Treatment of Early Stage Multiple Myeloma

早期多发性骨髓瘤的治疗

• 批准号: 6597481
• 负责人: S VINCENT RAJKUMAR
• 金额: $ 28.71万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-25 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6597481
• 关键词: CD34 molecule; angiogenesis; angiogenesis inhibitors; apoptosis; bone marrow; cell proliferation; clinical research; clinical trial phase III; enzyme linked immunosorbent assay; flow cytometry; growth factor receptors; human subject; human therapy evaluation; imidazole; immunocytochemistry; multiple myeloma; neoplasm /cancer chemotherapy; neoplastic process; patient oriented research; polymerase chain reaction; thalidomide; vascular endothelial growth factors

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：多发性骨髓瘤（MM）未用当前的治疗方法治愈。鉴于烷基化剂的白血病潜力和疾病无法治愈的性质，治疗被延迟，直到有症状性疾病（肾衰竭，贫血，高钙血症，溶质骨病变）。随着有效的非毒性生物学剂的出现，挑战这种范式的时候已经成熟了。我们的研究表明，症状MM的血管生成增加，具有预后价值，并且是通过血管内皮生长因子（VEGF）过表达介导的。相比之下，早期（闷烧和懒惰）MM的血管生成不会增加，这使抗血管生成疗法成为预防疾病进展的有吸引力的选择。 Thalidomide是一种具有抗血管生成特性的药物，在晚期MM患者中表现出显着的活性。我们的中心假设是，抗血管生成剂沙利度胺的早期治疗将在延迟无症状早期MM对症状MM的血管生成依赖性进展方面非常有效。我们拥有强大的初步数据，包括II期试验，即这种方法将延迟对侵略性化疗剂和干细胞移植的需求，并可以影响MM治疗的范式转移。我们提出了一项随机III期试验，以将时间差异与沙利度胺以及在早期无症状MM中单独使用唑来膦酸与唑来膦酸之间的进展差异（特定的AIM 1）。双膦酸盐（例如唑来膦酸）降低了MM中裂解病变和骨折的发生率，并在此试验中所有患者均指示。必须进行III期设计，以确保沙利度胺显然有益于其作为无症状患者的初始治疗。我们假设沙利度胺会降低VEGF的表达并抑制骨髓（BM）血管生成，从而导致血浆细胞凋亡增加，减少增殖和肿瘤反应。具体目标2将比较BM血管生成的变化以及治疗前后VEGF及其受体的表达水平，并将这些测量与对治疗的反应相关联。具体目标3将确定BM血管生成与MM细胞VEGF表达之间的关系与MM细胞凋亡，增殖和对治疗的反应的速率。将使用用于CD34的免疫染色（IHC）和体外人血管生成测定法研究BM血管生成。将使用IHC和定量RT-PCR研究VEGF表达。