Carfilzomib Benefits Outweigh Potential for Cardiac Toxicity in Relapsed/Refractory Myeloma

While clinical trials of the proteasome inhibitor carfilzomib for the treatment of multiple myeloma (MM) showed varying incidence rates of cardiovascular adverse events (AEs), a review of data from the phase I, II, and III trials leading to its approval suggest that the improvements in patient survival are worth the relatively low risk of cardiac failure or hypertension.

“Carfilzomib-based regimens have produced clinically meaningful responses and [have] shown significant improvement in the depth and duration of responses in [this setting] … including a nearly eight-month increase in overall survival,” lead author Ajai Chari, MD, of the Icahn School of Medicine at Mount Sinai in New York, told ASH Clinical News. “While optimization of cardiovascular health is important for all patients, the findings of this study demonstrate the risk of cardiovascular events is far outweighed by the benefit of carfilzomib treatment – as evidenced by improvements in overall survival,” he said.

The pooled analysis, which was published in Blood Advances, included data from 11 clinical trials evaluating carfilzomib in patients with relapsed/ refractory MM that reported incidence of cardiovascular-related AEs, comprising a total of 2,044 patients who received at least one dose of carfilzomib.

The researchers analyzed studies for all grade and grade ≥3 cardiovascularrelated AEs of interest, including cardiac failure, dyspnea, hypertension, and ischemic heart disease. For the purposes of the study, treatment-emergent AEs were defined as events that began on or following the first day of therapy or AEs that presented at baseline and worsened in severity following treatment.

Three trials (ASPIRE, ENDEAVOR, and FOCUS) also included analyses of the cardiac safety profile in 1,012 carfilzomib-treated patients compared with 998 patients in control arms who were treated with either lenalidomide plus dexamethasone, bortezomib plus dexamethasone, or best supportive care, respectively.

In the pooled analysis of all 11 trials, the most frequently reported cardiovascular-related AEs included anygrade incidences of:

• cardiac failure (6.7%)
• hypertension (18.5%)
• dyspnea (31.9%)

Grade ≥3 incidences of cardiac failure, hypertension, and dyspnea were reported in 4.4 percent, 5.9 percent, and 4.5 percent of patients, respectively.

Across the three phase III trials, the incidence of cardiac AEs was numerically higher in carfilzomib than control groups, but, after adjustment for duration of treatment exposure and follow-up, the incidences were similar between the treatment groups (TABLE).

Small proportions of patients in each of the phase III trials experienced cardiac failure events that led to missed doses of carfilzomib (2.6%, 3.5%, and 3.2% in ASPIRE, ENDEAVOR, and FOCUS, respectively). Most of these patients also were able to restart carfilzomib (70%, 75%, and 80%, respectively). Mortality related to cardiac failure was low across studies, the authors reported, ranging from 0.4 to 1.3 percent. “Treatment with carfilzomib in more than 1,000 patients in phase III studies was associated with low rates of cardiac events; however, the rates of treatment reduction and/or discontinuation and deaths due to cardiac events were very low and comparable in both arms,” Dr. Chari added.

In a substudy of 159 cardiopulmonary-evaluable patients enrolled in the phase III ENDEAVOR trial (80 who received carfilzomib plus dexamethasone and 79 who received bortezomib plus dexamethasone), the incidence of left ventricular ejection fraction (LVEF) reduction also was low: One patient in the bortezomib group experienced a >10 percent reduction in LVEF at 24 weeks, and three patients in each arm experienced a significant LVEF reduction at any time during the study period.

“As hematologist-oncologists, we are tasked with optimizing the risk-benefit profile of treatments for our patients,” Dr. Chari remarked. “This study highlights the difficulties in studying toxicities observed in single-arm studies in a disease like MM, where patients have comorbidities due to aging and myeloma itself.”

Limitations of the analysis included the lack of double-blind studies available for assessment and the lack of cardiology-based AE reports in each study analyzed. While the randomized design of the phase III trials worked to address confounding variables, Dr. Chari noted, the lack of blinding; coding of nonhematologic toxicities by hematology/oncology staff; and longer therapy times in the experimental arm relative to the control arm presented additional challenges in assessing attributable risk.

The researchers added that “careful monitoring and management of cardiovascular risk factors, including blood pressure and volume status, are recommended for all myeloma patients as good clinical practice.”

The authors reported a financial relationship with Onyx Pharmaceuticals, which funded the study.

Reference

Chari A, Stewart AK, Russell SD, et al. Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials. Blood Advances. 2018;2:1633-44.