mmrf imw aacr2017 highlights 1g ks...making sense of myeloma treatment advances webinar 1 – may...

Making Sense of Myeloma Treatment AdvancesWebinar 1 – May 17, 2017

1

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


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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?


3

Disease Biology and Risk Stratification

Asymptomatic Myeloma• What factors control progression?

– Up-front genetics?– Acquired changes?– Other factors?


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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


• In this model the genetic changes occur earlier and other factors determine when the disease becomes symptomatic


5

Tumor Mass, Proliferation, and Up-Front Factors Are Predictors of

Progression to Symptomatic Myeloma

M‐protein

Doubling time

UAMS70‐gene score


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.


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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


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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


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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


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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.


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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



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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


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



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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


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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.


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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



MEL200 mg/m2

Register and randomize


15

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.


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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.


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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



20

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


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%)


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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.


22

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.


23

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


24

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



BCL2Venetoclax


25

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)



26

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


There Are Several BCL2 Proteins That Block Apoptosis

MCL1

BCLX

AMG

176



BCL2Venetoclax


27

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


28

Questions & Answers

Closing


29

Resources for You!

Accelerator Magazine

Have questions about the trials or information you heard today?

Call our MMRF nurse specialists.

Knowledge. Resources. Research. Community.

Join our trusted multiple myeloma community! Continue the conversation with other

patients, caregivers, and experts!

Join today www.MMRFCommunityGateway.org

MMRF nurse specialist

MMRF CoMMunity Gateway

An MMRF nurse specialist can guide you through your multiple

myeloma journey every step of the way. Call Monday–Friday, 9–7 ET

Call now1-866-603-MMCT(6628)


30

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

mmrf imw aacr2017 highlights 1g ks...making sense of myeloma treatment advances webinar 1 – may...

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