U.S. Food and Drug Administration Approval: Carfilzomib for the Treatment of Multiple Myeloma

Abstract

The U.S. Food and Drug Administration (FDA) review leading to accelerated approval of carfilzomib is described. A single-arm trial enrolled 266 patients with multiple myeloma refractory to the most recent therapy who had received prior treatment with bortezomib and an immunomodulatory agent (IMID). Patients received carfilzomib by intravenous infusion over 2 to 10 minutes at a dose of 20 mg/m 2 on days 1, 2, 8, 9, 15, and 16 of the 28 days of cycle 1, and at a dose of 27 mg/m 2 on the same schedule in cycle 2 and subsequent cycles. The primary efficacy endpoint was overall response rate (ORR) as determined by an independent review committee using International Myeloma Working Group Uniform Response Criteria. The safety of carfilzomib was evaluated in 526 patients with multiple myeloma treated with various dosing regimens. The ORR was 23%. The median duration of response was 7.8 months. The most common adverse reactions associated with carfilzomib infusion were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and fever. The most common serious adverse events were pneumonia, acute renal failure, fever, and congestive heart failure. Infusion reactions to carfilzomib could be reduced by pretreatment with dexamethasone and intravenous fluids. On July 20, 2012, the FDA granted accelerated approval of carfilzomib for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an IMID and who have shown disease progression while on therapy or within 60 days of completion of the last therapy.

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials

“…11,28 Carfilzomib-based regimens have been generally well tolerated, but concerns for CV toxicity have been raised. 10,[13][14][15]29 Here, we assessed carfilzomib-associated CV AEs in phase 1-3 clinical trials. Across all RRMM phase 3 trials, treatment with carfilzomib was associated with a numeric increase in cardiac AE incidence.…”

“…12 In pivotal phase 2 and 3 studies, there has been a reported increase in CV AEs. 10,[13][14][15] In the phase 3 ASPIRE and ENDEAVOR studies, the grade $3 cardiac failure incidence was 3.8% (KRd) vs 1.8% (Rd) and 4.8% (Kd) vs 1.8% (Vd). 10,15 Post hoc analyses of ASPIRE and ENDEAVOR data according to age showed increased cardiac failure risk in elderly patients.…”

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

“…Although proteasome inhibitor treatment of cells may not represent a physiologic condition, it is important to understand the therapeutic effects of proteasome inhibitors as bortezomib (Velcade) and carfilzomib (Kyprolis) are approved drugs for the treatment of multiple myeloma (64,65). The reduction of 26S proteasome function is a physiologically relevant situation.…”

A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis

“…12,51 However, there is a pressing need to understand mechanisms of resistance to proteasome inhibitors such as bortezomib and to develop strategies active against such resistant cells. Previous efforts have highlighted the contribution of the antiapoptotic Bcl-2 family protein Mcl-1 to MM cell survival and bortezomib resistance, 52 but recent attention has focused on the role of proapoptotic BH3-only proteins (eg, Bim) in MM responsiveness to bortezomib.…”