Associations between proteasome inhibitors for treatment of multiple myeloma and cardiovascular toxicity were described in a report in the journal Current Problems in Cardiology.
“Proteasome inhibitors are an integral part of treatment regimens for multiple myeloma,” the researchers wrote in their report. Those agents approved for the treatment of multiple myeloma include bortezomib, carfilzomib, and ixazomib.
Multiple myeloma cells contain high proteasome activity, but this is a feature also present in cardiomyocytes. Various pathways affected by proteasome inhibitor activity may be engaged with their use, leading to cardiotoxicity. Some proposed mechanisms by which proteasome inhibitors may impact cardiomyocytes include downregulation of the ubiquitin-proteasome system, cell apoptosis, and impairment of endothelial nitric oxide synthase.
Cardiovascular toxicity that may manifest with the use of proteasome inhibitors involves a range of possible complications, including hypertension, pulmonary hypertension, heart failure, arrhythmias, ischemic heart disease, and thromboembolism. “Early detection, monitoring for cardiovascular toxicity during proteasome inhibitor therapy and management of toxicity are of significant importance,” the researchers wrote in their report. Cardiovascular adverse drug reactions can affect treatment courses and outcomes and may also reduce patient quality of life.
Patients known to have a high risk of cardiovascular toxicity may benefit from early referral for cardiology care before initiating proteasome inhibitor treatment. Oncologists also may adjust administration of proteasome inhibitor therapy in these patients through the infusion rate or dose modification. Some evidence suggests treatment with metformin or angiotensin II receptor blocker therapy may have prophylactic value in this setting. However, further research is warranted.
Additionally, certain agents may have potential to reverse cardiotoxicity linked to proteasome inhibitor use, such as apremilast, rutin, and dexrazoxane. Evidence is limited in support of this strategy, with available research so far having been conducted through the use of rat models.
“Notably, proteasome function is essential for maintaining the stability of the internal environment of cardiomyocytes, therefore their possible effects on cardiovascular function are important,” the researchers wrote in their report. They concluded that early detection, monitoring, and management of cardiotoxicity are important considerations with proteasome inhibitor therapy. They also highlighted the possible role of prophylactic agents and the need for further research on agents with potential to reverse cardiotoxicity related to proteasome inhibitor therapy.
Zheng Y, Huang S, Xie B, et al. Cardiovascular toxicity of proteasome inhibitors in multiple myeloma therapy. Curr Probl Cardiol. 2023;48(3):101536. doi:10.1016/j.cpcardiol.2022.101536