Clinical and preclinical validation of the serum free light chain assay: identification of the critical difference for optimized clinical use

Objectives The use of the assay for the measurements of free light chains in serum (sFLCs) is increasing. However, there are technical limitations that potentially affect the use in serial measurements. We need further knowledge on the standards of analytical precision, the utility of conventional population-based reference values and the critical difference (CD) between serial results required for significance. To answer these questions, the biological variation must be known. Methods We determined the biological variation in healthy individuals and patients with plasma cell dyscrasia (PCD). We assessed the imprecision of the analysis in use from FreeLite (TM) We determined the reference interval (RI) in 170 healthy individuals. Results The biological variation is identical for healthy individuals and patients with PCD. The imprecision of the sFLC analysis cannot fulfil the desirable performance standards for a laboratory test, but are within the manufacturer's +/- 20% variation for quality control samples. RI showed a significant increase for ? FLC and ?/? ratio with age, but not for ?. Critical difference was calculated to be 24% and 23% for ? and ?, respectively. Conclusions We suggest the use of an age-dependent RI. When monitoring patients with PCD, their own former results are the best reference, and knowledge on CD is a valuable tool, which we describe for the first time. Also, it challenges the recently proposed International Myeloma Working Group paraprotein relapse criteria, recommending an increase of more than 25% in the involved FLC to indicate the need for initiation of retreatment. We recommend revision of this criterion.