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

项目概要（项目1） 为了改善多发性骨髓瘤（MM）的总体结局，在当前资助期内，该项目 实现了两大目标：1：明确了移植在新药剂时代的作用--建立 将移植物与新试剂结合作为新诊断患者的标准护理2： 重新定义完全缓解，确定测量微小残留病变的可行性 (MRD)使用基于测序的方法及其对PFS延长的显著影响。在这 更新申请，我们现在建议建立在我们非常成功的合作临床研究， 解决下一个最重要的问题，低强度维持（1种药物）是否提供 与更高强度的维持治疗（2种药物）相比有足够的获益，以及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- 长期无病生存率，无论如何达到MRD阴性状态， 结果将是相似的。为了实现这些目标，在具体目标1中，我们将执行大量1，260 使用来那度胺、ixazomib和地塞米松联合达雷妥尤单抗（RID-Dara）作为 高剂量治疗后诱导和巩固。那些没有达到MRD阴性状态的人将 第二次HDT。所有MRD阴性患者将随机接受来那度胺与来那度胺治疗 加上达雷妥尤单抗维持治疗。本研究还将评价不同时间点的MRD状态， 研究早期与晚期MRD状态是否会影响总体结局。具体目标2： 重新定义新的风险分层，纳入MRD状态和所有基因组/表观基因组相关性。

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.