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

项目总结(项目1) 为了改善多发性骨髓瘤(MM)的整体预后，在当前的资助期内，该项目 实现了两个主要目标：1：明确了移植在新药时代的作用--建立 将移植与新药物相结合作为新诊断患者的标准护理2： 重新定义完全缓解，建立衡量最小残留病的可行性 (MRD)使用基于序列的方法及其对延长PFS的重大影响。在这 续期申请，我们现在建议在我们非常成功的合作临床研究的基础上 解决下一个最重要的问题，即不那么紧张的维持(1种药物)是否能提供 与更密集的维护(2种药物)相比，是否有足够的好处，以及是否处于MRD阴性状态 应该是最终目标。我们假设，达到MRD阴性状态将导致长期- 无病生存期，无论一个人如何达到MRD阴性状态，总体 结果将是相似的。为了实现这些目标，在具体目标1中，我们将执行大型1260 来那度胺、伊沙唑米和地塞米松与达拉图单抗(RID-DARA)联合应用的患者研究 大剂量治疗后的诱导和巩固。那些没有达到MRD阴性状态的人将 接收第二个HDT。所有MRD阴性的患者将被随机分为来那度胺和来那度胺。 外加达拉图玛单抗的维护。该研究还将评估不同时间点的MRD状态和 调查早期和晚期的MRD状态是否会影响总体结果。在具体目标2中，我们将 重新定义新的风险分层，包括MRD状态和所有基因组/表观基因组相关因素。

Project Summary (Project 1) To improve overall outcome in multiple myeloma (MM), in the current funding period this project achieved two major goals: 1: Defined the role of transplant in the era of novel agents –establishing integration of transplant with novel agents as the standard of care for newly-diagnosed patients 2: Redefined Complete Remission, establishing the feasibility of measuring minimal residual disease (MRD) using sequencing-based method and its significant impact on prolongation of PFS. In this renewal application, we now propose to build upon our highly successful collaborative clinical study to address the next most important question, whether less intense maintenance (1-drug) provides adequate benefit compared to more intense maintenance (2-drug) and whether MRD negative status should be the ultimate goal. We hypothesize that achieving MRD negative status will lead to long- term disease free survival, and that irrespective of how one gets to MRD negative status, the overall outcome will be similar. To achieve these goals, in Specific Aim 1 we will perform a large 1,260 patient study utilizing lenalidomide, ixazomib, and dexamethasone with daratumumab (RID-Dara) as induction and consolidation post high-dose therapy. Those not achieving MRD negative status will receive 2nd HDT. All MRD negative patients will be randomized to lenalidomide versus lenalidomide plus daratumumab maintenance. The study will also evaluate MRD status at various time points and investigate whether early versus late MRD status will affect overall outcome. In specific Aim 2, we will redefine new risk stratification incorporating MRD status and all genomic/epigenomic correlates.