Relapsed and Refractory Myeloma Case 2 James R. Berenson, MD Medical & Scientific Director Institute for Myeloma & Bone Cancer Research Los Angeles, CA

Relapsed/Refractory Multiple Myeloma: Case 2 (Case 1 cont’d) Patient starts lenalidomide 10 mg qd d1-21, 7 d off, & methylprednisolone 40 mg po qod After 4 months, IgG 1050 (from 1800), M-protein 0.50 (from 1.01), & 24 hour urine M-protein 50 mg (from 237 mg); hemoglobin 11.8 After 9 months, increasing back pain & fatigue Work up MRI shows new VCF at T7 Labs: IgG 1790, M-protein 1.33, 24 urine M-protein 287 mg, hemoglobin 9.8, creatinine 1.6 Treatment Kyphoplasty at T7 w/ pain relief Patient is continued on zoledronic acid monthly What else would you do?

Relapsed/Refractory Multiple Myeloma: Case 2 (Case 1 cont’d) What else could you do? Add clarithromycin Increase lenalidomide to 25 mg Add bortezomib and/or PLD Start carfilzomib Start pomalidomide w/ steroids All of the above are options

POM ± LoDEX in RRMM MM-002 Phase 2—Study Design Objective: To determine the efficacy and safety of POM ± LoDEX Primary endpoints: PFS Secondary endpoint: ORR, safety, DOR, OS R 1:1 N = 221 Age ≥ 18 y RRMM Prior Tx with LEN and BORTa Measurable M-protein ≥ 2 prior therapies Documented progression during or within 60 days of last Tx 28-day cycles POM (4 mg) D1-21 (n = 108) POM (4 mg) D1-21 + LoDEX (40 mg/wk)b (n = 113) Discontinue and follow up for survival and subsequent treatment Option to add LoDEX (40 mg/wk) (n = 64) Progressive disease Progressive disease a Prior Tx with ≥ 2 cycles of LEN and BORT (separately or in combination); b Patients aged > 75 years had a starting DEX dose of 20 mg/week. BORT: bortezomib; DOR: duration of response; LEN: lenalidomide; LoDEX: low-dose dexamethasone; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; POM: pomalidomide; R: randomized; RRMM: relapsed/refractory multiple myeloma; Tx: treatment. Jagannath S. Blood. 2012;120: [oral presentation, abstract 450]. 4

POM ± LoDEX in RRMM MM-002 Phase 2—Response by EBMT Criteria Response rates were higher with POM + LoDEX vs. POM Median DORa was similar (8.3 and 8.8 mo; HR = 0.89; P = 0.734) Median time to responsea was 1.9 and 3.7 mo, respectively a For patients achieving ≥ PR. CR: complete response; DOR: duration of response; EBMT: European Group for Bone Marrow Transplant; HR: hazard ratio; LoDEX: low-dose dexamethasone; MR: minimal response; POM: pomalidomide; PR: partial response; RRMM: relapsed/refractory multiple myeloma. Jagannath S. Blood. 2012;120: [oral presentation, abstract 450]. 5

MM-003 POM + LoDEX vs HiDEX in RRMM Phase 3 —Trial Design Primary endpoint: PFS Key secondary endpoints: OS, ORR (≥ PR), DOR, safety (n = 302) POM: 4 mg D1-21 LoDEX: 40 mg (≤ 75 years) 20 mg (> 75 years) D1, 8, 15, 22 Follow-up for OS and SPM until 5 years post- enrollment (n = 153) HiDEX: 40 mg (≤ 75 years) 20 mg (> 75 years) D1-4, 9-12, 17-20 28-day cycles PDa or intolerable AE PDa Companion trial MM-003C POM 21/28 days Thromboprophylaxis was indicated for those receiving POM or with DVT history a PD was independently adjudicated in real time. AE: adverse event; D: day; DOR: duration of response; DVT: deep vein thrombosis; HiDEX: high-dose dexamethasone; LoDEX: low-dose dexamethasone; MM: multiple myeloma; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; POM: pomalidomide; PR: partial response; RRMM: relapsed/refractory multiple myeloma; SPM: second primary malignancy. Dimopoulos MA. Blood. 2012;120: [oral presentation, abstract LBA-6]. 6

MM-003: PFS and OS 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 0.47 Refractory to lenalidomide 3.7 0.38 Refractory to bortezomib and lenalidomide 3.2 1.7 0.48 Median OS NR 7.8 0.53 8.1 0.56 .037 8.6 0.39 .003 7.4 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. 7

MM-005: A Phase I trial of Pom + Bortezomib + Low-Dose Dexamethasone (PVD) in RR MM (Lenalidomide-Refractory) MTD: Not reached MPD: 21-d cycles Bortezomib 1.3mg/m2 d1, 4, 8, & 11 Pomalidomide 4 mg qd d1-14 Dex 20 mg (10 mg for >75 yrs) d1, 2, 4, 5, 8, 9, 11, & 12 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 8

Phase I/II trial investigating Pom + Dex + PLD for R/R MM patients A Phase 1/2 Study of Pomalidomide (Pom), Dexamethasone (Dex) and Pegylated Liposomal Doxorubicin (PLD) for Patients with Relapsed/Refractory Multiple Myeloma Phase I/II trial investigating Pom + Dex + PLD for R/R MM patients Eligibility: progressive disease while on Phase 1: any regimen Phase 2: REFRACTORY to lenalidomide 28-d cycle containing Pomalidomide: daily 2, 3 or 4 mg qd d1-21 3 mg is current dose for Phase 2 study Dex IV: 40 mg d1, 4, 8, & 11 PLD: 5 mg/m2 on d1, 4, 8, & 11 Berenson et al. ASCO 2013

Results: Pom+PLD+Dex for RR MM Best Response # of Patients % # evaluable for efficacy 36 PD 6 17% SD 9 25% MR 5 14% PR 15 41% VGPR 0% CR 1 3% Overall Response Rate (PR+VGPR+CR) 16 44% Clinical Benefit Rate (MR+PR+VGPR+CR) 21 58%

Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy 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 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 Median PFS 8.2 mo Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813. 11

A Phase I/II Study of Carfilzomib as a Replacement for Bortezomib for Multiple Myeloma Patients Failing Bortezomib-Containing Regimens 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 compound Berenson et al. ASH 2013

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

Efficacy PD 3 8% SD 6 16% MR 7 19% PR VGPR CR 2 Overall Response Rate Best Response # of Patients* (N=37) % PD 3 8% SD 6 16% MR 7 19% PR VGPR CR 2 Overall Response Rate (PR+VGPR+CR) 13 43% Clinical Benefit Rate (MR+PR+VGPR+CR) 18 62% *- 5 pts not evaluable but counted in denominator

Relapsed/Refractory Multiple Myeloma: Case 2 (Case 1 cont’d) For patients failing both bortezomib and lenalidomide, there is very little likelihood that other IMiD compounds or proteasome inhibitors will be effective True False

Treatment of Relapsed/Refractory Myeloma CONFIRM PROGRESSION! Some patients can be watched Asymptomatic Slow progression No end organ damage that is new Determinants of therapy Cytogenetics/genetics ? Pace of progression Extent of end organ damage Life and work styles Co-morbid conditions (diabetes, CHF, etc.)

Treatment of Relapsed/Refractory Myeloma The old rules no longer apply! All of the following are often effective Escalate doses (IMiD drugs, carfilzomib ?) Add an antibiotic- clarithromycin Resistance to a PI or IMiD drug in combination Substituting another agent Different class (PLD for CY failure) Even the same class (bendamustine for CY or MEL failure) Adding an IMiD drug to a PI failure or vice versa Resistance to PI (BORT) – substitute another PI (carfilzomib) IMiD (Len)- substitute another IMiD drug (Thal or POM)