Plasma cell proliferative disorders are characterized by a clonal expansion of plasma cells (PCs) which usually secrete a monoclonal immunoglobulin (M-protein). If there is clinical suspicion of a plasma cell proliferative disorder, the patient’s serum and urine is typically tested for the presence of an M-protein. M-proteins are detected using a combination of protein gel electrophoresis (PEL), immunofixation (IFE) and/or quantitative free light chain (FLC) immunoassays. Generally if M-protein and/or signs or symptoms of multiple myeloma (MM) are present, a bone marrow biopsy is performed to confirm the presence of myeloma cells in the bone marrow (BM). If MM is diagnosed, treatment may be initiated.
Historically, the objective of MM treatment has been to achieve disease reduction and stabilization. As therapies for MM have improved, the use of PEL to define disease reduction and complete response has been transcended by more sensitive assays including IFE, the FLC assay, and multiparametric flow cytometry (MFC) to detect clonal plasma BM cells. Despite these newer methods, many of those with undetectable disease still relapse – which has been proven to be partially due to the presence of residual disease. To overcome this limitation, more sensitive methods such as Allele Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) as well as high sensitivity MFC have been used with some success to measure MRD(1). In current formats these methodologies require BM sampling which is invasive, costly and can miss patchy marrow infiltration and extramedullary disease, often characteristics of MM. There are several compelling reasons why improving the current approach of monitoring MRD and developing more sensitive serum based assays to detect M-proteins would be preferable. Serum-based testing is non-invasive, is free from much of the sampling bias observed with BM sampling, and has a low cost burden
Advances in the field of mass spectrometry (MS) have made it possible to detect intact proteins in complex matrices with improved sensitivity compared to traditional gel electrophoresis. These mass spectrometers have recently found a role in clinical diagnostics measuring intact proteins such as IGF1 and hemoglobin. This was recently extended to intact immunoglobulins light chains where the mass can be identified with high accuracy(2). Building on this work, we recently presented work at the 2014 annual AACC meeting demonstrating that in patients in stringent complete response (negative by PEL and IFE, normal FLC kappa/lambda ratio, absence of clonal plasma cells in BM by MFC) residual disease could be detected in some patients using an MS-based method termed, monoclonal immunoglobulin Rapid Accurate Mass Measurement (miRAMM). This method uses microflow liquid chromatography and time of flight MS to identify the accurate molecular mass of monoclonal light chains (mLC). The detection of residual disease in these patients illustrates the improved sensitivity of this serum method. Whether residual mLCs detected by miRAMM will be a reliable predictor of early relapse and overall survival remains to be determined. While it is easy to see miRAMM having immediate application in clarifying ambiguous gel interpretations and personalizing disease monitoring using accurate mass measurements, its use as a standalone clinical MRD test will require longer outcome-based multi-centered studies. Regardless of these unknowns, the discovery of residual monoclonal light chains in patients in sCR suggests that miRAMM has the potential to change how multiple myeloma and related disorders will be diagnosed and monitored in the future.
- Kumar SK, Rajkumar SV. The current status of minimal residual disease assessment in myeloma. Leukemia 2014;28:239-40.
- Barnidge DR, Dasari S, Botz CM, Murray DH, Snyder MR, Katzmann JA, et al. Using mass spectrometry to monitor monoclonal immunoglobulins in patients with a monoclonal gammopathy. J Proteome Res 2014;13:1419-27.