Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects

Simple Summary Multiple myeloma (MM) is a still uncurable tumor of mainly elderly patients originating from the terminally differentiated B cells. Introduction to the treatment of MM patients of a new class of drugs called proteasome inhibitors (bortezomib followed by carfilzomib and ixazomib) significantly improved disease control. Proteasome inhibitors interfere with the major mechanism of protein degradation in a cell leading to the severe imbalance in the protein turnover that is deadly to MM cells. Currently, these drugs are the mainstream of MM therapy but are also associated with an increased rate of the injuries to multiple organs and tissues. In this review, we summarize the current knowledge on the molecular mechanisms of the first-in-class proteasome inhibitor bortezomib-induced disturbances in the function of peripheral nerves and cardiac and skeletal muscle. The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially approved for the refractory forms of the disease but has now become, in combination with other drugs, the backbone of the frontline therapy for newly diagnosed MM patients, as well as in the maintenance therapy and relapsed/refractory setting. Despite being among the most widely used and highly effective agents for MM, bortezomib can induce adverse events that potentially lead to early discontinuation of the therapy with negative effects on the quality of life and outcome of the patients. Although peripheral neuropathy and myelosuppression have been recognized as the most relevant bortezomib-related adverse effects, cardiac and skeletal muscle toxicities are relatively common in MM treated patients, but they have received much less attention. Here we review the neuromuscular and cardiovascular side effects of bortezomib. focusing on the molecular mechanisms underlying its toxicity. We also discuss our preliminary data on the effects of bortezomib on skeletal muscle tissue in mice receiving the drug.