Objective:

To determine the comparative risk of incidence of neuropathy associated with proteasomal inhibitors (PIs) in multiple myeloma (MM) patients. 

Background:

PIs (bortezomib, carfilzomib, ixazomib) are commonly used in treating MM. Bortezomib is traditionally associated with peripheral neuropathy, but it remains unclear whether its adverse effects also mirror the class-specific neurotoxic profile of PIs. Newer oral proteasome inhibitor, ixazomib, has fewer incidences of neuropathy.  However, a direct comparison of neuropathy as a side effect of individual PIs has not been performed.

Design/Methods:

Published randomized control trials (RCTs) reporting neuropathy in MM patients (newly diagnosed and/or relapsed) treated with PI were searched up to May 2021. Studies where PIs were used along with chemotherapy vs. placebo, or no additional drugs (control) in the other arm were included. The primary outcome was the presence of neuropathy after follow-up. Pair-wise meta-analysis and network meta-analysis were performed using the frequentist’s approach to estimate the odds ratio (OR).

Results:

Eleven randomized clinical trials with a total of 3576 MM patients were evaluated in the analysis, which reported the incidence of neuropathic events.  A total of nine studies on bortezomib(6), ixazomib(2), and carfilzomib(1) reported neuropathic events against a control group. Two studies compared bortezomib to carfilzomib.  There was a significant increase in all grade (OR = 2.51, 95% CI 1.54-4.09) and high-grade neuropathy (based on CTCAE criteria) (OR = 3.37, 95% CI 2.36-4.81) among patients treated with any PI compared to control. Among the PIs, bortezomib was associated with a maximum risk of all-grade neuropathy (OR 4.00; 95% CI 3.30-4.85).

Conclusions:

Our results showed that treatment with bortezomib is associated with the highest risk of neuropathy among PIs in MM patients. This may warrant increased awareness among treating physicians and close monitoring of patients treated with these agents.