Light-chain MGUS defined as per the revised definition of the istopmm study: Experience from the university of calgary MGUS clinic

Abstract Background: Monoclonal Gammopathy of Undetermined significance (MGUS), the precursor of multiple myeloma (MM) and other lymphoproliferative disorders affects 4.2% of the general population over 50 years of age. A recent study (The Iceland Screens, Treats or Prevents Multiple Myeloma “iStopMM”) evaluated patients with Light chain- MGUS. LC-MGUS was defined as an FLC ratio outside the reference interval with an increase in the involved k or l FLC, without evidence of M protein on SPEP or IFE in the absence of myeloma defining events (Classic LC-MGUS definition). The standard FLC reference intervals (FLC ratio of 0.26-1.65; kFLC range 3.3-19.4 mg/L; and l FLC range, 5.6-26.3 mg/L) were used in cases with eGFR of 60 mL/min/1.73m2. Based on prospective screening of more than 75,000 individuals this group proposed a revision of the reference intervals for serum k FLC, l FLC, and FLC ratio, stratified by age, along with a new definition of LC-MGUS to significantly improve the diagnostic accuracy of this premalignant condition. In the new definition of LC-MGUS, the iStopMM report considered FLC ratio and kFLC and lFLC values based on age and eGFR cut-offs. In the current study, we aimed to describe the frequency of LC-MGUS based on the revised definition, as well as to assess clinical outcomes for patients deemed LC-MGUS with prior reference values. Methods: In 2014, we created a MGUS and MGCS (Monoclonal Gammopathy of Clinical Significance) clinic where patients with a suspected monoclonal gammopathy are assessed. This centralized clinic helped establish a formal evaluation of MGUS cases aimed at offering proper surveillance and investigations to patients with suspected clinically significant disorders. Since the inception of this clinic, patients have been assessed and monitored as per standard local and international guidelines. In the current study, we performed a retrospective chart review in all cases seen at our clinic from 01/2014 to 06/2025 and demographic variables were recorded. Patients with LC-MGUS as per the classical definition were evaluated and later the revised LC-MGUS criteria from the iStopMM study was applied. The primary objective of the study was to explore the clinically validation of the iStopMM criteria for the definition of LC-MGUS and compared with the classical definition. A p value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Progression-Free Survival (PFS) was defined as the time from treatment to disease progression or death, while overall survival (OS) was defined from the date of treatment to the date of death from any cause. All statistical analyses were performed by using the SPSS 24.0 software. Results A total of 457 patients with MGUS were evaluated in the study period. Median age was 68.9 years (range 18-95) and 268 were male (58.6%). From those, 103 were considered LC-MGUS based on the classical definition (22.5%). On these cases, 55 (53.4%) had an eGFR>60 mL/min/1.73m2, 19 (18.4%) (45-59 mL/min/1.73m2), 15 (14.6%) (30-44 mL/min/1.73m2) and 14 (13.6%) (<30 mL/min/1.73m2). After the new revised criteria was applied, LC-MGUS was considered present in only 20 cases (4.3%), representing a decrease of 81%. After a median follow up of 55 months, 18 patients in the LC-MGUS as per new criteria are alive. One patient defined as LC-MGUS using the new criteria has progressed from MGUS to SMM (Smouldering Multiple Myeloma) at 5 years from initial diagnosis without progression to symptomatic Multiple Myeloma. There has been no cases of progression to MM, Lymphoma or AL Amyloidosis in cases classified as LC-MGUS with the classic criteria only. Median OS has not been reached among patients classified with LC-MGUS based on the classic criteria and is similar to that seen for patients classified as LC-MGUS with the revised version as defined by the iStopMM group (p=0.2). Conclusion, Implementation of the new sFLC criteria defined as per the iStopMM group decreased the rate of false positive diagnosis of LC-MGUS, particularly for cases with preserved renal function (eGFR>60 mL/min/1.73m2).

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