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Advances in the Management of Myeloma

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Advances in the Management of Myeloma Advances in the Management of Myeloma Parameswaran Hari, MD Armand J. Quick/William F. Stapp Professor of Hematology Director, Adult Blood and Marrow Transplant Program Froedtert Hospital Medical College of Wisconsin Milwaukee, WI Induction/Transplant/Maintenance- what does it get us? UPDATED OS DATA from CALGB 100104 & IFM 2005-02 REF:https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm542791.htm Quest for a Better Initial Therapy for MM KRD-Dara vs KRD Outcome (%) After 4 Cycles After 8 Cycles KRD-DARA KRD KRD-DARA KRD N = 21 Non-SCT N = 15 Non-SCT N = 49 N = 44 CR/sCR 5% 18% 27% 34% ≥VGPR 71% 69% 87% 89% Judging with limited data is fraught with error Evolution CyBorD 41%> VGPR 53% > VGPR 1 year PFS -100% Kumar RVD 32%> VGPR 51%>VGPR 1 year PFS - 83% CVRD 33%> VGPR 58%>VGPR 1year PFS - 86% Jakubowiak A et al. ASCO 2017, Abstract 8000. Jakubowiak, A et al. Blood 2012;120:1801-9. Kumar et al. Blood. 2012 May 10;119(19):4375 MM Risk Categories Standard Risk (80%) High Risk (20%) Risk Factors (Expected OS: 6-7 Yrs) (Expected OS: 2-3 Yrs) del(17p), t(4;14)* FISH t(11;14), t(6;14) t(14;16), +1q21 Hypodiploidy Cytogenetics Hyperdiploidy del(13q) β2-microglobulin* Low (< 3.5 mg/L) High (≥ 5.5 mg/L) PCLI < 3% High (≥ 3%) Gene expression profile Good risk High risk • Other high risk features: − Extramedullary disease − Plasma cell leukemia − Plasmablastic morphology *Patients with t(4;14), β2-microglobulin < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease. Dispenzieri A, et al. Mayo Clin Proc. 2007;82:323-341. Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Mikhael JR, et al. Mayo Clin Proc. 2013;88:360-376. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2015. Chng WJ, et al. Leukemia. 2014;28:269-277. Phase III Stamina Trial— BMT CTN0702 Lenalidomide Maintenance** Any induction therapy MEL 200mg/m2 Lenalidomide VRD x 4* Randomize Maintenance** ASCT 2 MEL 200mg/m Lenalidomide ASCT Maintenance** * Bortezomib 1.3mg /m2 days 1, 4, 8,11 Lenalidomide 15mg days 1-15 Dexamethasone 40mg days 1, 8, 15 **Lenalidomide 15 mg daily x 3years • Estimated study completion date: 2020 • Estimated primary initial completion date: 5/2016 ClinicalTrials.gov Identifier: NCT01109004 BMT CTN0702 STaMINA Trial Results Post induction + R Maint only RVD→R Double ASCT-1 followed by: n=257 n=254 ASCT→R n=247 Median PFS, mos 52.2 56.7 56.5 Median OS, mos 83.4 85.7 82.0 High-risk patients, n 59 65 57 Median PFS, 40.2 48.3 42.2 mos Median OS, 79.5 77.5 79.3 mos No significant difference between the study arms ClinicalTrials.gov. NCT01109004. VRd Maintenance After ASCT in High Risk Disease • 45 patients received VRd maintenance after ASCT for 2 years − Bortezomib 1.3mg/m2 weekly − Lenalidomide 10mg d1-21 − Dexamethasone 40mg weekly. 100 High-risk Features n (%) 90 sCR% Del 17p 19 (42) 80 sCR+CR % Del 1p 9 (20) 70 ≥ VGPR % T (4;14) 2 (5) 60 ORR % T (14;16) 5 (11) 50 SD % PD % PCL 11 (24) 40 30 Others (aggressive presentation) 7 (16) 20 > 1 Cytogenetic abnormalities 34 (75) 10 0 Post-induction Post-ASCT day 60 Best PFS: 32 months Response Response Response 3-year OS: 93% from: Nooka, AK, et al. Leukemia.2014 28,690-693 Beyond First Trial– Ongoing Studies For Newly Diagnosed MM Patients Ineligible For Transplant Sponsor/Study Study Intervention Status Director Eloquent-1 Bristol-Myers Ongoing, but not Len/dex +/- Elotuzumab NCT01335399 Squibb/AbbVie recruiting Janssen Len/dex +/- MAIA Trial Research & Currently Daratumumab NCT02252172 Development, recruiting LLC Len/dex +/- KEYNOTE-185 Merck Sharp & Currently Pembrolizumab NCT02579863 Dohme Corp. recruiting Emerging Proteasome-inhibitor─based Regimens For Transplant Ineligible Patients Study n ≥ VGPR ORR Ixazomib, Lenalidomide, dex x12 65 58% 95% Ixazomib maintenance[1] Ixazomib, Cyclophosphamide 300/400, dex x13 80/73% 70 27/23% Ixazomib maintenance[2] Carfilzomib*, Cyclophosphamide, dex x9 58 71% 95% Carfilzomib maintenance[3] Weekly Carfilzomib**, Cyclophosphamide, dex x9 47 87% 87% Carfilzomib maintenance[4] *twice a week dosing 20mg/m2 on day 1, 2 and 36mg/m2 on day 8 and afterwards **weekly dosing 70 mg/m2 on days 1, 8, 15 1 Kumar SK, et al. Lancet Oncol. 2014;15:1503-1512, 2. Dimopoulos MA, et al. ASH 2015. Abstract 26. 3. Bringhen S, et al. Blood. 2014;124:63-69, 4. Palumbo A , et al. ASH 2014. Abstract 175. MODERN TRIPLETS FOR RELAPSE Carfilzomib – Len – Dex Ixazomib – Len – Dex Elotuzumab – Len –Dex Daratumumab – Len -Dex Bortezomib – Panabinostat – Dex Bortezomib - Daratumumab- Dex ASPIRE—Len/Dex ± Carfilzomib in R/R MM: PFS 1.0 Median PFS: Carfilzomib (KRd): 26.3 months 0.8 Control Group (Rd): 17.6 months 0.6 0.4 up 0.2 0.0 HR 0.69 (95%CI, 0.57-0.83) P < .0001 Proportion Proportion Surviving w/o Progression 0 6 12 18 24 30 36 42 48 Months Since Randomization Risk Group by KRd (n = 396) Rd (n = 396) FISH HR P Value n Median PFS, Mos n Median PFS, Mos High 48 23.1 52 13.9 0.70 .083 Standard 147 29.6 170 19.5 0.66 .004 13 Stewart , et al. N Engl J Med. 2015;372:142-152. ELOQUENT-2—Len/Dex ± Elotuzumab in R/R MM: PFS 14 Figure from Lonial, S. et al. N Engl J Med. 2015; 373:621-663. TOURMALINE-MM1— Len/Dex ± Ixazomib: PFS Median PFS: 1.0 IRd: 20.6 months Placebo-Rd: 14.7 months 0.8 free survival free - 0.6 0.4 0.2 Log-rank test P=.012 Hazard ratio (95% CI): 0.742 (0.587, 0.939) Number of events: IRd 129; placebo-Rd 157 Probability progression of Probability 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Number of patients at risk: Time from randomization (months) IRd 360 345 332 315 298 283 270 248 233 224 206 182 145 119 111 95 72 58 44 34 26 14 9 1 0 Placebo-Rd 362 340 325 308 288 274 254 237 218 208 188 157 130 101 85 71 58 46 31 22 15 5 3 0 0 • Median number of cycles IRD 13 (1-26) vs 12 Rd (1-25) • 55% (IRd) and 52% (IR) of patients remain on treatment Moreau, P. et al. ASH 2015 Abstract 727 15 Summary of PFS 30 26.3 25 20.6 20 19.4 17.6 14.9 14.7 15 Rd 10 KRd IRd EloRd 5 0 ASPIRE TOURMALINE ELOQUENT-2 Trial Design PFS Invest. arm PFS Rd arm HR ASPIRE Rd vs KRd 26.3mo 17.6mo 0.69 TOURMALINE Rd vs IRd 19.4mo 14.9mo 0.70 ELOUQUENT-2 Rd vs EloRd 20.6mo 14.7mo 0.74 Moreau, P. et al. ASH 2015 Abstract 727 Lonial, S. et al. N Engl J Med. 2015; 373:621-663. 16 Stewart, et al. N Engl J Med. 2015;372:142-150. MAb-Based Targeting of Myeloma Antibody-dependent Complement-dependent Apoptosis/growth cellular cytotoxicity (ADCC) cytotoxicity (CDC) arrest via targeting C1q signaling pathways Effector C1q cells: CDC MM MM FcR Daratumumab (CD38) Daratumumab (CD38) SAR650984 (CD38) SAR650984 (CD38) ADCC MM Elotuzumab (SLAMF7) Daratumumab (CD38) SAR650984 (CD38) Tai YT, et al. Bone Marrow Res. 2011;2011:924058. CD38 Antibodies – Immune Effects CASTOR: Study Design Multicenter, randomized, open-label, active-controlled phase 3 study Key eligibility criteria Primary Endpoint R DVd (n = 251) Daratumumab (16 mg/kg IV) • RRMM • PFS A Every week - cycle 1-3 • ≥1 prior line of Every 3 weeks - cycle 4-8 Secondary Endpoints N Every 4 weeks - cycles 9+ therapy D • TTP Vel: 1.3 mg/m2 SC, days 1,4,8,11 - cycle 1-8 • OS • Prior bortezomib O dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycle 1-8 exposure, but not M 1:1 • ORR, VGPR, CR refractory I • MRD Vd (n = 247) Z • Time to response E Vel: 1.3 mg/m2 SC, days 1,4,8,11 - cycle 1-8 • Duration of response dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycle 1-8 • Cycles 1-8: repeat every 21 days • Cycles 9+: repeat every 28 days Daratumumab IV administered in 1000 mL to 500 mL; gradual escalation from 50 mL to 200 mL/min permitted RRMM, relapsed or refractory multiple myeloma; DVd, daratumumab/bortezomib/dexamethasone; IV, intravenous; Vel, bortezomib; SC, subcutaneous; dex, dexamethasone; PO, oral; Vd, bortezomib/dexamethasone; PFS, progression-free survival; TTP, time to progression; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease. 19 Progression-free Survival 1.0 1-year PFS* Median : not reached 0.8 60.7% 0.6 DVd 0.4 26.9% 0.2 Median : 7.2 months Vd HR: 0.39 (95% CI, 0.28-0.53); P<0.0001 Proportion Proportion surviving without progression 0 0 3 6 9 12 15 No. at risk Months Vd 247 182 106 25 5 0 DVd 251 215 146 56 11 0 61% reduction in the risk of disease progression or death for DVd vs Vd *KM estimate; HR, hazard ratio. POLLUX – LENALIDOMIDE + DARA POLLUX STUDY 4 Major Triplets for Relapsed MM Do we know which triplet is better? KRD IRD ERD DRD DVD DPD ROLE OF RETRANSPLANTATION Second Transplant at Relapse Myeloma X: Salvage Transplant at Relapse Randomized 1:1 Melphalan 200mg/m2 IV + ASCT R/R MM; PAD induction (n = 89) >18 mos after prior ASCT 2-4 cycles (N = 293) Cyclophosphamide 400mg/m2 PO/wk x12 cycles (n = 85) Cook G et al; Lancet Haematol.
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