Carfilzomib-associated cardiovascular adverse events: A systematic review and meta-analysis.

Abstract

8018 Background: The incidence and nature of cardiovascular adverse events (CVAEs) with carfilzomib (CFZ) in multiple myeloma (MM) remain incompletely defined. We performed the first systematic review and meta-analysis of CFZ CVAEs. Methods: PubMed was queried for the keywords “carfilzomib,” “Kyprolis,” and “PX-171.” Phase 1-3 clinical trials of carfilzomib in MM with evaluable toxicity data were included. CVAEs were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grade ≥3 CVAEs and study characteristics were recorded. Summary incidence rates and relative risks (for randomized trials) with 95% confidence intervals were calculated using the logistic-normal random-effects model. Subgroup analyses were performed using study level covariates. Results: 514 studies were reviewed. 2623 MM patients from 25 eligible studies were included. Incidence rates are summarized in the table. All grade and grade ≥3 CVAEs were seen in 16.8% and 7.6 %, respectively. Phase 2 or 3 studies, carfilzomib doses ≥45mg/m2, and longer infusion length were study characteristics associated with high-grade cardiac AEs (p<0.05). Median age >65, prior MM therapies, and concurrent MM therapies were not associated with CVAEs (p>.05). For the three randomized trials, the relative risk of all-grade and grade ≥3 CVAEs were 1.75 and 2.25, respectively (p<0.001). Conclusions: CFZ is associated with a significant incidence of CVAEs, including heart failure, hypertension, ischemia, and arrhythmia. Phase I studies may be underdetecting CVAEs. Future studies are needed to: identify patients at high-risk for CVAEs, develop optimal monitoring strategies, and explore therapies to mitigate these risks. [Table: see text]

Phase II study of carfilzomib and dexamethasone therapy for newly diagnosed multiple myeloma

“…Cardiovascular adverse events are an important risk consideration with carfilzomib therapy. A systematic review and meta‐analysis of studies evaluating carfilzomib described a rate of grade ≥3 CVAEs in patients receiving carfilzomib doses of 45 mg/m 2 and higher of 11.9% . Our analysis yielded similar results with 11.1% of patients experiencing a grade ≥3 CVAE and an all grade occurrence rate of 25%.…”

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

“…Carfilzomib treatment has been associated with cardiovascular AEs, including low rates of grade 3/4 cardiac failure, dyspnea, and hypertension. 32,33 However, in randomized phase 3 studies, the incidence of treatment discontinuation or death due to these cardiac events is low and comparable between treatment arms, highlighting the importance of control arms in elucidating treatment-related toxicities. 33 In this study, median LVEF remained stable, cardiac TEAEs were manageable and typically resolved, and no patient discontinued study treatment or died from cardiac TEAEs.…”

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

“…An independent meta-analysis of all published carfilzomib clinical studies (2623 patients from 25 studies) estimated grade $3 Exposure to study treatment in phase 3 trials 30 Higher cardiac event rates have been observed in some retrospective single-center studies, with doxorubicin exposure associated with increased risk. 31,32 Real-world data based on the MarketScan Claims database showed an ;3% incidence of hospitalizations due to cardiac AEs during carfilzomib treatment, validating the low rate of grade $3 CV AEs reported across carfilzomib clinical trials in real-world practice.…”