A monoclonal gammopathy precedes multiple myeloma in most patients

Abstract

Preexisting plasma cell disorders, monoclonal gammopathy of undetermined significance, or smoldering myeloma are present in at least one-third of multiple myeloma patients. However, the proportion of patients with a preexisting plasma cell disorder has never been determined by laboratory testing on prediagnostic sera. We cross-referenced our autologous stem cell transplantation database with the Department of Defense Serum Repository. Serum protein electrophoresis, immunofixation electrophoresis, and serum free light-chain analysis were performed on all sera collected 2 or more years before diagnosis to detect a monoclonal gammopathy (M-Ig). In 30 of 90 patients, 110 prediagnostic samples were available from 2.2 to 15.3 years before diagnosis. An M-Ig was detected initially in 27 of 30 patients (90%, 95% confidence interval, 74%-97%); by serum protein electrophoresis and/or immunofixation electrophoresis in 21 patients (77.8%), and only by serum free light-chain analysis in 6 patients (22.2%). Four patients had only one positive sample within 4 years before diagnosis, with all preceding sera negative. All 4 patients with light-chain/nonsecretory myeloma evolved from a light-chain M-Ig. A preexisting M-Ig is present in most multiple myeloma patients before diagnosis. Some patients progress rapidly through a premalignant phase. Light-chain detected M-Ig is a new entity that requires further study.

Figure 1

Serum results before the diagnosis of myeloma. Positive results are shown by ●, ■, ▲, ×, and +. Samples that were negative for all 3 tests (ie, no M-Ig present) are shown by ○. ● represents positive SPEP, IFE, and sFLC assay; ■, positive SPEP and immunofixation; ×, positive sFLC assay only; ▲, positive IFE only; and +, serum-free light assay and immunofixation. The color indicates the myeloma isotype: red represents IgG; green, light-chain/nonsecretory; and blue, IgD. Because the sFLC assay was not available at diagnosis, all patients are depicted with ● at the time of diagnosis for clarity.

Figure 2

Two patterns of changes in monoclonal immunoglobulin level during progression to myeloma. (A) The change in monoclonal immunoglobulin level before the diagnosis of myeloma in patients with a diagnostic monoclonal immunoglobulin greater than 3 g/dL. (B) The change in monoclonal immunoglobulin level before the diagnosis of myeloma in patients with a diagnostic monoclonal immunoglobulin less than 3 g/dL.

Figure 3

An increasingly abnormal serum-free light chain ratio may be a harbinger of symptomatic myeloma. The temporal changes in monoclonal immunoglobulin level and involved serum free light-chain ratio (iFLC) are shown for 6 patients with intact immunoglobulin myeloma (A-F) and 1 patient with light-chain myeloma (G). The M-Ig is plotted on the outside axis and the iFLC ratio on the inside axis. The iFLC ratio is expressed as λ/κ for patients with clonal λ MM. For the 1 patient with light-chain myeloma (G), the involved sFLC is plotted on the outside axis and the involved free light-chain ratio is plotted on the inside axis.