Table 1.

An overview of the key clinical features, diagnostic and management considerations in IgM monoclonal gammopathy of clinical significance entities.

Subtype of IgM MGCS	Clinical Presentation	Diagnostic Process	Management Considerations
Neurological	Paraesthesia, painful neuropathy, ataxia. Rarely ophthalmoplegia in CANOMAD/CANDA.	Nerve conduction studies. Anti MAG, disialosyl antibodies. Neuroimaging when appropriate.	Rituximab based therapy is the first line option for anti MAG associated neuropathy. IVIG is a consideration in those who do not respond.
Cutaneous	Urticarial rash and fever in Schnitzler syndrome. Papular lesions are more common in macroglobulinosis. Ulcers and skin necrosis in cryoglobulinemia.	Skin biopsy and correlation with clinical features.	IL-1 antagonists are the first line therapy for Schnitzler syndrome. There is emerging data for IL-6 antagonists. Rituximab based therapy in selected cases.
Renal	Nephrotic syndrome. Asymptomatic rise in creatinine.	Renal biopsy and correlation with clinical features.	Rituximab based therapy for a lymphoplasmacytic clone. Bortezomib based therapy for a plasma cell driven MGCS.
IgM associated cryoglobulinaemia	Can present with skin , nerve and renal involvement. Skin lesions typically affect the extremities and non-healing ulcers can occur.	Detection of plasma cryoglobulins. Leukocytoclastic vasculitis in type 2 cryoglobulinaemia.	Rituximab based therapy should be considered for cryoglobulins with an underlying lymphoplasmacytic clone.
IgM AL Amyloidosis	Renal, neurologic and cardiac involvement are best described. Other organs can also be involved.	Histologic confirmation of amyloid. Mass spectrometry-based confirmation of the amyloid fibril subtype.	Rituximab based therapy for IgM amyloid driven by a lymphoplasmacytic clone. Bortezomib based therapy for those cases with a plasma cell clone.
IgM POEMS syndrome	Peripheral neuropathy is present in all cases. Skin lesions, endocrinopathy, organomegaly and bone lesions may also occur.	Nerve conduction studies to confirm demyelinating peripheral neuropathy. VEGF quantification Correlation with other clinical features.	No standard of care for POEMS syndrome driven by a lymphoplasmacytic clone. Rituximab based therapy to be considered. Lenalidomide based therapy for plasma cell driven cases.
Immuno-haematologic IgM MGCS	Symptomatic anaemia and acral cyanosis in primary cold agglutinin disease. Mucocutaneous bleeding in acquired VWD and ITP.	Peripheral blood film, biochemical indices of haemolysis, direct Coomb’s test and cold agglutinin titre. VWF antigen and ristocetin co factor activity. VWF multimer analysis. ITP is a diagnosis of exclusion, work up as for “idiopathic” ITP.	Rituximab based therapy for primary CAD. Rituximab monotherapy and bendamustine rituximab are considerations. No standard of care for AVWD, achievement of haemostasis and clone directed therapy to be considered. Steroid therapy as for idiopathic ITP is appropriate as first treatment. Clone directed therapy in patients who do not respond.

MGCS, monoclonal gammopathy of clinical significance; MGRS, monoclonal gammopathy of renal significance; POEMS, Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin abnormalities; CANOMAD, Chronic Ataxic Neuropathy, Ophthalmoplegia, IgM paraprotein, Cold Agglutinins, Disialosyl antibodies; DADS-M, Distal acquired demyelinating symmetric neuropathy. MAG, Myelin associated glycoprotein. CAD, Cold agglutinin disease, VWD, Von Willebrand disease, ITP, Immune thrombocytopaenic purpura. IVIG, intravenous immunoglobulin. IL-1, Interleukin 1; IL-6, Interleukin 6. VEGF, Vascular endothelial growth factor.