Monoclonal Gammopathy of Neurologic Significance: A Practical Framework for Diagnosis and Management

Monoclonal gammopathy of neurologic significance (MGNS) refers to peripheral neuropathies that are attributable to a monoclonal immunoglobulin produced by an underlying clonal plasma cell population or B-cell population in the absence of multiple myeloma, amyloid light chain amyloidosis, or polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes syndrome. Because the prevalence of both monoclonal gammopathy of undetermined significance (MGUS) and peripheral neuropathy increases with age, their coexistence is frequently incidental. However, population-based studies demonstrate a significantly higher risk of neuropathy among patients with MGUS compared with matched controls. Establishing causality requires careful clinical phenotyping, correlation with electrodiagnostic studies, and systematic exclusion of alternative and potentially life-threatening causes that require urgent intervention. This review presents a practical, stepwise diagnostic and therapeutic framework for MGNS, emphasizing multidisciplinary collaboration between hematology and neurology. The approach is illustrated through two representative clinical scenarios: IgM MGUS with anti–myelin-associated glycoprotein (anti-MAG) neuropathy and non-IgM MGUS with chronic inflammatory demyelinating polyneuropathy (CIDP) or its variants. Treatment approaches differ fundamentally between these subtypes. B-cell–directed therapy with rituximab is the most commonly used first-line treatment for IgM anti-MAG neuropathy, whereas non-IgM MGNS with CIDP is managed with immunomodulatory strategies including intravenous immunoglobulin, corticosteroids, and plasmapheresis. We also discuss novel therapeutics, including Bruton tyrosine kinase inhibitors and complement-directed therapies. This framework provides clinicians with a structured approach to assess causal likelihood, stratify patients by neuropathy subtype, and guide evidence-based treatment decisions across the MGNS spectrum.