尽管对多发性骨髓瘤（MM）发病生理学有了很多了解，但在一部分患者中导致快速进行的疾病的原因仍不清楚。 MM的进展是通过与周围骨髓（BM）细胞的复杂相互作用促进的，形成支持肿瘤生长和耐药性的微环境。了解免疫微环境对于识别促进MM快速进展的因素至关重要。为了实现这一目标，我们在18名患者中从48个CD138-BM样本中收集了102,207个单个细胞RNA测序（scRNA-seq）数据，这些患者被诊断为快速进展（无进展生存期（PFS）<18个月）或非进展（PFS> 4年）的疾病。三个中心的数据的比较分析表明了相似的转录组文件和细胞类型分布，表明scRNA-seq中存在细微的技术差异，为扩大多中心试验开辟了途径。快速进展者的GZMK +和TIGIT + Exhausted CD8 + T细胞（P = 0.022）的富集显着高于其他人，同时细胞溶解标记（PRF1，GZMB，GNLY）的表达降低。我们还观察到快速进展者中M2忍受性巨噬细胞的富集度明显增加，并激活了促增殖信号通路，例如BAFF，CCL和IL16。另一方面，非进展患者显示了不成熟的B细胞（即Pre / Pro B细胞）的富集，并表达了B细胞发育的标记（IGLL1，SOX4，DNTT）。这项多中心研究确定了快速进展疾病中各种促进肿瘤的细胞群和信号通路的富集现象，并进一步验证了在不同研究中心产生的scRNA-seq数据的稳健性。©2023. 作者（们）。

Despite advancements in understanding the pathophysiology of Multiple Myeloma (MM), the cause of rapid progressing disease in a subset of patients is still unclear. MM's progression is facilitated by complex interactions with the surrounding bone marrow (BM) cells, forming a microenvironment that supports tumor growth and drug resistance. Understanding the immune microenvironment is key to identifying factors that promote rapid progression of MM. To accomplish this, we performed a multi-center single-cell RNA sequencing (scRNA-seq) study on 102,207 cells from 48 CD138- BM samples collected at the time of disease diagnosis from 18 patients with either rapid progressing (progression-free survival (PFS) < 18 months) or non-progressing (PFS > 4 years) disease. Comparative analysis of data from three centers demonstrated similar transcriptome profiles and cell type distributions, indicating subtle technical variation in scRNA-seq, opening avenues for an expanded multicenter trial. Rapid progressors depicted significantly higher enrichment of GZMK+ and TIGIT+ exhausted CD8+ T-cells (P = 0.022) along with decreased expression of cytolytic markers (PRF1, GZMB, GNLY). We also observed a significantly higher enrichment of M2 tolerogenic macrophages in rapid progressors and activation of pro-proliferative signaling pathways, such as BAFF, CCL, and IL16. On the other hand, non-progressive patients depicted higher enrichment for immature B Cells (i.e., Pre/Pro B cells), with elevated expression for markers of B cell development (IGLL1, SOX4, DNTT). This multi-center study identifies the enrichment of various pro-tumorigenic cell populations and pathways in those with rapid progressing disease and further validates the robustness of scRNA-seq data generated at different study centers.© 2023. The Author(s).