Addressing racial disparities in monoclonal gammopathy of undetermined significance and progression to multiple myeloma from a prevention perspective

从预防角度解决意义不明的单克隆丙种球蛋白病的种族差异以及多发性骨髓瘤的进展

• 批准号: 10055834
• 负责人: Su-Hsin Chang
• 金额: $ 36.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055834
• 关键词: Address; Adult; African American; Age; Area; Artificial Intelligence; Big Data; Biological; Biological Markers; Body Weight decreased; Body mass index; Caucasians; Chemoprevention; Chemopreventive Agent; Clinical; Cost of Illness; Data; Data Analyses; Databases; Department of Defense; Diabetes Mellitus; Diagnosis; Disease; Disease Marker; Disease Progression; Economic Burden; Event; Future; General Population; Goals; Growth; Health; Hematologic Neoplasms; Incidence; Individual; International Agency for Research on Cancer; Intervention; Life; Life Cycle Stages; Link; Machine Learning; Malignant Neoplasms; Measures; Medicare/Medicaid; Metformin; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Neoplasms; Obesity; Patient observation; Patients; Pharmaceutical Preparations; Play; Population; Predisposition; Prevalence; Prevention; Prevention strategy; Prevention trial; Process; Proteins; Race; Rare Diseases; Risk; Risk Factors; Role; Serum; Solid Neoplasm; Subgroup; Variant; Veterans; base; carcinogenicity; clinical encounter; clinical practice; cost; diabetic; follow-up; genetic testing; glycemic control; health disparity; health economics; innovation; modifiable risk; multiple myeloma M Protein; preclinical study; premalignant; prevent; progression marker; prospective; racial difference; racial disparity; specific biomarkers; working group

PROJECT SUMMARY/ABSTRACT Multiple myeloma (MM) is a lethal neoplasm and a common hematologic malignancy. MM is uniformly preceded by monoclonal gammopathy of undetermined significance (MGUS). Unlike MM, patients with MGUS are asymptomatic. The current management for MGUS is watchful waiting for disease progression. A marked racial disparity in this disease area is long-established with a 2 to 3-fold increased risk in African Americans (AAs) compared to Caucasians. Moreover, obesity is a risk factor for MM independent of race. Obesity is prevalent in U.S. adults, and particularly more prevalent among AAs than Caucasians. As a result, without any intervention, racial disparities in this disease will continue to worsen. Metformin, a widely-used, safe, well- tolerated, and inexpensive medication, induces weight loss and has been found to be more effective in glycemic control in AAs compared to Caucasians. It has also been used in prospective trials for non-diabetes indications and solid tumor malignancies. We therefore hypothesize that metformin use in MGUS patients will prevent MM and reduce MM disparities. This project plans to focus on the precursor condition of MM – MGUS. The findings from the proposed project will inform biological mechanism studies and MGUS/MM prevention trials. The long-term goal is to identify intervention strategies to prevent the progression of MGUS to MM, reduce the overall burden of MM, and reduce MM disparities. We plan to identify whether high body mass index (BMI) and/or significant change in BMI over the life course are risk factors for MGUS by race (Aim 1), utilizing linked databases with nearly lifelong follow-up of BMI and other health measures ,as well as utilizing artificial intelligence, i.e., machine learning approaches, to perform big data analyses. We will then assess racial differences in the M-protein trajectory after MGUS diagnosis in metformin versus non-metformin users in a subgroup of MGUS patients diagnosed with diabetes mellitus (Aim 2.1) and the association of metformin use with the progression of MGUS to MM (Aim 2.2). Last, we will assess racial differences in the M-protein trajectory in the subgroup of MGUS patients without diabetes mellitus (Aim 3). This project is significant in its capability to 1) identify perhaps the only modifiable risk factor (high BMI) to inform interventions to prevent MM; 2) identify a dynamic marker for disease progression by race (M-protein concentration), where these biomarkers can be a surrogate for MM diagnosis in future prevention trials; and 3) reduce MM health disparities by a) identifying race-specific biomarkers for MGUS and MGUS progression, available through clinical encounters (as opposed to expensive genetic testing); and b) exploring metformin use as a chemopreventive measure. It is innovative in its 1) focus on MM prevention rather than treatment and 2) utilization of artificial intelligence to analyze big data. Successful completion of this study will provide evidence for a paradigm shift in current clinical practice of MGUS management and help prevent MM, an incurable and costly disease. More importantly, it will provide evidence to guide interventions to reduce MM disparities.

项目概要/摘要 多发性骨髓瘤（MM）是一种致命的肿瘤，也是一种常见的血液系统恶性肿瘤。 MM统一 先于意义未明的单克隆丙种球蛋白病（MGUS）。与 MM 不同，MGUS 患者 无症状。目前 MGUS 的治疗方法是观察疾病进展。一个标记的 该疾病领域的种族差异由来已久，非洲裔美国人的患病风险增加了 2 至 3 倍 （AA）与白种人相比。此外，肥胖是 MM 的危险因素，与种族无关。肥胖是 在美国成年人中普遍存在，尤其是在 AA 中比白种人更普遍。结果，没有任何 如果不采取干预措施，这种疾病的种族差异将继续恶化。二甲双胍是一种广泛使用、安全、良好的 耐受且廉价的药物可引起体重减轻，并且已被发现更有效 与白种人相比，AA 人群的血糖控制情况。它还被用于非糖尿病的前瞻性试验 适应症和实体瘤恶性肿瘤。因此，我们假设 MGUS 患者使用二甲双胍会 预防MM并减少MM差异。该项目计划重点研究MM的先兆条件——MGUS。 拟议项目的研究结果将为生物机制研究和 MGUS/MM 预防提供信息 试验。长期目标是确定干预策略以防止 MGUS 进展为 MM， 减轻MM的整体负担，缩小MM的差距。我们计划确定体重是否过高 指数 (BMI) 和/或生命历程中 BMI 的显着变化是按种族划分的 MGUS 的危险因素（目标 1）， 利用链接数据库对 BMI 和其他健康指标进行近终生跟踪，并利用 人工智能（即机器学习方法）来执行大数据分析。然后我们将评估 二甲双胍使用者与非二甲双胍使用者在 MGUS 诊断后 M 蛋白轨迹的种族差异 诊断患有糖尿病的 MGUS 患者亚组（目标 2.1）与二甲双胍使用的关联 随着 MGUS 进展为 MM（目标 2.2）。最后，我们将评估 M 蛋白的种族差异 无糖尿病 MGUS 患者亚组的轨迹（目标 3）。该项目的重大意义在于 能够 1) 确定可能是唯一可改变的风险因素（高 BMI），为预防 MM 的干预措施提供信息； 2) 确定按种族划分的疾病进展的动态标记（M 蛋白浓度），其中这些 生物标志物可以在未来的预防试验中替代多发性骨髓瘤诊断； 3) 降低 MM 健康状况 a) 确定 MGUS 和 MGUS 进展的种族特异性生物标志物，可通过 临床接触（相对于昂贵的基因检测）； b) 探索二甲双胍的用途 化学预防措施。它的创新之处在于：1) 重点关注多发性骨髓瘤的预防而不是治疗，2) 利用人工智能来分析大数据。成功完成这项研究将提供证据 改变当前 MGUS 管理临床实践的范式，并帮助预防 MM 这一无法治愈的疾病 昂贵的疾病。更重要的是，它将提供证据来指导减少 MM 差异的干预措施。