Cardiac events and pulmonary complications are commonly seen in patients with multiple myeloma (MM), most of whom are over 60 years of age at the time of their diagnosis. These events and complications may be consequences of age-related comorbidities, or effects of the disease itself or current or previous treatment received. In this last category, patients who receive autologous stem cell transplant or treatment with anthracyclines, alkylating agents, immunomodulatory agents, or the proteasome inhibitor bortezomib have been found to be at increased risk for cardiovascular complications. In addition, treatment with an immunomodulatory agent or bortezomib has also been associated with pulmonary complications, which often manifest as dyspnea. An understanding of the cardiopulmonary adverse events associated with anti-MM treatment is, therefore, an important component of therapy selection. Carfilzomib is a selective proteasome inhibitor that was recently approved in the United States for the treatment of patients with relapsed and/or refractory MM who had received two or more prior therapies, including bortezomib and an immunomodulatory agent, and who demonstrated disease progression within 60 days of completion of the last therapy. This article presents an overview of the cardiac and pulmonary safety profile of single-agent carfilzomib therapy in patients with relapsed and/or refractory MM from an analysis of four phase II clinical studies, and provides practical recommendations for the management of patients at risk for cardiac events and pulmonary complications.