Abstract
Light chain monoclonal gammopathy of undetermined significance (LC-MGUS) is an asymptomatic precursor of multiple myeloma (MM) and related disorders defined by abnormal free light chain (FLC) testing. Recently, revised FLC reference intervals were proposed by the iStopMM study group. We evaluated their performance in a large population-based cohort. MGUS cases were identified from the Danish Lymphoid Cancer Research (DALY-CARE) data resource, including only individuals with Freelite FLC-measurements. Cases were classified by original and revised LC-MGUS criteria, hereby identifying cases only fulfilling original but not revised criteria (reclassified as normal). Outcomes were progression to MM or related disorders. Cumulative incidence of progression with death as competing risk was examined using Aalen-Johansen estimation. Annual progression risk was assessed using a person-years approach. In total, 360 individuals classified by original criteria, 215 by revised, while 150 (40%) were reclassified as normal. In the revised group, there were 21 (9.8%) progressions; 11 (5.1%) to MM and seven (3.3%) to AL amyloidosis. Only two individuals (1.3%) progressed in the reclassified group, none to MM or AL amyloidosis. For revised LC-MGUS, the 2- and 5-year cumulative incidence of progression was 5.8% and 8.9%, respectively, with an annual progression rate of 3%. This study validates the performance of the iStopMM revised LC-MGUS criteria in a clinical cohort. Applying the revised criteria reduced LC-MGUS diagnoses by 40% without missing cases progressing to MM or AL amyloidosis. These findings confirm the accuracy of the revised criteria and support their implementation to improve diagnostics and ensure follow-up of individuals truly at risk.