Project 1: Developing MRD-based therapeutic strategy in newly diagnosed multiple myeloma

项目摘要-项目1-图卢兹/DFCI 为了改善多发性骨髓瘤(MM)的整体疗效，本项目在目前的资助期间实现了三项 主要目标：1：明确移植在新药时代的作用，并进行长期维护；2： 建立了在10-6灵敏度下测量微小残留病(MRD)的可行性，并论证了其 对延长PFS的显著影响，无论使用哪种治疗方法；以及3)证明 四胞胎治疗获得高频率的MRD阴性反应。在此续期申请中，我们现在 建议在我们高度成功的协作临床研究的基础上，解决下一个最重要的问题 问题是，大剂量治疗(HDT)是否仍能为达到MRD阴性状态的患者提供好处。 我们假设，四胞胎治疗后的ASCT将达到更深的MRD阴性状态(10-6)，并且 持续的MRD阴性将具有重要的治疗意义。我们建议的研究将：1)确定 ASCT在四胞胎诱导治疗多发性骨髓瘤中的作用；确定ASCT是否能进一步减少肿瘤 负担，增加MRD阴性率(NGS，10-6)，改善患者预后；并定义是否 早期、晚期和持续的MRD阴性会影响临床结果(Sp目标1)。我们将进行一次大规模的 (n=716)使用伊索妥昔单抗、卡非佐米、来那度胺和地塞米松(IsaKRD)诱导疗法的研究 然后将MRD阴性的患者随机分为IsaKRD和HDT两组。以特定的目标 2，我们将重新定义新的风险分层，将MRD状态与现代生化、基因组、 表观基因组学，与免疫和微环境相关。我们建议的研究将确定 MRD提示预后和治疗。 。

Project Summary – Project 1 CHU-Toulouse / DFCI To improve overall outcome in multiple myeloma (MM), period this project in the current funding achieved three major goals: 1: Defined the role of transplant in the era of novel agents with long term maintenance; 2: Established the feasibility of measuring minimal residual disease (MRD) at 10-6 sensitivity, and demonstrated its significant impact on prolongation of PFS irrespective of the type of treatment used; and 3) Demonstrated that quadruplet therapies achieve high frequency of MRD negative response. In this renewal application, we now propose to build upon our highly successful collaborative clinical study to address the next most important question, whether high-dose therapy (HDT) can still provide benefit in patients achieving MRD negative status. We hypothesize that quadruplet therapy followed by ASCT will achieve deeper MRD negative status (10-6), and that sustained MRD negativity will be of therapeutic importance. Our proposed study will: 1) define the role of ASCT in MM in the context of quadruplet induction therapy; determine whether ASCT further decreases tumor burden, increases MRD negativity rates (NGS, 10-6), and improves patient outcome; and define whether achieving early, late, and sustained MRD negativity impacts clinical outcome (Sp Aim 1). We will conduct a large (n=716) study using induction therapy with isatuximab, carfilzomib, lenalidomide and dexamethasone (IsaKRD) and then randomize those patients who are MRD negative to either further IsaKRD versus HDT. In Specific Aim 2, we will redefine new risk stratification incorporating MRD status and modern biochemical, genomic, epigenomic, and immune and microenvironmental correlates. Our proposed study will determine the impact of MRD informing prognosis and therapy. .