Elevated Risk of Cardiovascular Adverse Events Identified in Meta-Analysis of Carfilzomib Studies

A study in JAMA Oncology involving 2594 patients taking carfilizomb (Kyprolis) experienced 18.1% all-grade CVAEs and 8.2% highgrade CVAEs, respectively, compared with control patients, according to lead author Adam J. Waxman, MD, and researchers at the Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Carfilzomib was approved in 2012 and this analysis suggests that clinicians should be aware of the risk of CVAEs in a higher than expected percentage of patients. In addition, clinical trials involving doses greater than 45 mg/m2 reported higher CVAE rates in patients. The researchers said in randomized clinical trials, the rate of high-grade CVAEs was more than double in carfilzomib-treated patients than in controls.

The researchers restricted their analysis to prospective clinical trials in which adult, human participants received carfilzomib for multiple myeloma. To compare between trials, only studies in which adverse events were reported using the Common Terminology Criteria for Adverse Events (CTCAE) version 3 or 4 in the English language were included.

“Like any cancer therapy, the concern with this approach is that it may have an effect on an otherwise healthy part of the body—in this case, the heart,” said Waxman, a hematology oncology fellow at the Perelman School of Medicine at the University of Pennsylvania, in a statement.

Researchers gathered data from 24 studies reported from 2007 through 2017. They found 18.1% of patients who took carfilzomib experienced CVAE, with 8.2% of those cases being grade 3 or higher, meaning they are categorized as severe. For comparison, a similar review of bortezomib found 3.8% of patients experienced CVAE and only 2.3% were severe.

In a subgroup analysis, heterogeneity was explored using subgroup analysis on the basis of study-level patient- and therapy-associated characteristics. The researchers noted that rates of CVAE differ according to trial phase, with phase I trials having a rate of 2.3% compared with 9.5% for phase II and III trials (P= .02), and doses of carfilzomib smaller than 45 mg/m2 having a rate of 6.4% compared with 11.9% for doses of 45mg/m2 or more (P= .02). Taken together, the authors concluded that these findings indicate that carfilzomib confers an elevated risk of CVAE.

The most common CVAEs were hypertension (12.2%) and heart failure (4.1%). Arrhythmias (2.4%) and ischemic events (1.8%) were observed less commonly. Researchers also found that higher doses of carfilzomib are associated with higher rates of CVAE, and that carfilzomib was associated with an elevated risk of CVAE compared with control groups who did not receive the agent.

Researchers say these findings are particularly important since there are already overlapping risk factors for both multiple myeloma and cardiovascular disease, such as older age and obesity. Previous studies have shown nearly two-thirds of patients with multiple myeloma had cardiovascular disease at baseline, and 70% experienced cardiovascular events within 6 years.

“Clinicians should be paying attention to who may be at highest risk for these events so they can tailor their therapy accordingly,” Waxman said.

Researchers also called for further clinical trials to specifically evaluate this connection, arguing that it may beunderrepresented by current data.

“If you’re not specifically looking for this, you might report it differently,” Waxman concluded.

Reference:

Waxman AJ, Clasen S, Hwang WT, et al. Carfilzomib-associated cardiovascular adverse events: a systematic review and meta-analysis. JAMA Oncol. 2017. [Epub ahead of print]. Dec 28:e174519. doi: 10.1001/jamaoncol.2017.4519.