Disclosures for Philip McCarthy, MD

The presentation will include off-label use of drugs for multiple myeloma treatment

Research Support/P.I. Celgene

Employee No relevant conflicts of interest to declare

Consultant Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Millennium, Onyx, Sanofi, The Binding Site

Major Stockholder No relevant conflicts of interest to declare

Speakers Bureau No relevant conflicts of interest to declare

Honoraria Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Millennium, Onyx, Sanofi, The Binding Site

Scientific Advisory Board No relevant conflicts of interest to declare

Role of Stem Cell Transplant and Maintenance Therapy in Plasma Cell Disorders

Philip McCarthy

Roswell Park Cancer Institute

Buffalo, NY

April 2017

David Robinson et al. Blood 2014;124:5676

3650 days

Eric M Maiese et al. Blood 2016;128:5944 Abstract ASH 2016

©2016 by American Society of Hematology

10 yrs

Multiple Myeloma Therapy in the Era of Novel Agents

Before the new drugs, treating Multiple Myeloma was like waiting for a taxi and none would come

Then all of a sudden, 5 come at once

Dr. Khalid Al Hashmi

Senior Consultant Hemato - Oncologist AFH, Oman

Maintenance for fixed time

or not if in CR

Maintenance until PD

Transplant Eligible

Supportive Care: Infectious Disease prophylaxis, Antivirals, DVT prophylaxis, Bisphosphonates,

Mitigation of Steroid effects,

Slide Adapted from Andrew Spencer

ASCT Induction

Maintenance until PD ASCT Induction

Consolidation Maintenance

ASCT Induction

Transplant Eligible

Supportive Care: Infectious Disease prophylaxis, Antivirals, DVT prophylaxis, Bisphosphonates,

Mitigation of Steroid effects,

0

20

40

60

80

100ORR

≥VGPR

CR

Selected induction regimens and response in MM patients

1. Lokhorst HM, et al. Haematologica. 2008;93:124-7. 2. Rajkumar SV, et al 2008 J Clin Oncol 26:2171-77. 3. Harousseau JL, et al 2010 J Clin Oncol 28:4621-4629. 4. Rajkumar SV, et al Lancet Oncol 2010; 11: 29–37. 5. Sonneveld P, et al J Clin Oncol 2012; 30:2946-55. 6. Moreau P et al Blood 2016; 127:2569-257. 7. Durie et al Lancet 2017; 389:519; 8. Attal et al NEJM 2017; 376:1311-1320 . 9. Jakubowiak AJ, et al Blood. 2012 30;120:1801-9. 10. Bringhen S et al Blood 2014; 124:63-9 11. Kumar S, et al . Lancet Oncology 2014; 15:1503-12. 11. Kumar S, et al. Blood 2012 119: 4375-82.

Pa

tie

nts

re

sp

on

din

g (

%)

ASCT vs Chemotherapy for NDMM

Adapted from: McCarthy PL, et al. J Natl Compr Canc Netw 2013;11:35-42

ASCT vs Chemotherapy

n Regimen EFS (PFS) OS Benefit? EFS/OS

Attal et al. NEJM 1996

100 (IT)

100 (NIT)

V+MCP/BVAP with Mel140/TBI vs V+MCP/BVAPx18

IFN maintenance

Median EFS

27 vs 18 mo (P<0.01)

5 yr EFS

28% vs 10% (P=0.01)

Median OS NR vs 37.4 mo (P<0.03)

5 yr OS

52% vs 12% (P=0.03)

+/+

Child et al. NEJM 2003

201 (IT)

200 (NIT)

V+APC with Mel200 or Mel140/TBI vs ABCMPx12

IFN maintenance

Median PFS

31.6 vs 19.6 mo (P<0.01)

Median OS 54.1 vs 42.3 mo (P<0.03) +/+

Palumbo A et al NEJM 2014

200 (IT) 202 (NIT)

Rd followed by Mel200x2 vs MPRx 6, followed by R vs no maintenance

Median PFS 43.3 vs 22.4 mo (P<0.01)

4 yr OS 81.6% vs 65.3% (P=0.02) +/+

Gay et al Lancet Oncology 2015

195 (IT) 194 (NIT)

Rd followed by Mel200x1 or 2 vs CRD, All followed by RP or R

Median PFS 43.3 vs 28.6 mo (P=0.003)

3 yr OS 86% vs 73% (P=0.004) +/+

Attal et al NEJM 2017

350 (IT) 350 (NIT)

RVd x 3 followed by with Mel200 & RVd x2 vs RVd x 5, All followed by R

x 1 yr

Median PFS 50 vs 36 mo (P< 0.001)

4-year OS 81 vs 82 % (P=0.87)

+/ND

Cavo et al ASCO 2016, ASH 2016 A673

415 (IT)

199 (NIT)

VCd followed by Mel200 x 1 vs 2 vs VMP, followed by RVd vs no

consolidation, All followed by R

Median PFS NR vs 44 mo 3 year PFS 66% vs 57.5% (P=0.003)

OS No Difference

+/ND

EFS: Event-free survival; OS: Overall Survival; PFS: Progression-Free Survival; ND; No difference; IT: Intensive Therapy, NIT: Non IT; NR: Not reached; NS: Not Significant; VMCP/BVAP: Vincristine, Melphalan, Cyclophosphamide, Predinsone/ Carmustine, V, doxorubicin, P; R: Lenalidomide; VCd: Bortezomib, Cyclophosphamide, dexamethasone; IFN: Interferon

Single vs Tandem ASCT for NDMM

Adapted from: McCarthy PL, et al. J Natl Compr Canc Netw 2013;11:35-42

N Regimen EFS (PFS) OS Benefit? EFS/OS

Attal et al NEJM 2003

200: ASCTx2 199: ASCTx1

V+AD followed by ASCTx2: Mel 140 & Mel140/Total Body Irradiation (8Gy)

vs ASCTx1: Mel140/TBI IFN maintenance

Median EFS 30 vs 25 mo (P=0.03)

Median OS 58 vs 48 mo (P=0.01)

+/+

Cavo et al JCO 2007

158: ASCTx2 163: ASCTx1

V+AD followed by ASCTx2: Mel200 & Mel120 Busulfan 4mg/kg x 3d vs Mel

200 only, IFN maintenance

Median EFS 35 vs 23 mo (P=0.001)

Median OS 71 vs 65 mo (P=0.9)

+/+

Mai et al BJ Haem 2016

181: ASCTx2 117: ASCTx1

Mel200x2 vs Mel200x1 IFN Maintenance

Median EFS 28.7 vs 25 mo (P=NS)

Median OS 75.3 vs 73 mo (P=NS) ND/ND

Cavo et al ASH 2016

A991

207: ASCTx2 208: ASCTx1

VCd followed by Mel200 x 1 vs 2 vs VMP, followed by RVdx2 consolidation

or none, R maintenance

Median PFS NR vs 45 mo

3 year PFS 73% vs 60% P=0.03)

OS No Difference +/ND

Stadtmauer et al ASH

2016 LBA-1

254 (ACM) 247 (TAM) 257 (AM)

Within 12 mo of start of any induction followed by ASCTx1 & RVD

consolidation vs Tandem ASCT vs Single ASCT, R Maintenance

38 mo PFS 57% vs 56% vs 52%

(P=NS)

38 mo OS 86% vs 82% vs 83%

ND/ND

ACM: ASCT+RVD Consolidation+Lenalidomide Maintenance (M); TAM Tandem ASCTM: AM: Single ASCTM; N: Number of patients; Mo: months; SC: Subcutaneous; IT: Intensive Therapy; IFN: Interferon; IV: Intravenous; NIT: Non-intensive therapy; MV: Multi-variate; OS: Overall Survival; PFS: Progression-Free Survival; R: lenalidomide; wks: weeks; yrs: years; ND: no difference; VMP: Bortezomib, melphalan, prednisone; R: lenalidomide; D: Dexamethasone; Rx: Therapy; V+AD: Vincristine Adriamycin Dexamethasone; VCd: Bortezomib, Cyclophosphamide, Dexamethasone

The DETERMINATION Trial IFM/DFCI 2009 Phase 3 Study

Newly Diagnosed MM (SCT candidates; n= originally 1000, now 1360)

RVDx3

RVD x 2

RVD x 5

Lenalidomide

Melphalan

200mg/m2 + ASCT

Induction

Consolidation

Maintenance

IFM: for 1 year

USA: until progression

CY (3g/m2)

MOBILIZATION Goal: 5 x106 cells/kg

RVDx3

CY (3g/m2)

MOBILIZATION Goal: 5 x106 cells/kg

Randomize

Collection

Lenalidomide

SCT at relapse

RVD=Revlimid ® ,Velcade ®, dexamethasone. Cy=Cyclophosphamide, Courtesy P Richardson

USA: 660 & IFM: 700 patients

IFM/DFCI 2009: PFS/OS

Attal et al NEJM 2017

IFM/DFCI 2009: PFS by Arm & MRD Status

Attal et al NEJM 2017

IFM/DFCI 2009: SPM Report

Attal et al NEJM 2017

PET-CT normalisation before maintenance Impact on OS (62% normalised)

p = 0.003

94.6%

69.9%

Courtesy P Moreau ASH 2015

VMP x 4 cycles

Bortezomib 1.3 mg/m2 d 1,4,8,11,22,25,29,32/42

Melphalan 9 mg/m2 d 1-4/42

Prednisone 60 mg/m2 d 1-4/42

(497 pts)

Melphalan (HDM) 200 mg/m2 x 1-2

courses* + single or double ASCT

(695 pts)

VCD induction

x 3-4 cycles +

PBSC collection

VRD consolidation

x 2 cycles

R1

No consolidation

All pts received lenalidomide maintenance until PD

R2

EMN02/HO95 MM trial: study design

Stratification: ISS I vs. II vs. III

Randomization to VMP or HDM was 1:1 in centers with a fixed single ASCT policy

Randomization to VMP or HDM-1 or HDM-2 was 1:1:1 in centers with a double ASCT policy

0.00

0.50

1.00

Pro

gres

sion

-fre

e su

rviv

al (

%)

497 400 298 142 27 1VMP695 596 449 192 39 2ASCT

Number at risk

0 12 24 36 48 60Time (months)

ASCT VMP

PFS by randomization 1 (VMP vs. ASCT)

ASCT VMP

PFS median, mos NR 42.5

PFS at 3 yrs, % 65.0 57.1

HR (95% CI): 0.73 (0.61-0.88); p = 0.001

0.00

0.50

1.00

% P

roba

bilit

y

208 171 132 50 9 0HDM1207 185 145 69 19 1HDM2

Number at risk

0 12 24 36 48 60months

HDM2 HDM1

PFS : HDM1 vs HDM2PFS by randomization 1 (HDM-1 vs HDM-2)

HDM-2 HDM-1

PFS median, mos NR NR

PFS at 3 yrs, % 73.6 62.2

HR (95% CI): 0.70 (0.49-1.01); p = 0.05

Median follow-up: 32 months (IQR 26-41)

EMN02 / HO95 MM 20

no consolidationVRDCox LR P=0.045 (adjusted for 1st random.)

N435450

F137115

no consolidation

VRD

At risk:435450

336371

187196

4952

no consolidation

VRD

0

25

50

75

100

Cum

ulat

ive

perc

enta

ge

months0 12 24 36

Progression free survival

HR = 0.78 (0.61-1.00)

PFS by R2 (VRD consolidation vs no consolidation)

Sonneveld P et al, Abs 242, ASH 2016

OS by randomization 1 (VMP vs ASCT)

ASCT VMP

PFS median, mos NR NR

PFS at 3 yrs, % 86.3 84.6

HR (95% CI): 0.98 (0.72-1.33); p = 0.899

BMT CTN 0702 Stem Cell Transplantation for Multiple Myeloma

Incorporating Novel Agents: SCHEMA

Register and

Randomize MEL 200mg/m2 VRD x 4*

Lenalidomide

Maintenance**

Lenalidomide

Maintenance**

Lenalidomide

Maintenance

MEL 200mg/m2

**Lenalidomide x 3years :

10mg/d for 3 cycles , then 15 mg/d

Amendment in 2014 changed Lenalidomide maintenance

until disease progression after report of CALGB 100104.

*Bortezomib 1.3mg/m2

days 1, 4, 8,11

Lenalidomide 15mg days 1-15

Dexamethasone 40mg

days 1, 8, 15

Every 21 days

** N=750 pts (250 in each arm)

N=257

N=254

N=247

N at risk

Auto/Auto 247 200 153 87

Auto/RVD 254 215 172 99

Auto/Maint 257 213 158 80

Primary Endpoint: Progression-free Survival

23

100

0

20

40

60

80

Pro

ba

bili

ty, %

0 12 38 24

Months from Randomization

Auto/Maint: 52.2 (45.4, 58.6)

Auto/Auto: 56.5 (49.4, 62.9)

Auto/RVD: 56.7 (50.0, 62.8)

38 Month Estimate and 95% CI

N at risk

Auto/Auto 247 231 204 147

Auto/RVD 254 246 229 166

Auto/Maint 257 247 227 148

Overall Survival

24

100

0

20

40

60

80

Pro

ba

bili

ty, %

0 12 38 24

Months from Randomization

Auto/Maint: 83.4 (77.9, 87.7)

Auto/Auto: 82.0 (76.3, 86.5)

Auto/RVD: 85.7 (80.5, 89.5)

38 Month Estimate and 95% CI

BMT CTN 0702: Regimens prior to Transplant

Auto/Auto (N=247) Auto/RVD (N=254) Auto/Maint (N=257)

N % N % N %

Initial Therapy

141 57.1 134 52.8 143 55.6 Bort/Len/Dex

Cy/Bort/Dex 33 13.4 35 13.8 40 15.6

Len/Dex 24 9.7 28 11.0 22 8.6

Bort/Dex 28 11.3 32 12.6 32 12.5

Other 21 8.5 25 9.8 20 7.8

25

Bort, bortezomib; Cy, cyclophosphamide; Dex, dexamethasone; Len, lenalidomide

Stadtmauer et al ASH 2016, Courtesy M Pasquini

Conclusion

26

• In the era of thalidomide analogues and proteasome inhibitors

used in the initial therapy for myeloma (in this study >90%

either, >50% both) and the use of prolonged maintenance

therapy with lenalidomide, post transplant consolidation with

cycles of RVD or a second transplant do not produce

incremental PFS benefit.

Prognostic Immunophenotyping in Myeloma Response (PRIMeR)

Study Update: Ancillary Study for BMT CTN 0702

Theresa Hahn, PhD

Roswell Park Cancer Institute

Buffalo, NY

PRIMeR Study Schema

Arm C

Arm A

Arm B

MM patients meeting eligibility criteria

R

a

n

d

o

m

i

z

a

t

i

o

n

AutoHCT

RVD Maintenance

Bone marrow aspirate collected as part of STaMINA and PRIMeR

Bone marrow aspirate collected as part of PRIMeR only

Maintenance

Maintenance

AutoHCT

AutoHCT

AutoHCT

MRD Pattern Baseline/Pre-Maint/1 Yr

N=136

Neg/Neg/Neg 50

Pos/Neg/Neg 42

Pos/Pos/Pos 10

Pos/Pos/Neg 8

Pos/Neg/Pos 7

Other 19

PRIMeR MRD Assessments

Evolution of MRD testing at RPCI ASH Abstract # 2274, Saturday 12/3/16

Ammannagari, et al.

Evolution of MRD testing at RPCI ASH Abstract # 2274, Saturday 12/3/16

Ammannagari, et al.

Multiple Myeloma Post ASCT Consolidation/Maintenance Studies

– Thalidomide (T) improves PFS & in some studies OS, but hard to use long term • T: Attal et al. Blood 2006, Barlogie et al. Blood 2008, Lokhorst et al. Blood 2010, Morgan et al. Blood 2012*

(*T inferior in high risk cytogenetic patients)

• T + Steroids: Spencer et al. J Clin Oncol 2009, Krishnan et al. Lancet Oncol 2011, Maiolino et al. Am J Hematol 2012, Stewart et al. Blood 2013

– IFN vs T vs bortezomib + T (VT) x 3 yrs: VT PFS benefit in good risk cytogenetic patients Rosinõl et al. Blood 2012

– VTD vs TD for 2 cycles followed by D Maintenance: improved PFS in poor risk cytogenetic patients Cavo et al. Blood 2012

– V vs T x 2 years: benefit in del17p & renal failure pts Sonneveld et al. JCO 2012

– V vs no consolidation x 20 or 16 doses: Improved PFS, no difference in OS • Mellqvist et al Blood 2013, Straka et al ASCO 2015

Multiple Myeloma Post ASCT Consolidation/Maintenance Studies

– Lenalidomide (R)RVd x 2 cycles vs no consolidation: PFS benefit when adjusting for 1st randomization otherwise no PFS difference, No difference in OS

Sonneveld et al ASH 2016 A242

– RVd x 4 cycles vs no consolidation: No difference in PFS/OS Stadtmauer et al ASH 2016 LBA-1

– R until progression improves PFS in all, OS in one of four studies and OS improvement in a meta-analysis

• R daily: Attal M et al. NEJM 2012, Attal et al. ASH 2013, R stopped at median 2 yrs due to SPM concern,

• R daily: McCarthy et al. NEJM 2012, Holstein et al. ASCO 2015, R continued until PD • R 21 /28 days until PD: Palumbo et al. NEJM 2014 , Jackson et al ASH 2016 A1143 • R daily or 21/28 days until PD: Meta-analysis demonstrating OS benefit for R, Attal et al

ASCO 2016, McCarthy et al EHA 2016 • R 21/28 days + Prednisone until PD: Gay et al Lancet Oncology 2015

Thalidomide maintenance following AHSCT

Adapted from: McCarthy PL, et al. J Natl Compr Canc Netw 2013;11:35-42

Maintenance versus no maintenance

n Initial dose

(mg) EFS (PFS) OS

Benefit? EFS/OS

Attal et al. Blood 2006 597 400 3 year EFS 52 vs 37% (P<0.009)

4-year OS 87 vs 74% (P<0.04) +/+

Barlogie et al. Blood 2008 668 400 5 year EFS 56 vs 45% (P<0.001)

8-year OS 57 vs 44% (P=0.09) +/trend+

Lokhorst et al. Blood 2010 556 50 Median EFS 43 vs 22 mo (P<0.001)

Median OS 73 vs 60 mo (P=0.77) +/trend -

Morgan et al. Blood 2012 820*^ 50 Median PFS (HSCT) 30 vs 23 mo (P=0.003)

3-year OS 75 vs 80% (P=0.26) +/ND

Spencer et al. J Clin Oncol 2009 243 200# 3-year PFS 42 vs 23% (P< 0.001)

3-year OS 86 vs 75% (p < 0.004) +/+

Krishnan et al. Lancet Oncol 2011 436+ 200# 3 year PFS

49 vs 43% (P=0.08)

3 year OS

80 vs 81% (P=0.817)

ND/ND

Maiolino et al. Am J Hematol 2012 108 200# 2 year PFS

64 vs 30% (P=0.002)

2 year OS

85 vs 70% (P=0.27)

+/ND

Stewart et al. Blood 2013 332 200# 4-year PFS

32 vs 14% (P< 0.0001)

4-year OS

68 vs 60% (p=0.18) +/ND

* This cohort was part of a 1910 patient study examining transplant and non-transplant therapies; # Glucocorticoids given with thalidomide. + This cohort was part of a 710 patient study examining allogeneic HSCT and autologous HSCT ^ Update: + for low risk FISH disease only, Morgan et al CCR 2013 EFS: Event-free survival; OS: Overall Survival; PFS: Progression-Free Survival; ND: No difference.

Bortezomib-containing Consolidation/Maintenance following ASCT

Adapted from: McCarthy PL, et al. J Natl Compr Canc Netw 2013;11:35-42

Maintenance versus no maintenance Benefit? EFS/OS

N Regimen EFS (PFS) OS

Sonneveld et al ASH 2015

827 Bortezomib (V): every 2 wks or Thalidomide (T) daily for 2 years (V after PAD versus T after VAD)

Med PFS 34 vs 28 mo (P=0.001)

Median FU 91.4 mo Restricted mean survival time

at 8 yr: 4.8 mo (P=0.04)

+/+

9-year OS 42% Both arms

+/+

Cavo et al Blood 2012

241 239

VTD or TD for 2 Cycles followed by Dex maintenance

3 yr PFS 60% vs 48% (P=0.42)

3 yr OS 90% vs 88% (P=0.39)

+/+

Rosiñol et al Blood. 2012

386 3 yrs of V every 3 mo + T daily or T daily or IFN SC 3x wk

2 year PFS 78% vs 63% vs 49% (P=0.01)

OS ND

+/ND

Mellqvist et al Blood 2013

370 V x 20 doses for 21 weeks or no Rx

Median PFS 27 vs 20 mo (P=0.05)

3 year OS both arms 80%

+/ND

Straka et al ASCO 2015

271 V x 16 dose for 20 wk or no Rx Median PFS 34 vs 28 mo (P=0.006)

Median OS not reached in both arms

+/ND

Sonneveld et al ASH 2016

A242

903 of 1211

VCd followed by Mel200 x 1 vs 2 vs VMP, followed by RVd vs no consolidation, All

followed by R

PFS from Consolidation 65% vs 60%

Low Risk Cytogenetic Benefit

3 year OS 87% vs 86%

+/-/ND

Stadtmauer et al ASH

2016 LBA-1

254 (ACM) 247 (TAM) 257 (AM)

12 mo any induction followed by ASCT RVD Consolidation vs Tandem ASCT vs

Single ASCT, all followed by R Maintenance

38 mo PFS 57% vs 56% vs 52% (P=NS)

38 mo OS 86% vs 82% vs 83%

ND/ND

ACM: ASCT+RVD Consolidation+Lenalidomide Maintenance; TAM Tandem ASCTM: AM: ASCTM; N: Number of patients; Mel: Melphalan; Mo: months; SC: Subcutaneous; IT: Intensive Therapy; IFN: Interferon; IV: Intravenous; NIT: Non-intensive therapy; MV: Multi-variate; OS: Overall Survival; PFS: Progression-Free Survival; R: lenalidomide; wks: weeks; yrs: years; ND: no difference; Rx: Therapy; VCD Bortezomib, cycophosphamide, dexamethasone,; RVD: R, bortezomib, dexamethasone, VMP,: Bortezomib, melphalan, prednisone

Randomization

MM Stage II or III, Age 18–65

CAD + GCSF

3 x VAD

CAD + GCSF

3 x PAD

MEL 200 + PBSCT

Depending on local

policy for patients PR MEL 200

+ PBSCT

MEL 200 + PBSCT

Depending on local policy for

patients PR MEL 200 +

PBSCT

Thalidomide

50 mg/day for

2 years maintenance

Allogeneic Tx

Bortezomib

1.3 mg/m2 / 2 weeks for 2 years

maintenance

Phase III: PAD vs VAD induction, HDM and bortezomib or

thalidomide maintenance HOVON 65 MM / GMMG-HD4

Slide courtesy P Sonneveld et al. Sonneveld P et al. J Clin Oncol. 2012, 30:2946-55.

n=371 n=373

n=744, median age 57

PAD:

Bortezomib 1.3 mg/m2 D1,4,8,11

Doxorubicin 9 mg/m2 D1-4

Dex 40 mg D 1-4, 9-12, 17-20

(480 mg total)

PFS and OS for Thalidomide (Arm A) vs Bortezomib (Arm B) Induction and Maintenance by Cytogenetic Risk

Slide courtesy Sonneveld P et al. JCO 2012;30:2946-2955

©2012 by American Society of Clinical Oncology

del(17p)

t(4;14)

del(13/13q)

VAD T

PAD B PAD B

VAD T

Lenalidomide Maintenance after Auto HSCT

Adapted from: McCarthy PL. J Natl Compr Canc Netw 2013;11:35-42

Maintenance versus control

N Initial dose (mg)

EFS or PFS or TTP OS Benefit? EFS/OS

McCarthy P et al NEJM 2012

460 10 TTP 46 vs 27 mo (P<0.001)

34 mo median F/U 85 vs 77% (P=0.028)

+/+

Holstein S et al ASCO 2015

Update TTP 53 vs 26 mo (P<0.001)

65 mo median F/U 71 vs 57% (P=0.008)

+/+

Attal M et al NEJM 2012

614 10 PFS 41 vs 23 mo (P<0.001)

45 mo median F/U 74 vs 76% (P=0.7)

+/ND

Attal M et al ASH 2013

Update 5 year PFS 42 vs 18 mo (P<0.001)

5 year OS 68 vs 67%

+/ND

Palumbo A et al NEJM 2014

200 (IT) 202 (NIT)

10: 21/28 days

Median PFS 42 vs 22 months (p<0.001)

3 year OS (NIT and IT): 88 vs 79% (p=0.14)

+/+-

Jackson GH et al ASH 2016 A1143

828 (TE) 722 (TNE)

10: 21/28 days

Median PFS 60 vs 28 mo (p<0.0001)

26 mo median F/U OS Not reported

+/NR

Gay et al Lancet Oncology 2015

195 (IT) 194 (NIT)

10: 21/28 days +/- Pred

50: qod

Median PFS (TE and TNE) RP: 38%, R: 29% (P=0.34)

52 mo median F/U 3 year OS (TE and TNE) ND

4 year OS 86%

ND/ND

EFS: Event-free survival; IT: Intensive Therapy: mg: milligrams; N: Number of patients; ND: No difference; NIT: Non-intensive therapy; NR: Not Reported; OS: Overall Survival; PFS: Progression-Free Survival; TNE: Transplant not-eligible; TE: Transplant-eligible; TTP: Time to progression

Meta-Analysis of Lenalidomide Maintenance after ASCT CALGB 100104

(accrual 8/2005 – 11/2009)

INDUCTION ASCT 1:1 RANDOMIZATION “NO EVIDENCE OF PD” Primary Endpoint: PFS

LEN MNTCa (n = 231)

PLACEBO (n = 229)

CROSSOVER BEFORE PD ALLOWED

CONTINUED TREATMENT

IFM 2005-02 (accrual 6/2006 – 8/2008)

INDUCTION ASCT 1:1 RANDOMIZATION “NO EVIDENCE OF PD” Primary Endpoint: PFS

LEN: 2 COURSES

LEN MNTCa

(n = 307) PLACEBO (n = 307)

ALL TREATMENT DISCONTINUED Jan 2011

CONTINUED TREATMENT NO CROSSOVER

BEFORE PD ALLOWED

INTERIM ANNG

a Starting dose of 10 mg/day on days 1-28/28 was increased to 15 mg/day if tolerated and continued until PD. b Patients received 10 mg/day on days 1-21/28 until PD.

ASCT, autologous stem cell transplant; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; MNTC, maintenance; MPR, melphalan, prednisone, and Len; PD, progressive disease.

Dec 2009 Jan 2010

Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT Attal et al ASCO 2016

McCarthy et al EHA 2016

INTERIM ANALYSIS AND UNBLINDING

GIMEMA (RV-MM-PI-209) (accrual 11/2007 – 7/2009)

MPR: 6 COURSES

LEN MNTCb (n = 67)

NO TREATMENT (n = 68)

LEN MNTCb NO TREATMENT

ASCT

CONTINUED TREATMENT

CONTINUED TREATMENT

PRIMARY ANALYSIS

2 × 2 DESIGN LEN + DEX × 4 INDUCTION Primary Endpoint: PFS

Overall Survival: Median Follow-Up of 80 Months

0.0 0 10 20 30 40 50 60 70 80 90 100 1 10 120

0.2

0.4

0.6

0.8

1.0

There is a 26% reduction in risk of death, representing an estimated

2.5-year increase in median survivala

605 578 555 509 474 431 385 282 200 95 20 1 0

604 569 542 505 458 425 350 271 174 71 10 0

Overall Survival, mos

Su

rviv

al P

rob

ab

ilit

y

Patients

at risk

7-yr OS

62%

50%

N = 1209 LENALIDOMIDE CONTROL

Median OS

(95% CI), mos

NE

(NE-NE)

86.0

(79.8-96.0)

HR (95% CI)

P value

0.74 (0.62-0.89)

.001

a Median for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). HR, hazard ratio; NE, not estimable; OS, overall survival.

Attal et al ASCO 2016

McCarthy et al EHA 2016

Cumulative Incidence of SPMs

a HR based on Cox proportional hazards model. b P value is based on log-rank test.

SPM, second primary malignancy.

0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 0.0

586 559 514 465 422 365 251 139 38 1 586 554 508 458 415 360 251 136 35 0

602 559 525 468 428 340 248 119 28 0 602 559 520 461 417 328 241 117 28 0

Time to Hematologic SPM Onset, mos Time to Solid Tumor SPM Onset, mos

Cu

mu

lati

ve

In

cid

en

ce

Cu

mu

lati

ve

In

cid

en

ce

Lenalidomide

Control

HR (95% CI): 2.03a (1.14-3.61)

P = .015b

Lenalidomide

Control

HR (95% CI): 1.71a (1.04-2.79)

P = .032b

0.20

0.40

0.60

0.80

1.00

0.0

0.20

0.40

0.60

0.80

1.00 Hematologic Solid Tumor

Patients

at risk

Patients

at risk

Attal et al ASCO 2016

McCarthy et al EHA 2016

Time to Death by Cause of Death

AE, adverse event; LEN, lenalidomide; maint, maintenance; MM, multiple myeloma; SPM, second primary malignancy.

No. at Risk

Placebo/Observation: caused by MM 603 569 542 505 459 425 351 270 174 71 10 0

LEN maint: caused by MM 605 577 555 508 473 431 385 282 200 95 20 1 0

LEN maint: caused by SPM 605 577 555 508 473 431 385 282 200 95 20 1 0

Placebo/Observation: caused by SPM 603 569 542 505 459 425 351 270 174 71 10 0

LEN maint: caused by AE 605 577 555 508 473 431 385 282 200 95 20 1 0

Placebo/Observation: caused by AE 603 569 542 505 459 425 351 270 174 71 10 0

0.2

1.0

0.8

0.6

0.4

0.0

Pro

po

rtio

n o

f P

ati

en

ts

Time to Death (Months)

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

Placebo/Observation: caused by MM

LEN maint: caused by MM

LEN maint: caused by SPM

Placebo/Observation: caused by SPM

LEN maint: caused by AE

Placebo/Observation: caused by AE

Myeloma XI

N=1551 (TE=828; TNE=723)

Median follow-up: 27 months (IQR 13‒43)

Exclusion criteria

• Failure to respond to lenalidomide as induction IMiD, or development of PD

• Previous or concurrent active malignancies

Lenalidomide 10 mg/day, days 1‒21/28

Observation

Maintenance

NDMM

Treated on Myeloma XI

induction protocols

IQR, interquartile range; NDMM, newly diagnosed multiple myeloma; PD, progressive disease

R 1:1

Induction

Jackson GH et al ASH 2016, Courtesy G Morgan

Median PFS, months

[95% CI]

Lenalidomide (n=451) 50 [44, ∞]

Observation (n=377) 28 [23, 32]

HR=0.47; 95% CI 0.38, 0.60

Log-rank p<0.0001

Transplant eligible Significant improvement in PFS from 28 to 50 months, HR=0.47

No. of patients at risk:

Lenalidomide

Observation

451

377

397

326

356

306

330

261

285

237

254

198

215

175

196

143

163

121

144

105

130

86

107

70

92

52

76

39

61

32

43

21

30

16

17

8

10

2

5

1

2

1

1

1

0

0

Time since randomisation (months)

100

0

Pa

tie

nts

aliv

e a

nd

pro

gre

ssio

n-f

ree

(%

)

80

60

40

20

0

18 33 51 66 3 6 9 12 15 21 24 27 30 36 39 42 45 48 54 57 60 63

Jackson GH et al ASH 2016, Courtesy G Morgan

Impact of maintenance by cytogenetic risk status

No. of patients at risk:

Lenalidomide –

standard risk

high risk

Observation –

standard risk

high risk

97

99

118

91

93

92

109

80

87

86

104

71

87

80

93

54

83

72

83

47

81

67

69

39

74

58

57

36

71

53

49

28

62

39

42

25

59

30

37

16

51

29

26

15

41

24

21

11

34

21

18

7

30

16

13

6

20

9

11

5

17

5

9

3

13

1

6

3

8

0

2

1

4

1

0

1

0

0

Outcome of high risk subgroup is clearly improved by the use of maintenance lenalidomide

Time since randomisation (months)

1.0

0

0.8

0.6

0.4

0.2

0

18 33 51 63 3 6 9 12 15 21 24 27 30 36 39 42 45 48 54 57 60

Pro

po

rtio

n a

live

an

d p

rog

ressio

n-f

ree

Lenalidomide –

standard risk

high risk

Observation –

standard risk

high risk

Log-rank

⅔=51.4972

p<0.0001

Jackson GH et al ASH 2016, Courtesy G Morgan

http://www.flickr.com/photos/dcml/217552761/

What is on the horizon?

Immune cell population analysis before and after autotransplant for Multiple Myeloma

• Are there modifiable immune cell populations that correlate with improved

outcomes?

• Are there immune cell subsets correlating with improved PFS/OS?

• 101 multiple myeloma (MM) patients receiving first ASCT at RPCI from

8/2007 - 1/2014

• Immunophenotyping performed pre- AHSCT (n = 101), D+30 (n = 70) and

D+100 post-AHSCT(n = 80)

Ho et al. Blood 2016, Manuscript submitted

Higher T γδ pre-BMT & at Day 100 post AHSCT correlate with improved PFS for MM Patients

Pre-BMT Pre-BMT

Day 100 Day 100

Higher T γδ pre-BMT & at Day 100 post AHSCT correlate with improved OS for MM Patients

Pre-BMT Pre-BMT

Day 100 Day 100

C16019 Study Design Takeda Millennium Ixazomib Maintenance

3:2

N = 652

Primary endpoint: PFS

Key secondary endpoint: OS

Secondary endpoints: QoL, MRD, ORR, G3/4 AEs, SPM

Study Duration: 110 mo, 32 mo enrollment, 78 mo F/U p LPI IA1 @ 44 months p FPI

Daratumumab trial in transplant eligible NDMM

Hovon/IFM

VTD +

Dara Dara

Courtesy P Sonneveld

Observation

Induction

4 cycles

Maintenance until progression

Endpoints:

• sCR

• PFS, OS

VTD

R HDM

ASCT

Str

ati

fy b

y:

da

ra t

rea

tme

nt,

re

sp

on

se

, M

RD

sta

tus

R

VTD +

Dara

VTD

Consolidation

2 cycles

GMMG HD6: NDMM transplant-eligible

EudraCT: 2014-003079-40 Clinical Trials.Gov NCT02495922

A, Adriamycin; C, Cyclophosphamide; D, Dexamethasone; Elo, Elotuzumab; HDT, High Dos Therapy (melphalan); R, lenalidomide; SCT, Stem Cell Tranplant; V, Bortezomib.

Symptomatic MM patients requiring 1st line treatment aged 18-70 years

Randomization

3 x RVD+Elo 3 x RVD

CAd + G-CSF + leukapheresis

HDT + autologous SCT

HDT + autologous SCT (if no CR)

R+d+Elo R+d

RVD RVD+Elo

R+d+Elo R+d

RVD RVD+Elo

Phase III

Enrollment: n=516, ongoing FPI Q42014, LPI planned Q4 2017 Primary endpoint: PFS

Maintenance for 26 cycles

GIMEMA FORTE: NDMM transplant-eligible GIMEMA Italy

*Sequenta’s ClonoSIGHT™ for minimal residual disease (MRD) testing for prognosis and monitoring

Phase III Enrollment: n=477, ongoing Estimated LPE: Dec 2016 Primary endpoint: VGPR of CCyd or CRd after 4 cycles of induction in NDMM transplant-eligible pts C: Carfilzomib Cy: Cyclophosphamide R: Lenalidomide

Induction:

R

Mel-200 Bu-Mel

Consolidation:

Maintenance

R

Maintenance (GEM14 MAIN)

ASCT

* Patients with positive MRD will continue with LEN/DEX for 3 more years

LEN/DEX x 2 yrs*. LEN/DEX + MLN9708 x 2 yrs*.

VRDx6

VRDcon x 2

MRD

MRD

MRD

MRD+ Rd x 3 yrs MRD- Stop Maintenance

MRD

MRD

4, 21-day cycles

Len: 25 mg PO D1-14

Bort: 1.3 mg/m2 SC

D1, 4, 8, 11

Dex: 20 mg PO

D1,2,8,9,15,16

Stem cell

mobilization:

G-CSF ± Plerixafor

2, 21-day cycles

Len: 25 mg PO D1-14

Bort: 1.3 mg/m2 SC D1,

4, 8, 11

Dex: 20 mg PO

D1,2,8,9,15, 16

56-day cycles

Len: 10 mg daily

Induction Maintenance*

4, 21-day cycles

Len: 25 mg PO D1-14

Bort: 1.3 mg/m2 SC

D1, 4, 8, 11

Dex: 20 mg PO

D1,2,8,9,15,16

Dara: 16 mg/kg IV D1,

8, 15

Stem cell

mobilization:

G-CSF ± Plerixafor

2, 21-day cycles

Len: 25 mg PO D1-14

Bort: 1.3 mg/m2 SC D1,

4, 8, 11

Dex: 20 mg PO

D1,2,8,9,15,16

Dara: 16 mg/kg IV D1

56-day cycles

Len: 10 mg daily

Dara: 16 mg/kg IV D1

MEL 200

mg/m2

MEL 200

mg/m2

Transplant Consolidation

Ran

do

miz

ati

on

Stratification Factors: ISS stage, CrCl

N=

10

0

N=

10

0

*Maintenance on protocol therapy lasts 2 years but patients are encouraged to remain on lenalidomide

monotherapy until disease progression thereafter

AFT-29 / MMY2004. A randomized, phase II study of lenalidomide, bortezomib

and dexamethasone +/- daratumumab with Safety Run-in: P.I. Peter Voorhees

Mel200 ASCT

Restaging days 90-100

Registration/Randomization

Len Durvalumab + Len

PD

Off study PD

PD

ACY241 + Len

Extended follow-up

PD

• Stratification: R-ISS (I/II vs III vs unknown), IMiD induction (yes vs no) • Primary endpoint: CR rate after one year of maintenance • Secondary endpoints: safety profile, PFS, OS, proportion of patients who convert to MRD-neg • Translational endpoints: MRD, immune profiling

Elotuzumab + Len

PD

Multiple Myeloma: US Cooperative Group Trials

April 2017

E1A11: KRd vs VRd S1211: VRd vs. VRd-Elo

Change to KRd vs KRd-Dara C: 1302: High risk Allo

AFT-29:Rd vs Rd-Dara for HSCT Ineligible

A: RVd vs RVd-Dara HSCT Eligible

E1A11 R 2 yrs vs until PD C: 1401: Len vs Len DC Vaccine

post Auto C: Extension of R 0702

S:Len vs Len/Dara post Auto AFT-29: RVd vs RVD Dara HSCT

eligible: Len Dara vs Len maintenance

AFT40: Phase II Pick the Winner Maintenance

E3A06: Phase II Len vs. Obs

S0777: Rd vs VRd E1A06: MPT vs. MPR C: 0702

A: CALGB 100104 Len vs Placebo

S1304: K high & low dose

A061202: Ibrutinib Rd

A: PomDIxa vs PomD A: PVD Dara

A061402: Plasmacytoma Zol vs Ixa-Len-Dex-Zol

A: Alliance, E: ECOG, S: SWOG, C: BMT CTN Adapted from Slide courtesy of V Rajkumar 2016

DETERMINATION: RVD Early SCT vs RVD Late HSCT

Induction

Rx 66666 Asymptomatic

& Early

Consolidation

and/or

Maintenance

Stem Cell

Transplant

Non

Transplant

Consolidation

Relapse

Conclusions • 2016 ASH Meeting Abstract search using Myeloma and Immune

– 103 abstracts and an Education and Scientific Sessions: Examples • Foureau et al Immune Profiling (IP) and MRD post ASCT A378 Sunday PM Oral Presentation

• Ho et al IP & PFS/OS post ASCT A3454 Sunday PM Poster Presentation

• Paiva et al Tumor Associated macrophages & MM A482, Sunday PM Oral Presentation

• Adams et al CyTOF study of RRMM Pts Rx with Dara: IM as mechanism of action A4521 Monday Poster Session

• Mehta et al Adaptive NK Cell Expansion: Lower relapse of MM/NHL post ASCT A515 Sunday PM Oral Session

• New and Emerging Immune-Based Approaches, Sat and Sun

• Immunotherapy for Myeloma Sat and Sun

• Search using Minimal Residual Disease and Myeloma

– 45 abstracts,nearly all examining MRD and outcome

• OS has increased with improved induction, ASCT and maintenance

• There is a need to define and establish earlier surrogate endpoints for OS including MRD testing and Immune Profiling

Conclusions • ASCT

– ASCT improves PFS when compared to chemotherapy in the era of novel agents

– Future analyses will determine the effect of ASCT on OS

– There is fluidity with regard to the roles of post-ASCT consolidation and tandem ASCT when compared to single ASCT

– In the absence of recent Phase III data, ASCT remains a treatment for Amyloidosis patients

• Maintain response and long term disease control – Maintenance with lenalidomide is a standard

– Investigate new agents to deepen and maintain response • Ixazomib, anti-CD38 antibodies, anti-CS-1 (SLAMF-7), HDAC inhibitors eg Panobinostat, ACY241,

Checkpoint Inhibition, Selective Inhibitors of Nuclear Transport, BITE technology, Cellular therapy including NK Cells and CAR-T cells, targeting MM antigens such as BCMA, APRIL

• Can MM patients be cured?

Acknowledgements • The patients and caregivers who participated in these studies

• The clinicians who provided care for these patients

• The site research staff for protocol monitoring

• The Alliance, ECOG, SWOG, BMT-CTN, IFM, and GIMEMA colleagues participating in the lenalidomide meta-analysis

– P Richarson, K Anderson, S Holstein, C Linker, K Owzar, C Hofmeister, D Hurd, R Vij, J Moreb, NS Callander, K van

Besien, T Gentile, L Isola, R Maziarz, D Gabriel, A Bashey, T Shea, S Devine, H Hassoun, D Weisdorf, T Martin, E

Stadtmauer, S Giralt, M Pasquini, A Krishnan, M Horowitz,, D Sargent, and Duke and Mayo Alliance Statistical

Centers

– M Attal, P Moreau, V Lauwers-Cances, C Hulin, D Caillot, G Marit, T Facon, AM Stoppa, L Benboubker, L Garderet, O

Decaux, S Leyvraz, M-C Vekemans, L Voillat, M Michallet, B Pegourie, C Dumontet, M Roussel, Z Leleu, C Mathiot, C

Payen, H Avet-Loiseau, J-L Harousseau

– A Palumbo, F Cavallo, P Tosi, V Magarotto, F Gay, M Petrucci, F Di Raimondo, DB Yehuda, S Pezzatti, T Caravita, C

Cerrato, E Ribakovsky, M Genuardi, A Cafro, M Marcatti, L Catalano, M Offidani, AM Carella, E Zamagni, F Patriarca,

P Musto, A Evangelista, G Ciccone, P Omedé, C Crippa, P Corradini, A Nagler, M Boccadoro, and M Cavo

• The NCI: R Little, H Streicher

• RPCI: T Hahn, P Wallace, S Balderman, G Chen, F Hernandez, C Ho, K Lee, M Ross, P Torka

• Jane and our family who support my work schedule

Thank you very much

l 402 patients (younger than 65 years) randomized from 62 centres

l Patients: Symptomatic disease, organ damage, measurable disease

MPR vs MEL200 Treatment schedule

* MPR vs MEL 200; R maintenance vs no maintenance; Anti-thrombotic substudy: Aspirin vs Low molecular weight heparin

Rd (R: 25 mg/d, days 1-21; d: 40 mg/d, days 1,8,15,22); MPR (M: 0.18 mg/Kg/d, days 1-4; P: 2 mg/Kg/d, days 1-4; R: 25 mg, d 1-21), MEL 200 (M: 200 mg/m2 day -2); R maint (R: 10 mg/day,

days 1-21); # One course MEL 200 if patients achieves VGPR after cycle 1

R: lenalidomide; MEL200: melphalan 200 mg/m2 and autologous stem cell transplant; MPR: melphalan-prednisone-lenalidomide; NDMM: newly diagnosed multiple myeloma.

Palumbo et al N Engl J Med. 2014 371:895-905

Rd four 28-day courses

MEL 200 Two courses#

NO MAINTENANCE

R MAINTENANCE 28-day courses until PD

MPR six 28-day courses

R MAINTENANCE 28-day courses until PD

NO MAINTENANCE

*Randomisation (2x2 design)

MPR six 28-day courses

MEL 200 Two courses#

Slide Courtesy Antonio Palumbo

MPR vs Mel 200

Analysis from Initiation of Consolidation

Progression-free survival Overall survival

Months Months

Palumbo et al N Engl J Med. 2014 371:895-905

4yr OS 81.6% vs 65.3% Median PFS 43 mo vs 22.4 mo

Slide Courtesy Antonio Palumbo

Overall Survival

Median overall survival

ASCT2 67 months (95% CI 55, ∞)

NTC 52 months (95% CI 42,60) Log Rank p=0.022

Cook et al, The Lancet Haematology, 2016 (in press)

Myeloma X Study

for relapse >18 mo

after first ASCT

PAD Salvage

followed by ASCT

vs

cyclophosphamide