mmrf imw aacr2017 highlights 1g ks...making sense of myeloma treatment advances webinar 1 – may...
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Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Making Sense of Myeloma Treatment Advances
Webinar 1, May 17, 2017Updates From the 16th International Myeloma Workshop and the American Association for
Cancer Research 2017 Annual Meeting
SpeakersModerator: • Mary DeRome
Multiple Myeloma Research FoundationNorwalk, Connecticut
Faculty:• Lawrence Boise, PhD
Emory UniversityAtlanta, Georgia
• Shaji Kumar, MDMayo ClinicRochester, Minnesota
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Topics for Discussion• Disease biology and risk stratification• Newly diagnosed myeloma• Stem cell transplantation• Minimal residual disease (MRD) in
myeloma• Relapsed myeloma• Venetoclax• New immune therapies
Myeloma Treatment Paradigm
Induction
Induction followed by continuous therapy
Consolidation Maintenance
SC
T
Elig
ible
SC
T
Inel
igib
le
Dia
gn
osi
s &
Ris
k S
tra
tific
atio
n
Tumor Burden
SCT, stem cell transplant
Treatment of
relapsed disease
Treatment-free interval?
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Disease Biology and Risk Stratification
Asymptomatic Myeloma• What factors control progression?
– Up-front genetics?– Acquired changes?– Other factors?
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Acquired Changes in Myeloma
MGUS AMM MM pre‐MGUS
B
A
Seckinger A et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-015.
• In this model a change to a cell with asymptomatic disease results in symptomatic myeloma.
Up-Front Genetics in Myeloma
MM
AMM
MGUS
MGUS AMM MM pre‐MGUS
B
Seckinger A et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-015.
• In this model the genetic changes occur earlier and other factors determine when the disease becomes symptomatic
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Tumor Mass, Proliferation, and Up-Front Factors Are Predictors of
Progression to Symptomatic Myeloma
M‐protein
Doubling time
UAMS70‐gene score
Seckinger A et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-015.
Disease Progression: More Than One Way to Evolve
Neutrally evolving
Darwinian selection (Non-neutral)
Johnson D et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-016.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Neutral-Evolution Disease Responds Differently to Non-Intensive Therapy
Intensive TreatmentOverall Survival
Median not reached
Non-intensive TreatmentOverall Survival
Median 27.3 vs. 49.6 months (P<0.001)
Johnson D et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-016.
Using Next-Generation Sequencing for Myeloma Staging
CA, chromosomal abnormalities; iFISH, interphase fluorescent in situ hybridization; ISS, International Staging System; LDH, lactate dehydrogenase; MM, multiple myeloma; R-ISS, revised International Staging System.Fiala M et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-029.Palumbo A, et al. J Clin Oncol. 2015;33:2863.
Prognostic Factor Criteria
ISS stage
ISerum β2M <3.5 mg/Lserum albumin ≥3.5 g/dL
II Not ISS stage I or III
III Serum β2M ≥5.5 mg/L
CA by iFISH
High riskPresence of del(17p) and/or translocation t(4;14) and/ortranslation t(14;16)
Standard risk No high-risk CA
LDH
Normal Serum LDH < the upper limit of normal
High Serum LDH > the upper limit of normal
A new model for risk stratification for MM R-ISS stage
I ISS stage I and standard-risk CA by iFISH and normal LDH
II Not R-ISS stage I or III
III ISS stage III and either high-risk CA by iFISH or high LDH
Standard Risk Factors for MM and the R-ISS
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Using Next-Generation Sequencing for Myeloma StagingData: Interim analysis 9 from the MMRF CoMMpass study.
Controlling for Age (>65 vs ≤65) and Sex
Fiala M et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-029.
Sequencing From the Blood (or do we need to do so many bone marrows?)
• Circulating tumor cells (CTCs) are rare myeloma plasma cells found in the blood
• Circulating free DNA (cfDNA) is DNA released from dead cells into the bloodstream
Manier S et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-004.
733 non-silent mutations
BM cells10%
63%
CTCs7%
cfDNA8%
Sequencing from CTCs or cfDNA can provide similar results to sequencing from the bone marrow
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Developing New Ways to Measure Disease
• Current standard methods for measuring M protein in the blood or urine were developed in the 1960s
• New antibody therapies interfere with these methods ©2013 MFMER | slide‐13
Purify Ig using Camelids
Release of light chain
DTT Analyze on 5600 Q-TOF
MS
Inject on microLC
miRAMM—Screen + MRD*
Y Y Y Y Y
Y
Y Y
Y
Y Y
Y Y Y
Y
Y Y Y Y Y Y Y Y Y Y
Y Y
Y Y Y Y Y Y Y
Y
Y Y
Y Y Y
Y
Y
Y
Y Y
Y Y Y Y Y
Y Y Y Y
Y Y
Y Y
Y Y Y
m/z
Inte
nsity
+11 +12
+13 +14 +15
+16 +17
+18 +19
+20
+10
Polyclonal LCs
22,850.7 Da
M-protein (mIg)
Mass (Da)
Inte
nsity
Mass reconstruction
Mass (Da)
Inte
nsity
+2
+1
Analyze on MASS-FIX
Screen
miRAMM MRD
T‐mAbs 100 X IFE
ESI
Using mass spectrometry to measure antibodies or light chains is more sensitive (MRD) and more precise (no therapeutic antibody interference).
Murray D et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-030.
Newly Diagnosed Myeloma
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Bortezomib 1.3/mg2 IVDays 1, 4, 8, and 11
Lenalidomide 25 mg/day PODays 1-14
Dexamethasone 20 mg/day PODays 1, 2, 4, 5, 8, 9, 11, 12
Eight 21-Day Cycles of VRd
Lenalidomide 25 mg/day PODays 1-21
Dexamethasone 40 mg/day PODays 1, 8, 15, 22
Six 28-Day Cycles of Rd
RandomizationN=525
Stratification:• ISS (I, II, III)• Intent to
transplant @ progression (yes/no)
Lenalidomide 25 mg/day PO Days 1-21
Dexamethasone 40 mg/day PO Days 1, 8,15, 22
ISS, International Staging System; Rd, lenalidomide + dexamethasone; SWOG, Southwest Oncology Group; VRd, bortezomib + lenalidomide + dexamethasone
Durie BG et al. Lancet. 2017;389:519.
SWOG S0777: VRd vs Rd
Response and Survival Outcomes
Progression free survival Overall Survival
Durie BG et al. Lancet. 2017;389:519.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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*Carfilzomib was administered for 2 weeks out of 3 twice per cycleMelphalan dose was 7 mg/m2 if age was >75 years or CrCL was 30 to <50 mL/min; 5 mg/m2 if CrCl was 15 to <30 mL/min.
Maximum 9 cycles VMP
Bortezomib 1.3 mg/m2 Days 1, 4, 8, 11, 22, 25, 29, 32 (Days 4, 11, 25, 32 omitted for cycles 5+) IV or SC
Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1–4
Maximum 9 cycles KMP
Carfilzomib* 36 mg/m2 Days 1, 2, 8, 9, 22, 23, 29, 30 (20 mg/m2 days 1, 2, cycle 1 only) IV over 30 minutes
Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1–4
Randomization 1:1
N=955
Stratification:
• ISS stage
• Route of bortezomib administration (if randomized to VMP)
• Region
• Age
Primary end point: PFS
Secondary end points: OS, CRR, ORR, grade ≥2 PN rate, HRQoL, safety and tolerability
Exploratory end point: MRD
CLARION Study Design
Facon T et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-044.
• Median follow-up time: 22.2 months for KMP and 21.6 months for VMP• The absence of PFS difference was consistent across subgroups
Primary End Point:Progression-Free Survival
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n E
ven
t-F
ree
0Months
KMPVMP
KMP(n=478)
207 (43.3)22.3
VMP(n=477)
214 (44.9)22.1
0.91 (0.75–1.10)1-sided P=0.16
Disease progression or death – n (%)Median PFS – monthsHR for KMP vs VMP (95% CI)
12 18 24 366 30
478477
327309
217202
8577
00
384367
159
Number at risk:KMPVMP
Facon T et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-044.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Median DOR: 25.2 months (95% CI, 21.3–NE) for KMP vs 22.8 months (95% CI, 20.2–25.8) for VMP
25.9%
61.3%
84.3%
23.1%
49.3%
78.8%
0
20
40
60
80
100
CRR (≥CR) ≥VGPR ORR (≥PR)
KMP
VMP
Odds ratio (95% CI): 1.41 (1.01–1.97)
Odds ratio (95% CI): 1.18 (0.88–1.59)
n=124 n=110 n=293 n=235 n=403 n=376
Pat
ient
s (%
)
Odds ratio (95% CI): 1.65 (1.27–2.14)
Secondary End Point:Response Rates
Facon T et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-044.
Hematologic AE %KMP (n=474) VMP (n=470)
All grade Grade ≥3 All grade Grade ≥3
Anemia 36.7 16.9 31.1 13.6
Thrombocytopenia 18.4 10.8 19.8 12.1
Neutropenia 25.7 17.3 25.7 19.1
Febrile neutropenia 1.1 1.1 1.9 1.7
Nonhematologic AE % (≥20% in either arm)
Pyrexia 36.3 2.1 18.3 0.4
Nausea 35.4 1.3 28.3 0.4
Vomiting 24.9 1.5 19.4 1.3
Diarrhea 20.3 1.3 28.3 5.7
Constipation 13.9 0.4 24.3 1.3
Peripheral neuropathy 6.1 0.2 33.0 7.9
Adverse Events
Facon T et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-044.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Induction:• 9 cycles of 35 days
• Carfilzomib (20 mg at D1C1 then 36-45-56 or 70 mg/m² depending on cohort) Weekly IV (day 1,8,15,22) followed by a 13-day rest
• In combination with melphalan 0.25 mg/kg/d and prednisone 60 mg/m² by mouth on days 1 to 4 (patient diary)
13 days rest
κ κ κ κ
MP
J1 J2 J3 J4 J22J8 J15
Cycle 1 of 35 days Cycle 2
KMP Once-Weekly K, phase 1
MP, melphalan prednisone; κ, carfilzomib
Leleu X et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-012.
Maintenance: • 13 cycles of 28 days.
• Carfilzomib: 36 mg/m² twice a month (day 1 and 15) IV for 1 year
KMP With Weekly K• The MTD of K will be at 70 mg/m2 up to 75 years old, and 56 above• The CR rate of KMP weekly is remarkable, possibly greater than
previous reports of VMP and KMP (twice a week 36)
1. Moreau P et al. Blood. 2015;125:3100. 2. San Miguel J et al. N Engl J Med. 2008;359:906.3. Mateos MV et al. Lancet Oncol. 2010;11:934.4. Palumbo A et al. J Clin Oncol. 2010;28:5101.Leleu X et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-012.
Study Schema Design PIORR,
%≥ CR,
%IFM 2012-03 KMP Weekly C1 87 46
Carmysap1 KMP Bi-Weekly 90 12
Vista2 VMP Bi-Weekly 74 33
Mateos3 VMP Weekly C2 80 20 (39 end maintenance)
Palumbo4 VMPVMPT-VT Weekly C1 81
892438
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Carfilzomib 36, 45, or 56 mg/m2 IVDays 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)
Infusion duration: 30 minutes for all doses
Cyclophosphamide 300 mg/m2 oralDays 1, 8, 15
Dexamethasone 40 mg, oral or IVDays 1, 8, 15, 22
Champion-2Study Design
28-day cycles × 8 cycles, or progressive disease, unacceptable toxicity, or withdrawal of consent
Boccia R et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-023.
Champion-2Best Overall Response and Time to Response
56 mg/m2 dose cohort:• ORR: 87.5% (95% CI, 61.7%–98.4%)• Median time to response: 1 month (range, 0.9–2.8 months)
36 mg/m2
(N = 3)45 mg/m2
(N=3)56 mg/m2
(N=16)
Best overall response, n (%)Stringent complete response Complete response Very good partial responsePartial response Stable diseaseProgressive disease
0 (0.0)0 (0.0)
1 (33.3)1 (33.3)0 (0.0)
1 (33.3)
0 (0.0)0 (0.0)
2 (66.7)1 (33.3)0 (0.0)0 (0.0)
0 (0.0)1 (6.3)
7 (43.8)6 (37.5)2 (12.5)0 (0.0)
Boccia R et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-023.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Transplant
N=254
N=247
†Lenalidomide × 3 years :
10 mg/d for 3 cycles, then 15 mg/dAmendment in 2014 changedLenalidomide maintenance until diseaseprogression after report of CALGB 100104.
*Bortezomib 1.3 mg/m2 days 1, 4, 8,11Lenalidomide 15 mg days 1–15Dexamethasone 40 mg days 1, 8, 15Every 21 days
N=750 pts (250 in each arm)
BMT CTN 0702Stem Cell Transplantation for Multiple Myeloma
Incorporating Novel Agents: SCHEMA
Lenalidomide maintenance†
MEL200 mg/m2
VRD × 4*
N=257
Lenalidomide maintenance†
Lenalidomide maintenance†
MEL200 mg/m2
Register and randomize
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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0
Pro
ba
bili
ty,%
20
40
0 12 3824
38-month estimate and 95% CI
Auto/Auto: 56.5 (49.4, 62.9)
Auto/RVD: 56.7 (50.0, 62.8)
Auto/Maint: 52.2 (45.4, 58.6)
Stamina: PFS
Stadtmauer EA et al. Blood. 2016;128: Abstract LBA-1.
60
80
100
Lenalidomide Maintenance: Meta-Analysis
There is a 25% reduction in risk of death, representing an estimated 2.4-year increase in median survival (March 2015 data cutoff)a
No. at RiskLEN maint 605 577 555 508 473 431 385 282 200 95 20 1 0Placebo/Observation
603 569 542 505 459 425 351 270 174 71 10 0
0.2
1.0
0.8
0.6
0.4
0.0
Sur
viva
l Pro
babi
lity
0 10 20 30 40 50 60 70 80 90 100 110 120Overall Survival (Months)
Events/nMedian OS
(95% CI), moHR (95% CI)
P value
LEN maint 215/605 NR(NR–NR) 0.75 (0.63–0.90)
.001Placebo/Observation 275/603 86.0
(79.8–96.0)
7-yr OS
62%
50%
aLog-rank test and Cox model stratified by study to assess impact of lenalidomide maintenance on overall survival. Median for lenalidomide treatment arm was extrapolated to be 115 months based on median of the control arm and HR (median, 86 months; HR = 0.75).
HR, hazard ratio; maint, maintenance; NR, not reached; OS, overall survival.
Attal M et al. J Clin Oncol,. 2016;34: Abstract 8001.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Overall Survival: Subgroup Analysis
a Number of patients. b For CALGB and IFM, age at randomization is available/used. For GIMEMA, only age at diagnosis is available. c The ISS stage was based on β2 microglobulin and albumin at diagnosis for GIMEMA and IFM and at registration for the CALGB. d Four patients upon central review did not meet the criteria for SD. e LDH data were available only for IFM and GIMEMA. f Cytogenetic data were available only for IFM and GIMEMA. gThe patients with missing CrCl at diagnosis data were in CALGB and IFM. hCrCl post-ASCT data were available only for CALGB and IFM. ASCT, autologous stem cell transplant; CR, complete response; CrCl, creatinine clearance; HR, hazard ratio; ISS, International Staging System; LDH, lactate dehydrogenase; LEN, lenalidomide; maint, maintenance; PR, partial response; SD, stable disease; ULN, upper limit of normal; VGPR, very good partial response.
LEN maintaPlacebo/
Observationa HR (95% CI)
Ageb372 375 0.68 (0.54-0.86)233 228 0.85 (0.64-1.12)
Sex 322 349 0.66 (0.52-0.83)283 254 0.92 (0.70-1.21)
ISS stagec411 439 0.66 (0.52-0.82) 113 90 1.06 (0.73-1.54)
Response after ASCT (prior to maint)
65 80 0.63 (0.34-1.15)314 334 0.70 (0.54-0.90)227 215 0.88 (0.66-1.17)
LDHe270 283 0.91 (0.70-1.18)45 45 1.17 (0.62-2.21)
Adverse-risk cytogenetics at diagnosisf
56 36 1.17 (0.66-2.09)232 243 0.79 (0.59-1.06)
CrCl at diagnosisg60 37 1.28 (0.71-2.31)
327 360 0.69 (0.54-0.89)
CrCl after ASCTh33 25 0.73 (0.33-1.60)
379 404 0.74 (0.59-0.92)
HR0.25 0.5 1 2 4
< 60 y≥ 60 y
< 50 mL/min≥ 50 mL/min
Female
CR/VGPRPR/SDd
Normal> ULN
Male
I/IIIII
CR
Yes
No
< 50 mL/min≥ 50 mL/min
Favors placebo/observation
Favors LEN maint
Attal M et al. J Clin Oncol,. 2016;34: Abstract 8001.
Denosumab vs Zoledronic Acid
HR (95% CI) = 0.98 (0.85, 1.14); P=0.01 (Noninferiority)
Raje N et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-046.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Progression-Free Survival
HR (95% CI) = 0.82 (0.68, 0.99); P=0.036 (Descriptive)
Median duration (95% CI), months Denosumab - 46.09 (34.30, not estimable)Zoledronic acid - 35.38 (30.19, not estimable)
Raje N et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-046.
MRD in Myeloma
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MRD Negativity: Daratumamab Results in Deeper Responses in Combinations with
Revlimid or Velcade
% of MRD-negative patients among those who achieved ≥CR
CASTORPOLLUX
ITT
po
pu
latio
n, %
0
5
10
15
25
20
DVd Vd
10–4
MRD negative MRD positive
DVd Vd DVd Vd
10–5 10–6
60
35
37
2216
9
ITT
po
pu
latio
n, %
0
10
20
30
40
DRd Rd
10–4
MRD negative MRD positive
DRd Rd DRd Rd
10–5 10–6
65
42
52
27
26
13
* *† †
*P<0.005; †P<0.05Avet-Loiseau H et al. Blood. 2016;128. Abstract 246.
Relapsed Myeloma
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* Carfilzomib was administered for 3 weeks out of 4
Primary end point: PFS by IRC
Secondary end points:
• OS
• ORR
• DOR
• Grade ≥2 PN rate
• Safety
ENDEAVOR: Study Design
ISS, International Staging System; IV, intravenous; Kd, carfilzomib and dexamethasone; PD, progressive disease; Vd, bortezomib and dexamethasone; V, bortezomib.
Siegel DS et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract PS-254.
VdBortezomib 1.3 mg/m2 (3–5 second IV bolus or
subcutaneous injection)Days 1, 4, 8, 11
Dexamethasone 20 mg Days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycles until PD or unacceptable toxicity
KdCarfilzomib* 56 mg/m2 IV
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1)Infusion duration: 30 minutes for all doses
Dexamethasone 20 mg Days 1, 2, 8, 9, 15, 16, 22, 23
28-day cycles until PD or unacceptable toxicity
Randomization 1:1
N=929
Stratification:
• Prior proteasome inhibitor therapy
• Prior lines of treatment
• ISS stage
• Route of V administration
Treat to progression
Treat to progression
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n S
urv
ivin
g W
ithou
t Pro
gre
ssio
n
0
Months Since Randomization
KdVd
Kd(n=464)
171 (37)18.7
Vd(n=465)
243 (52)9.4
0.53 (0.44–0.65)1-sided P<0.0001
Disease progression or death – n (%)Median PFS – monthsHR for Kd vs Vd (95% CI)
Median follow-up: 11.2 months
6 12 18 24 30
Primary End Point: Progression-Free Survival
Siegel DS et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract PS-254.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Kd(n=464)
189 (40.7)47.6
Vd(n=465)
209 (44.9)40.0
0.791 (0.648–0.964)1-sided P=0.0100
Death – n (%)Median OS – monthsHR for Kd vs Vd (95% CI)
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n S
urv
ivin
g
0Months
KdVd
12 18 246 48
464465
373351
335293
308256
423402
105
Number at risk:KdVd
30
270228
36
162140
42
6639
Overall Survival
Siegel DS et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract PS-254.
Pembrolizumab, Pomalidomide, Dexamethasone
Characteristic N=48
Median lines of prior therapy (Range) >3
3 (2-5)13 (27%)
Prior therapy – no. (%)ASCTProteasome inhibitors
BortezomibCarfilzomib
IMiDsLenalidomide
31 (72%)48 (100%)
48 (100%)24 (50%)
48 (100%)48 (100%)
RefractoryProteasome inhibitorsLenalidomideDouble-refractory to IMiDs and PI
38 (79%)43 (90%)35 (73%)
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Responses
Response Category
Evaluable Patients(N=45)
Double refractory
N=32
High risk cytogenetics
N=27
Overall response – no. (%) 29 (65) 22 (68) 15 (56)
Best response – no. (%)
sCR 3 (7) 1 (3) 2 (7)
CR 1 (2) 1 (3) 1 (4)
VGPR 9 (20) 6 (18) 1 (4)
PR 16 (36) 14 (44) 11 (41)
Isatuximab• Pts received prophylaxis against infusion
reactions prior to treatment*
• IARs reported in 9/20 pts (45%); all Gr 1/2 severity
• IARs occurred predominantly during the first infusion
– IAR after first infusion in three pts; one IAR after 18th infusion
• No treatment discontinuations due to IARs
• Initial infusion rate: 87.5 mg/h (5 mg/kg);175 mg/h (10 and 20 mg/kg)
• Median infusion duration, hrsFirst infusion: 4.4 (10 mg/kg), 4.7 (20 mg/kg)
Subsequent infusions: 2.6 (10 mg/kg), 4.6 (20 mg/kg)
0
20
40
60
80
100Grade 1 Grade 2
1st >1 >1>1 1st1st
(n=8) (n=8) (n=6) (n=6) (n=6) (n=6)
5 mg/kg 10 mg/kg 20 mg/kg
Isatuximab dose
Pa
tien
ts (
%)
IARs by infusion and dose
Data cut-off August 15, 2016. *Diphenhydramine 50 mg IV (or equivalent), ranitidine 50 mg IV (or equivalent), and acetaminophen 650–1000 mg orally
Richardson P et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-027.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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25.033.5 29.0
25.0
33.529.0
12.57.0
0
20
40
60
80
100
5 QW/Q2W(n=8)
10 QW/Q2W(n=6)
All patients(n=14)
OR
R (
%)
PR VGPR CR
62.5%67.0% 64.0%
Among IMiD-refractory pts, the confirmed ORR was 64% (7/11)
Three pts with high-risk cytogenetics (del17p or t[4:14]): one attained VGPR and another minimal response (MR)
Response Summary
Data cut-off August 15, 2016. aEfficacy data for the 20 mg/kg cohort are not yet mature.
CR, complete response; ORR, overall response rate; PR, partial response; VGPR, very good partial response
Richardson P et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-027.
Baseline Demographics and Clinical Characteristics
6
Characteristic
DARA + POM-DN=103
Prior lines of therapy, n (%)Median (range)
>34 (1-13)53 (52)
Prior ASCT, n (%) 76 (74)
Prior PI, n (%)Prior BORTPrior CARF
102 (99)101 (98)34 (33)
Prior LEN, n (%) 103 (100)
Prior PI + IMiD, n (%) 102 (99)
Refractory to, n (%)LENBORTCARF
92 (89)73 (71)31 (30)
Refractory to PI + IMiD, n (%) 73 (71)
Characteristic
DARA + POM-DN=103
Age, yMedian (range) 64 (35-86)
Cytogenetic profile, n (%)*Standard riskHigh risk
del17pt(4;14)t(14;16)
n=8765 (75)22 (25)16 (18)6 (7)1 (1)
ISS, International Staging System; ASCT, autologous stem cell transplant; PI, proteasome inhibitor; BORT, bortezomib; CARF, carfilzomib; LEN, lenalidomide; IMiD, immunomodulatory drug.
*Based on FISH or karyotyping. Percentages based on n=87 as denominator.
Chari A et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-024.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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18
25
9
8
0
10
20
30
40
50
60
70
DARA + POM-D (N = 103)
OR
R, %
PR VGPR CR sCR
ResponsesDARA + POM-D
(N=103)
n (%) 95% CI
ORR(sCR+CR+VGPR+PR) 62 (60) 50.1-69.7
Best responsesCRCRVGPRPRMRSDPDNE
8 (8)9 (9)
26 (25)19 (18)2 (2)
26 (25)3 (3)
10 (10)
3.4-14.74.1-15.9
17.2-34.811.5-27.30.2-6.8
17.2-34.80.6-8.34.8-17.1
VGPR or better (sCR+CR+VGPR) 43 (42) 32.1-51.9
CR or better (sCR+CR) 17 (17) 9.9-25.1
ORR = 60%
42%VGPR
or better
17%CR or better
Deep responses were observed with DARA + POM-D
Chari A et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-024.
Venetoclax
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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BCL2 Proteins Regulate Cell Survival
“Cellular Stress” Apoptosis(a mechanism by which cells die)
Examples include:Most Cancer Therapies“Becoming” Cancer
BCL2
BCL2 Proteins Regulate Cell Survival
“Cellular Stress” Apoptosis(a mechanism by which cells die)
Examples include:Most Cancer Therapies“Becoming” Cancer
BCL2Venetoclax
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Types of Initial Therapy
p=0.148
34.4(n=124)
42.6(n=156)
14.7(n=54) 8.2
(n=30)
36.8(n=49)
39.8(n=53)
19.6(n=26)
3.8(n=5)
29.9(n=179)
48.2(n=289)
14.9(n=89)
7.0(n=42)
0.00
10.00
20.00
30.00
40.00
50.00
60.00
PI-based IMiD-based PI+IMiD-based Others
t(11;14) Non-t(11;14) translocations No translocation
Kumar S et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-045.
Per
cent
age
of p
atie
nts
Survival
No translocation
t(11;14)
Non-t(11;14) translocation
PFS, median (95% CI) P value OS, median (95% CI) P value
No translocation (n=599)
28.3 (25.7-30.9)
<0.0001
103.6 (85.2-112.3)
<0.0001t(11;14) (n=366) 23.0 (20.7-27.6) 83.8 (73.1-92.5)
Non-t(11;14) translocation (n=133)
19.0 (15.9-22.7) 49.8 (39.9-63.9)
Kumar S et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-045.
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Single-Agent Venetoclax
0
10
20
30
40
50
Per
cen
tag
e o
f P
ati
ents
sCR CR VGPR PR
All PatientsN=66
t(11;14)n=30
ORR 21%
ORR 40%
non-t(11;14)n=36
ORR 6%
6%
8%13%
4%
10%
13%
3%3%
3%
4%
Data cutoff of 19Aug2016
Kumar S et al. Presented at the 16th International Myeloma Workshop, March 1-4, 2017. Abstract OP-045.
There Are Several BCL2 Proteins That Block Apoptosis
MCL1
BCLX
AMG
176
“Cellular Stress” Apoptosis(a mechanism by which cells die)
Examples include:Most Cancer Therapies“Becoming” Cancer
BCL2Venetoclax
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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New Immune Therapies
New Immune Therapies in Myeloma
CAR T-cells Bi-specifics
Myeloma targets for both CAR T-cells and Bispecifics include: BCMA and SLAMF7
Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017
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Questions & Answers
Closing
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Resources for You!
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Upcoming MMRF WebinarsSummer 2017
Series Topic Date Time
Immunotherapy
Monoclonal antibodies June 14, 2017 1:00 PM ET
Vaccines July 2017 1:00 PM ET
Engineered Immune Cells August 9, 2017 1:00 PM ET
Meeting Highlights
American Society of Clinical Oncology and the European Hematology Association
July 2017 1:00 PM ET
For more information or to register, visit: theMMRF.org
MMRF Multiple Myeloma SummitsFall 2017
Saturday, September 16, 2017Chicago, IllinoisAndrzej Jakubowiak, MD–ChairUniversity of Chicago Medical Center
Saturday, October 14, 2017Charlotte, North CarolinaSaad Z. Usmani, MD−Chair
Friday, November 3, 2017New York City, New YorkSundar Jagannath, MD–ChairThe Mount Sinai Medical CenterTisch Cancer InstituteMount Sinai School of MedicineLevine Cancer Institute
Saturday, November 18, 2017Los Angeles, CaliforniaJames Berenson, MD–Co-Chair Institute for Myeloma and Bone
Cancer Research
Amrita Y. Krishnan, MD–Co-ChairJudy and Bernard Briskin Center for
Multiple Myeloma ResearchCity of Hope Medical Center
To register, please visit:theMMRF.org/Patient