Photo courtesy of Amgen
The US Food and Drug Administration (FDA) has approved carfilzomib (Kyprolis) in combination with lenalidomide and dexamethasone to treat patients with relapsed multiple myeloma (MM) who have received 1 to 3 prior lines of therapy.
Carfilzomib already has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last treatment.
The FDA’s expanded approval was based on results of the phase 3 ASPIRE trial.
The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive lenalidomide and dexamethasone with or without carfilzomib for 18 cycles.
Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.
There was a statistically significant prolongation of progression-free survival (PFS), as determined by an independent review committee, in the carfilzomib arm (hazard ratio=0.69, P=0.0001). The median PFS was 26.3 months in the 3-drug arm and 17.6 months in the 2-drug arm.
A treatment effect was observed across all subgroups tested, but the magnitude of the treatment effect was reduced in patients with higher tumor burden at baseline. The improvement in median PFS was 11 months for patients with International Staging System (ISS) Stage I disease, 8 months for ISS Stage II, and 2 months for ISS Stage III.
An interim analysis of overall survival, the key secondary endpoint, was conducted at the same time. The difference in overall survival did not reach the prespecified boundary for statistical significance.
The overall response rate (partial response or better) was 87% in the 3-drug arm and 67% in the 2-drug arm.
The safety profile of carfilzomib in the 3-drug combination was similar to that described on the current label.
Cardiovascular events, venous thromboembolic events (VTE), and thrombocytopenia occurred more frequently in the 3-drug arm than in the 2-drug arm. In cycles 1 to 12, the VTE rate was 13% and 6%, respectively, despite protocol-mandated use of thromboprophylaxis.
The revised labeling for carfilzomib includes new Warnings and Precautions for VTE, cardiac toxicities, acute renal failure, pulmonary toxicities, and hypertension. The increased safety risks, including mortality, for elderly patients is described. Detailed safety information in the prescribing information was also updated for the use of carfilzomib monotherapy.
The recommended dose schedule for carfilzomib has been revised for both monotherapy and combination treatment. For details, see the full prescribing information.
Carfilzomib is marketed as Kyprolis in the US by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.
