Multiple myeloma is characterized by periods of remission followed by relapse, and eventually the disease becomes refractory to treatment. While patients with multiple myeloma frequently receive multiple lines of treatment, antimyeloma agents are associated with a number of toxicities that can impact their use and influence future treatment options. Patients with relapsed and/or refractory multiple myeloma are particularly challenging to treat due to the advanced state of their disease, typically greater resistance to treatment, and the presence of disease- and treatment-related comorbidities. An understanding of the safety profile of the therapeutic agents used in treating multiple myeloma is thus crucial for appropriate patient management. Single-agent carfilzomib has been approved in the United States for the treatment of patients with relapsed and refractory multiple myeloma, and has been shown to be efficacious and well-tolerated in this setting. This review examines the frequency of common and significant hematologic and nonhematologic adverse events following administration of single-agent carfilzomib in four phase II trials in relapsed and/or refractory multiple myeloma, and provides practical recommendations for their management