Clinical Information

Monoclonal gammopathy is a general term which includes a spectrum of diagnoses including malignancies of plasma cells or B cells (eg, multiple myeloma [MM], Waldenstrom macroglobulinemia, plasmacytoma, and B-cell lymphomas and leukemias), symptomatic disorders directly related to the M-protein (eg, immunoglobulin light chain [AL] amyloidosis, light chain deposition disease, cryoglobulinemia, monoclonal gammopathy of clinical significance [MGCS], monoclonal gammopathy of renal significance [MGRS], monoclonal gammopathy of thrombotic significance [MGTS] and POEMS syndrome [polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes]) and asymptomatic premalignant conditions (eg, monoclonal gammopathy of undetermined significance [MGUS] and smoldering MM). While the identification of the monoclonal gammopathy is a laboratory diagnosis, the specific clinical diagnosis is dependent on several other laboratory and clinical assessments.

Monoclonal proteins (M-proteins) are the marker of monoclonal gammopathies. An M-protein is defined by the presence of a monoclonal immunoglobulin which is expressed above the polyclonal background. The International Myeloma Working Group (IMWG) guidelines state that to adequately document the presence of a monoclonal protein, a serum protein electrophoresis (SPEP), serum free light chain (FLC) analysis, and serum immunofixation electrophoresis (IFE) or serum mass spectrometry, should all be used. If AL amyloidosis is suspected, a 24-hour urine monoclonal protein study should be performed when all serum testing is negative.

Mass-Fix has been demonstrated to be more analytically and clinically sensitive than IFE in detecting M-proteins. Mass-Fix results have also been shown to better predict patient's progression free survival time than IFE in treated MM patients. In addition, Mass-Fix can detect M-proteins with glycosylated light chains, which were demonstrated to be a risk factor for AL amyloidosis, cold agglutin disease, and MGUS progression. When matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) results are combined with quantitative immunoglobulin measurements, the assay can replace traditional SPEP for M-protein quantitation for common M-protein isotypes IgG, IgA, and IgM. M-proteins, which consist of only light chains are best quantitated using serum free light chains measurements.

If a M-protein pattern is detected by Mass-Fix or serum FLC measurements, a diagnosis of a monoclonal gammopathy is established. The patient should be assessed clinically for symptomatic conditions such as multiple myeloma and the other diagnoses listed above. Once symptomatic disease is ruled out, a diagnosis of MGUS can be established. The IMWG guidelines suggests follow-up M-protein testing at 6 months for the first two years following a MGUS diagnosis. If the M-protein concentration remains stable over this period (ie, less than 0.5 g/dL increase) and the patient remains asymptomatic, testing can reduce to once per year.

The Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study involving 75,422 participants has online resources to predict the chance that a bone marrow biopsy will have greater than 10 percent plasma cells given the isotype, M-protein concentrations, free light chain ratio and total IgG, IgA, and IgM. This could be an important resource for physicians trying to decide if their patient should have a follow up bone marrow evaluation (https://istopmm.com/riskmodel/).