Serum free light chain measurements move to center stage.

For more than 150 years, the presence of Bence Jones protein [immunoglobulin free light chains (FLCs)] in the urine has been an important diagnostic marker for multiple myeloma. Indeed, it was the first cancer test, and 100 years before any others (1 ). Over the last few years, however, interest in FLCs has undergone a renaissance. Development of serum tests for free and free has opened the door to new applications and increased their clinical importance (2 ). By way of comparison, the management of diabetes mellitus was hugely improved when blood replaced urine for glucose analysis. The report by Katzmann et al. (3 ) in this issue of Clinical Chemistry adds valuable confirmatory data on serum FLC testing. It is the first report of the assays being used in routine clinics with analysis of results on 1020 samples. As the authors point out, the performance of the tests has matched up to the retrospective studies that have been published previously. From a physiologic viewpoint, blood tests for small proteins have clear advantages over urine tests. Serum FLCs are cleared rapidly through the renal glomeruli with a serum half-life of 2–6 h and are then metabolized in the proximal tubules of the nephrons. Under ordinary circumstances, little protein escapes to the urine (4 ), and serum FLC concentrations have to increase manyfold before the absorption mechanisms are overwhelmed. This makes urinalysis a fickle witness to changing FLC production. Conversion to a serum test provides clarity in assessing disease processes that were previously hidden from view. Serum concentrations of FLCs are dependent on the balance between production (by plasma cells and their progenitors) and renal clearance. When there is increased polyclonal immunoglobulin production and/or renal impairment, both and FLC concentrations can increase 10to 20-fold. However, the relative concentration of to , i.e., the / ratio, remains unchanged. In contrast, tumors produce a monoclonal excess of only one of the light chains, often with bone marrow suppression of the other light chain, so that / ratios become highly abnormal. Accurate measurement of / ratios underpins the utility of the serum FLC immunoassays and provides a numerical indicator of clonality (5 ). Urine / ratios are not as dependable because the nontumor light chain production is too low to pass consistently through the nephrons. Electrophoretic tests are used only to quantify the monoclonal light chain peak because they are not sensitive enough to identify the nontumor FLC concentrations. Early clinical studies with serum FLC tests were in patients with Bence Jones (light chain) multiple myeloma. In two studies, on 270 sera taken at the time of clinical presentation, highly abnormal serum FLC concentrations were found in every case (6, 7 ). Furthermore, during chemotherapy, urine tests frequently normalized, whereas serum tests remained abnormal, indicating their increased sensitivity for residual disease. In this patient group, urinalysis can now be replaced by serum FLC tests. This is particularly helpful for frail, elderly patients because 24-h urine samples are difficult to collect and results may be unreliable (8 ). Of patients with multiple myeloma, 3–4% have socalled nonsecretory disease. By definition, these patients have no monoclonal proteins by serum and urine electrophoretic tests. Nevertheless, in a study by Drayson et al. (9 ), serum FLC tests identified monoclonal proteins in 70% of 28 patients. The current study by Katzmann et al. (3 ) found that all five patients with nonsecretory myeloma had abnormal FLC concentrations. It is apparent that these patients’ tumor cells produce small amounts of monoclonal protein. Their serum FLC concentrations are below the detection limits of serum electrophoretic tests and below the threshold for clearance into the urine. Importantly, these patients can now be closely monitored by serum FLC tests rather than repeated bone marrow biopsies or whole-body scans. Approximately 20% of all patients with myeloma have light chain or nonsecretory disease. Among the remaining patients who produce intact monoclonal immunoglobulins, FLCs are abnormal in 96% at disease presentation (10 ). Interestingly, the serum concentrations of FLCs and intact monoclonal immunoglobulins are not correlated (R 0.02). Monoclonal serum FLCs are, therefore, independent markers of the disease process. This is of potential clinical use when the tumor produces large amounts of FLCs and small amounts of intact monoclonal immunoglobulins. Patients who are in apparent remission, as judged by study of their intact monoclonal immunoglobulins, may still have monoclonal FLCs, indicating residual disease. Using a similar argument, when these patients relapse, FLC concentrations may increase first. FLC “breakthrough” is thought to occur in 2–5% of patients who relapse after modern, intensive treatment. An additional feature of serum FLCs is that, in contrast to intact immunoglobulin molecules, they are potentially nephrotoxic. In many patients with intact monoclonal immunoglobulins, the serum FLC concentrations are 1000 mg/L (50–100 times the upper limit of the reference interval). This is characteristic of patients with IgD multiple myeloma, but is also apparent in 5–10% of IgGand IgA-producing patients. The FLC assays now allow assessment of the prerenal load of monoclonal light chains. There is early evidence that in some patients, treatment should be aimed at normalizing serum FLC concentrations to prevent renal damage (Nowrousian MR, et al. Using serum free light chain assays in the myeloma clinic, submitted for publication). One particularly interesting aspect of serum FLCs involves their short half-lives in the blood: 2–3 h for , and 5–6 h for . This is 150 times shorter than the 21-day half-life of IgG molecules. Hence, responses to treatment are seen in “real time”. This is apparent from the good Editorials