IV. PATHOPHYSIOLOGY

Plasma cell dyscrasias are a spectrum of disorders characterized by the growth and/or survival of a population of clonal plasma cells. At the benign end of the spectrum, if the plasma cell clone does not expand, the disorder is monoclonal gammopathy of undetermined significance (MGUS). MGUS patients will progress to malignant disease, usually multiple myeloma, at a rate of 1% per year. The vast majority of MGUS patients never progress to overt malignancy because of competing causes of death (e.g., cardiovascular, cerebrovascular or non-plasma cell malignancy). If the clonal plasma cell population expands over time, typically associated with lytic bone lesions, the disease is multiple myeloma. Criteria for the diagnosis of multiple myeloma are: bone marrow containing monoclonal plasma cells and M-protein in serum, M-protein in urine and evidence of end-organ damage. (A mnemonic for end-organ damage, which is the hallmark of multiple myeloma, is CRAB, for hypercalcemia, renal insufficiency, anemia and lytic bone lesions.)

A distinct clinical entity is solitary plasmacytoma – a focal mass of malignant plasma cells that occurs in isolation, anywhere in the body, without involvement of the bone marrow or significant end-organ damage. A patient with a solitary plasmacytoma is at risk for progressing to multiple myeloma, but may be cured with radiotherapy alone.

Primary amyloidosis is characterized by a relatively stable plasma cell clone that secretes protein that forms insoluble, congo-red-staining fibrils in tissues, leading to multi-organ dysfunction. Light chain deposition disease is similar except that deposits of light chains are not fibrillar but granular, and they do not stain with congo red.

Genetics of myeloma and plasma cell dyscrasias

While it is likely that specific genetic lesions exist in each plasma cell dyscrasia, at present the differences are not well understood. The description below is written in reference to multiple myeloma, but can apply to other dyscrasias as well.

Broadly, multiple myeloma can be divided into hyperdiploidy and hypodiploidy based on DNA content. Hypodiploid multiple myeloma has a worse prognosis, as do the immunoglobulin translocations t(4;14) and t(14;16) and chromosomal abnormalities such as del13 and 17p-.

Recently a common pathologic molecular mechanism has been proposed for multiple myeloma based on expression microarray data (see Bergsagel ref). Nearly all multiple myeloma samples overexpress one of the cyclin D family members (cyclin D1, cyclin D2, cyclin D3). Each cyclin D gene is a target of Ig translocations, but even translocation-negative cases overexpress at least one of these genes.

At present the only widely available genetic tests are FISH to detect translocations and conventional cytogenetics on bone marrow aspirates to detect del 13 and complex chromosomal changes.