Tailored monitoring of patients with monoclonal gammopathy to improve early detection of myeloma and monoclonal gammopathy of clinical significance

早期发现对患者来说是重中之重，并可提高生存率：如果在早期诊断，84%的骨髓瘤患者可存活50年，而如果在晚期诊断，这一比例仅为26%。骨髓瘤最常被诊断为晚期（症状出现后3-6个月），并且在所有癌症中诊断延迟时间最长，在急性症状出现时，30%的新诊断的骨髓瘤患者的生存期缩短，骨髓癌症是世界上第20位最常见的癌症死亡原因，仍然无法治愈。骨髓瘤（MM）通常在晚期被诊断出来，因为它对患者的整体健康有多重影响，包括骨病、肾病和免疫系统减弱。最近的治疗提高了预期寿命和生活质量。越早诊断和治疗骨髓瘤，越有效地控制症状，提高患者存活率，降低治疗晚期骨髓瘤和伴随的合并症相关的医疗费用。每一种骨髓瘤都起源于一种称为未确定意义单克隆γ病（MGUS）的前期无症状且未确诊的疾病，发生在约3%的50岁及以上人群中。使用现有的廉价的诊断性血液检查筛查bbb50的MGUS和监测进展，可以实现骨髓瘤的早期诊断，但不太可能具有成本效益，因为大多数MGUS患者不会发展为MM。临床意义单克隆γ病（MGCS）是最近创造的一个术语，用于捕获一组有肾损害、神经损伤、与单克隆蛋白的存在或沉积直接相关的骨折或皮肤病变。缺乏对这种临床关联的认识导致诊断延迟和对受累器官的不可逆损害。因此，我们的目标是明确识别进展为骨髓瘤和/或MGCS的高风险MGUS患者。目的1：了解症状负担，以及驱动检测要求的其他临床参数，从而得出MGUS的偶然诊断是关键。使用临床实践研究数据链（CPRD）对编码为单克隆伽玛病的患者的初级保健记录的访问来生成该数据集。我们将确定从mggs到MM转变的一组预测因子。CPRD数据也将能够确定最近被描述为MGCS条件的临床关联。目标2：牛津大学医院，我们最近在牛津郡临床调试小组的资助下建立了OxCom临床服务，以改善牛津郡社区患者的连续MGUS监测。这笔资金已用于解决缺乏对MGUS患者的连续随访的问题；患者经常失去随访，全科医生无法解决初级保健中MGUS患者产生的临床问题。OxCom的基础设施使我们能够生成包含详细临床和实验室数据的前瞻性数据集。从CPRD数据集产生的假设生成观测可以在这个前瞻性MGUS数据库中得到验证。我们将在OxCom数据库中验证初级保健预防模型。目的3：最近的观察表明，MGUS患者分泌的轻链的异常变化可以帮助预测谁会发展为MGCS，和/或可能转变为骨髓瘤。通过与牛津大学化学系的合作，我们可以在OxCom服务中获得的剩余患者样本中前瞻性地评估这些初步观察结果。这些共享的研究资源将有助于推动NHS早期诊断和MGUS/骨髓瘤护理的改善。我的愿景是利用牛津大学在大数据分析（初级保健数据）方面的多学科专业知识，结合二级保健临床服务和蛋白质化学专业知识，改善对MGCS患者的监测，并实现MGCS和骨髓瘤的早期诊断。

Earlier detection is a high priority for patients and improves survival: 84% of people with myeloma survive for >5 years if diagnosed at the earliest stage, compared with only 26% if diagnosed at advanced stage. Myeloma is most frequently diagnosed late (>3-6 months post symptom presentation) and has the longest diagnostic delay of any cancer, with emergency presentations in >30% of newly diagnosed myeloma patients who have shortened survival, cancer arising from bone marrow, is the 20th most common cause of cancer deaths worldwide and remains incurable. Myeloma (MM) is often diagnosed at an advanced stage when it has multiple effects on patients' overall well-being, including bone disease, kidney disease, and a weakened immune system. Recent treatments have improved life expectancy and quality of life. The earlier that myeloma is diagnosed and treated, the more effectively symptoms are controlled, improving patient survival and reducing healthcare costs associated with treating late-stage myeloma and attendant co-morbidities. Every myeloma arises from a preceding, often symptomless and undiagnosed condition called Monoclonal Gammopathy of Undetermined Significance (MGUS), occurring in ~3% people aged 50 years and over. Screening >50s for MGUS and monitoring for progression using the existing inexpensive diagnostic blood test would enable myeloma early diagnosis but is unlikely to be cost-effective as most people with MGUS do not develop MM. Monoclonal gammopathy of clinical significance (MGCS) is a recently coined termed to capture a set of monoclonal gammopathy patients who have kidney impairment, nerve damage, bone fractures or skin lesions directly linked to the presence or deposition of the monoclonal protein. Lack of recognition of this clinical association leads to diagnostic delay and irreversible damage to organs involved. Therefore, we aim to specifically identify MGUS patients at high risk of progression to myeloma and / or MGCS. Objective 1: Understanding the symptom burden, and additional clinical parameters driving the test request, which lands an incidental diagnosis of MGUS is key. Using access to Clinical practice research data link (CPRD) primary care records on patients coded as monoclonal gammopathy to generate this dataset. We will identify set of predictors for transformation from MGUS to MM. CPRD data will also enable identification of clinical associations recently described as MGCS conditions. Objective 2: Oxford University Hospital, we have recently established the OxCom clinical service funded by Oxfordshire Clinical Commissioning Group to improve serial MGUS monitoring for patients in the Oxfordshire community. This funding has been allocated to address the lack of serial follow up of MGUS patients; patients are often lost to follow up, and GPs' are unable to address clinical concerns generated by MGUS patients in primary care. This OxCom infrastructure enables us to generate a prospective dataset with detailed clinical and laboratory data. Hypothesis generating observations generated from the CPRD datasets can be validate in this prospective MGUS database. We will validate the primary care prection model in the OxCom database. Objective 3: Recent observations have shown that aberrant changes to light chains secrete dby MGUS patients can help predict who would develop MGCS, and/or potentially transform to myeloma. Working with Department of Chemistry at Oxford we can prospectively evaluate these preliminary observations in the surplus patient samples obtained from the OxCom service. These shared research-enabling resources will help drive improvements in early diagnosis and MGUS/myeloma care in the NHS.My vision is to harness the multidisciplinary expertise in Oxford across big data analysis (primary care data), joined up secondary care clinical services and protein chemistry expertise to improve monitoring of MGUS patients, and enable early diagnosis of MGCS and myeloma.