Multiple myeloma is a malignant neoplasm, usually involving a single clone of plasma cells, which produce immunoglobulins of uniform structure (Most commonly IgG, but all other immunoglobulin chains are also represented). This disorder usually strikes individuals 60 years of age or older, but can occur in much younger individuals. New cases number approximately 20000 individuals in the United States. It is typically characterized by proliferation of plasma cells throughout the marrow displacing normal plasma cells and causing anemia, thrombocytopenia, and a reduction in leukocytes. Osteolytic lesions are often observed as well as a reduction in normal immunoglobulin production resulting in a depression of immunosystem function. Renal function may also become progressively impaired. Observation of bone lesions by radiology, neoplastic plasma cells in bone marrow aspirate, and the presence of monoclonal paraprotein in serum or urine, are all hallmarks of this disease. There are individuals who have apparent monoclonal immunoglobulin production but do not exhibit significant disease progression. This state is called monoclonal gamopathy of unknown significance (MGUS).
Bence Jones proteins in the urine consisting of immunoglobulin free light chains associated with multiple myeloma has been observed for over 150 years and represent the first tumor marker assay. Since that time a number of other markers and techniques for the investigation of multiple myeloma have come into use. These include serum protein electrophoresis (SPEP) for monoclonal protein concentration determination, immunofixation electrophoresis (IFE) of specific monoclonal immunoglobulin heavy and light chains, and nephlometric determination of total serum immunoglobulins and serum free light chains (FLC). Other useful markers for identification and staging of this disorder include albumin, calcium, and creatinine, as well as lactate dehydrogenase and Beta-2-microglobulin determinations. Some confounding factors include submission of plasma samples resulting in an apparent M-protein migrating in the beta-gamma region caused by the presence of fibrinogen and the potential for missing elevated quantitative immunoglublin/free light chain concentrations due to antigen excess.
A great deal of effort has gone into the development of new markers for multiple myeloma, as well as more efficient use of existing markers. Recent work has indicated that effective initial screening for multiple myeloma may be achieved by the use of FLC and SPEP alone. Our understanding of potential prognostic indicators for survival such as Free Light Chain κ/λ ratios continues to grow. Exciting work continues in exploring strong genetic markers for prognosis and potential treatment modification. Finally, immunoassays for the intact Ig subsets; IgGκ, IgGλ, IgAκ and IgAλ (heavy chain/light chain immunoassays or HLC) have recently become available, and early evaluations indicate that this marker may have prognostic as well as diagnostic value. These and other markers may also be indicative of risk of progression from MGUS as well.
There have been marked improvements in treatment in the last 30 years. Aided by concurrent improvements in the diagnosis and monitoring of multiple myeloma, more patients are surviving for longer periods of time, and living better with longer periods of clinical remission. Further improvements appear to be on the horizon.
- Kyle RA, Rajkumar SV “Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma.” Leukemia. (2009); 23(1):3-9.
- Fonesca et. al. “International Myeloma Working Group molecular classification of multiple myeloma: spotlight review.” Leukemia. (2009); 23(12):2210-21.
- Keren, D.F. “Heavy/Light-chain analysis of monoclonal gammopathies. Clin Chem, (2009); 55, 1606-1608.