Carfilzomib-Induced Cardiovascular Events Can Be Predicted in Myeloma Patients

Baseline left ventricular diastolic dysfunction (LVDD) was associated with the incidence of severe carfilzomib-induced cardiovascular adverse events in patients with relapsed or refractory multiple myeloma, according to the results of a small Japanese study published in Blood Advances.

Based on these results, “assessment of left ventricular diastolic function before treatment may thus have the potential to establish risk-adapted modifications of carfilzomib-based chemotherapy,” wrote Yoshiaki Abe, PhD, of Kameda Medical Center in Kamogawa, Japan, and colleagues.

According to the study, carfilzomib has been associated with severe cardiovascular adverse effects, occurring soon after initiation of the drug. Incidence has been shown to be higher in certain populations, like the elderly or Asians, but there are currently no predictors for these severe adverse effects.

In this single-center retrospective study, Abe and colleagues looked at 72 consecutive patients with relapsed or refractory myeloma treated with a carfilzomib-based regimen between August 2016 and September 2018. All patients had undergone pretreatment echocardiography for evaluating left ventricular diastolic function within 2 weeks of treatment initiation.

LVDD was classified into three categories: negative, intermediate, and definite. Doses of carfilzomib were based on the ASPIRE or ENDEAVOR studies, and were not reduced in any patient prior to development of severe cardiovascular adverse effects, defined as grade 3 or worse events. Only one patient had confirmed prior exposure to anthracyclines.

Twelve of the 72 patients (16.7%) had severe carfilzomib-induced cardiovascular adverse effects. The most common adverse effect was acute heart failure, which occurred in seven patients. Other severe adverse events included hypertension, left ventricular ejection fraction decrease, acute coronary syndrome, and QT prolongation. Three patients died of severe carfilzomib-induced cardiovascular events: two from heart failure and one from acute myocardial infarction.

These severe carfilzomib-induced cardiovascular adverse effects occurred more commonly in patients with worse performance status, a higher number of previous treatment regimens, or definite LVDD.

Nine of the 20 patients (45%) with definite LVDD developed carfilzomib-induced cardiovascular adverse effects compared with 1 patient with negative LVDD (3.7%) and 2 patients with intermediate LVDD (8.0%). Time to event curves confirmed that patients with definite LVDD had significantly higher cumulative incidence of severe cardiovascular adverse events compared with patients with either negative (P = .002) or intermediate (P = .006) LVDD.

“Although this study has several limitations, including its retrospective nature, heterogeneous treatment, the presence of possible confounding factors, and small sample size, it proposes a promising approach for predicting severe carfilzomib-induced cardiovascular adverse effects,” the researchers wrote. “This has been eagerly sought in real-life clinical settings.”

According to Ajai Chari, MD, of Mount Sinai, treatment with carfilzomib has led to improved response rates, progression-free survival, and importantly, overall survival in both the ASPIRE and ENDEAVOR randomized phase III studies, demonstrating its potent anti-myeloma activity. However, a pooled analysis of carfilzomib clinical trials by Chari et al has shown a grade 3+ heart failure rate of 4.4%.

"In the ENDEAVOR study of serial echocardiograms read by cardiologists blinded to treatment arm, there was no difference in the ejection fraction of carfilzomib- and bortezomib-treated patients during the entire course of the study, reflecting a likely different mechanism of cardiotoxicity than drugs like anthracyclines," Chari said. "Here, Abe et al found in a retrospective study of 72 consecutive carfilzomib-treated patients, baseline left ventricular diastolic dysfunction predicted severe heart failure complications. While the population is an older one, a population known to have higher risk of cardiotoxicity, this is an important observation, particularly given preclinical data of increased vascular tone with carfilzomib. If confirmed by other studies, baseline LVDD could identify patients requiring closer monitoring and management by cardiologists."