Carfilzomib and the cardiorenal system in myeloma: an endothelial effect?

Abstract

Carfilzomib (Cfz) has been associated with an ~5% incidence of unexplained and unpredictable cardiovascular toxicity in clinical trials. We therefore implemented a detailed, prospective, clinical cardiac and renal evaluation of 62 Cfz-treated myeloma patients, including serial blood pressure (BP), creatinine, troponin, NT-proBNP and pre- and post-treatment echocardiograms, including ejection fraction (EF), average global longitudinal strain and compliance. Pre-treatment elevations in NT-proBNP and BP, as well as abnormal cardiac strain were common. A rise in NT-proBNP occurred frequently post-treatment often without corresponding cardiopulmonary symptoms. A rise in creatinine was common, lessened with hydration and often reversible. All patients had a normal EF pre-treatment. Five patients experienced a significant cardiac event (four decline in EF and one myocardial infarction), of which 2 (3.2%) were considered probably attributable to Cfz. None were rechallenged with Cfz. The ideal strategy for identifying patients at risk for cardiac events, and parameters by which to monitor for early toxicity have not been established; however, it appears baseline echocardiographic testing is not consistently predictive of toxicity. The toxicities observed suggest an endothelial mechanism and further clinical trials are needed to determine whether or not this represents a class effect or is Cfz specific.

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials

“…Careful clinical volume status assessment may be a useful measure to proactively manage patients at risk for developing heart failure. Increasing evidence suggests a possible effect of proteasome inhibition on vascular endothelium, [34][35][36][37] rather than cardiac myocytes. Therefore, vascular impact biomarkers should be investigated.…”

How I manage the toxicities of myeloma drugs

“…The exact pathophysiology remains unknown, but endothelial effects 41 and inhibition of proteasome-dependent sarcomeric protein turnover in cardiomyocytes 42 have been discussed as contributing factors. Cardiac failure is thought to be a class effect of PIs because it has also occasionally been reported with bortezomib 43 and ixazomib.…”

“…Hypertension and any other cardiovascular risk factors should be adequately controlled prior to starting carfilzomib. During treatment, regular clinical surveillance with blood pressure control is recommended; serial monitoring of cardiac function by echocardiogram 47 or cardiac biomarkers such as N-terminal prohormone of brain natriuretic peptide 41 are considered of limited value in mitigating the risk for carfilzomib-induced cardiac failure. Whenever cardiac failure is suspected, carfilzomib treatment should be discontinued and a detailed cardiopulmonary evaluation performed.…”

Prevention and management of adverse events of Novel agents in multiple myeloma: A consensus of the european myeloma network

“…The exact mechanism has not yet been clarified, but an effect of carfilzomib on endothelial cells and a common acute rise in NT-proBNP has been reported. 83 A decline in ejection fraction in few patients was shown. 83,84 In the ENDEAVOR study, events of heart failure and pulmonary hypertension were more frequently reported in Kd versus Vd patients and similar findings were also reported in the CLARION study comparing KMP with VMP.…”

“…83 A decline in ejection fraction in few patients was shown. 83,84 In the ENDEAVOR study, events of heart failure and pulmonary hypertension were more frequently reported in Kd versus Vd patients and similar findings were also reported in the CLARION study comparing KMP with VMP. 85 Reported reductions in left ventricular ejection fraction were mostly reversible.…”