Light Chain Monoclonal Gammopathy of Undetermined Significance: Diagnosis, Biology, and Clinical Management

Light chain monoclonal gammopathy of undetermined significance (LC-MGUS) is defined by an abnormal serum free light chain ratio and elevated involved light chain in the absence of a detectable immunoglobulin heavy chain on immunofixation and of end-organ damage attributable to a plasma cell disorder. It is the least characterized of the MGUS subtypes and the one whose accurate diagnosis is most dependent on the precision of the reference intervals used to interpret free light chain measurements. Population-based screening has demonstrated that standard reference intervals substantially overdiagnose LC-MGUS through three independent mechanisms: age-related physiological free light chain elevation, impaired renal clearance in chronic kidney disease, and ancestry-related differences in individuals of African descent. Revised age-stratified and kidney function-adjusted reference intervals reduce LC-MGUS prevalence by 82%, with no observed progressions among reclassified individuals during available follow-up of 4.6 years and have been validated across multiple independent international cohorts. For individuals of African ancestry, ancestry-adjusted reference intervals provide a further essential and independent correction. True LC-MGUS progresses along two biologically distinct trajectories: clonal expansion toward light chain multiple myeloma and toxic light chain misfolding toward AL amyloidosis. These pathways differ fundamentally in biology, determinants of progression, and clinical consequences. Risk models designed to predict myeloma progression incompletely capture the risk of amyloidogenic transformation. Because amyloidogenic transformation can occur in the setting of low clonal burden and only modestly abnormal free light chain levels, clinical evaluation must independently and explicitly address both trajectories at every patient encounter.