On January 1 2000 there were estimated to be 47 000 patients with multiple myeloma (MM) in the USA, reflecting a yearly incidence of nearly 14 000 and a median survival of about 3 years. It remains an incurable malignancy that is often preceded by an exceptionally common (3.4% of the population over the age of 50) premalignant tumor—monoclonal gam-mopathy of undetermined significance (MGUS). Monoclonal gammopathies are usually asymptomatic, but they may sometimes cause primary amyloidosis as a result of pathological, and ultimately lethal, deposits of monoclonal immunoglobulin (Ig) in critical tissues. Although MGUS is stable, it progresses stochastically to frankly malignant MM at a rate of 0.6-3% per year depending on the level of monoclonal Ig. For both MGUS and MM, the incidence is markedly age-dependent, about twofold higher in American blacks than in Caucasians, and significantly higher in males. Although for many years the incidence of MM has appeared to be increasing, since 1992 the incidence appears to have become stable. The roles of genetic background and environment are poorly defined, although there may be clustering within families.

Multiple myeloma is usually—but perhaps not always—preceded by an age-dependent premalignant tumor called mono clonal gammopathy of undetermined significance (MGUS), which is present in 1% of adults over the age of 25 (rarely before the age of 40 but 10% of individuals in their tenth decade). MGUS cells secrete monoclonal immunoglobulin (Ig) and progress to malignant MM, expressing the same Ig, at the rate of 1% per year. Amyloidosis, which accounts for about 4000 deaths per year in the USA, usually has the same pathology as MGUS except that the monoclonal Ig forms pathological deposits in various tissues (generally the intact or fragmented Ig light chain). These tumors occur at multiple intramedullary (within the bone marrow) sites. Multiple myeloma is distinguished from MGUS by having a greater intramedullary tumor cell content (>10%), osteolytic bone lesions and/or an increasing tumor mass. Smoldering myeloma has a stable intramedullary tumor cell content of >10% but no osteolytic lesions or other complications of malignant myeloma. Progression of intramedullary myeloma is associated with increasingly severe secondary features (lytic bone lesions, anemia, immunodeficiency, renal impairment), and in a fraction of patients the occurrence of tumor in extramedullary locations. Extramedullary MM is a more aggressive tumor that is often called secondary or primary plasma cell leukemia, depending on whether preceding intramedullary myeloma has been recognized. Immortalized, Epstein-Barr virus-negative human multiple myeloma cell lines (HMCL) can sometimes be generated but, with very rare exceptions, only from extra-medullary myeloma. The highly proliferative HMCL can be viewed as the ultimate stage of tumor progression, providing

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