New Horizons in Multiple Myeloma

2013

James R. Berenson, MD

Medical & Scientific Director

Institute for Myeloma & Bone Cancer Research

Los Angeles, CA

Treatment Choices for

Myeloma Patients

• The number of choices is growing rapidly! – More new combinations involving already approved

drugs

– Clinical trials of drugs recently and not yet approved

• Thus, it is becoming more difficult to come up with a clearcut paradigm – i.e. it’s becoming much more complicated

• Patient wants the longest life possible with therapy and a disease that has the least impact on their life!

Initial Therapy for Myeloma: Treatment Choices

IMiDs Proteasome

inhibitors Chemotherapy

Steroids Clarithromycin

Clinical Trials

+

+ +

+

+

+

Investigational

Drugs Novel

Combinations

Thal

Len

Dex

Medrol

Prednisone

Alkylating agents •Melphalan

•Cyclophosphamide

•Bendamustine

Anthracyclines •Doxorubicin

•PLD

+

Bortezomib Carfilzomib

Pom

• Len + Dex significantly increased overall response rate compared with

Placebo + Dex (P < .0001)

• Rate of VGPR or better was significantly higher for Len + Dex compared

with Placebo + Dex (63% vs 16%, P < .001)

Lenalidomide + Dexamethasone in NDMM:

SWOG Trial–Response

CR, complete response; Len+ Dex, lenalidomide, dexamethasone; NDMM, newly

diagnosed multiple myeloma; ORR, overall response rate; PR, partial response;

SWOG, Southwest Oncology Group; VGPR, very good partial response. Zonder J, et al. Blood. 2010;116:5838-5841.

ORR: 78%

ORR: 48%

(n = 77) (n = 80)

48% ORR to

DEX Alone!

Newly Diagnosed Multiple Myeloma: Lenalidomide 25 mg d1-21 (28 days per cycle)

48%

Lenalidomide + Dexamethasone in NDMM: ECOG E4A03 Trial–Overall Survival

Months

6 12 24 30 36 42 18

1.0

0.2

0.4

0.6

0.8

Ove

rall

Su

rviv

al

Rd

• One-year OS was significantly better for Rd compared with RD regardless of age

– < 65 years of age: 98% vs 91%; P = .01

– ≥ 65 years of age: 94% vs 83%; P = .004

a P = .0002 vs RD.

ECOG, Eastern Cooperative Oncology Group; NDMM, newly diagnosed multiple

myeloma; OS, overall survival; Rd, lenalidomide, low-dose dexamethasone; RD,

lenalidomide, high-dose dexamethasone.

RD

0

0

Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

1-y OS 2-y OS

87% 75%

96%a 87%

Len 25 mg + Dex 40 mg d1-4, 9-12, 17-20

Len 25 mg + Dex 40 mg d1, 8, 15, & 22

MP

M: 0.18 mg/kg, days 1-4

P: 2 mg/kg, days 1-4

PBO: days 1-21

MPR

M: 0.18 mg/kg, days 1-4

P: 2 mg/kg, days 1-4

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

Placebo

Placebo

MPR-R

M: 0.18 mg/kg, days 1-4

P: 2 mg/kg, days 1-4

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

RA

ND

OM

IZA

TIO

N

Double-Blind Treatment Phase

Disease

Progression

Maintenance

Lenalidomide

(25 mg/day)

+/-

Dexamethasone

Open-Label

Extension Phase

Lenalidomide 10 mg/day days 1-21

Cycles (28-day) 1-9 Cycles 10+

ISS, International Staging System; MP, melphalan, prednisone; MPR, melphalan,

prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide

maintenance; NDMM, newly diagnosed multiple myeloma; PBO, placebo.

• Primary comparison: MPR-R vs MP

Lenalidomide + Melphalan + Prednisone w/ or w/o

Lenalidomide Maintenance Therapy in NDMM MM-015–Study Design

Palumbo A, et al.N Engl J Med 2012

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)

Pati

en

ts (

%)

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%

Pati

en

ts (

%)

25

50

75

10

100

HR 0.898 P = .579

HR 1.089P = .648

Time (Months)

Phase III VISTA Trial (VcMP vs MP): Trial Design and Dosing

► Endpoints: Primary: TTP; Secondary: CR, ORR, TTR, DOR, PFS, TNT, OS,

QoL

Previously Untreated

San Miguel J et al. N Engl J Med 2008359(9):906-917

Randomized, international, phase III trial in previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT due to age (≥65 yrs) or co-morbid conditions

1. Bladé et al. Br J Haematol 1998;102:1115-23.

ARM A (VMP) VMP: Four 6-week cycles: Cycles 1-4 Bortezomib 1.3mg/m2 days 1, 4, 8, 11, 22, 25, 29, 32; Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4 Followed by five 6-week cycles: Cycles 5-9 Bortezomib 1.3mg/m2 days 1, 8, 22, 29; Melphalan 9mg/m2 and prednisone 60mg/m2 once daily on days 1–4

ARM B (MP) MP: Nine 6-week cycles: Cycles 1-9 Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4

Max of 9 cycles (total 54 weeks) in both Arms

R

A

N

D

O

M

I

Z

E

► Study Schema:

– 682 pts randomized

151 centers

22 countries worldwide

– IDMC recommended study

stop in September 2007

Based on protocol-specified

interim analysis

– VMP was significantly

superior for all efficacy

endpoints

TOC

VISTA: Time to Progression

and Overall Survival

San Miguel JF, et al. N Engl J Med. 2008;359(9):906-917. Mateos MV, et al. J Clin Oncol. 2010 Apr

19. [Epub ahead of print].

VMP: 24.0 months (83 events)

MP: 16.6 months (146 events)

HR=0.483, P<.000001

Median follow-up: 16.3 months

VMP: median not reached (45 deaths)

MP: median not reached (76 deaths)

HR = 0.61, P = .008

Time, months

Pa

tie

nts

W

ith

ou

t E

ve

nt,

%

0 4 8 12 16 20 24 28 32 36 40 0

10

20

30

40

50

60

70

80

90

100

Time, months 0 3 6 9 12 15 18 21 24 27

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

W

ith

ou

t E

ve

nt,

%

VMP

MP

VMP

MP

Time to progression Overall survival

• 3-yr OS: 72% in VMP arm vs 69.5% in MP arm

Bortezomib + Pegylated Liposomal

Doxorubicin (Doxil) + Dexamethasone for

Patients with Previously Untreated Myeloma: A Phase II Trial

Days 1 2 3 4 5 6 7 8 9 10 11 29

Cycle repeats Bortezomib: 1.0 mg/m2 IV

Doxil: 5 mg/m2 IV infusion

Dexamethasone 40 mg IV

Berenson et al. Brit J Haematol, 2011

Response Type Number of Patients

(N = 35)

Complete Response (CR) (no serum M-protein)

7 (20%)

Very Good Partial Response (VGPR) (≥ 90% decrease in serum M-protein)

3 (8.6%)

Partial Response (PR) (50-74% decrease in serum M-protein)

15 (42.9%)

Minor Response (MR) (25-49% decrease in serum M-protein)

5 (14.3%)

Objective Response (CR+VGPR+PR+MR) 30 (85.8%)

Stable Disease (SD) (no serum M-protein)

3 (8.6%)

Disease Control (CR+VGPR +PR+MR+SD) 33 (94.4%)

Progressive Disease (PD) (>25% increase in serum M-protein)

2 (5.7%)

DVD: Response Rates

Phase II Study of Lenalidomide, Bortezomib,

and Dexamethasone in Newly Diagnosed MM

Response Rates

Response, n

(%)

All patients

(N = 66)

Phase II

(N = 35)

Through 4 cycles

(N = 66)

Through 8 cycles

(N = 66)

CR 19 (29) 13 (37) 0 (0) 6 (9)

nCR 7 (11) 7 (20) 4 (6) 9 (14)

VGPR 18 (27) 6 (17) 3 (5) 20 (30)

PR 22 (33) 9 (26) 42 (64) 28 (42)

CR/nCR/VGPR 44 (67) 26 (74) 7 (11) 35 (53)

• Response improvement from cycle 4 through 8 was seen in 42/56

(75%) who continued beyond 4 cycles of treatment

• Further improvement was seen in 20/37 patients (54%) who

continued beyond 8 cycles of treatment

• Median duration of response had not been reached

– 68% of patients have remained in response for > 18 months

CR; complete response; nCR, near complete response; PR, partial response;

VGPR, very good partial response.

Main NDMM

Richardson PG, et al. Blood. 2009;114(22):501-502 [poster presentation].

CRD: Responses After Extended Treatment

74 82

55 61

0

20

40

60

80

100 ≥nCR sCR*

Best response N=53

Median 22 CRd cycles

(range 2–24)

8+ Cycles n= 44

Median 24 CRd cycles

(range 12–24)

Pa

tie

nts

(%

)

*Of patients in sCR, 25% had high-risk cytogenetics

Jakubowiak, et al. ASCO 2013 (abstract 8543).

CRD: Progression-Free Survival

*For patients in sCR, estimated 24-month PFS was 97%

Jakubowiak, et al. ASCO 2013 (abstract 8543).

N=53

Median follow-up 25 months (range 5–37)

24-month rate 94%*

0 5 10 15 20 25 30 35 40

1.0

0.8

0.6

0.4

0.2

0.0

PF

S P

robabili

ty

Months

Principles of Treating

Relapsed/Refractory Multiple Myeloma

• Be sure a patient has really progressed before changing therapy – REPEAT MYELOMA LABS!

• Try to use drugs patient has not seen before • HOWEVER,

– progression on one drug in combination does not mean that drug will not be effective w/ another agent

• e.g., pts progressing from bortezomib w/ melphalan often respond to bortezomib w/ PLD

• Even different drugs in the same class may be active so that – bortezomib+melphalan failures may respond to other alkylating

agents- cyclophosphamide or bendamustine – LEN failures may respond to THAL and vice versa

– pts progressing from a drug at one dose may respond to the same drug at a higher dose- e.g., LEN

– the same combination may be effective again if the patient has not seen the combination in a long time

Efficacy and Safety of Bendamustine plus

Bortezomib in R/RMM: A Phase 1/2 trial

Patients were assigned to one of 3 cohorts receiving doses of intravenous bendamustine at 50 mg/m2 (cohort 1), 70 mg/m2 (cohort 2), or 90 (cohort 3) mg/m2 in combination with a fixed dose of intravenous bortezomib (1.0 mg/m2) according to the schedule in Figure 1.

Berenson et al., Brit J Haematol 2012

No DLT was observed at any dose level. 50 mg/m2 (n = 5) 70 mg/m2 (n = 4) 90 mg/m2 (n = 5)

The maximum dose of bendamustine (90 mg/m2) was well tolerated in combination with bortezomib 1.0 mg/m2 and was designated as the MTD Overall response rate

Overall 48% (1 CR, 2 VGPR, 9 PR, & 7 MR) At MTD (90 mg/m2) 52% Bortezomib-exposed (n=31) 42% Alkylator-exposed (n=28) 46%

Bendamustine & Bortezomib: Results

IFM 2009-01: Phase II study of bendamustine

+ bortezomib + Dex in elderly pts with

relapsed/refractory MM

• Objectives: Primary: response rate; Secondary:

time to best response, PFS, OS, toxicity

• Patients: 73 pts in first relapse or refractory to first-

line therapy; median age 76 yrs (66–86); no prior

bortezomib or bendamustine; Dose and schedule:

28-day cycles: bortezomib 1.3 mg/m2 IV and Dex 20

mg days 1, 8, 15, 22; bendamustine 70 mg/m2 days

1, 8; regimen given in 3 phases: – Induction: 4 consecutive cycles. Pts achieving ≥PR proceed to:

– Consolidation: 2 consecutive cycles; pts maintaining response

proceed to:

– Maintenance: 6 cycles, 1 cycle given every 2 mos

Rodon P, et al. ASH 2012, abstract #4044 Relapsed/Refractory MM

IFM 2009-01: Phase II study of bendamustine

+ bortezomib + Dex in elderly pts with

relapsed/refractory MM

• Results: Analysis restricted to first 6 cycles

• Adverse prognostic factors for response

(ORR) – Prior IMiD: yes, 61%; no, 100% (p=0.006)

– Del 17p: present, 20%; absent, 72% (p=0.036)

• 6-mo PFS: 67%; 6-mo OS: 81%

Rodon P, et al. ASH 2012, abstract #4044

Response (N=73)

ORR

(≥PR)

CR VGPR PR MR

67% 12% 17% 38% 8%

Relapsed/Refractory MM

Bendamustine (B) w/ Lenalidomide (L)

and Dexamethasone (D): Phase 1/2 Trial

• R/R MM patients

• N=29

• Regimen (28-day cycles) – B 75-100 mg/m2 d1 & 2

– L 5-10 mg qd d1-21

– Dex 40 mg PO weekly

• MTD: B 75/ L 10/ D 40

• Results (only 25 considered evaluable for response) – ORR (> PR): 52% w/ 24% VGPR

– MR 24%

– PFS: 6.1 mo Lentzsch et al. Blood 2012

Retreatment w/ IMiDs for MM Patients

• Retrospective study in 140 pts treated firstline w/ – THAL/DEX- 58%

– LEN/DEX- 42%

• Retreatment w/ a regimen containing – THAL- 24%

– LEN- 76%

• # of treatments before retreatment - median of 2 (range 1-6)

• 89% received IMiD w/ DEX

• 113 considered evaluable for response – 44% > PR

– MR not reported

Madan et al. Blood 2011

LEN

LEN

(n=48)

LEN

THAL

(n=11)

THAL

LEN

(n=58)

THAL

THAL

(n=23)

> PR 54% 20% 48% 30%

DVD-R (Bortezomib + Pegylated Liposomal

Doxorubicin (Doxil) + Dexamethasone +

Lenalidomide [Revlimid]) for Patients with R/R MM: A Phase II Trial

Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 29

Cycle repeats Bortezomib: 1.0 mg/m2 IV

Doxil: 4 mg/m2 IV infusion

Dexamethasone 40 mg IV

Berenson et al., Leukemia 2012

Revlimid 10 mg po qd d1-14

DVD-R: Response Rate N=39

Perc

en

t w

/o P

rog

ressio

n

Complete Response (CR) 8* (21%)

(no serum M-protein)

Very Good Partial Responses (VGPR) 4 (10%)

(> 90% decrease in serum M-protein)

Partial Response (PR) 7 (18%)

(50-74% decrease in serum M-protein)

Minor Response (MR) 14 (36%)

(25-49% decrease in serum M-protein)

Objective Response (CR+VGPR+PR+MR) 30 (85%)

Stable Disease (SD) 4 (10%)

(change in M-protein + 25%)

Disease Control (CR+VGPR+PR+MR+SD) 37 (95%)

Progressive Disease (PD) 2 (5%)

(>25% increase in M-protein)

*Based on the modified Blade’ criteria

*Based on the modified Blade’ criteria *Based on the modified Blade’ criteria

*Based on the modified Blade’ criteria

1. Chanan-Khan AA, et al. J Clin Oncol. 2008;26:1544-1552.

2. Richardson P, et al. Blood. 2010;116:377-378.[abstract 864].

3. Lacy MQ, et al. J Clin Oncol. 2009;27:5008-5014.

4. Lacy MQ, et al. Leukemia. 2010;24:1934-1939.

5. Lacy M, et al. J Clin Oncol. 2010;28:573s.[abstract 8002].

6. Lacy M, et al. Blood. 2010;116:377.[abstract 863].

7. Leleu X, et al. Blood. 2010;116:375.[abstract 859].

Pomalidomide: Background

• Pomalidomide (CC-4047) is a distinct IMiD®

immunomodulatory compound with anti-

angiogenic and potent anti-proliferative and pro-

apoptotic activities1

– Combines structures of lenalidomide and thalidomide

• Pomalidomide is now FDA-approved for the

treatment of patients with multiple myeloma who

have been treated with bortezomib and an IMiD

and are currently progressing while on therapy2-7

N H 2

N

N H

O O

O

O

RRMM, relapsed/refractory multiple myeloma.

Study Ph Na Treatment Population

Median Prior

Therapies

(Range)

ORR

(≥ PR)

Lacy1 2 60

Pom: 2 mg

(28/28-day cycle)

Dex: 40 mg/week

1-3 prior

therapies 2 (1-3) 63%

Lacy2

2 34

Pom: 2 mg

(28/28-day cycle)

Dex: 40 mg/week

Len-refractory 4 (1-7+) 32%

Lacy3 2 35

Pom: 2 mg

(28/28-day cycle)

Dex: 40 mg/week

Len- and Bort-

relapsed/refract

ory

6 (3-9) 26%

Lacy4 2 70

Pom: 2 mg vs 4 mg

(28/28-day cycle)

Dex: 40 mg/week

Len- and Bort-

relapsed/refract

ory

6 (2-8+) 26%

1. Lacy MQ, et al. J Clin Oncol. 2009;27:5008-5014.

2. Lacy MQ, et al. Leukemia. 2010;24:1934-1939.

3. Lacy M, et al. J Clin Oncol. 2010;28:573s.[abstract 8002].

4. Lacy M, et al. Blood. 2010;116:377.[abstract 863].

Pomalidomide in R/R Multiple Myeloma Clinical Trial Overview

a Four separate populations of a single phase 2 trial.

Bort, bortezomib; Dex, dexamethasone; Len, lenalidomide; ORR,

overall response rate; Pom, pomalidomide; PR, partial response.

• Pomalidomide, in combination with low-dose dexamethasone, is effective in patients with prior lenalidomide treatment and/or bortezomib, including those who are refractory

MM-003: Pomalidomide +

LoDEX vs Single-Agent HiDEX • Patients with relapsed/refractory myeloma have

few therapeutic options, except high-dose

dexamethasone as a salvage therapy

• Patients stratified by number of

previoustherapies, refractory and

relapsed/refractory disease – Refractory to both lenalidomide and bortezomib: 73% in POM

+ LoDEX and 71% in HiDEX arms Dimopoulos MA, et al. ASH 2012. Abstract LBA-6.

POM + LoDEX Pomalidomide 4 mg on Days 1-21 +

Dexamethasone 40 mg (≤ 75) or 20 mg (> 75 yrs) on Days 1, 8, 15, 22

(n = 302)

HiDEX Dexamethasone 40 mg (≤ 75) or 20 mg

(> 75 yrs) on Days 1-4, 9-12, 17-20 (n = 153)

Patients with relased/

refractory MM

(N = 455)

Until PD or intolerable AE

Until PD

Follow-up for OS and SPM until 5 yrs

postenrollment

Companion trial MM-003C

Pomalidomide 21/28 days

MM-003: PFS and OS

• In patients with poor renal function, POM + LoDEX

provided longer PFS and OS as compared with HiDEX

Dimopoulos MA, et al. ASH 2012. Abstract LBA-6.

Survival Outcomes by Patient

Group, Mos

POM + LoDEX

(n = 302)

HiDEX

(n = 153) HR P Value

Median PFS

• ITT population 3.6 1.8 0.45 < .001

• Refractory to bortezomib 3.6 1.8 0.47 < .001

• Refractory to lenalidomide 3.7 1.8 0.38 < .001

• Refractory to bortezomib and

lenalidomide 3.2 1.7 0.48 < .001

Median OS

• ITT population NR 7.8 0.53 < .001

• Refractory to bortezomib NR 8.1 0.56 .037

• Refractory to lenalidomide NR 8.6 0.39 .003

• Refractory to bortezomib and

lenalidomide NR 7.4 0.56 .003

MM-003: Adverse Events

7% of POM + LoDEX and 6% of HiDEX patients discontinued due to AEs

Dimopoulos MA, et al. ASH 2012. Abstract LBA-6.

HiDEX POM+LoDEX All grades

% of patients experiencing ≥ grade 3 adverse event

Neutropenia

Febrile neutropenia

Anemia

Thrombocytopenia

Infection

Pneumonia

Hemorrhage

Glucose intolerance

Fatigue

VTE*

PN*

*

0 10 20 30 40 50

MM-005: A Phase I trial of Pom + Bortezomib +

Low-Dose Dexamethasone (PVD) in RR MM

• Objectives: Primary: MTD; Secondary: Safety,

response, OS, TTR, DOR

• Patients: 22 patients with RR MM; median age 57 yrs

(36-75); median 2 lines prior therapy (1-4); lenalidomide-

refractory; not refractory to bortezomib; no Gr ≥2 PN

• Dose and Schedule: 21-day cycles of bortezomib IV 1-1.3

mg/m2 days 1, 4, 8, and 11 (days 1 and 8 for cycles 9+),

pomalidomide (POM) 1-4 mg/day days 1-14, and low-

dose Dex 20 mg day of and after bortezomib (10 mg for

pts >75 yrs); thromboprophylaxis (aspirin or LMWH)

and antiviral prophylaxis required

Richardson PG et al. ASCO 2013., abstract # 8584

Relapsed/Refractory MM

MM-005: A Phase I trial of Pom + Bortezomib +

Low-Dose Dexamethasone (PVD) in RR MM

• MTD: Not reached

• MPD: Bortezomib 1.3mg/m2, pomalidomide 4 mg, Dex 20 mg (10 mg

for >75 yrs)

• DLT: None

• Safety (n=21): Median 6 cycles (2-16); most common Gr 3/4 AE

included neutropenia, thrombocytopenia, hypophosphatemia,

peripheral edema, dizziness, hypokalemia, anemia, and back pain;

no Gr 3/4 PN, no DVT

– With dose adjustments per protocol, no pts discontinued study treatment due to

AE

• 1 pt discontinued bortezomib due to persistent Gr 2 PN, without discontinuing

POM or Dex

• Response (n=20): 75% ORR (>PR), 30% >VGPR; median TTR: 1

cycle (1-3); responses seen in pts with adverse cytogenetics

Richardson PG et al. ASCO 2013., abstract # 8584

Relapsed/Refractory MM

• Phase I/II trial investigating Pom+Dex+PLD in R/R MM patients

• Eligibility: progressive disease while on – Phase 1: any regimen – Phase 2: lenalidomide-containing regimen

• 28-d cycle containing – Pomalidomide: daily 2, 3 or 4 mg qd d1-21 – Dex: 40 mg d1, 4, 8, & 11 – PLD: 5 mg/m2 on d1, 4, 8, & 11

A Phase 1/2 Study of Pomalidomide (Pom),

Dexamethasone (Dex) and Pegylated

Liposomal Doxorubicin (PLD) for Patients

with Relapsed/Refractory Multiple Myeloma

Berenson et al. ASCO 2013

Best Response # of Patients %

# evaluable for efficacy 36

PD 6 17%

SD 9 25%

MR 5 14%

PR 15 41%

VGPR 0 0%

CR 1 3%

Overall Response Rate

(PR+VGPR+CR)

16 44%

Clinical Benefit Rate

(MR+PR+VGPR+CR)

21 58%

Results: Pom+PLD+Dex for RR MM

PX-171-003-A0 (N=46)

PX-171-003-A1 (N=266)

Phase 2 Study

Population

Dosing regimen,

premedication,

and hydration

were defined in

003-A0

KyprolisTM

(carfilzomib) for

Injection*

days 1,2,8,9,15,16

(28-day cycles) Maximum 12 cycles

Progressive disease required

at study entry

Relapsed from

≥2 prior lines of therapy

• Must include bortezomib

• Must include thalidomide

or lenalidomide

Refractory to last regimen

Carfilzomib: PX-171-003 Study Overview

Study expanded to registration trial

• Primary endpoint: Overall response rate

– Assessed by an Independent Review Committee, using

International Myeloma Working Group criteria

*Cycle 1, 20 mg/m2

Cycle 2 and beyond, 27 mg/m2

Adapted from Siegel D, et al. ASCO 2011. Abstract 8027 (poster presentation).

PX-171-003-A1: Response

N=266

Response rates*

Overall response rate (ORR)

Complete response

Very good partial response

Partial response

61 (22.9%)

1 (0.4%)

13 (4.9%)

47 (17.7%)

Median duration of response

(95% CI)

7.8 months

(5.6-9.2)

*As assessed by the Independent Response Review Committee

Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies

Bortezomib-Treated Cohort 1 (20 mg/m2 Carfilzomib)

n = 34

ORR 21%

CBR (> MR) 33%

Median TTP 8.1 months

Median DOR (> PR) 11.5 months

Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts.

2011;118(21):813.

Bortezomib-naïve

Cohort 1 (20 mg/m2)

n = 59

Cohort 2 (20→27 mg/m2)

n = 70

ORR 42% 52%

CBR 59% 64%

CR 3% 2%

VGPR 14% 27%

Median TTP 8.3 mo Not reached

Median DOR 13.1 mo Not reached

Median PFS 8.2 mo Not reached

• Nontraditional intrapatient Phase I/II trial • Eligibility: Progressive disease while on

bortezomib or relapsed within 12 wks of the last dose of bortezomib in a combination regimen

• Carfilzomib replaces bortezomib in combination with: – Alkylating agent – Anthracycline – Glucocorticosteroid – IMiD

A Phase I/II Study of Carfilzomib as a Replacement

for Bortezomib for Multiple Myeloma Patients Failing

Bortezomib-Containing Regimens

Study Design (cont’d)

• Study treatment – Carfilzomib

• starting at 20 mg/m2 for the 1st cycle

• increased to 27, 36 and 45 mg/m2 during cycles 2, 3 and 4, respectively if no DLT is observed

– DLT considered > Grade 2

• administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle

– Cycle length, schedule(s) and dose(s) of other drugs identical to that of the previous bortezomib-containing regimen

• A patient must complete a minimum of a full cycle without DLT before continuing onto a subsequent cycle (cycles 1-4 only)

• Maximum # of cycles- 8

Results

Demographics

Enrolled (N) 38

Efficacy (N) 37

Age (median) 67

Sex (M:F) 25:13

Prior Regimens

Number of prior

regimens-

median (range)

6 (1-23)

Number of prior

bortezomib-

containing

regimens-

median (range)

2 (1-13)

Regimen Details

Cycle

length

8 pts- 21-day

24 pts- 28-day

Cycles

completed,

median

(range)

3

(range 0-12)

Follow-up

median

(range)

5.9 mo

(0.4-14.4 mo)

Number of

DLTs

8 (25%)

Regimen in addition to carfilzomib (N=37)

Cyclophosphamide+ ascorbic acid 5 (16%)

Cyclophosphamide+ascorbic

acid+dexamethasone

1 (3%)

Dexamethasone 12 (32%)

Dexamethasone+PLD 6 (16%)

Melphalan 1 (3%)

Bendamustine 3 (8%)

Bendamustine+methylprednisolone 1 (3%)

Lenalidomide 2 (6%)

PLD 1 (3%)

Lenalidomide + dexamethasone 4 (11%)

Lenalidomide + dexamethasone + PLD 1 (3%

Thalidomide + dexamethasone 1 (3%)

Thalidomide + lenalidomide + bendamustine +

biaxin + methylprednisolone

1 (3%)

Best Response # of Patients*

(N=37)

%

PD 3 8%

SD 6 16%

MR 7 19%

PR 7 19%

VGPR 6 16%

CR 2 8%

Overall Response Rate

(PR+VGPR+CR)

13 43%

Clinical Benefit Rate

(MR+PR+VGPR+CR)

18

62%

Efficacy

*- 5 pts not evaluable but counted in denominator

Ixazomib (MLN9708) Plus Lenalidomide and

Dexamethasone in Untreated MM • Ixazomib (MLN9708) is an orally available,

reversible proteasome inhibitor, targeting the 20S subunit

• Low rates of peripheral neuropathy as a single agent

• Study design

– Patients: no previous therapy, no peripheral neuropathy ≥ grade 2

– Phase I dose escalation: 3 + 3 design, up to twelve 28-day cycles

• Induction: oral ixazomib 1.68-3.95 mg/m2 on Days 1, 8, 15; lenalidomide 25 mg on Days 1-21; dexamethasone 40 mg on days 1, 8, 15, 22

• Maintenance: ixazomib until disease progression or toxicity

– Phase II expansion: ixazomib at 2.23 mg/m2

Kumar SK, et al. ASH 2012. Abstract 332.

Ixazomib + Lenalidomide/Dexamethasone

Responses and Efficacy

Kumar SK, et al. ASH 2012. Abstract 332.

Ixazomib at 2.23 mg/m2

Pati

en

ts (

%)

≥ VGPR 58%

≥ VGPR 49% ≥ VGPR

58%

ORR 94% ORR 95% ORR 90%

Estimated probability of survival at 1 yr: 93%

CR

VGPR

PR

100

90

80

70

60

50

40

30

20

10

0 After 4 Cycles

(n = 47) After 8 Cycles

(n = 19)

Overall (n = 52)

45

30

19

37

26

32

32

35

23

PANORAMA 2 Phase II Trial of the Histone Deacetylase

Inhibitor Panobinostat + Bortezomib + Dex in Relapsed and

Bortezomib-Refractory Multiple Myeloma: Clinical

Response by Baseline Characteristics

• Dose and Schedule: All pts entered phase 1; those with

clinical benefit went to phase 2 – Treatment phase 1: Up to eight 21-day cycles of: bortezomib 1.3 mg/m2 IV

days 1, 4, 8, 11; panobinostat 20 mg days 1, 3, 5, 8, 10, 12; Dex 20 mg

days 1, 2, 4, 5, 8, 9, 11, 12

– Treatment phase 2 (n=17): 42-day cycles until PD of: bortezomib 1.3

mg/m2 IV days 1, 8, 22, 29; panobinostat 20 mg days 1, 3, 5, 8, 10, 12, 22,

24, 26, 29, 31, 33; Dex 20 mg days 1, 2, 8, 9, 22, 23, 29, 30

• Safety: Most common grade 3/4 AE: 64%

thrombocytopenia, 20% diarrhea, 20% fatigue, 15% each

anemia, neutropenia, and pneumonia

• Quality of life (QoL): 16/17 pts in phase 2 were assessed

for QoL; PN and other QoL measures appeared to be

unchanged over course of the study Alsina, et al. ASCO 2013, abstract #8531 Relapsed/Refractory MM

PANORAMA 2 Phase II Trial of Pan + Bort + Dex in

Relapse and Refractory Multiple Myeloma

Alsina, et al. ASCO 2013, abstract #8531

Relapsed/Refractory MM

Baseline characteristics n ORR, %

(95% CI)

CBR, %

(95% CI)

PFS, mos

(95% CI)

All patients 5

5 35 (22–49) 53 (39-66) 5.4 (3.5-6.7)

Dex in last

bortezomib-

containing

regimen

Yes 45 27 (15-42) 47 (32-62) 4.9 (2.6-6.7)

No 10 70 (35-93) 80 (44-98) 6.2 (2.6-8.3)

Dex in last prior

line of therapy

Yes 37 32 (18-50) 54 (37-71) 4.2 (2.6-6.7)

No 18 39 (17-64) 50 (26-74) 6.5 (2.6-9.7)

Anti-CS-1 Antibody Elotuzumab and Bortezomib for R/R MM: A Phase I Trial

Jakubowiak AJ et al. ASH 2010, abs #3023

•Objectives: Primary: MTD; Secondary: safety, efficacy, elotuzumab PK/PD

•Patients: 28 pts; median age 63 (41–77); median 2 (1–3) prior therapies; 39% prior bortezomib; 43% refractory to last treatment, 14% refractory to bortezomib

•Dose: 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; elotuzumab 2.5, 5, 10, or 20 mg/kg on days 1 and 11; premed w/ methylprednisolone 50 mg, diphenhydramine and acetaminophen; pts with ≥SD after 4 cycles continued therapy until progression; Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 added at cycle 3 in 2 pts

Jakubowiak AJ et al. J Clin Oncol 2012

Elotuzumab and Bortezomib for R/R MM: Results

•MTD: Not reached at doses up to elotuzumab at 20 mg/kg with bortezomib 1.3 mg/m2 d1, 4, 8, & 11 on a 21-day cycle

DLT: None observed

•ORR (> PR): 48%* (7% CR; 41% PR)

•MR: 15%

•CBR: 63%

•Median TTP: 9.5 mo

Jakubowiak AJ et al. J Clin Oncol 2012

*however, only 39% previously exposed to

bortezomib and only 11% refractory to bortezomib

Elotuzumab (E), Lenalidomide (L) & Dexamethasone (D) for R/R MM: A Phase I Trial

Jakubowiak AJ et al. ASH 2010, abs #3023

Objectives: Primary: MTD; Secondary: safety, efficacy, immunogenicity, pharmacokinetics, & pharmacodynamics

•Patients: 29 pts; median age 60 (40–83); median 3 (1–10) prior therapies: L 21%, bortezomib 69%, thalidomide 59%; 41% refractory to last treatment, ? refractory to L

•Dose: 28-day cycles of E at 5, 10, or 20 mg/kg on days 1, 8, 15, & 22 during cycles 1 & 2 and days 1 & 15 subsequently (steroids & diphenhydramine allowed); L 25 mg qd d1-21; D 40 mg qwk

Lonial et al. J Clin Oncol 2012

Elotuzumab (E), Lenalidomide (L) &

Dexamethasone (D) for R/R MM: Results

•MTD: Not reached at doses up to E at 20 mg/kg with L 25 mg, and D 40 mg

•DLT: None observed

•89% infusion reactions

•ORR (> PR): 82% (32% > VGPR; 50% PR)

• 95% ORR among lenalidomide-naïve pts

• However, only 33% ORR among lenalidomide-exposed pts

•Median TTP: Not reported

Jakubowiak AJ et al. J Clin Oncol 2012

Novel Combinations and New Drugs Greatly Expand

the Therapeutic Options for R/R Myeloma Patients!

• Approved drugs – Novel combinations

– Modifications of dose and schedule

• Improve efficacy

• Better tolerability

• Many new drugs in development – Similar targets

• Proteasome inhibitors- carfilzomib- FDA-approved

• IMiDs- pomalidomide- FDA-approved

– New classes of agents

• Monoclonal antibodies

– Anti-CS-1- elotuzumab

– Anti-CD40- dacetuzumab

• MTOR inhibitors- temsirolimus

• PI3K inhibitors- perifosine

• HDAC inhibitors- vorinostat, panobinostat

• Antibody-based conjugates