Multiple myeloma (MM) remains incurable despite novel therapeutics. A major contributor to the development of relapsed/refractory and resistant MM is extraosseous extramedullary disease (EMD), whose molecular biology is still not fully understood. We analyzed 528 MM patients who presented to our institution between 2014 and 2021 and who had undergone molecular testing. We defined EMD as organ plasmacytoma distinct from bones and evaluated patients for the development of EMD with the goal of defining their molecular characteristics. Here, we show that RAS/BRAF mutations are likely essential for the development of EMD. Our results also indicate that the underlying reason for the negative outcomes in patients with poor prognostic factors such as duplication 1q and deletion 17p is largely due to the development of EMD. However, the presence of TP53 mutation remains a poor prognostic factor regardless of EMD development. Furthermore, mutation sites of TP53 were different between EMD versus non-EMD patients, with gain-of-function mutations enriched in patients with EMD. Our data highlights distinct molecular abnormalities in patients with EMD and provides potential mechanistic insights for novel therapeutic targets for the future.

尽管有新的治疗方法，多发性骨髓瘤 （MM） 仍然无法治愈。复发/难治性和耐药性 MM 发展的主要因素是骨外髓外疾病 （EMD），其分子生物学仍不完全清楚。我们分析了 528 年至 2014 年间到我们机构就诊并接受过分子检测的 MM 患者。我们将 EMD 定义为不同于骨骼的器官浆细胞瘤，并评估患者发生 EMD 的情况，目的是确定他们的分子特征。在这里，我们表明 RAS/BRAF 突变可能对 EMD 的发展至关重要。我们的结果还表明，具有不良预后因素（例如重复 1q 和缺失 17p）的患者出现不良结果的根本原因主要是由于 EMD 的发展。然而，无论 EMD 的发展如何，TP53 突变的存在仍然是一个不良的预后因素。此外，EMD 患者与非 EMD 患者 TP53 的突变位点不同，EMD 患者富含功能获得性突变。我们的数据突出了 EMD 患者的不同分子异常，并为未来的新治疗靶点提供了潜在的机制见解。