Pomalidomide Plus Low-Dose Dex vs High-Dose Dex in Rel/Ref Myeloma

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Pomalidomide Plus Low-Dose Dex vs High-Dose Dex in Rel/Ref Myeloma Slideset on: San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14: 1055-1066. This program is supported by educational grants from

Introduction Few effective treatments and no standard of care exist for patients with relapsed/refractory myeloma following failure of proteasome inhibitors (eg, bortezomib) and immunomodulatory drugs (eg, lenalidomide) Median OS: 9 mos (3 mos without further treatment)[1] Pomalidomide monotherapy offers limited benefit in relapsed myeloma[2,3] but is synergistic with dexamethasone (phase II studies)[4-7] PR rates up to 35% in patients who had received bortezomib and/or lenalidomide OS, overall survival; PR, partial response. 1. Kumar SK, et al. Leukemia. 2012;26:149-157. 2. Schey SA, et al. J Clin Oncol. 2004;22:3269-3276. 3. Streetly MJ, et al. Br J Haematol. 2008;141:41-51. 4. Jagannath S, et al. ASH 2012. Abstract 450. 5. Leleu X, et al. Blood. 2013;121:1968-1975. 6. Richardson PG, et al. Blood. 2013;121:1961-1967. 7. Lacy MQ, et al. ASH 2012. Abstract 201.

Phase II MM-003 Study: Pom/LD Dex vs HD Dex in Rel/Ref Myeloma Randomized 2:1; stratified by age (< vs > 75 yrs), disease status (refractory vs rel/ref vs bortezomib intolerant), number of prior treatments (2 vs ≥ 3) Pom 4 mg/day on Days 1-21 + LD Dex 40 mg/day on Days 1,8,15,22 for 28-day cycles (n = 302) Patients with relapsed/refractory myeloma* (N = 455) PD or toxicity HD Dex 40 mg/day (20 mg/day if > 75 yrs) on Days 1-4, 9-12, 17-20 for 28-day cycles (n = 153) *After ≥ 2 cycles bortezomib/ lenalidomide within previous 60 days or progressed within 6 mos of achieving PR to bortezomib Dex, dexamethasone; DoR, duration of response; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Pom, pomalidomide; PR, partial response; QoL, quality of life, rel/ref, relapsed/refractory; TTP, time to progression. Primary endpoint: PFS Secondary endpoints: OS, ORR, TTP, DoR, safety, QoL San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

MM-003 Results: PFS (ITT Population) Median PFS by prior treatment for Pom/LD Dex vs HD Dex Len refractory: 3.9 vs 1.9 mos* Len and Bort refractory: 3.7 vs 2.0 mos* Bort intolerant: 4.0 vs 2.0 mos Len as last Tx: 4.6 vs 1.9 mos* Bort as last Tx: 3.8 vs 1.9 mos* Median PFS Pom/LD Dex: 4.0 mos HD Dex: 1.9 mos HR: 0.48 (P < .0001) 100 80 60 Patients (%) 40 Bort, bortezomib; Dex, dexamethasone; HD, high dose; ITT, intent to treat; LD, low dose; Len, lenalidomide; PFS, progression-free survival; Pom, pomalidomide. *P < .0001 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Mos San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

MM-003 Results: PFS by Subgroup Pomalidomide + Low-Dose Dexamethasone High-Dose Dexamethasone HR (95% CI) ITT population 233/302 133/153 0.48 (0.39-0.60) Men 139/181 76/87 0.48 (0.36-0.64) Woman 94/121 57/66 0.47 (0.34-0.66) Age ≤ 75 yrs 215/278 122/141 0.50 (0.40-0.63) Age > 75 yrs 18/24 11/12 0.36 (0.16-0.83) Refractory 191/249 107/125 0.50 (0.39-0.63) Relapsed and refractory 4/8 5/5 0.18 (0.04-0.81) Intolerant to bortezomib 38/45 21/23 0.48 (0.28-0.84) 2 previous treatments 12/17 7/8 0.47 (0.18-1.25) More than 2 previous treatments 221/285 126/145 0.48 (0.39-0.61) Cytogenetics, non-high risk 72/91 41/47 0.50 (0.33-0.74) Cytogenetics, moderate high risk 64/77 30/35 0.46 (0.30-0.72) At least PR after cycle 2 26/51 2/3 0.58 (0.14-2.48) Less than PR after cycle 2 207/251 131/150 0.58 (0.47-0.73) Refractory to lenalidomide 224/286 121/141 0.50 (0.40-0.62) Refractory to lenalidomide and bortezomib 176/225 95/113 0.52 (0.41-0.68) Last previous treatment was lenalidomide 64/85 42/49 0.38 (0.26-0.58) Last previous treatment was bortezomib 97/132 56/66 0.52 (0.37-0.73) PFS, progression-free survival; PR, partial response. 0.25 0.50 1.00 2.00 Favors pomalidomide + low-dose dexamethasone Favors high-dose dexamethasone San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

MM-003 Results: OS (ITT Population) Median OS by subgroup for Pom/LD Dex vs HD Dex Len refractory: 12.7 vs 8.0 mos Len and Bort refractory: 11.1 vs 7.7 mos Bort intolerant: 15.5 vs 8.6 mos Len as last Tx: 12.3 vs 7.3 mos Bort as last Tx: 13.1 vs 12.3 mos Median OS Pom/LD Dex: 12.7 mos HD Dex: 8.1 mos HR: 0.74 (P = .0285) 100 80 60 Patients (%) 40 Bort, bortezomib; Dex, dexamethasone; HD, high dose; ITT, intent to treat; LD, low dose; Len, lenalidomide; OS, overall survival; Pom, pomalidomide. 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 OS (Mos) San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

MM-003 Results: OS by Subgroup Pomalidomide + Low-Dose Dexamethasone High-Dose Dexamethasone HR (95% CI) ITT population 145/302 82/153 0.74 (0.56-0.97) Men 86/181 42/87 0.84 (0.58-1.22) Woman 59/121 40/66 0.61 (0.41-0.92) Age ≤ 75 yrs 135/278 74/141 0.78 (0.59-1.04) Age > 75 yrs 10/24 8/12 0.40 (0.15-1.05) Refractory 120/249 67/125 0.76 (0.56-1.03) Relapsed and refractory 3/8 2/5 0.85 (0.14-5.13) Intolerant to bortezomib 22/45 13/23 0.59 (0.29-1.20) 2 previous treatments 7/17 5/8 0.44 (0.14-1.40) More than 2 previous treatments 138/285 77/145 0.76 (0.58-1.01) Cytogenetics, non-high risk 42/91 20/47 1.02 (0.60-1.73) Cytogenetics, moderate high risk 47/77 21/35 0.69 (0.41-1.16) At least PR after cycle 2 11/51 1/3 0.46 (0.06-3.67) Less than PR after cycle 2 134/251 81/150 0.86 (0.65-1.14) Refractory to lenalidomide 140/286 77/141 0.73 (0.55-0.96) Refractory to lenalidomide and bortezomib 113/225 62/113 0.77 (0.56-1.05) Last previous treatment was lenalidomide 41/85 29/49 0.53 (0.33-0.87) Last previous treatment was bortezomib 56/132 30/66 0.87 (0.56-1.36) OS, overall survival; PR, partial response. 0.25 0.50 1.00 2.00 Favors pomalidomide + low-dose dexamethasone Favors high-dose dexamethasone San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

MM-003 Results: Responses ORR significantly higher with Pom plus LD Dex vs HD Dex, both in overall population and in subgroups DoR not significantly different regardless of previous treatment Response Pom + LD Dex (n = 302) HD Dex (n = 153) P Value ORR, all patients, % 31 10 < .0001 CR or sCR 1 VGPR 5 < 1 PR 26 9 Previous treatment, % Refractory to Len 30 Refractory to Len and Bort 28 12 .0003 Intolerant to Bort 13 .1423 Len as last treatment 33 6 Bort as last treatment 34 .0011 Median DoR, mos 7.0 6.1 .0631 Bort, bortezomib; CR, complete response; Dex, dexamethasone; HD, high dose; DoR, duration of response; LD, low dose; Len, lenalidomide; ORR, overall response rate; Pom, pomalidomide; PR, partial response; sCR, stringent complete response; VGPR, very good partial response. San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

MM-003 Results: Safety AEs generally similar between arms and across subgroups Most common grade 3/4 AEs: neutropenia, anemia, thrombocytopenia ≥ Grade 3 PN in 15% with pomalidomide plus LD Dex vs 11% with HD Dex AE, % Pom + LD Dex (n = 300) HD Dex (n = 150) Grade 3 Grade 4 Grade 5 Infections and infestations 24 6 4 19 5 9 Anemia 31 2 -- 32 Neutropenia 26 22 7 Fatigue Thrombocytopenia 13 17 Pyrexia 3 < 1 1 Diarrhea Constipation Cough Back pain Dyspnea Febrile neutropenia 8 AE, adverse event; Dex, dexamethasone; HD, high dose; LD, low dose; PN, peripheral neuropathy; Pom, pomalidomide. San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

Summary In pts with relapsed/refractory myeloma, pomalidomide plus low-dose dexamethasone produced significantly longer PFS and OS than high- dose dexamethasone alone Median PFS: 4.0 vs 1.9 mos, respectively Median OS: 12.7 vs 8.1 mos, respectively Benefit observed even though 50% of pts in high-dose dexamethasone arm crossed over to receive pomalidomide ORR significantly higher with pomalidomide plus low-dose dexamethasone vs high-dose dexamethasone alone (31% vs 10%) Treatment was well tolerated with predictable, manageable AEs Pomalidomide plus low-dose dexamethasone is a potential new treatment option for advanced refractory/relapsed myeloma in pts who have failed bortezomib and lenalidomide AE, adverse event; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.