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Changing Landscape of Treatment for Multiple Myeloma

Changing Landscape of Treatment for Multiple Myeloma. Ravi Vij MD Associate Professor Section of BMT and Leukemia Washington University School of Medicine, . 1989–1994. 1995–2000. 2001–2006. M. Trends in Overall Survival of MM. 1.0. Diagnosis period Median OS 1996–2006 45 months

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Changing Landscape of Treatment for Multiple Myeloma

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  1. Changing Landscape of Treatment for Multiple Myeloma Ravi Vij MD Associate Professor Section of BMT and Leukemia Washington University School of Medicine,

  2. 1989–1994 1995–2000 2001–2006 M Trends in Overall Survival of MM 1.0 Diagnosis period Median OS 1996–2006 45 months 1971–1996 30 months (P<0.001) 0.8 2001–2006 OS, overall survival. 0.6 Survival 0.4 1971–1976 0.2 1977–1982 1983–1988 0 0 20 40 60 80 100 120 140 Time from diagnosis (Months) Overall survival 1971–2006 Kumar SK, et al. Blood. 2008;111:2516-2520.

  3. Trends in 10-Year Relative Survival of MM Period estimates of 10-year relative survival of patients with MM by major age groups in defined calendar periods from 1984-1986 to 2002-2004 50 Age range 45 40 15-49 35 30 25 10-year relative survival (%)* 20 15 10 5 0 1984-1986 1987-1989 1990-1992 1993-1995 1996-1998 1999-2001 2002-2004 Calendar period 50-59 60-69 70-79 80+ *Relative survival reflects survival of patients with cancer compared with survival of the general population. Brenner H, et al. Blood. 2008;111:2521-2526.

  4. Overall and Event-Free Survival in Patients Relapsing and Refractory to Bortezomib and Thalidomide/Lenalidomide Kumar S. EHA 2010

  5. Proteasome Inhibitors in MM Bortezomib Optimization in combination with other agents Phase I Phase II/IIb Phase Ib/II Ph III Heme Malig. R/R w/ Rd Newly Diagnosed R/R Carfilzomib Phase I Marizomib Phase I/II CEP-18770 FDA approval 1st-line MLN9708 (oral) Phase I/II Accelerated FDA approval R/R Full FDA approval R/R Phase I/II ONX 0912 (oral) 2001 2003 2005 2007 2009 2011 2012 NIH clinical trials. Available at: www.clinicaltrials.gov. Accessed February 2012. R/R: relapsed/refractory

  6. Differentiation of Proteasome Inhibitors b1: Caspase-like site; b2: Trypsin-like site; b5: Chymotrypsin-like site. NR, not reported. Dick LR and Fleming PE. Drug Discov Today. 2010;15(5/6):243-249. Demo SD, et al. Cancer Res. 2007;67:6383-6391. Parlati F, et al. Blood. 2009;114(16):3439-3447. Miller CP, et al. Blood. 2007;110(1):267-277. Piva R, et al. Blood. 2008;111(5):2765-2775. Kupperman E, et al. Cancer Res. 2010;70(5):1970-1980. Chauhan D, et al. Blood. 2010;116(23):4906-4915.

  7. CarfilzomibMonotherapy in Heavily Pre-Treated MM Patients, Phase IIb 003-A0 MM: Progressive disease > 2 prior therapy lines for relapsed disease including bortezomib, thalidomide or lenalidomide, an alkylating agent, or an anthracycline alone or in combination 003-A1 Carfilzomib 20 mg/m2 days 1, 2, 8, 9, 15, 16 every 28 days N = 46 Carfilzomib Dose escalation to 27 mg/m2 after cycle 1 up to 12 cycles N = 266 Primary Endpoints: overall response rate (ORR; ≥ partial response) Secondary Endpoints: clinical benefit response rate (≥ minimal response), duration of response (DOR), progression-free survival, overall survival (OS), and safety Siegel DS, et al. Blood. 2012;120(14):2817-25

  8. CarfilzomibMonotherapy in Heavily Pre-Treated MM Patients, Phase IIb *** 266 patients evaluable for safety & 257 evaluable for efficacy (9 patients excluded because of missing baseline and/or post-baseline disease assessment) Siegel DS, et al. Blood. 2012;120(14):2817-25

  9. CarfilzomibMonotherapy in Heavily Pre-Treated MM, 003 Trial ORR ≥ partial response * Calculated from 61 patients with partial response or better Bz, bortezomib; len, lenalidomide; imid, lenalidomide or thalidomide; mo, month; NR, not reported. Unfavorable cytogenetics did not significantly impact response rates or DOR Siegel DS, et al. Blood. 2012 ;120(14):2817-25.

  10. Selected Adverse Events With Carfilzomib in Heavily Pre-Treated MM Patients * Grouped PN all events of neuropathy, peripheral neuropathy, peripheral sensory neuropathy, & peripheral motor neuropathy Siegel DS, et al. Blood. 2012 ;120(14):2817-25.

  11. Carfilzomib in MM Patients Following 1-3 Prior Therapies Bortezomib-treated (n=35) 004, Phase II Bortezomib-naïve (n=59) Carfilzomib Cohort 1 20 mg/m2 (all treatment cycles) Relapsed / Refractory Multiple Myeloma 1-3 Prior Therapies N = 164 1:1 Carfilzomib Cohort 2 20 mg/m2 (cycle 1)→27 mg/m2 Bortezomib-naïve (n=70) Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles Vij R, et al. Blood. 2012; 119(24):5661-70. Vij R, et al. Br J Haematol. 2012 Sep;158(6):739-48.

  12. CarfilzomibMonotherapy MM Patients With 1-3 Prior Therapies • †Precise estimate not determined since 4/6 patients with responses had DOR censored at study close • * Calculated for ORR patients Vij R, et al. Blood. 2012; 119(24):5661-70. Vij R, et al. Br J Haematol. 2012 Sep;158(6):739-48.

  13. Dose Escalation of Carfilzomib • CFZ 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 + DEX 8 mg premedication (28-day cycle) • Cycle 1, day 1 and 2 20 mg/m2 followed by escalation to 56 mg/m2 • 78% BTZ-refractory; 21% prior alloHSCT • Results (N=34) • ORR (completed 4 cycles or PD prior to 4 cycles): 58% (1 CR, 7 VGPR, 6 PR) • ORR (after 4 cycles): 57% (BTZ-refractory) • ORR (ITT): 50% • Median PFS: 4.6 months • Median OS: not reached (median follow-up 9.6 months) • 35% patients required a dose reduction Lendvai N, et al. Blood. 2012;120. Abstract 947.

  14. Dose Escalation of Carfilzomib is Feasible • CFZ 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 • Cycle 1 (Day 1/2) 20 mg/m2 → escalation to 45 or 56 mg/m2 • DEX 20 mg prior to CFZ on Days 1, 2, 8, 9, 15, and 16 • DEX 40 mg administered on Day 22 • Median 4 lines treatment; 96% patients prior BTZ • Results (in patients completing at least 2 cycles); n=20 • ORR: 55% (VGPR: n=2; PR: n=9); SD: n=6; PD: n=3 • Discontinued due to PD: N=7 (45 mg/m2) • Discontinued due to SAE: N=1 (56 mg/m2) Badros AZ, et al. Blood. 2012;120. Abstract 4036.

  15. MLN9708 and Marizomib MTD, maximum tolerated dose; PR, partial response; CR, complete response; MR, marginal response; SD, stable disease; GI, gastrointestinal; Gr, grade; DVT, deep vein thrombosis; DLT, dose limiting toxicity; PN, peripheral neuropathy; min, minute. Richardson PG, et al. ASH Annual Meeting Abstracts. 2011;118(21):301. Berdeja JG, et al. ASH Annual Meeting Abstracts. 2011;118(21):479. Richardson PG, et al. ASH Annual Meeting Abstracts. 2011;118(21):302.

  16. Oprozomib (ONX 0912) Phase 1b Study Design Phase 1b open-label dose escalation study Hematologic malignancies 3 + 3 dose-escalation schema Oprozomib BID Days 1 – 5 of a 14 day cycle Starting dose 60 mg BID (doses administered at least 4-6 hours apart) Escalation in 30 mg increments • Primary endpoint: • Safety and tolerability and to determine the maximum tolerated dose • Secondary endpoints • Pharmacokinetic and pharmacodynamic analyses Confidential: For Internal Use Only Savona MR, et al. Blood. 2012;120. Abstract 203.

  17. Lenalidomide 15-25 mg/d Myelosuppression Skin rash DVT Thalidomide 100-200 mg/d Neuropathy Constipation Sedation DVT Pomalidomide 1-4 mg/d O O H N N O O N H 2 Structurally similar, but functionally different both qualitatively and quantitatively Pomalidomide

  18. Discontinue and follow up for survival and subsequent treatment MM-002: Phase 2 Study Design Progressive disease POM (4 mg days 1–21 of 28-day cycles) Option to add LoDEX*(40 mg/week) • Primary endpoint: PFS • Secondary endpoints: ORR,1,2 safety, DOR, OS • Stratification factors: Age (≤75 vs >75 yrs), prior THAL, and 2 vs >2 prior treatments Randomization Progressive disease Progressive disease POM (4 mg days 1–21 of 28-day cycles) + LoDEX* (40 mg/week) Aspirin (80–100 mg) or equivalent was mandated for all patients * Patients aged > 75 years had a starting DEX dose of 20 mg/week. DOR, duration of response; G-CSF, granulocyte colony-stimulating factor; LoDEX, low-dose dexamethasone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; POM, pomalidomide; RBC, red blood cell; yrs, years. 1. Bladé J, et al. Br J Haematol. 1998;102:1115-23; 2. Richardson PG, et al. N Engl J Med. 2003;348:2609-17.

  19. Pomalidomide Alone or With Low-Dose Dexamethasone in RRMMEfficacy • Patients in both arms were heavily pretreated with a median of 5 prior therapies • Median number of cycles received was 5 (range 1-17) • Disease control (≥SD) was observed in 76% of overall patients Discrepancies in totals are due to rounding. Responses assessed by IRAC review using EBMT criteria. ITT Population. Vij R, et al. ASCO 2012. Abstract 8016.

  20. Pomalidomide Alone or With Low-Dose Dexamethasone in RRMMEfficacy in Refractory Patients Patients could be classified under more than one category. Discrepancies in totals are due to rounding. Vij R, et al. ASCO 2012. Abstract 8016.

  21. Response to Pomalidomide + Low Dose Dexamethasone According to Age *For patients who achieved ≥PR. MR, minimal response; PR, partial response. Jagannath S, et al. Blood. 2012; 120. Abstract 450 (oral presentation). Confidential: For Internal Use Only

  22. Mayo Clinic StudiesPomalidomide / Dexamethasone by Previous Therapy ORR, overall response rate; MR, marginal response; DOR, duration of response; PFS, progression-free survival; OS, overall survival; len, lenalidomide; bor, bortezomib; Pom, pomalidomide; mo, month; N/A, not applicable. Lacy MQ, et al. ASH Annual Meeting Abstracts. 2011;118(21):3963.

  23. Pomalidomide / Dexamethasone: Administration Schedule MM, multiple myeloma; 21/28, 21 days of 4 mg pomalidomide on a 28-day cycle; 28/28, 28 days of 4 mg pomalidomide on a 28-day cycle; ORR, overall response rate; DOR, duration of response. Leleu X. et al. ASH Annual Meeting Abstracts. 2011;118(21):812.

  24. Pomalidomide plus Low Dose Dex vs. High Dose Dex Primary refractory or relapsed and refractory MM PD during treatment or within 60 days of last MM treatment (including ≥ cycles LEN or BTZ) • Primary endpoint: PFS • Secondary endpoints: safety, OS, ORR (≥PR), DoR, TTP, QoL Randomization (N=455) 2:1 Arm A: POM – loDEX (n=302) Pomalidomide 4mg/day D1-21 Dexamethasone: 40 mg, D1, 8,15,22 28-day cycles Arm B: High dose DEX (n=153) Dexamethasone: 40 mg,D 1-4, 9-12,and 17-20 28-day cycles Continue treatment until PD or unacceptable toxicity Patients were stratified by age (≤ 75 vs > 75 years), disease population (refractory vs refractory and relapsed vs refractory and intolerant [intolerant to BTZ only]), and number of prior therapies (2 vs > 2). Dimopoulos M, et al. Blood. 2012;120. Abstract LBA-6.

  25. Pomalidomide + Low Dose Dex vs. High Dose Dex • Patient population • Median number of prior therapies: 5 (range, 1-17) • Refractory to both LEN and BTZ: 72% • Treatment results Dimopoulos M, et al. Blood. 2012;120. Abstract LBA-6.

  26. Pomalidomide + Low Dose Dex vs. High Dose Dex • Efficacy *P<.001 • Safety 1% of patients in each group developed neuropathy (Grade 3/4); 1% Arm A developed VTE. Dimopoulos M, et al. Blood. 2012;120. Abstract LBA-6.

  27. Immunomodulatory Agents Immunomodulatory Direct anti-tumor effects Induce p21, p27, & p15 cell cycle arrest Alterations in (ERG)-1,2 3 and SPARC ↓ NFkB Inhibit caspase 3,8,9 T cell co-stimulation Treg suppression Th1 cytokine NK and NKT cell activation ADCC CEREBLON BINDING ↓ IRF-4 Anti-angiogenesis Anti-inflammatory ↓ adhesion molecules Anti-osteoclastogenic Tumor micro-environment

  28. Blockade of Ubiquitinated Protein Catabolism with HDAC inhibitors Protein Ub Ub Protein aggregates (toxic) Ub Ub Ub 26S Proteasome Ub HDAC6 Bortezomib Ub Ub Tubacin LBH, vorinostat HDAC6 Dynein Ub Ub Lysosome Aggresome HDAC6 Ub Ub Ub Dynein Ub Ub Ub Microtubule Autophagy Tai YT, et al. Cancer Res. 2005;65(13):5898-5906. Hideshima T, et al. Clin Cancer Res. 2005;11(24 Pt 1):8530-8533. Catley L, et al. Blood. 2006;108(10):3441-3449.

  29. Vorinostat / BortezomibVANTAGE 088, Phase III Bortezomib + Vorinostat Multiple Myeloma 1-3 Prior Therapies N = 637 R Bortezomib + Placebo ORR, overall response rate; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival. Dimopoulos MA, et al. ASH Annual Meeting Abstracts. 2011;118(21):811.

  30. PANORAMA 2 Study DesignPhase II, Simon 2-stage study in BTZ-refractory MM Treatment Phase 1Eight 3-wk cycles Treatment Phase 26-wk cycles until PD Screening • Adult pts • Relapsed and BTZ-refractory MM • ≥ 2 prior lines of therapy • Exposed to IMiDs Panobinostat BTZ Dexamethasone Panobinostat BTZ Dexamethasone After 8 cycles, continuation into treatment phase 2 in pts with clinical benefit Primary endpoint: overall response rate (CR + nCR + PR)aKey secondary endpoints: PFS, TTP, OS, MR, TTR, DOR a Response measured according to modified European Group for Blood and Marrow Transplantation 1998 criteria. CR, complete response; nCR, near CR; DOR, duration of response; OS, overall survival; PD, disease progression; PFS, progression-free survival; PR, partial response; TTP, time to progression; TTR, time to response. Alsina et al. ASCO 2012. ABSTRACT 8012.

  31. Preliminary Response DataActivity in BTZ-refractory MM patients • VGPR observed in 3 pts • Responses were typically observed after 1 to 2 cycles • Stable disease observed in 3 pts, progressive disease in 18 pts; 3 pts not evaluable, 3 pts with unconfirmed response 1. Anderson KC, et al. Leukemia. 2008;22:231-239. 2. Richardson PG, et al. Br J Haematol. 2009;144:895-903. 3. Niesvizky R, et al. Br J Haematol. 2009;143:46-53. Alsina et al. ASCO 2012. ABSTRACT 8012.

  32. Current Phase III PANORAMA I Relapsed or Refractory MM R Panobinostat Bortezomib Dexamethasone Placebo Bortezomib Dexamethasone Trial has met accrual goals Clinical trial ID: NCT01023308 National Institutes of Health. Available at: www.clinicaltrials.gov. Accessed March 2011.

  33. AKT InhibitorsPerifosine, Bortezomib, and Dexamethasone • Common grade 1/2 AE • Nausea, diarrhea, fatigue and musculoskeletal pain, upper respiratory infection, anorexia, constipation • Grade 3/4 AE • Thrombocytopenia (23%), neutropenia (15%), anemia (14%), pneumonia (12%), musculoskeletal pain (11%), bleeding (10%) MM, multiple myeloma; CR, complete response; PR, partial response; MR, marginal response; SD, stable disease; PFS, progression-free survival; OS, overall survival; dex, dexamethasone. Richardson PG, et al. ASH Annual Meeting Abstracts. 2011;118(21):815.

  34. Monoclonal antibodies

  35. CS1 is highly and uniformly expressed on MM cells Restricted expression on NK cells Little to no expression on normal tissues In an MM xenograft mouse model lenalidomide enhanced the anti-tumor effect of elotuzumab Elotuzumab: Anti-CS1 Hsi ED, et al. Clin Cancer Res. 2008;14(9):2775-2784. Tai YT, et al. Blood. 2008;112(4):1329-1337. van Rhee F, et al. Mol Cancer Ther. 2009;8(9):2616-2624. Lonial S, et al. Blood.2009;114. Abstract 432. MM, multiple myeloma; NK, natural killer.

  36. Elotuzumab, Lenalidomide, and Dexamethasone in RR Lenalidomide-naïve MM Elotuzumab (10 mg) Lenalidomide Dexamethasone RRMM Phase 2 (1 – 3 prior therapies) Elotuzumab (20 mg) Lenalidomide Dexamethasone • Elotuzumab:10 or 20 mg/kg IV, d1, 8, 15, 22 cycles 1-2; d1, 15 for subsequent cycles • Lenalidomide: 25 mg, daily, days 1-21 • Dexamethasone: 40 mg, weekly. • Premedication Regimen: 30-60 minutes prior to each elotuzumab infusion • Methylprednisolone 50 mg IV or dexamethasone 8 mg IV, diphenhydramine 25-50 mg PO or IV (or equivalent), ranitidine 50 mg IV (or equivalent), acetaminophen 650-1000 mg PO Richardson P, et al. Blood. 2012;120. Abstract 202. Moreau P, et al. J ClinOncol. 2012;30. Abstract 8020.

  37. Elotuzumab, Lenalidomide, Dex in RR Lenalidomide-naïve MM *High-dose dex. CR, complete response; IMWG, International Myeloma Working Group; ORR, objective response rate; PFS, progression-free survival; PR, partial response; VGPR, very good partial response; len / dex, lenalidomide and dexamethasone. 1. Richardson P, et al. Blood. 2012;120. Abstract 202 (oral presentation). 2. Moreau P, et al. J Clin Oncol. 2012;30 (15 suppl):8020. 3. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 4. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. Confidential: For Internal Use Only

  38. Siltuximab + BTZ vs BTZ Alone in Relapsed/Refractory MM • Siltuximab: chimeric IgG1k anti–human IL-6 antibody • High affinity, half-life ≈ 3 wks • Tolerability: no DLT up to ≥ 15 mg/kg • Study design: phase II, randomized, double-blind, placebo-controlled • Patients:1-3 previous lines of therapy; no previous BTZ • Treatment • BTZ 1.3 mg/m2, 8 x 42-day cycles on Days 1, 4, 8, 11, 22, 25, 29, 32 followed by maintenance, 4 x 35-day cycles on Days 1, 8, 15, 22 • Placebo or siltuximab 6 mg/kg every 2 wks • Patients progressing had option to end BTZ and start DEX 40 mg on Days 1-4, 9-12, 17-20 and maintenance therapy at 40 mg on Days 1-4 Orlowski R, et al. ASCO 2012. Abstract 8018.

  39. Siltuximab + BTZ Efficacy • Nonsignificant trend toward improved ORR with siltuximab • Nonsignificant, marginal effect on overall PFS • Regional differences in PFS noted • Significant increase in NA and WE (P = .01) vs no effect for rest of world • Patients outside of NA and WE less often pretreated, which was thought to obviate benefit of adding siltuximab • Siltuximab continues to be developed for frontline therapy Orlowski R, et al. ASCO 2012. Abstract 8018.

  40. Daratumumab: Phase I/II Study in Relapsed/Refractory MM • Daratumumab: anti-CD38 antibody; kills MM cells via ADCC, CDC, and induction of apoptosis • Patients: relapsed/refractory MM (≥ 2 different therapies), not eligible for ASCT; 3 patients/dosing group • Efficacy based on serum and/or urine M-component analyses • At the highest dose (4 mg/kg), patients had a 49%, 55%, and 64% reduction in serum M-component and a 80%, 89%, and 97% reduction in plasma cells • Adverse events were manageable Plesner T, et al. ASCO 2012. Abstract 8019.

  41. Proteosome Inhibitors (CEP 18770, NPI 0052, MLN 2238) Other targets FGFR3 IGF-1 Hsp-90 DAC PI-3-Akt-Mtor, bcl-2 CDK IKK /p38MAPK Aurora kinases Met HGF Monoclonal antibodies( CD 138, CD40, CD56,1L-6, TRAIL-R) Targeting MM cell Bone marrow stromal cells Targeting bone marrow milieu Targeting Myeloma Cells in the Bone Marrow Microenvironment

  42. Massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs. • Mutation of : • genes involved in protein translation (seen in nearly half of the patients), • genes involved in histonemethylation, • genes involved in blood coagulation. • in 11 members of the NF-kBpathway • kinaseBRAF in 4%of patients, 4 M A R C H 2 0 1 1 | VO L 4 7 1 | N AT U R E | 4 6 7

  43. Key Genetic Changes

  44. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cellleukemia reveals genomic initiating events, evolution, and clonal tides Egan et al Blood. 2012;120(5):1060-1066)

  45. Clonal competition with alternating dominance in multiple myeloma ( Keats et al. Blood. 2012;120(5):1067-1076)

  46. The Goal: Cure Ineffective treatment Dexamethasone Alkylators Tumor Volume → High-Dose Therapy Limit ofdetection Goal of newertherapy options Time →

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