Patterns of Cardiac Toxicity Associated With Irreversible Proteasome Inhibition in the Treatment of Multiple Myeloma

• Case series of cardiotoxicity with carfilzomib, a proteasome inhibitor for myeloma.
• There was a common clinical syndrome of dyspnea with LV systolic dysfunction.
• Presentations ranged from exertional dyspnea to acute decompensated heart failure.
• Cardiac function often improves with stopping the drug and initiating HF therapies.

Carfilzomib is a novel irreversible proteasome inhibitor (PI) used with increasing frequency to treat patients with relapsed and/or refractory multiple myeloma (RRMM). This agent is an effective treatment for this challenging population, but proteasome inhibition has the potential of significant cardiac toxicity via the accumulation of intracellular protein aggregates. Although large clinical trials have not suggested an excess of heart failure with PI therapy, nonhuman animal studies and case reports in humans with the PI bortezomib have suggested otherwise. We describe the clinical presentation and management of 6 patients with RRMM who experienced significant cardiac toxicity associated with carfilzomib treatment. A common clinical syndrome of dyspnea associated with left ventricular systolic and/or diastolic dysfunction was identified. These abnormalities were largely reversible with prompt cessation of PI therapy and initiation of traditional heart failure treatments. Safe readministration of carfilzomib with dose modification was possible in some cases.