Biological Drivers of IMiD-Induced Peripheral Neuropathy in Multiple Myeloma

The introduction of immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide and pomalidomide, have led to significant improvements in multiple myeloma (MM) treatment. Many patients now live 10 years or longer with their disease, making treatment-related side effects increasingly important. Peripheral neuropathy (PN) is a common side effect of IMiD therapy, with a substantial impact on patients' quality of life, and no preventive or targeted therapeutic strategies are currently available. This review explores pathomechanisms and genetic factors likely underlying IMiD-induced PN, considering oxidative stress, microvascular changes, immune-mediated injury and neuroinflammation, neurotrophin dysregulation, as well as heritable susceptibility. Particular focus is given to potential mechanisms explaining the distinct neurotoxicity profile of thalidomide compared to second-generation IMiDs. In this context, the review highlights the need for standardized clinical trial assessments, larger genetic studies and robust preclinical models to elucidate causality and manage this complex toxicity effectively. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.