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）是第二常见的血液系统恶性肿瘤，几乎总是在 不确定意义（MGUS）和闷烧骨髓瘤（SMM）的单克隆性伽马病。最近的 随机试验表明，在SMM阶段的早期治疗干预可以改善进展 自由和整体生存。这表明有症状的MM之前的早期检测和治疗干预 发生可能导致其他并发症（例如骨骼骨折）的生存率提高和发病率降低， 肾功能衰竭和住院与骨髓瘤的最终器官损伤有关。早期检测需要一个 全面筛查有发展MM的风险的人口。开发MM的已知风险因素 包括衰老，种族（黑人）和血液学恶性肿瘤的家族史。我们的筛选初步数据 〜使用敏感的定量质量质量，有7,500个种族多样的人有可能开发MM的人 光谱法显示了45％的单克隆蛋白患病率> 50岁，并且具有 早期的免疫失调，我们称为不确定潜力（MGIP）的单克隆性颅脑病。 在黑人参与者和家族血液学的参与者中，MGU明显更为普遍 与没有HM家族史的白人参与者相比，恶性病史（HM）的历史。开始描绘 这些早期MGIP克隆发展到MGU并进一步导致MM的机制，我们计划探索 宿主的内在（年龄，种族，种系风险因素）和获得（炎症，抗原激活）风险因素 在影响其行为的不断扩展的克隆及其环境上。我们相信MM的下一个边界 研究是了解人们如何发展骨髓瘤并在最终器官损伤之前对其进行治疗。 识别和防止MM最早阶段的发展将导致变革性的方法 治疗并充当预防癌症的典范。我们假设将风险定义为祖先 分数和基因组签名，而不是通过自我认同种族来定义风险，可以改善风险 MM的预测。同样，我们将测试 假设有效的骨髓生态位年龄赋予了生物发展MM的生物学风险。 我们认为，这些研究将有助于定义致癌的机械基础 链接到MM的过程。这种方法将使该领域从纯粹的人口统计学定义过渡 到一个生物学。