IgM monoclonal gammopathy of undetermined significance: clinicopathologic features with and without IgM-related disorders

Abstract

A subset of patients with IgM monoclonal gammopathy of undetermined significance (MGUS) develop IgM-related disorders (IgM-RD) including peripheral neuropathy, cryoglobulinemia and/or cold agglutinin disease (CAD). We examined the clinical and bone marrow pathologic findings in 191 IgM MGUS patients (2016 WHO criteria). Clonal plasma cells were identified in 41/171 (24%) cases by immunohistochemistry (IHC) and clonal B-cells in 43/157 (27%). IgMRD was identified in 82 (43%) cases, including peripheral neuropathy (n=67, 35%), cryoglobulinemia (n=21, 11%), and CAD (n=10, 5%). Cases of CAD showed distinctive features including lack of MYD88 mutations (p=0.048), supporting the concept of primary CAD as a distinct clinicopathologic disorder. Following exclusion of CAD, comparison of the remaining cases with (n=72) or without (n=109) IgM-RD showed IgM-RD to be more frequent in men than women (p=0.02) and to be more highly associated with MYD88 L265P (p=0.011). Cases with and without IgM-RD otherwise showed similar features including serum IgM concentrations, presence of lymphoid aggregates, clonal B-cells by flow cytometry or clonal plasma cells by IHC. No differences were observed in overall survival between cases with and without IgM-RD. No cases in this series met criteria for plasma cell type IgM MGUS as defined in the 2022 International Consensus Classification of lymphoid neoplasms. These results show IgM-RD to be common in patients with IgM MGUS. While CAD shows distinctive features, the remaining cases of IgM-RD largely show pathologic findings similar to IgM MGUS without IgM-RD.

Cold agglutinin disease and cryoglobulinaemia: A frequent coexistence with clinical impact

“…In a cohort of 134 patients with type I cryoglobulinaemia, concurrent CAD was found in 15%, 6 compared to a series of 82 MGCS with only 2% overlap. 5 Our frequent coexistence was identified as a result of routine screening for cryoglobulin in all CAD patients. Note: Treatment and responses in all treated patients and stratified by those with CAD and coexistent cryoglobulins and those without cryoglobulins.…”

“…4 Cold-induced symptoms are characteristic of both conditions; however, the coexistence of these disorders is not well described. 5 We recently reported on 134 patients with type I cryoglobulinaemia and found concurrent CAD in 15%. 6 It is not known, however, whether these conditions interrelate and what effect this overlap has on the clinical phenotype.…”

Clinical and clonal characteristics of monoclonal immunoglobulin M‐associated type I cryoglobulinaemia

“…small sample sizes or mixed cohorts. 2,3 When first defined, approximately 10% of monoclonal IgM conditions were reported to have cryoglobulins, and presenting symptoms were noted in 80%. 4 However, recent data demonstrate a variable proportion (up to 90%) of symptomatic cases, likely reflecting the practice of cryoglobulinaemia screening.…”