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Developments in the Treatment of Multiple Myeloma Kenneth C. Anderson, M.D.

Developments in the Treatment of Multiple Myeloma Kenneth C. Anderson, M.D. Kraft Family Professor of Medicine Harvard Medical School Director, Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute. Conflict of Interest: Kenneth C. Anderson, M.D.

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Developments in the Treatment of Multiple Myeloma Kenneth C. Anderson, M.D.

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  1. Developments in the Treatment of Multiple Myeloma Kenneth C. Anderson, M.D. Kraft Family Professor of Medicine Harvard Medical School Director, Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute

  2. Conflict of Interest: Kenneth C. Anderson, M.D. Consultancy: Celgene, Onyx, Sanofi Aventis, and Gilead Scientific Founder: Acetylon, Oncopep

  3. Bortezomib, Lenalidomide, Thalidomide, Doxil, Carfilzomib, Pomalidamide Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo Effective in relapsed/refractory, relapsed MM and now part of induction, consolidation, and maintenance therapy Nine FDA approvals in the last decade and median survival prolonged from 2-3 yrs to at least 5-7 yrs, with additional prolongation seen from maintenance New approaches needed to treat and ultimately prevent relapse Integration of Novel Therapy Into Myeloma Management

  4. Chromosomes and Prognosis in Multiple Myeloma For conventional low and high dose theapy: Nonhyperdiploid worse prognosis than hyperdiploid t(11;14), hyperdiplody -standard risk t(4;14), t(14;16),t(14;20), del(17p), del(13q14)-high risk For novel treatments Bortezomib, but not lenalidomide, can at least partially overcome t(4;14), del(13q14)- del(17p) p53 remains high risk

  5. Combinations in the Upfront Treatment of MM Stewart AK, Richardson PG, San Miguel JF Blood 2009

  6. Lenalidomide and Bortezomib/Lenalidomide-BasedConsolidation 1Attal et al. Haematologica 2011; 96 (s1): S23; oral presentation at IMW 2011 2Roussel et al. ASH 2010 (Abstract 624), oral presentation

  7. ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo. McCarthy PL. N Engl J Med. 2012;366:1770-1781. CALGB 100104:LEN Maintenance significantly prolonged PFS & OS vs. placebo PFS OS

  8. Lenalidomide Maintenance Therapy Meta-Analysis Oral Abstract #407 - Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized TrialsMonday, December 9, 2013: 11:30 AM 393-394 • There was significant prolongation of both PFS (HR 0.49, 95% CI, 0.41–0.58, p<0.001) and OS (HR 0.77, 95% CI, 0.62–0.95, p=0.013) with LM vs. placebo/no maintenance Singh M, et al. ASH 2013. Abstract 407.

  9. Bortezomib induction and maintenance in ASCT NDMM, TE, sge 18–65 y Randomization 3 x PAD 3 x VAD CAD + GCSF CAD + GCSF MEL 200 + PBSCT MEL 200 + PBSCT In GMMG 2nd MEL 200 + PBSCT Allogeneic Tx In GMMG 2nd MEL 200 + PBSCT Bortezomib Maintenance 1.3 mg/m2 / 2 weeks for 2 years Thalidomide maintenance 50 mg/day for 2 years Sonneveld et al, ASH 2013

  10. Results • Bortezomib-based treatment consistently improves PFS (median 27 m vs 36 m) and OS (median 84 m vs not reached, p=0.05) in patients with newly diagnosed MM who are transplant eligible • Bortezomib significantly improves the long-term outcome of patients presenting with renal failure (p<0.001) Sonneveld et al, ASH 2013

  11. Carfilzomib With Thalidomide and Dexamethasone in ASCT Intensification* (1 cycle) Induction (4 28-day cycles) Consolidation(4 28-day cycles) Carfilzomib, 20/27 mg/m2 Days 1,2,8,9,15,16 Carfilzomib, 27 mg/m2 Days 1,2,8,9,15,16 Phase IIopen-label dose- escalation trial (N=70) Thalidomide, 200 mg Days 1-28 Thalidomide, 50 mg Days 1-28 Dexamethasone, 40 mg Days 1,8,15,21 Dexamethasone, 40 mg Days 1,8,15,21 *High-dose melphalan 200 mg/m2 plus ASCT Carfilzomib 27 mg/m2 dose escalation: Cohort 1 treatment as above; Cohort 2 to 36 mg/m2; Cohort 3 to 45 mg/m2; Cohort 4 to 56 mg/m2. Sonneveld P, et al. ASH 2013. Abstract 688.

  12. Carfilzomib/Thalidomide/ Dexamethasone: Response and AEs *t(4;14) and/or del(17p) and/or 1q and/or ISS3. • Grade 3/4 AEs ≥ 5% by carfilzomib dose: • 20/27 mg/m2=GI toxicity, 16%, skin, 12%; metabolism, 10%; myelotoxicity, 8%; fatigue, 8%; cardiovascular, 6% • 20/36 mg/m2=metabolism, 10%; myelotoxicity, 8%; GI toxicity, 5% • Neuropathy < 5% in both cohorts Sonneveld P, et al. ASH 2013. Abstract 688.

  13. Impact of Novel Agents in the Treatment of Elderly Pts with Newly Diagnosed MM Substantial improvements in PFS and OS *Median OS not reached N/A: not available 1Palumbo et al. Blood 2008; 112:3107–3114 2Facon et al. Lancet 2007; 370:1209–1218 3Hulin et al. J Clin Oncol 2009; 27:3664-70 4Waage et al. Blood 2010; 116:1405-12 5Wijermans et al. J Clin Oncol 2010; 28:3160-6 6Beksac et al. Eur J Haematol 2011;86:16-22 7San Miguel et al. N Engl J Med 2008; 359(9): 906–917; Supplementary Appendix 8Mateos et al. J Clin Oncol 2010; 28(13): 2259-2266 9Palumbo et al. ASH 2010 (Abstract 622) 10Mateos et al. Lancet Oncol 2010; 11(10): 934-941 11Palumbo et al. ASH 2010 (Abstract 620)

  14. FIRST Trial: Study Design Active Treatment + PFS Follow-up Phase Screening LT Follow-Up PD or Unacceptable Toxicity RANDOMIZATION 1:1:1 PD, OS and Subsequent anti-MM Tx LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm A Continuous Rd LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm B Rd18 MEL + PRED + THAL 12 Cycles1(72 wks) MELPHALAN 0.25mg/kg D1-4/42 PREDNISONE 2mg/kg D1-4/42 THALIDOMIDE 200mg D1-42/42 Arm C MPT Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4 • Stratification: age, country and ISS stage ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival 1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70. Facon T, et al. Blood. 2013;122:abstract 2.

  15. 100 80 60 40 20 0 FIRST Trial: Final Progression-free Survival Hazard ratio Rd vs. MPT: 0.72; P = 0.00006 Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349 Patients (%) 42% (Rd) 23% (Rd18) 23% (MPT) 6 12 18 24 30 36 42 48 54 60 0 Time (months) mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone. Facon T, et al. Blood. 2013;122:abstract 2.

  16. FIRST Trial: Consistent PFS Benefit Across Subgroups 0.125 8 0. 25 0.5 1 2 4 Subgroup Hazard ratio (HR) and 95% CI HR (95% Cl) Age > 75 Age ≤ 75 Gender: female Gender: male Asia Europe North America and Pacific ISS stage: I or II ISS stage: III CrCI < 30 ml/min CrCI30 – 50 ml/min CrCI 50 – 80 ml/min CrCI ≥ 80 ml/min ECOG PS Grade 0 ECOG PS Grade 1 ECOG PS Grade 2 LDH < 200 IU/l LDH ≥ 200 IU/l Cytogenetics High-risk Cytogenetics Non-high Risk ITT patients 0.81 (0.62 - 1.05) 0.68 (0.56 - 0.83) 0.73 (0.58 - 0.93) 0.71 (0.57 -0.88) 0.61 (0.33 - 1.14) 0.77 (0.63 - 0.93) 0.64 (0.46 - 0.89) 0.70 (0.57 - 0.87) 0.75 (0.59 - 0.95) 0.76 (0.44 - 1.30) 0.66 (0.48 - 0.91) 0.74 (0.58 - 0.95) 0.71 (0.51 - 1.01) 0.54 (0.39 - 0.74) 0.81 (0.65 - 1.01) 0.80 (0.57 - 1.12) 0.69 (0.58 - 0.83) 0.96 (0.66 - 1.39) 1.23 (0.78 - 1.93) 0.69 (0.53 - 0.90) 0.72 (0.61 - 0.85) Favoring MPT Favoring Rd ITT, intention to treat; ITT comparison for continuous Rd vs. MPT Facon T, et al. Blood. 2013;122:abstract 2. • Cytogeneticshigh-risk included t(4;14), t(14;16), del(17p)

  17. 100 80 100 60 80 60 40 40 20 0 0 6 6 12 12 18 18 24 24 30 30 36 36 42 42 48 48 54 54 60 60 20 0 Rd Rd18 MPT 535 541 547 445 451 422 371 375 351 319 331 293 275 266 239 224 181 177 142 111 101 77 61 42 28 16 9 3 2 1 0 0 0 0 FIRST Trial: TTP and Time to 2nd Anti-myeloma Therapy Time to Progression Time to 2nd AMT Patients (%) Rd Rd18 MPT 535 541 547 398 389 379 318 317 303 263 265 242 218 167 169 167 108 115 105 56 58 55 30 28 19 7 6 2 2 1 0 0 0 Patients (%) Hazard ratio Rd vs. MPT: 0.68; P=0.00001 Rd vs. Rd18: 0.62; P≤0.00001 Rd18 vs. MPT: 1.11; P=0.21718 Hazard ratio Rd vs. MPT: 0.66; P<0.00001 Rd vs. Rd18: 0.74; P=0.00067 Rd18 vs. MPT: 0.88; P=0.12333 TTP (months) Time to 2nd AMT (months) Facon T, et al. Blood. 2013;122:abstract 2.

  18. FIRST Trial: Conclusions Continuous Rd significantly extended PFS, with an OS benefit vs. MPT PFS: HR= 0.72 (P= 0.00006) Consistent benefit across most subgroups Rd better than Rd18 (HR= 0.70, P= 0.00001) 3 yr PFS: 42% Rd vs. 23% Rd18 and MPT Planned interim OS: HR= 0.78 (P= 0.0168) Rd was superior to MPT across all other efficacy secondary endpoints Safety profile with continuous Rd was manageable Hematological and non-hematological AEs were as expected for Rd and MPT Incidence of hematological SPM was lower with continuous Rd vs. MPT In NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care Facon T, et al. Blood. 2013;122:abstract 2.

  19. Larocca et al ASH 2013

  20. Larocca et al, ASH 2013

  21. Bringhen et al ASH 2013

  22. Bringhen et al ASH 2013

  23. Oral MLN 9708 Len Dex in Newly Diagnosed MM Maintenance Induction: up to 16 x 21-day treatment cycles 1 2 4 5 8 9 11 12 15 21 MLN9708 maintenance Days 1, 4, 8, 11 21-day cycles MLN9708 MLN9708 MLN9708 MLN9708 Dex* Dex* Dex* Dex* Lenalidomide 25 mg, days 1–14 *Dex 20/10 mg cycles 1–8 / 9–16 Thromboembolism prophylaxis with aspirin 81–325 mg QD or LMWH while receiving len-dex mandatory • Phase 1: oral MLN9708 dose-escalation (dose of 3.0 and 3.7 mgs) • Standard 3+3 schema, 33% dose increments, based on cycle 1 DLTs • Phase 2: oral MLN9708 at the RP2D from phase 1 • Stem cell collection allowed after cycle 4, with ASCT deferred until after 8 cycles • MLN9708 maintenance continued at tolerated dose until progression or unacceptable toxicity Richardson et al ASH 2013

  24. Ixazomiblenalidomidedexamethasone in newly diagnosed multiple myeloma Dose level (cohort): Ph 1, 3.0 mg Ph 2, 3.0 mg 0 –20 –25% –40 –50% % decreases in M-protein –60 –80 –90% –100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 Subject identifier for the study • 56 pts treated at the RP2D were evaluable for response (7 phase 1, 49 phase 2) • 61% of pts had 100% decreases in M-protein or serum free light chain from baseline Richardson et al ASH 2013

  25. Pomalidomide With Low-Dose Dexamethasone Relapsed and Refractory Multiple Myeloma • POM was effective in heavily pretreated patients who had already received LEN and bortezomib and who progressed on their last line of therapy • The combination of POM with LoDEX improves the ORR due to synergy between immunomodulatory agents and glucocorticoids • POM + LoDEX, 34%; POM alone, 15% • Response was durable with POM regardless of the addition of LoDEX • POM + LoDEX, 8.3 months ; POM alone, 8.8 months • POM is generally well tolerated, with low rates of discontinuations due to AEs • Age had no impact on ORR, DoR, or safety Jagannath S, et al. ASH 2012 abstract 450.

  26. MM-003 Design: POM + LoDEX vs. HiDEX 28-day cycles (n = 302) POM: 4 mg/day D1-21 + LoDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22 RANDOMIZATION 2:1 Follow-Up for OS and SPM Until 5 Years Post Enrollment PDa orUnacceptable AE PDa orUnacceptable AE (n = 153) HiDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1-4, 9-12, 17-20 Thromboprophylaxis was required for those receiving POM or at high risk for DVT Companion trialMM-003C POM 21/28 days Stratification Age (≤ 75 vs. > 75 yrs) Number of prior Tx ( 2 vs. > 2) Disease population (primary refractory vs. relapsed/refractory vs. intolerance/failure) a Progression of disease was independently adjudicated in real time. Dimopoulos MA, et al. ASH 2013 [abstract 408].

  27. PFS Based on Cytogenetic Profile • POM + LoDEX significantly improved PFS vs. HiDEX regardless of the presence of del17p or t(4;14) POM + LoDEXa HiDEXa HR (95% CI) Subgroup 253/302 138/153 0.49 (0.40-0.61) ITT Population del(17p)/t(4;14) 0.44 (0.28-0.68) 71/77 32/35 Standard-RiskCytogenetics 126/148 63/72 0.55 (0.40-0.75) 0.5 1 2 0.25 Favors POM + LoDEX Favors HiDEX Note: Data shown only for pts with available cytogenetics; totals will not sum. a Number of events/number of patients. Dimopoulos MA, et al. ASH 2013 [abstract 408].

  28. Forest Plot of OS Based on Prior Treatment HR (95% CI) Subgroup HiDEXa POM + LoDEXa 0.72 (0.56-0.92) 176/302 101/153 ITT Population 0.56 (0.33-0.96) 41/70 22/33 ≤ 3 Prior Tx 0.76 (0.58-1.00) 135/232 79/120 > 3 Prior Tx 0.75 (0.55-1.03) 102/173 64/93 Prior THAL 0.66 (0.45-0.99) 74/129 37/60 No Prior THAL 0.70 (0.55-0.90) 168/286 94/141 LEN Ref 0.77 (0.58-1.01) 142/238 79/121 BORT Ref 0.77 (0.58-1.02) 135/225 74/113 LEN and BORT Ref 0.56 (0.36-0.88) 47/85 32/49 LEN as Last Prior 0.92 (0.63-1.36) 76/134 39/66 BORT as Last Prior 0.25 0.5 1 2 a Number of events/number of pts. San Miguel JF, et al. ASH 2013 [abstract 686]. Favoring POM-LoDex Favoring HiDEX

  29. MM-003: PFS and OS by M-Protein ReductionPatients Assigned to POM + LoDEX 1.0 1.0 0.8 0.8 0.6 0.6 Proportion of Patients 0.4 0.4 0.2 0.2 0.0 0.0 0 0 4 4 8 8 12 12 16 16 20 20 28 24 24 OS (mos) PFS (mos) San Miguel JF, et al. ASH 2013 [abstract 686]. • Median PFS was 4.0 mos and median OS was 13.1 mos overall for POM + LoDEX

  30. Pom low dose dex and bortezomib in relapsed MM Richardson et al, ASH 2013

  31. Carfilzomib: A Novel Proteasome (Chymotryptic) Inhibitor Novel chemical class with highly selective and irreversible proteasome binding Improved antitumor activity with consecutive day dosing No neurotoxicity in animals 23% Responses lasting 7.8 months with survival 15.4 months in relapsed and relapsed/ refractory MM w/o Tetrapeptide Epoxyketone Demo et al Cancer Res 2007; 67:6383 Kirk et al, Blood 2008, 112: 2765 ; Siegel et al Blood 2012:120:2817.

  32. CRd in Relapsed and Upfront MM • Response to CRd therapy in RRMM was high, with an ORR of 78% • 41% VGPR or better • CRd well-tolerated with durable responses • ASPIRE phase 3 open-label, international, multicenter trial comparing CRd to Rd in R/R MM fully enrolled. • Remarkable extent and frequency of response to CRd upfront in ND MM (94% ORR, with 80% CR,nCR after 12 cycles in a subset of pts) Wang et al ASCO 2011; Jakubowiak et al, Blood 2012

  33. CarfilzomibPomalidomide Low dose Dex • Median of 5 prior lines of therapy; 49% of patients had high/intermediate risk cytogenetics at baseline • Response rates, PFS, and OS were preserved independent of FISH/cytogenetic risk status • Well tolerated with no unexpected toxicities • ≥ VGPR 27% • ORR 70% • CBR 83% • DOR (median) 17.7 months • PFS (median) 9.7 months • OS (median) > 18 months Shah et al ASH 2013

  34. Effector cells: C1q C1q MM MM FcR MM MAb-Based Therapeutic Targeting of Myeloma Antibody-dependent Cellular cytotoxicity (ADCC) Apoptosis/growth arrest via targeting signaling pathways Complement-dependent Cytotoxicity (CDC) CDC ADCC • Daratumumab (CD38) • huN901-DM1 (CD56) • nBT062-maytansinoid (CD138) • 1339 (IL-6) • BHQ880 (DKK1) • RAP-011 (activin A) • Daratumumab (CD38) • Lucatumumab or Dacetuzumab (CD40) • Elotuzumab (CS1) • Daratumumab (CD38) • XmAb5592 (HM1.24) Tai & Anderson Bone Marrow Research 2011

  35. CS1 is highly and uniformly expressed on MM cells Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting CS1 Clinical trial of Elo in MM achieved SD Anti-MM activity of Elo enhanced by lenalidomide (len) in preclinical models Phase I/II trials: 80-90% response to lendexelo in relapsed MM with prolonged (> month 33 PFS) Phase III trial of lendexelo versus lendex in relapsed MM for new drug approval Elotuzumab Anti-CS MoAb in MM Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784; Tai YT et al. Blood. 2008;112:1329-1337; Van Rhee F et al. Mol Cancer Ther. 2009;8:2616-2624; Lonial S et al. Blood. 2009;114:432; Richardson et al Blood 2010:864 Lonial et al, ASH 2012

  36. Martin et al ASH 2013

  37. Martin et al 2013

  38. PHASE I/II STUDY OF DARATUMUMAB CD38 MONOCLONAL ANTIBODY IN RELAPSED/REFRACTORY MM Favorable safety profile as monotherapy In 15 of 32 (47%) showed benefit 4 patients achieving PR (13%) 6 patients achieving MR (19%) 5 patients achieving SD (16%) At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%) To be combined with lenalidomide dexamethasone Plesner et al ASH 2012

  39. Daratumumab and lenalidomidedexamethasone in relapsed MM The best change in response paraprotein evaluated according to IMWG 2011. A: serum M-protein, B: urine-M-protein Plesner et al ASH 2013 44

  40. Kelley et al ASH 2013

  41. Kelly et al ASH 2013

  42. Background: Targeting KSP with ARRY-520 (Filanesib) • Filanesibis a targeted Kinesin Spindle Protein (KSP) inhibitor • KSP is a microtubule motor protein critical to the function of proliferating cells • KSP inhibition induces aberrant mitotic arrest and rapid cell death • Novel mechanism of action for MM • Preferentially acts on MCL-1 dependent cells including MM • Not expected to be cross-resistant with other drugs Lonial et al ASH 2013

  43. Low AAG is Associated with Higher ORR Lonial et al ASH 2013 1 5 patients did not have a baseline AAG measurement 2 4 patients did not have a baseline AAG measurement,including 1 responder

  44. Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub dynein dynein Ub Ub Ub Ub Ub Ub HDAC6 HDAC6 HDAC6 Development of Rationally-Based Combination Therapies (HDAC and Proteasome Inhibitors) Protein protein aggregates (toxic) 26S proteasome Bortezomib, Carfilzomib, NPI0052, MLN9708, ONX 0912 Panibinostat, Vorinostat, ACY1215 Lysosome Aggresome Microtubule Autophagy Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:3441-9.

  45. VANTAGE 088: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat or Placebo with Bortezomib in Relapsed MM • The combination of vorinostat + bortezomib is active in patients with relapsed and refractory MM • Significant improvement in response rate • ORR 54% vs 41% (P<0.0001); CBR 71% vs 53% (P<0.0001) • PFS and TTP were prolonged in the combination arm compared with bortezomib alone PFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4) versus 6.83 months (5.7–7.7) • Diarrhea, fatigue, and thrombocytopenia limited tolerability. Dimopoulos et al Lancet Oncol 2013; 14: 1129-40.

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