NEW ORLEANS—Bortezomib was associated with a low rate of grade 3 or higher heart failure in patients with multiple myeloma treated in either the upfront or relapsed and/or refractory settings, a retrospective analysis of data from key phase 2 and 3 studies reported at the 55th American Society of Hematology Annual Meeting and Exposition.

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Patients with multiple myeloma are living longer due to treatment advances; therefore, quality of life and managing adverse events (AEs) related to therapy are increasingly important, noted Jacob P. Laubach, MD, of the Dana-Farber Cancer Institute, Boston, MA, and colleagues. For example, patients with multiple myeloma are at risk of cardiac events, both due to age and disease-related factors as well as potential treatment-related cardiotoxicity from anthracyclines, proteasome inhibitors, and high-dose therapy.

Safety information for the two U.S. Food and Drug Administration–approved proteasome inhibitors include warnings about cardiac toxicity for bortezomib and, for carfilzomib, cardiac arrest, congestive heart failure, and myocardial ischemia.

Dr. Laubach pointed out that development of bortezomib “involved numerous large, controlled clinical trials, providing a benchmark for the expected incidence of heart failure with proteasome inhibitors.” The investigators retrospectively analyzed databases from the phase 2 and 3 studies for AEs of grade 3 or higher heart failure.

Included in the relapsed/refractory setting were the phase 2 SUMMIT trial (bortezomib ± dexamethasone) and the phase 3 APEX (bortezomib vs. dexamethasone), MMY-3001 (bortezomib plus liposomal doxorubicin vs. single-agent bortezomib), and MMY-3021 (subcutaneous vs. intravenous bortezomib ± dexamethasone) trials.

In the upfront setting, the trials included phase 3 VISTA (bortezomib-melphalan-prednisone [VMP] vs. MP) in elderly transplant-ineligible patients and a pooled analysis of three phase 3 trials (IFM 2005-01, HOVON-65/GMMG-HD4, PETHEMA GEM2005MENOS65) of bortezomib-based compared with non–bortezomib-based induction therapy (N = 779 vs. 776) in transplant-eligible patients. None of the non-bortezomib comparator arms involved a proteasome inhibitor.

Cardiac exclusion criteria included New York Heart Association class III/IV (≥ II in MMY-3001), myocardial infarction within 6 months, and electrocardiogram (ECG) evidence of acute ischemia. Heart function tests (primarily ECG) were incorporated in study designs. Heart failure events were analyzed and re-coded for consistency across studies using standardized MedDRA query preferred terms with grouping of clinically related events.

Included in the analysis were 2,509 patients treated with bortezomib in the phase 2 and 3 trials and an additional 1,445 patients treated with non–bortezomib-based therapies in the control arms of the phase 3 studies.

“Among all bortezomib-treated patients, rate of grade 3 or higher heart failure was 2.1%; the rate was 2.2% in newly diagnosed patients and 2.0% in relapsed and/or refractory patients,” Dr. Laubach reported.

“Across the comparative studies (APEX and VISTA) and the pooled pre- transplant induction analysis, the overall rates across the bortezomib-based and non–bortezomib-based arms were 2.2% and 1.7%, respectively (P = 0.29).” Risk factors, including prior anthracycline exposure and history of cardiac complications, were balanced between bortezomib and non-bortezomib arms.

“Data from ongoing prospective and comparative studies are necessary to determine whether proteasome inhibitors—including bortezomib, carfilzomib, and proteasome inhibitors at earlier stages of clinical development—have different cardiotoxicity profiles,” Dr. Laubach stated, adding that “a better understanding of the mechanism of proteasome inhibitor-induced cardiotoxicity, risk factors, and potential biomarkers identifying the at-risk patient population will be critical.”

This will include improving the monitoring and reporting of cardiovascular AEs and the detection of cardiotoxicity in the context of oncology clinical trials; specifically, future studies of proteasome inhibitors. For example, current National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) may not be able to identify early, asymptomatic cardiac changes, he noted.

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