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.

项目概要 多发性骨髓瘤 (MM) 影响美国约 35,000 名成年患者，每年导致约 12,000 人死亡 年。新型免疫调节药物和有效的多药组合改善了患者的预后 患者，但绝大多数患者最终会复发。即使在患者中也达到了完全 响应，2 年内进步约 25%。大多数 MM 复发可归因于可测量的持续存在 （最小）残留病灶（MRD）。 MRD 状态已成为最重要的预后标志之一， 具有治疗意义，并已纳入国际骨髓瘤工作组反应标准 用于治疗反应评估。 MRD 评估的黄金标准包括多参数流量 基于骨髓抽吸物的细胞计数和下一代测序（NGS）。然而，评价 仅使用骨髓抽吸物进行 MRD 时，由于疾病涉及的斑片状，很容易出现假阴性， 骨抽出物的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，因此不能频繁执行来监测 MRD。正电子发射断层扫描/计算机 断层扫描 (PET/CT) 是对骨髓评估的补充，但仍存在差距。我们已经展示了 5-羟甲基胞嘧啶 (5hmC)，一种由活性 DNA 产生的稳定表观遗传标记 血浆游离 DNA (cfDNA) 中的去甲基化可以与 PET/CT 互补，并与 MM 患者的总生存期。在这里，我们建议应用全基因组的高度灵敏的作图 cfDNA 中的 5hmC，以确定基于 cfDNA 的系列 5hmC 标记与 PET/CT 的最佳组合 检测 MRD 的出现。我们的中心假设是 cfDNA 中 5hmC 特征的改变与 通过 PET/CT 和/或 NGS 进行临床可检测的疾病，从而提供准确但更少的机会 侵入性方法可补充 NGS 进行的基于骨髓的 MRD 评估。具体来说，我们建议 识别 cfDNA 中与 MRD 阳性相关的 5hmC（目标 1），确定基于 cfDNA 的时间动态 与 MRD 相关的 5hmC 和氟脱氧葡萄糖 (FDG)-PET/CT 变化（目标 2），并评估 不同 MRD 模式在现实世界患者中的表现（目标 3）。为了实现这些目标，我们 组建了一支具有广泛且互补的专业知识的跨学科团队。该研究利用 芝加哥大学骨髓瘤流行病学研究的资源以及我们在三项临床试验中的领导地位 包括储存的系列血样、骨髓配对外周血以及 NGS 已知的 MRD 状态。这 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应用： 正确组合连续 MRD 评估（即 cfDNA、PET/CT 和骨髓）以进行灵敏跟踪 MRD 的研究，并为表观遗传对 MM 进展的贡献提供新的见解。识别 成功治疗后病情进展高风险的患者将能够及时实施额外的治疗 可能最终降低 MM 患者发病率和死亡率的治疗策略。