Multiple Myeloma Highlights From the 2015 ASCO Annual Meeting and the 20 th Congress of EHA

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1 Multiple Myeloma Highlights From the 2015 ASCO Annual Meeting and the 20 th Congress of EHA July 13, 2015 Welcome and Introductions Anne Quinn Young, MPH Multiple Myeloma Research Foundation Norwalk, CT 2 1

2 2015 ASCO Annual Meeting and the 20 th Congress of EHA Faculty Shaji Kumar, MD Mayo Clinic Rochester, MN Jeffrey Wolf, MD University of California San Francisco San Francisco, CA ASCO Annual Meeting and the 20 th Congress of EHA Jeffrey Wolf, MD University of California San Francisco San Francisco, CA 4 2

3 Improvement in Overall Survival in the Treatment of Myeloma (By Decade) Proportion Surviving Follow up from Diagnosis (Years) Wolf J Presentation at 2015 ASCO 5 Diagnostic Criteria for MGUS, SMM, and MM MGUS SMM MM Monoclonal Component Bone Marrow Plasma Cells (%) < 3 g/dl serum AND < 10% 3 g/dl serum AND/OR 10-60% Present (serum/urine) AND > 10% b AND AND AND End-organ Damage Absent Absent Present MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; SMM, smoldering multiple myeloma. Mateos M-V. Presentation at ASCO

4 New Definitions for Smoldering Multiple Myeloma and Symptomatic Multiple Myeloma Changes to smoldering classification criteria CRAB criteria Calcium elevation Renal insufficiency Anemia Bone disease Plasmacytosis 60% Light chains involved/uninvolved >100 1 focal lesion on magnetic resonance imaging (MRI) Rajkumar et al. Lancet Oncol. 2014;15(12):e Natural History of Multiple Myeloma M-protein (g/l) Asymptomatic monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM) ACTIVE MYELOMA Symptomatic FIRST RELAPSE Plateau remission SECOND RELAPSE REFRACTORY RELAPSE First-line therapy Second-line Third-line Myeloma is always preceded by MGUS or SMM Mateos M-V. presentation at ASCO

5 Smoldering Multiple Myeloma All patients with smoldering myeloma are not equal Probability of progression to symptomatic disease increases with increased number of risk factors: Evolving M protein pattern Immunoparesis Bone marrow plasma cell involvement 20% One Minus Cumulative Survival risk factors P < risk factors 1 risk factor No risk factors Time to Progression to Symptomatic Myeloma, Years Mateos M-V. Presentation at ASCO 2015; de Larrea et al. Blood. 2014;124(21):Abstract Transplant Inelegible Patients Update from the FIRST study Newly diagnosed patients Continuous lenalidomide/dex (N = 535) 18 cycles of lenalidomide/dex (N = 541) 12 cycles of melphalan, prednisone, thalidomide (N = 547) Median follow-up of 45.5 months Cont. Len/dex 18 cycles Len/dex MPT Median OS (months) MPT, melphalan prednisone thalidomide; OS, overall survival Facon T et al J Clin Oncol 33, 2015 (suppl; abs 8524) 10 5

6 Transplant Versus No Transplant Lenalidomide, 6 cycles: cyclophosphamide, lenalidomide, (CRD) Mel200/ASCT N = 389 Mel200/ASCT CRD P value 4-year PFS 87% 71% Grade 3 or 4 hematologic AEs 84% 26% Grade 3 or 4 non-hematologic AEs 39% 22% AE, adverse event; ASCT, autologous stem cell transplant; PFS, progression-free survival. Gay F et al. EHA 2015 (abs S101) 11 Maintenance With Lenalidomide (Revlimid) ASCT CR PR SD Placebo Lenalidomide Time to Progression Overall Survival Median: 53 vs 26 mos Hazard ratio 0.54 (p<0.001) Probability Probability Median: NR vs 76 mos Hazard ratio 0.60 (p=0.001) 0.2 Placebo Lenalidomide 0.2 Placebo Lenalidomide Time Since ASCT (Months) Time to progression and overall survival were significantly improved Regardless of response Lenalidomide may be associated with a risk of secondary primary malignancies CR, complete response; NR, not reached; PR, partial response; SD, stable disease. Holstein SA et al J Clin Oncol 33, 2015 (suppl; abs 8523) Time Since ASCT (Months) 6

7 Lenalidomide (Revlimid) Plus Dexamethasone ±ASCT Proportion Alive Lenalidomide, Arm A (Ld+ASCT) Collect stem cells Overall Survival Arm B (Ld alone) HR (Arm B [Ld alone]: Arm A [Ld+ASCT] = 0.73; 95% CI, ; p= Time from First Treatment (Months) Lenalidomide, (N = 29) ASCT (n = 31) Continue lenalidomide, Response rates, progression-free survival, and overall survival were similar in patients with and without ASCT Lentzsch S et al J Clin Oncol 33, 2015 (suppl; abs 8530) Proportion Alive or Progression Free Progression-free Survival Arm A (Ld+ASCT) Arm B (Ld alone) HR (Arm B [Ld alone]: Arm A [Ld+ASCT] = 1.02; 95% CI, ; p= Time to Progression or Death (Months) MMRC Phase 2 Trial; Carfilzomib in Newly Diagnosed Patients Induction Phase 2 trial from the MMRC Open-label, single-arm Primary endpoint: rate of scr after 8 cycles of carfilzomib (Kyprolis), lenalidomide (Revlimid), and ASCT Consolidation Maintenance with KRd Maintenance with Rd Cycles 1-4 Cycles 5-8 Cycles 9-18 Cycles 19+ CR, complete response; KRd, Kyprolis Revlimid ; ncr, near complete response; Rd, Revlimid ; scr, stringent complete response; VGPR; very good partial response. Zimmerman TM et al J Clin Oncol 33, 2015 (suppl; abs 8510) 14 7

8 MMRC Phase 2 Trial (cont.); Minimal Residual Disease *MRD by 10-color flow cytometry from indicated number of patients available for MRD evaluation Carfilzomib plus lenalidomide and with ASCT produced higher rates of scr than was seen previously with this treatment without transplant Responses improved with duration of treatment Adverse events were as expected with this treatment MRD, minimum residual disease. Zimmerman TM et al J Clin Oncol 33, 2015 (suppl; abs 8510) 15 ASPIRE Phase 3 Trial Relapsed / refractory 1-3 prior therapies Carfizomib, lenalidomide and Lenalidomide and 1 prior therapy 2 prior therapies No prior therapies Carf/Len/dex Len/dex Carf/Len/dex Len/dex PFS (months) ORR 87% 70% 87% 64% Stringent CR 13% 3% 15% 5% CR 21% 4% 15% 6% VGPR 42% 36% 34% 28% PR 11% 27% 23% 26% Dimopoulos MA et al J Clin Oncol 33, 2015 (suppl; abs 342); Dimopoulos MA et al EHA abs S

9 ENDEAVOR Phase 3 Trial Relapsed / refractory Carfilzomib plus N = 464 Bortezomib plus N = 465 Patients had received 1-3 prior treatments Treated until disease progression or unacceptable toxicity Median PFS with carfilzomib was 18.7 months vs 9.4 months with bortezomib (P<.0001) Rates of grade 2 peripheral neuropathy were 6.3% vs 32.0% (P<.0001) Carfilzomib/dex Bortezomib/dex ORR 77% 63% CR 13% 6% VGPR 54% 29% ORR, overall response rate. Dimopoulos MA et al J Clin Oncol 33, 2015 (suppl;abs 8509); Dimopoulos MA et al EHA LB Summary Anne Quinn Young, MPH Multiple Myeloma Research Foundation Norwalk, CT 18 9

10 2015 ASCO Annual Meeting and the 20 th Congress of EHA Shaji Kumar, MD Mayo Clinic Rochester, MN 19 Panobinostat: Update From PANORAMA 1 Panobinostat (Farydak) combined with bortezomib and was recently approved for patients with relapsed/refractory multiple myeloma Treated with 2 prior therapies including IMiDs (lenalidomide, thalidomide, or pomalidomide) and bortezomib Subgroup analysis showed: Progression-free survival benefit in patients with prior treatment with: IMiDs or bortezomib and IMiDs Bortezomib and IMiDs and 2 prior therapies More patients had ncr or VGPR, and these were associated with longer PFS IMiD, immunomodulatory drug. San-Miguel JF et al J Clin Oncol 33, 2015 (suppl; abs 8526); Hungria VTM et al J Clin Oncol 33, 2015 (suppl; abs 8575) 20 10

11 Ongoing Trials With Panobinostat Panobinostat, lenalidomide, and Patients had a median of 3 prior therapies 15 (74%) were refractory to lenalidomide 7 (35%) refractory to pomalidomide 9 (45%) refractory to bortezomib 6 (30%) refractory to carfilzomib ORR was 45% 1 CR, 3 VGPR, 5 PR Additionally, there were 8 MR, 2 SD, and 1 PD for a clinical benefit rate of 85% No grade 3 or 4 gastrointestinal toxicities reported Panobinostat Plus Carfilzomib All patients had received prior bortezomib and/or carfilzomib 81% had received prior IMiDs 58% previously had ASCT Responses so far: 1 (3%) CR, 10 (29%) VGPR, 14 (45%) PR, 4 (13%) MR, 4 (13%) SD ORR was 77% Most gastrointestinal toxicities were grade 1 or 2 Grade 3/4 toxicities: Thrombocytopenia (47%) Neutropenia (8%) Anemia (9%) Diarrhea (6%) MR, minimum response. Chari A et al J Clin Oncol 33, 2015 (suppl; abs 8528) 21 ELOQUENT Phase 3 trial Relapsed/Refractory 1-3 prior therapies not lenalidomide refractory Elotuzumab, lenalidomide, and (N = 321) Lenalidomide and (N = 325) Median number of prior therapies was 2 Elotuzumab added very little toxicity Elo/Len/dex Len/dex P value PFS (months) ORR 79% 66% Lonial S et al J Clin Oncol 33, 2015 (suppl; abs 8508) 22 11

12 Phase 2 Trial: Daratumumab Relapsed/refractory 1-3 prior therapies Daratumumab 16 mg/kg (N = 106) Median of 5 prior therapies Median time to progression: 3.7 months ORR: 29.2% 3 scr, 10 VGPR, and 18 PR Median duration of response: 7.4 months Estimated 1-year OS: 65% Lonial S et al J Clin Oncol 33, 2015 (suppl; abs LBA8512) 23 Novel Agents & New Combinations For Relapsed, Refractory Patients Drug CAR-T cells CUDC-907 Ixazomib Melflufen MOR202 Oprozomib Ricolinostat SAR Venetoclax (ABT-199) Class Immunotherapy Histone deacetylase inhibitor Oral proteasome inhibitor Alkylator Monoclonal antibody against CD38 Oral proteasome inhibitor Histone deacetylase inhibitor Monoclonal antibody against CD38 BCL-2 inhibitor Raab M EHA 2015, abs S789; Raab M ASCO abs 8574; Raje N et al EHA 2015 P279; Magarotto V et al EHA P285; Moreau P EHA P289; Kumar S EHA P658; Oki Y et al EHA P325; Vij R et al EHA P

13 Summary Anne Quinn Young, MPH Multiple Myeloma Research Foundation Norwalk, CT ASCO Annual Meeting and the 20 th Congress of EHA Question and Answer Shaji Kumar, MD Mayo Clinic Rochester, MN Jeffrey Wolf, MD University of California San Francisco San Francisco, CA 26 13

14 Closing Remarks Anne Quinn Young, MPH Multiple Myeloma Research Foundation Norwalk, CT To learn more about the MMRF, please visit: