Serum Free Light Chain (FLC) Analysis: A Guiding Light in Monoclonal Gammopathy Management.

BACKGROUND: Monoclonal free light chains (FLCs) were first reported by Dr. Henry Bence Jones over 150 years ago in the urine of patients with multiple myeloma. Now established as important tumor markers, they aid not only in the diagnosis of monoclonal gammopathies but also in their clinical management by indicating the response to treatment and persistence of residual disease. CONTENT: A particular focus over the past 15 years has been on the replacement of urine with serum analysis for monoclonal FLC measurement. Because of the limited sensitivity and practical constraints of urine assessment, a combination of serum electrophoresis and serum FLC analysis has been adopted by many laboratories as a first-line screen for patients with a suspected monoclonal gammopathy. Early myeloma diagnosis may translate into improved clinical outcomes, and a new study, iStopMM, is underway to ascertain the benefit of population-wide screening protocols for early detection of the disease in its asymptomatic phase. Laboratory algorithms that include measurement of both monoclonal intact immunoglobulins and FLCs are important for assessing possible changes in myelomic clones in response to treatment, and recent data from Intergroupe Francophone du Myelome trials validate serum FLC as a clinically relevant disease biomarker. Whether sensitive serum techniques such as FLC analysis can be used to guide the use of more invasive procedures for detection of minimal residual disease is the subject of emerging studies. SUMMARY: Here we review the current and evolving utility of serum FLC measurements for the management of patients with monoclonal gammopathies.

Analytical issues of serum free light chain assays and the relative performance of polyclonal and monoclonal based reagents.

Serum free light chain (FLC) assays have been incorporated into routine clinical practice and their use is recommended in international guidelines for the management of monoclonal gammopathies. Given that FLCs are not simple analytes, laboratories should be aware of potential analytical issues when using FLC assays, including antigen excess, lot-to-lot variation and non-linearity. Whilst manufacturers of monoclonal antibody-based assays claim that they overcome such issues, the evidence available to date does not support this. Here we review and compare the technical performance of both polyclonal and monoclonal antibody-based assays. The evidence suggests that the Freelite assay, based on polyclonal antisera, gives a broader recognition of monoclonal FLCs than the N Latex assay, based on monoclonal antisera, and despite being cited as a technical concern, we show that lot-to-lot variation of the Freelite assay is good. Both non-linearity and antigen excess are characteristic of FLC analysis and laboratories should be aware of these phenomena regardless of the assay system they use. Comparisons of the absolute values of sFLCs determined using monoclonal and polyclonal antibody-based assays show poor quantitative agreement and, because current guidelines have been established using the polyclonal antibody-based Freelite assay, it should not be assumed that assays utilizing monoclonal antibodies will give compliance with these guidelines.

Quantification of ß-region IgA monoclonal proteins - should we include immunochemical Hevylite® measurements? Point.

Accurate measurement of IgA monoclonal proteins presents a significant challenge to laboratory staff. IgA heavy/light chain (Hevylite, HLC) analysis is an alternative methodology for monoclonal protein assessment, giving an independent measure of IgAκ and IgAλ concentrations. Clonality is assessed by calculating the ratio of involved immunoglobulin to background uninvolved immunoglobulin concentrations (e.g. IgAκ/IgAλ in an IgAκ patient). Here we discuss the challenges faced by the laboratory in IgA monoclonal protein assessment, and compare the performance of Hevylite assays with electrophoresis and total IgA results. We present data which validates the use of Hevylite for response assessment: in most cases, Hevylite provides comparable response assignment to that provided by serum protein electrophoresis (SPE) and total IgA; in other cases Hevylite provides additional information, such as detection of residual disease or relapse.

Serum free light chains in clinical laboratory diagnostics.

Monoclonal free light chains (FLCs) are important disease biomarkers in patients with plasma cell-proliferative disorders. The increasing evidence for clonal diversity and evolution in multiple myeloma highlights the importance of laboratory algorithms that measure both intact immunoglobulins and monoclonal FLCs, at diagnosis and when monitoring response to treatment. A particular focus in the field has been on the utility of serum FLC (sFLC) assays to replace urine electrophoresis for monoclonal FLC measurement. Due to the limited sensitivity and practical constraints of urine analysis, a serum-based algorithm of SPE and sFLC has been adopted by many laboratories as a first line screen in patients with suspected monoclonal gammopathies. This review will discuss the data supporting the use of this simple serum-based algorithm at initial diagnosis, including its utility for the rapid identification of monoclonal FLC in the setting of unexplained acute kidney injury, and provide a comprehensive review of the diagnostic sensitivity of sFLC in patients with multiple myeloma, AL amyloidosis and light chain deposition disease.