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    Plasma Cell precursor and Other Disorders

    (OA-41) Clinical Validation of Revised Diagnostic Criteria for Light Chain MGUS and Risk of Progression to Malignancy

    Saturday, September 20, 2025
    09:10 - 09:20 East Coast USA Time
    Location: Room 718
    Introduction: Light chain monoclonal gammopathy of undetermined significance (LC-MGUS) is a precursor to LC multiple myeloma (MM) and other lymphoproliferative disorders (LPD). LC-MGUS is defined by an abnormal free light chain (FLC) ratio, elevated level of the involved LC, and absence of monoclonal heavy chain immunoglobulins and end-organ damage. Previous studies estimate an annual progression risk to malignant disease of 0.3%. However, the criteria for LC-MGUS were recently revised by the iStopMM study group, following updated FLC reference intervals. Here, we aim to evaluate the performance of the revised criteria to better characterize the natural history of LC-MGUS and identify risk factors associated with progression.

    Methods: We used data from the Danish Lymphoid Cancer Research (DALY-CARE) resource including individuals with LPD from Danish national registries. Identified cases were classified by which LC-MGUS criteria they met; A) original, B) revised, or C) only original (some overlapping in A and B). Outcomes were progression to LPD (MM, non-Hodgkin lymphoma, Waldenström’s macroglobulinemia and AL amyloidosis). A subgroup analysis stratified individuals by involved/uninvolved FLC-ratio ≥10. Cumulative incidence of progression with death as competing risk was examined using Aalen-Johansen estimation, and hazard ratio (HR) of progression risk was assessed using Cox regression model adjusted for age and sex.

    Results:

    359 individuals classified as LC-MGUS by original criteria, 214 by revised (of which 209 met both original and revised criteria and 5 only the revised), and 150 (41%) met only original criteria. In the revised group, 21 progressed during follow-up, hereof 11 to MM and 7 to AL amyloidosis. Only 2 progressed in the original-only group (none to MM or AL amyloidosis) yielding a significantly lower risk of progression (HR 0.08, 95% CI: 0.02-0.36) compared to revised LC-MGUS. For revised LC-MGUS, the 2- and 5-year cumulative incidence of progression to LPD was 6% and 9.2%, respectively, thus an annual progression risk of approximately 1.8% the first 5 years. Comparing individuals with FLC-ratio ≥10 vs < 10 did not show a significant difference in risk of progression to LPD (HR 0.99, 95% CI: 0.39-2.52): notably, only 2 of the 7 individuals, who progressed to AL amyloidosis, had a baseline FLC-ratio >10.

    Conclusions: This study validates the performance of the iStopMM revised criteria of LC-MGUS in a clinical cohort. Applying the revised criteria reduced LC-MGUS diagnoses by 41% with no progressions to MM or AL amyloidosis in the group no longer classifying as LC-MGUS. The annual progression risk of revised LC-MGUS was 1.8%, more comparable to that of conventional MGUS. FLC-ratio ≥10 was not an optimal predictor of progression in our cohort, especially failing to capture patients at risk of AL amyloidosis. This study illustrates the utility and validity of the revised definition of LC-MGUS and underscores the importance and need of more nuanced risk stratification for LC-MGUS.