Compared to bortezomib treatment, multiple myeloma (MM) treatment with the proteasome inhibitor carfilzomib is associated with a higher incidence of cardiovascular adverse events. However, the mechanism underlying such cardiopathogenic side effects in MM patients remains elusive. Here, we show that carfilzomib-specific proteasome inhibition profoundly impairs cardiomyocyte contractility. Using an unbiased multiomics approach in vitro and in vivo, followed by in vitro validation, we elucidated carfilzomib-related changes in contractility proteins and cellular translation, retinol oxidative metabolism, and the angiotensin II derivative, angiotensin A. Subsequently, all-trans retinoic acid and angiotensin II type 1 receptor inhibitor prevented cardiomyocytes from experiencing carfilzomib-induced toxicity in human and murine in vitro and in vivo models through stabilization of protein and metabolic homeostasis. Our data reveal a mechanism underlying carfilzomib-induced cardiotoxicity that closely mirrors clinical observations and may open new avenues for management of such potentially lethal side effects in patients with MM.