Strategies for Cure in Newly Diagnosed Multiple Myeloma

新诊断的多发性骨髓瘤的治疗策略

• 批准号: 6997892
• 负责人: BART BARLOGIE
• 金额: $ 20.83万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-16 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6997892
• 关键词: DNA damage; antineoplastics; bone marrow; bone marrow transplantation; boronic acids; clinical trial phase II; combination cancer therapy; combination chemotherapy; dexamethasone; gene expression profiling; human subject; human therapy evaluation; multiple myeloma; neoplasm /cancer chemotherapy; neoplasm /cancer remission /regression; patient oriented research; thalidomide

The resistance to curative therapy in multiple myeloma (MM) may be linked to its genomic instability, accentuated by survival signals provided by the marrow microenvironment (ME). Toward the P01's grand theme of MM growth control, the overall goal of this project is to increase the frequency of durable CR as a prerequisite for long-term survival and to interpret treatment failure in the context of gene expression profiles (GEP) of both MM and ME. In the previous P01 funding cycle, 600 of eventually 660 patients were randomized to Total Therapy 2 (TT2) + thalidomide (THAL) and received post-transplant consolidation therapy. CR frequency was higher with added THAL (51% vs 36%, P=.002). For the 2/3 of patients lacking cytogenetic abnormalities (CA), 74% of TT2 (vs 40% of patients receiving predecessor TT1, P<.001) remained in continuous CR at 3 yr from onset of CR. The overall hypothesis for the new Project is that the ME provides MM-dependent sanctuary mechanisms that can be inactivated by agents co-targeting the ME and MM cells (THAL, dexamethasone, Revimid(R), and VelcadeTM). Thus, this project will pursue 3 major specific aims. Aim 1 will assess the long-term outcomes (event-free [EFS] and overall survival [OS]) and obstacles to sustaining CR among TT2 patients; TT2 patients who relapse or progress will be randomized to treatment with MM and ME co-targeting salvage therapies. In Aim 2, the successor to TT2--a phase 2 trial of TT3--will attempt to improve CR by incorporating Velcade (exhibiting marked activity in end-stage disease) into induction and consolidation therapies as part of melphalan-based tandem autotransplants and intersperse THAL and dexamethasone peri-transplant to provide continuous treatment during treatment-free gaps of TT2. Functional imaging will be used as a potential early prognostic indicator of improved treatment outcome. GEP analysis, in collaboration with Dr. Shaughnessy's project 3, will be used to discern MM-associated ME signatures and their alteration by therapies, to better understand mechanisms of treatment success or failure. In Aim 3, the maturing data of TT2 and TT3 trials will form the basis of TT4, which will be developed in Year 4 with the goal of introducing GEP-based risk-adapted therapy. Future studies generated by this P01 will test, in collaboration with NCI, promising novel agents for previously treated patients, once pre-clinical studies have validated that critical signaling pathways identified have indeed been targeted. Thus, in concert with 4 projects and access to 4 cores, this project will advance comprehensive treatment for sustained disease control in MM in a highly translational fashion.

多发性骨髓瘤（MM）对治愈性治疗的抵抗可能与其基因组不稳定性有关，骨髓微环境（ME）提供的生存信号加重了这种不稳定性。为了实现P01的MM生长控制的宏伟主题，该项目的总体目标是增加持久CR的频率，作为长期生存的先决条件，并在MM和ME的基因表达谱（GEP）的背景下解释治疗失败。最终660例患者中的600例被随机分配至全面治疗2（TT 2）+沙利度胺（塔尔）组，并接受移植后巩固治疗。添加塔尔的CR频率更高（51% vs 36%，P= 0.002）。2/3的患者缺乏 细胞遗传学异常（CA），74%的TT 2（对40%的接受前一个TT 1的患者，P<0.001）在CR发生后3年保持连续CR。新项目的总体假设是ME提供MM依赖性保护机制，该机制可被共同靶向ME和MM细胞的试剂（塔尔、地塞米松、Revimid（R）和VelcadeTM）灭活。因此，该项目将追求三大具体目标。目的1将评估TT 2患者的长期结局（无事件[EFS]和总生存期[OS]）和维持CR的障碍;复发或进展的TT 2患者将随机接受MM和ME联合靶向挽救治疗。在目标2中，TT 2的后续试验--TT 3的2期试验--将试图通过加入万珂（在终末期表现出显著的活性）来改善CR 疾病）纳入诱导和巩固治疗作为基于美法仑的串联自体移植的一部分，并在移植周围散布塔尔和地塞米松以在TT 2的无治疗间隙期间提供连续治疗。功能成像将被用作改善治疗结果的潜在早期预后指标。GEP分析与Shaughnessy博士的项目3合作，将用于识别MM相关的ME特征及其通过治疗的改变，以更好地了解治疗成功或失败的机制。在目标3中，TT 2和TT 3试验的成熟数据将构成TT 4的基础，TT 4将在第4年开发，目标是引入基于GEP的风险适应性治疗。由该P01产生的未来研究将与NCI合作，测试用于先前治疗的有希望的新型药物 一旦临床前研究证实， 确实是被盯上了因此，该项目将与4个项目和4个核心项目相结合，以高度转化的方式推进MM持续疾病控制的综合治疗。