Iceland’s iStopMM Study Revises Definition of Free Light Chains in Serum and Light Chain Monoclonal Gammopathy of Undetermined Significance (MGUS) 

Dr. Thorir Einarsson Long discusses an aspect of the iStopMM study, a large population-based trial, that focused on light chain monoclonal gammopathy of undetermined significance (MGUS), and how serum free light chain (FLC) measurement — consisting of serum free kappa, serum free lambda, and a calculated FLC ratio (kappa/lambda) — plays a pivotal role in the diagnosis, risk stratification, and management of plasma cell disorders. 

Abstract title:

Revised Definition of Free Light Chains in Serum and Light Chain Monoclonal Gammopathy of Undetermined Significance: Results of the iStopMM Study Presented at ASH 2023   

What is the purpose of this trial?  

This trial aims to enhance the understanding of light chain monoclonal gammopathy of undetermined significance (LC-MGUS) by refining the measurement of serum free light chains (FLC) in individuals. Serum FLC, encompassing free kappa, free lambda, and the calculated FLC ratio (kappa/lambda), serves a critical role in diagnosing, assessing risk, and managing plasma cell disorders. LC-MGUS is characterized by an abnormal FLC ratio, with elevated involved FLC, and an absence of heavy chain M protein or organ damage due to the plasma cell disorder. 

Previous reference intervals for serum kappa (3.3–19.4 mg/L) and lambda (5.7–26.3 mg/L) FLC, as well as FLC ratio (0.26–1.65), were established in a limited cohort of healthy individuals. However, these intervals lacked accuracy for those with impaired kidney function. This trial addresses this limitation through a comprehensive, large-scale study, particularly focusing on individuals with an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73m². The results of this study are anticipated to redefine reference intervals, providing more accurate benchmarks tailored to patients with chronic kidney disease, thereby improving the precision of diagnosis and management in plasma cell disorders. 

In this video: 

Thorir Einarsson Long, MD, PhD, (University of Iceland — Reykjavík, Iceland) discusses how the iStopMM trial, a large population-based study, focused on individuals with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. Results of the study led to redefined reference intervals for patients with chronic kidney disease.   

Conclusion: 

Based on prospective screening of more than 40,000 individuals and after 3.5 years of follow-up, the iStopMM study showed that standard reference intervals for serum FLC and FLC ratio appear inaccurate for persons with preserved kidney function. Researchers proposed “a revision of the reference intervals for serum FLC and FLC ratio, and a new definition of LC MGUS (Figure). Implementation of new reference intervals will decrease the rate of false positive diagnosis of LC-MGUS in individuals with preserved kidney function by more than 80%. This, in turn, will reduce the unnecessary psychological and financial burden driven by clinical evaluation and lifelong monitoring of these individuals.” 

Trial information: Abstract #535 

Doctor bio: 

Thorir Einarsson Long, MD, PhD, is currently working at the University of Iceland, studying kidney disease and myeloma. He is on the team at the IMF's Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM) study.