IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenstrom Macroglobulinaemia (WM) and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/l with a lymphoplasmacytic bone marrow infiltration of less than 10%. A significant proportion, however develop unique immunological and biochemical manifestations related to the monoclonal protein itself in the absence of overt malignancy and are termed IgM-related disorders or more recently Monoclonal Gammopathy of Clinical Significance (MGCS). Treatment indication in these patients is dictated by the pathological characteristics of the circulating IgM rather than the tumour itself. The clinical workup and treatment options vary widely and differ from the regular treatment for WM. The aim of this review is to alert clinicians to IgM MGCS and to provide practical guidance of when to screen for these phenotypes. We discuss clinical characteristics, the underlying clonal profile, diagnostic workup and treatment considerations for five important subtypes: Cold agglutinin disease, type I and II cryoglobulinemia, IgMassociated peripheral neuropathy (PN), Schnitzler syndrome and IgM-associated AL Amyloidosis. The inhibition of the pathogenetic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centred on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and PN are the least well developed. A multidisciplinary approach is required particularly for IgM-related neuropathies and Schnitzler syndrome. Future work exploring novel clone directed agents and pathogenetic IgM-directed therapies is welcomed.
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