Multiple Myeloma in Session 2015: An Online Journal Club for Hematology/Oncology Fellows This program is supported by educational grants from Celgene Corporation and Onyx Pharmaceuticals.

ASPIRE: Carfilzomib Plus Rd Significantly Improves PFS vs Rd Alone in Pts With Relapsed MM Slideset on: Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152.

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Background Lenalidomide plus dexamethasone approved for treatment of relapsed MM Phase III data report improved PFS in newly diagnosed MM associated with continuous treatment with Rd[1] Carfilzomib: second-generation, irreversible proteasome inhibitor approved as monotherapy for pts who have received at least 2 prior therapies[2] Dose of 20 mg/m2 with escalation to 27 mg/m2 selected for study in phase III trials based on toxicity profile in phase II studies and demonstrated ORR of 23.7%[3,4] Phase I/II data show clinical activity of KRd in pts with relapsed MM[5.6] Current study evaluated safety and efficacy of KRd vs Rd alone in pts with relapsed MM[7] KRd, carfilzomib/lenalidomide/low-dose dexamethasone; MM, multiple myeloma; ORR, overall response rate; PFS, progression-free survival; Rd, lenalidomide/low-dose dexamethasone. 1. Benboubker L, et al. N Engl J Med. 2014;371:906-917. 2. Carfilzomib [package insert]. 3. Siegel DS, et al. Blood. 2012;120-2817-2825. 4. Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2012;12:310-318. 5. Niesvizky R, et al. Clin Cancer Res. 2013;19:2248-2256. 6. Wang M, et al. Blood. 2013;122-3122-3128. 7. Stewart AK, et al. N Engl J Med. 2015;372:142-152.

ASPIRE: Study Design Planned interim analysis of a randomized, open-label phase III trial Stratified by β2-microglobulin, prior bortezomib, and prior lenalidomide Pts with relapsed or progressive MM, 1-3 prior treatments with ≥ PR in ≥ 1 prior regimen, ECOG PS 0-2, and CrCl ≥ 50 mL/min (N = 792) Until PD or unacceptable toxicity KRd Carfilzomib Days 1, 2, 8, 9, 15, 16/cycles 1-12, Days 1, 2, 15, 16/cycles 13-18, discontinued after cycle 18 + Lenalidomide Days 1-21 + Dexamethasone Days 1, 8, 15, 22 28-day cycle (n = 396) Rd Lenalidomide Days 1-21 + Dexamethasone Days 1, 8, 15, 22 28-day cycle (n = 396) CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; KRd, carfilzomib/lenalidomide/low-dose dexamethasone; MM, multiple myeloma; PD, progressive disease; PR, partial response; PS, performance status; Rd, lenalidomide/low-dose dexamethasone. Carfilzomib: 20 mg/m2 Days 1, 2 of cycle 1; 27 mg/m2 thereafter. Lenalidomide: 25 mg. Dexamethasone: 40 mg. Stewart AK, et al. N Engl J Med. 2015;372:142-152.

ASPIRE: Responses in ITT Population KRd (N = 396) Rd P Value ≥ CR, % sCR CR 31.8 14.1 17.7 9.3 4.3 5.1 < .001 ≥ VGPR% % 69.9 40.4 SD or PD, % 3.5 14.9 Median TTR, mos 1.0 Median DoR, mos (95% CI) 28.6 (24.9-31.3) 21.2 (16.7-25.8) CR, complete response; DoR, duration of response; ITT, intent to treat; KRd, carfilzomib/lenalidomide/low-dose dexamethasone; ORR, overall response rate; PD, progressive disease; Rd, lenalidomide/low-dose dexamethasone; sCR, stringent complete response; SD, stable disease; TTR, time to response; VGPR, very good partial response. Significant improvement in ORR in KRd arm vs Rd (87.1% vs 66.7%, respectively; P < .001) Stewart AK, et al. N Engl J Med. 2015;372:142-152.

Proportion Surviving Without Progression Mos Since Randomization ASPIRE: PFS Significant improvement in PFS in KRd arm vs Rd arm KRd (n = 396) Rd (n = 396) Disease progression or death, n (%) 207 (52.3) 224 (56.6) Median PFS, mos 26.3 17.6 HR for KRd vs Rd (95% CI) 0.69 (0.57-0.83) 1.0 P = .0001 0.8 0.6 Proportion Surviving Without Progression KRd Rd KRd, carfilzomib/lenalidomide/low-dose dexamethasone; PFS, progression-free survival; Rd, lenalidomide/low-dose dexamethasone. 0.4 0.2 6 12 18 24 30 36 42 48 Mos Since Randomization Stewart AK, et al. N Engl J Med. 2015;372:142-152.

Mos Since Randomization ASPIRE: OS OS trend toward improvement for KRd arm, although results did not reach prespecified stopping boundary for OS at interim analysis KRd (n = 396) Rd (n = 396) Death, n (%) 143 (36.1) 162 (40.9) Median OS, mos NE HR for KRd vs Rd (95% CI) 0.79 (0.63-0.99) 1.0 P = .04 0.8 KRd 0.6 Proportion Surviving KRd, carfilzomib/lenalidomide/low-dose dexamethasone; NE, not estimable; OS, overall survival. Rd 0.4 0.2 6 12 18 24 30 36 42 48 Mos Since Randomization Stewart AK, et al. N Engl J Med. 2015;372:142-152.

ASPIRE: Safety AE , % KRd (n = 392) Rd (n = 389) All Grades Grade ≥ 3 Any grade 3/4 AE   83.7 80.7 Nonhematologic AE Diarrhea 42.3 3.8 33.7 4.1 Fatigue 32.9 7.7 30.6 6.4 Cough 28.8 0.3 17.2 Pyrexia 28.6 1.8 20.8 0.5 Upper respiratory tract infection 19.3 1.0 Hypokalemia 27.6 9.4 13.4 4.9 Muscle spasms 26.5 21.1 0.8 Other AEs of interest Peripheral neuropathy 17.1 NR 17.0 Dyspnea 19.4 2.8 14.9 Hypertension 14.3 4.3 6.9 Acute renal failure 8.4 3.3 7.2 3.1 Cardiac failure Ischemic heart disease 5.9 4.6 2.1 AEs, adverse events; KRd, carfilzomib/lenalidomide/low-dose dexamethasone; NR, not reached; Rd, lenalidomide/low-dose dexamethasone. Stewart AK, et al. N Engl J Med. 2015;372:142-152.

ASPIRE: Strengths and Weaknesses Study demonstrates significantly improved outcomes from KRd in pts with relapsed MM Weaknesses FISH and cytogenetics not assessed in all pts Treatment fatigue in pts 65 yrs of age or older FISH, fluorescence in situ hybridization; KRd, carfilzomib/lenalidomide/low-dose dexamethasone; MM, multiple myeloma. Stewart AK, et al. N Engl J Med. 2015;372:142-152.

ASPIRE: Conclusions KRd significantly improved PFS vs Rd alone (26.3 vs 17.6 mos, respectively) in pts with relapsed MM Survival benefit observed regardless of previous bortezomib or lenalidomide exposure or cytogenetic risk ≥ CR observed in 31.8% of carfilzomib group vs 9.3% of control group OS favored KRd vs Rd (HR: 0.79) but did not cross prespecified stopping boundary for OS at interim analysis Rate of grade 3/4 AEs and serious AEs similar between KRd and Rd arms AEs reported more frequently in KRd group included diarrhea, cough, fever, hypertension Study extends and reinforces evidence in support of this 3-drug regimen AEs, adverse events; CR, complete response; KRd, carfilzomib/lenalidomide/low-dose dexamethasone; MM, multiple myeloma; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide/low-dose dexamethasone. Stewart AK, et al. N Engl J Med. 2015;372:142-152.

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