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

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 multiplemyeloma with evaluable toxic effects data were eligible formeta-analysis. DATA EXTRACTION AND SYNTHESIS Datawere 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 eventswere 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 multiplemyeloma. 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 45mg/m(2) or higher were associated with high-grade CVAE. Median age older than 65 years, priormyeloma therapies, and concurrentmyeloma 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 studiesmay 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.