IgM monoclonal gammopathies of clinical significance: diagnosis and management

Abstract

IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenström macroglobulinemia 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. The indication for treatment in affected patients is dictated by the pathological characteristics of the circulating IgM rather than the tumor itself. The clinical workup and treatment options vary widely and differ from those for Waldenström macroglobulinemia. The aim of this review is to alert clinicians to IgM monoclonal gammopathy of clinical significance and to provide practical guidance on 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, IgM-associated peripheral neuropathy, Schnitzler syndrome and IgM-associated AL amyloidosis. The inhibition of the pathogenic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centered on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and IgM-associated peripheral neuropathy 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 pathogenic IgM-directed therapies is welcomed.

Figure 1.

Management of cold agglutinin disease. DAT: direct antiglobulin test; CA: cold agglutinin; CAS: cold agglutinin syndrome; computed tomography; LDH: lactate dehydrogenase; EPO: erythropoietin; BR: bendamustine and rituximab; BTKi: Bruton tyrosine kinase inhibitor.

Figure 2.

Management of cryoglobulinemia. *Virology testing includes a full hepatitis B profile, hepatitis C, and human immunodeficiency virus. **Emergency indications include symptomatic hyperviscosity, critical ischemia, severe neuropathy, and progressive renal impairment. CNS: central nervous system; NCS/EMG: nerve conduction studies, electromyography; uPCR, urine protein creatinine ratio; CT: computed tomography; BR: bendamustine and rituximab; DRC: dexamethasone, rituximab, cyclophosphamide; BTKi: Bruton tyrosine kinase inhibitor.

Figure 3.

Management of IgM-associated amyloidosis. *Histological assessment includes targeting affecting organ, consider abdominal fat biopsy. Exclude other acquired and hereditary amyloidoses. **Organ assessment includes comprehensive evaluation of organs including cardiac, renal, neurological, gastrointestinal and soft tissue involvement. M-protein: monoclonal protein; SPEP: serum protein electrophoresis; SFLC: serum free light chains; LPL: lymphoplasmacytic lymphoma; CT: computed tomography; PET: positron emission tomography; MRI: magnetic resonance imaging; PPCN: pure plasma cell neoplasm; R-Bendamustine: rituximab plus bendamustine; BEAM: carmustine, etoposide, cytarabine, melphalan; Mel, melphalan; ASCT: autologous stem cell transplantation; AL: AL amyloidosis.

Figure 4.

Management of IgM-related neuropathies. *Nerve biopsy after consultation with an expert neurologist, in selected cases only. CNS: central nervous system; HIV: human immunodeficiency virus; CIDP: chronic inflammatory demyelinating polyneuropathy; MAG: myelin-associated glycoprotein; Ab: antibody; NCS/EMG: nerve conduction studies/electromyography; MRI: magnetic resonance imaging; CSF: cerebrospinal fluid; CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM M-protein, cold agglutinins and disialosyl ganglioside antibodies; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin abnormalities; BR: bendamustine plus rituximab; DRC: dexamethasone, rituximab, cyclophosphamide.