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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\u2010based screening has demonstrated that standard reference intervals substantially overdiagnose LC\u2010MGUS through three independent mechanisms: age\u2010related physiological free light chain elevation, impaired renal clearance in chronic kidney disease, and ancestry\u2010related differences in individuals of African descent. Revised age\u2010stratified and kidney function\u2013adjusted reference intervals reduce LC\u2010MGUS prevalence by 82%, with no observed progressions among reclassified individuals during available follow\u2010up of 4.6\u2009years and have been validated across multiple independent international cohorts. For individuals of African ancestry, ancestry\u2010adjusted reference intervals provide a further essential and independent correction. True LC\u2010MGUS 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.<\/jats:p>","DOI":"10.1111\/ejh.70258","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T12:08:19Z","timestamp":1783080499000},"page":"1159-1167","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Light Chain Monoclonal Gammopathy of Undetermined Significance: Diagnosis, Biology, and Clinical Management"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4964-7476","authenticated-orcid":false,"given":"Sigur\u00f0ur Yngvi","family":"Kristinsson","sequence":"first","affiliation":[{"name":"Faculty of Medicine University of Iceland  Reykjavik Iceland"},{"name":"Landspitali University Hospital  Reykjavik 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