WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.
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Dr. R. Frank Cornell
In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.
In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.
The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.
The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.
The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).
In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.
“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
IMiDs and thromboembolism
In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.
“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.
There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.
Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.
“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.
He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.