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

A Rosenthal, J Luthi, M Belohlavek, K M Kortüm, F Mookadam, A Mayo, R Fonseca, P L Bergsagel, C B Reeder, J R Mikhael, A K Stewart, A Rosenthal, J Luthi, M Belohlavek, K M Kortüm, F Mookadam, A Mayo, R Fonseca, P L Bergsagel, C B Reeder, J R Mikhael, A K Stewart

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.

Trial registration: ClinicalTrials.gov NCT01568866 NCT01818752.

Conflict of interest statement

KAS is a consultant for Celgene, Novartis, BMS and AMGEN. LB is a consultant for Onyx. RF is a consultant for Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millenium and AMGEN, and has received research funding from Cylene and Onyx. JM has received research funding from Celgene, Abbvie, Onyx, and Sanofi. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Change in NT-proBNP following treatment with carfilzomib (days 1 and 2).
Figure 2
Figure 2
Change in ejection fraction pre-/post-treatment with carfilzomib (*post-treatment refers to ejection fraction assessment following four cycles of treatment with carfizomib).

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