MSN, ANP-BC, AOCNP1*, R.

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1 R2V2: Lenalidomide, Bortezomib, and Dexamethasone (RVD) in Combination with Vorinostat As Front-Line Therapy for Patients with Multiple Myeloma (MM): Results of a Phase 1 Study Jonathan L. Kaufman, MD 1, Jatin J. Shah, M.D. 2, Jacob P. Laubach, MD 3, Alaina R. Mitchell, BS 1*, Cathy Sharp, R.N. 1*, Zhengjia Chen, PhD Colleen Lewis, MSN, ANP-BC, AOCNP 1*, R. Donald Harvey, PharmD 1, Charise Gleason, MSN, ANP-BC, AOCNP 1*, Daniela Casbourne, FNP-BC, AOCNP 1*, Lorrie Graham 1, Emily Cao 2, Heather Goddard 3, Ajay K. Nooka, MD, MPH, FACP 1, Leonard T Heffner, MD 1, Paul G. Richardson, MD 3, Robert Z. Orlowski, M.D., Ph.D. 2 and Sagar Lonial, MD 1 1Department of Hematology and Medical Oncology Winship Cancer Institute of Emory University, Atlanta, GA 2Department of Lymphoma/Myeloma, University of Texas M. D. Anderson Cancer Center, Houston, TX 3LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA

2 Disclosures Research Funding: Celgene, Merck, Onyx, Novartis Speaking : None Consultant: Onyx, Celgene, Millenium, Novartis

3 Background The combination of bortezomib, lenalidomide and dexamethasone (RVD) is safe and effective in patients with newly diagnosed myeloma 1 Overall response rate of 100% and VGPR rate or better of 74% in the phase II population Addition of anthracyclines or alkylating agents to RVD has been feasible, but not associated with improved outcome 2, 3 We hypothesize that the addition of novel agents can be safe, increase CR rate and enhance depth of response 1. Richardson et al; Blood; 5 August 2010; 115; Jakubowiak et al; Blood; 21 July 2011; 118; 3, Kumar et al; Leukemia Jul;24(7):

4 R2V2: Preclinical Rationale Preclinical studies demonstrate synergy with combination of bortezomib, dexamethasone and immunomodulatory drugs with histone deacetylase inhibitors 1, 2, 3 1. Pei et al, Clin Cancer Res Jun 1;10(11): Nawrocki et al, Blood Oct 1;112(7): Mitsiades et al, Proc Natl Acad Sci U S A Jan 13;101(2):540-5.

5 R2V2: Clinical Rationale 095 Study in Bortezomib refractory patients Vorinostat + Bortezomib N = 143 ORR 17% CBR ( MR) 31% DCR ( SD) 77% Median PFS 3.13 mos Median OS 11.2 mos ORR, overall response rate; CBR, clinical benefit rate; MR, marginal response; DCR, disease control rate; SD, stable disease; PFS, progression-free survival; OS, overall survival. Response Vorinostat / Lenalidomide / Dexamethasone N = 28 ORR 46% CR 7% > SD 86% Serious AE Neutropenia, diarrhea, QTc, extrasystole, dehyd ration, troponin, fever Grade 3 DVT in 2 pts No treatment-related deaths Siegel DS, et al. ASH Annual Meeting Abstracts Abstract 480. Siegel D, et al. Blood. 2009;114(22). Abstract 305. Vorhees PM, et al. Blood. 2009;114(22). Abstract 306.

6 Study Objectives Primary Objective: To determine the MTD of the combination of vorinostat with RVD in newly diagnosed multiple myeloma patients Secondary Objectives: Efficacy as measured by response rate and time related endpoints Evaluate tolerability and toxicity Evaluate impact on stem cell collection and transplant feasibility

7 R2V2: Patients Key Inclusion criteria: Newly diagnosed MM No previous systemic MM therapy (bisphosphonates permitted) Karnofsky Performance Status (KPS) 60% Key Exclusion criteria: Peripheral Neuropathy G 2 Creatinine Clearance < 60 ml/min Platelets <50,000 cells/mm 3 Absolute neutrophil count (ANC) <1,000 cells/mm 3 Hemoglobin <8.0 g/dl Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) 2 upper limit of normal (ULN)

8 R2V2: Treatment Schedule Dose escalation of Vorinostat Up to eight 21-day cycles Bz Bz Bz Bz Dex Dex Dex Dex Vorinostat Lenalidomide *Dex, 20 mg/day Days 1, 2, 4, 5, 8, 9, 11 and 12; 10 mg, cycles 5 8 Pts PR may proceed to ASCT after 4 cycles Maintenance therapy permitted after C8 in pts SD using lenalidomide and/or bortezomib (investigator s choice) Risk-directed anti-thrombotic therapy with daily aspirin (81 or 325 mg) or LMWH or Coumadin (with target INR 2-3) Antiviral therapy as prophylaxis against Herpes Zoster required

9 R2V2: Study Schema Dose Level Assigned Therapy Level 1 25 mg lenalidomide daily on days 1-14 followed by 7-day rest every 21 d. 1.3 mg/m 2 bortezomib daily on days 1, 4, 8 and mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, mg vorinostat daily days 1-14 followed by 7 day rest every 21 days Level 2 25 mg lenalidomide daily on days 1-14 followed by 7-day rest every 21 d. 1.3 mg/m 2 bortezomib daily on days 1, 4, 8 and mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12 and 200mg vorinostat daily days 1-14 followed by 7 day rest every 21 days Level 3 25 mg lenalidomide daily on days 1-14 followed by 7-day rest every 21 d. 1.3 mg/m 2 bortezomib daily on days 1, 4, 8 and mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12 and 300mg vorinostat daily days 1-14 followed by 7 day rest every 21 days Level 4 25 mg lenalidomide daily on days 1-14 followed by 7-day rest every 21 d. 1.3 mg/m 2 bortezomib daily on days 1, 4, 8 and mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12 and 400mg vorinostat daily days 1-14 followed by 7 day rest every 21 days

10 Statistical Design: Escalation with Overdose Control 1 (EWOC) Tighiouart M, Rogatko A, Babb JS. Stat Med Jul 30;24(14):

11 DLT Definition; DLT determined in Cycle 1 Grade 3 or greater non-hematologic toxicity except the following, Nausea or vomiting that responds to symptomatic therapy Fatigue that responds to maximal management Grade 4 hematologic toxicities defined as : i) Grade 4 thrombocytopenia of any duration; ii) failure of ANC to recover to 1,000/μL or platelets to 50,000/μL within 14 days of the last treatment. Inability to receive Day 1 dose for Cycle 2 due to continued drug related toxicity from cycle one or drug related toxicity newly encountered on day 1 of cycle 2.

12 R2V2: Baseline characteristics N=30 Characteristic Median age (range), years 56 (40-76) Male, n (%) 19 (63) Myeloma type, n (%) IgG 20 (67) IgA 7 (21) light-chain only 3 (10) ISS stage II/III at diagnosis, n (%) 12 (40)

13 Comparison of recommended dose versus actual dose VORINOSTAT (mg) * * ** * ** * * MTD=265mg Dose EWOC *=DLT Patient Number

14 Toxicities occurring in 10% Adverse Event: n=30 Grade 1/2 Grade 3 Grade 4 Grade 5 Agitation 1 1 ALT Elevation 1 3** 1* Anorexia 4 Anxiety 7 1 Cardiovascular 1 1 1* Constipation 18 Confusion 3 Diarrhea 10 Dizziness 5 Dyspepsia 7 Dyspnea 3 Edema 7 Eye/Vision 7 Fatigue 10 1 Hypokalemia 6 Hypotension 1 1* Increased Creatinine 1 1* Infection 5 1 Insomnia 7 Memory Difficulty 5 Muscle Weakness 1 Nausea/Vomiting 10 Neutropenia 3 Pulmonary Embolism 2* Rash 5 Sensory Neuropathy 9 2 Syncope 2* Taste Disturbance 3 Thrombocytopenia 2* Tremor 4 Upper respiratory illness 8

15 All grade 3 of higher toxicities Adverse Event Grade 3 Grade 4 Grade 5 % of Total n=30 ALT Elevation 3** 1* 0 13 Anxiety Cardiovascular 1 1 1* 10 Fatigue Hypotension 1* Creatinine 1* Infection Weakness Neutropenia PE/DVT Neuropathy Syncope 2** Thrombocytopenia *=DLT

16 R2V2: Response to Treatment scr % ncr + CR % VGPR % ORR % Response after cycle 4 (N=24) Response after cycle 8 (N=12) Overall response (N=30) 4 cycles 8 cycles Overall Response scr % ncr or CR % VGPR % ORR %

17 Stem Cell Mobilization/Transplant All attempts at stem cell collection were successful Number of cells collected (median): 9.87 * 10 6 CD34+cell/kg in two days Seven patients were transplanted All patients engrafted with no unexpected toxicity Pre-transplant Response PR (n=2) VGPR (n=2) ncr (n=2) scr (=2) scr (n=1) Post-transplant Response VGPR (n=1); scr (n=1) ncr (n=1); scr (n=1) scr (n=1)

18 R2V2: Event Free Survival

19 R2V2: Overall Survival

20 R2V2: Future Plans Evaluate Day 8 SFLC change as predictor of outcome Evaluate post cycle 8 bone marrow for MRD by flow Evaluate activity in high risk myeloma (adverse cytogenetics, extramedullary disease) Evaluate level of acetylated tubulin; (expected to be increased in the setting of HDAC 6 inhibition)

21 Conclusions/Future Directions Combination of RVD with vorinostat using the classical dose and schedule proved most tolerable at 200mg vorinostat dosing D1-14 every 21 days. High CR and rapid VGPR rate (75% at four cycles) along with favorable PFS suggest that this is a highly effective combination Alternative dosing and schedule of vorinostat may improve tolerability and so enhance clinical benefit, thus warranting further study.

22 Acknowledgments The patients and their families Research nurses, coordinators and other staff at all study sites Merck Pharmaceuticals Celgene Corporation