Patients with immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) can develop IgM-related disorders, such as cold agglutinin disease (CAD), peripheral neuropathy, and/or cryoglobulinemia, according to findings from a study published in Haematologica.

Individuals with IgG or IgA MGUS usually develop multiple myeloma or other plasma cell neoplasms, whereas those with IgM MGUS typically progress to lymphoplasmacytic leukemia or other lymphoproliferative conditions. The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition, defines IgM MGUS as “the presence of an IgM paraprotein with a serum concentration of less than 3 g/dL, less than 10% clonal lymphoplasmacytic cell infiltration in the bone marrow, and lack of myeloma-defining clinical features.”

The researchers sought to evaluate the comprehensive clinicopathologic findings in a cohort of patients who fulfilled the 2016 World Health Organization (WHO) criteria for IgM MGUS. They compared their results in those with vs those without IgM-related disorders. Additionally, they explored the effect of the recently published 2022 International Consensus Classification (ICC) diagnostic criteria for IgM with those of the WHO criteria.

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Patients with an IgM serum paraprotein who were seen at the Cleveland Clinic between 2002 and 2021 were reviewed retrospectively; those who had undergone a bone marrow biopsy were identified. Among 1222 patients in whom IgM paraprotein had been detected, 238 individuals met the 2016 WHO IgM MGUS criteria and had bone marrow biopsies available. Following exclusions, the final cohort comprised 191 individuals.

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The mean participant age at bone marrow biopsy was 69.6 years. The male-to-female ratio in the patient cohort was 1.5:1. Laboratory values included a median IgM serum paraprotein of 452 mg/dL and a median hemoglobin level of
13 g/dL.

Light chain immunohistochemistry detected clonal plasma cells in 24% (41 of 171) of individuals who underwent evaluation. Flow cytometric analyses, which were performed in 157 participants, identified a clonal B-cell population in 27% (43 of 157) of patients, including 30 individuals with CD5-negative clonal B cells and 13 individuals with CD5-positive clonal B cells. In all 30 patients with CD5-negative B cells, the monotypic light chain on the B cells matched the IgM paraprotein light chain. In contrast, B-cell light chains and IgM paraprotein light chains were concordant in only 54% (7 of 13) of the CD5-positive B cells (P =.0003).

Overall, the presence of IgM-related disorders was recognized in 43% (82 of 191) of patients, including CAD in 5% (10 of 191) of participants, cryoglobulinemia in 11% (21 of 191), and peripheral neuropathy in 35% (67 of 191). Patients with CAD exhibited recognizable characteristics, including the absence of MYD88 mutations (P =.048), which reinforced the theory of primary CAD as a distinct clinicopathologic disorder.

When CAD was excluded from the comparison, the remaining 72 cases with and 109 without IgM-related disorders demonstrated that IgM-related disorders were significantly more common among men than women (P =.02) and were more highly associated with MYD88 L265P (P =.011). None of the cases fulfilled the 2022 ICC criteria for IgM MGUS.

“These results show IgM-RD [IgM-related disorders] to common in patients with IgM MGUS,” the researchers noted. “While CAD shows distinctive features, the remaining cases of IgM-RD largely show pathologic findings similar to IgM MGUS without IgM-RD,”  they concluded.


Bruehl FK, Mannion P, Barbato E, Nakashima MO, Cook JR. IgM monoclonal gammopathy of undetermined significance: clinicopathologic features with and without IgM-related disorders. Haematologica. Published online April 6, 2023. doi:10.3324/haematol.2022.282389