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Serum Free Light Chains

Traditional methods for detection and quantitation of monoclonal proteins include urine and serum protein electrophoresis and immunofixation. For the past 20 years, electrophoresis of concentrated urine and immunofixation have been the tests of choice for detecting monoclonal free light chains in urine. Patients with light chain disease often demonstrate hypogammaglobulinemia in the serum with detectable monoclonal kappa or lambda light chains in the urine. Unfortunately, these methods are not very sensitive for detection of free light chains. FLCs must be elevated 20 to 200 times above normal levels to be detected by serum protein electrophoresis and 10 to15 times to be detected by immunofixation. An immunoassay for quantitation of serum free light chains has proven to be 3 orders of magnitude more sensitive than traditional methods. This assay measures only free light chains and not the light chains attached to intact immunoglobulin molecules. Numerous studies have demonstrated that addition of serum free light chain to routine serum protein electrophoresis improves the detection of clinically significant monoclonal gammopathies.

The serum FLC assay offers several clinical advantages. It can replace urine electrophoresis and immunofixation in the initial evaluation of patients suspected of having a monoclonal gammopathy. Studies from Mayo Medical Laboratories have demonstrated that 99.5% of cases of multiple myeloma can be detected by a combination of serum FLC analysis with serum protein electrophoresis and immunofixation (Katzman JA, et al. Clin Chem 2009;55:1517-22).  The International Myeloma Working Group has concluded that a combination of serum FLC, serum protein electrophoresis and serum immunofixation is sufficient to test for monoclonal gammopathies. They no longer recommend 24 hour urine protein electrophoresis or immunofixation for diagnosis, except for amyloidosis (Dispenzieri A, etal. Leukemia 2009;23:215-24). The international guidelines also recommend that serum FLCs be performed at the time of diagnosis to provide prognostic information for patients with multiple myeloma, MGUS, smoldering multiple myeloma, solitary plasmacytoma and amyloidosis.

The National Comprehensive Cancer Network (NCCN) also recommends including serum FLC in the standard diagnostic workup in newly diagnosed patients with plasma cell dyscrasias (Anderson KC. J Nat’l Compr Canc Netw 2011;9:1146-83).

The vast majority of patients who have monoclonal gammopathies detected in serum are eventually classified as MGUS, which is defined as a monoclonal gammopathy less than 3 g/dL, a bone marrow with less than 10% plasma cells and absence of related organ or tissue damage such as renal disease, anemia, and hypercalcemia.  Overall, individuals with MGUS have about a 1% per year chance of progressing to multiple myeloma or another B cell lymphoproliferative disorder. Quantitation of serum FLCs assists in stratifying the risk of progression. Lower risks of progression are associated with an M-protein less than 1.5 G/dl, IgG isotype and a normal serum FLC ?/? ratio.

Light chain myeloma accounts for approximately 20% of all cases of multiple myeloma. It is characterized by the presence of monoclonal FLC in the serum or urine, the absence of intact monoclonal immunoglobulins, presence of clonal plasma cells in the bone marrow and evidence of end organ damage. Screening with serum protein electrophoresis alone misses 40% of cases. Addition of serum FLC measurement detects >99% of cases.

Nonsecretory myeloma accounts for 1 to 5% of multiple myeloma cases and is characterized by the absence of monoclonal proteins in serum and urine by electrophoresis and immunofixation. It may result from synthesis of truncated immunoglobulin molecules or intracellular degradation. Serum FLC test is sensitive enough to detect monoclonal FLC in more than half of these cases. Addition of serum FLC tests allows for quicker diagnosis and facilitates therapeutic monitoring.

Primary systemic amyloidosis (AL amyloidosis) is caused by deposition of insoluble light chain fragments, usually lambda type, in organs such as the kidney and heart. Up to 20% of AL amyloidosis cases have no detectable monoclonal protein by serum or urine electrophoresis and immunofixation. In contrast, FLC assays detect monoclonal free light chains in 75 to 90% of cases. The International Working group recommends ordering serum FLC in addition to serum and urine electrophoresis.

Reference ranges are 3.30-19.40 mg/L for kappa free light chain, 5.71 to 26.30 mg/L for lambda light chain, and 0.26-1.65 for kappa to lambda ratio. Lower limit of detection is 1.50 mg/L for kappa and 3.00 mg/L for lambda light chains.

It is especially important to pay attention to the kappa to lambda ratio in the diagnosis of patients with plasma cell disorders. An abnormal kappa to lambda ratio suggests a clonal expansion of plasma cells. On the other hand, a normal kappa to lambda ratio in the presence of elevated levels of kappa and lambda light chain concentrations, suggests renal impairment, polyclonal expansion of plasma cells or rarely a biclonal gammopathy with different light chain types. Caution should also be exercised in interpreting borderline abnormal kappa to lambda ratios because they may occasionally occur in these same conditions.

Specimen requirement is a red top tube of blood. Moderate to marked lipemia may interfere with the ability to perform testing.

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