This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVES: Multiple myeloma (MM) is a severely debilitating, incurable, and uniformly fatal neoplastic disease of beta-cell origin. The tumor cells have a plasma cell morphology and commonly produce monoclonal immunoglobulins. Although much effort has been directed at devising effective treatments for these patients, their prognosis and survival have been relatively unchanged over the last 20 years. The major source of morbidity and possible mortality associated with MM, in addition to recurrent bacterial infections, is osteolytic lesions throughout the axial skeleton. Lytic bone lesions are common in these patients and are frequently associated with severe bone pain, pathologic fractures, and hypercalcemia. The bone lesions result from increased osteoclastic bone resorption that occurs adjacent to the myeloma cells and not in areas of normal bone marrow. New bone formation that normally occurs at the sites of bone destruction is also absent. The objective of this proposal is to determine the cytokines responsible for the bone destruction in these patients. RESEARCH PLAN: (a) Measure IL-6, IL-1, TNF-alpha and TNF-beta levels in serum and marrow plasma samples from patients with myeloma and determine if levels of any or all of these cytokines singly or in combination correlate with the clinical stage of the disease; (b) Determine if levels of IL-6, IL-1, TNF-alpha, and TNF-beta alone or in combination correlate with the extent of bone disease and/or hypercalcemia in patients with myeloma; (c) Determine if novel factors that stimulate osteoclast formation, which have been identified in our in vivo model of human myeloma bone disease, are also expressed in patients; and (d) Determine if the levels of these novel osteoclast stimulatory factors correlate with the extent of myeloma bone disease. METHODS: The hypothesis to be tested in the protocol is that bone destruction in patients with myeloma is due to increased osteoclastic bone resorption and inhibited osteoblast growth. The factors responsible for the bone destruction in these patients are not clearly identified. We propose that novel cytokines produced by myeloma cells, but not cytokines which previously have been associated with myeloma disease activity such as interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha, or tumor necrosis factor-beta, are responsible for the bone destruction in these patients and correlate with the extent of their bone disease. At each clinic visit, one serum sample (10 ml) will also be collected, and leftover marrow plasma samples which are obtained when marrow aspirates and biopsies are done for clinical indications will be tested for IL-6, IL-1, TNF-alpha, and TNF-beta levels using commercially available ELISA assays. In addition, as novel factors are identified in our in vivo model of myeloma bone disease and immunoassays for these factors are developed, these factors will also be measured in the serum and residual marrow plasma samples from these patients. Patients will be followed prospectively as their illness progresses. Correlations will then be done between the cytokine levels, individually and in combination, clinical stage of myeloma in the patients as well as the extent of their bone disease as assessed by serum calcium levels and skeletal x-rays.
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