Liquid biopsy in myeloma to inform outcome and treatment decisions

骨髓瘤液体活检可为结果和治疗决策提供信息

• 批准号: 10562684
• 负责人: Jens G Lohr
• 金额: $ 40.72万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-10 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562684
• 关键词: Affect; Biological Markers; Biopsy; Blood; Bone Marrow; Bone Marrow Involvement; Bone marrow biopsy; Cancer Patient; Caring; Cells; Clinical; DNA; Databases; Detection; Detection of Minimal Residual Disease; Diagnosis; Disease; Disease Marker; Drug Targeting; Drug resistance; Drug resistance pathway; Evolution; Failure; Genetic; Genetic Diseases; Genomics; Goals; Guidelines; Hematological Disease; Heterogeneity; Immunotherapy; Malignant Neoplasms; Methods; Molecular; Monitor; Multiple Myeloma; National Comprehensive Cancer Network; Nature; Neoplasm Circulating Cells; Newly Diagnosed; Outcome; Patients; Performance; Plasma Cells; Principal Investigator; Proxy; Recommendation; Recurrent disease; Refractory; Relapse; Residual Neoplasm; Resolution; Risk; Risk Reduction; Sampling Biases; Sensitivity and Specificity; Site; Source; Technology; Testing; Therapeutic; Time; Tissues; United States National Institutes of Health; Variant; Writing; burden of illness; cell free DNA; circulating cancer cell; clinical care; clinical decision-making; clinically actionable; clinically relevant; cohort; effective therapy; exome; experience; experimental study; genetic predictors; genetic variant; genome sequencing; genomic predictors; innovative technologies; insight; liquid biopsy; molecular dynamics; multimodality; novel; novel strategies; optimal treatments; outcome prediction; prognostic; prognostication; relapse prediction; response; standard of care; success; survival prediction; targeted sequencing; treatment choice; treatment response; whole genome

Project Summary Although effective therapies exist in many cancers, an initial response to therapy is often followed by relapse. An extreme example is multiple myeloma, a plasma cell malignancy in the bone marrow, which responds to treatment in almost all patients, but which cannot be cured. Myeloma patients therefore receive many different lines of therapy during the course of their disease. Repeated bone marrow biopsies are crucial for monitoring of treatment response and for informing the optimal choice of treatment and are therefore currently recommended with any change in treatment. However, the excessive number of biopsies over time creates an enormous burden for patients, and these tissue biopsies are often not performed beyond initial diagnosis. In addition, bone marrow biopsies only capture myeloma cells from a single site, and therefore do not provide a complete representation of the heterogeneity and ongoing evolution of this multifocal disease that is characterized by patchy bone marrow involvement. It is therefore imperative to develop novel approaches that allow to frequently assess myeloma evolution during therapy and choose those treatments that are most efficacious. We are proposing to use novel “liquid biopsy” approaches to replace bone marrow biopsy by interrogating circulating myeloma cells and cell-free DNA in myeloma patients, obtained from a simple blood draw. We hypothesize that liquid biopsy provides more comprehensive and clinically relevant insights into the molecular dynamics and genomic evolution of myeloma than can be obtained through single-site bone marrow biopsies. To accomplish this task, we have pioneered technologies for highly sensitive isolation and deep molecular and genomic characterization of circulating multiple myeloma cells (CMMCs) with single cell resolution, as well as whole genome and targeted sequencing of cell-free DNA (cfDNA). We will leverage these technologies to inform clinical decision-making in a way that is impossible with the current practice of using bone marrow biopsies as standard-of-care. Specifically, we will demonstrate that: 1) Liquid biopsy is a better predictor of survival than parameters currently used in clinical routine, 2) Liquid biopsy has greater sensitivity and specificity to detect established prognostic and predictive genetic disease variants than bone marrow biopsy, the current gold-standard, 3) Liquid biopsy provides a therapeutically more relevant representation of the clonal composition and actionable treatment targets of myeloma than bone marrow biopsy, 4) Liquid biopsy outperforms bone marrow biopsy in determining minimal residual disease (MRD) status. Importantly, replacing repeated invasive biopsies with liquid biopsy from a simple blood draw will dramatically reduce risk and discomfort for patients. We expect that the concepts we are investigating will be practice-changing for the care of myeloma patients and will be broadly relevant across many different cancers and produce important new opportunities for therapies.

项目摘要 尽管许多癌症都有有效的治疗方法，但对治疗的最初反应往往是复发。 一个极端的例子是多发性骨髓瘤，一种骨髓中的浆细胞恶性肿瘤， 几乎所有的患者都能接受治疗，但无法治愈。因此，骨髓瘤患者接受许多不同的 在他们的疾病过程中的治疗路线。反复骨髓活检对于监测至关重要 治疗反应和告知治疗的最佳选择，因此目前 建议在治疗的任何变化。然而，随着时间的推移，过多的活组织检查会造成 这给患者带来了巨大的负担，并且这些组织活检通常在初步诊断之后不进行。在 此外，骨髓活检仅从单个部位捕获骨髓瘤细胞，因此不能提供对骨髓瘤的诊断。 这是一种多灶性疾病的异质性和持续演变的完整表现， 以斑片状的骨髓受累为特征。因此，必须开发新的方法， 允许在治疗期间经常评估骨髓瘤的演变，并选择那些最适合的治疗方法。 灵验。我们建议使用新的“液体活检”方法来取代骨髓活检， 询问骨髓瘤患者的循环骨髓瘤细胞和无细胞DNA，从简单的血液中获得 画画我们假设液体活检提供了更全面和临床相关的见解， 骨髓瘤的分子动力学和基因组进化，而不是通过单一位点骨髓 活组织检查为了完成这一任务，我们开创了高灵敏度隔离和深度隔离技术， 循环多发性骨髓瘤细胞（CMMCs）的分子和基因组特征 分辨率，以及全基因组和无细胞DNA（cfDNA）的靶向测序。我们将利用这些 技术，以告知临床决策的方式是不可能的，目前的做法， 骨髓活检作为标准治疗具体来说，我们将证明：1）液体活检是一种更好的 与目前临床常规使用的参数相比，液体活检具有更高的敏感性 和特异性，以检测已建立的预后和预测性遗传疾病变异比骨髓 活检，目前的金标准，3）液体活检提供了一个治疗更相关的代表性， 骨髓瘤的克隆组成和可操作的治疗靶点高于骨髓活检; 4）液体活检 在确定微小残留病（MRD）状态方面优于骨髓活检。重要的是，替换 通过简单抽血进行液体活检的重复侵入性活检将显著降低风险， 患者的不适。我们希望我们正在调查的概念将改变护理实践 骨髓瘤患者，并将在许多不同的癌症广泛相关，并产生重要的新的 治疗的机会。