Wei Ai, M.D., Ph.D. June 2012

I. Lymphoma: bendamustine II. CLL/SLL: Btk inhibitor III. Pre-B ALL: Bite biphasic antibody IV. Multiple Myeloma: Carfilzomib

National LymphoCare Study N = 2728 Friedberg, et al., JCO 2009 R + chemotherapy: RegimenUsers (%) RCHOP 55.0% RCVP23.1% R-fludarabine15.5% Other6.4%

 Newly diagnosed indolent lymphoma or mantle cell lymphoma: - Follicular lymphoma (grade 1-3a), small lymphocytic lymphoma, marginal zone lymphoma, wadenstroms, mantle cell lymphoma (elderly)  Stage III and IV  Meet criteria for initiating treatment

Samantha Mary Jaglowski, et al. The Ohio State University

 BTK inhibitor, an oral agent, showed promising activity as a single agent in untreated elderly pts (>65 yo) with CLL/SLL (John Byrd 2012 ASCO) - N = 26 - ORR 81%, CR 12% with medium f/u 14 mos  Ofatumumab is active in fludarabine- or alemtumumab-refractory CLL/SLL pts: ORR approximately 50% Wierda, et al., JCO 2010

 Ibrutinib 420 mg po qd  Oftumumab mg C2, day mg C2,days 8, 15, mg C3, days 1, 8, 15, mg C4-8, day 1 only

 To determine the toxicity of the combination regimen - Tolerability is defined as no more than 1 DLT in the first 6 pts treated for 2 cycles  To evaluate ORR at one year: N = 27, including the initial 6

 CLL/SLL or Richter’s transformation  Two or more prior therapy, including a purine analog- containing regimen  More than 10% CD20 expression on CLL cells by flow cytometry  Adequate organ functions

 Ibrutinib combined with ofatumumab is a well tolerated and highly active regimen in patients with relapsed and refractory CLL/SLL

Max Topp et al.

Topp, et al., JCO % 15 ug/m 2 /24 hrs CIV x 4 weeks, 2 weeks off, q 6wk-cycle

 Dose-finding Phase: - Cohorts: 1, 2a, 2b  Expansion Phase:  Dosing: CIV 4 wks on, 2 wks off, for up to 5 cycles - CR/CRh within the first 2 cycles -> allo  Primary Endpoint: CR/CRh within 2 cycles

 R/R ALL, > 5% blasts in BM  Ph+ and relapsed after allo were permitted

 Selected dose for expansion cohort based on lowest treatment-related AEs (3/5 pts): 5ug/m2/d CIV week 1, then 15ug/m2/d CIV thereafter

N = 23 Median Age 31 (21 – 66) Refractory1 (4%) Relapsed21 (91%) 1 st relapse <= 18 mos 9 (43%) 1 st relapse > 18 mos4 (19%) >= 2 nd relapse8 (38%) Prior SCT10 (43%) Ph +2 (9%) T (4,11)1 (4%) Blasts in BM >60%12 (52%) 10% - 60%6 (24%) < 10%4 (17%)

 Cytokine release syndrome - Risks: high tumor burden ans without cytoreductive phase - Prevention: cytoreduction 5ug/m2 wk 1 and give Dex for BM>50%  CNS Adverse Events: - 3 seizures and 3 encephalopathy: fully reversible - all 6 pts continued at 5 ug/m2  One pt died of fungal infection

 CR/CRh: 17/23 pts (74%)  All but 2 responders achieved molecular remission  High remission rate in all pt groups, including Ph+  13 pts received an allogeneic SCT  With a median follow-up of 4.5 months, median duration of response was 8.9 for all cohorts, not yet reached for the expansion cohort

 Well-tolerated at 5 ug/m2/d followed by 15 ug/m2/d CIV, 4 weeks on, 2 weeks off  High hematologic and molecular response rate  Median duration of complete hematologic response was 8.9 months  Median survival was 9 months

Carfilzomib Coming to the Front-line

 Disease status - High risk, intermediate risk vs low risk - special clinical scenarios: plasma leukemia, renal failure  Patient factors - Transplant eligibility - PS and comorbidity  Clinical benefit - response and OS - QOL  Toxicity and convenience  Cost

 Newly approved second-in-class proteasome inhibitor  Well tolerated, no neurotoxicity  Overcome bortezomib resistance in vitro  Active alone and in combination regimens for relapsed/refractory MM Kuhn et al., Blood 2007, O’Connor Clin Cancer Res 2009, Wang, M et al., JCO 2011 Abstract 8052, Vij, et al., Blood, 2012

CMP carfilzomib, melphalan, prednisone CYCLONE carfilzomib, cyclophosphamide thalidomide dexamethasone CRd carfilzomib, lenalidomide dexamethasone Key CriteriaTransplant ineligible >65 yo Transplant eligibleTransplant ineligible or eligible Comparative or Parent regimens VMPCyBorD CTD RVD,VTD, VTD

 Carfilzomib: 20mg/m 2 first week, 27mg/m 2 thereafter

Stringent complete response (sCR) in patients with newly diagnosed multiple myeloma (NDMM) treated with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) AJ Jakubowiak, 1 K Griffith, 2 D Dytfeld, 3 DH Vesole, 4 S Jagannath, 5 T Anderson, 2 B Nordgren, 2 K Detweiler-Short, 2 D Lebovic, 2 K Stockerl-Goldstein, 6 T Jobkar, 2 S Wear, 7 A Al-Zoubi, 2 A Ahmed, 2 M Mietzel, 2 D Couriel, 2 M Kaminski, 2 M Hussein, 8 H Yeganegi, 9 R Vij 6 1 University of Chicago, Chicago, IL; 2 University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; 3 Poznan University of edical Sciences, Poznan, Poland; 4 John Theurer Cancer Center, Hackensack, NJ; 5 Mount Sinai Medical Center, New York, NY; 6 Washington University School of Medicine, St. Louis, MO; 7 Multiple Myeloma Research Consortium, Norwalk, CT; 8 Celgene, Inc, Summit, NJ; 9 Onyx Pharmaceuticals, South San Francisco, CA

Objectives Primary Phase 1: MTD of CRd Phase 1/2: rate of ≥nCR Secondary Overall response rate (≥PR) TTP, DOR, PFS, and OS Tolerability and toxicity For transplant candidates, evaluate the impact of CRd on stem cell mobilization Evaluate prognostic factors and markers of response 4

Eligibility Key inclusion criteria Newly-diagnosed MM requiring first-line therapy 1 - Transplant-eligible and -ineligible Measurable disease per IMWG Criteria 1 ECOG performance status 0-2 Key exclusion criteria Grade 3/4 peripheral neuropathy ANC <1.0 x10 9 /L, Hgb <8.0 g/dL, platelets <75,000/µL Creatinine clearance <50 mL/min or serum creatinine ≥2 g/dL Serious co-morbidities 1. Durie BGM, et al. Leukemia. 2006;20:

Treatment Schema Transplant- eligible and -ineligible patients CRd Induction - CRd Cycles 1-4CRd Cycles 5-8 Transplant-eligible ≥PRASCT Stem cell collection CRdLenalidomide Maintenance(off protocol) CRd Cycles 9-24LEN Cycles 25+ Until disease progression or unacceptable toxicity Assessments on D1 and 15 of C1 and D1 thereafter using modified IMWG Criteria with nCR Cycles CFZ mg/m 2 Days 1-2, 8-9, LEN 25 mg Days 1-21 DEX 40 mg weekly Cycles 1- 4, 20 mg weekly Cycles 5-8 Cycles CFZ on Days and only CFZ, LEN, DEX at last best tolerated doses Cycles 25+ LEN at last best tolerated dose 1. Jakubowiak AJ, et al. Blood. 2011;118: abstract

Best Response Median 12 cycles (range 1-25 ) ≥PR ≥VGPR≥nCRsCR All patients N=53 There was no difference by disease stage and cytogenetics 9

Progression-free Survival Median follow-up of 13 months (range 4-25) 2 patients progressed All patients with sCR have maintained response for median 9 months (range 1-20) 12

Updated Toxicity of CRd Induction Thrombocytopenia Grade 3/4 Anemia Neutropenia Any grade Hyperglycemia Edema Hypophosphatemia Fatigue Muscle cramping LFTs Rash Diarrhea Infection Phlebitis Peripheral neuropathy Dyspnea DVT/PE Renal Constipation Mood alterations Patients (%) Toxicity for cycles 1-8 is similar to previously reported 1 Limited dose modifications 1. Jakubowiak AJ, et al. Blood. 2011;118: abstract

CMP carfilzomib, melphalan, prednisone N = 35 CYCLONE carfilzomib, cyclophosphamide thalidomide dexamethasone N = 24 CRd carfilzomib, lenalidomide dexamethasone N = 53 Transplant ineligible >65 yo Transplant eligibleTransplant ineligible or eligible Comparative or Parent regimens VMPCyBorD CTD RVD,VTD, VTD ORR - CR - sCR - nCR - VGPR - PR 31(89%) 1 (3%) 14 (40%) 16 (46%) 23 (96%) 7 (29%) 11 (46%) 5 (21%) 52 (98%) 33 (62%) 22 (42%) 11 (20%) 10 (19%) 9 (17%)

 Highly active as a first-line treatment for MM  The quality of response seems improved in some studies  Tolerability seems improved with minimum peripheral neuropathy, although comparison with SQ bortezomib remain to be investigated

 Lymphoma and CLL/SLL The Stil trial established R-Benda as the preferred first-line treatment for FL and MCL Ofatumumab + ibrutinib (Btk inhibitor) is highly active in relapsed/refractory CLL/SLL  Acute Leukemia Blinatumumab (Bite biphasic antibody) is highly active in relapsed/refractory ALL  Multiple Myeloma Carfilzomib is moving to the front line

Grade 3/4 CHOP-R N =253 BR N = 261 Neutropenia69%29% lymphopenia43%74%

Topp, et al., JCO 2011