Use of nonclonal serum immunoglobulin free light chains to predict overall survival in the general population

Abstract

Objective: To determine whether the free light chain (FLC) assay provides prognostic information relevant to the general population.

Methods: After excluding persons with a known plasma cell disorder, we studied 15,859 Olmsted County, Minnesota, residents 50 years or older in whom unmasked data and samples for FLC testing were available. Baseline information was obtained between March 13, 1995, and November 21, 2003, and follow-up status and cause of death were identified through June 30, 2009. The κ and λ FLC sum (Σ FLC) was evaluated for its ability to predict overall survival. Specific causes of death were also investigated.

Results: In 158,003 person-years of follow-up, 4348 individuals died. A high Σ FLC was significantly predictive of worse overall survival; the risk ratio for death for those with the highest decile of Σ FLC (ie, ≥ 4.72 mg/dL) was 4.4 (95% confidence interval, 4.1-4.7) relative to the remaining study participants. Multivariate analyses demonstrated that this excess risk of death was independent of age, sex, and renal insufficiency, with a corrected risk ratio of 2.1 (95% confidence interval, 1.9-2.2). The increased mortality was not restricted to any particular cause of death because the observed-to-expected risk of death from most causes was significantly higher among those individuals with an antecedent Σ FLC of 4.72 mg/dL or higher, which is near the upper limit of normal for the test.

Conclusion: A nonclonal elevation of Σ FLC is a significant predictor of worse overall survival in the general population of persons without plasma cell disorders.

FIGURE 1

Relationship between the κ and λ free light chain sum (Σ FLC) and the free light chain ratio (rFLC). Most study participants had both normal Σ FLC and rFLC (section v, 86.3%). By definition of light chain monoclonal gammopathy of undetermined significance, no participant had both a high Σ FLC and an abnormal rFLC (low [section iii] or high [section ix]). The distribution of the remaining participants by section was as follows: i, 0.1%; ii, 0.4%; iv, 1.2%; vi, 11.2%; vii, 0.1%; and viii, 0.8%. Blue represents the reference range for Σ FLC (0.95-4.35 mg/dL), yellow represents the reference range for rFLC (0.26-1.65), and green represents those study participants in whom both the Σ FLC and rFLC were normal.

FIGURE 2

Risk of death by κ and λ free light chain sum (Σ FLC) decile. The higher the Σ FLC, the lower the overall survival from the time of sample ascertainment. A, All patients, crude data. B, A patients, corrected for age and creatinine level based on the overall distribution in the study.

FIGURE 3

Time to death as a function of cause of death and κ and λ free light chain sum (Σ FLC) decile. Time between sample ascertainment to death among 4348 dead Olmsted County residents by International Statistical Classification of Diseases, 10th Revision (ICD-10) chapter. Those with the highest Σ FLC deciles died sooner than those with lower (deciles 1-9) Σ FLC deciles. A, Circulatory. B, Neoplasms. C, Respiratory. D, Mental. E, Nervous system. F, Digestive. G, External causes. H, Endocrine. I, Genitourinary. J, Infectious. K, Musculoskeletal. Data for the chapters “ill-defined” and “external causes” are not shown because of small numbers and no significant differences between groups. The red bars represent the 25th, 50th, and 75th percentiles.