A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car- Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma

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1 A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car- Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma Jatin J. Shah, MD 1, Edward A. Stadtmauer, MD 2, Rafat Abonour, MD 3, Adam D. Cohen, MD 4, William I. Bensinger, MD 5, Cristina Gasparetto, MD 6, Jonathan L. Kaufman, MD 7, Suzanne Lentzsch, MD 8, Dan T. Vogl, MD 2, Robert Z. Orlowski, MD, PhD 1, Erica L. Kim, MPH 9, Marti McKinley, BSN, MBA 9, Brian G.M. Durie, MD 10 1 MD Anderson Cancer Center, Houston, TX, USA 2University of Pennsylvania Abramson Cancer Center, Philadelphia, PA, USA 3Indiana University Simon Cancer Center, Indianapolis, IN, USA 4Fox Chase Cancer Center, Philadelphia, PA, USA 5Fred Hutchinson Cancer Research Center, Seattle, WA, USA 6Duke University Medical Center, Durham, NC, USA 7Winship Cancer Institute of Emory University, Atlanta, GA, USA 8Columbia University Herbert Irving Comprehensive Cancer Center, NY, NY, USA 9 Academic Myeloma Consortium (AMyC), CORE Science Solutions, A Criterium Company, Culver City, CA, USA 10Cedars Sinai Samuel Oschin Cancer Center, Los Angeles, CA, USA Academic Myeloma Consortium (AMyC)

2 PI Disclosures Research Funding: Onyx, Celgene, Novartis, Array Biopharma, Millennium Speaking : None Advisory Board: Onyx, Celgene, Array

3 Background Carfilzomib 1, a novel irreversible proteasome inhibitor (PI), has demonstrated single agent activity in relapsed and refractory MM, and recently received FDA regulatory approval for this indication Pomalidomide 2 is the third drug in the Immunomodulatory Drug (IMiD) class in clinical development with single agent activity in Lenalidomide refractory patients. Preclinical data 3 support the combination of proteasome inhibitors and Imids to overcome resistance and improve response rates Combination of Bortezomib and Lenalidomide/dex 4 and early data with Carfilzomib and Lenalidomide/Dex result in encouraging high response rates in newly diagnosed and relapsed MM The hypothesis is that the combination of Carfilzomib and Pomalidomide with dexamethasone (Car-Pom-d) is highly active in RRMM 1 Jagannath S, et al. Clin Lymphoma Myeloma Leuk Oct;12(5): doi: /j.clml Vij R, et al. Br J Haematol Sep;158(6): doi: /j x. Epub 2012 Jul Siegel, et al. Blood Oct 4;120(14): doi: /blood Epub 2012 Jul 25 2 Lacy MG, et al. Leukemia November; 24 (11): Mitsiades N, et al. Blood 99: (2002). 3 Hideshima T, et al. Blood 96: (2002). 4 Richardson PG, et al. Blood Aug 5;116(5): Epub 2010 Apr Richardson PG, et al. J Clin Oncol Dec 1;27(34): Epub 2009 Sep Niesvizky R, et al. Blood (ASH Annual Meeting Abstracts). Nov 2009; 114: 304.

4 Study Objectives Primary Objectives: To evaluate the safety and determine the maximum tolerated dose (MTD) of the combination of Carfilzomib and Pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma (RRMM) Secondary Objectives: To perform a preliminary evaluation of the efficacy of Car-Pom-d including: Overall response (SD, MR, PR, VGPR, CR, scr) Time to progression (TTP) Progression free survival (PFS) Time to next therapy Overall survival (OS)

5 Study Design Phase 1 Dose Escalation Study with dose expansion at Maximum Tolerated Dose (MTD) 3+3 Dose Escalation Carfilzomib Pomalidomide Dexamethasone Start Dose Level Cohort mg/m 2 * 3 mg 40 mg** Cohort 1 (initial dose level) 27 mg/m 2 * 4 mg 40 mg** Cohort 2 36 mg/m 2 * 4 mg 40 mg** Cohort 3 45 mg/m 2 * 4 mg 40 mg** Cohort 4 56 mg/m 2 * 4 mg 40 mg** * Carfilzomib doses on days 1 and 2 of Cycle 1 for all cohorts was 20 mg/m 2 ; all subsequent dosing will be as shown in the table above. ** Dexamethasone reduced to 20 mg after cycle 4

6 Study Schema Cycle 1-6: 28 day cycle Carfilzomib Pomalidomide 1 21 Dexamethasone Cycle 7 + : Maintenance Cycles Carfilzomib dosed on days 1, 2, 15, 16; Pomalidomide/dex unchanged Patients treated until Progressive Disease / Unacceptable toxicity Concomitant Medications: Anti-viral therapy Anticoagulation: Aspirin 81 mg; LMWH in ASA intolerant

7 Key Inclusion Criteria Relapsed and/or refractory multiple myeloma All patients must have received prior lenalidomide therapy and have been determined to be refractory Refractory defined as 25% response or progression during therapy or within 60 days after completion of a regimen containing full or maximally tolerated dose of lenalidomide administered for a minimum of at least two completed cycles of therapy. Measurable disease ECOG 0-2 Adequate hematologic, renal, liver, cardiac function

8 Patient Demographics Gender ECOG PS N = 32 Male: 20 (62.5%) Female:12 (37.5%) 0 : 16 (50%) 1 : 14 (44%) 2 : 2 (6%) Age, Median (Range) 63.5 yrs (44 to 78) N prior regimens, Median (Range) 6 regimens (1 to 15) Yrs since initial Dx Median (Range) 5.0 yrs (1.2 to 9.1)

9 Prior Therapies Prior stem cell transplant 21 (65.6%) Prior bortezomib 31 (97%) All but 2 refractory* Prior lenalidomide 32 (100%) All refractory * Includes multiple bortezomib combos

10 FISH / Cytogenetics (n=31*) Hyperdiploid 9 (33%) del(1) 2 (7%) del(13) 10 (33%) del(17p) / p53 6 (19%) t(11;14) 6 (21%) t(14;16) 1 (4%) t(4;14) 3 (10%) * FISH/cytogenetics missing in 1 patient

11 Phase I MTD Cohort level 1: 1 of 6 patients experienced a protocol-defined DLT of febrile neutropenia Cohort level 2 (carfilzomib 20/36 mg/m 2, pomalidomide 4 mg, dexamethasone 40 mg): 2 of 6 patients experienced DLTs consisting of grade 4 thrombocytopenia and grade 3 rash The MTD was established as the starting dose level (carfilzomib 20/27 mg/m 2, pomalidomide 4mg, dexamethasone 40 mg) 12 patients enrolled in phase I + 20 additional patients enrolled at MTD

12 Hematologic Adverse Events (Grade 1-4) n=32 G 1 G 2 G 3 G 4 Total Anemia Thrombocytopenia Neutropenia Febrile neutropenia Low Incidence of Febrile Neutropenia of 6% Toxicities reversible and manageable

13 Non-hematologic Adverse Event ( 20% patients) G 1 G 2 G 3 G 4 total Diarrhea (31%) Fatigue (56%) Dyspnea (28%) Skin, Rash, Pruritis (21%) Creatinine elevated (26%) Hypocalcemia (34%) No Grade 3/4 Peripheral Neuropathy Notable SAE: G3 Pnuemonia ( n=3) ; Pulmonary Emboli ( n=1); Congestive Heart Failure (n=1) Numbers (%)

14 Response Rates N = 30 Overall Response Rate ( PR) 15 (50%) VGPR 4 (13%) PR 11 (37%) MR 5 (17%) SD 7 (23%) PD 3 (10%) Clinical Benefit Rate ( MR) of 67%

15 Progression Free Survival 100% Progression-Free Survival Percentage 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Car-Pom-Dex PFS (N = 32) 95% Confidence Interval Median PFS = 7.4 months Time in Study (Months)

16 Overall Survival (months) 100% 90% Overall Survival Percentage 80% 70% 60% 50% 40% 30% 20% 10% 0% Car-Pom-Dex OS (N = 32) 95% Confidence Interval Time in Study (Months)

17 Responses by Risk Status* VGPR PR MR SD PD High (n=5) 17p- positive / t(14:16) Intermediate (n=6) t(4;14) positive / hypodiploid Standard (n=18) Hyperdiploid / t(11;14) Total Patients (n=29) * msmart Risk Classification ** 1 pt did not have FISH/cytogenetics data Responses are preserved in patients with high risk FISH/cytogenetics

18 Survival and Risk Status Progression Free Survival Overall Survival Progression-Free Survival Percentage 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% High & Intermediate Standard Standard Risk (N = 18) Intermediate + High Risk (N = 13) Time in Study (Months) Overall Survival Percentage 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% High & Intermediate Standard Standard Risk (N = 18) Intermediate + High Risk (N = 13) Time in Study (Months) Responses and survival are sustained and durable independent of risk status

19 Conclusions The maximum tolerated dose was Carfilzomib 20/27 mg/m 2, Pomalidomide 4 mg, and dexamethasone 40 mg in relapsed/refractory myeloma There are limited G 3 and 4 non hematologic toxicities; the regimen was tolerated well with no unexpected toxicity The combination of Car-Pom d is highly active in this heavily pretreated, refractory patient population VGPR 13% ORR 50% CBR 67% PFS (median) 7.4 months OS 1 year The combination has encouraging preserved response rate and survival independent of FISH/cytogenetic risk status Enrollment is ongoing in an 82 patient phase II trial within AMyC

20 Acknowledgment Academic Myeloma Consortium: Dr. Brian Durie Unique Collaboration of Academic Myeloma Centers of Excellence Onyx and Celgene: Collaboration between two pharmaceutical companies Patients/Caregivers/Families Research staff

21 Columbia University Department of Medicine Division of Hematology/Oncology