Developments in the Treatment of Multiple Myeloma

Kenneth C. Anderson, M.D.

Kraft Family Professor of MedicineHarvard Medical School

Director, Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute

Conflict of Interest: Kenneth C. Anderson, M.D.

Consultancy: Celgene, Onyx, Sanofi Aventis, and Gilead

Scientific Founder: Acetylon, Oncopep

Integration of Novel Therapy Into Myeloma Management

Bortezomib, Lenalidomide, Thalidomide, Doxil, Carfilzomib, Pomalidamide

Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo

Effective in relapsed/refractory, relapsed MM and now part of induction, consolidation, and maintenance therapy

Nine FDA approvals in the last decade and median survival prolonged from 2-3 yrs to at least 5-7 yrs, with additional prolongation seen from maintenance

New approaches needed to treat and ultimately prevent relapse

Chromosomes and Prognosis in Multiple Myeloma

For conventional low and high dose theapy:

Nonhyperdiploid worse prognosis than hyperdiploid t(11;14), hyperdiplody -standard risk t(4;14), t(14;16),t(14;20), del(17p), del(13q14)-high risk

For novel treatmentsBortezomib, but not lenalidomide, can at least partially overcome t(4;14), del(13q14)-

del(17p) p53 remains high risk

Stewart AK, Richardson PG, San Miguel JF Blood 2009

Combinations in the Upfront Treatment of MM

Lenalidomide and Bortezomib/Lenalidomide-BasedConsolidation

Study details Response data

IFM 2005-021

•Len consolidation (2 mos)•Maintenance randomization: Len vs placebo

IFM 20082

•VRD induction•ASCT•VRD consolidation (2 cycles)•Len maintenance

1Attal et al. Haematologica 2011; 96 (s1): S23; oral presentation at IMW 20112Roussel et al. ASH 2010 (Abstract 624), oral presentation

n=572 Pre-consolidation

Post-consolidation p

CR (IF–) 14% 20% <0.0001

≥ VGPR 58% 67% <0.0001

n=31 Post-induction

Post-ASCT

Post-consolidation

sCR 13% 26% 38%

CR 10% 10% 10%

≥ VGPR 62% 68% 84%

≥PR 94% 91% 94%

5

CALGB 100104:LEN Maintenance significantly prolonged PFS & OS vs. placebo

ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo.

McCarthy PL. N Engl J Med. 2012;366:1770-1781.

PFS OS

• There was significant prolongation of both PFS (HR 0.49, 95% CI, 0.41–0.58, p<0.001) and OS (HR 0.77, 95% CI, 0.62–0.95, p=0.013) with LM vs. placebo/no maintenance

Oral Abstract #407 - Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized TrialsMonday, December 9, 2013: 11:30 AM 393-394

Lenalidomide Maintenance Therapy Meta-Analysis

Singh M, et al. ASH 2013. Abstract 407.

Randomization

NDMM, TE, sge 18–65 y

CAD + GCSF

3 x VAD

CAD + GCSF

3 x PAD

MEL 200 + PBSCT

In GMMG 2nd MEL 200 + PBSCT

MEL 200 + PBSCT

In GMMG 2nd MEL 200 + PBSCT

Thalidomidemaintenance 50 mg/day for 2 years

Allogeneic Tx

Bortezomib Maintenance1.3 mg/m2 / 2 weeks for 2 years

Bortezomib induction and maintenance in ASCT

Bortezomib 1.3 mg/m2i.v.

Doxorubicin 9 mg/m2

Dexameth 40 mg

Sonneveld et al, ASH 2013

Results

• Bortezomib-based treatment consistently improves PFS (median 27 m vs 36 m) and OS (median 84 m vs not reached, p=0.05) in patients with newly diagnosed MM who are transplant eligible

• Bortezomib significantly improves the long-term outcome of patients presenting with renal failure (p<0.001)

Sonneveld et al, ASH 2013

Carfilzomib With Thalidomide and Dexamethasone in ASCT

Induction (4 28-day cycles)

Carfilzomib, 20/27 mg/m2

Days 1,2,8,9,15,16

Dexamethasone, 40 mgDays 1,8,15,21

Thalidomide, 200 mgDays 1-28

Intensification* (1 cycle)

Phase IIopen-labeldose-escalationtrial (N=70)

*High-dose melphalan 200 mg/m2 plus ASCT

Sonneveld P, et al. ASH 2013. Abstract 688.

Carfilzomib, 27 mg/m2

Days 1,2,8,9,15,16

Dexamethasone, 40 mgDays 1,8,15,21

Thalidomide, 50 mgDays 1-28

Consolidation(4 28-day cycles)

Carfilzomib 27 mg/m2 dose escalation: Cohort 1 treatment as above; Cohort 2 to 36 mg/m2; Cohort 3 to 45 mg/m2; Cohort 4 to 56 mg/m2.

Carfilzomib/Thalidomide/ Dexamethasone: Response and AEs

Patient Response, %

High-risk* Patients Standard Risk Patients

All Patients

CR/sCR 57 48 51

≥VGPR 90 76 84

PR 90 90 96

*t(4;14) and/or del(17p) and/or 1q and/or ISS3.

• Grade 3/4 AEs ≥ 5% by carfilzomib dose:• 20/27 mg/m2=GI toxicity, 16%, skin, 12%; metabolism, 10%;

myelotoxicity, 8%; fatigue, 8%; cardiovascular, 6%• 20/36 mg/m2=metabolism, 10%; myelotoxicity, 8%; GI

toxicity, 5%• Neuropathy < 5% in both cohorts

Sonneveld P, et al. ASH 2013. Abstract 688.

Impact of Novel Agents in the Treatment of Elderly Pts with Newly Diagnosed MM

Substantial improvements in PFS and OS

*Median OS not reachedN/A: not available

7San Miguel et al. N Engl J Med 2008; 359(9): 906–917; Supplementary Appendix8Mateos et al. J Clin Oncol 2010; 28(13): 2259-22669Palumbo et al. ASH 2010 (Abstract 622)10Mateos et al. Lancet Oncol 2010; 11(10): 934-94111Palumbo et al. ASH 2010 (Abstract 620)

1Palumbo et al. Blood 2008; 112:3107–31142Facon et al. Lancet 2007; 370:1209–12183Hulin et al. J Clin Oncol 2009; 27:3664-704Waage et al. Blood 2010; 116:1405-125Wijermans et al. J Clin Oncol 2010; 28:3160-66Beksac et al. Eur J Haematol 2011;86:16-22

Median PFS (mos) Median OS (mos)

MP1-8 11–20 29.1–49.4

MPT1-6 15–27.5 29–51.6

VMP7,8,11 21.7–27.4 68.5% (3-yr OS)*

MPR-R9 31 N/A

VMP-VT/VP10 34 74% (3-yr OS)*

VMPT-VT11 37.2 85% (3-yr OS)*

Facon T, et al. Blood. 2013;122:abstract 2.

RA

ND

OM

IZA

TIO

N 1

:1:1

Arm BRd18

Arm CMPT

LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN 0.25mg/kg D1-4/42PREDNISONE 2mg/kg D1-4/42THALIDOMIDE 200mg D1-42/42

PD

, OS

an

d

Su

bse

qu

ent

anti

-MM

Tx

PD

or

Un

acce

pta

ble

To

xici

ty

Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4

15

• Stratification: age, country and ISS stage

1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.

FIRST Trial: Study Design

LEN + Lo-DEX ContinuouslyLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

Arm AContinuous Rd

ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival

Facon T, et al. Blood. 2013;122:abstract 2.

Median PFS

Rd (n=535)

25.5 mos

Rd18 (n=541)

20.7 mos

MPT (n=547)

21.2 mos

Rd 535 400 319 265 218 168 105 55 19 2 0

Rd18 541 391 319 265 167 108 56 30 7 2 0

MPT 547 380 304 244 170 116 58 28 6 1 0

Hazard ratio Rd vs. MPT: 0.72; P = 0.00006 Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349

Time (months)

Pat

ien

ts (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

16

42% (Rd)

23% (Rd18) 23% (MPT)

FIRST Trial: Final Progression-free Survival

mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone.

FIRST Trial: Consistent PFS Benefit Across Subgroups

ITT, intention to treat; ITT comparison for continuous Rd vs. MPT

Facon T, et al. Blood. 2013;122:abstract 2.

Subgroup

Age > 75Age ≤ 75

Gender: femaleGender: male

AsiaEurope

North America and PacificISS stage: I or II

ISS stage: IIICrCI < 30 ml/min

CrCI 30 – 50 ml/minCrCI 50 – 80 ml/min

CrCI ≥ 80 ml/minECOG PS Grade 0ECOG PS Grade 1ECOG PS Grade 2

LDH < 200 IU/lLDH ≥ 200 IU/l

Cytogenetics High-risk Cytogenetics Non-high Risk

ITT patients

Hazard ratio (HR) and 95% CI HR (95% Cl)

0.81 (0.62 - 1.05)0.68 (0.56 - 0.83)0.73 (0.58 - 0.93)0.71 (0.57 -0.88)0.61 (0.33 - 1.14)0.77 (0.63 - 0.93)0.64 (0.46 - 0.89)0.70 (0.57 - 0.87)0.75 (0.59 - 0.95)0.76 (0.44 - 1.30)0.66 (0.48 - 0.91)0.74 (0.58 - 0.95)0.71 (0.51 - 1.01)0.54 (0.39 - 0.74)0.81 (0.65 - 1.01)0.80 (0.57 - 1.12)0.69 (0.58 - 0.83)0.96 (0.66 - 1.39)1.23 (0.78 - 1.93)0.69 (0.53 - 0.90)

0.72 (0.61 - 0.85)

0.125 0. 25 0.5 1 2 4 8

Favoring MPTFavoring Rd

17

Cytogenetics high-risk included t(4;14), t(14;16), del(17p)

FIRST Trial: TTP and Time to 2nd Anti-myeloma Therapy

Facon T, et al. Blood. 2013;122:abstract 2.

RdRd18MPT

535541547

398389379

318317303

263265242

218167169

167108115

1055658

553028

1976

221

000

TTP (months)

Pa

tie

nts

(%

)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

Hazard ratio Rd vs. MPT: 0.68; P=0.00001 Rd vs. Rd18: 0.62; P≤0.00001 Rd18 vs. MPT: 1.11; P=0.21718

Time to Progression Time to 2nd AMT

RdRd18MPT

535541547

445451422

371375351

319331293

275266239

224181177

142111101

776142

28169

321

000

Time to 2nd AMT (months)

100

80

60

40

20

0

Hazard ratioRd vs. MPT: 0.66; P<0.00001Rd vs. Rd18: 0.74; P=0.00067Rd18 vs. MPT: 0.88; P=0.12333

0 6 12 18 24 30 36 42 48 54 60

Pa

tie

nts

(%

)

Median TTP

Rd (n=535)

32.5 mos

Rd18 (n=541)

21.9 mos

MPT (n=547)

23.9 mos

Median Time to 2nd AMT

Rd (n=535)

39.1 mos

Rd18 (n=541)

28.5 mos

MPT (n=547)

26.7 mos

18

FIRST Trial: Conclusions

• Continuous Rd significantly extended PFS, with an OS benefit vs. MPT– PFS:

• HR= 0.72 (P= 0.00006)• Consistent benefit across most subgroups• Rd better than Rd18 (HR= 0.70, P= 0.00001)• 3 yr PFS: 42% Rd vs. 23% Rd18 and MPT

– Planned interim OS: HR= 0.78 (P= 0.0168)– Rd was superior to MPT across all other efficacy secondary endpoints

• Safety profile with continuous Rd was manageable – Hematological and non-hematological AEs were as expected for Rd and

MPT– Incidence of hematological SPM was lower with continuous Rd vs. MPT

• In NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care

Facon T, et al. Blood. 2013;122:abstract 2.

19

20

0

HR, hazard ratio; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; OS, overall survival; PFS, progression-free survival; TTP, time to progression.

ProgressionProgression--Free and Overall SurvivalFree and Overall SurvivalAll PatientsAll Patients

• TTP HR advantages were similar: MPR-R vs MP = 0.337; MPR vs MP = 0.826

Time (Months)

Pa

tie

nts

(%

)

HR 0.395 P < .001

HR 0.796P = .135

0 10 20 30 400

25

50

75

100

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

0 20 30 40 50 60

4-year OS

MPR-R 59%

MPR 58%

MP 58%

4-year OS

MPR-R 59%

MPR 58%

MP 58%

Pa

tie

nts

(%

)

25

50

75

10

100

HR 0.898 P = .579

HR 1.089P = .648

Time (Months)

21

Second Primary MalignanciesSecond Primary MalignanciesAll PatientsAll Patients

SPM, n (IR per 100 per year)MPR-R

(n = 150)MPR

(n = 152)MP

(n = 153)

Total Invasive SPMs 12 (3.04) 10 (2.57) 4 (0.98)

Hematologic 7 (1.75) 6 (1.54) 1 (0.24)

Solid tumors 5 (1.26) 5 (1.28) 3 (0.74)

Non-melanoma skin cancer 2 (0.50) 5 (1.29) 6 (1.50)

SPM, n (IR per 100 per year)MPR-R

(n = 150)MPR

(n = 152)MP

(n = 153)

Total Invasive SPMs 12 (3.04) 10 (2.57) 4 (0.98)

Hematologic 7 (1.75) 6 (1.54) 1 (0.24)

Solid tumors 5 (1.26) 5 (1.28) 3 (0.74)

Non-melanoma skin cancer 2 (0.50) 5 (1.29) 6 (1.50)

Pat

ien

ts (

%)

100

75

50

25

0

100

75

50

25

0

100

75

50

25

00 20 40 60 0 20 40 60 0 20 40 60

Time (Months) Time (Months) Time (Months)

MPR-R MPR MP

PD/Death Hematologic SPM Solid TumorPD/Death Hematologic SPM Solid Tumor

IR, incidence rate; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; PD, progressive disease; PY, person-year; SPM, second primary malignancy.

Treatment schema

VPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22P: 50 mg, 3 times wk

VCPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22C: 50 mg, 3 times wkP: 50 mg, 3 times wk

MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15

VMPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22M: 2 mg, 3 times wkP: 50 mg, 3 times wk

MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15

MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15

VPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22P: 50 mg, 3 times wk

VCPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22C: 50 mg, 3 times wkP: 50 mg, 3 times wk

MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15

VMPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22M: 2 mg, 3 times wkP: 50 mg, 3 times wk

MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15

MAINTENANCE 28-day course until relapseVsc: 1.3 mg/sqm, d 1, 15

Vsc, subcutaneous bortezomib; C, cyclophosphamide; M, melphalan; P, prednisone

152 patients

≥ 75 years or younger with co-morbidities

At baseline: geriatric assessment (ADL, IADL, Charlson)

Larocca et al ASH 2013

Subgroup analysis: AgeP

ati

en

ts(%

)

OS, Age 75-80 vs Age<75, HR=0.79 p=0.571OS, Age 80 vs Age<75, HR=0.99 p=0.990

Progression-free Survival Overall Survival

PFS, Age 75-80 vs Age<75, HR=0.96 p=0.865PFS, Age 80 vs Age<75, HR=0.80 p=0.449

0

25

50

75

100

0 6 12 18 24 30

Time (months)

Age 75-80 yearsAge <75 yearsAge 80 years

0

25

50

75

100

0 6 12 18 24 30

Time (months)

Age 75-80 yearsAge <75 yearsAge 80 years

Time (months)

0

25

50

75

100

0 6 12 18 24 30

Age 75-80 yearsAge <75 yearsAge 80 years

0

25

50

75

100

0 6 12 18 24 30

Age 75-80 yearsAge <75 yearsAge 80 years

Conclusions

• The global population is rapidly aging. Aging is associated with an increased incidence of co-morbidity, frailty, and disability.

• PFS and OS appeared similar between the 2- drug and the 3-drug combinations

• Melphalan seemed more toxic than cyclophosphamide

• Fit patients

Unfit patients

Frail patients

Full dose therapy

Reduced-dose therapy

Further reduced-dose therapy

Larocca et al, ASH 2013

• Phase II

• Multicenter (10 centres)

Study design

CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5

Dexamethasone40 mg orally

Cyphosphamide300 mg/m2 orally

CarfilzomibDose (mg/m2)

Dosing

Cycle day 1 2 15 16 1 2 8 9 1516 22

20 36 36 36 36 36

1 2 8 9 1516 22 1 2 8 9 1516 22

CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE

36 36 36

1 2 15 16 1 2 15 16

36 36 36 3636 36

Response Assessments

CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5

Dexamethasone40 mg orally

Cyphosphamide300 mg/m2 orally

CarfilzomibDose (mg/m2)

Dosing

Cycle day 1 2 15 16 1 2 8 9 1516 22

20 36 36 36 36 36

1 2 8 9 1516 22 1 2 8 9 1516 22

CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE

36 36 36

1 2 15 16 1 2 15 16

36 36 36 3636 36

Response Assessments

CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5

Dexamethasone40 mg orally

Cyphosphamide300 mg/m2 orally

CarfilzomibDose (mg/m2)

Dosing

Cycle day 1 2 15 16 1 2 8 9 1516 22

20 36 36 36 36 36

1 2 8 9 1516 22 1 2 8 9 1516 22

CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCECYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE

36 36 36

1 2 15 16 1 2 15 16

36 36 36 3636 36

Response Assessments

CCd Induction C MaintenanceCycles 1-9 Until progression

CCd Induction C MaintenanceCycles 1-9 Until progression

Bringhen et al ASH 2013

Conclusions 1

CCd MPT VMP Rd

Response rates

≥ VGPR 77% 36% 41% 40%

nCR/CR/sCR 47% 27% 30%* 14%

Long-term outcomes

2-yr PFS 76% 47% ~47% ~47%

2-yr OS 87% 76% 79% 87%

CCd MPT VMP Rd

Response rates

≥ VGPR 77% 36% 41% 40%

nCR/CR/sCR 47% 27% 30%* 14%

Long-term outcomes

2-yr PFS 76% 47% ~47% ~47%

2-yr OS 87% 76% 79% 87%

* CR only, nCR not reported

Palumbo at al, Lancet, 2006 ;367:825-31.Fayers et al, Blood 2011; 118:1239-47; San Miguel et al, N Eng J Med 2008;359:906-17; Rajkumar et al, Lancet Oncol 2010; 11:29-37

Bringhen et al ASH 2013

Oral MLN 9708 Len Dex in Newly Diagnosed MM

• Phase 1: oral MLN9708 dose-escalation (dose of 3.0 and 3.7 mgs)– Standard 3+3 schema, 33% dose increments, based on cycle 1 DLTs

• Phase 2: oral MLN9708 at the RP2D from phase 1

• Stem cell collection allowed after cycle 4, with ASCT deferred until after 8 cycles

• MLN9708 maintenance continued at tolerated dose until progression or unacceptable toxicity

1 8 15 21

MLN9708

maintenance

Days 1, 4, 8, 11

21-day cycles

Induction: up to 16 x 21-day treatment cycles Maintenance

MLN9708 MLN9708 MLN9708

Dex* Dex* Dex*

Lenalidomide 25 mg, days 1–14

MLN9708

Dex*

4 11

*Dex 20/10 mg cycles 1–8 / 9–16Thromboembolism prophylaxis with aspirin 81–325 mg QD or LMWH while receiving len-dex mandatory

2 5 9 12

Richardson et al ASH 2013

Ixazomib lenalidomide dexamethasone in newly diagnosed multiple myeloma

• 56 pts treated at the RP2D were evaluable for response (7 phase 1, 49 phase 2)

• 61% of pts had 100% decreases in M-protein or serum free light chain from baseline

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

0

–20

–40

–60

–80

–100

% d

ec

rea

se

s i

n M

-pro

tein

–25%

–50%

–90%

20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56

Subject identifier for the study

Dose level (cohort): Ph 1, 3.0 mg Ph 2, 3.0 mg

Richardson et al ASH 2013

Pomalidomide With Low-Dose Dexamethasone Relapsed and Refractory Multiple Myeloma

• POM was effective in heavily pretreated patients who had already received LEN and bortezomib and who progressed on their last line of therapy

• The combination of POM with LoDEX improves the ORR due to synergy between immunomodulatory agents and glucocorticoids

POM + LoDEX, 34%; POM alone, 15%

• Response was durable with POM regardless of the addition of LoDEX

POM + LoDEX, 8.3 months ; POM alone, 8.8 months

• POM is generally well tolerated, with low rates of discontinuations due to AEs

• Age had no impact on ORR, DoR, or safety

Jagannath S, et al. ASH 2012 abstract 450.

MM-003 Design: POM + LoDEX vs. HiDEX

(n = 302)

POM: 4 mg/day D1-21 +

LoDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22

RA

ND

OM

IZA

TIO

N 2

:1

Follow-Up for OS and SPM

Until 5 Years Post Enrollment

(n = 153)

HiDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1-4, 9-12, 17-20

28-day cycles

PDa or

Unacceptable AE

Companion trialMM-003C

POM 21/28 days

Stratification• Age (≤ 75 vs. > 75 yrs)

• Number of prior Tx ( 2 vs. > 2)

• Disease population (primary refractory vs. relapsed/refractory vs. intolerance/failure)

Thromboprophylaxis was required for those receiving POM or at high risk for DVT

PDa or

Unacceptable AE

a Progression of disease was independently adjudicated in real time.

Dimopoulos MA, et al. ASH 2013 [abstract 408].

0.25 0.5

PFS Based on Cytogenetic Profile• POM + LoDEX significantly improved PFS vs. HiDEX regardless of the

presence of del17p or t(4;14)

Note: Data shown only for pts with available cytogenetics; totals will not sum.a Number of events/number of patients.Dimopoulos MA, et al. ASH 2013 [abstract 408].

ITT Population

del(17p)/t(4;14)

Standard-RiskCytogenetics

SubgroupPOM + LoDEXa HiDEXa HR (95% CI)

0.49 (0.40-0.61)

0.44 (0.28-0.68)

0.55 (0.40-0.75)

138/153

32/35

63/72

253/302

71/77

126/148

1

Favors POM + LoDEX

2

Favors HiDEX

Forest Plot of OS Based on Prior Treatment

a Number of events/number of pts.

San Miguel JF, et al. ASH 2013 [abstract 686].

Subgroup HiDEXa HR (95% CI)

0.72 (0.56-0.92)

0.56 (0.33-0.96)

0.76 (0.58-1.00)

0.75 (0.55-1.03)

0.66 (0.45-0.99)

0.70 (0.55-0.90)

0.77 (0.58-1.01)

0.77 (0.58-1.02)

0.56 (0.36-0.88)

0.92 (0.63-1.36)

101/153

22/33

79/120

64/93

37/60

94/141

79/121

74/113

32/49

39/66

176/302

41/70

135/232

102/173

74/129

168/286

142/238

135/225

47/85

76/134

ITT Population

≤ 3 Prior Tx

> 3 Prior Tx

Prior THAL

No Prior THAL

LEN Ref

BORT Ref

LEN and BORT Ref

LEN as Last Prior

BORT as Last Prior

POM + LoDEXa

0.25 0.5 1 2

Favoring POM-LoDex Favoring HiDEX

MM-003: PFS and OS by M-Protein ReductionPatients Assigned to POM + LoDEX

San Miguel JF, et al. ASH 2013 [abstract 686].

• Median PFS was 4.0 mos and median OS was 13.1 mos overall for POM + LoDEX

M-Protein Reduction

Median PFS

≥ 25 % (n = 163) 7.4 mos

≥ 50 % (n = 113) 8.4 mos

< 25% (n = 96) 2.3 mos

M-Protein Reduction

Median OS

≥ 25 % (n = 163) 17.2 mos

≥ 50 % (n = 113) 19.9 mos

< 25% (n = 96) 7.5 mos

PFS (mos)

0.0

0.2

0.4

0.6

0.8

1.0

4 8 12 16 20 240

Pro

po

rtio

n o

f P

atie

nts

OS (mos)

0.0

0.2

0.4

0.6

0.8

1.0

4 8 12 16 20 280 24

Pom low dose dex and bortezomib in relapsed MM

Table 4. Summary of Best Response (IMWG) in Intravenous BORT Cohorts

OutcomeCohort 1

(n = 3)Cohort 2

(n = 3)Cohort 3

(n = 3)Cohort 4

(n = 3)

Cohort 5 + Exp Cohort

(n = 9)a

Overall response, n (%) 2 (67) 1 (33) 3 (100) 3 (100) 6 (67)

sCR/CR 0 0 0 0 1 (11)

VGPR 1 (33) 0 2 (67) 1 (33) 4 (44)

PR 1 (33) 1 (33) 1 (33) 2 (67) 1 (11)

SD 1 (33) 2 (67) 0 0 3 (33)

Median cycles received (range) 5 (4-16) 6 (4-18) 16 (5-20) 10 (4-13) 11 (6-15)

a 8 of 9 patients were evaluable for response; one patient discontinued study treatment in cycle 2 due to treatment-unrelated metastatic pancreatic cancer. CR, complete response; Exp, expansion; IMWG, International Myeloma Working Group; PR, partial response; SC, subcutaneous; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.

Richardson et al, ASH 2013

Carfilzomib: A Novel Proteasome (Chymotryptic) Inhibitor

• Novel chemical class with highly selective

and irreversible proteasome binding

• Improved antitumor activity with

consecutive day dosing

• No neurotoxicity in animals

• 23% Responses lasting 7.8 months with survival 15.4 months in relapsed and relapsed/ refractory MM w/o

Demo et al Cancer Res 2007; 67:6383 Kirk et al, Blood 2008, 112: 2765 ; Siegel et al Blood 2012:120:2817.

HN

NH

O HN

O

O

NHO

NO O

O

Epoxyketone

Tetrapeptide

CRd in Relapsed and Upfront MM

• Response to CRd therapy in RRMM was high, with an ORR of 78%

41% VGPR or better

• CRd well-tolerated with durable responses

• ASPIRE phase 3 open-label, international, multicenter trial comparing CRd to Rd in R/R MM fully enrolled.

• Remarkable extent and frequency of response to CRd upfront in ND MM (94% ORR, with 80% CR,nCR after 12 cycles in a subset of pts)

Wang et al ASCO 2011; Jakubowiak et al, Blood 2012

Carfilzomib Pomalidomide Low dose Dex

• Median of 5 prior lines of therapy; 49% of patients had high/intermediate risk cytogenetics at baseline

• Response rates, PFS, and OS were preserved independent of FISH/cytogenetic risk status

• Well tolerated with no unexpected toxicities

≥ VGPR 27% ORR 70% CBR 83% DOR (median) 17.7

months PFS (median) 9.7 months OS (median) > 18

months

Shah et al ASH 2013

Antibody-dependentCellular cytotoxicity

(ADCC)

ADCC

Effector cells:

MM

FcR

Complement-dependentCytotoxicity (CDC)

CDC

MM

C1q

C1q

Apoptosis/growth arrest

via targetingsignaling pathways

MM

Lucatumumab or Dacetuzumab (CD40)Elotuzumab (CS1)Daratumumab (CD38)XmAb5592 (HM1.24)

huN901-DM1 (CD56)nBT062-maytansinoid

(CD138)1339 (IL-6)BHQ880 (DKK1)RAP-011 (activin A)Daratumumab (CD38)

Daratumumab (CD38)

MAb-Based Therapeutic Targeting of Myeloma

Tai & Anderson Bone Marrow Research 2011

• CS1 is highly and uniformly expressed on MM cells • Elotuzumab (Elo) is a humanized monoclonal IgG1

antibody targeting CS1 • Clinical trial of Elo in MM achieved SD • Anti-MM activity of Elo enhanced by lenalidomide (len)

in preclinical models• Phase I/II trials: 80-90% response to len dex elo in

relapsed MM with prolonged (> month 33 PFS)• Phase III trial of len dex elo versus len dex in relapsed

MM for new drug approval

Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784; Tai YT et al. Blood. 2008;112:1329-1337; Van Rhee F et al. Mol Cancer Ther. 2009;8:2616-2624; Lonial S et al. Blood. 2009;114:432; Richardson et al Blood 2010:864 Lonial et al, ASH 2012

Elotuzumab Anti-CS MoAb in MM

Martin et al ASH 2013

Martin et al 2013

PHASE I/II STUDY OF DARATUMUMAB CD38 MONOCLONAL ANTIBODY IN

RELAPSED/REFRACTORY MM • Favorable safety profile as monotherapy

• In 15 of 32 (47%) showed benefit

– 4 patients achieving PR (13%)– 6 patients achieving MR (19%)– 5 patients achieving SD (16%)

• At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%)

• To be combined with lenalidomide dexamethasone

Plesner et al ASH 2012

44

Daratumumab and lenalidomide dexamethasone in relapsed MM

The best change in response paraprotein evaluated according to IMWG 2011.

A: serum M-protein, B: urine-M-protein

Plesner et al ASH 2013

Kelley et al ASH 2013

Kelly et al ASH 2013

Background: Targeting KSP with ARRY-520 (Filanesib)

• Filanesib is a targeted Kinesin Spindle Protein (KSP) inhibitor

– KSP is a microtubule motor protein critical to the function of proliferating cells

• KSP inhibition induces aberrant mitotic arrest and rapid cell death

– Novel mechanism of action for MM– Preferentially acts on MCL-1

dependent cells including MM– Not expected to be cross-resistant

with other drugs

47Lonial et al ASH 2013

Low AAG is Associated with Higher ORR

48

1 5 patients did not have a baseline AAG measurement2 4 patients did not have a baseline AAG measurement, including 1 responder

Filanesib Single-agent Filanesib + Dex

All Pts1 AAG-High AAG-Low All Pts2 AAG-High AAG-Low

n 32 6 21 55 15 36

ORR (≥ PR) 5 (16%) 0 (0%) 5 (24%) 8 (15%) 0 (0%) 7 (19%)

CBR (≥ MR) 7 (22%) 0 (0%) 7 (33%) 11 (20%) 0 (0%) 10 (28%)

Duration of Response (months) 8.6 - 8.6 5.1 - 5.1

Time to Next Treatment (months) 3.7 2.6 5.3 3.4 2.0 5.1

OS (months) 19.0 4.5 23.3 10.5 2.9 10.8

Lonial et al ASH 2013

Protein

protein aggregates(toxic)

UbUb

UbUb

26S proteasome

UbUb

Ub Ub

Ub

Aggresome

Panibinostat,Vorinostat, ACY1215

dynein

UbUb

dynein

MicrotubuleAutophagy

Bortezomib, Carfilzomib, NPI0052, MLN9708, ONX 0912

Ub Ub

Ub

Lysosome

HDAC6

HDAC6

HDAC6

Ub

Ub

Development of Rationally-Based Combination Therapies (HDAC and Proteasome Inhibitors)

Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:3441-9.

VANTAGE 088: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat

or Placebo with Bortezomib in Relapsed MM

• The combination of vorinostat + bortezomib is active in patients with relapsed and refractory MM– Significant improvement in response rate– ORR 54% vs 41% (P<0.0001); CBR 71% vs 53% (P<0.0001)

• PFS and TTP were prolonged in the combination arm compared with bortezomib alone

PFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4)versus 6.83 months (5.7–7.7)

• Diarrhea, fatigue, and thrombocytopenia limited tolerability.

Dimopoulos et al Lancet Oncol 2013; 14: 1129-40.

Ricolinostat (HDAC 6 inhibitor) alone and in combination with bortezomib in relapsed

refractory MM• Monotherapy

• 6/15 patients had stable disease (SD) as their best response.

• Combination with bortezomib and dexamethasone

• 20/22 were evaluable for response assessment in six combination cohorts

• Overall response rate (≥PR): 25% in heavily pretreated patients

• 5 patients withdrew after one cycle and 3 had progressive disease after 2 cycles

• Clinical benefit rate (≥SD): 60%

• 6/10 patients refractory to bortezomib had ≥SD (1 VGPR, 1 MR, 4 SD)

• Responding patients have been on study 2 to 16 cycles

• All 3 patients treated 240 mg QD cohort had MR or better

VGPR

2

PR 3

MR1 2

SD 5

Monotherapy response data from Final CSR. Combination response data pulled from live database Nov 8, 2013

51

1 One patient had a 26% decrease in M Protein after Cycle 2 and withdrew after two subsequent cycles with SD

Ricolinostat (HDAC 6 inhibitor) lenalidomide dexamethasone in relapsed refractory MM

• 11/16 pts (69%) had PR or better

• 16/16 pts (100%) had clinical benefit (including MR and SD)

CR 1

VGPR 3

PR1 7

MR 2

SD 3

Yee, et al, Poster #3190, ASH 201352

M protein % change

PKB115125 Akt Inhibitor: Dose Limiting Toxicities

Afur / Bor / Dex dose (mg)

n DLT Comment

75- 1.0- 20 4 None -

100 - 1.3- 20 6 1/6 LFT elevation G2

125 - 1.3- 20 6 1/6 Erythema Multiforme G3

150 - 1.3- 20 6 None -

175 - 1.3- 20 6 2/6 Rash G3Rash G3 / Diarrhea G3 /Thrombocytopenia G3

150 -1.3- 40 6 NA -

MTD / RP2D:Afuresertib 150 mg PO dailyBortezomib 1.3 mg/m2 IV/SC on days: 1,4,8,11Dexamethasone 40 mg PO on days: 1,4,8,11

All DLTs were reversible

Voorhees et al ASH 2013

Maximum % change in M-protein or FLC from baseline

Voorhees et al ASH 2013

Treatment of Multiple Myeloma: Conclusions

• In newly diagnosed transplant candidates, three drug regimens incorporating immunomodulatory drugs and proteasome inhibitors before and after transplant can prolong PFS and OS.

• Lenalidomide dex until progression is standard of care for non transplant patients with newly diagnosed myeloma.

• Lenalidomide maintenance until progression prolongs PFS and OS, with an increased risk of secondary cancers in patients who have received MP or high dose therapy and ASCT.

Treatment of Multiple Myeloma: Conclusions

• Pomalidomide low dose dex is active in relapsed refractory MM, (including 17p deletion)

• Bortezomib or Carfilzomib and pomalidomide low dose dex increases response and is tolerated in relapsed refractory MM

• Novel agents including oral proteasome inhibitor ixazomib, monoclonal antibodies SAR650984 and daratumumab, immunotoxin indatuximab, KSP inhibitor filanesib, Akt inhibitor afuresertib, and HDAC6 inhibitor ricolinostat demonstrate promising activity in relapsed refractory MM

• Incorporation of novel therapies at all stages of disease is further improving patient outcome in MM