On July 24, 2015, the U. S. Food and Drug Administration approved carfilzomib (Kyprolis, Onyx Pharmaceuticals, Inc., an Amgen subsidiary) in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.
The approval was based on a demonstration of improved progression-free survival (PFS) in a multicenter, open-label trial (PX-171-009 ASPIRE). The trial enrolled 792 patients with relapsed or refractory multiple myeloma after 1-3 lines of prior therapies. 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.
A statistically significant prolongation of PFS, as determined by an independent review committee, was demonstrated [HR 0.69 (95% CI: 0.57, 0.83); p = 0.0001, stratified log-rank test]. 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 study baseline (improvement in median PFS 11 months for ISS Stage I, 8 months for ISS Stage II and 2 months for ISS Stage III).
An interim analysis of overall survival (OS), the key secondary endpoint, was conducted at the same time. The difference in OS did not reach the prespecified boundary for statistical significance. A partial response or better was achieved by 87% of patients on the 3-drug arm and 67% on the 2-drug arm.
The safety profile of carfilzomib in the 3-drug combination was similar to that described in 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 1-12 of therapy, the VTE rate was 13% vs 6%, respectively, despite protocol-mandated use of thromboprophylaxis.
The revised labeling 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 use of carfilzomib monotherapy.
Healthcare providers should note that the recommended dose-schedule for carfilzomib has been revised for use as monotherapy or in combination with lenalidomide and dexamethasone.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202714s009lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).