Multiple Myeloma
MRI and FDG-PET in Multiple Myeloma
> 3 focal lesions or SUV > 4.2 at diagnosis results in shorter PFS and OS[1]
65% of pts PET/CT negative 3 mos after ASCT with longer PFS and OS vs PET positive[1]
Complete FDG suppression associated with durable disease control and prolonged OS[1]
Skeletal survey (radiography, MRI, or CT) recommended in cases of plasmacytoma, extramedullary disease, suspected spinal cord compression as well as with new symptoms or suspected progression [2]
MRI and/or PET/CT indicated when symptomatic areas show no abnormality on radiograph[3]
1. Zamagni E, et al. Blood. 2011;118:5989-5995. 2. Ludwig H, et al. Leukemia. 2014;28:981-992. 3. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. 4. Boot M, et al. Novel prognostic modalities in multiple myeloma. 2013.
MRI FDG PET
Imaging Techniques[4]
clinicaloptions.com/oncologyBest Practices in Multiple Myeloma
MRI and FDG-PET in Multiple Myeloma
> 3 focal lesions or SUV > 4.2 at diagnosis results in shorter PFS and OS[1]
65% of pts PET/CT negative 3 mos after ASCT with longer PFS and OS vs PET positive[1]
Complete FDG suppression associated with durable disease control and prolonged OS[1]
Skeletal survey (radiography, MRI, or CT) recommended in cases of plasmacytoma, extramedullary disease, suspected spinal cord compression as well as with new symptoms or suspected progression [2]
MRI and/or PET/CT indicated when symptomatic areas show no abnormality on radiograph[3]
1. Zamagni E, et al. Blood. 2011;118:5989-5995. 2. Ludwig H, et al. Leukemia. 2014;28:981-992. 3. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. 4. Boot M, et al. Novel prognostic modalities in multiple myeloma. 2013.
MRI FDG PET
Imaging Techniques[4]
Prognosis (NEJM Sep 22,2011)
Treatment
Supportive
Chemotherapy
Transplant
Newer Agents
Depth of response
CURRENT TREATMENT SCHEME: FIT, YOUNGER PTS Thal/Dex triple induction
harvest stem cells
Velcade/Dex Auto
Revlimid
THE YIN/YANG OF MYELOMA
UNDERSTANDING MYELOMA GENOMICS HAS NOT YIELDED TREATMENT AS EFFECTIVE AS IMIDS AND PI, DRUGS WHOSE ACTIVITY WOULD NOT HAVE BEEN PREDICTED BY “RATIONAL” DEFINITION
IF GENOMICS DOES NOT PREDICT DRUG ACTIVITY, WHAT DOES?
The “YIN”: REPRESENTATIVE OF THE NORMAL ASPECTS OF PLASMA CELLS THAT IS RETAINED IN MYELOMA EVOLUTION
The “YANG”: CLASSIC GENETIC ABNORMALITIES OF MALIGNANT PLASMA CELLS
THE TAO OF MYELOMA
TWO BIOLOGIES EXIST WITHIN MALIGNANT PLASMA CELLS, BOTH REQUIRED FOR MYELOMA SURVIVAL
WHY ARE PIs MORE ACTIVE IN MYELOMA THAN OTHER CANCERS? IT MAY HAVE TO DO WITH NORMAL PLASMA CELL BIOLOGY; NOTE EFFECTIVENESS OF PI THERAPY IN DEPLETING NORMAL PLASMA CELL IN ANTIBODY MEDIATED REJECTION.
CONCLUSION: EFFECTIVE AGENTS MAY NEED TO TARGET BOTH PLASMA CELL BIOLOGIES: COMBINE SELECTIVE PLASMA CELL INHIBIITORS AND PROTEINS SELECTIVELY ACTIVATED IN MYELOMA
MYELOMA-REDEFINED
OLD CRITERIA PREVENTED THERAPY PRIOR TO INITIATING THERAPY
NEW CRITERIA: IF BIOMARKERS CONFIRM AN 80% CHANCE OF PROGRESSION TO MYELOMA IN 24 MONTHS, THEN MYELOMA CAN BE DIAGNOSED AND TREATED
NOW:
1. M PROTEIN NOT MANDATORY FOR DIAGNOSIS
2. BONE MARROW BIOPSY PREFERRED TO ESTABLISH BONE MARROW PLASMACYTOSIS
3. BONE LESIONS DEFINED BY CT/PET, MRI VS XRAY
clinicaloptions.com/oncologyBest Practices in Multiple Myeloma
Should Patients With High-Risk Smoldering Myeloma Be Treated? Previously, no benefit shown with alkylating agents,
bisphosphonates, interleukin-1β antagonists, and thalidomide[1]
Lenalidomide vs observation: phase III randomized trials
– PETHEMA (N = 119): Lenalidomide/dexamethasone delayed time to progression (median: not reached vs 21 mos, respectively; HR: 0.18; 95% CI: 0.09-0.32; P < .001) and improved OS vs observation[2]
– ECOG-E3A06: Ongoing phase II/III trial of lenalidomide vs observation in smoldering MM (planned N = 380)
– Initial phase II data: 33% ORR; grade 3 neutropenia and fatigue [4]
1. Landgren O, et al. Clin Cancer Res. 2011;17:1243-1252. 2. Mateos MV, et al. N Engl J Med. 2013;369:438-447. 3. ClinicalTrials.gov. NCT01169337. 4. Lonial S, et al. ASH 2013. Abstract 3174.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
UPFRONT THERAPY 2015
FIT, YOUNGER PATIENTS
UNFIT, OLDER PATIENTS
WHAT IS THE GOAL? QUALITY OF LIFE? LENGTH OF SURVIVAL? PATHWAY TO TRANSPLANT? CR IS USUALLY OPTIMAL (BUT NOT ALWAYS)
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
FIRST: Lenalidomide/Dexamethasone vs MPT in NDMM SCT-Ineligible Pts
Ran
dom
ized
1:1
:1
Arm BRd18
Arm CMPT
Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28LoDex 40 mg Days 1, 8, 15, 22/28
Mel + Pred + Thal 12 cycles[2] (72 wks)Melphalan 0.25 mg/kg Days 1-4/42Prednisone 2 mg/kg Days 1-4/42Thalidomide 200 mg Days 1-42/42
PD
, OS
, and
subs
eque
nt a
nti-M
M T
x
PD
or
unac
cept
able
toxi
city
Active treatment + PFS follow-up phase
Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal 100 mg Days 1-42/42; Mel 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage.
Len + LoDex ContinuouslyLenalidomide 25 mg Days 1-21/28LoDex 40 mg Days 1, 8, 15, 22/28
Arm AContinuous Rd
1. Hulin C, et al. ASH 2014. Abstract 81. 2. Facon T, et al. Lancet. 2007;370:1209-1218. 3. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670. 4. Benboubker L, et al. N Engl J Med. 2014;371:906-917
Phase III(N = 1623)
FIRST Trial: OS by Age Stratification
Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.
Aged 75 Yrs or Younger100
80
60
40
20
0
Pts
(%
)
0 6 12 18 24 30 36 42 48 54 60
OS (Mos)
HR (95% CI)Rd vs MPT: 0.77 (0.59-1.01)Rd vs Rd18: 0.88 (0.67-1.16)Rd18 vs MPT: 0.88 (0.68-1.14)
Rd Rd18MPT
3-Yr OS, %747067
Aged Older Than 75 Yrs100
80
60
40
20
0
Pts
(%
)
0 6 12 18 24 30 36 42 48 54 60
OS (Mos)
HR (95% CI)Rd vs MPT: 0.80 (0.59-1.09)Rd vs Rd18: 0.94 (0.69-1.29)Rd18 vs MPT: 0.85 (0.63-1.15)
Rd Rd18MPT
3-Yr OS, %635854
FIRST Trial: Grade 3/4 Adverse Events
Grade 3/4 Treatment-Emergent AE, %
Dose for Pts Aged ≤ 75 Yrs Dose for Pts Aged > 75 Yrs
Continuous Rd
(n = 347)
Rd18(n = 348)
MPT(n = 357)
Continuous Rd
(n = 185)
Rd18(n = 192)
MPT(n = 184)
Hematologic in ≥ 10% of pts
Neutropenia 28 25 47 28 29 40
Anemia 18 12 20 19 23 17
Thrombocytopenia 8 9 13 9 7 7
Leukopenia 5 6 11 4 5 8
Nonhematologic
Infection 29 21 16 29 23 20
Cardiac disorders 12 6 6 12 9 13
Fatigue 6 8 5 9 10 8
Peripheral sensory neuropathy
1 1 10 1 0 8
Cataracts 7 3 < 1 3 2 1
DVT and/or PE 8 5 6 7 6 4
Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.
FIRST Trial: Conclusions
Continuous Rd improved PFS vs MPT or 18 cycles of Rd for newly diagnosed MM regardless of age Median and 3-yr PFS both extended with
continuous Rd vs MPT or Rd18 whether pts were younger or older than 75 yrs of age
3-yr OS extended with continuous Rd vs MPT whether pts were younger or older than 75 yrs of age
Analysis of FIRST results based on age consistent with overall trial results
Toxicity profile of Rd similar among pts 75 yrs of age or younger and older than 75 yrs of age
Hulin C, et al. ASH 2014. Abstract 81.
FIT, YOUNGER PATIENTS
3 DRUG COMBINATIONS GIVE VERY HIGH RESPONSE RATES, INCLUDING ~30% CR. 2 DRUG REGIMENS NOT QUITE AS HIGH A RESPONSE, BUT NO CLEAR DECREASE IN OS VS 3 DRUG REGIMEN
OPTIONS ARE RVD, CYBORD, VPT
LENALIDOMIDE: SIDE EFFECTS ARE HEMATOLOGIC, CONSTITUTIONAL, GI, FETAL
VELCADE: LESS TOXICITY WITH SC THERAPY. NEUROLOGIC, HEMATOLOGIC TOXICITY MOST LIKELY
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
RELAPSED, REFRACTORY PATIENTS
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Pomalidomide/Bortezomib/Dexamethasone for Lenalidomide Refractory MM Phase I/II trial to determine MTD; assess safety and efficacy of
pomalidomide/bortezomib/dexamethasone
– Included pts with relapsed MM who had 1-4 previous lines of therapy and were resistant/refractory to lenalidomide
– Accrual: 50 pts (phase I: 3 at dose level 1, 6 at dose level 2; phase II: 41)
Current analysis: 47 pts treated at MTD (dose level 2 + phase II)
Lacy MQ, et al. ASH 2014. Abstract 304.
Pomalidomide 4 mg/day on Days 1-21
Bortezomib 1.3 mg/m2 (IV or SC) and dexamethasone 40 mg
Day 1 Day 8 Day 15 Day 22
8 cycles
Pomalidomide 4 mg/day until PD
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
AnxietyGeneralized muscle
weaknessEdema limbsConstipation
DyspneaInsomniaDizziness
Thromboembolicevent
Lung infectionVomitingNausea
DiarrheaPeripheral
neuropathyFatigue
Pomalidomide/Bortezomib/Dexamethasone: Summary of Adverse Events
Lacy MQ, et al. ASH 2014. Abstract 304. Reproduced with permission.
Hematologic Toxicity
Grade 3+ All grades
AnemiaThrombocytopeniaNeutropenia
2%70%
2%81%
89%68%
Pts (n)
0 10 20 30 40 50
Pts (n)
0 5 10 15 20 3525 30
Nonhematologic Toxicity
45%
64%
70%
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Pomalidomide/Bortezomib/Dexamethasone: Conclusions Pomalidomide/bortezomib/dexamethasone associated
with high response rate (85%) in pts with relapsed MM who are resistant/refractory to lenalidomide
Weekly administration of bortezomib and dexamethasone enhanced tolerability and convenience of treatment
Pomalidomide/bortezomib/dexamethasone associated with manageable AEs, consisting primarily of mild cytopenias
Lacy MQ, et al. ASH 2014. Abstract 304.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
ASPIRE: Phase III Trial Comparing Len/ Dexamethasone ± Carfilzomib in R/R MM Randomized, open-label, multicenter phase III trial
KRd* (n = 396)Carfilzomib 27 mg/m2 IV
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only) Lenalidomide 25 mg Days 1-21
Dexamethasone 40 mg Days 1, 8, 15, 22
Rd (n = 396)Lenalidomide 25 mg Days 1-21
Dexamethasone 40 mg Days 1, 8, 15, 22
Stratified by β2-microglobulin, prior bortezomib, and prior lenalidomide
*After cycle 12, carfilzomib given on Days 1, 2, 15, 16. After cycle 18, carfilzomib discontinued.
Stewart AK, et al. ASH 2014. Abstract 79.
Pts with symptomatic R/R MM after 1-3 prior treatments with ≥ PR to ≥ 1 prior regimen
(N = 792)
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ASPIRE: PFS in ITT Population (Primary Endpoint)
KRd Rd(n = 396) (n =
396)
Median PFS, mos 26.3 17.6HR (KRd/Rd) (95% CI) 0.69 (0.57-0.83)P value (1 sided) < .0001
1.0
0.8
0.6
0.4
0.2
0.0
Pro
port
ion
Sur
vivi
ngW
ithou
t P
rogr
essi
on
KRdRd
0 6 12 18 24 30 36 42 48Mos Since Randomization
Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.
Risk Group by FISH
KRd (n = 396) Rd (n = 396) HR P Value
n Median PFS, Mos n Median PFS, Mos
High 48 23.1 52 13.9 0.70 .083
Standard 147 29.6 170 19.5 0.66 .004
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ASPIRE: Interim OS Analysis
Median follow-up: 32 mos
Median OS was not reached; results did not meet prespecified statistical boundary (P = .005) at interim analysis
KRd Rd(n = 396) (n = 396)
Median OS, mos NR NRHR (KRd/Rd) (95% CI) 0.79 (0.63-0.99)P value (1 sided) .018
1.0
0.8
0.6
0.4
0.2
0.0
Pro
port
ion
Sur
vivi
ng
KRdRd
0 6 12 18 24 30 36 42 48Mos Since Randomization
Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
ASPIRE: Response Rates and PFS by Response
Per
cent
age
of P
ts
1.0
0.8
0.6
0.4
0.2
0.0S
urvi
val P
roba
bilit
y
0 10 20 30 40 50
Mos From Randomization
sCRCRVGPRPRMRSDPD
Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.
PFS by Response With KRd Tx
AEs consistent with previous studies; no unexpected toxicities observed
100
80
60
40
20
0≥ CR ≥ VGPR ORR
(≥ PR)
KRdRd
31.8
9.3
69.9
40.4
87.1
66.7
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
ASPIRE: Conclusions
PFS significantly improved by 8.7 mos in pts treated with KRd vs Rd relapsed/refractory MM (HR: 0.69; P < .0001)
– Median PFS of 26.3 mos with triplet combination unprecedented in this setting
Interim OS analysis reveals trend favoring KRd
Increased ORR with KRd vs Rd: 87.1% vs 66.7%
– More pts achieved CR or better with triplet: 31.8% with KRd vs 9.3% with Rd
Acceptable safety profile observed with KRd
KRd potentially new standard of care for treatment of relapsed MM
Stewart AK, et al. ASH 2014. Abstract 79.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Combination Therapy With Carfilzomib and Panobinostat Multiple Myeloma Research Consortium multicenter
phase I trial to determine MTD; assess safety and efficacy of panobinostat and carfilzomib
Kaufman JL, et al. ASH 2014. Abstract 32.
Cohort Panobinostat(TIW 3 of 4 wks)
Carfilzomib(Days 1/2, 8/9, 15/16
q4w)
Dexamethasone (Prior to Carfilzomib Dose)
1 15 mg 20 mg/m2 lead-in followed by 27 mg/m2 4 mg cycle 1, then optional
2 20 mg 20 mg/m2 lead-in followed by 27 mg/m2 4 mg cycle 1, then optional
3 20 mg 20 mg/m2 lead-in followed by 36 mg/m2 4 mg cycle 1, then optional
4 20 mg 20 mg/m2 lead-in followed by 45 mg/m2 4 mg cycle 1, then optional
MTD
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Combination Therapy With Carfilzomib and Panobinostat: Conclusions Combination carfilzomib/panobinostat appears safe and
effective in pts with relapsed/refractory MM
– MTD of the combination: carfilzomib 36 mg/m2 + panobinostat 20 mg TIW for 3 of 4 wks
Promising response rate, DoR, PFS, and OS
Manageable adverse events in pts with no unexpected toxicities
Kaufman JL, et al. ASH 2014. Abstract 32.
DOES DEFINING MINIMAL RESIDUAL DISEASE INFORM TREATMENT?
clinicaloptions.com/oncologyBest Practices in Multiple Myeloma
MRD by High-Throughput Sequencing Predicts Prognosis in Patients With CR Quantitative; with amplification and sequencing of immunoglobulin gene
segments using consensus primers for: immunoglobulin heavy-chain locus complete (IGH-VDJH), IGH incomplete (IGH-DJH), and immunoglobulin κ locus (IGK)
MRD stratifies the CR population into 2 groups with strikingly different prognosis
Martinez-Lopez, et al. Blood. 2014;123:3073-3079.
TT
P (
%)
100
80
60
40
20
0100 1500 50
Mos
P = .0009
n = 26
n = 36
TTP (CR Patients)MRD negativeMRD positiveThreshold: 10-5
clinicaloptions.com/oncologyBest Practices in Multiple Myeloma
ASO-PCR Flow Cytometry Next Generation Sequencing (HTS)
Sensitivity Limited by cell number and sometimes background: > 10-5
Limited by technical applicability of antibodies 4-color assay (> 10-4),Higher sensitivity with 8 colors and new bioinformatical tools
Limited by cell number: > 10-6
Very low intrinsic background
Intraclonal variability
Hypersomatic mutations can affect target identification and assay sensitivity
Clones expressing aberrant phenotypes can emerge
May affect subclone identification in mature lymphoid malignancies and hamper MRD assessment
Bioinformatical algorithms needed
Labor intensity Needs 5-7 working days for assay establishment
Fast, experienced investigators needed
Dependent on HTS device
Bioinformatical expertise is crucial
Standardization Easily adaptable to MM
Ongoing process Performed only on a service basis (EUROCLONALITY, EUROMRD initiative on NGS ongoing)
Comparing Flow Cytometry and RQ-PCR: Different Point of View and Novel Incumbent
NEW AGENTS
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Phase Ib/II: Single-Agent Oprozomibin Relapsed/Refractory MM Open-label phase Ib/II dose escalation study of oprozomib
– Oprozomib is a selective, irreversible oral epoxyketone proteasome inhibitor with promising antitumor activity
– In pts who relapsed after ≥ 1 prior lines of therapy
Vij R, et al. ASH 2014. Abstract 34.
Trial Parameter 2/7 Schedule(n = 21)
5/14 Schedule(n = 47)
2/7 Step-up Schedule(n = 10)
5/14 Step-up Schedule
(n = 9)
Phase Ib Ib/II II II
Schedule, every 2 wks Days 1, 2, 8, 9 Days 1-5 Days 1, 2, 8, 9 Days 1-5
Dose, mg/day 150-330 150-270 240/300 150/180
Median tx duration, wks (range) 23.4 (0.3-76.4) 6.7 (0.7-93.1) 5.6 (0.1-11.3) 6.7 (3.0-16.7)
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Single-Agent Oprozomib in Relapsed/ Refractory MM: Conclusions Single-agent oprozomib appears safe, with promising activity in
pts with relapsed/ refractory MM
– Continues to show promising antitumor activity; ORR between 23% and 31% overall
– Preliminary data suggest that step-up dosing is associated with improved tolerability, with few grade ≥ 3 GI adverse events observed
Enrollment on phase II 2/7 and 5/14 schedules ongoing
– Target enrollment for the phase II portion: 94 pts with MM
All current and newly enrolled pts will receive new, extended-release tablet formulation
Vij R, et al. ASH 2014. Abstract 34.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Ibrutinib ± Dexamethasone: Overall Response and PFS Response rate PFS
Pts
(%
)
Cohort 1(n = 13)
Cohort 2(n = 18)
Cohort 3(n = 18)
Cohort 4(n = 20)
Vij R, et al. ASH 2014. Abstract 31. Reproduced with permission.
0 6 12
Mos
0
20
40
60
80
100
Pts
(%
)
Cohorts 1, 2, and 3Cohort 4
93
Cohort: 1 2 3 4
Median PFS, mos
1.0 4.3 2.8 5.6
50
40
30
20
10
0
PR MR SD ≥ 4 cycles
8%
8%
22%
6%
33%
25%
20%
5%
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Ibrutinib ± Dexamethasone: Safety
22% of pts required a dose modification due to an AE, while 10% led to treatment discontinuation
Hematologic AEs Nonhematologic AEs
Vij R, et al. ASH 2014. Abstract 31. Reproduced with permission.
Grades 3-5All grades
Anemia
Thrombocytopenia
Neutropenia
Pts (%)
0 20 40 60 80 100
Cohort 4
All
Cohort 4
All
Cohort 4
All
Diarrhea
Fatigue
Nausea
Pts (%)
0 20 40 60 80 100
Cohort 4
All
Cohort 4
All
Cohort 4
All
Dizziness
Muscle Spasms
Arthralgia
Pts (%)
0 20 40 60
Cohort 4
All
Cohort 4
All
Cohort 4
All
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Ibrutinib ± Dexamethasone: Conclusions
Ibrutinib ± weekly dex appears safe, with promising activity in heavily pretreated pts with relapsed/refractory MM
– Highest activity was seen in cohort 4 with:
– 25% CBR
– Sustained SD in an additional 25%
– Median PFS of 5.6 months
– Safety profile tolerable, with AE rates consistent with those seen in other histologies
Enrollment of 23 additional pts in cohort 4 is complete; evaluation is ongoing
Further study of ibrutinib in combination with other backbone agents is warranted
Vij R, et al. ASH 2014. Abstract 31.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Phase I Trial: Daratumumab in Combination With Len/Dex in Rel/Ref MM Phase I/II dose-escalation trial of daratumumab in combination with
len/dex in rel/ref MM (safety cohort: n =45; efficacy cohort: n = 43)
– Daratumumab is a human mAb targeting CD38-expressing cells
– Dose escalation: daratumumab 2-16 mg/kg/wk for 8 wks, twice monthly for 16 wks, then once monthly for 24 mos in total or until PD, unmanageable AE
– Lenalidomide 25 mg on Days 1-21 of each 28-day cycle
– Dexamethasone 40 mg/wk for of each 28-day cycle
Median prior lines of therapy: 2 (range: 1-4); most with prior exposure to IMiDs and/or a proteasome inhibitor; 3 pts refractory to len
MTD: daratumumab 16 mg/kg + len 25 mg and dex 40 mg/wk
Plesner T, et al. ASH 2014. Abstract 84.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Daratumumab in Combination With Len/Dex: Safety Daratumumab related serious AEs
– Pneumonia, neutropenia, diarrhea (1 pt each receiving 16 mg/kg, early infusion program)
– Laryngeal edema (1 pt receiving 16 mg/kg, accelerated infusion program)
19/45 pts reported infusion-related reactions; mostly grade 1/2
– 18/19 pts with infusion-related reactions recovered and were able to continue the subsequent infusion
≤ 8 mg/kgPart 1
(n = 10)
16 mg/kgPart 1(n = 3)
16 mg/kgPart 2
Current InfusionProgram (n = 21)
16 mg/kgPart 2
Accelerated InfusionProgram (n = 11)
Plesner T, et al. ASH 2014. Abstract 84. Reproduced with permission.
60
40
20
0
Pts
(%
)
20.0 20.0
33.338.1
4.8
63.6Infusion-Related Reactions
First Infusion
Subsequent Infusion
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Phase I Trial: SAR650984 in Combination With Len/Dex in Relapsed/Refractory MM Phase Ib trial of SAR650984 + len/dex in relapsed/refractory MM
– SAR650984 is a humanized IgG1 mAb to the CD38 receptor widely expressed in many heme malignancies
– Dose escalation: SAR650984 3-10 mg/kg on Days 1 and 15 of each 28-day cycle + lenalidomide 25 mg on Days 1-21 of each 28-day cycle and dexamethasone 40 mg/wk during each 28-day cycle
Martin TG, et al. ASH 2014. Abstract 83.
Previous MM Treatment
SAR650984 Dose, mg/kg q2w
Overall(N = 31)3 (n = 4) 5 (n = 3) 10 (n = 24)
Median prior regimens, n (range) 10 (3-14) 7 (6-7) 6 (2-12) 7 (2-14)
Median prior lines, n (range) 6 (2-11) 6 (4-6) 4 (1-9) 4 (1-11)
Median time on last Len, mos (range)
7 (3-17) 3 (3-10) 10 (1-54) 9 (1-54)
Relapsed/refractory to IMiD 3 (75) 2 (67) 21 (88) 26 (84)
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
SAR650984 + Len/Dex: PFS by Previous Lines of Therapy
Pro
bab
ility
0
10
20
30
40
50
60
70
80
90
100
Mos
50 1 2 3 4 6 7 8 9 10 11 12 13 14 15 16 17
≥ 3 prior lines (n = 24)
Overall (N = 31)
Median PFS: NR (95% CI: 6.2-NR)
Median PFS: 6.2 mos (95% CI: 4.80-13.33)
Median PFS: 5.8 mos (95% CI: 2.10-10.30)
1-2 prior lines (n = 7)
Martin TG, et al. ASH 2014. Abstract 83. Reproduced with permission.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
SAR650984 + Len/Dex: Efficacy Analysis
DoR: 9.13 mo (range: 1.2-15.2)
Martin TG, et al. ASH 2014. Abstract 83. Reproduced with permission.
Response, % Total (N = 31)
ORR 58
sCR 6
VGPR 23
PR 29
CBR 65
MR 6
SD 19
PD 13
Not evaluable 3
Pts
(%
)
SAR650984 Dose Level, mg/kg q2w
ORR 25%CBR 50%
ORR 67%CBR 67%
ORR 63%CBR 67%
ORR 58%CBR 65%
100
80
60
40
20
03
(n = 4)5
(n = 3)10
(n = 24)Overall(n = 31)
25
25
67
8
29
6
29
6
25 23
4
PR sCRVGPRMR
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
SAR650984 plus Len/Dex: Tx-Emergent AEs in ≥ 30% (Any) or 5% (Grade 3/4) of Pts
There were 15 incidences of infusion reaction, all occurring in the first 2 cycles – 2 pts discontinued treatment: 1 serious grade 3 anaphylactic reaction in cycle 1 and
1 nonserious grade 3 maculopapular rash in cycle 2 (AEs resolved in both pts)
– Remaining incidents were grade 1/2 and did not lead to treatment discontinuation
Pts
(n
= 3
1) (
%)
Thro
mbo
cyto
peni
a
Febrile
neut
rope
nia Mus
cle
spas
ms
Martin TG, et al. ASH 2014. Abstract 83. Reproduced with permission.
100
80
60
40
20
0
Grade 1 Grade 2 Grade 3 Grade 4Ane
mia
Neutro
peni
a
Diarrh
ea
Fatig
ueIn
som
nia
Nause
aPne
umon
ia
Pyrex
ia
URTI
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
SAR650984 + Len/Dex: Conclusions
Combination SAR650984 with len/dex appears safe and effective in heavily pretreated pts with relapsed/refractory MM
– ORR was 58%; 63% at the SAR650984 10 mg/kg dose level
– Manageable safety profile, consistent with those of individual agents
– At 9-mo follow-up, overall median PFS was 6.2 mos
Martin TG, et al. ASH 2014. Abstract 83.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Phase I Trial: Elotuzumab in Combination With Len/Dex in Relapsed/Refractory MM Phase Ib/II 1703 trial of elotuzumab + len/dex in relapsed/refractory
MM
– Elotuzumab is a humanized IgG1 mAb targeting SLAMF7, a glycoprotein highly expressed on myeloma and NK cells
– Elotuzumab 10 or 20 mg/kg on Days 1, 8, 15, 22 for cycles 1-2; Days 1, 15 for subsequent cycles
– Lenalidomide 25 mg on Days 1-21 of each 28-day cycle
– Dexamethasone 28 mg + 8 mg IV on elotuzumab dosing days, or 40 mg/wk for of each 28-day cycle
Current analysis on phase II data to assess efficacy and safety of combination
– ~ 60% of pts received previous treatment with bortezomib and/or thalidomide and 20% to 30% were refractory to previous treatment
Richardson PG, et al. ASH 2014. Abstract 302.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Elotuzumab in Combination With Len/Dex: Conclusions Combination elotuzumab with len/dex appears safe and
effective in heavily pretreated pts with relapsed/refractory MM
– ORR: 92% with 10 mg/kg elotuzumab; 84% overall
– Median PFS: 32.5 mos with 10 mg/kg; 29 mos overall
Favorable safety profile; most common treatment-related AEs included diarrhea, fatigue, muscle spasms, constipation
Accelerated infusion well tolerated and pretreatment regimen decreased rate of infusion reactions
Phase III trials with elotuzumab + len/dex in newly diagnosed MM and relapsed/refractory MM currently ongoing
Richardson PG, et al. ASH 2014. Abstract 302.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Combination Therapy With Carfilzomib and Panobinostat: Preliminary SafetyAny Grade AEs in ≥ 20% of Pts, %
Overall(n = 26)
All 100
Nausea 65
Diarrhea 50
Thrombocytopenia 50
Fatigue 38
Vomiting 35
Hypokalemia 31
Pyrexia 31
Decreased appetite 27
Hypocalcemia 27
Insomnia 23
Grade 3/4 AEs in ≥ 5% of Pts, %
Overall (n = 26)
≥ 1 grade 3/4 AE 77
Anemia 38
Thrombocytopenia 38
Neutropenia 19
Fatigue 12
Decreased appetite 8
Diarrhea 8
Elevated creatinine 8
Hyperglycemia 8
Hypertension 8
Hyponatremia 8
Kaufman JL, et al. ASH 2014. Abstract 32.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Combination Therapy With Carfilzomib and Panobinostat: Conclusions Combination carfilzomib/panobinostat appears safe and
effective in pts with relapsed/refractory MM
– MTD of the combination: carfilzomib 36 mg/m2 + panobinostat 20 mg TIW for 3 of 4 wks
Promising response rate, DoR, PFS, and OS
Manageable adverse events in pts with no unexpected toxicities
Kaufman JL, et al. ASH 2014. Abstract 32.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Weekly Carfilzomib + Cyclophosphamide/ Dex: Preliminary EfficacyOutcome Phase I (n = 12) MTD (n = 19) Total (N = 28)
Median cycles received, n (range) 9 (1-9) 4 (1-9) 8 (1-9)
ORR (≥ PR), n (%) 11 (92) 15 (79) 24 (86)
≥ VGPR 9 (75) 11 (58) 18 (64)
sCR + CR + nCR 4 (33) 4 (21) 7(25)
1. Palumbo A, et al. ASH 2014. Abstract 175. 2. Bringhen S, et al. Blood. 2014;124:63-69.Reproduced with permission.
Once weekly[1] Twice weekly[2]
At Least nCR At Least VGPR50
40
30
20
10
0
Pts
(%
)
Cycle 4 Cycle 9
3024
4147 100
80
60
40
20
0
Pts
(%
)
Cycle 4 Cycle 9
89
57
9177
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Melphalan/Dexamethasone ± Bortezomib in AL Amyloidosis: Efficacy Summary
Kastritis E, et al. ASH 2014. Abstract 35. Reproduced with permission.
Response After Cycle 3, n (%)
Response MDex (29 pts) BMDex (30 pts) P
Overall Hem 15 (52) 22 (73) .086
CR 1 (3) 4 (13) .173
VGPR 9 (31) 11 (37) .648
PR 4 (14) 7 (23) .347
Cardiac 5/23 (22) 4/17 (23) .893
Renal 6/15 (40) 3/16 (19) .193
Best Response (Median 5 Cycles), n (%)
Response MDex (29 pts) BMDex (30 pts) P
Overall Hem 15 (52) 23 (77) .045
CR 6 (21) 7 (23) .807
VGPR 6 (21) 11 (37) .176
PR 3 (10) 5 (17) .478
Cardiac 5/23 (22) 4/17 (23) .893
Renal 7/15 (47) 5/16 (31) .378
100
80
60
40
20
0
Su
rviv
al P
rob
abil
ity
(%)
PFS
P = .109
BMDexMDex
Mos0 12 24 36 40
100
80
60
40
20
0
Su
rviv
al P
rob
abil
ity
(%)
OS
P = .504
BMDexMDex
Mos0 12 24 36 40
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Melphalan/Dexamethasone ± Bortezomib in AL Amyloidosis: Conclusions Higher hematologic response rates BMDex vs MDex in
treatment-naive pts with systemic AL amyloidosis
– Best overall hematologic response: 77% vs 52%, respectively (P = .045)
– Overall hematologic response after 3 cycles: 73% vs 52%, respectively (P = .086)
BMDex was well tolerated, with cytopenias the only grade ≥ 3 AE occurring in > 2% of pts
Additional follow-up needed to assess differences in organ improvement, survival
Kastritis E, et al. ASH 2014. Abstract 35.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Actual treatment <65
Thal/Dex triple induction
harvest stem cells
Velcade/Dex Auto
Revlimid
AUTOTRANSPLANT IN MYELOMA
COMPARED TO OLDER CHEMOTHERAPY ALONE, PROVEN BENEFIT FOR BETTER SURVIVAL WITH HD MELPHALAN
STUDIES COMPARING AUTOTRANSPLANT GIVEN AFTER NOVEL INDUCTION THERAPY (VS NOVEL THERAPY ALONE) ARE PENDING
PFS CAN BE IMPROVED WITH HD MELPHALAN, AND AUTO TRANSPLANT IS STILL COMMONLY USED FOR CONSOLIDATION IN THE US
MAINTENANCEALL THE TIME? MOST OF THE TIME?
clinicaloptions.com/oncologyBest Practices in Multiple Myeloma
Maintenance in Myeloma: Still a Work in Progress? Provides PFS advantage
– Longer follow-up needed
OS improvements noted
Toxicities of treatment
– Myelosuppression
– Second primary malignancies
– Quality of life
Unknown response to higher doses of lenalidomide at relapse; potential development of resistant clones
Observation is still an option
Unclear whether all patients benefit from maintenance
– Tailor treatment choice to individual patient
Van de Donk N, et al. Cancer Management Res. 2012;4:253-268.
clinicaloptions.com/oncologyBest Practices in Multiple Myeloma
Lenalidomide Maintenance Therapy: Meta-analysis of Randomized Trials In a study of 4 RCTs (N = 1935), lenalidomide maintenance
vs no maintenance or placebo associated with:
– Improved PFS (overall HR: 0.49; P < .001)
– Trend toward improved OS (overall HR: 0.77; P = .071)
– Significantly higher risk of grade 3/4 neutropenia, VTE, thrombocytopenia, fatigue
– Significantly higher risk of secondary malignancies (overall OR: 1.62; P = .006)
Patient subset most benefitting from lenalidomide maintenance therapy remains undefined
Singh PP, et al. ASH 2013. Abstract 407.
Ixazomib Maintenance: Efficacy and Safety
Safety in maintenance period similar to induction period No grade 4 AEs, grade 3
drug-related AEs reported in 62% of pts
52% during induction
14% during maintenance
Limited new onset AEs during maintenance New onset AEs ≤ 10%
except:
Diarrhea (~ 45%)
Nausea (~ 20%)
Pain in extremities (~ 15%)
Kumar S, et al. ASH 2014. Abstract 82. Reproduced with permission.
1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ility
of
PF
S
0 3 6 9 12 15 18 21 24 27 30 33
Phase II pts who received maintenance
All phase II pts (pts who proceeded to ASCT [n = 14] were censored at last response assessment before ASCT)
Median PFS among censored phase II pts who received maintenance (n = 21): not reached, 10 pts progressed
‒ Estimated 2-yr PFS: 57%
Median PFS among all phase II pts (n = 50): 28.7 mos
‒ Estimated 2-yr PFS: 50%
Mos
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Ixazomib Maintenance: Efficacy and Safety
Safety in maintenance period similar to induction period
– No grade 4 AEs, grade 3 drug-related AEs reported in 62% of pts
– 52% during induction
– 14% during maintenance
Limited new onset AEs during maintenance
– New onset AEs ≤ 10% except:
– Diarrhea (~ 45%)
– Nausea (~ 20%)
– Pain in extremities (~ 15%)Kumar S, et al. ASH 2014. Abstract 82. Reproduced with permission.
1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ility
of
PF
S
0 3 6 9 12 15 18 21 24 27 30 33
Phase II pts who received maintenance
All phase II pts (pts who proceeded to ASCT [n = 14] were censored at last response assessment before ASCT)
Median PFS among censored phase II pts who received maintenance (n = 21): not reached, 10 pts progressed
‒ Estimated 2-yr PFS: 57%
Median PFS among all phase II pts (n = 50): 28.7 mos
‒ Estimated 2-yr PFS: 50%
Mos
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Ixazomib Maintenance: Conclusions
All-oral regimen of ixazomib/lenalidomide/dexamethasone associated with high response rate in pts with NDMM
– 90% of pts had PR or better
– 48% of pts had deepening of response with ixazomib maintenance
Regimen was tolerable with no grade 4 AEs
– Most common AEs: skin and subcutaneous tissue disorders, diarrhea, fatigue, nausea, peripheral neuropathy
Ongoing phase III trial comparing ixazomib vs placebo in combination with lenalidomide/dexamethasone in pts with NDMM
Kumar S, et al. ASH 2014. Abstract 82.
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Weekly Carfilzomib + Cyclophosphamide/ Dex: Preliminary EfficacyOutcome Phase I (n = 12) MTD (n = 19) Total (N = 28)
Median cycles received, n (range) 9 (1-9) 4 (1-9) 8 (1-9)
ORR (≥ PR), n (%) 11 (92) 15 (79) 24 (86)
≥ VGPR 9 (75) 11 (58) 18 (64)
sCR + CR + nCR 4 (33) 4 (21) 7(25)
1. Palumbo A, et al. ASH 2014. Abstract 175. 2. Bringhen S, et al. Blood. 2014;124:63-69.Reproduced with permission.
Once weekly[1] Twice weekly[2]
At Least nCR At Least VGPR50
40
30
20
10
0
Pts
(%
)
Cycle 4 Cycle 9
3024
4147 100
80
60
40
20
0
Pts
(%
)
Cycle 4 Cycle 9
89
57
9177
clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders
Weekly Carfilzomib in Combination With Cyclophosphamide/Dex in NDMM Phase I/II trial to assess feasibility of reduction of carfilzomib dosing
from twice weekly to once weekly when used in combination with cyclophosphamide/dexamethasone in elderly pts with NDMM
– Carfilzomib given weekly using standard 3+3 phase I dose-escalation (starting at 45 mg/m2, increasing to 56 or 70 mg/m2)
Phase I data (n = 12) identified MTD as 70 mg/m2
– 3 of 12 pts in phase I portion received MTD
Phase II cohort currently enrolling
– 18 pts included in current analysis
Similar baseline characteristics across all pts in phase I and II cohorts, with 30% of pts aged ≥ 75 yrs and 33% with unfavorable cytogenetics
Palumbo A, et al. ASH 2014. Abstract 175.
clinicaloptions.com/oncologyBest Practices in Multiple Myeloma
Phase III Maintenance Studies: Transplantation-Ineligible PatientsTrial N Regimen Outcomes
MM-015[5] 459 MPR followed by R maintenance vs MPR vs MP, transplantation-ineligible pts
Median PFS: 31 vs 14 vs 13 mos
Median OS: 56 vs 52 vs 54 mos
GIMEMA-MM-03-05[2]
511 VMPT followed by bortezomib/thalidomide maintenance vs VMP
Median PFS:35 mo vs 25 mos
5-yr OS: 61% vs 51%
GEM2005MAS65[3]
260 VMP followed by bortezomib/thalidomide maintenance vs VTP followed by
bortezomib/prednisone maintenance
Median PFS:39 vs 32 mos
5-yr OS: 69% vs 50%
1. Dimopoulos MA, et al. ASH 2013. Abstract 405. 2. Palumbo A, et al. J Clin Oncol. 2014;32:634-640. 3. Mateos MV, et al. Blood. 2012;120:2581-2588.
clinicaloptions.com/oncologyOptimal Approaches for the Care of Veterans With Multiple Myeloma
What We Know and Don’t Know
New drugs improve induction CRs, higher CRs after ASCT
– Which drug combinations are optimal for patients proceeding to transplantation?
Do higher response rates observed after novel drug combinations plus ASCT improve survival?
Some new drugs affect stem cell yields
If a patient achieves CR after novel induction therapies, is a transplantation optional?
Gertz MA, Dingli D. Blood. 2014;124:882-890.Giralt S, et al. Bio Blood Marrow Transplant. 2014;20:295-308.
THANK YOU!
Thank you!
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clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders