Serum-free light-chain assay: clinical utility and limitations

Abstract

In the last decade, the introduction of the serum-free light-chain (sFLC) assay has been an important advance in the diagnosis and management of plasma cell dyscrasias, particularly monoclonal light-chain diseases. The immunoassay was developed to detect free light chains in serum by using anti-FLC antibodies which specifically recognised epitopes on light chains that were 'hidden' in intact immunoglobulins. Since its introduction in 2001, there have been several publications in the English language literature discussing the clinical utility as well as analytical limitations of the sFLC assay. These studies have highlighted both positive and negative aspects of the assay particularly with regard to its sensitivity and specificity and the technical challenges that can affect its performance. The contribution and significance of the sFLC assay in the management of light-chain myeloma, primary amyloid light-chain (AL) amyloidosis and non-secretory myeloma are well recognised and will be addressed in this review. The aim of this article is to also review the published literature with a view to providing a clear understanding of its utility and limitations in the diagnosis, prognosis and monitoring of plasma dyscrasias including intact immunoglobulin multiple myeloma (MM) and monoclonal gammopathy of unknown significance (MGUS). The increasing interest in using this assay in other haematological conditions will also be briefly discussed.

Analytical Criticalities Associated to Different Immunological Methods for Serum Free Light Chain Detection in Plasma Cell Dyscrasias: A Description of Particular Clinical Cases

“…This implies that two FLC assays cannot be used interchangeably for the follow-up of patients affected by MG. Given the extreme structural heterogeneity of FLC in myeloma, it is possible that individual FLC may exhibit antigenic determinants which may, in turn, not be properly recognized by one of the antibody mixtures employed [20,26]. …”

“…The evaluation of these parameters are recommended for patient management, including screening, prognosis, therapy, and patient monitoring, as well as for the diagnosis and monitoring of all conditions where M-protein is barely detectable and hardly quantifiable [10,18,19,20]. The introduction of sFLC measurement has since then emphasized the crucial role of an altered κ/λ ratio (sFLC ratio >1.65 or <0.26) as a predictor of progression from MGUS to MM [10,15,17].…”

“…In such cases, FLC levels may decrease compared to previous immunoglobulin patterns. It is clear that sFLC quantification enables early detection of disease progression compared to SPE and immunofixation (IFE) [14,20]. …”

“…Comparative studies conducted in order to evaluate the concordance between the two assays have produced varied results [20,26,27]. It is therefore recommended that the same method be used, especially for monitoring therapy responses [28,29,30,31,32,33,34].…”

Serum Free Light Chain Assay and κ/λ Ratio: Performance in Patients With Monoclonal Gammopathy-High False Negative Rate for κ/λ Ratio

“…Even normally, light chains are produced in excess of heavy chains and a monoclonal lesion producing intact immunoglobulin also produces excess free light chains. In some cases, the immunoglobulin or light chain is not secreted or only poorly secreted, referred to as non-secretory or oligo-secretory myeloma [15, 16]. Malignant lesions of plasma cells may manifest as MM, or solitary lesions of malignant plasma cells in bone or extra-osseous sites, designated as plasmacytomas [17-19].…”