Implementing Revised Reference Intervals for Free Light Chains Improves Risk Stratification of Monoclonal Gammopathy of Undetermined Significance
Authors: Mæng Cecilie Velsø , Rögnvaldsson Sæmundur , Long Thorir , Brieghel Christian , Niemann Carsten Utoft , Gronbaek Kirsten , Kristinsson Sigurdur Y , Thorsteinsdottir Sigrun 
Published: December 2024

Background
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor to multiple myeloma (MM) and some lymphoproliferative disorders. Effective risk stratification is important to guide work-up and follow-up of individuals with MGUS. A key part of the current risk stratification is serum free light chain (FLC) levels and ratio, included as part the Mayo Clinic risk stratification model. However, existing refence intervals have been shown to be inaccurate, partly due to the effect of age and renal function. This has led to the development of revised reference intervals, based on FLC measures from 75,422 individuals in the Iceland screen, treats, or prevents multiple myeloma (iStopMM) study (Long, 2023). The revised intervals improve light-chain MGUS diagnostics, but the implications for MGUS with monoclonal (M) proteins is unknown.
Methods
We used the nationwide Danish Lymphoproliferative Cancer Research Center (DALY-CARE) data resource on patients with lymphoid cancers between 2008 to 2023 (Brieghel, 2024). We extracted ICD10 coded MGUS diagnoses and included individuals with relevant laboratory data available, including FLC measurements (from laboratories using the Freelite assay), creatinine, and a detectable M protein. Date of MGUS diagnosis was set at the first detection of an M protein with adjacent FLC measurement. We excluded patients with a concomitant diagnosis of MM, lymphoma, or AL amyloidosis prior to or &lt;90 days after of MGUS diagnosis.
First, individuals were stratified into 1) abnormal FLC ratio according to revised reference intervals, 2) abnormal FLC ratio according to old reference intervals only, and 3) normal FLC ratio by both old and the revised reference intervals. In the revised intervals, the FLC ratio is only considered abnormal with a concurrent abnormal absolute FLC level. Second, we stratified individuals into the Mayo Clinic MGUS risk groups using the old and revised reference intervals, respectively. In both analyses, outcome was defined as progression to either a) MM or b) MM, lymphoma, or AL amyloidosis. We used cause-specific Cox regression with censoring upon death, end of follow-up, or progression to lymphoproliferative disease not included in the outcome.
Results
A total of 6,401 individuals with MGUS met the inclusion criteria. These had a median age of 72 years (IQR: 64-79), 47% were female, and the median follow-up time was 4.1 years (2.0-6.4). During follow-up, 248 (3.9%) progressed to MM, 77 (1.2%) to lymphoma, and 19 (0.3%) to AL amyloidosis. At MGUS diagnosis, the FLC ratio was abnormal in 2,556 (40%) and 1,223 (19%) individuals according to old and revised intervals, respectively.
The FLC ratio of 1,333 (21%) individuals reclassified from abnormal to normal, when changing from the old to revised reference interval. When comparing these to the individuals with normal FLC ratio), we found no difference in the risk of progression to MM (HR 1.04, 95%CI: 0.73-1.49) or to MM, lymphoma, or AL amyloidosis combined (HR 1.17, 95%CI: 0.87-1.58). By contrast, the 1,223 (19%) individuals with abnormal FLC ratio according to the revised reference intervals had an increased risk of progression to MM (HR 2.81, 95%CI: 2.14-3.70) and the grouped diagnoses (HR 2.64, 95%CI: 2.08-3.35).
Using the revised reference intervals, the number of cases classified as low-risk MGUS increased from 2488 to 3194 (1.3-fold increase). Still, the 5-year cumulative incidence of MM progression for low-risk MGUS was similar when using the old and revised reference intervals (3.7% and 3.6%, respectively). The 765 individuals who were reclassified to low-risk from a higher risk group did not have a higher MM progression risk compared to individuals who classified as low-risk using both reference intervals (HR 0.91, 95% CI: 0.56-1.49).
Conclusion
This population-based study identified fewer MGUS individuals with abnormal FLC and FLC ratio with the revised iStopMM reference intervals compared to the old. Importantly, for the cases where FLC ratio was reclassified from abnormal to normal, the risk of progression did not differ from those with normal FLC ratios. Using the revised reference intervals, more MGUS individuals were categorized as low-risk without altering the risk of MM progression. The findings validate the revised reference interval for FLC and demonstrate that they can improve the prognostic value of FLC testing and optimize care to individuals with MGUS.