Correlation of Serum Free Light Chains and Bone Marrow Plasma Cell Infiltration in Multiple Myeloma.

Abstract

Diagnostic criteria for multiple myeloma include abnormal plasma cell infiltration of the bone marrow plus the presence of monoclonal immunoglobulin in the serum and/or monoclonal free light chains in the urine. However, recent studies have indicated that measurement of free light chains in the serum (sFLC) is more sensitive than urine assays. Also, because of the slow clearance of IgG from serum (half-life ~20 days compared with 2–6 hours for sFLC) intact immunoglobulin assays can be slow to reflect the full extent of response to treatment. The aim of this study was to compare the relative sensitivity and specificity of serum free light chain (sFLC) measurement, urine free light chain measurement (uFLC) and serum immunofixation (sIFE) with bone marrow analysis for assessment of myeloma. All 45 patients studied were enrolled in the UK MRC Myeloma VII trial and 75 serum samples were selected for sFLC measurement and sIFE. The sera had been collected at various times before, during and after treatment but all within 4 days of a bone marrow assessment and uFLC measurement (by radial immunodiffusion assay). sFLC results were classified as abnormal if the kappa/lambda ratio was outside the normal range and for uFLC, if there was >40mg/L. The bone marrow assessment was called abnormal if 5% or greater plasma cell infiltration was recorded in aspirate or trephine, in accordance with the EBMT criteria. The results of the comparisons are summarised in the table.Summary of paraprotein assaysBone MarrowNormalAbnormalSerum Free Light ChainsNormal194Abnormal547Urine Free Light ChainsNormal2121Abnormal330Serum ImmunofixationNormal105Abnormal1446Of the three paraprotein assays, sFLC had the highest concordance with bone marrow biopsy. Compared with the bone marrow assessment, the relative sensitivity and specificity of the sFLC assays was 92% and 79% respectively. For uFLC the values were 59% and 88%, respectively and for sIFE, 90% and 42% respectively. Of the 5 sera abnormal by the sFLC assays but with concurrent normal bone marrow results, all were abnormal by sIFE. Of the 4 patients with normal sFLC results but abnormal marrows, 3 were sIFE positive and of the 5 with negative sIFE results but abnormal marrows, 4 had abnormal sFLC ratios. Only 1 patient had an abnormal marrow with normal sFLC and sIFE results. In this comparison sFLC measurement showed a good degree of correlation with bone marrow assessments of myeloma, while uFLC assays were considerably less sensitive. Both sFLC and sIFE assays appeared to identify disease in 5 patients who had normal bone marrow assessments. This was presumably because the serum assays sample monoclonal protein produced throughout the body while distribution of the disease in the bone marrow is occasionally “patchy”. The sIFE results were positive in a much higher number (14) of bone marrow-negative patients. The 9 “extra” positives, which had normal bone marrow results and free light chain ratios, might result from a greater sensitivity for detecting tumours producing intact immunoglobulin with low levels of free light chains. Some of the 9 subsequently became sIFE negative so the slow clearance of monoclonal intact immunoglobulin is an alternative explanation for the discordant results. This could not be proven, however, as all patients had some form of treatment in the intervening period.