Plasma cell disorders are a group of related diseases arising from a common progenitor belonging to the B-cell lineage. They are characterized by the expansion of plasma cells in the bone marrow (BM) and nearly always accompanied by the presence of a monoclonal immunoglobulin (Ig) or Ig fragment in the serum and/or urine of patients (1). Monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), Waldenstrom's macroglobulinemia (WM), primary amyloidosis, and heavy chain diseases (HCD) all belong to this group of disorders. Dysproteinemias or plasma cell dyscrasias are some of the other terms used to refer to this unique group of disorders.
Normal B-cell differentiation is characterized by a process of Ig VDJ rearrangement, somatic mutation, and Ig class switching resulting in maturation of antibody-producing plasma cells. Ig variable (VH) gene sequence analysis indicates that myeloma tumor cells are postfollicular, and originate from a memory cell undergoing isotype switch events. Translocations involving switch regions indicate that the final oncogenic molecular event in myeloma occurs late in B-cell ontogeny. Five heavy-chain isotypes (M, G, A, D, E) and two light-chain isotypes (κ and λ) are present and are typically identified by serum or urine protein electrophoresis as a sharp spike in the gamma region. The isotype is further identified and quantitated by immunofixation and is referred to as the monoclonal component, that is, arising from the neoplastic clone. This is a useful biomarker and helps determine responses in patients with plasma cell disorders. More recently an ELISA-based assay is being used to detect light chains in the serum. This is particularly useful in patients with amyloidosis, light chain MM, and nonsecretory MM.
MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE
Monoclonal gammopathy of undetermined significance (MGUS) is seen in 1% of patients over age 50 and 3% of people over age 70 and is associated with the presence of a monoclonal Ig which is less than 3.5 g/l (2). It is differentiated from MM by fewer than 5% monoclonal BM plasma cells and lack of end organ damage like bone lesions, anemia, hypercalcemia, or renal dysfunction. In a large series of 1384 patients followed longitudinally at the Mayo Clinic, 115 patients progressed to MM (relative risk [RR] 25), IgM lymphoma (RR 2.4), primary amyloidosis (RR 8.4), macroglobulinemia (RR 46), chronic lymphocytic leukemia (RR 0.9), or plasmacytoma (RR 8.5). The risk of progression of MGUS to MM or related disorders is about 1% per year (2); risk factors for progression include high serum monoclonal protein (≥1.5 g/dl), non-IgG MGUS, and abnormal serum free light chain ratio (3). At this time, treatment for MGUS and smoldering MM consists of risk stratification and close observation (2). Clinical trials are however being conducted to target this population.