Multiple Myeloma Drugs Ranked by Nerve Damage Risk Across Three Neuropathy Types

Multiple myeloma (MM) treatment has been transformed over the past two decades by immunomodulatory drugs (IMIDs — thalidomide, lenalidomide, pomalidomide) and proteasome inhibitors (PIs — bortezomib, carfilzomib, ixazomib). While these agents have dramatically improved survival, drug-induced peripheral neuropathy remains one of the most clinically significant adverse effects, affecting quality of life, driving dose reductions, and increasing healthcare costs. A Brazilian cross-sectional study cited in this paper found that 90.3% of MM patients reported chemotherapy-induced peripheral neuropathy, with 62.7% experiencing severe symptoms. Despite this burden, comparative data on neuropathy subtypes — sensory, motor, and autonomic — across these six drugs has been limited.

This retrospective pharmacovigilance study mined VigiBase, the WHO's global database of individual case safety reports (ICSRs), extracting all deduplicated reports filed between December 1, 2001 and May 31, 2023 that involved at least one PI or IMID as a suspected or interacting drug. Peripheral neuropathy cases were identified using four MedDRA preferred terms (neuropathy peripheral, autonomic neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy) and the standardized MedDRA query (SMQ) for peripheral neuropathy. Disproportionality was assessed using the reporting odds ratio (ROR) with 95% confidence intervals and the Bayesian information component (IC), with signals defined as ROR lower CI > 1 and IC > 0.

All six drugs generated disproportionality signals for peripheral sensory neuropathy and for the broad SMQ peripheral neuropathy category. However, the drugs diverged markedly for motor and autonomic subtypes. Bortezomib produced the strongest motor neuropathy signal of any drug analyzed (ROR 63.87; 95% CI: 51.78–78.80), followed by thalidomide (ROR 30.62; 95% CI: 22.67–41.40), pomalidomide (ROR 5.03; 95% CI: 2.91–8.69), and lenalidomide (ROR 2.95; 95% CI: 2.11–4.14). Carfilzomib and ixazomib did not generate significant motor neuropathy signals, suggesting a more favorable motor safety profile for second-generation PIs.

For autonomic neuropathy, signals were detected for bortezomib (ROR 12.90; 95% CI: 9.01–18.47), ixazomib (ROR 19.01; 95% CI: 7.89–45.80), carfilzomib (ROR 9.35; 95% CI: 3.01–29.10), and thalidomide (ROR 8.86; 95% CI: 4.21–18.70). Notably, lenalidomide and pomalidomide did not show autonomic neuropathy signals, suggesting that newer IMIDs carry lower autonomic risk. Within-group comparisons showed bortezomib had significantly higher neuropathy reporting than carfilzomib and ixazomib across most neuropathy subtypes, while thalidomide had higher signals than lenalidomide and pomalidomide.

These findings carry direct clinical implications. Clinicians managing MM patients should recognize that bortezomib poses the highest combined risk for both motor and autonomic neuropathy, while second-generation PIs (carfilzomib, ixazomib) appear safer for motor function. Among IMIDs, thalidomide carries the broadest neuropathy risk profile. The study supports subtype-stratified monitoring strategies — for example, screening for orthostatic hypotension and gastric motility issues in patients on bortezomib or ixazomib, and for distal weakness in those on thalidomide. Limitations include the inherent biases of spontaneous reporting systems (underreporting, confounding by indication, and inability to establish causality), as well as the fact that MM patients often receive combination regimens, making it difficult to attribute neuropathy to a single agent.