Molecular Prediction of Myeloma Initiation Molecular Prediction of Myeloma Initiation

骨髓瘤起始的分子预测 骨髓瘤起始的分子预测

• 批准号: 10698026
• 负责人: Irene M. Ghobrial
• 金额: $ 101.96万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2029-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698026
• 关键词: Age; Aging; Behavior; Biological; Black Populations; Black race; Bone Marrow; Chronology; Data; Development; Disease; Early Diagnosis; Environment; Family history of; Fracture; Goals; Hematologic Neoplasms; Hospitalization; Immune; Individual; Inflammation; Kidney Failure; Lead; Link; MALDI-TOF Mass Spectrometry; Molecular; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Morbidity - disease rate; Multiple Myeloma; Organ; Participant; Populations at Risk; Prevalence; Prevention; Process; Proteins; Race; Recording of previous events; Research; Risk; Risk Factors; Symptoms; Testing; Therapeutic Intervention; Tissues; anticancer research; cancer prevention; carcinogenicity; ethnic diversity; frontier; genomic signature; improved; paragon; prevent; randomized trial; risk prediction; screening; trait

SUMMARY Multiple Myeloma (MM) is the second most common hematologic malignancy and is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Recent randomized trials have shown that early therapeutic intervention at the stage of SMM can improve progression- free and overall survival. This indicates that early detection and therapeutic intervention before symptomatic MM occurs may lead to improved survival and decreased morbidity from other complications such as bone fractures, renal failure and hospitalizations related to end-organ damage from myeloma. Early detection requires a comprehensive screening of the population at risk for developing MM. Known risk factors for developing MM include aging, race (Blacks), and familial history of hematologic malignancies. Our preliminary data of screening ~7,500 ethnically diverse individuals at risk of developing MM using a sensitive quantitative MALDI-TOF mass spectrometry has shown a prevalence rate of monoclonal protein in 45% in individuals of age >50y and having an early immune dysregulation that we termed Monoclonal Gammopathy of Indeterminate Potential (MGIP). MGUS was significantly more prevalent in Black participants and participants with familial hematologic malignancy (HM) history than in White participants with no family history of HM. To begin to delineate mechanisms by which these early MGIP clones progress to MGUS and further lead to MM, we plan to explore the host intrinsic (age, race, germline risk factors) and acquired (inflammation, antigenic activation) risk factors on the expanding clone and its environment that influence its behavior. We believe the next frontier in MM research is to understand how one develops myeloma and treat it early before end-organ damage. Identifying and preventing the development of the earliest stages of MM will lead to transformative approaches to treatment and serve as a paragon of cancer prevention. We hypothesize that defining risk as ancestry scores and genomic signatures, instead of defining risk by self-identified race, can improve risk prediction for MM. Similarly, instead of using chronological age as a risk factor for MM, we will test the hypothesis that the effective age of the bone marrow niche confers biological risk of developing MM. Together, we believe that these studies will help define the mechanistic underpinnings of the carcinogenic process linked to MM. This approach will allow the field to transition from a purely demographic definition of risk to a biological one.

概括 多发性骨髓瘤 (MM) 是第二常见的血液恶性肿瘤，几乎总是排在第二位 意义未明的单克隆丙种球蛋白病（MGUS）和冒烟性骨髓瘤（SMM）。最近的 随机试验表明，SMM 阶段的早期治疗干预可以改善进展—— 自由和整体生存。这表明在出现症状的 MM 之前进行早期发现和治疗干预 发生可能会提高生存率并降低其他并发症（例如骨折）的发病率， 肾衰竭和与骨髓瘤终末器官损伤相关的住院治疗。早期发现需要 对有患 MM 风险的人群进行全面筛查。发生 MM 的已知风险因素 包括衰老、种族（黑人）和血液系统恶性肿瘤家族史。我们的初步筛选数据 使用灵敏的定量 MALDI-TOF 质量数，约 7,500 名面临罹患 MM 风险的不同种族个体 光谱测定法显示，年龄 > 50 岁且患有此类疾病的个体中，单克隆蛋白的患病率为 45% 一种早期的免疫失调，我们称之为不确定性单克隆丙种球蛋白病（MGIP）。 MGUS 在黑人参与者和患有家族性血液病的参与者中显着更为普遍 恶性肿瘤（HM）史高于没有 HM 家族史的白人参与者。开始描绘 这些早期 MGIP 克隆进展为 MGUS 并进一步导致 MM 的机制，我们计划探索 宿主内在（年龄、种族、种系风险因素）和获得性（炎症、抗原激活）风险因素 关于不断扩大的克隆及其影响其行为的环境。我们相信 MM 的下一个前沿 研究的目的是了解骨髓瘤是如何发生的，并在终末器官损伤之前尽早治疗。 识别并预防 MM 早期阶段的发展将带来变革性方法 治疗并成为癌症预防的典范。我们假设将风险定义为血统 分数和基因组特征可以提高风险，而不是通过自我识别的种族来定义风险 MM的预测。同样，我们不会使用实际年龄作为 MM 的危险因素，而是测试 假设骨髓生态位的有效年龄赋予发生 MM 的生物学风险。 我们相信，这些研究将有助于确定致癌的机制基础。 进程链接到MM。这种方法将使该领域从纯粹的人口统计风险定义转变 到生物的。