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Treatment Advances in Multiple Myeloma: Expert Perspectives on Translating Clinical Data to Practice

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Treatment Advances in Multiple Myeloma: Expert Perspectives on Translating Clinical Data to Practice Friday, December 2, 2016 San Diego, California This program is supported by educational grants from
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Treatment Advances in Multiple Myeloma: Expert Perspectives on Translating Clinical Data to Practice Friday, December 2, 2016 San Diego, California This program is supported by educational grants from Amgen, Celgene Corporation, Karyopharm, Takeda Oncology, and The Binding Site. Image: Copyright 2016 DNA Illustrations. All Rights Reserved Program Director Brian G.M. Durie, MD Medical Director, AMyC Co-Chair Myeloma Committee, SWOG Chairman, International Myeloma Foundation Specialist in Multiple Myeloma and Related Disorders Cedars-Sinai Outpatient Cancer Center Los Angeles, California Brian G.M. Durie, MD, has disclosed that he has received consulting fees from Celgene, Johnson & Johnson, Onyx, and Takeda. Faculty Philippe Moreau, MD Professor of Clinical Hematology Head, Hematology Department University Hospital Hôtel-Dieu Nantes, France Philippe Moreau, MD, has disclosed that he has received consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, and Takeda. How Do You Choose the Best Treatment Regimens for Relapsed/Refractory Disease? Moderator Brian G.M. Durie, MD Faculty Presenter Philippe Moreau, MD Image: Copyright 2016 DNA Illustrations. All Rights Reserved Pt Case Example A 61-yr-old male teacher (English) who plays golf regularly and is fit presents with bone pain, fatigue over the last 3 mos X-rays reveal lytic lesions on spine MRI shows diffuse bone lesions Laboratory assays show hemoglobin of 11.0 g/dl, creatinine of 80 mm/l, calcium of 2.24 mm/l, β 2 -M of 5.6 mg/l, albumin of 38 g/l Additional workup reveals SPEP: M-spike 46 g/l; IF: IgG K Bone marrow aspirate: 32% plasma cells FISH: t(4;14) LDH: 2 x ULN Symptomatic MM, ISS 3, R-ISS 3 Pt Case Example He began VCD for 4 cycles M-spike: decreased from 46 to 3.2 g/l Achieved VGPR ASCT, prepared by mel mos following HDT: normal SPEP, IF negative Bone marrow: 2% plasma cells Free light chain ratio: N Achieved scr Lenalidomide maintenance: 15 mg/day, 1 yr, stopped because of fatigue, GI toxicity grade 2 SPEP: normal, sustained CR Pt Case Example 6 mos later (20 mos following ASCT), pt complains of bone pain Additional exam reveals: M-spike increasing from 0 to 6 g/l PET/CT shows positive, diffuse focal lesions Cytogenetics: t(4;14), no 17p How would you treat this pt now? A. Carfilzomib, dexamethasone B. Carfilzomib, lenalidomide, dexamethasone C. Carfilzomib, pomalidomide, dexamethasone D. Ixazomib, lenalidomide, dexamethasone E. Panobinostat, bortezomib, dexamethasone F. Elotuzumab, lenalidomide, dexamethasone G. Daratumumab, lenalidomide, dexamethasone H. Daratumumab, pomalidomide, dexamethasone I. Daratumumab, bortezomib, dexamethasone J. Unsure Expert Recommendations Expert Brian G.M. Durie, MD Shaji Kumar, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Daratumumab/len/dex or Carfilzomib/len/dex Carfilzomib/len/dex or Daratumumab/bortezomib/dex Daratumumab/len/dex Daratumumab/len/dex S. Vincent Rajkumar, MD Daratumumab/len/dex Jesús F. San-Miguel, MD, PhD Carfilzomib/len/dex or Daratumumab/len/dex Pt Case Example Our pt progressed 6 mos after stopping lenalidomide maintenance (20 mos following ASCT after VCD induction) He was treated with KRd and achieved VGPR after 3 cycles During cycle 17, this pt progressed, with new bone lesions, and M-spike 10 g/l How would you treat this pt now (2nd relapse)? A. Pomalidomide, dexamethasone B. Pomalidomide, cyclophosphamide, dexamethasone C. Daratumumab, pomalidomide, dexamethasone D. Elotuzumab, pomalidomide, dexamethasone E. Daratumumab, bortezomib, dexamethasone F. Daratumumab, dexamethasone G. Daratumumab monotherapy H. Unsure Expert Recommendations Expert Brian G.M. Durie, MD Shaji Kumar, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Daratumumab/pomalidomide/dex Daratumumab or Daratumumab/pomalidomide/dex Daratumumab/pomalidomide/dex Elotuzumab/pomalidomide/dex S. Vincent Rajkumar, MD Daratumumab/bortezomib/dex Jesús F. San-Miguel, MD, PhD Daratumumab/dex or Daratumumab/pomalidomide/dex Treating Relapsed Myeloma Philippe Moreau, MD 1-3 Prior Lines of Therapy - Len/dex or - Len/dex + 3rd agent? Lenalidomide/Dex +? - Carfilzomib (ASPIRE) [1] - Elotuzumab (ELOQUENT) [2] - Ixazomib (TOURMALINE) [3] - Daratumumab (POLLUX) [4] 1. Stewart AK, et al. N Engl J Med. 2015;372: Dimopoulos MA, et al. Blood. 2015;126:Abstract Moreau P, et al. N Engl J Med. 2016;374: Dimopoulos M, et al. EHA Abstract LB238. ASPIRE Trial: Progression-Free Survival (Primary Endpoint) ITT Population (N=792) Proportion Surviving Without Progression No. at Risk: KRd Rd KRd Rd KRd (n=396) Rd (n=396) Median PFS, mo HR (KRd/Rd) (95% CI) 0.69 ( ) P value (one-sided) Months Since Randomization Stewart AK, et al. N Engl J Med. 2015;372: ELOQUENT-2: Extended Progression-Free Survival year PFS 2-year PFS Extended follow-up 0.9 E-Ld Ld Probability progression free % 57% 41% 27% Median PFS (95% CI) 26% 18% HR 0.73 (95% CI 0.60, 0.89); p= mo (16.6, 22.2) Ld E-Ld 14.9 mo (12.1, 17.2) 0.0 No. of patients at risk: E-Ld 321 Ld PFS (months) E-Ld treated patients had a 27% reduction in the risk of disease progression or death and a 44% relative improvement in PFS vs Ld-treated patients Dimopoulos MA, et al. ASH Abstract 28. TOURMALINE-MM1 Final PFS analysis: A significant, 35% improvement in PFS with IRd vs placebo-rd Probability of progression-free survival Log-rank test p=0.012 Hazard ratio (95% CI): (0.587, 0.939) Number of events: IRd 129; placebo-rd Time from randomization (months) Median PFS: IRd: 20.6 months Placebo-Rd: 14.7 months Median follow-up: ~15 months Number of patients at risk: IRd Placebo-Rd Moreau P, et al. N Engl J Med. 2016;374: POLLUX: Progression-free Survival month PFS* 18-month PFS* 83% Proportion surviving without progression % 78% 52% Rd Median PFS: 18.4 months DRd 0.2 No. at risk Rd DRd Months HR: 0.37 (95% CI, ; P 0.0001) % reduction in the risk of disease progression or death for DRd vs Rd *KM estimate; HR, hazard ratio. Dimopoulos M, et al. EHA Abstract LB238. Best choice?? Rd + Carfil? Elo? Dara? Ixa? Criteria to select the optimal option: - Efficacy: PFS/OS - Safety - QOL - Cost - Convenience (oral) - Frontline therapy, duration of first response Lenalidomide-Based Studies POLLUX DRd vs Rd [1] ASPIRE KRd vs Rd [2] ELOQUENT-2 ERd vs Rd [3,4] TOURMALINE-MM1 IxaRd vs Rd [5] PFS HR (95% CI) 0.37 ( ) 0.69 ( ) 0.73 ( ) 0.74 ( ) ORR 93% VGPR 76% CR 43% 87% 79% 78% 70% 34% 48% 32% 5% 14% Duration of response, mos NE OS HR (95% CI) 0.64 ( ) 0.79 ( ) 0.77 ( ) NE 1. Dimopoulos M, et al. EHA Abstract LB Stewart AK, et al. N Engl J Med. 2015;372: Lonial S, et al. N Engl J Med. 2015;373: Dimopoulos MA, et al. Blood. 2015;126:Abstract Moreau P, et al. N Engl J Med. 2016;374: Dimopouos M, et al. EHA Abstract LB2238. Burden on Healthcare System and Pts Route of administration Dosing schedule Hospital/clinic visit Minimum clinic visits based on 18 cycles Administration time in clinic/ hospital per visit Ixazomib-Rd Carfilzomib-Rd Elotuzumab-Rd Dara-Rd PO IV IV IV Days 1, 8, and 15 of 28-day cycle Days 1, 2, 8, 9, 15, and 16 of 28-day cycle Days 1, 8, 15, 22 of 28-day of cycles 1-2 then Days 1 and 15, cycle 3+ Every 4 ks Twice a k Weekly x 8 then twice montly Days 1, 8, 15, 22 of cycles 1-2 Days 1, 15 of cycles 3-6 Day 1 of cycle 7+ Weekly x 8 then twice monthly hours Over 2 hrs (130 mins) About 5 hrs (290 mins) Premedication N N Y Y 1 day 6 hrs Prehydration N Additional IV hydration needed especially before each dose in cycle 1, maybe in other cycles N N Relapse Following Len/Dex Vd Vd-Elo Vd-Dara Vd-Panobinostat Vd-Pom Kd??? VCD Panorama 1 : VD vs VD-panobinostat, PFS Progression-free survival Probability (%) PAN-BTZ-Dex Pbo-BTZ-Dex Events PAN-BTZ-Dex 207/387 Pbo-BTZ-Dex 260/381 Median PFS (95% CI) months HR (95% CI) 12.0 (10.3, 12.9) (7.6, 9.2) ( ) P value Number of patients at risk Months PAN-BTZ-Dex Pbo-BTZ-Dex San-Miguel JF, et al. Lancet Oncol. 2014;15: San-Miguel JF, et al. ASH Abstract 3026. ENDEAVOR Primary End Point: Progression-Free Survival Intent-to-Treat Population (N=929) Proportion Surviving Without Progression Kd Vd Disease progression or death n (%) Median PFS months HR for Kd vs Vd (95% CI) Months Since Randomization Kd (n=464) Vd (n=465) 171 (37) 243 (52) ( ) 1-sided P Median follow-up: 11.2 months CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; Kd, carfilzomib and dexamethasone; PFS, progression-free survival; Vd, bortezomib and dexamethasone. Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38. CASTOR: PFS With Addition of Daratumumab to Vd yr PFS 80 PFS (%) Median PFS, DVd Mos Vd NR 7.2 HR: 0.39 (95% CI: ; P .0001) 60.7% 26.9% Mos 61% reduction in the risk of disease progression or death for DVd vs Vd Palumbo A, et al. ASCO Abstract LBA4. Slide credit: clinicaloptions.com PI-Based Studies Daratumumab DVd vs Vd Carfilzomib Kd vs Vd [1] Panobinostat PVd vs Vd [2,3] Elotuzumab EVd vs Vd [4] PFS HR (95% CI) 0.39 ( ) 0.53 ( ) 0.63 ( ) 0.72 ( ) PFS Median mo NE VGPR 59% CR 19% 54% 28% 36% 13% 11% 4% Duration of response, mos NE OS HR (95% CI) 0.77 (0.47, 1.26) 0.79 ( ) 0.94 ( ) 0.61 ( ) 1. Dimopoulos MA, et al. Lancet Oncol. 2016;17: San-Miguel JF, et al. Lancet Oncol. 2014;15: San-Miguel JF, et al. Blood. 2015;126:Abstract Jakubowiak A, et al. Blood. 2016;[Epub ahead of print]. Palumbo et al. Presented at ASCO 2016 (Abstract LBA4), oral presentation Adverse Events Trial Treatment Regimen Grade 3/4 AE, % ASPIRE Rd + Carfilzomib Hypertension (4) Cardiac failure (4) Acute renal failure (3) ELOQUENT Rd + Elotuzumab Infusion reaction (1) TOURMALINE Rd + Ixazomib Rash (5) POLLUX Rd + Daratumumab Infusion reaction (5) PANORAMA Vd + Panobinostat Diarrhea (25) Fatigue (24) Vomiting (7) ENDEAVOR Kd Hypertension (9) Dyspnea (5) Cardiac Failure (5) POLLUX Vd + Daratumumab Infusion reaction (9) Hypertension (7) 30 Beyond 1-3 Prior Lines of Therapy Design: POM + LoDEX vs HiDEX Refractory MM Pts Who Have Exhausted BORT and LEN 28-day cycles (n = 302) RANDOMIZED 2:1 POM: 4 mg/day Days LoDEX: 40 mg ( 75 yrs) 20 mg ( 75 yrs) Days 1, 8, 15, 22 HiDEX: (n = 153) 40 mg ( 75 yrs) 20 mg ( 75 yrs) Days 1-4, 9-12, PD* PD* Follow-up for OS and SPM until 5 years post enrollment Companion trial MM-003C POM 21/28 days * Progression of disease was independently adjudicated in real time. San Miguel JF, et al. Lancet Oncol 2013; sep3 Thromboprophylaxis was indicated for those receiving POM or with DVT history Stratification Age ( 75 vs 75 yrs) Number of prior Tx ( 2 vs 2) Disease population (primary refractory vs relapsed/refractory vs intolerance/failure) Overall Survival ITT Population Updated March (median follow-up 10 mos) POM + LoDEX (n = 302) HiDEX (n = 153) Median OS 12.7 mos 8.1 mos Proportion of Pts HR: 0.74 P = Pts at Risk, n POM + LoDEX HiDEX San Miguel JF, et al. ASCO Abstract Overall Survival (Mos) 76 pts (50%) in the HiDEX arm received POM Phase II Trial: Pomalidomide/Cyclophosphamide/Dexamethasone PomDex PomCycloDex Arm PomDex PomCycloDex Cyclophosphamide : 400 mg PO Days 1, 8, 15 Baz R, et al. Blood. 2016;127: Usmani, SZ et al. Blood 2016;128: Daratumumab: Single Agent Activity Usmani, SZ et al. Blood 2016;128: Daratumumab: Single Agent Activity Usmani, SZ et al. Blood 2016;128: Daratumumab: Single Agent Activity OS by Response Category Go Online for More CCO Coverage of Multiple Myeloma! Capsule Summaries of all the key data Additional CME-certified slideset on multiple myeloma with expert faculty commentary on all the key studies Online Treatment Decision Aid with recommendations from 5 experts for your individual patients with myeloma myeloma.org/videos/ash-satellite-symposium-2016 clinicaloptions.com/oncology clinicaloptions.com/myelomatool
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