Cardiovascular Toxicity of Proteasome Inhibitors in Multiple Myeloma Therapy

Abstract

The treatment for multiple myeloma has advanced significantly over the past few decades. Proteasome inhibitors have become the cornerstone of the treatment of multiple myeloma. However, proteasome inhibitors have shown cardiovascular complications such as hypertension, pulmonary hypertension, heart failure, arrhythmias, ischaemic heart disease and thromboembolism. Detection, monitoring and management of proteasome inhibitor-related cardiovascular toxicity are essential to improve clinical outcomes for patients. Proposed mechanisms of proteasome inhibitor-related cardiovascular toxicity are apoptosis, prolonged inhibition of the ubiquitin-proteasome system, accumulation of improperly folded proteins within cardiomyocytes and higher protein phosphatase 2A activity. To better understand the mechanisms underlying cardiotoxicity, further in vitro and in vivo experiments are required to investigate these hypotheses. Combined use of metformin or angiotensin II receptor blockers with the proteasome inhibitor, carfilzomib, showed an emerging role as a prophylactic therapy because they can preserve heart function in multiple myeloma patients. Metformin is expected to be an effective therapeutic intervention for the management of carfilzomib-induced cardiotoxicity. There has been evidence that three compounds, apremilast, rutin, and dexrazoxane, can reverse carfilzomib-induced cardiotoxicity in rats. The future transition from animal experiments to clinical trials is worth waiting for.