Strategies for Cure in Newly Diagnosed Multiple Myeloma

多发性骨髓瘤(MM)对治疗的抵抗可能与其基因组的不稳定有关，骨髓微环境(ME)提供的生存信号加剧了其基因组的不稳定。对于P01‘S关于MM生长控制的宏伟主题，该项目的总体目标是增加耐久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。在之前的P01资助周期中，最终660名患者中的600名被随机分为总体治疗2(TT2)+沙利度胺(THAL)组，并接受移植后巩固治疗。加入Thal后CR率升高(51%比36%，P=0.002)。对于三分之二的患者来说 细胞遗传学异常(CA)，74%的TT2患者(接受前身TT1治疗的患者中有40%)自CR3年后仍处于持续CR状态。新项目的总体假设是，ME提供了MM依赖的避难所机制，可以通过共同靶向ME和MM细胞的药物(THAL、地塞米松、REVIDID(R)和VelcadeTM)来灭活。因此，这个项目将追求三个主要的具体目标。目的1将评估TT2患者的长期结果(无事件[EFS]和总生存期[OS])和维持CR的障碍；复发或进展的TT2患者将随机接受MM和ME联合靶向抢救治疗。在目标2中，TT2的继任者--TT3的第二阶段试验--将尝试通过加入VELCADE(在结束阶段表现出显著的活动)来改进CR 作为基于马法兰的串联自体移植的一部分，将THAL和地塞米松作为自体移植的一部分进行诱导和巩固治疗，并在TT2的无治疗间隙期间穿插THAL和地塞米松以提供持续治疗。功能成像将被用作改善治疗结果的潜在早期预后指标。GEP分析将与Shaughnessy博士的项目3合作，用于识别与MM相关的ME特征及其治疗方法的改变，以更好地了解治疗成功或失败的机制。在目标3中，TT2和TT3试验的成熟数据将构成TT4的基础，TT4将在第4年开发，目标是引入基于GEP的风险适应疗法。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前景的新药 患者，一旦临床前研究证实关键信号通路被识别 确实已经成为了攻击目标。因此，结合4个项目和4个核心项目，该项目将以一种高度可转化的方式推进MM持续疾病控制的综合治疗。

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.