Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR = 2.4, p = 0.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. Conversely, we identified significantly upregulated EZH2 and CD70 as potential future therapeutic options. For the first time, we report on the tumor microenvironment of EMM, revealing CD8+ T cells and NK cells as predominant immune effector cells using single-cell sequencing. Finally, this is the first longitudinal study in EMM revealing the molecular changes from the time of diagnosis to EMM relapse.

髓外多发性骨髓瘤 (EMM) 是多发性骨髓瘤 (MM) 的一种侵袭性形式。 这项研究代表了迄今为止最全面的 EMM 肿瘤 ( N = 14)下一代测序分析，揭示了关键分子特征并描述了肿瘤微环境。我们在 79% 的 EMM 样本中观察到 1q21 增益/扩增和 MAPK 通路突变同时发生，表明这些是 EMM 发育中的关键突变事件。 我们还使用大型 CoMMpass 数据集的数据证明，诊断时KRAS突变和 1q21 增益/扩增的患者发生 EMM 的风险显着较高（HR = 2.4， p = 0.011）。我们发现 CXCR4 的下调和细胞增殖的增强，以及治疗靶点（CD38、SLAMF7、GPRC5D、FCRH5）表达的减少，可能解释了免疫疗法疗效下降的原因。相反，我们发现显着上调的 EZH2 和 CD70 作为未来潜在的治疗选择。我们首次报告了 EMM 的肿瘤微环境，利用单细胞测序揭示了 CD8+ T 细胞和 NK 细胞是主要的免疫效应细胞。最后，这是第一个 EMM 纵向研究，揭示了从诊断到 EMM 复发的分子变化。