7/28/2014 Winship Cancer Institute of Emory University Current Management of Relapsed/Refractory Multiple Myeloma Kenneth C. Anderson, MD Program Director and Chief, Division of Hematologic Neoplasias Kraft Family Professor of Medicine Jerome Lipper Multiple Myeloma Center Harvard Medical School Dana ‐ Farber Cancer Institute Disclosures • Consulting fees from: ─ Bristol ‐ Myers Squibb, Celgene, Gilead, Millennium, Onyx, and Sanofi • Stock or stock options from: ─ Acetylon Pharmaceuticals, Inc. and OncoPep 1
7/28/2014 Integration of Novel Therapy Into Myeloma Management 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, induction, consolidation, and maintenance therapy Nine FDA approvals and median survival prolonged from 3-4 to 6-7 years, with additional prolongation from maintenance New approaches needed to treat and ultimately prevent relapse 2
7/28/2014 Efficacy and Toxicity by Bortezomib schedule VMP* VMP VMP (VISTA) twice weekly N=63 once weekly N=190 CR 30% 27% 23% PFS @ 3 years NA 32% 35% Sensory PN Any grade 44% 43% 21% Grade 3-4 13% 14% 2% PN discontinuation NA 16% 4% Total planned dose 67.6 67.6 mg/m 2 46.8 mg/m 2 Total delivered dose NA 41 mg/m 2 40 mg/m 2 *Mateos * Mateos et al. J et al. J Clin Clin Oncol Oncol 2010; 2010; PN: peripheral neuropathy Palumbo et al ASH 2010 abstr 620 SC vs IV Bortezomib for Relapsed/Refractory Myeloma Moreau et al, ASH 2010 abstr 312 EQUIVALENT EFFICACY Bortezomib IV Bortezomib SC P- (N=74) value* (N=148) Peripheral Neuropathy Any PN event, % 53 38 0.04 Grade 2, % 41 24 0.01 Grade 3, % 16 6 0.03 Risk factors for PN, % Grade 1 PN at baseline 28 23 Diabetes at baseline 11 13 Exposure to prior neurotoxic agents 85 86 *P-values are based on 2-sided Fisher’s exact test 3
7/28/2014 7 MM-002 Ph2: POM ± LoDEX in RRMM Trial Design • Objective: To determine the efficacy and safety of POM ± LoDEX in RRMM pts • Primary endpoint: PFS • Secondary endpoints: ORR, safety, time to response, DOR, OS a Prior Tx with ≥ 2 cycles of LEN and BORT (separately or in combination); b Patients aged > 75 years had a starting DEX dose of 20 mg/week. BORT: bortezomib; DOR: duration of response; LEN: lenalidomide; LoDEX: low-dose dexamethasone; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; POM: pomalidomide; pts: patients; R: randomized; RRMM: relapsed/refractory multiple myeloma; SD: stable disease; Tx: treatment. Richardson PG, et al. Blood . 2014;123:1826-1832. 5 • Response rates were higher with POM + LoDEX vs. POM – In pts achieving ≥ PR, median DOR was 8.3 mos for POM + LoDEX vs. 10.7 mos for POM alone (median follow-up: 16.1 and 12.3 mos, respectively) • 60% of pts on the POM-alone arm received LoDEX following PD a Data cutoff: February 1, 2013; intent-to-treat population. CR: complete response; DOR: duration of response; EBMT: European Group for Blood and Marrow Transplantation; LoDEX: low-dose dexamethasone; MR: minimal response; PD: progressive disease; POM: pomalidomide; PR: partial response; pts: patients. Richardson PG, et al. Blood . 2014;123:1826-1832. 4
7/28/2014 9 MM-002 Ph2: Adverse Events • Grade 3-4 AEs were primarily hematologic POM + LoDEX POM a Grade 3-4 Adverse Events ≥ 10% (%) (n = 112) (n = 107) Hematologic Neutropenia 41 48 Anemia 22 24 Thrombocytopenia 19 22 Leukopenia 10 7 Nonhematologic Pneumonia 22 15 Fatigue 14 11 Dyspnea 13 8 Back pain 10 14 Hypercalcemia 1 10 • Other AEs of clinical interest: – Peripheral neuropathy: no grade 3-4 – DVT: 2% with POM + LoDEX; 3% with POM a Includes patients who subsequently received LoDEX. AE: adverse event; DVT: deep vein thrombosis; LoDEX: low-dose dexamethasone; POM: pomalidomide. Richardson PG, et al. Blood . 2014;123:1826-1832. 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. 5
7/28/2014 Pomalidomide plus Low Dose Dex is Active and Well Tolerated in Bortezomib and Lenalidomide Refractory Mutliple Myeloma Leleu et al Blood 2013 12 POM + LoDEX vs. HiDEX in RRMM MM-003 Phase 3—Trial Design a PD was independently adjudicated in real time. AE: adverse event; D: day; DOR: duration of response; DVT: deep-vein thrombosis; HiDEX: high-dose dexamethasone; LoDEX: low-dose dexamethasone; MM: multiple myeloma; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; POM: pomalidomide; PR: partial response; RRMM: relapsed/refractory multiple myeloma; SPM: second primary malignancy. San Miguel JF. Lancet Oncology. 2013; 14:1055-1066. 6
7/28/2014 Prior Therapies POM + LoDEX HiDEX (N = 302) (N = 153) Median number, n (range) 5 (2-14) 5 (2-17) Prior DEX (%) 98 99 Prior THAL (%) 57 61 Prior ASCT (%) 71 69 Prior LEN (%) 100 100 Prior BORT (%) 100 100 Prior alkylator (%) 100 100 Refractory disease (%) 82 82 LEN refractory 95 92 BORT refractory 79 79 BORT intolerance 15 15 LEN and BORT refractory 75 74 ASCT, autologous stem cell transplant; BORT, bortezomib; DEX, dexamethasone; HiDEX, high-dose dexamethasone; LEN, lenalidomide; LoDEX, low-dose dexamethasone; POM, pomalidomide; THAL, thalidomide. San Miguel J., et al. Lancet Oncol . 2013. DOI: 10.1016/S1470-2045(13)70380-2. Response – ITT Population • Response rate consistent among all subgroups, including LEN and BORT as last prior a Response based on investigator assessment and IMWG criteria, except for MR (based on EBMT criteria). b Kaplan-Meier median, patients with ≥ PR only. BORT, bortezomib; CI; confidence interval; CR, complete response; DOR, duration of response; HiDEX , high-dose dexamethasone; ITT, intent to treat; LEN , lenalidomide; LoDEX, low-dose dexamethasone; MR, minimal response; ORR, overall response rate; PFS, progression-free survival; POM, pomalidomide; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response. San Miguel J., et al. Lancet Oncol . 2013. DOI: 10.1016/S1470-2045(13)70380-2. 7
7/28/2014 POM + LoDEX significantly improved PFS vs. HiDEX POM + HiDEX a HR (95% CI) Subgroup LoDEX a 253/302 138/153 0.49 (0.40-0.61) ITT Population del(17p)/t(4;14) 71/77 32/35 0.44 (0.28-0.68) Standard-Risk 126/148 63/72 0.55 (0.40-0.75) Cytogenetics 0.25 0.5 1 2 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]. Forest Plot of OS Based on Prior Treatment Subgroup HiDEX a HR (95% CI) POM + LoDEX a 176/302 0.72 (0.56-0.92) ITT Population 101/153 ≤ 3 Prior Tx 41/70 22/33 0.56 (0.33-0.96) > 3 Prior Tx 135/232 79/120 0.76 (0.58-1.00) 102/173 0.75 (0.55-1.03) Prior THAL 64/93 74/129 0.66 (0.45-0.99) No Prior THAL 37/60 LEN Ref 168/286 94/141 0.70 (0.55-0.90) BORT Ref 142/238 79/121 0.77 (0.58-1.01) LEN and BORT Ref 135/225 74/113 0.77 (0.58-1.02) 47/85 32/49 0.56 (0.36-0.88) LEN as Last Prior BORT as Last Prior 76/134 39/66 0.92 (0.63-1.36) 0.25 0.5 1 2 Favoring POM-LoDex Favoring HiDEX a Number of events/number of pts. San Miguel JF, et al. ASH 2013 [abstract 686]. 8
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