BEST OF ASH 2015 MULTIPLE MYELOMA AND PLASMA CELL DYSCRASIAS

Yvonne Efebera MD. MPH

Disclosure: Takeda: Speaker, adjudication Committee

GOOD NEWS!!!!!

Overall Survival from Time of Diagnosis in 6-yr Intervals based on date of Diagnosis

3

Kumar SK et al, Blood 2008: 111: 2516

Corticosteroids, Alkylating agents,

radiation, etc.

Thalidomide, lenalidomide, Bortezomib

4

Old regimen (VAD regimen)

New regimen incorporating Novel

agents

Overall response rate (ORR)

50-60% 80-100%

Complete response (CR) 16-25% 40-60%

Very good partial response (VGPR)

5-10% 20-30%

5 yr Overall survival (OS) ~30-40% 60-80%

Median time to disease progression (PFS)

15 months 25-30 months. Improved to 53 mos with Maintenance

Palumbo A et al, 2006, Lancet p825; Mateos MV et al, Blood 2010, p 2259; Facon T et al, lancet 2007, p 1209; Sacchi s, Leuk lymphoma 2011, p 1942;

A GREAT YEAR for Multiple Myeloma • 4 New drugs approved for relapsed/refractory MM • Daratumumab: Nov 16, 2015: monoclonal ab, anti-CD38, single agent • Elotuzumab: Nov 30,2015: monoclonal ab, SLAM-7 and NK cell activation, in

combination with lenalidomide and Dex • Ixazomib: Nov 20, 2015: oral proteosome inhibitor, in combination with lenalidomide

and Dex • Panobinostat: Feb 28, 2015: HDAC inhibitor, in combination with bortezomib and Dex

Approved Newly Dx MM Newly Diagnosed Regimen Approved Relapsed MM

Thalidomide (T) Lenalidomide (R ) Bortezomib (V) Dexamethasone (D) Prednisone (P)

VRD CVD (CyborD) CRD RD VD Melphalan based (transplant ineligible)

Pomalidomide Carlfizomib Panobinostat Daratumumab Ixazomib Elotuzumab

Cyclophosphamide (C ) Vincristine Doxil Melphalan

Newly diagnosed Myeloma- Transplant eligible Patient

Induction treatment: to reduce burden of disease and prevent complications

2-6 cycles

Autologous Stem cell Transplant

Maintenance treatment.

Supportive Management

Radiation

Bisphosphonate

Newly diagnosed Myeloma- Not Transplant eligible Patient

Induction treatment: to reduce burden of disease, prevent complications,

With goal towards complete response 8-12 cycles

Maintenance treatment.

Supportive Management

Radiation:

Bisphosphonate

Overview • Newly diagnosed Multiple Myeloma

• Autologous stem cell transplant vs chemotherapy (early

vs delayed SCT) • Relapse Multiple Myeloma

• Treatment of older Adults

• AL Amyloidosis

INDUCTION REGIMEN FOR NEWLY DX MM

VTD x 4 versus VCD x 4 as induction therapy prior to ASCT Symptomatic de novo MM less than 66 years Primary end-point : VGPR rate after cycle 4 340 patients overall (170 per arm).

Abstract 393 Bortezomib, Thalidomide and Dexamethasone (VTD) Is Superior to Bortezomib, Cyclophosphamide and Dexamethasone (VCD) Prior to

Autologous Stem Cell Transplantation for Patients with De Novo Multiple Myeloma. Results of the Prospective IFM 2013-04 Trial. Philippe Moreau et al

ISS1 / 2 versus ISS 3 t(4;14) and / or del17p versus others

Arm A : Induction Therapy: 4 cycles VTD Each cycle : 21 days Thalidomide® 100 mg/d, PO D1 to D21 o Velcade® 1.3 mg/m²/d, SC D1, 4, 8 and 11 o Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 ARM B: Induction Therapy : 4 cycles of VCD Each cycle : 21 days o Cyclophosphamide 500 mg/m²/d, PO D1, 8, 15 o Velcade® 1.3 mg/m²/d, SC D1, 4, 8 and 11 o Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12

VTD 169

VCD 169

Total 338

Male Female Median age ISS1 ISS2 ISS3 No t(4;14), no17p t(4;14) and/or 17p

103 66

59.4

38 (22%) 94 (56%) 37 (22%)

137 (81%) 32 (19%)

108 61

60.2

43 (25%) 90 (53%) 36 (21%)

140 (83%) 29 (17%)

211 127

59.9

81 (24%)

184 (54%) 73 (22%)

277 (82%) 61 (18%)

Patients Characteristics

Cytogenetics: centralized analysis (Pr Avet-Loiseau, Toulouse)

VTD N = 169

VCD N = 169

P value

≥ CR

≥ VGPR

≥ PR

13.0%

66.3%

92.3%

8.9%

56.2%

83.4%

0.22

0.05

0.01

Intent-to-treat analysis

Response: centralized assessment (Dr Dejoie, Nantes), IMWG criteria 2011

VTD N = 157

VCD N = 154

P value

> = CR

> = VGPR

> = PR

14.0%

70.7%

98.7%

9.1%

60.4%

90.3%

0.17

0.05

0.001

Per protocol analysis

VTD, n = 169 Grade 3-4 %

VCD, n= 169 Grade 3-4 %

p value

Any Aes Anemia Neutropenia Infection Thrombocytopenia Thrombosis Cardiac disorders Cystitis GI symptoms Periph. Neuropathy PN grade 2-4

63.9 4.1 18.9 7.7 4.7 1.8 1.2 0

5.3 7.7 21.9

68.2 9.5 33.1 10.1 10.6 1.8 0

0.6 3.5 2.9 12.9

0.40 0.05 0.003 0.45 0.04 0.99 0.16 0.32 0.42 0.05 0.008

Toxicity

Toxicities assessed according to NCI CTCAE, version 4.0.

Toxicity Five patients died during induction therapy (1.5%), 2 in arm A from infections (1) and pulmonary embolism (1) 3 in arm B from progression to extramedullary myeloma (1) and infections (2).

VTD, n = 169 VCD, n = 169 Dexamethasone 100% dose reduction Discontinuation DOSE-INTENSITY Bortezomib 100% dose reduction Discontinuation DOSE-INTENSITY Thalidomide / Cyclophosphamide 100% dose reduction Discontinuation DOSE-INTENSITY

76.3% 14.2% 9.5% 92.4%

76.9% 16.0% 7.1% 94.9%

62.7% 21.3% 16%

81.9%

84.6% 10.9% 8.6%

96.1%

78.1% 13.6% 8.3%

96.4%

71.3% 16.6% 12.1% 94.5%

VTD

N = 157

VCD

N = 154

p value

CD34+ (106 / kg)

10.68

9.17

0.05

Stem cell harvest

Conclusions

- First prospective randomised trial : VTD vs VCD

- VGPR and PR rates are significantly superior in the VTD arm: synergistic activity of PI + IMiD

- Hematologic toxicity increased in the VCD arm, while Peripheral Neuropathy rate was higher in the VTD arm

- Median number CD34+ stem cells higher in the VTD

- Our data support the preferential use of VTD rather than VCD in preparation for ASCT

Bortezomib-thalidomide-dexamethasone (VTD) is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) as induction therapy prior to autologous stem cell transplantation in multiple myeloma. Cavo et al leukemia:2015 ,2429-2431

All patients VTD (n=236) VCD (n=236) P Complete response 44 (19%; 14–24) 13 (6%; 3–8) <0.001

Very good partial response or better 151 (64%; 58–70) 87 (37%; 31–43) <0.001

Partial response or better 220 (93%; 90–96) 192 (81%; 76–86) <0.001 Stable disease 16 (7%; 4–10) 38 (16%; 11–21) 0.001

Progressive disease 0 (0%) 6 (3%; 1–5) 0.015

Patients with ISS 2-3 VTD (n=129) VCD (n=129) Complete response 26 (20%; 13–27) 5 (4%; 1–7) <0.001

Very good partial response or better 86 (67%; 59–75) 45 (35%; 27–43) <0.001

Patients with t(4;14) and/or del(17p) VTD (n=53) VCD (n=53)

Complete response 12 (23%; 11–34) 4 (8%; 0–15) 0.030 Very good partial

response or better 44 (83%; 73–93) 25 (47%; 34–61) <0.001

Dose and schedule same as Moreau et al. except- V and C given IV, 3 cycles each before SCT

Toxicity VTD (n=236) VCD (n=236) P

Any grade 3 or 4 adverse event 64 (27%) 61 (26%) 0.754

Any grade 3 or 4 non-hematological adverse event Skin rash 19 (8%) 2 (1%) <0.001 Peripheral neuropathy 17 (7%) 5 (2%) 0.009

Gastrointestinal events 15 (6%) 8 (3%) 0.135

Liver toxicity 5 (2%) 8 (3%) 0.399

Any grade 3 or 4 hematological adverse event Neutropenia 5 (2%) 19 (8%) 0.003

Anemia 0 16 (7%) <0.001

Thrombocytopenia 1 (<1%) 10 (4%) 0.006

Study protocol discontinuation during induction therapy Toxic effects 8 (3%) 4 (2%) 0.242

Disease progression 0 3 (1%) 0.124

Early death 1 (<1%) 2 (1%) 0.500

Abstract 25 Bortezomib, Lenalidomide and Dexamethasone (Rd)Vs. Lenalidomide and Dexamethasone in Patients (Pts)(VRd) with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant (ASCT): Results of the Randomized Phase III Trial SWOG S0777 Brian Durie, MD et al

• Randomized phase III: 2008-2012 • Stratified to ISS stage (I,II,III), Intent to transplant (Yes, NO)

• Lenalidomide/dex (Rd): 232 patients: R 25 mg days 1-21, dex 40 mg/d days 1

8, 15, 22, cycle q 28 days x 6 cycles

• Bortezomib/Rd (VRd): 242 patients: R 25 mg days 1-14, dex 20 mg/d days 1-4, 8-12, velcade 1.3 mg/m2 IV push days 1,4,8,11. cycle q 21 days x 8 cycles

• Maintenance: Rd until progression • DVT prophylaxis: ASA 325 mg/d; HSV prophylaxis with VRd

• Differences b/w gps :

• Fewer women VRd(37% vs 47% p=0.033) • Fewer older pts VRd (≥ 65yrs 38% vs 48% p=0.042)

• Primary Endpoint: PFS

Abstract 25 . Brian Durie, MD et al VRd Rd P-value

ORR 71.07% 63.79%

Median PFS 43 mos 31 mos 0.0066

Median OS NR 63 mos 0.0114

≥Grade 3 hem tox (%) Anemia Neutropenia thrombocytopenia

13 19 18

16 21 14

≥Grade 3 non- hem tox (%) Neuropathy Thrombosis/embolism

24 8

5 9

<0.0001

Second primary malignancy 7 pts (3%) 9(4%)

VRd provides meaningful improvement in PFS and OS with acceptable toxicity

What did we Learn? • The combination of A proteosome inhibitor (bortezomib) ,

and an immune modulator( thalidomide, lenalidomide) as induction treatment is a preferable regimen

• 3-drug regimen with Novel agents is superior to 2-drug regimen with Novel agent as Induction regimen

AUTOLOGOUS SCT AS CONSOLIDATION IN NEWLY DX MM VS CONTINUATION OF THERAPY (EARLY VS DELAYED SCT) IN THE ERA OF NOVEL THERAPIES

389 patients (younger than 65 years) randomized from 59 centers

Patients: Symptomatic disease, organ damage (CRAB), measurable disease

392: Autologous Transplantation versus cyclophosphamide-lenalidomide-prednisone followed by lenalidomide-prednisone versus lenalidomide maintenance in multiple myeloma: long-term results of a phase

III trial. Gay et al- lancet oncology Dec 2015 p1617

Rd four 28-day courses R: 25 mg/d, days 1-21

d: 40 mg/d, days 1,8,15,22

CRD six 28-day courses C: 300 mg/sqm, days

1,8,15 R: 25 mg/d, days 1-21

D: 40 mg days 1,8,15,22

MEL200-ASCT two courses

M: 200 mg/m2 day -2 Stem cell support day 0

RP MAINTENANCE 28-day courses until

relapse R: 10 mg/day, days 1-21 P: 50 mg every other day

R MAINTENANCE 28-day courses until

relapse R: 10 mg/day, days 1-21

R A N D O M I Z A T I O N

1°

R A N D O M I Z A T I O N

2°

R, lenalidomide; D, dexamethasone; C, cyclophosphamide; P, prednisone; Rd, lenalidomide-dexamethasone; CRD, cyclophosphamide-lenalidomide-dexamethasone; MEL200-ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; RP lenalidomide-prednisone,

CRD vs MEL200-ASCT

CRD six 28-day courses

C: 300 mg/m2/d, days 1,8,15 R: 25 mg/d, days 1-21

D: 40 mg/d days 1,8,15,22

MEL200-ASCT two courses

M: 200 mg/m2 day -2 Stem cell support day 0

R A N D O M I Z A T I O N

1°

CRD, cyclophosphamide-lenalidomide-dexamethasone; C, cyclophosphamide; D, dexamethasone; R, lenalidomide; MEL200-ASCT, melphalan 200 mg/m2 followed by autologous stem-cell transplantation

CRD vs MEL200-ASCT

CRD, cyclophosphamide-lenalidomide-dexamethasone; MEL200-ASCT, melphalan 200 mg/m2 followed by autologous stem-cell transplantation; ISS, International Staging System

MEL200-ASCT (n=127)

CRD (n=129)

Age median >60 years

57 34

56 31

ISS Stage I II III

51% 36% 13%

45% 50% 16%

Chromosomal Abnormalities t (4;14) t (14;16) del 17 High-risk [t (4;14) or t(14;16) or del17]

9% 5% 5%

18%

13% 5% 8%

23%

Patients Characteristics

CRD vs MEL200-ASCT Median follow-up from consolidation : 47 months

Median PFS MEL200-ASCT 43.3 months CRD 28.6 months

MEL200–ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD cyclophosphamide lenalidomide dexamethasone; PFS progression-free survival

Progression-free survival

HR 2.51 95% CI 1.60-3.94 P< 0.0001 0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60 Months

Prop

ortio

n of

pat

ient

s

Overall Maintenance

Lenalidomide Lenalidomide-Prednisone

Age ≤ 60 > 60

ISS I II III

Cytogenetic risk Standard High Missing

2.51 (1.60, 3.94)

2.18 (1.23, 3.88) 2.66 (1.50, 4.71)

1.78 (1.07, 2.97) 3.92 (2.00, 7.71)

3.15 (1.62, 6.13) 1.97 (1.08, 3.60) 1.72 (0.76, 3.90)

2.01 (1.06, 3.80) 3.81 (1.83, 7.93) 2.12 (1.06, 4.24)

HR (95% CI) Interaction -

2.51 (1.60, 3.94)

2.18 (1.23, 3.88) 2.66 (1.50, 4.71)

1.78 (1.07, 2.97) 3.92 (2.00, 7.71)

3.15 (1.62, 6.13) 1.97 (1.08, 3.60) 1.72 (0.76, 3.90)

2.01 (1.06, 3.80) 3.81 (1.83, 7.93) 2.12 (1.06, 4.24)

HR (95% CI)

.58

.04

.38

.32

- p

1 .126 7.93

CRD vs MEL200-ASCT

MEL200–ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD cyclophosphamide lenalidomide dexamethasone; PFS, progression-free survival.

Subgroup Analysis of PFS

CRD vs MEL200-ASCT Median follow-up from consolidation : 47 months

MEL200–ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD cyclophosphamide lenalidomide dexamethasone; OS: overall survival

4-year OS MEL200-ASCT 86% CRD 73%

Overall survival

HR 2.40 95% CI 1.32-4.38 P= 0.004 0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60 Months

Prop

ortio

n of

pat

ient

s

Overall Maintenance

Lenalidomide Lenalidomide-Prednisone

Age ≤ 60 > 60

ISS I II III

Cytogenetic risk Standard High Missing

2.40 (1.32, 4.38)

1.46 (0.58, 3.65) 3.17 (1.41, 7.12)

0.89 (0.43, 1.86) 7.83 (2.60, 23.56)

4.59 (1.26, 16.75) 1.59 (0.66, 3.62) 1.42 (0.51, 3.93)

1.46 (0.54, 3.96) 1.79 (0.73, 4.37) 9.38 (1.21, 72.98)

HR (95% CI)

.21

.32

Interaction -

2.40 (1.32, 4.38)

1.46 (0.58, 3.65) 3.17 (1.41, 7.12)

0.89 (0.43, 1.86) 7.83 (2.60, 23.56)

4.59 (1.26, 16.75) 1.59 (0.66, 3.62) 1.42 (0.51, 3.93)

1.46 (0.54, 3.96) 1.79 (0.73, 4.37) 9.38 (1.21, 72.98)

HR (95% CI)

.001

.27

p

1 .0137 1 73

CRD vs MEL200-ASCT

MEL200–ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CRD cyclophosphamide lenalidomide dexamethasone; OS, overall survival.

Subgroup Analysis of OS

RP maintenance vs R maintenance

R, lenalidomide; P, prednisone

R A N D O M I Z A T I O N

2°

R maintenance 28-day courses until relapse

R: 10 mg/day, days 1-21

RP MAINTENANCE 28-day courses until relapse

R: 10 mg/day, days 1-21 P: 25 mg every other day

RP, lenalidomide-prednisone; R, lenalidomide; ISS, International Staging System; Percentage may not total 100 because of rounding

RP (n=117)

R (n=106)

Age median >60 years

57

56

ISS Stage I II III

51% 38% 11%

49% 39% 12%

Chromosomal Abnormalities t (4;14) t (14;16) del 17 High-risk [t (4;14) or t(14;16) or del17]

13% 4% 3%

19%

5% 7% 8%

18%

RP maintenance vs R maintenance Patients Characteristics

RP maintenance vs R maintenance

Median PFS RP 37.5 months R 28.5 months

Progression-free survival Median follow-up from maintenance 41 months

HR 0.84, 95% CI 0.59-1.20, P =.34

Months

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50

RP: lenalidomide-prednsone; R lenalidomide; PFS progression-free survival

Prop

ortio

n of

pat

ient

s

RP maintenance vs R maintenance

3-year OS RP 83% R 88%

Overall survival Median follow-up from maintenance 41 months

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 Months

HR 1.53, 95% CI 0.79-2.98, P =.21

Prop

ortio

n of

pat

ient

s

RP: lenalidomide-prednsone; R lenalidomide; OS overall survival

AE, adverse event; GI, gastrointestinal events; RP: lenalidomide prednisone; R lenalidomide.

% of patients

P=.193

P=1.000

P=.417

P=.174

P=.449

P=.301

P=.117

RP maintenance vs R maintenance Grade 3-4 AEs

P=.349

AE, adverse event; GI, gastrointestinal events; RP: lenalidomide prednisone; R lenalidomide.

% of patients

P=.0.004

RP maintenance vs R maintenance Dose reductions

• Main reasons for prednisone dose reduction: psychiatric disorders, endocrinopathy, hyperglicemia

• Main reasons for lenalidomide dose reductions:

RP: gastrointestinal AEs; R: hematological and dermatological AEs

Induction Consolidation Maintenance Rd MEL200-ASCT CRD RP R

N° of SPM - Hematologic - Solid - Skin cancer

0 3 1

0 0 0

0 0 0

0 4 4

0 3 3

Second Primary Malignancies

R, lenalidomide; D, dexamethasone; C, cyclophosphamide; P, prednisone; Rd, lenalidomide-dexamethasone; CRD, cyclophosphamide-lenalidomide-dexamethasone; MEL200-ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; RP lenalidomide-prednisone; AEs adverse

events; SPM, second primary malignancies

Rd four 28-day courses R: 25 mg/d, days 1-21

d: 40 mg/d, days 1,8,15,22

CRD six 28-day courses

C: 300 mg/sqm, days 1,8,15 R: 25 mg/d, days 1-21

D: 40 mg days 1,8,15,22

MEL200-ASCT two courses

M: 200 mg/m2 day -2 Stem cell support day 0

RP MAINTENANCE 28-day courses until relapse

R: 10 mg/day, days 1-21 P: 50 mg every other day

R MAINTENANCE 28-day courses until relapse

R: 10 mg/day, days 1-21

R A N D O M I Z A T I O N

1°

R A N D O M I Z A T I O N

2°

6 of 7 patients who developd skin cancer during maintenance received previous MEL200-ASCT

4 of 7 patients who developed a solid tumor during maintenance received previous CRD

CRD MEL200 P value Median PFS 28.6 months 43.3 months <0.001 4-year OS 86% 73% 0.004

RP maint. R maint. P value Median PFS 37.5 months 28.5 months 0.34 3-year OS 83% 88% 0.21

Conclusions

CRD, cyclophosphamide-lenalidomide-dexamethasone; MEL200, melphalan 200 mg/m2; R, lenalidomide, P prednisone; PFS, progression-free survival; OS, overall survival

CRD vs MEL200

RP vs R maintenance

Abstract 391: IFM/DFCI 2009 Study (US and France) Newly Diagnosed MM (N=1,360 combined)

RVDx3

RVD x 2

RVD x 5

Lenalidomide*

Melphalan 200mg/m2* +

ASCT

Induction

Consolidation

Maintenance

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

Calibration

MRD

MRD

MRD

MR

D @

CR

MR

D @

CR

Richardson et al, ASH 2014 *IFM vs. US: 1yr vs. Continuous

Best Response RVD arm

N=350 Transplant arm

N=350 p-value

CR 49% 59%

VGPR 29% 29% 0.02

PR 20% 11%

<PR 2% 1%

At least VGPR 78% 88% 0.001

Neg MRD by FCM , n (%) 228 (65%) 280 (80%) 0.001

ASH 2015 (Attal et al): IFM 2009: PFS (9/2015)

P < 0 .0 01

0

10

20

30

40

50

60

70

80

90

10 0

Pa

tie

nts

(%

)

3 5 0 296 2 28 12 8 24no H D T35 0 309 2 61 15 3 27H D T

N a t risk

0 12 24 36 48

M o n th s o f f o l lo w -u p

H D T

no H D T

3 yr PFS: 61% HDT vs 48 % no HDT

P N S

0

10

20

30

40

50

60

70

80

90

10 0

Pa

tient

s (%

)

3 5 0 33 8 3 20 24 4 56no H D T35 0 32 8 3 09 22 6 55H D T

N a t risk

0 12 24 36 48

M o n th s o f f o l lo w -u p

H D T

no H D T

IFM 2009: OS (9/2015)

3 yr OS: 88% both arms

IFM 2009: PFS.

0.20

0.97

0.53

0.69

Overall 158 / 350 204 / 350

<60 years 84 / 185 123 / 196 >=60 years 74 / 165 81 / 154

Stage I 44 / 118 58 / 115 Stage II 81 / 171 103 / 170 Stage III 33 / 61 43 / 65

Standard 87 / 213 118 / 212 High Risk 28 / 46 31 / 44

At least VGPR 93 / 180 122 / 190 PR SD PD 60 / 164 77 / 154

Transplant better RVD better 1 .4 .6 .8 1 1.2 1.4

Response after induction

Cytogenetics

ISS

Age

Nb of events / Nb of patients Transplant RVD Arm Hazard Ratio for

Progression or death p-value for interaction

ASH 2015: IFM 2009: Causes of Death (9/2015) RVD arm

N=48 Transplant

N=54

Myeloma, n (%) 40/48 (83%) 35/54 (65%)

Toxicity, n (%) 4/48 (8%) 9/54 (16%)

SPM (AML/MDS) 1/48 (2%) 6/54 (11%)

Others 3/48 (6%) 4/54 (7%)

IFM 2009: Conclusions This second interim analysis demonstrates that transplantation :

• Is feasible: 93% • Is associated with an acceptable Transplant Related Mortality: 1.4%. • Is associated with an increased rate of neg MRD (80% vs 65%, p<0.01). • Is associated with an improved 4-year PFS (47% vs 35%, p<0.001). • Is associated with an improved 4-year TTP (49% vs 35%, p<0.001).

A longer follow up is required to draw any conclusion concerning OS, • Since the 4-year survival is high in both arms (80% vs 83%). • However, transplantation is already associated with a reduced risk of

death due to myeloma, but has a higher rate of toxicity (acute and long term)

in the era of new drugs, Transplantation is

“A Standard of Care” but key questions remain.

Results of the US Trial remain Crucial. To confirm or not the PFS benefit of transplant using

maintenance until progression. To define the best Lenalidomide duration (inter trial):

• 1 year, what can be regarded as a consolidation strategy.

• Until progression, a real maintenance strategy. To answer the key question of OS (meta-analysis),

since none of the 2 trials has been powered for OS (but for PFS).

To better evaluate the benefit of transplant in cytogenetic subgroups… (meta-analysis). The remaining US effort is crucial for the 2 trials !

What did we learn? • In the era of novel agents, Autologous SCT remains

important in the management of newly diagnosed MM- improved PFS and maybe OS

• HOWEVER • Could this be affected by a longer maintenance

?(indefinite)- the importance of the US study.

• No benefit to adding steroid to lenalidomide maintenance- higher toxicity and trend towards decrease OS

IMAJEM (NCT01309334), 134 patients

RVDx3

RVD x 2

RVD x 5

Revlimid 1 year

Melphalan 200mg/m2* +

ASCT

CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg

RVDx3

CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg

Randomize

Revlimid 1 year

ARM A ARM B

ASCT at relapse

PET-CT / MRI at diagnosis

PET-CT / MRI after 3 cycles

PET-CT / MRI before maintenance

Abstract 395: Prospective Evaluation of MRI and PET-CT at Diagnosis and before Maintenance Therapy in Symptomatic Patients with Multiple Myeloma Included in

the IFM/DFCI 2009 Trial

Primary Endpoint: Compare MRI (spine and pelvis) vs PET-CT regarding the number of bone lesions at diagnosis. Secondary Endpoint: Prognostic Impact: PFS, OS

• At diagnosis MRI was positive in 127/134 (94.7%), and PET-CT in 122/134 (91%) patients, (McNemar test = 0.94, p-value = 0.33). • MRI of the spine and pelvis and whole-body PET-CT are

equally effective to detect bone involvement in symptomatic patients at diagnosis.

• Blindly reviewed by independent Committee: 2 radiologist, 2 nuclear medicine Physicians

Following 3 cycles of RVD. Impact on PFS

p = 0.04

78.7%

54.8%

PET-CT normalisation following 3 cycles of RVD. Impact on PFS (32% normalised)

61.6%

p = 0.29

MRI normalisation following 3 cycles of RVD Impact on PFS (3% normalised)

Following 3 cycles of RVD Impact on OS

p = 0.12

92.8%

81.8%

PET-CT normalisation following 3 cycles of RVD Impact on OS (32% normalised)

MRI normalisation following 3 cycles of RVD Impact on OS (3% normalised)

86.1%

p = 0.61

Before maintenance: Impact on PFS

p < 0.001

69%

51.6%

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

MRI normalisation before maintenance Impact on PFS (11% normalised)

83.9%

60.7%

p = 0.30

Before Maintenance: Impact on OS

p = 0.003

94.6%

69.9%

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

85.1%

p = 0.30

MRI normalisation before maintenance Impact on OS (11% normalised)

Adjusted on other prognostic factors p = 0.009 Univariate log-rank, p = 0.027

PET-CT pre-maintenance is a prognostic factor for PFS in Arm A: RVD x 8 cycles

Adjusted on other prognostic factors p = 0.01 Univariate log-rank, p = 0.01

PET-CT pre-maintenance is a prognostic factor for PFS in Arm B: frontline ASCT

Adjusted on other prognostic factors p = 0.008 Univariate log-rank, p < 0.001

PET-CT pre-maintenance is a prognostic factor for OS in Arm B: frontline ASCT

86 / 134 patients had also MRD evaluation pre-maintenance by CMF*

PET-CT pos

PET-CT neg

MRD pos

11 20

MRD neg

14 41

Fisher exact test: p = 0.33 McNemmar test: p = 0.39

* Avet-Loiseau et al. ASH 2015

p = 0.02

PFS for patients with negative PET-CT and negative MRD by flow

(47.7% of patients) pre-maintenance vs others

89.6%

54.5%

CONCLUSION - PET-CT and MRI are equally effective to detect bone involvement in symptomatic patients at diagnosis.

- MRI is not a good imaging method during follow-up - PET-CT after 3 cycles of RVD and pre-maintenance is a powerful prognostic marker for PFS - PET-CT pre-maintenance is a powerful prognostic marker for OS

Older Adult Myeloma • Upfront AHSCT is safe Elderly MM (#1989)

• Median 68 yo (64-74) • Standard induction AHSCT 82% consolidation • 2-year PFS 76% and OS 88%

• MRD negativity = survival advantage even in Older adults (#4181)

• Real World Management of Older adults • RVD-lite (#4217): ORR 90%, 1y PFS 95%, OS: NR • VMP-lite (#3043): Melphalan use at 6mg/m2 • GEM2010: Sequential VMP/Rd for high risk MM (#4243)

60

RELAPSED MULTIPLE MYELOMA

Abstract 29 Clinical Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma. Usmani et al

• ≥18 years of age, ECOG status ≤21,2

• GEN5011

• Open-label, multicenter, phase 1/2, dose-escalation and dose-expansion study

• Relapsed from or refractory to ≥2 prior lines of therapy including PIs and IMiDs

• SIRIUS2

• Open-label, multicenter, phase 2 study • Patients had received ≥3 prior lines of

therapy, including a PI and an IMiD, or were double refractory to a PI and an IMID

• DARA was approved by the FDA on November 16, 2015, based on these studies

16 mg/kg (n = 16)

8 mg/kg (n = 18)

16 mg/kg (n = 106)

Response evaluated

Randomization

Additional 90 patients enrolled at

DARA 16 mg/kg

SIRIUS

Safety and response evaluated

Dose-escalation

Doses from 0.005-24 mg/kg

(n = 32)

Dose-expansion

GEN501

16 mg/kg (n = 42)

8 mg/kg (n = 30)

1. Lokhorst HM, et al. N Engl J Med. 2015;373(13):1207-1219. 2. Lonial S, et al. Lancet. 2015. In press.

16 mg/kg N = 148

62

Baseline Characteristics 16 mg/kg

GEN501, Part 2 n = 42

SIRIUS n = 106

Combined N = 148

Median (range) age, y ≥65 years of age, n (%)

64.0 (44-76) 20 (48)

63.5 (31-84) 48 (45)

64 (31-84) 68 (46)

Female/male sex, % 36/64 51/49 53/47

ECOG score, n (%) 0 1 2

12 (29) 28 (67) 2 (5)

29 (27) 69 (65) 8 (8)

41 (28) 97 (66) 10 (7)

Median (range) time since diagnosis, y 5.8 (0.8-23.7) 4.8 (1.1-23.8) 5.1 (0.8-23.8)

Median (range) number of prior lines >3 prior lines, n (%)

4 (2-12) 26 (62)

5 (2-14) 87 (82)

5 (2-14) 113 (76)

Prior ASCT, n (%) 31 (74) 85 (80) 116 (78)

Prior PI, n (%) Bortezomib Carfilzomib

42 (100) 42 (100) 8 (19)

106 (100) 105 (99) 53 (50)

148 (100) 147 (99) 61 (41)

Prior IMiD, n (%) Lenalidomide Pomalidomide Thalidomide

40 (95) 40 (95) 15 (36) 19 (45)

106 (100) 105 (99) 67 (63) 47 (44)

146 (99) 145 (98) 82 (55) 66 (45)

63

Baseline Refractory Status 16 mg/kg

Refractory to, n (%)

GEN501, Part 2 n = 42

SIRIUS n = 106

Combined N = 148

Last line of therapy 32 (76) 103 (97) 135 (91)

Both PI and IMiD PI only IMiD only

27 (64) 3 (7) 4 (10)

101 (95) 3 (3) 1 (1)

128 (86) 6 (4) 5 (3)

PI + IMiD + alkylating agent 21 (50) 79 (75) 100 (68)

Bortezomib 30 (71) 95 (90) 125 (84)

Carfilzomib 7 (17) 51 (48) 58 (39) Lenalidomide 31 (74) 93 (88) 124 (84)

Pomalidomide 15 (36) 67 (63) 82 (55) Thalidomide 12 (29) 29 (27) 41 (28)

Alkylating agent only 25 (60) 82 (77) 107 (72)

64

Summary of Clinical Safety

• AEs were consistent with the individual GEN501 and SIRIUS studies; no new safety signals were identified

• 48% of patients had infusion-related reactions • 46%, 4%, and 3% occurred during the first, second, and subsequent

infusions, respectively

Treatment-emergent adverse event, n (%) Any grade

N = 148 Grade ≥3 N = 148

Fatigue 61 (41) 3 (2)

Nausea 42 (28) 0

Anemia 41 (28) 26 (18)

Back pain 36 (24) 3 (2)

Cough 33 (22) 0

Neutropenia 30 (20) 15 (10)

Thrombocytopenia 30 (20) 21 (14)

Upper respiratory tract infection 30 (20) 1 (<1)

65

Efficacy in Combined Analysis

18%

10%

1% 2%

0

5

10

15

20

25

30

35

16 mg/kgO

RR

, %

PR VGPR CR sCR

ORR = 31% 16 mg/kg (N = 148)

n (%) 95% CI

Overall response rate (sCR+CR+VGPR+PR) 46 (31) 23.7-39.2

Best response sCR CR VGPR PR MR SD PD NE

3 (2) 2 (1)

14 (10) 27 (18)

9 (6) 68 (46) 18 (12)

7 (5)

0.4-5.8 0.2-4.8

5.3-15.4 12.4-25.4 2.8-11.2

37.7-54.3 7.4-18.5 1.9-9.5

VGPR or better (sCR+CR+VGPR) 19 (13) 7.9-19.3

CR or better (sCR+CR) 5 (3) 1.1-7.7

• ORR = 31% • ORR was consistent in subgroups including age, number of prior lines of therapy,

refractory status, or renal function 66

3% CR or better

13% VGPR or

better

N = 148

Progression-free Survival

Responders: NE (7.4, NE)

MR/SD: 3.2 (2.8-3.7) months

PD/NE: 0.9 (0.9-1.0) months

67

0

Patie

nts

prog

ress

ion-

free

and

aliv

e, %

2 6 8 12 14 18 20

Time from first dose, months Patients at risk

Responders MR/SD PD/NE

0

25

50

75

100

4 10 16

Responders

MR/SD

PD/NE

46 77 25

46 45 0

35 13 0

27 3 0

13 1 0

5 0 0

3 0 0

0 0 0

41 21 0

14 2 0

3 0 0

Overall Survival

• For the combined analysis, median OS = 19.9 (95% CI, 15.1-NE) months • 1-year overall survival rate = 69% (95% CI, 60.4-75.6)

68

0

Patie

nts

aliv

e, %

2 6 8 12 14 18 22

Time from first dose, months Patients at risk

Responders MR/SD PD/NE

Responders

0

25

50

75

100

4 10 16

MR/SD

PD/NE

46 77 25

46 74 16

45 63 11

44 57 7

42 47 5

29 37 4

3 1 0

0 0 0

46 67 12

43 53 7

15 10 1

20

13 5 1

Responders: NE (19.9, NE)

MR/SD: 17.5 (15.1-NE) months

PD/NE: 3.7 (1.7-7.6) months

Conclusions • As a single agent, DARA induced rapid, deep, and durable responses in a heavily pretreated/highly refractory

population • Remarkable depth of response observed in patients

refractory to newer agents, including pomalidomide and carfilzomib

• DARA conferred an OS benefit even in patients who achieved stable disease or minimal response

• Updated analysis of the combined dataset of GEN501 and SIRIUS did not identify any new safety signals

• DARA has immune-mediated and immunomodulatory mechanisms that may be contributing to a survival benefit

69

Daratumumab in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed or Relapsed and Refractory Multiple Myeloma: Updated Results of a Phase 1/2 Study (GEN503). Plesner et al

DARA* IV 2-16 mg/kg + LEN PO 25 mg (Days 1-21) +

DEX PO 40 mg QW

DARA* IV 16 mg/kg + LEN PO 25 mg (Days 1-21) +

DEX PO 40 mg QW

Key eligibility • Measurable disease by M-protein • Patients refractory or intolerant to

LEN were excluded Part 1

• Relapsed MM following 2 to 4 prior lines of therapy

Part 2 • Relapsed MM following ≥1 prior

line of therapy (no upper limit)

Endpoints Primary endpoint

• Incidence of adverse events Key secondary endpoints

• Rate of response • Pharmacokinetics

• Time to progression • Duration of response

• Progression-free survival

Part 1 - Dose escalation (N = 13)

Open-label, IV infusions (28-day cycle) Dose escalation: 3 + 3 scheme

Part 2 - Expansion cohort (N = 32)

Open-label, single-arm IV infusion at 16 mg/kg (28-day cycle)

*QW for Months 1-2, Q2W for Months 3-6, and Q4W beyond.

70

Baseline Characteristics N = 32

Median (range) age, y ≥65 years of age, n (%)

60 (41-76) 9 (28)

Female/male sex, % 31/69

ECOG score, n (%) 0 1 2

19 (59) 12 (38) 1 (3)

Median (range) time since diagnosis, y 3.2 (0.9-12.7)

Median (range) number of lines of prior therapy ≥2 prior lines of therapy, n (%)

2 (1-3) 17 (53)

Refractory to last line of therapy 7 (22)

Prior autologous stem cell transplant, n (%) 25 (78)

Prior PI, n (%) Bortezomib

29 (91) 28 (88)

Prior IMiD, n (%) Lenalidomide Thalidomide

23 (72) 11 (34) 14 (44)

Prior chemotherapy, n (%) Alkylating agents Anthracyclines

32 (100) 29 (91) 15 (47)

71

Overall Response Rate: DARA + LEN/DEX

N = 32 n (%) 95% CI

Overall response rate (sCR+CR+VGPR+PR)

26 (81) 63.6-92.8

Best response sCR CR VGPR PR

8 (25) 3 (9) 9 (28) 6 (19)

11.5-43.4 2.0-25.0 13.7-46.7 7.2-36.4

VGPR or better (sCR+CR+VGPR)

20 (63) 43.7-78.9

CR or better (sCR+CR) 11 (34) 18.6-53.2

19%

28%

9%

25%

0

10

20

30

40

50

60

70

80

90

100

16 mg/kg

OR

R, %

sCR CR VGPR PR

ORR = 81%

34% CR or better

63% VGPR or

better

• ORR = 81% • Clinical benefit rate (ORR + minimal response) = 88%

N = 32

72

Progression-free Survival: DARA + LEN/DEX

0

Patie

nts

prog

ress

ion-

free

and

aliv

e, %

3 6 9 12 15 18 21

Time from first dose, months

32 28 26 24 21 13 2 0 Patients at risk

0

20

40

60

80

100

18-month PFS rate = 72% (95% CI, 51.7-85.0)

73

Overall Survival:DARA + LEN/DEX

0

Patie

nts

aliv

e, %

3 6 9 12 15 18 21

Time from first dose, months

32 32 31 29 28 18 6 0 Patients at risk

0

20

40

60

80

100

18-month OS rate = 90% (95% CI, 73.1-96.8)

74

Conclusions • DARA + LEN/DEX induced rapid, deep, and durable

responses • At a median follow-up time of 15.6 months, ORR was 81%

including 28% VGPR and 34% CR/sCR • Median time to first response was 1 month • PFS rate of 72% at 18 months • OS rate of 90% at 18 months

• DARA can be safely combined with LEN/DEX with no additional safety signals

• Randomized phase 3 studies of DARA are ongoing: • DARA + LEN/DEX in relapsed/refractory patients (POLLUX)* • DARA + LEN/DEX in newly diagnosed patients (MAIA)†

*ClinicalTrials.gov Identifier: NCT02076009 †ClinicalTrials.gov Identifier: NCT02252172 75

Open-label, Multicenter, Phase 1b Study of Daratumumab in Combination With Pomalidomide and Dexamethasone in Patients With ≥2 Lines of Prior Therapy and Refractory or Relapsed and Refractory Multiple Myeloma (MM). Ajai et al

Treat 6 patients with DARA + POM-D

If ≤1 patient has DLTs

Enroll 6 additional patients

Expand up to 88 patients

Eligibility criteria • Refractory to last line of therapy • ≥2 prior lines of therapy, including

2 consecutive cycles of lenalidomide and bortezomib

• Pomalidomide naïve • ECOG score ≤2 • Absolute neutrophil count

≥1.0×109/L, and platelet count ≥75×109/L for patients with <50% plasma cells (>50×109/L, otherwise)

• Calculated creatinine clearance ≥45 mL/min/1.73 m2

76

DARA* IV 16 mg/kg + Pomalidomide 4 mg (Days 1-21) +

Dexamethasone 40 mg QW

Open-label, multicenter, six-arm, Phase 1b study

(28-day cycles)

*QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W beyond.

Prior Therapy Status • Patients were heavily pretreated and highly refractory per inclusion

criteria DARA + POM-D

N = 98 Median (range) time since MM diagnosis, y 5.2 (0.4-16.0)

N = 97 Median (range) number of prior lines of therapy 4.0 (2-13) Prior Autologous stem cell transplant PI Carfilzomib Bortezomib IMiD

73 (75)

97 (100) 31 (32) 96 (98)

97 (100)

N = 98 Refractory to PI Bortezomib Carfilzomib Lenalidomide PI and IMiD

74 (76) 65 (66) 29 (30) 87 (89) 66 (67)

Overall Response Rate:DARA + POM-D

• ORR = 71% • ORR in double-refractory patients = 67% • Clinical benefit rate (ORR + minimal response) = 73%

DARA + POM-D (N = 75)

n (%) 95% CI

Overall response rate (sCR+CR+VGPR+PR) 53 (71) 59.0-80.6

Best response sCR CR VGPR PR MR SD PD

4 (5) 3 (4)

25 (33) 21 (28)

2 (3) 17 (23)

3 (4)

1.5-13.1 0.8-11.2

22.9-45.2 18.2-39.6

0.3-9.3 13.8-33.8 0.8-11.2

VGPR or better (sCR+CR+VGPR) 32 (43) 31.3-54.6

CR or better (sCR+CR) 7 (9) 3.8-18.3

ORR = 71%

78

43% VGPR or

better

9% CR or better

28%

33%

4% 5%

0

10

20

30

40

50

60

70

80

16 mg/kg

OR

R, %

PR VGPR CR sCR

N = 75

Progression-free Survival at 6 Months: DARA + POM-D

79

0

Patie

nts

prog

ress

ion-

free

and

aliv

e, %

2 6

Time from first dose, months

0

20

60

80

100

4

40

Patients at risk 98 67 39 19

6-month PFS rate = 66% (95% CI, 52.3-75.9)

• Median follow-up of 4.2 months

Abstract 28 Eloquent-2 Update: A Phase 3, Randomized, Open-Label Study of Elotuzumab in Combination with Lenalidomide/Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma - 3-Year Safety and Efficacy Follow-up Dimopoulos et al

• ELOQUENT-2 is an open-label, randomized, multicenter, phase 3 trial

• Statistical analysis • Threshold for interim OS significance was 0.014 based on 295/427 events required for final analysis

Patients

• RRMM

• 1–3 prior lines of therapy

• Prior Len

permitted in 10% of patients (if not

refractory)

Elotuzumab plus Len/Dex (E-Ld):

n=321 • Elo: Cycles 1 and 2 weekly, then

every other week, 10 mg/kg IV • Len: D1–21, 25 mg PO

• Dex: weekly equivalent, 40 mg

Endpoints

Co-primary • PFS • ORR

Others • OS

• Safety • Duration of

response • Quality of life

Database lock: November 2014

(ASCO/EHA 2015) Minimum follow-up: 24 months

Database lock: August 2015 (ASH 2015)

Minimum follow-up: 33 months

June 2011 start

Premedication administered prior to elotuzumab infusion to mitigate infusion reactions

Len/Dex (Ld): n=325

• Len: D1–21, 25 mg PO • Dex: weekly, 40 mg PO

ELOQUENT-2: 2-Year Follow-up

Co-primary endpoint: ORR E-Ld Ld

% 95% CI

79 74, 83

66 60, 71

1. Lonial S et al. N Engl J Med 2015;373:621–31.

ELOQUENT-2 demonstrated clinical benefits of E-Ld compared with lenalidomide and dexamethasone (Ld) alone1

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

38 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 No. of patients at risk:

E-Ld Ld

321 325

303 295

279 249

259 216

232 192

215 173

195 158

178 141

157 123

143 106

128 89

117 72

85 48

59 36

42 21

32 13

12 7

7 2

57%

68%

27%

41%

1-year PFS 2-year PFS

PFS (months)

Prob

abili

ty p

rogr

essi

on fr

ee

1 0

0 0

Hazard ratio, 0.7 (95% CI, 0.57-0.85)

P<0.001

Co-primary endpoint: PFS

From N Engl J Med, Lonial S et al, Elotuzumab therapy for relapsed or refractory multiple myeloma, 373, 621–31. Copyright © 2015, Massachusetts Medical Society. Reprinted with permission

E-Ld Ld

Characteristic E-Ld (n=321) Ld (n=325) International Staging System disease stage,* n (%)

I 141 (44) 138 (42) II 102 (32) 105 (32) III 66 (21) 68 (21)

Cytogenetics (FISH),*† n (%)

del(17p) Yes 102 (32) 104 (32) No 213 (66) 218 (67)

t(4;14) Yes 30 (9) 31 (10) No 285 (89) 290 (89)

Prior regimens, median (range) 2 (1–4) 2 (1–4) Prior therapies, n (%)

Bortezomib 219 (68) 231 (71) Melphalan (PO or IV) 220 (69) 197 (61) Thalidomide 153 (48) 157 (48) Lenalidomide 16 (5) 21 (6)

Response to most recent line of therapy,‡ n (%)

Refractory 113 (35) 114 (35) Relapsed 207 (65) 211 (65)

Prior stem cell transplantation, n (%) 167 (52) 185 (57)

Baseline Demographics and Disease Characteristics

*‘Not reported’ not shown; †No minimum cut-off for del(17p) positivity; ‡Response for 1 E-Ld patient unknown. FISH=fluorescence in situ hybridization. From N Engl J Med, Lonial S et al, 373, 621–31. Copyright © 2015, Massachusetts Medical Society. Reprinted with permission

Treatment Summary E-Ld (n=318) Ld (n=317)

Number of treatment cycles, median (Q1–Q3) 19 (9–37) 14 (6–25) Patients on treatment, n (%) 83 (26) 43 (14) Reasons off treatment Disease progression 153 (48) 161 (51) Study drug toxicity 30 (9) 44 (14) Adverse event unrelated to study drug 22 (7) 32 (10) Other* 31 (10) 36 (11)

Patients receiving full dose (relative dose intensity ≥90%), % Elotuzumab 83 – Lenalidomide 51 51 Dexamethasone 46 47

*‘Other’ includes: patient request, patient withdrew consent, other, death, patient no longer met criteria, poor/non-compliance

Extended Progression-Free Survival

E-Ld Ld

HR 0.73 (95% CI 0.60, 0.89); p=0.0014

Median PFS (95% CI)

19.4 mo (16.6, 22.2)

14.9 mo (12.1, 17.2)

E-Ld-treated patients had a 27% reduction in the risk of disease progression or death and a 44% relative improvement in PFS vs Ld-treated patients at 36

months

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

No. of patients at risk: E-Ld Ld

321 325

293 266

259 215

227 181

171 130

144 106

125 80

107 67

94 60

85 51

59 36

34 15

19 7

8 3

PFS (months)

Prob

abili

ty p

rogr

essi

on fr

ee

3 0

195 157

E-Ld Ld 0.1

1-year PFS 2-year PFS Extended follow-up

0 0

68%

41%

26%

57%

27% 18%

Progression-Free Survival

Parameter Progression-free survival

E-Ld Ld Relative difference

Median PFS (months) 19.4 14.9 1-year PFS (%) 68 57 19

2-year PFS (%) 41 27 52

3-year PFS (%) 26 18 44 2-year follow-up

Hazard ratio (95% CI)

0.70 (0.57–0.85)

p=0.0004 3-year follow-up

Hazard ratio (95% CI) 0.73 (0.6–0.89)

Overall Survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

No. of patients at risk: E-Ld Ld

321 325

314 305

303 287

291 269

283 255

266 241

250 228

239 218

224 208

217 200

196 184

190 171

152 134

95 88

48 41

15 17

1-year OS 2-year OS

OS (months)

Prob

abili

ty a

live

5 3

0 0

E-Ld

Ld

No. of patients at risk:

3-year OS E-Ld Ld

HR 0.77 (95% CI 0.61, 0.97; 98.6% CI 0.58; 1.03); p=0.0257

Median OS (95% CI)

43.7 mo (40.3, NE)

39.6 mo (33.3, NE)

Interim survival analysis demonstrated sustained benefit of E-Ld vs Ld that was maintained over time

Adverse Events Of Special Interest

• Most infusion reactions were Grade 1 or 2 and occurred during the first treatment cycle • There were no Grade 4 or 5 infusion reactions

Adverse event, n (%)

E-Ld (n=318) Ld (n=317) Any

Grade Grade

3–4 Grade

5 Any

Grade Grade

3–4 Grade

5 Infusion reactions 33 (10) 4 (1) 0 - - -

Cardiac failure 3 (1) 1 (0.3) 0 5 (2) 2 (1) 0

GI disorders 256 (81) 33 (10) 0 214 (68) 30 (10) 1 (0.3)

Peripheral neuropathy 48 (15) 5 (2) 0 27 (9) 5 (2) 0

Respiratory disorders 201 (63) 34 (11) 2 (1) 169 (53) 25 (8) 1 (0.3)

Renal/urinary disorders 78 (25) 13 (4) 1 (0.3) 58 (18) 14 (4) 1 (0.3)

Deep vein thrombosis 26 (8) 20 (6) 0 13 (4) 8 (3) 0

Hypertension 33 (10) 4 (1) 0 22 (7) 7 (2) 0

Summary • The addition of elotuzumab, an immunostimulatory monoclonal antibody, to

Ld demonstrated an overall clinically relevant benefit in PFS vs Ld alone that was maintained over time • Relative improvement in PFS at 3 years was 44% in the E-Ld vs Ld-treated

patients • Time to next treatment was delayed in the E-Ld arm vs the Ld arm

• Interim 3 year overall survival analysis demonstrated a strong trend in the

long-term benefit of E-Ld vs Ld • PFS benefit was associated with a reduction in deaths in the E-Ld arm vs

the Ld arm

• The updated safety and tolerability data are consistent with previous findings, confirming that there are minimal incremental toxicities associated with the addition of elotuzumab

Study Drugs # patients Median # priors

ORR (%) Comments/ Toxicities

San Miguel #505

Pembrolizumab len/dex

50(26 evaluable)

4 (1-5) 65 (+23% SD) Hematologic (23-47%)

Badros #506 Pembrolizumab Pomalidomide/dex

33 3(2-5) 60 (+30% SD) 4 pt dose reduction

*Efebera # 1838

MDV9300(Pidilizumab, CT011/len

13 2(2-11) 61.5% Steroid free. No infusion reaction

*Sbarov #1835 Reolysin/carlfizomib/dex

12 (1 pt dialysis) 2(1-4) 75% clinical benefit (includes SD)

Flu-like sx, 1 pt myocarditis

Shah #378 Oprozomib(oral)/pom/dex

31 4(1-22) 71% clinical benefit (includes SD)

Gr3 mucositis/rash

Vorhees et al Ixazomib/pom/dex 22 3(2-10) 55 (+30% SD) Dose reduction 50%. Hem tox

Ramasamy #374

Pomalidomide/dex in renal insuff +dialysis

39 4 This study focused on tolerability

Max dose 4 mg pom can be safely used in HD pts. GCSF in 53%

Shah #376 Filanesib(FIL) iv (Arry520)/Carlfizomib (CFZ)

45 eval. Carlf naïve

5(1-15) 44 (+44% SD). No response in 11 CFZ refractory

Pts received scheduled GCSFx5 after each dosing.

Zonder #728 Filanesib/Carlfizomib vs CFZ.

30 CFZ+FIL 20 CFZ. All CFZ naive

4(2-11) 37% vs 20% (clinical benefit)

Chari #4226 Panobinostat/len/dex 26 2 73% clinical benefit(includes SD)

No doses held or reduced for GI Tox.

Martin #509 Isatuximab (anti CD38)

96 5(2-140

Raab #3035 Mor201(anti-CD38) 44 4(2-11)

Relapse/Refractory Studies

Other Drugs in relapse/refractory MM

• Ibrutinib/len/dex: all Oral. will be in Phase II with Alliance this Yr • AR42 (HDAC inhibitor)/Pom/dex: all Oral. Will be opening soon • Cpi-0610: BET inhibitor • Melflufen: peptidase Targeted Therapy • TG02: oral CDK9 inhibitor • Selinexor( (KPT-330): XP01 inhibitor • Ricolinostat (ACY-1215): HDAC6 inhibitor • CD-839: First in Class Glutaminate inhibitor • Marizomib: proteosome inhibitor (IV) • Linsitinib(OSI 906): IGF-1 receptor inhibitor • Sotatercept(ACE-011): activin type IIa receptor fusion protein: improves Hgb

and bone mineral density

Toxicities • Cytokine release storm:

• Fever, tachycardia, hypotension, elevated LFTs, elevated CK, elevated IL-6

• Cytopenia

Smoldering Myeloma(SMM) • #4246: PVX-410 multi-peptide vaccine alone (12 pts) or +len (10 pts)

• SMM at risk for progression, HLA-2+ • Vaccine q 2 wks x 6 doses (0.1mg/peptide or 0.2 mg)+ 3 cycles len 25 mg d1-21 q 28 days • Followed x 12 mos

• Vaccine alone (12 pts): 5 progressed, 7 SD • Vaccine +len (9 evaluable): 5 MR/PR, 3SD, 1 progressed

• Randomized Phase 2 Trial to Evaluate Three Daratumumab Dose Schedules in Smoldering Multiple Myeloma- ongoing

• Alliance Proposals: lenalidomide alone, len/dex vs placebo

AL amyloid • #732 Wechalekar: case control study of oral Doxycycline(possible cardio

protective effect) concurrent with chemo vs control +chemo • Doxy 100 mg bid (30 pts) vs 73 matched control (matched to cardiac stage,

NT proBNP, age, dFLC).

• #188 Langer et al: Chimeric Fibril-Reactive Monoclonal Ab 11-1F4

• Relapsed pts, EF >40%, Ivsd <2.5 cm, CrCl >30 cc/min, bil <3.0mg/dl • Given once ( dose 0.5 – 500 mg/m2): MTD was 500 • 8 pts median stage 2, median organs involved 2 • 4 organ response: 3 decreased NT-proBNP, 1 decreased diarrhea

Median fu 13 mos

Doxy duration median 6 (1-24 mos)

Control P-value

Heme CR 56% 35%

VGPR 10 8

PR 30 37

At 2.3 mos 16% died 72% died

12 and 24 mos OS

82 and 82% 53 and 40%

<0.0001

WHAT DO YOU REMEMBER?

What is the preferred regimen for newly Dx MM eligible for autologous SCT A. A: Bortezomib, lenalidomide,

dex (VRD) B. B: Bortezomib,

cyclophosphamide, dex (VCD, CyBord)

C. C: Bortezomib, melphalan, dex (VMD)

D. D: Melphalan, dex, Lenalidomide (MDR)

A: Borte

zomib, le

nalidom...

B: Borte

zomib, c

yclopho...

C: Borte

zomib, m

elphalan...

D: Melphalan, d

ex, Le

nal...

0% 0%0%0%

What is the appropriate length of Maintenance?

A. A: 6 months B. B: 1 year C. C: minimum 3 years D. D: Until progression/relapse

A: 6 m

onths

B: 1 ye

ar

C: minim

um 3 years

0% 0%0%0%

How Long is Lenalidomide Maintenance? • Minimum – 3 years. • Disease Relapse/progression – many ongoing studies

103

CALGB 100101 McCarthy NEJM 2012

IFM Attal NEJM 2012

MM0-15 Palumbo NEJM MPR-R vs MPR (non SCT)

IFM VRD chemo vs auto SCT

DFCI VRD chemo vs auto SCT

BMT/CTN 0702

BMT/CTN 0702- LTFU

Length maintenance

Until relapse/prog

Median 2 yrs (1-3)

Until relapse/prog

1 year Until relapse/prog

3 years Until relapse/prog

Median F/U 48 mos 45 mos 30 mos 39 mos

PFS-median 53 mos vs 27 placebo

41 mos vs 23 31 mos vs 14

3-yr PFS 61% auto arm

OS NR NR 45.2 mos

3 yr OS 88% 88% 70% 88%

SPM 7.8 % vs 2.6% placebo

8 vs 4 % 7 vs 3% 11%

Induction regimen

any any MPR VRD VRD any any

BMT CTN 0702: SCHEMA

Lenalidomide * Maintenance

Lenalidomide Maintenance**

Lenalidomide Maintenance**

N=750 pts (250 in each arm)

Register and Randomize

MEL 200mg/m2 VRD x 4*

MEL 200mg/m2

Bortezomib 1.3mg/m2 days 1, 4, 8,11

Lenalidomide 15mg days 1-15 Dexamethasone 40mg

days 1, 8, 15

**Lenalidomide x 3years : 10mg /d for 3 cycles , then 15 mg /d

MM patients on Hemodialysis are excluded from autologous SCT A. A: True B. B: False

A: True

B: False

0%0%

Upfront Trials: OSU-14069 Phase III Comparing Conventional Dose RVD to High-Dose w PSCT in Initial Management of

Myeloma OSU-14298 Ph 3 Comparing DRd vs Rd in Sbjcts w/ Previously Untreated MM Ineligible for High Dose Therapy

OSU-15003 Randomized Phase 2 Trial to Evaluate Three Daratumumab Dose Schedules in Smoldering Multiple Myeloma

Relapsed/Refractory Trials: ALLIANCE-A061202 Ph I/II Pom, Dex & Ixazomib vs Pom + Dex for MM Refractory to Lenalidomide and PI-based

Therapy OSU-13128 Ph I/II Lenalidomide in Combination w/ Anti-PD-1 mab CT-011 in Pts w/ Relapsed/Refractory MM

OSU-14049 Ph I Elotuzumab in Combination w/ either Lirilumab or Urelumab in Subjects with Multiple Myeloma

OSU-15004 (opening Feb) A phase 1b trial of AR-42 with Pomalidomide in Relapsed Multiple Myeloma

OSU-15196 (opening Feb) Ph1b Durvalumab Either As Monotherapy Or In Combination w Pom with or without Low Dose Dex In Subjects with Relapsed / Refractory MM

BMT Trials:

OSU-15124 (opening Feb) Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies

Trials for all MM:

BMT-CTN1302 Ph II Placebo Controlled Maintenance Ixazomib after Allogeneic HSCT for High Risk Multiple Myeloma

OSU-15045 BMT/CTN 1401 (pending)

Ph II of IRD for Consolidation Therapy followed by Ixazomib or Lenalidomide for Multiple Myeloma Phase II Multicenter Trial of Single Autologous Hematopoietic Cell Transplant Followed by Lenalidomide Maintenance for Multiple Myeloma with or without Vaccination with Dendritic Cell /Myeloma Fusions

Enrolling Studies at OSU

We Thank YOU for your Referrals

Don Benson MD ,PhD Associate Professor of Medicine Myeloma Program, 614-293-8605 Don.Benson@osumc.edu

Craig Hofmeister MD, MPH Associate Professor of Medicine Myeloma Program 614-293-3507 Craig.Hofmeister@osumc.edu

Yvonne Efebera MD, MPH

Associate Professor of Medicine. Myeloma Program 614-293-2268 yvonne.efebera@osumc.edu

Ashley Rosko MD Assistant professor of medicine Myeloma Program 614-293-2268 Ashley.rosko@osumc.edu