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

 描述(申请人提供)：多发性骨髓瘤是一种无法治愈的骨髓浆细胞恶性肿瘤。在过去的二十年里，随着自体干细胞移植(ASCT)的广泛应用和有效的抗骨髓瘤药物的开发，患者的存活率稳步提高。现在高达30%的患者达到完全应答(CR)。然而，即使对于获得完全缓解的患者，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CR患者复发的微小残留病(MRD)的方法。这种方法应该允许频繁和非侵入性的MRD跟踪，以便可以将治疗滴定到尽可能最深的缓解程度。为了解决这一未得到满足的需求，我们建议验证免疫球蛋白基因高通量测序(Ig HTS)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、等位基因特异性聚合酶链式反应和免疫球蛋白高敏反应对ASCT后CR患者进行MRD评估的预后价值。然而，这些研究依赖于对采用现已过时的方案治疗的患者的骨髓样本的分析。我们提出的研究将推动这一领域的发展，首次使用外周血检测来评估MRD的预后价值，并在接受现代方案治疗的患者中这样做。我们将使用外周血和骨髓样本以及750名患者的BMT-CTN 0702试验的临床数据，该试验比较了ASCT后的三种治疗策略和最近完成的收益。IG HTS是我们研究的理想选择，因为它比流式细胞术更灵敏，而且不需要定制设计针对患者的分析方法。IG HTS通过探测独特的免疫球蛋白基因序列来追踪MRD，该基因序列将每个患者的恶性浆细胞克隆与正常B细胞和浆细胞区分开来。在这项研究中，我们将：1)确定Ig HTS患者外周血中MRD评估的预后价值；2)确定ASCT后重建的非恶性免疫谱系的特征是否可以预测无进展生存(PFS)。这些分析将为未来研究的设计提供信息，在该研究中，ASCT后维持治疗个性化到MRD状态，以最小的毒性和成本获得尽可能好的PFS。在外周血液中使用有效的Ig HTS MRD检测也将促进将MRD状态用作评估ASCT后新疗法的替代终点的研究。最后，这些分析还将对ASCT后免疫重建的生物学产生新的见解，并可能产生新的ASCT后多发性骨髓瘤治疗反应的候选生物标记物。

 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.