High-throughput immunoglobulin gene sequencing as a peripheral blood minimal residual disease assay to predict post-transplant relapse risk in multiple myeloma

 描述（由申请方提供）：多发性骨髓瘤是骨髓浆细胞的一种不可治愈的恶性肿瘤。在过去的二十年中，随着自体干细胞移植（ASCT）的广泛使用和强效抗骨髓瘤药物的开发，生存率稳步提高。目前，高达30%的患者达到完全缓解（CR）。然而，即使对于达到CR的患者，复发也是不可避免的。因此，治疗多发性骨髓瘤的进展需要灵敏地测量导致达到CR的患者复发的微小残留病（MRD）的方法。这些方法应允许频繁和非侵入性MRD跟踪，以便可以将治疗滴定到最深可能的缓解。为了解决这一未满足的需求，我们建议验证免疫球蛋白基因（IG HTS）的高通量测序作为多发性骨髓瘤MRD评估的非侵入性外周血检测。几项研究已经证明了使用流式细胞术、等位基因特异性PCR和IG HTS对ASCT后CR患者进行MRD评估的预后价值。然而，这些研究依赖于对接受现已过时的方案治疗的患者的骨髓样本进行分析。我们提出的研究将推进该领域的第一个使用外周血检测评估MRD的预后价值，并在现代治疗方案治疗的患者中进行评估。我们将使用来自750例患者BMT-CTN 0702试验的外周血和骨髓样本以及临床数据，该试验比较了三种ASCT后治疗策略和最近完成的累积。IG HTS是我们研究的理想方法，因为它比流式细胞术更灵敏，并且不需要定制设计患者特异性测定。IG HTS通过探测独特的免疫球蛋白基因序列来跟踪MRD，该基因序列将每个患者中的恶性浆细胞克隆与正常B细胞和浆细胞区分开。在本研究中，我们将：1）确定在具有IG HTS的外周血中MRD评估的预后价值和2）确定ASCT后重建的非恶性免疫库的特征是否预测无进展生存期（PFS）。这些分析将为未来研究的设计提供信息，在这些研究中，ASCT后维持治疗根据MRD状态进行个性化，以达到最佳的PFS，同时毒性和成本最低。在外周血中使用经验证的IG HTS MRD检测试剂盒也将有助于将MRD状态用作替代终点以评价新型ASCT后治疗的研究。最后，这些分析还将产生对ASCT后免疫重建生物学的新见解，并可能产生对ASCT后多发性骨髓瘤治疗反应的新候选生物标志物。

 DESCRIPTION (provided by applicant): Multiple myeloma is an incurable malignancy of bone marrow plasma cells. Survival has steadily improved over the last twenty years with widespread use of autologous stem cell transplantation (ASCT) and the development of potent anti-myeloma drugs. Up to 30% of patients now attain complete responses (CR). However, even for patients who attain CR, relapse is inevitable. Progress towards a cure for multiple myeloma therefore requires methods to sensitively measure the minimal residual disease (MRD) that leads to relapse in patients who achieve CR. Such methods should allow frequent and non-invasive MRD tracking so that therapy can be titrated to the deepest possible remissions. To address this unmet need, we propose to validate high-throughput sequencing of immunoglobulin genes (Ig HTS) as a non-invasive peripheral blood assay for MRD assessment in multiple myeloma. Several studies have demonstrated the prognostic value of MRD assessment in patients in CR after ASCT using flow cytometry, allele-specific PCR, and Ig HTS. However, these studies relied on analysis of bone marrow samples from patients treated with now-obsolete regimens. Our proposed study would advance the field by being the first to assess the prognostic value of MRD using a peripheral blood assay and to do so in patients treated with modern regimens. We will use peripheral blood and bone marrow samples and clinical data from the 750-patient BMT-CTN 0702 trial, which compared three post-ASCT treatment strategies and recently completed accrual. Ig HTS is ideal for our study because it is more sensitive than flow cytometry and requires no custom design of patient-specific assays. Ig HTS tracks MRD by probing for the unique immunoglobulin gene sequence that distinguishes the malignant plasma cell clone in each patient from normal B cells and plasma cells. In this study we will: 1) determine the prognostic value of MRD assessment in the peripheral blood with Ig HTS and 2) determine if features of the reconstituting non-malignant immune repertoire post ASCT are predictive of progression-free survival (PFS). These analyses will inform the design of future studies in which post-ASCT maintenance therapy is personalized to MRD status to attain the best possible PFS with the least toxicity and cost. The use of a validated Ig HTS MRD assay on peripheral blood will also facilitate studies in which MRD status is used as a surrogate endpoint for evaluating novel post-ASCT therapies. Finally, these analyses will also yield novel insights into the biology of post-ASCT immune reconstitution and potentially yield new candidate biomarkers of response to post-ASCT multiple myeloma therapy.