Pathogenetic relation between monoclonal gammopathies of undetermined significance and multiple myeloma.

Plasma cell atypia and cell proliferation changes which occur during the progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are accompanied by critical changes in neoplastic plasma cells and marrow stromal cells. Key elements include paracrine secretion of interleukin 6 (IL-6) by marrow stromal cells resulting from interleukin 1 beta (IL-1 beta) secreted by myeloma cells. In addition, there are stable elevated levels of serum soluble IL-6 receptor (sIL-6R) in MM and MGUS. They are higher than levels seen in normals. Oncogenes such as c-myc and ras probably play a major role as do cell adhesion molecules and loss of apoptosis. Immune regulatory cells may also play a role. A key element yet to be clearly defined is delineating the role of circulating plasma cells and their precursors in spreading the disease.