Carfilzomib, a proteasome inhibitor, known as a therapeutical option for people who have already received one or more previous treatments for multiple myeloma, has well known cardiac and systemic adverse effects. There is evidence supporting that adverse effects are dose dependent, yet there is no known patient phenotype characterized by worse associated consequences, nor are there widely accepted monitoring protocols. In this article we describe two patients with cardiovascular adverse events related to carfilzomib treatment and their clinical course. Our goal was to present two cases of daily practice, which highlighted the complexity of their management and led to underline how baseline evaluation and close follow-up with echocardiography and cardiac biomarkers, including natriuretic peptides, remain an important tool for the cardiotoxicity surveillance. These reflections should lead to further studies in order to identify high risk patients for cardiovascular adverse event and clarify the real incidence of cardiotoxicity of this drug and adequate follow-up timing. Finally further research is needed to evaluate strategies for prevention and attenuation of cardiovascular complications of cancer therapy.