Relapsed Refractory Myeloma: The Case for Single Agent Approach Ruben Niesvizky MD Myeloma Center Myelomacenter.org run9001@med.cornell.edu

Time to Response Outcomes Outcome of Pts Who Have Become Refractory to Bortezomib and at Least One IMiD (IMWG Study) 286 pts with relapsed MM; refractory to Bz and were relapsed following, refractory to, or ineligible to receive an IMiD (thal and/or len) Time to Response Outcomes Survival Outcomes 100 24-Month Events/N Estimate Minor response Partial response Very good partial response Complete response 94/213 69/213 19/213 7/213 51% 38% 11% 4% 100 Median Events/Nn Months Overall survival Event-free survival 170/286 217/286 9 (7,11) 5 (4,6) 80 80 60 60 Patients (%) Patients (%) 40 40 20 20 4 8 12 16 20 24 28 32 36 40 44 48 12 24 36 48 60 Months Months IMiD, immunomodulatory drug Kumar SK et al. Leukemia. 2012;26:149.

Clinical Factors When Choosing Therapy for Relapsed Disease Comorbid conditions Previous therapy Time from previous therapy Mode of drug administration Genetic risk profile Potential role of second ASCT Laubach JP et al. Leukemia. 2009;23:2222. Blade J, Rosinol L. Haematologica. 2009;94:163.

Treatment of Relapsed/Refractory MM Single agents vs combinations? Duration of treatment: fixed cycles or until maximum response or until progression? Stop and transplant a second time?

Management of Relapsed MM Available Choices Cytotoxic agents Transplant options Thalidomide Bortezomib Lenalidomide Carfilzomib Pomalidomide/dex Research studies Initial therapy Salvage therapy

Combinations Appear More Active and Result in High ORRs and High CR/nCR Rates but 4 is not better than 3 3-Drug 4-Drug 100 ≥PR CR/nCR 80 60 40 20 RCD4 RCP5 MP-V6 RAD7 BPV8 VMD9 VDT10 VTD11 CyBorD1 CyBorD2 CyBorD3 DVd-T12 DVd-R13 RMPT14 VMPT15 VMDT16 1 novel agent 2 novel agents 1 novel agent 2 novel agents 1. Fu W et al. Am J Clin Oncol. 2012;35:562; 2. Kropff M et al. Br J Haematol. 2007;138:330; 3. Reece DE et al. J Clin Oncol. 2008;26:4777; 4. Schey SA et al. Br J Haematol. 2010;150:326; 5. Reece DM et al. Blood. 2008;112. Abstract 1723; 6. Romano A et al. Ann Oncol. 2012; Nov 7 [Epub ahead of print]; 7. Knop S et al. Blood. 2009;113:4137; 8. Ponisch W et al. J Cancer Res Clin Oncol. 2012;Nov 25 [Epub ahead of print]; 9. Popat R et al. Br J Haematol. 2009;144:887; 10. Chanan-Khan A et al. Leuk Lymphoma. 2009;50:1096; 11. Pineda-Roman N et al. Leukemia. 2008;22:1419; 12. Hussein MA et al. Mayo Clin Proc. 2006;81:889; 13. Baz R et al. Ann Oncol. 2006;17:1766; 14. Palumbo A et al. Leukemia. 2010;24:1037; 15. Palumbo A et al. Blood. 2007;109:2767; 16. Terpos E et al. Leukemia. 2008;22:2247.

Relapse Approaches EARLY AGGRESSIVE, RAPID, OR MULTIPLE RELAPSE CONSIDER CLINICAL TRIAL WITH A NOVEL AGENT EARLY LENALIDOMIDE-BASED Initial therapy with bz Underlying PN BORTEZOMIB-BASED Initial therapy len / thal Long DOR with prior bz Renal dysfunction TRANSPLANT No previous SCT Long remission post-SCT AGGRESSIVE, RAPID, OR MULTIPLE RELAPSE CT-BASED DCEP vs DT-PACE Oral vs IV CT PS plays an important role CT + NOVEL AGENT Combinations of len and / or bz with other agents SCT-BASED Likely to be short-lived Quick disease control Reconstitute marrow ? Consider combination therapy. Don’t wait for symptomatic relapse. Bz, bortezomib; PN, peripheral neuropathy; len, lenalidomide; thal, thalidomide; CT, chemotherapy; SCT, stem cell transplant; PS, performance status. Lonial S, et al. Clin Cancer Res. 2011;17:1264-1277.

Petrucci et al, Br J Haem 2013,160,649-659

Petrucci et al, Br J Haem 2013,160,649-659

Vorinostat, Panobinostat Novel Agents Activity 2nd GENE R A T I ON 2nd Generation Agents MONOT HERAP Y Carfilzomib Pomalidomide +/- dexamethasone N EW C L A S S E S Vorinostat, Panobinostat Elotuzumab Perifosine Bendamustine ENHANCER + bortezomib or lenalidomide +/- dexamethasone

Carfilzomib Monotherapy in Heavily Pre-Treated MM Patients, Phase IIb 20 mg/m2 days 1, 2, 8, 9, 15, 16 every 28 days N = 46 MM: Progressive disease > 2 prior therapy lines including bortezomib and thalidomide or lenalidomide Carfilzomib Dose escalation to 27 mg/m2 after cycle 1 up to 12 cycles N = 266 Patient Baseline Characteristics N = 266 Age 63 years (range, 37-87) Median time since diagnosis 5.4 years (range, 0.5-22.3) ECOG < 1 87% Baseline grade 1/2 neuropathy 77% Prior lines of therapy > 4 prior lines Median # anti-MM agents PD at study entry Refractory to last therapy Refractory or intolerant to bortezomib 5 (range, 1-20) 82% 13 100% 95% 88% Siegel DS, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8027.

Carfilzomib Monotherapy in Heavily Pre-Treated MM DCR = 69% CBR = 37% ORR = 24% Carfilzomib N = 257 Median OS 15.6 months Median OS for > PR 20.7 months Median PFS 3.7 months Median PFS for > MR 9.5 months Median DOR 8 months Median follow-up = 14.3 months Unfavorable cytogenetics did not significantly impact response rates or DOR. CR, complete response; VGPR, very good partial response; PR, partial response; MR, marginal response; SD, stable disease; PD, progressive disease; DCR, disease control rate; CBR, clinical benefit rate; ORR, overall response rate; OS, overall survival. Siegel DS, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8027. Jakubowiak AJ, et al. ASH Annual Meeting Abstracts. 2011;118(21):1875.

Adverse Events With Carfilzomib in Heavily Pre-Treated MM Patients > Grade 3 Hematologic: Anemia (> 15%) Thrombocytopenia Lymphopenia Neutropenia 24% 29% 20% 11% Non-hematologic: Fatigue Dyspnea Upper respiratory tract infection Headache 7.5% 3.4% 4.5% 1.9% Other: Febrile neutropenia Peripheral neuropathy 0.8% Siegel DS, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8027.

Carfilzomib in MM Patients Following 1-3 Prior Therapies Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy Carfilzomib in MM Patients Following 1-3 Prior Therapies 004, Phase II 1:1 Carfilzomib Cohort 1 20 mg/m2 Relapsed / Refractory Multiple Myeloma 1-3 Prior Therapies N = 165 Cohort 2 20 mg/m2→27 mg/m2 Bortezomib-treated Bortezomib-naïve Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles Bortezomib-naïve Bortezomib-treated N 129 36 Median age 65 years 63 years Median # prior therapies 2 3 Stewart AK, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8026. Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813.

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.

Carfilzomib: Toxicity Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy Carfilzomib: Toxicity 004, Phase II, Bortezomib-Naïve Patients > Grade 3 AE Cohort 1 (20 mg/m2) n = 59 Cohort 2 (20→27 mg/m2) n = 70 Lymphopenia 14% 19% Anemia 12% 17% Thrombocytopenia 15% 11% Neutropenia Pneumonia Fatigue 1% Dyspnea 5% 6% Peripheral Neuropathy 1 patient (grade 3) No treatment discontinuations due to PN Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813. Abstract 1099. 17

Current Phase III Studies US Europe Multiple Myeloma 1-3 Prior Therapies Relapsed / Refractory Multiple Myeloma* R R 1:1 1:1 Carfilzomib Lenalidomide Dexamethasone Lenalidomide Dexamethasone Carfilzomib Best Supportive Care Stratified by b2M levels Prior bortezomib Prior lenalidomide *Prior treatment must have included: Bortezomib Lenalidomide or thalidomide Alkylating agent Corticosteroid Anthracycline Trial has met accrual goal. National Institutes of Health. Available at: www.clinicaltrials.gov. Accessed March 2011.

Median No. Prior Regimens Refractory to Recent Therapy (%) Pomalidomide Pts, n Median No. Prior Regimens Refractory to Recent Therapy (%) ORR (%) Pomalidomide ± dex1 191 5 100 2534 Pomalidomide, dex2 70 6 NR 2629 Pomalidomide, dex3 84 85 3435 Pomalidomide, cyclophosphamide, prednisone4 32 (1 to 3) 44* 59 Pomalidomide, dex, clarithromycin5 46 NR (at least 3) 60 *Len specifically 1. Vij R et al. J Clin Oncol. 2012;30. Abstract 8016. 2. Lacy MQ et al. Blood. 2011;118:2970. 3. Leleu X et al. Blood. 2011;118. Abstract 812. 4. Palumbo A et al. Blood. 2011;118. Abstract 632. Mark TM et al. Blood. 2011;118. Abstract 635.

Pomalidomide in Relapsed/Refractory Multiple Myeloma POM + LoDEX achieved responses in pts with prior LEN and/or BORT treatment, including those who are refractory1-4 Study Phase N Treatment Population Median Prior Tx (Range) ≥ PR Lacy4 2 60 POM: 2 mg (28/28-day cycle) Dex: 40 mg/week 1-3 prior Tx, relapsed/refractory 2 (1-3) 65% 34 LEN-refractory 4 (1-14) 32% 35 DEX: 40 mg/week LEN- and BORT- refractory 6 (3-9) 26% POM: 4 mg 1-3 prior Tx, LEN-refractory 37% 6 (2-11) 29% 1. Lacy MQ et al. J Clin Oncol. 2009;27:5008. 2. Lacy MQ et al. Leukemia. 2010;24:1934. 3. Lacy MQ et al. Blood. 2011;118:2970. 4. Lacy MQ et al. Blood. 2011;118: Abstract 3963. 27

MM-003 POM + LoDEX 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 aPD was independently adjudicated in real time. Dimopoulos MA et al. Blood. 2012;120: Abstract LBA-6.

MM-003 POM + LoDEX in RRMM Phase 3 — Patient Characteristics and Disposition POM + LoDEX arm: 45% ongoing; 55% discontinued (7% due to AEs) HiDEX arm: 25% ongoing; 75% discontinued (6% due to AEs) 29% of pts on HiDEX received POM after PD Baseline Characteristics POM + LoDEX (n = 302) HiDEX (n = 153) Median age, years (range) 64 (35-84) 65 (35-87) Median time from diagnosis, years 5.3 6.1 Median no. prior Tx, n (range) 5 (1-14) 5 (2-17) Prior LEN, % 100 Prior BORT, % Prior SCT, % 71 69 LEN-refractory, % 93 90 BORT-refractory, % 78 77 LEN- and BORT-refractory, % 73 Dimopoulos MA et al. Blood. 2012;120: Abstract LBA-6.

MM-003 POM + LoDEX in RRMM Phase 3 — Progression-Free Survival, ITT Populationa a Based on adjudicated data; IMWG criteria. Dimopoulos MA et al. Blood. 2012;120: Abstract LBA-6.

MM-003 POM + LoDEX in RRMM Phase 3 — Overall Survival, ITT Population OS was significantly longer with POM + LoDEX vs. HiDEX, despite 29% of pts receiving POM after progression on HiDEX Dimopoulos MA et al. Blood. 2012;120: Abstract LBA-6.

MM-003 POM + LoDEX in RRMM Phase 3 — Adverse Events Discontinuation due to AEs: 7% POM + LoDEX; 6% HiDEX VTE, all grades: 3% POM + LoDEX; 2% HiDEX Peripheral neuropathy, all grades: 12% POM + LoDEX; 11% HiDEX Grade 3-4 AEs, % POM + LoDEX (n = 300) HiDEX (n = 149) Neutropenia 42 15 Febrile neutropenia 7 Anemia 27 29 Thrombocytopenia 21 24 Infections 23 Pneumonia 9 Hemorrhage 3 5 Glucose intolerance Fatigue Dimopoulos MA et al. Blood. 2012;120: Abstract LBA-6.

ClaPd: Study Design Day A single-center, phase 2 study of Clarithromycin (Biaxin®) combined with Pomalidomide + Low Dose Dexamethasone in RRMM 1 2 8 9 15 16 21 22 28 Day Dex 40mg PO Pomalidomide 4 mg PO Clarithromycin 500mg PO BID p.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.

Patient Baseline Characteristics Median (range) N = 100 Age, years 63 (42–87) Sex 46 male, 54 female β2-Microglobulin, mg/L 3.4 (1.2–12.4) Albumin, g/dL 3.5 (0.7–4.5) Lactate dehydrogenase, U/L 171 (110–1353) Hemoglobin, g/dL 10.4 (6.4–14.6) Creatinine, mg/dL 0.9 (0.44–2.5) Calcium, mg/dL 9.1 (7.8–12.3) Number of prior therapies 5 (3–15)

Baseline MM Stage and Cytogenetic Abnormalities Durie-Salmon stage, N = 100 Ia 42 IIa 43 IIb 3 IIIa 11 IIIb 1 International Staging System stage, N = 84 I 32 (38) II 29 (35) III 23 (27) Cytogenetics*, N = 96 Standard risk 41 (43) High risk 55 (57) *Standard risk, n (%), defined by the presence of one or more of the following: t(11;14): 4(16); hyperdiploidy, 12(46); FISH del 13q14, 12(46); no abnormality: 5(19). High risk, n (%), defined by the presence of one or more of the following: del 17p: 5(19); karyotype del 13q: 3(12); amp 1q/ del 1p: 5(19); t(14;20): 1 (6); t(14;16): 1(6); t(4;14): 1(6); or other complex cytogenetic abnormalities.

Results Best Response (IMWG Criteria) n (%) Overall (N = 98) ORR (≥ PR) 56 (57) CBR (≥ MR) 65 (66) sCR 6 (6) VGPR 17 (17) PR 33 (34) MR 9 (9) SD 23 (23) PD 10 (10) 98 patients completed at least 1 cycle of ClaPD. median number of cycles received was 6 (range 1–25) median study follow-up was 9.6 months (range 1.0–25.6) In responding patients, median time to PR was 1 cycle (range 1–7). Median time to best response was 2 cycles (range 1-14). IMWG, International Myeloma Working Group; CBR, clinical benefit rate; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.

Treatment History With Len/Bort Did Not Influence Response to ClaPD Best Response (IMWG Criteria) n (%) Overall (N = 98) Lenalidomide refractory (N = 83) Bortezomib Refractory (N = 82) Lenalidomide and bortezomib refractory (N = 72) ORR (≥ PR) 56 (57) 47 (63) 46 (56) 39 (54) CBR (≥ MR) 65 (66) 56 (67) 54 (65) (65) sCR 6 (6) 6 (7) 5 (6) 5 (7) VGPR 17 (17) 13 (16) 9 (13) PR 33 (34) 28 (34) 25 (35) MR 9 (9) 8 (10) 8 (11) SD 23 (23) 18 (22) 19 (23) 16 (22) PD 10 (10) 8 (12) 9 (11) IMWG, International Myeloma Working Group; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.

PFS by cytogenetic risk Results PFS by cytogenetic risk 1.00 Standard risk High risk At latest analysis, adverse cytogenetics did not appear to influence the risk of progression: HR = 1.23, 95% CI (0.73,2.07), P = 0.448 0.75 No progression (%) 0.50 0.25 0 200 400 600 800 Time (days) Number of patients at risk Standard risk 41 19 7 5 0 High risk 55 21 8 2 0

Results PFS by Lenalidomide AND Bortezomib history 1.00 Not double-refractory Double-refractory 0.75 No progression (%) 0.50 0.25 0 200 400 600 800 Time (days) Number of patients at risk Relapsed 26 14 5 3 0 D-Refractory 74 27 11 5 0 There was no difference seen in PFS in double-refractory patients. HR 1.35, 95% CI (0.75,2.43), P = 0.307 Bort, bortezomib; Len, lenalidomide.

Results OS Median survival has not been reached. 1.00 Median survival has not been reached. After median follow-up time for survival of 9.6 months, 72% of patients are alive 0.75 Survival (%) 0.50 0.25 0 200 400 600 800 Time (days) Number of patients at risk 99 62 36 20 0

OS by double-refractory state Results OS by cytogenetic risk OS by double-refractory state 1.00 1.00 0.75 0.75 Survival (%) 0.50 Survival (%) 0.50 Standard risk High risk Not double-refractory Double-refractory 0.25 0.25 0 200 400 600 800 0 200 400 600 800 Time (days) Time (days) Number of patients at risk Relapsed 41 26 16 10 0 Refractory 54 33 18 9 0 Number of patients at risk Relapsed 26 18 13 6 0 Refractory 74 44 23 14 0 Adverse cytogenetics did not appear to influence risk of death as of last study follow-up. HR 1.05, 95%CI (0.49,2.26), P = 0.888 A history of being double-refractory, however, approached a significant effect on survival time. HR 2.67, 95%CI (0.93,7.69), P = 0.068

Grade 3/4 Adverse Events* Anemia 21 4 Thrombocytopenia 17 16 Neutropenia 33 14 Lymphopenia 31 6 Hyperglycemia 7 3 Febrile neutropenia 2 1 Pulmonary embolism DVT Three patients withdrew from study due to adverse events: 1 grade 3 fatigue 1 grade 4 muscular weakness 1 grade 4 neutropenic sepsis There was no treatment-related mortality *Occurring in ≥ 10% of patients.

Conclusions ClaPD has proven to be a highly effective regimen for a large cohort of heavily treated relapsed or refractory MM patients. The addition of clarithromycin to pomalidomide + low dose dexamethasone appears to enhance expected efficacy. ClaPD demonstrates clinical activity in patients with advanced MM who have received multiple prior therapies, including many who are refractory to both lenalidomide and bortezomib. PFS in patients treated with ClaPD is sustained for > 8 months in the majority of patients.

Conclusions (2) High-risk cytogenetics did adversely impact PFS or OS in patients treated with ClaPD. A history of being refractory to prior lenalidomide, bortezomib, or double-refractory to both agents did not adversely influence PFS in patients treated with ClaPD; however, there is a trend towards shorter survival in double-refractory patients. Incidence of venous thrombosis while on low-dose aspirin prophylaxis was 5% Discontinuation rate due to adverse events was low at 3%.

MyelomaCenter. org Morton Coleman Roger N Pearse Tomer Mark Adriana Rossi Koen Van Besien Linda Tegnestam Kathleen Pogonowski Joseph Lane Alan Weinstein Selina Chen-Kiang Monica Guzman Scott Ely John Allen Yashpal Agrawal David S. Jayabalan Stanley Goldsmith Paul Christos Susan Mathew Laura Prescod