Cardiovascular Complications of Proteasome Inhibitors Used in Multiple Myeloma

The use of proteasome inhibitors (PI) as targeted chemotherapeutics have significantly improved survival in patients with multiple myeloma (MM). However, rare and serious cardiovascular complications have occurred as a result of their use, most commonly congestive heart failure, hypertension, and arrhythmias. MM occurs in an aged population with many concurrent cardiovascular risk factors. The primary disease process also contributes to cardiovascular complications. Furthermore, many MM patients have prior exposure to cardiotoxic chemotherapy such as anthracyclines. Because of these occurrences, the identification, prevention, and management of cardiovascular complications is made increasingly difficult. Various clinical studies and case reports have documented cardiotoxicity among all 3 of the currently approved PIs, bortezomib, carfilzomib, and ixazomib. Carfilzomib has shown the highest rates of cardiotoxicity, whereas there is conflicting evidence regarding bortezomib's role in producing cardiotoxicity. However, various case reports have documented the existence of adverse cardiac effects. Higher frequencies of complications have also been seen in "real-life" populations with cardiovascular co-morbidities who were originally excluded from clinical studies. Ixazomib, the most recently approved PI, has also been proposed to cause cardiotoxicity, elucidating a possible class effect. PIs are thought to cause cardiotoxicity through the unfolded protein response, leading to apoptosis in cardiac myocytes. Apremilast and rutin have been used in an animal model to reverse this signaling. Standardized guidelines identifying patients at greatest risk, to prevent and manage complications, have not yet been developed. Efforts have been made to prioritize patients older than 60 years with anthracycline exposure, cardiovascular risk factors, or amyloidosis. Withholding medication, using slower-infusion times, limiting fluids and providing supportive therapy have been successful. Screening echocardiograms have not been proven effective.