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. 2025 Apr 28;15(1):80.
doi: 10.1038/s41408-025-01289-7.

Revised free light chain reference intervals enhance risk stratification in monoclonal gammopathy of undetermined significance and reduce overdiagnosis

Cecilie Velsoe Maeng  1   2 , Sæmundur Rögnvaldsson  3   4 , Thórir Einarsson Long  3   5   6 , Christian Brieghel  7   8 , Emil Hermansen  7 , Carsten Utoft Niemann  7   8   9 , Kirsten Grønbæk  7   10   9 , Sigurður Yngvi Kristinsson  3   4 , Sigrún Thorsteinsdóttir  7   3
Affiliations

Revised free light chain reference intervals enhance risk stratification in monoclonal gammopathy of undetermined significance and reduce overdiagnosis

Cecilie Velsoe Maeng et al. Blood Cancer J. .

Erratum in

Abstract

The free light chain (FLC) ratio is a critical part of risk stratification for monoclonal gammopathy of undetermined significance (MGUS). Recently, revised FLC reference intervals developed using the iStopMM cohort, accounting for age and renal function, have reduced the rate of abnormal findings. Here, we examine the implications of the revision in an independent Danish MGUS cohort. Of 6993 MGUS individuals, 2641 had an abnormal FLC ratio by the original intervals, of whom 844 (32%) were reclassified as normal using the revised intervals. Reclassified individuals had no significantly increased risk of progression compared to those with a normal FLC ratio (hazard ratio (HR): 1.07, 95% confidence interval (CI) 0.74-1.57). Those with an abnormal FLC ratio by the revised reference intervals had an increased risk of progression (HR 2.23, 95% CI 1.79-2.78). Using the revised reference intervals, 490 individuals (16%) were reclassified to low-risk from a higher risk group. These individuals had a similar progression risk compared to others in the low-risk group. The findings validate the revised FLC reference intervals, enhancing prognostic accuracy and improving risk stratification to accurately identify MGUS individuals at risk of progression while reducing unnecessary classifications as high-risk.

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Conflict of interest statement

Competing interests: CVM has participated in a conference supported by Daiichi Sankyo. SR has received honoraria for scientific talks from Siemens Healthineers and Johnson & Johnson. TL has no conflicts of interest to declare. CB has received an honorarium from AbbVie. EH reports honoraria for lectures and educational materials from Amgen, Bristol Myers Squibb, Johnson & Johnson, Pfizer, Sanofi, and Takeda, research cooperation with Bristol Myers Squibb, Johnson & Johnson, and Sanofi, participation in conferences supported by Bristol Myers Squibb, Pfizer, Roche, and Takeda, and advisory board consultancy to Johnson & Johnson, Sanofi, and Oncopeptides. CUN has received research funding from AbbVie, Johnson & Johnson, AstraZeneca, Novo Nordisk Foundation, Genmab, and Octapharma, and has provided consultancy for AbbVie, BeiGene, Janssen, Roche, AstraZeneca, CSL Behring, Genmab, Takeda, Octapharma, MSD, Synamics, and Lilly. KG has received research funding from Janssen. SYK reports research funding from Amgen and Celgene, and an Independent Data Monitoring Committee for Johnson & Johnson. ST has received honoraria for scientific talks from AbbVie and Thermo Fisher Scientific. Ethics approval and consent to participate: The study was conducted under the approval of Danish Lymphoid Cancer Research (DALYCARE) protocol by the Danish National Ethics Committee (1804410) and Data Protection Agency (P-2020-561). All methods were performed in compliance with all relevant guidelines and regulations for use of Danish data, including legal exemption from informed consent as a nationwide epidemiological study.

Figures

Fig. 1
Fig. 1. CONSORT diagram showing the inclusion and exclusion of individuals with MGUS.
The diagram outlines the total number of MGUS individuals in the Danish Lymphoid Cancer Research (DALY-CARE) data resource, and individuals excluded (orange) and included (green) in the final analyses. Abbreviations: MGUS monoclonal gammopathy of undetermined significance, FLC free light chain, AL amyloid light chain, M protein monoclonal protein.
Fig. 2
Fig. 2. Cumulative incidence curves showing the progression risk of MM, NHL, or AL amyloidosis in individuals with MGUS, using Aalen–Johansson estimation and considering death as a competing risk.
The individuals were stratified into normal FLC ratio using any reference interval (black), FLC ratio reclassified from abnormal to normal (blue), and abnormal FLC ratio using the revised reference intervals (red). Abbreviations: MGUS monoclonal gammopathy of undetermined significance, FLC free light chain, MM multiple myeloma, NHL non-Hodgkin’s lymphoma, AL amyloid light chain .
See this image and copyright information in PMC

References

    1. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564–9. - PubMed
    1. Sigurbergsdóttir AÝ, Rögnvaldsson S, Thorsteinsdóttir S, Sverrisdóttir I, Sigurðardóttir GÁ, Viðarsson B, et al. Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts: results from the population-based iStopMM study. Haematologica. 2023;108:3392–8. - PMC - PubMed
    1. Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113:5412–7. - PMC - PubMed
    1. Xu H, Tian J, Li L, Liu F, Ren Y, Guo G, et al. Risk factors for the outcome and prognosis of multiple myeloma patients with pathological fractures undergoing percutaneous vertebroplasty. Am J Cancer Res. 2024;14:2946–56. - PMC - PubMed
    1. Courant M, Orazio S, Monnereau A, Preterre J, Combe C, Rigothier C. Incidence, prognostic impact and clinical outcomes of renal impairment in patients with multiple myeloma: a population-based registry. Nephrol Dial Transplant. 2021;36:482–90. - PubMed

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