Extended Use of Serum Free Light Chain as a Biomarker in Lymphoproliferative Disorders

A Comprehensive Review

Khalil M. Charafeddine, MD; Mark N. Jabbour, MD; Raneem H. Kadi; Rose T. Daher, PhD


Am J Clin Pathol. 2012;137(6):890-897. 

In This Article

Abstract and Introduction


Serum free light chain (sFLC) assays were shown to improve detection, management, and prognostication in plasma cell disorders. Recently, sFLC assays improved detection of M proteins when combined with standard methods of protein electrophoresis/immunofixation in patients with non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL). Incidence of abnormal sFLC ratio (sFLCr) varied from 0% to 36% and 29.7% to 59% in NHL and CLL, respectively. Increased sFLC levels or abnormal sFLCr predict shorter overall survival in early-stage CLL. Furthermore, abnormal sFLCr correlated with advanced disease stage and poorer outcome. In diffuse large B-cell lymphomas, increased sFLC was demonstrated as an independent, adverse prognostic factor for overall/event-free survival. Moreover, abnormal sFLCr can be a diagnostic tool in central nervous system lymphomas. Finally, the quantitative FLC assay has the potential to become a new, easily measured biomarker for predicting prognosis and enhanced detection in NHL/CLL. It may be used serially at follow-up evaluations to provide clues to relapse.


Normal immunoglobulin secretion is a function of terminally differentiated B cells that proceeds from heavy- and light-chain gene assembly with V(D)J recombination in early bone marrow precursor cells to somatic hypermutation in the germinal centers of secondary lymphatic organs. The result is terminally differentiated B cells that are released into the periphery as plasma cells or long-lived memory B cells with the capacity to produce antibodies with high affinity for the immunizing antigen composed of 2 heavy and 2 light chains.

The repertoire of tests used to evaluate and quantify the monoclonal immunoglobulin (Ig) protein (M protein) that indicates the presence of a monotypic population of B cells in the marrow or nodal tissue includes serum and urine protein electrophoresis (SPEP and UPEP) and immunofixation electrophoresis (IFE). Nephelometric measurement of serum Igs can also be used; however, measurement of the M-protein peak is the best method for quantitation of the M spike.[1] Around 3% of multiple myeloma (MM) and most patients with amyloidosis are of nonsecretory types. Therefore, non-secretory myeloma and light chain diseases are difficult to diagnose and monitor during and after treatment with these aforementioned methods.[2,3] With the emergence of immunoassays specific for Ig free light chains (FLCs) that bind to the hidden area of the light chain in an intact Ig model and do not recognize κ and λ bound to heavy chain, it has become clear that serum FLC (sFLC) testing is more sensitive than protein electrophoresis (PEL) and IFE for detecting FLCs. Immunofixation can detect κ and λ FLCs at a minimum concentration of 100 to 150 mg/L, whereas sFLC assay has a detection limit of 3 to 4 mg/L. The sFLC concentrations have also been shown to correlate with disease activity.[4] These sensitive sFLC assays may now allow detection of M proteins produced by other B-cell malignancies, which were only occasionally positive on PEL and IFE. Currently, an abnormal sFLC ratio (sFLCr) is known to play a role as a prognostic factor in Waldenström macroglobulinemia, MM, and AL amyloidosis.[5–7] Moreover, an abnormal sFLCr is considered a risk factor for progression of monoclonal gammopathy of unknown significance (MGUS), solitary plasmacytoma, and smoldering multiple myeloma into MM.[8–12] Although sFLC testing has now become a routine test for patients with MGUS, smoldering MM, MM, and AL amyloidosis,[13] its application has been limited in conditions such as B-cell non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL).[14] Data presented in this review were selected after an extensive and comprehensive search in the English literature through Medline and PubMed. All relevant references were included. The main search terms used included serum free light chain, free light chain ratio, lymphoproliferative disorder(s), non-Hodgkin lymphoma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, central nervous system lymphoma, multiple myeloma, monoclonal gammopathy of unknown significance, prognostic factor, and survival. Different keywords were merged using "OR" or "AND" operators. Because of the scarcity of literature related to this topic, the only search limit applied was to articles about humans. The final articles were screened by 2 of us (K.M.C. and R.T.D.). Because all articles and abstracts obtained were included in this review, no selection bias should occur. The aim of this review is to highlight the importance of sFLC and sFLCr as prognostic factors and indicators of progression in NHL and specifically in CLL diseases similar to its importance in plasma cell dyscrasia.