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

Abstract

Carfilzomib is a selective proteasome inhibitor approved for the treatment of relapsed and/or refractory multiple myeloma (RRMM). It has significantly improved outcomes, including overall survival (OS), and shown superiority vs standard treatment with lenalidomide plus dexamethasone and bortezomib plus dexamethasone. The incidence rate of cardiovascular (CV) events with carfilzomib treatment has varied across trials. This analysis evaluated phase 1-3 trials with >2000 RRMM patients exposed to carfilzomib to describe the incidence of CV adverse events (AEs). In addition, the individual CV safety data of >1000 patients enrolled in the carfilzomib arm of phase 3 studies were compared with the control arms to assess the benefit-risk profile of carfilzomib. Pooling data across carfilzomib trials, the CV AEs (grade ≥3) noted included hypertension (5.9%), dyspnea (4.5%), and cardiac failure (4.4%). Although patients receiving carfilzomib had a numeric increase in the rates of any-grade and grade ≥3 cardiac failure, dyspnea, and hypertension, the frequency of discontinuation or death due to these cardiac events was low and comparable between the carfilzomib and control arms. Serial echocardiography in a blinded cardiac substudy showed no objective evidence of cardiac dysfunction in the carfilzomib and control arms. Moreover, carfilzomib had no significant effect on cardiac repolarization. Our results, including the OS benefit, showed that the benefit of carfilzomib treatment in terms of reducing progression or death outweighed the risk for developing cardiac failure or hypertension in most patients. Appropriate carfilzomib administration and risk factor management are recommended for elderly patients and patients with underlying risk factors.

Conflict of interest statement

Conflict-of-interest disclosure: A.C. has received consulting fees, research grants, and research funding from and is on the advisory board for Takeda, Celgene, Novartis, Amgen, and Janssen; grants and research funding were also provided by Pharmacyclics. A.K.S. has received honoraria and consulting fees from Abbvie, Amgen, BMS, Celgene, Janssen, Roche, Seattle Genetics, and Takeda and has received clinical trials support from Celgene, Amgen, Seattle Genetics, Karyopharm, and Roche. P.M. has received consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, and Takeda. J.H. has received consulting fees from Bristol-Myers Squibb and royalties from Elsevier. J.B. has received research grants from Astellas and is a consultant for Biomedical Systems Corporation. R.H. has received research grants from Celgene, Amgen, and Novartis and consulting fees from Janssen, Amgen, BMS, and Takeda. J.G. has received research grants from Amgen and consulting fees from Takeda. A.R.L. has acted as a consultant and is on the advisory board for Amgen, Novartis, Pfizer, Boehringer Ingelheim, Servier, Eli Lily, Stealth Peptides, and Roche. S.R., M.H., and K.S.I. and employed by and own stock in Amgen. D.L. has received research grants from Takeda and consulting fees from Roche, Amgen, BMS, Janssen, and Prothena. The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Change in LVEF from baseline: results from the ENDEAVOR cardiopulmonary substudy.

Figure 2.

Time to first event of cardiac failure (CF) and survival analyses in the ASPIRE and ENDEAVOR trials. (A) Time to first event of grade ≥3 CF and progression or death in the ASPIRE (A) and ENDEAVOR (C) trials. Time to first event of grade ≥3 CF and mortality in the ASPIRE (B) and ENDEAVOR (D) trials. The x-axis shows months since first dose for grade ≥3 CF AEs and months since randomization for PFS or OS.