Integrating liquid biopsy-based epigenetic and imaging modalities to evaluate disease response in multiple myeloma

整合基于液体活检的表观遗传学和成像方式来评估多发性骨髓瘤的疾病反应

• 批准号: 10651370
• 负责人: BRIAN C-H CHIU
• 金额: $ 69.17万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651370
• 关键词: Address; Adult; Affect; Aftercare; Age; Algorithms; Biological; Biological Assay; Blood Specimen Collection; Blood specimen; Bone Marrow; Bone Marrow Aspiration; Bone marrow biopsy; Cells; Cessation of life; Chemicals; Clinical; Clinical Trials; Complement; DNA; Data; Detection; Diagnosis; Disease; Drug Combinations; Early Diagnosis; Epigenetic Process; Evaluation; Extramedullary; Flow Cytometry; Genome Mappings; Glycolysis; Goals; Hematologic Neoplasms; Hemodilution; Heterogeneity; Image; In complete remission; Infiltration; International; Knowledge; Label; Leadership; Lesion; Measurable; Metabolic; Modality; Modeling; Modernization; Monitor; Morbidity - disease rate; Morphology; Multiple Myeloma; Neoadjuvant Therapy; Newly Diagnosed; Observational Study; Oligonucleotides; Patient Care; Patients; Performance; Plasma; Plasma Cells; Positron-Emission Tomography; Procedures; Prognostic Marker; Progression-Free Survivals; Relapse; Residual Neoplasm; Resolution; Resources; Sampling; Specimen; Techniques; Testing; Therapeutic; Time; Translating; Tumor Volume; Tumor-Associated Process; United States; Work; X-Ray Computed Tomography; aspirate; bone; bone cell; bone imaging; cell free DNA; clinical decision-making; demethylation; epidemiology study; fluorodeoxyglucose positron emission tomography; genome-wide; high risk; imaging modality; immune modulating agents; improved; insight; liquid biopsy; mortality; neoplastic cell; next generation sequencing; non-invasive monitor; novel; participant enrollment; patient prognosis; patient response; peripheral blood; phase II trial; prevent; prognostication; progression risk; prospective; response; seal; sex; standard of care; treatment effect; treatment response; tumor specificity; working group

PROJECT SUMMARY Multiple myeloma (MM) affects ~35,000 adult patients in the United States and causes ~12,000 deaths each year. Novel immunomodulatory drugs and effective multidrug combinations have improved the prognosis for patients, but the vast majority of patients eventually relapse. Even among patients achieve a complete response, ~25% progress within 2 years. Most MM relapses can be attributed to the persistence of measurable (minimal) residual disease (MRD). MRD status has emerged as one of the most important prognostic markers, has therapeutic implications, and is incorporated in the International Myeloma Working Group response criteria for therapeutic response assessment. The gold standard of MRD assessment includes multiparameter flow cytometry and next-generation sequencing (NGS) based on bone marrow aspirates. However, evaluation of MRD using only bone marrow aspirates is prone to false-negatives due to patchy disease involvement, hemodilution of bone aspirate, and extramedullary disease. In addition, bone marrow biopsy is an invasive procedure, hence cannot be performed frequently to monitor MRD. Positron emission tomography/computed tomography (PET/CT) is complementary to bone marrow assessment although gaps remain. We have shown that the 5-hydroxymethylcytosine (5hmC), a stable epigenetic marks generated from active DNA demethylation, in plasma cell-free DNA (cfDNA) could be complementary to PET/CT and was associated with overall survival of patients with MM. Here we propose to apply the highly sensitive mapping of genome-wide 5hmC in cfDNA to identify the optimal combination of serial cfDNA-based 5hmC markers with PET/CT for detecting emergence of MRD. Our central hypothesis is that altered 5hmC signatures in cfDNA are associated with clinically detectable disease by PET/CT and/or NGS, thus offering opportunities for accurate yet less invasive approaches to complement bone marrow-based MRD assessment by NGS. Specifically, we propose to identify 5hmC in cfDNA associated with MRD-positivity (Aim 1), determine cfDNA-based temporal dynamics of 5hmC and fluorodeoxyglucose (FDG)-PET/CT changes associated with MRD (Aim 2), and evaluate performance of different MRD modalities in real-world patients (Aim 3). To address these aims, we have assembled an interdisciplinary team with extensive and complementary expertise. The study leverages the established resources of the UChicago Myeloma Epidemiology Study and our leadership in three clinical trials with banked serial blood samples, bone marrow-paired peripheral blood, and known MRD status by NGS. The knowledge gained from this application may improve clinical utilization of MRD in clinical decision making by proper combination of serial MRD assessments (i.e., cfDNA, PET/CT, and bone marrow) for sensitive tracking of MRD as well as provide novel insights into the epigenetic contribution to MM progression. Identifying patients at high risk of progression after successful treatment will allow for timely implementation of additional therapeutic strategies that may ultimately reduce morbidity and mortality among MM patients.

项目摘要 多发性骨髓瘤（MM）影响美国约35，000名成人患者，并导致约12，000人死亡 年新型免疫调节药物和有效的多药联合治疗改善了 患者，但绝大多数患者最终复发。甚至在患者中实现完全的 反应，2年内约25%的进展。大多数MM复发可归因于持续的可测量的 （微小）残留病（MRD）。MRD状态已成为最重要的预后标志之一， 具有治疗意义，并被纳入国际骨髓瘤工作组反应标准 用于治疗反应评估。MRD评估的金标准包括多参数流 基于骨髓抽吸物的细胞计数和下一代测序（NGS）。然而，评价 仅使用骨髓抽吸物的MRD由于斑片状疾病累及而易于出现假阴性， 骨抽吸物血液稀释和髓外疾病。此外，骨髓活检是一种侵入性检查， 程序，因此不能频繁执行以监测MRD。正电子发射断层扫描/计算机 断层扫描（PET/CT）是骨髓评估的补充，尽管仍存在差距。我们已经表明 5-羟甲基胞嘧啶（5 hmC）是活性DNA产生的稳定的表观遗传标记， 血浆游离DNA（cfDNA）中的去甲基化可以与PET/CT互补，并与 MM患者的总生存率。在这里，我们建议应用高度敏感的全基因组定位， cfDNA中的5 hmC，以鉴定基于cfDNA的系列5 hmC标志物与PET/CT的最佳组合， 检测MRD的出现。我们的中心假设是cfDNA中改变的5 hmC特征与 通过PET/CT和/或NGS临床可检测到的疾病，从而提供准确但更少的机会， 侵入性方法，以补充NGS基于骨髓的MRD评估。具体来说，我们建议 为了识别与MRD阳性相关的cfDNA中的5 hmC（目标1），确定基于cfDNA的时间动态 与MRD相关的5 hmC和氟脱氧葡萄糖（FDG）-PET/CT变化（目的2），并评估 不同MRD模式在真实世界患者中的性能（目标3）。为了实现这些目标，我们 组建了一个具有广泛和互补专业知识的跨学科团队。这项研究利用了 建立了芝加哥大学骨髓瘤流行病学研究的资源和我们在三项临床试验中的领导地位 与库中的系列血液样本、骨髓配对外周血和NGS已知的MRD状态。的 从该应用中获得的知识可以通过以下方式提高MRD在临床决策中的临床利用率： 系列MRD评估的适当组合（即，cfDNA、PET/CT和骨髓）用于灵敏追踪 以及提供新的见解表观遗传学的MM进展的贡献。识别 成功治疗后进展风险高的患者将允许及时实施额外的 最终可能降低MM患者发病率和死亡率的治疗策略。