Onset and biomarkers for progression of monoclonal gammopathies

项目摘要/摘要 多发性骨髓瘤(MM)是一种威胁生命的浆细胞恶性肿瘤。它在黑人中的发病率是黑人的2-3倍 与白人相比。多发性骨髓瘤有一种临床可检测到的较长的癌前阶段，称为单克隆期。 可通过检测分泌物确定的未确定意义的伽马病(MGUS) 单克隆性免疫球蛋白(通常称为单克隆性蛋白)。MM是一个严重的不治之症 恶性，最好的治疗方法是通过早期干预预防终末器官损害。这是 最好是以中间无症状阶段的患者为目标，称为阴燃多发性 位于MGUS和MM之间的骨髓瘤(SMM)。在过去的5年里，我们广泛地 调查了多发性硬化症在黑人中比白人更常见的原因，证明了第一- 多发性骨髓瘤患者的程度亲属有很高的风险患有前驱MGUS病变，并被确定 几个预测SMM即将进展的风险的生物标志物。我们的研究表明，一个主要原因是 在非裔美国人中，MM的高风险在于他们有先兆MGUS疾病的高风险，这 我们还发现，与白人相比，黑人的年龄要早得多。最近，我们做了一次 利用DNA测序进行系谱分析的重要发现：3种特殊的细胞遗传学异常 MM是造成种族差异的主要原因。我们的研究因最近的发现而显得更加紧迫。 早期干预(高危SMM期)可以预防终末器官损害，延长总体生存时间。 这次更新的目标是进一步确定发病率种族差异背后的机制。 MM，为需要治疗的高危SMM寻找新的生物标志物，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SENSIVE， 基于质谱法检测&gt；12,000份NHANES样本中的克隆蛋白，并鉴定 与黑人多发性骨髓瘤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 新的生物标志物与从SMM进展到症状性MM的高风险相关，特别是 利用单克隆蛋白的质谱学表征，循环克隆的测定 通过研究克隆多样性和免疫图谱。在目标3中，我们将制定和确定 确定符合早期干预条件的SMM的筛查方法的可行性和影响 针对高危人群，特别是非裔美国人、一级亲属和高危人群 总蛋白质水平。我们的赠款将对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MM患者。

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.