Onset and biomarkers for progression of monoclonal gammopathies

描述(申请人提供)：多发性骨髓瘤(MM)是一种危及生命的血液系统恶性肿瘤。尽管取得了重大进展，中位生存期仍然只有5年。骨髓瘤有一个很长的临床可检测的癌前阶段，称为未确定意义的单克隆性伽马病(MGUS)，使用分泌的生物标记物单克隆性免疫球蛋白(M蛋白)可以很容易地识别这种疾病。还有一个中间的临床阶段，称为阴燃多发性骨髓瘤(SMM)。SMM包括约50%的MGUS患者有克隆性非恶性疾病和50%的早期MM患者有生物学上的恶变，但临床上尚不明显。骨髓瘤在癌症中是独一无二的，因为发病率存在显著的种族差异；例如，年轻的黑人患这种疾病的风险是白人的3倍。其次，我们最近发现，近亲的发病率有所增加：一级亲属患上MGUS的风险是前者的2-3倍。第三，尽管有SMM的中间阶段，早期干预的时机已经成熟，但我们预防骨髓瘤的能力受到削弱，因为我们无法区分恶性疾病(MM)和克隆性非恶性疾病(MGUS)，除非临床上存在或不存在终末器官损害。迫切需要能够可靠地区分这两者的生物标志物。我们已经确定了需要回答的3个基本问题：1)MGUS起源于何时和为什么？2)黑人和一级亲属风险增加的原因是什么，它能告诉我们什么关于疾病的病因？3)哪些特定的生物标志物可以准确地识别患有早期恶性肿瘤并因此注定在2年内进展为有症状的MM的SMM患者？我们为理解MGUS、SMM和MM做出了重大贡献，并已做好准备解决这三个关键问题。在目标1中，我们将首次通过研究12,540名年龄在10-49岁的患者的血液样本来确定MGUS的发病和危险因素，这些患者代表了美国少数民族代表过多的分层随机抽样。在目标2中，我们将研究MGUS在MM患者的一级亲属中的发病率和危险因素。在目标3中，我们将寻找指示SMM恶性转化的生物标志物，从而预测即将进展为症状性MM。我们相信，我们的研究具有很高的创新性，将对我们理解MGUS的病因、种族差异和家族发病率增加的原因产生深远的影响，并为早期发现恶性肿瘤提供生物标志物。我们还相信，我们的结果将从根本上改变这种疾病的早期诊断和治疗。 与公共卫生相关：在50岁以上的人群中，有3%的人会发生意义不明的单克隆性伽马病，并具有发展为多发性骨髓瘤的终生风险；鉴于多发性骨髓瘤的不治之症的性质，研究MGUS的发生时间和原因及其向恶性发展是至关重要的。重要的第一步是确定MGUS和MM发病率的显著种族/民族差异以及MM患者一级亲属MGUS风险增加2-3倍背后的性质和原因。我们还需要确定进展为多发性骨髓瘤的高风险患者，以便考虑未来的预防策略。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a life-threatening hematologic malignancy. Despite major advances, median survival is still only 5 years. Myeloma has a long clinically detectable premalignant phase called monoclonal gammopathy of undetermined significance (MGUS) that can be identified easily using the secreted biomarker monoclonal immunoglobulin (M protein). There is also an intermediate clinical stage referred to as smoldering multiple myeloma (SMM). SMM consists of approximately 50% of patients with MGUS who have clonal but nonmalignant disease and 50% of patients with early stage MM in whom the malignant transformation has occurred biologically but is not yet clinically apparent. Myeloma is unique among cancers because of the dramatic racial disparity in incidence; young blacks for example have a 3 fold higher risk of the disease than whites. Second, there is an increased incidence in close relatives that we have recently identified: first degree relatives hav a 2-3 fold higher risk of MGUS. Third, despite having an intermediate SMM stage that is ripe for early intervention, we are crippled in our ability to prevent myeloma since we are unable to discriminate malignant disease (MM) from clonal non malignant disease (MGUS) except through the presence or absence of clinical end-organ damage. Biomarkers that can reliably distinguish the two are critically needed. We have identified 3 fundamental questions that need to be answered: 1) When and why does MGUS originate? 2) What is the reason for the increased risk in blacks and in first degree relatives and what can it teach us about the etiology of the disease? 3) What are the specific biomarkers that can accurately identify SMM patients who have early malignancy and therefore destined to progress to symptomatic MM within 2 years? We have made major contributions to the understanding of MGUS, SMM, and MM and are well poised to address these 3 crucial questions. In Aim 1, we will determine for the first tim the onset and risk factors for MGUS by studying blood samples from 12,540 patients age 10-49 representing a stratified random sampling of the United States with overrepresentation of minorities. In Aim 2, we will study the incidence and risk factors for MGUS in first-degree relatives of patients with MM. In Aim 3, we will identify biomarkers that indicate the presence of malignant transformation in SMM, and thereby predict for imminent progression to symptomatic MM. We believe that our studies are highly innovative, and will have a far-reaching impact on our understanding of the etiology of MGUS, the reasons for the racial disparity and increased familial incidence, and provide biomarkers for early detection of malignancy. We also believe our results will fundamentally alter the early diagnosis and treatment of this disease. PUBLIC HEALTH RELEVANCE: Monoclonal gammopathy of undetermined significance occurs in >3% of the population over the age of 50 and carries a lifelong risk of progression to multiple myeloma; and given the incurable nature of MM it is vital to study the timing and causes of origin of MGUS and its progression to malignancy. An important first step is to define the nature and reasons behind the significant racial/ethnic disparities in the incidence of MGUS and MM and the 2-3 fold increased risk of MGUS in first-degree relatives of MM patients. We also need to identify patients who are at high risk of progression to MM in order to consider future preventive strategies.