Overall Survival of Relapsed/Refractory Multiple Myeloma Patients Treated with Carfilzomib and Dexamethasone Vs Bortezomib and Dexamethasone: Results from the Phase 3 Endeavor Study According to Age Subgroup

Background: Elderly patients with multiple myeloma are a challenging population to treat, and there is a need for effective treatment options. Carfilzomib, a selective proteasome inhibitor, is approved in the United States and other countries for the treatment of relapsed or refractory multiple myeloma (RRMM). A subgroup analysis of interim results from the randomized, phase 3 ENDEAVOR study showed that carfilzomib (56 mg/m²) and dexamethasone (Kd56) resulted in longer median progression-free survival (PFS) and higher overall response rates (ORRs) than bortezomib and dexamethasone (Vd) in patients with RRMM, regardless of age (Table; Ludwig et al, Leuk Lymphoma . 2017;58:2501-2504). Mature overall survival (OS) data has recently been reported from ENDEAVOR and demonstrated that Kd56 resulted in statistically and clinically significant improvement in OS compared with Vd in the intention-to-treat (ITT) population (median, 47.6 months vs 40.0 months; hazard ratio [HR], 0.791; 95% confidence interval [CI], 0.648-0.964; 1-sided P=0.0100; Dimopoulos et al, Lancet Oncol . In press). Here, we report a subgroup analysis from ENDEAVOR to evaluate OS and updated safety outcomes by age.

Methods: Adults with RRMM who received 1-3 prior regimens were eligible for the ENDEAVOR trial. Patients treated with Kd56 received carfilzomib (30-min intravenous [IV] infusion) on days (D) 1, 2, 8, 9, 15, and 16 (20 mg/m² on D1, 2 [cycle 1]; 56 mg/m² thereafter) and dexamethasone (20 mg) on D1, 2, 8, 9, 15, 16, 22, and 23 of 28-day cycles. In the Vd arm, patients received bortezomib (1.3 mg/m²; IV or subcutaneously) on D1, 4, 8, and 11 and dexamethasone (20 mg) on D1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles. Patients were treated until disease progression, withdrawal of consent, or unacceptable toxicity. OS was compared between treatment arms in patients grouped according to age (i.e., <65, 65-74, and ≥75 years of age) using an unstratified Cox proportional hazards model.

Results: The ITT population included 929 patients enrolled in the study (<65 years: Kd56, n=223; Vd, n=210; 65-74 years: Kd56, n=164; Vd, n=189; ≥75 years: Kd56, n=77; Vd, n=66). OS was improved with Kd56 vs Vd within each age subgroup (<65 years: median, 47.6 months vs 41.9 months [HR, 0.847; 95% CI, 0.634-1.132]; 65-74 years: median, not estimable vs 37.0 months [HR, 0.706; 95% CI, 0.508-0.981]; ≥75 years: median, 42.4 months vs 25.9 months [HR, 0.841; 95% CI, 0.522-1.355]) (Table). Kaplan-Meier OS curves by age are shown in the Figure. In the safety population (n=919), the median duration of treatment was longer with Kd56 than with Vd within each age subgroup (<65 years: median, 49.0 weeks vs 27.0 weeks; 65-74 years: 49.9 weeks vs 27.6 weeks; ≥75 years: 43.3 weeks vs 20.6 weeks). Rates of any-grade adverse events (AEs) and grade ≥3 AEs of interest are shown in the Table. Grade ≥3 hypertension, dyspnea, cardiac failure, acute renal failure, and cardiac ischemia were generally more common with Kd56 vs Vd within each age subgroup, whereas grade ≥3 peripheral neuropathy occurred more often with Vd vs Kd56 within each subgroup (Table). AEs were not adjusted for exposure.

Conclusions: Clinically meaningful improvements in OS were observed with Kd56 compared with Vd across all age groups examined, including patients aged ≥75 years. The safety results were comparable to those reported in the age subgroup analysis of the PFS interim results for ENDEAVOR. Overall, these data support the favorable benefit-risk profile of Kd56 in patients with RRMM, regardless of age.

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