Background: Immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (IgM) is rare making up 15% MGUS but carries a high risk of progression to many hematologic disorders, most notably Waldenstrom Macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) or non-Hodgkin lymphoma (NHL). These diseases can be associated with high cost of care, morbidity, and mortality. To date epidemiologic data on the progression events from IgM MGUS have been reported in small studies largely consisting of White patients. As such, there is a need for descriptive analyses reporting the frequencies and types of progression events from IgM MGUS in a large and racially diverse cohort.

Methods: The study included patients diagnosed with IgM MGUS from 10/1/1999-1/22/2025 in the Veterans Health Administration. MGUS was identified via natural language processing algorithms; furthermore, laboratory values, including M-protein concentration and immunoglobulin subtype were extracted (Wang M, et al. JCO CCI 2023). Patients progressing ≤365 days of MGUS diagnosis were excluded since they may have already progressed at the time of MGUS diagnosis. Progression events were captured by international classification of diseases-9/10 (ICD-9/10) codes, including WM/LPL 273.3/C88.0, amyloidosis 277.39/E85, NHL 200 and 202 /C82-86, multiple myeloma (MM) 203/C90.0, and hyperviscosity R70.1. For amyloidosis, MM, and hyperviscosity diagnoses, progression was further confirmed by receipt of treatment or current procedural terminology code for disease specific intervention. The corresponding date of the first treatment was defined as the date of progression. For WM/LPL and NHL, since some patients never require treatment, the diagnoses were confirmed by the presence of two separate outpatient ICD-9/10 codes ≥30 days apart or ≥1 inpatient codes, and the date of the first code was determined to be the progression date. For patients with multiple progression events (e.g., WM/LPL, amyloidosis, and hyperviscosity), the time to first progression event was used for the composite outcome of time to progression. The exception is that if patients had ICD-9/10 codes for both WM/LPL and NHL, they were categorized as WM/LPL regardless of their NHL diagnosis. The patients were followed until progression, death, or censoring on the date of last data retrieval (7/21/2025), whichever comes first. We performed descriptive analyses to summarize progression events.

Results: We identified 6,363 patients with IgM MGUS with a median follow up of 41.6 (interquartile range [IQR]: 23.0-73.1) months. Among them, 98.8% were male; 11.0% were non-Hispanic Black, 1.8% were Hispanic, 79.7% were non-Hispanic White, and 1.4% were other race; 71.6% were IgM Kappa and 28.4% IgM Lambda; at MGUS diagnosis, 13.7% had monoclonal protein (M-protein) ≥1.5 g/dL and 69.3% had M-protein <1.5 g/dL. Median age was 70 (IQR: 63-76) years and median Charlson Comorbidity Index was 3 (IQR: 1-6) at MGUS diagnosis. The composite outcome of progression occurred in 655 patients (10.3%) at a median of 41.6 (IQR: 22.7-72.0) months. The progression events were WM/LPL (n=406 [6.4%]), amyloidosis (n=19 [0.3%]), NHL (n=209 [3.3%]), MM (n=43 [0.7%]), and hyperviscosity (n=3 [0.1%]). Among patients progressing to WM/LPL, 35.5% required treatment with the first treatment occurring at a median of 39.8 (IQR: 19.7-76.4) months from WM/LPL diagnosis. Among patients progressing to NHL cohort, 21.5% required treatment occurring at a median of 40.3 (IQR: 21.7-62.7) months from NHL diagnosis.

Conclusions: In a racially diverse cohort of US Veterans with IgM MGUS, we report low rates of composite progression (10.3%) to malignant disorders including: WM/LPL (6.4%), NHL (3.3%), and MM (0.7%). It is important for future studies to characterize factors associated with progression risk to inform prevention.

L.L. and B.S. contributed equally.

M.A.S. and S.H.C. contributed equally.

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2025
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