Revised definition of LC-MGUS with FLC measurements stratified by age: The iStopMM study

02 Feb 2024

Light chain monoclonal gammopathy of undetermined significance (LC-MGUS) requires lifelong monitoring, which poses substantial psychological and financial burdens on the patients.1 An accurate diagnosis can mitigate these burdens in patients who may not progress to lymphoproliferative disorders.1 Serum free light-chain (FLC) measurements play an important role in detecting, prognosticating, and monitoring lymphoproliferative disorders.1 They consist of kappa FLC, lambda FLC, and the calculated FLC ratio (kappa/lambda).1 LC-MGUS is defined by an abnormal FLC ratio with elevated levels of the involved FLC, but with no end-organ damage attributed to the plasma cell proliferative disorder or any evidence of monoclonal heavy chains.1 The existing reference intervals for serum kappa FLC, lambda FLC, and the FLC ratio, were previously defined based on a small cohort (n=282) which may not accurately represent the FLC distribution in the general population.1

The Iceland screens, treats, or prevents multiple myeloma (iStopMM) study, had demonstrated that FLC measurements may be affected by kidney function and proposed new reference intervals for patients with an estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2.1 The iStopMM study further sought to assess the FLC distribution in individuals with preserved kidney function (>60mL/min/1.73m2), with the goal of revising FLC reference intervals and proposing a new definition of LC-MGUS.1 In the ASH Annual Meeting & Exposition 2023, Thorir Long from Skåne University Hospital, Lund, Sweden, shared the findings from the analysis.

In this study, around 51% of individuals (n=75,422) aged ≥40 years in the Icelandic population were screened for MGUS by serum protein electrophoresis (SPEP), immunofixation (IFE), and the FLC Freelite assay.1 Patients with positive IFE, eGFR <60mL/min/1.73m2, missing creatine measurements, or had known lymphoproliferative disorders were excluded from the study.1 The 0.5th and 99.5th percentiles of the study population were identified and the central 99th percentile was used to determine the reference intervals for the kappa FLC, lambda FLC, and the FLC ratio.1 The same was done in subgroups stratified by age, sex and eGFR.1

The median value of kappa FLC and lambda FLC were was 14.3mg/L (interquartile range [IQR]: 11.6-17.8mg/L) and 14.2mg/L (IQR: 11.6-17.5) respectively with a median FLC ratio of 1.02 (IQR: 0.85-1.21).1 A strong correlation was observed between age with serum kappa FLC (Spearman’s ρ=0.27; p<0.001) and lambda FLC (Spearman’s ρ=0.14; p<0.001) as well as the FLC ratio (Spearman’s ρ=0.16; p<0.001), thus new reference intervals partitioned by age <70 years and 70 years were established.1 Using these revised reference intervals, individuals with eGFR >60mL/min/1.73m2 below the age of 70 are diagnosed with LC-MGUS if the FLC ratio is <0.44 or >2.16, where the kappa FLC is >39.0mg/L or lambda FLC >36.7mg/L.1 Similarly, for individuals with eGFR >60mL/min/1.73m2 aged 70 years or above, a diagnosis of LC-MGUS is made if the FLC ratio is <0.46 or >2.59 with a kappa FLC >55.8mg/L or lambda FLC >48.0mg/L.1

To facilitate the diagnosis of LC-MGUS, researchers of the iStopMM study have also created an online calculator which helps determine if a patient has LC-MGUS based on their serum kappa FLC, lambda FLC, age, and eGFR values.1 Using the revised standards, the prevalence of LC-MGUS in the iStopMM cohort was 0.26% (95% CI: 0.23-0.30) compared to 1.54% (95% CI: 1.46-1.63) based on the standard definition.1 Under the revised definition, there was an 83% decrease in the number of individuals who met the diagnostic criteria for LC-MGUS, none of which had progressed to a lymphoproliferative disorder after follow-up over a median time of 3.5 years.1

In summary, novel reference intervals for serum free kappa FLC, lambda FLC, and the FLC ratio stratified for individuals aged <70 years and 70 years with preserved kidney function have been proposed.1 Based on the results of the current study and previous findings in individuals with impaired kidney function, a new definition of LC-MGUS has been proposed which may mitigate the rate of false diagnosis by more than 80%. As such, the unnecessary psychological and financial burden driven by clinical evaluation and lifelong monitoring of these individuals may be reduced.1

Get access to our exclusive articles.