The FDA has approved carfilzomib (Kyprolis) in combination with dexamethasone or with lenalidomide plus dexamethasone for patients with relapsed/refractory multiple myeloma following prior treatment with 1 to 3 lines of therapy, based on findings from the phase III ENDEAVOR trial.
In addition to the combination approvals, this decision also converts carfilzomib’s single-agent accelerated approval in this setting to a full approval. Carfilzomib is now approved as a monotherapy for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 or more lines of therapy.
"Multiple myeloma remains an incurable disease where relapse inevitably occurs and over time patients become resistant to treatments," Ruben Niesvizky, MD, director of the Multiple Myeloma Center at Weill Cornell Medicine and New York-Presbyterian/Weill Cornell Medical Center, said in a statement. "As a clinician, I'm pleased with the tremendous progress that we have seen in the past 12 months in multiple myeloma treatment. This FDA approval is important because it provides physicians with flexible options for Kyprolis use in helping to manage this challenging disease."
In the ENDEAVOR study,1
carfilzomib and dexamethasone reduced the risk of progression by 47% compared with bortezomib (Velcade) and dexamethasone. The median progression-free survival (PFS) with carfilzomib was 18.7 versus 9.4 months with bortezomib (HR, 0.53; 95% CI, 0.44-0.65; P
In the phase III study, 929 patients were randomized to receive carfilzomib as a 30-minute infusion along with dexamethasone (n = 464) or bortezomib and dexamethasone (n = 465). Carfilzomib was administered at a starting dose of 20 mg/m2
on days 1 and 2 of cycle 1. If tolerated, the dose was escalated to 56 mg/m2
on day 8 of cycle 1. After this point, the 56 mg/m2
dose was maintained on days 9, 15, and 16 and throughout subsequent cycles. In the control arm, patients received bortezomib at 1.3 mg/m2
. The majority of patients received bortezomib subcutaneously (75%).
The median age of patients enrolled in the trial was 65 years. All but 7% of patients had ECOG PS of 0 or 1 (about 50% ECOG 0), and about 20% of the patients had high-risk cytogenetic by fluorescence in situ hybridization. The primary endpoint was PFS, with overall survival (OS), objective response rate (ORR), duration of response, and safety as secondary measures.
The advantage in PFS seen with carfilzomib was consistent across subgroups. The median OS was 24.3 months in the bortezomib arm but had not yet been reached in the carfilzomib arm (HR, 0.79; P
= .066). However, at the time of the primary analysis, survival data were not yet mature.
The ORR was 77% with carfilzomib versus 63% with bortezomib. The complete response rate with carfilzomib was 13% versus 6% with bortezomib. The rate of very good partial response or better with carfilzomib was 54% compared with 29% with bortezomib.
Grade 3 adverse events (AEs) occurred more frequently in the carfilzomib arm compared with bortezomib (73% vs 67%). Additionally, serious AEs were more common with carfilzomib (48% vs 36%). However, dose reductions associated with AEs were more frequent with bortezomib versus carfilzomib (48% vs 23%). Treatment discontinuation due to AEs and on-study deaths were comparable between the two arms.
Grade ≥3 hematologic adverse events occurred in a similar proportion of patients in both groups, including anemia, thrombocytopenia, neutropenia, upper respiratory infection, and pneumonia. However, there was an increase in the incidence of hypertension and dyspnea with carfilzomib versus bortezomib. The most frequent non-hematologic grade ≥3 AEs were diarrhea, fatigue, dyspnea, pyrexia, constipation, and insomnia.
Peripheral neuropathy occurred in 5% of patients treated with bortezomib and 1.3% of those in the carfilzomib arm. The proportion of patients with grade ≥2 peripheral neuropathy was significantly higher with bortezomib (32% versus 6%; P
Carfilzomib was previously approved in July 2015 in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received at least 1 to 3 prior lines of therapy, based on results from the phase III ASPIRE trial.
In the pivotal ASPIRE trial,2
the combination of carfilzomib, lenalidomide, and low-dose dexamethasone reduced the risk of progression by 31% compared with lenalidomide and low-dose dexamethasone alone in patients with relapsed multiple myeloma. The median PFS with carfilzomib was 26.3 months compared with 17.6 months without the proteasome inhibitor (HR, 0.69; 95% CI, 0.57-0.83; P
"Kyprolis is the only approved therapy for relapsed multiple myeloma with proven efficacy as a single agent, doublet, and triplet combination that is offered in a variety of doses to meet individual patient needs," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, the developer of carfilzomib, said in a statement. "Importantly, this new approval supports the use of Kyprolis as a backbone therapy for the management of relapsed multiple myeloma, a difficult-to-treat blood cancer."
Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): results from the phase III study ENDEAVOR. J Clin Oncol. 2015;(suppl; abstr 8509).
Stewart KA, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients with relapsed multiple myeloma: interim results from ASPIRE, a randomized, open-label, multicenter phase 3 study. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014, San Francisco, CA. Abstract: 79.