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. 2025 Jul 1;11(7):753-761.
doi: 10.1001/jamaoncol.2025.1285.

New Definition of Light Chain Monoclonal Gammopathy of Undetermined Significance

Thorir Einarsson Long  1   2   3 , Saemundur Rognvaldsson  1   4 , Sigrun Thorsteinsdottir  1   5 , Ingigerdur Solveig Sverrisdottir  1   6 , Elias Eythorsson  1   4 , Jon Thorir Oskarsson  1 , Olafur Skuli Indridason  4 , Runolfur Palsson  1   4 , Thor Aspelund  1 , Brynjar Vidarsson  4 , Pall Torfi Onundarson  1   4 , Bjarni Agnar Agnarsson  1   4 , Margret Sigurdardottir  4 , Ingunn Thorsteinsdottir  4 , Isleifur Olafsson  4 , Asdis Rosa Thordardottir  1 , Asbjorn Jonsson  1   7 , Gauti Gislason  1 , Andri Olafsson  1 , Malin Hultcrantz  8 , Brian G M Durie  9 , Stephen Harding  10 , Thorvardur Jon Love  1   4 , Ola Landgren  11 , Sigurdur Yngvi Kristinsson  1   4
Affiliations

New Definition of Light Chain Monoclonal Gammopathy of Undetermined Significance

Thorir Einarsson Long et al. JAMA Oncol. .

Abstract

Importance: Recent studies suggest standard reference intervals for serum free light chains (FLC) are inaccurate and that this problem can only be partially remedied by using separate reference intervals for individuals with impaired kidney function. This decreases the utility of FLC testing in the clinical evaluation and follow-up of plasma cell disorders, particularly affecting the diagnosis of light chain (LC) monoclonal gammopathy of undetermined significance (MGUS).

Objective: To evaluate the distribution of serum FLC and FLC ratios in individuals with preserved kidney function and to propose revised reference intervals and a new definition of LC-MGUS.

Design, setting, and participants: The Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM) study is a nationwide prospective study of 75 422 participants (more than 50% of the Icelandic population) 40 years and older who were screened for MGUS. Data were collected from September 2016 to May 2023, and data were analyzed from June 2023 to May 2024.

Exposure: Samples were analyzed by serum protein electrophoresis and immunofixation electrophoresis and FLC assay. Participants were actively followed up for progression.

Main outcomes and measures: The rate of abnormal FLC results using standard reference intervals was assessed, and revised age-stratified 99% reference intervals were calculated using nonparametric regression. The prevalence of LC-MGUS based on standard and revised reference intervals was evaluated along with progression to lymphoproliferative disorders.

Results: In total, 41 882 participants met inclusion criteria; a total of 23 786 (56.8%) were female, and the median (IQR) age was 60 (52-68) years. Using standard FLC reference intervals, 7316 κ FLC (17.5%), 1668 λ FLC (4.0%), and 1543 FLC ratios (3.7%) were abnormal. Revised reference intervals were calculated for those younger than 70 years (κ FLC, 6.3-39.0 mg/L; λ FLC, 5.9-36.7 mg/L; FLC ratio, 0.44-2.16) and 70 years or older (κ FLC, 7.0-55.8 mg/L; λ FLC, 6.4-48.0 mg/L; FLC ratio, 0.46-2.59). The prevalence of LC-MGUS was 1.54% (95% CI, 1.46-1.63) using standard intervals and 0.27% (95% CI, 0.23-0.30) using the revised intervals, yielding a decrease of 82%. None of the 1006 persons meeting LC-MGUS criteria based on standard intervals but not based on revised intervals progressed to a lymphoproliferative disorder during a median (range) follow-up of 4.6 (2.5-6.7) years.

Conclusions and relevance: In this study, a new definition of LC-MGUS based on revised, more accurate FLC reference intervals decreased the false-positive rate of FLC testing by 82%.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Einarsson Long reported grants from Icelandic Center for Research during the conduct of the study. Dr Rognvaldsson reported personal fees from Siemens Healthineers and Johnson & Johnson outside the submitted work. Dr S. Thorsteinsdottir reported personal fees from Thermo Fischer Scientific outside the submitted work. Dr Hultcrantz reported research funding from Beigene, Bristol Myers Squibb, Johnson & Johnson, fand AbbVie, GlaxoSmithKline, SpringWorks Therapeutics, Cosette Pharmaceuticals, Daiichi-Sankyo, and The Binding Site as well as personal fees from Johnson & Johnson and Bristol Myers Squibb outside the submitted work. Dr Harding reported personal fees from The Binding Site outside the submitted work. Dr Landgren reported grants from Amgen, Johnson & Johnson, and Pfizer; serves on the independent data monitoring committee for Johnson & Johnson, Takeda, and Merck; and personal fees from Sanofi, Johnson & Johnson, and Pfizer outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Distribution of κ and λ Free Light Chains (FLC) and FLC Ratios in Individuals With Estimated Glomerular Filtration Rate of 60 mL/min/1.73 m2 or Greater Compared With Standard Reference Intervals by Age Categories
A, Serum κ FLC (vertical blue lines, 3.3-19.4 mg/L). B, Serum λ FLC (vertical blue lines, 5.7-26.3 mg/L). C, FLC ratio (vertical blue lines, 0.26-1.65). κ and λ FLC are truncated at 60 mg/L and the FLC ratio at 3.5 in the figure panels for better visualization.
Figure 2.
Figure 2.. New Definition of Light Chain Monoclonal Gammopathy of Undetermined Significance
Reference intervals for estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 have been previously published. Involved free light chain (FLC) defined as high λ FLC with abnormally low FLC ratio and high κ FLC with elevated FLC ratio.
Figure 3.
Figure 3.. Prevalence of Light Chain Monoclonal Gammopathy of Undetermined Significance Using the New Definition by Age and Sex
The shaded area indicates 95% CIs.
See this image and copyright information in PMC

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