Strategies for Cure in Newly Diagnosed Multiple Myeloma

多发性骨髓瘤（MM）对治愈性治疗的耐药性可能与其基因组不稳定性有关，骨髓微环境（ME）提供的生存信号加剧了这种不稳定性。对于P01关于MM生长控制的宏大主题，本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）背景下解释治疗失败。在之前的P01资助周期中，最终660名患者中有600名随机接受总治疗2 (TT2) +沙利度胺（THAL）并接受移植后巩固治疗。添加THAL后，CR频率更高（51% vs 36%， P= 0.002）。2/3的患者缺乏

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.