Multiple myeloma (MM) is not cured with current therapy. Given the leukemogenic potential of alkylating agents and incurable nature of the disease, therapy is delayed until symptomatic disease (renal failure, anemia, hypercalcemia, lytic bone lesions) occurs. With the advent of effective non-cytotoxic biologic agents, the time is ripe to challenge this paradigm. Our studies show that angiogenesis is increased in symptomatic MM, has prognostic value, and is mediated by overexpression of vascular endothelial growth factor (VEGF). In contrast, angiogenesis is not increased in early stage (smoldering and indolent) MM, making antiangiogenic therapy an attractive option to prevent disease progression. Thalidomide, an agent with antiangiogenic properties, has shown remarkable activity in patients with advanced MM. Our central hypothesis is that early therapy with the antiangiogenic agent thalidomide will be highly effective in delaying the angiogenesis dependent progression of asymptomatic early stage MM to symptomatic MM. We have strong preliminary data including a phase II trial that this approach will delay the need for aggressive chemotherapy agents and stem cell transplantation and can effect a paradigm shift in MM therapy. We propose a randomized phase III trial to compare differences in time to progression between thalidomide plus zoledronic acid versus zoledronic acid alone in early stage asymptomatic MM (Specific Aim 1). Bisphosphonates, such as zoledronic acid, decrease the incidence of lytic lesions and fractures in MM and are indicated for all patients on this trial. A phase III design is necessary to ensure that thalidomide is clearly beneficial to warrant its use as initial therapy for asymptomatic patients. We hypothesize that thalidomide decreases the expression of VEGF and inhibits bone marrow (BM) angiogenesis, resulting in increased plasma cell apoptosis, decreased proliferation and tumor response.
Specific Aim 2 will compare changes in BM angiogenesis and the level of expression of VEGF and its receptors before and after therapy and correlate these measurements with response to therapy.
Specific Aim 3 will determine the relationship between BM angiogenesis and MM cell VEGF expression with rates of MM cell apoptosis, proliferation and response to therapy. BM angiogenesis will be studied using immunostaining (IHC) for CD34 and an in vitro human angiogenesis assay. VEGF expression will be studied using IHC and quantitative RT-PCR.
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