Carfilzomib-Associated Cardiovascular Adverse Events: A Systematic Review and Meta-analysis.

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Carfilzomib-Associated Cardiovascular Adverse Events: A Systematic Review and Meta-analysis.

JAMA Oncol. 2017 Dec 28;:e174519

Authors: Waxman AJ, Clasen S, Hwang WT, Garfall A, Vogl DT, Carver J, O'Quinn R, Cohen AD, Stadtmauer EA, Ky B, Weiss BM

Abstract
Importance: Cardiovascular adverse events (CVAE) with carfilzomib in patients with multiple myeloma can be potentially life-threatening and remain incompletely characterized. We performed the first systematic review and meta-analysis of carfilzomib-associated CVAE.
Objective: To determine the incidence of carfilzomib-associated CVAE and to compare the rates of carfilzomib CVAE among different doses and companion therapies.
Data Sources: PubMed, EMBASE, Web of Science, and clinicaltrials.gov were queried for the keywords "carfilzomib," "Kyprolis," and "PX-171" through January 1, 2017.
Study Selection: Phase 1 to 3 prospective clinical trials of carfilzomib in patients with multiple myeloma with evaluable toxic effects data were eligible for meta-analysis.
Data Extraction and Synthesis: Data were independently extracted by 2 reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Pooled incidence rates and relative risks (for randomized trials) and 95% confidence intervals were calculated using a random effects model. Subgroup analyses were performed to assess study-level characteristics associated with CVAE.
Main Outcomes and Measures: Cardiovascular adverse events were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grades 3 or higher AEs and study characteristics were recorded.
Results: A total of 514 studies were assessed for eligibility. Of those, 24 studies were eligible, including a total of 2594 patients with multiple myeloma. All-grade and grades 3 and higher CVAE were seen in 617 (18.1%) and 274 (8.2%), respectively. Phase 2 or 3 studies and carfilzomib doses of 45 mg/m2 or higher were associated with high-grade CVAE. Median age older than 65 years, prior myeloma therapies, and concurrent myeloma therapies were not associated with CVAE. For the 3 randomized clinical trials, the summary relative risk of all-grade and grade 3 or higher CVAE for patients receiving carfilzomib compared with noncarfilzomib-receiving control patients were 1.8 and 2.2, respectively.
Conclusions and Relevance: Carfilzomib was associated with a significant incidence of CVAE, with higher rates seen with higher doses of carfilzomib. Phase 1 studies may be underdetecting CVAE. Future studies are needed to identify patients at high risk for CVAE, develop optimal monitoring strategies, and explore strategies to mitigate these risks.

PMID: 29285538 [PubMed - as supplied by publisher]

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