iStopMM study: A revised definition for LC MGUS in patients with preserved kidney function

Light-chain monoclonal gammopathy of undetermined significance (LC MGUS) is a form of MGUS characterized by an abnormal free light-chain (FLC) ratio with elevated serum free kappa and lambda light chains. The current definition for LC MGUS is based on a small cohort (n = 282) of healthy individuals. It has since been developed for individuals with impaired kidney function, but not those with preserved kidney function.¹

During the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, Einarsson Long presented results from the iStopMM study (NCT03327597), highlighting a novel definition for LC MGUS based on serum FLC measurements in individuals with normal kidney function (estimated glomerular filtration rate ≥60 mL/min/1.73 m²).

Design¹

The overall trial design of the iStopMM study has been previously outlined by the Multiple Myeloma Hub.

The standard definition for LC MGUS in patients with preserved kidney function is:

• serum kappa; 3.3–19.4 mg/L;
• serum lambda; 5.7–26.3 mg/L; and
• FLC ratio; 0.26–1.65.

This analysis aimed to redefine the reference intervals for individuals with preserved kidney function, to limit overdiagnosis of LC MGUS. Overall,

• 75,422 individuals from the total iStopMM population aged ≥40 were screened for LC MGUS using serum protein electrophoresis, immunofixation, and serum FLC assay;

• 41,882 individuals who had normal kidney function were screened for FLC reference intervals; and
• two-thirds of MGUS cases were randomized for follow-up.

Results¹

• A correlation was observed between increasing age and serum kappa FLC (p = 0.27; p < 0.001), lambda FLC (p = 0.14; p < 0.001), and FLC ratio (p = 0.16; p < 0.001).

• A revised set of reference values was recommended for individuals with normal kidney function (Table 1).

Table 1. Revised intervals by age*

FLC, free light chain. *Adapted from Einarsson Long.1
Reference intervals, mg/L (unless otherwise specified)	Age <70 years (n = 33,181)	Age >70 years (n = 8,701)
Kappa	6.3–39.0	7.0–55.8
Lambda	5.9–36.7	6.4–48.0
FLC, ratio	0.44–2.16	0.46–2.59

• Prevalence of LC MGUS based on the standard definition was 1.54% (95% confidence interval [CI], 1.46–1.63) compared with 0.26% (95% CI, 0.23–0.30) using the iStopMM criteria;
• this equates to an 83% decrease in LC MGUS diagnosis with the novel criteria; and
• individuals who met the standard criteria for LC MGUS but not the revised definition showed no progression within a 3.5-year follow-up period.

An outline of the revised definition for LC MGUS is shown in Figure 1.

eGFR, estimated glomerular filtration rate; FLC, free-light chain; LC MGUS, light-chain monoclonal gammopathy of undetermined significance.
*Adapted from Einarsson Long.¹

Conclusion

Previously, the standard reference intervals for LC MGUS diagnosis were based on a small cohort of patients and lead to inaccurate thresholds, especially for younger individuals. This revised definition of LC MGUS, based on the iStopMM study, demonstrated significantly lower rates of false positive diagnoses, which could reduce unnecessary health anxiety in patients and aid in the provision of healthcare resources.