Onset and biomarkers for progression of monoclonal gammopathies

项目总结/摘要 多发性骨髓瘤（MM）是一种危及生命的浆细胞恶性肿瘤。它在黑人中是2-3倍 与白人相比。MM具有延长的临床可检测的癌前阶段，称为单克隆 未确定意义的丙种球蛋白病（MGUS），可以通过检测分泌的 单克隆免疫球蛋白（通常称为单克隆蛋白）。严重的MM是无药可救 恶性肿瘤，最好的治疗方法是通过早期干预预防终末器官损伤。这是 最好是针对处于中间无症状阶段（称为阴燃多发性硬化）的患者， 骨髓瘤（SMM），居住在MGUS和MM之间。在过去的5年里，我们已经广泛 调查了MM在黑人中比白人更常见的原因，证明了首先- MM患者的一级亲属具有高风险的前驱MGUS病变，并确定 几种生物标志物预测SMM即将进展的风险。我们的研究表明， 非裔美国人MM高风险的原因是他们有高风险的前体MGUS条件， 我们还发现，与白人相比，黑人的年龄要早得多。最近，我们做了一个 使用基于DNA测序的祖先分析的重要发现， MM占种族差异的大部分。我们的研究已经承担了更大的紧迫性与最近的发现 早期干预（在高危SMM阶段）可以预防终末器官损伤并延长总生存期。 这一更新的目标是进一步确定种族差异发生率背后的机制， MM，以确定需要治疗的高风险SMM的新生物标志物，并开发可行的筛查方法 识别SMM患者的策略。在目标1中，我们将使用敏感的， 基于质谱（MS）的检测> 12，000个NHANES样本中的单克隆蛋白，并识别 与黑人MM易感性相关的新的细胞遗传学异常。在目标2中，我们将确定 与从SMM进展为症状性MM的高风险相关的新生物标志物，特别是 利用单克隆蛋白质的质谱表征，测量循环克隆 浆细胞，并通过研究克隆多样性和免疫概况。在目标3中，我们将制定并确定 通过以下方式确定适合早期干预的SMM筛查方法的可行性和影响： 针对高风险人群，特别是非洲裔美国人，一级亲属和高风险人群， 总蛋白水平。我们的资助将对SMM和MM患者的管理产生重大影响， 尤其是非裔美国人和一级亲属或患有MM的人。

PROJECT SUMMARY/ABSTRACT Multiple myeloma (MM) is a life-threatening plasma cell malignancy. It is 2-3 times more common in blacks compared with whites. MM has a prolonged clinically detectable premalignant phase called monoclonal gammopathy of undetermined significance (MGUS) that can be identified by detection of the secreted monoclonal immunoglobulin (commonly referred to as a monoclonal protein). MM is a serious incurable malignancy, and the best approach for treatment is to prevent end organ damage by early intervention. This is best done by targeting patients with an intermediate asymptomatic stage referred to as smoldering multiple myeloma (SMM) that resides between MGUS and MM. Over the last 5 years of this grant we have extensively investigated the reasons why MM is more common in blacks compared with whites, demonstrated that first- degree relatives of patients with MM have a high risk of having the precursor MGUS lesion, and identified several biomarkers that predict risk of imminent progression in SMM. Our studies show that a principal reason for high risk of MM in African Americans is that they have a high risk of the precursor MGUS condition, which we also found is present at a much earlier in age in blacks compared with whites. More recently we made an important discovery using DNA sequencing based ancestry analysis that 3 specific cytogenetic abnormalities in MM account for most of the racial disparity. Our research has assumed greater urgency with recent findings that early intervention (in high-risk SMM stage) can prevent end-organ damage and prolong overall survival. The goals of this renewal are to further determine the mechanisms behind the racial disparity in incidence of MM, to identify new biomarkers for high risk SMM needing therapy, and to develop a feasible screening strategy to identify patients with SMM. In Aim 1 we will determine the age at onset of MGUS using sensitive, mass spectrometry (MS)-based detection of monoclonal protein in >12,000 NHANES samples, and identify new cytogenetic abnormalities that are associated with predisposition to MM in blacks. In Aim 2 we will identify new biomarkers that are associated with high risk of progression from SMM to symptomatic MM, specifically utilizing mass spectroscopic characterization of the monoclonal protein, measurement of circulating clonal plasma cells, and by studying clonal diversity and immune profile. In Aim 3, we will institute and determine the feasibility and impact of a screening approach for identification of SMM eligible for early intervention, by targeting high risk populations, specifically African Americans, first-degree relatives, and persons with high total protein levels. Our grant will have a major impact on the management of patients with SMM and MM, especially African Americans and first-degree relatives or persons with MM.