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

Abstract

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.

Keywords: bortezomib; cardiotoxicity; multiple myeloma; muscle toxicity; peripheral neuropathy; proteasome inhibitors.

Figure 1

Molecular mechanisms of action of bortezomib. Bortezomib induces several downstream effects, among which the endoplasmic reticulum (ER) stress and the inhibition of transcription factor nuclear factor-κB (NF-κB) play a central role in mediating its cellular toxicity.

Figure 2

Adverse events associated with bortezomib treatment. Highlighted in red the side effects addressed in the review.

Figure 3

Chymotrypsin-like proteasome activity in skeletal muscle and blood of control mice and mice treated for 7 or 14 days with bortezomib. Chymotrypsin-like activity decreases significantly in skeletal muscle and blood of treated mice compared to control group. The graph presents mean fluorescence intensity ± SD; n = 3; * p < 0.05 vs controls in one-way Anova with Dunnet’s post hoc test.

Figure 4

Light microscopy of gastrocnemius (A–C) and tibialis anterior (D–F) muscles from control mice (A,D) and mice treated for 7 (B,E) or 14 days (C,F) with bortezomib. H&E stain shows no morphological abnormalities in control mice and in mice treated with bortezomib. Images were obtained with obj ×20. Bars: 100 μm.

Figure 5

Transmission electron micrographs of gastrocnemius muscles from control mice (A,B) and mice treated for 14 days with bortezomib (C–E). Note the large-sized subsarcolemmal (sm) and intermyofibrillar (im) mitochondria in C and E compared to the mitochondria in A and B, and the sarcoplasmic enlargements in D (asterisks). Nucleus (n). Bars: 500 nm. (F) Histograms in F show the mean ± SE values of sectional area and inner/outer membrane ratio of subsarcolemmal and intermyofibrillar mitochondria in gastrocnemius muscles from control mice and mice treated for 7 or 14 days with bortezomib. All values are significantly different from each other.