Multiple Myeloma, Killer Without a Cure

Multiple myeloma (MM) is a tumor of mature, isotope-switched plasma cells. Malignant plasma cells replace normal blood cells in the bone marrow and bloodstream, causing anemia, bleeding disorders, and painful bone deterioration. It has recently been determined that MM is characterized by recurrent chromosome translocations to the immunoglobulins heavy chain gene on chromosome 14q32. The neoplastic event in myeloma may involve cells earlier in B-cell differentiation than the plasma cells. Circulating B-cells bearing surface immunoglobulin that share the idiotype of the M component are present in myeloma patients. It is possible that the malignant clone escapes normal control mechanisms at a pre-plasma cell stage of differentiation and the chronic exposure to a particular antigenic stimulus drives the cell to terminal differentiation.

Approximately 14,400 cases or myeloma were diagnosed in 1996, and 10,400 people died from the disease. There is a correspondingly greater incidence of myeloma with age. The median age at diagnosis is 68 years, and occurence in people younger than 40 years of age is very rare. Males are more commonly affected than females, and there is nearly twice the incidence among African Americans then among Caucasians. There is no cure for MM, nor any effective treatment.

Bone pain is the most common symptom of myeloma and is generally felt in the back and ribs. Bone lesions are caused by the proliferation of tumor cells and osteoclast activation, and result in the destruction of bone. Osteoclast proliferation is a response to osteoclast activating factors secreted by the myeloma cells. The overabundance of nonfunctional antibodies produced by the abnormal cells also inhibits the production of normal protective antibodies, which frequently results in infection. Kidney failure is a common side effect, occurring as a consequence of bone breakdown and increased antibody proteins. Associated complaints include hypercalcemia, nausea, confusion, polyuria and constipation. Many of the complications associated with MM are treatable on a symptom by symptom basis.

Several methods are available for both a preliminary diagnosis and staging of the disease. Peripheral blood examinations can be used as a first diagnostic check for rare plasma cells, normocytic anemia, thrombocytopenia, and leucopenia. Blood chemistry should reveal hypercalcemia, hyperuricemia, increased serum creatinine and renal failure. Bone marrow examination will show focal or diffuse plasma cells. Radiological studies may reveal osteolytic lesions but a complete bone survey is essential for evaluating monoclonal gammopathies. Aspiration and biopsy of bone marrow is used to evaluate cell morphology, and CT and MRI can be used to check for bone destruction.

Several major advances have been made in the treatment of MM. Standard treatment has involved chemotherapy including intermittent pulses of an alkylating agent (melphalan, cyclophosphamide or chlorambucil) and prednisone administered for 4 to 7 days every 4 to 6 weeks. High-dose therapy with hematopoietic support is being investigated in younger patients. Sequential treatment with combination chemotherapy regimens followed by two successive high-dose melphalan treatments, each supported with peripheral blood stem cell transplants, have achieved complete responses in 50% of patients treated within a year of diagnosis. The use of thalidomide has been studied and appears indirectly to inhibit the growth and survival of myeloma cells, bone marrow and/or stromal cells. The mechanism of action of thalidomide is unknown, although it has been postulated to inhibit angiogenesis, cutting off blood supply to the tumors. Novel experimental approaches involve the development of a myeloma vaccine. Vaccination of myeloma patients against a myeloma specfic molecule could be used as an adjunct to conventional therapy to eliminate minimal residual disease and prevent re-emergence of the tumor. One group is investigating the use of bacterial DNA- based vaccines to generate immune responses capable of preventing B cells from expressing a tumor-associated immunoglobulin. Another is using customized vaccines made from each patient's myeloma in association with dendritic cells from a sibling donor to help the immune system recognize the myeloma as abnormal. Both of these methods are in preliminary stages of investigation and results may not be available for some time.

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  2. Multiple Myeloma Research Foundation (