Background/Objectives: Multiple myeloma (MM) is a challenging, B cell malignancy characterised by the uncontrolled proliferation of plasma cells within the bone marrow. Despite significant advances in treatment options nowadays, MM remains an incurable malignancy, with the majority of patients succumbing to the disease. MM develops from a pre-malignant state known as monoclonal gammopathy of unknown significance (MGUS), which then has the potential to evolve either into smouldering (asymptomatic) multiple myeloma (SMM) or into MM. Since novel drug discovery takes years to reach the clinic, drug repurposing, which concerns the detection of existing drugs for a novel disease, can be applied. Methods: To address this critical and still unmet medical need, we present a comprehensive signature-based drug-repurposing approach using all the publicly available bulk transcriptomics datasets on mGUS, sMM, and MM. Results: Our study included an in-house scoring scheme approach enabling further filtering and prioritisation, resulting in 25 candidate repurposed drugs for mGUS, 23 for sMM, and 66 for MM. The corresponding gene targets and the related functional terms have been analysed, providing extra information for stage-specific underlying mechanisms in myeloma. Lastly, enabled by a specific computational workflow, we propose drug combinations between our top candidate repurposed drugs and FDA-approved drugs for MM. Conclusions: Together, these results deliver a stage-specific, transparent resource for MM drug repurposing and combination design, intended to accelerate translation toward earlier disease intervention and improved patient outcomes.
背景/目的：多发性骨髓瘤（MM）是一种具有挑战性的B细胞恶性肿瘤，其特征是骨髓中浆细胞不受控制地增殖。尽管目前治疗方案已取得显著进展，MM仍是一种无法治愈的恶性肿瘤，大多数患者最终会死于该疾病。MM由一种称为意义未明的单克隆丙种球蛋白病（MGUS）的癌前状态发展而来，随后可能演变为冒烟型（无症状）多发性骨髓瘤（SMM）或进展为MM。由于新药研发需多年才能进入临床应用，药物再利用策略——即针对新疾病筛选现有药物——可为此提供解决方案。 方法：为应对这一关键且尚未满足的临床需求，我们基于所有公开可用的MGUS、SMM和MM批量转录组学数据集，提出了一种全面的基于分子特征的药物再利用研究方法。 结果：本研究采用自主研发的评分方案进行进一步筛选和优先级排序，最终获得25种针对MGUS、23种针对SMM以及66种针对MM的候选再利用药物。通过分析相关基因靶点及功能术语，我们揭示了骨髓瘤不同发展阶段特异的潜在机制。最后，依托特定计算流程，我们提出了候选再利用药物与FDA批准MM药物之间的联合用药方案。 结论：本研究构建了一个阶段特异性、可溯源的MM药物再利用与联合用药设计资源库，有望加速早期疾病干预的临床转化，从而改善患者预后。
Computational Drug Repurposing Across the Multiple Myeloma Spectrum: From MGUS to MM
肿瘤(癌症)患者之家