在多发性骨髓瘤中，次克隆结构、分子标记和微环境组成的空间差异尚未得到很好的描述。为了解决这个缺点，我们对17名新诊断患者的随机骨髓和病灶样本进行了多区域测序。使用单细胞RNA和ATAC-seq的方法，我们发现每个患者平均有6个肿瘤次克隆，并且在病灶中存在独特的次克隆。基因相同的次克隆在空间转录可塑性方面表现出不同的水平，包括几乎相同的基因表达谱和不同部位的明显异质性，其中可以包括免疫治疗靶点CD20和CD38的差异表达。巨噬细胞在病灶的微环境中明显减少。我们观察到T细胞库中的比例变化，但在骨髓内病灶中没有特定位置的T细胞克隆扩张。总之，我们的研究结果展示了考虑多发性骨髓瘤的空间异质性的相关性，对细胞间相互作用和疾病进展模型可能具有重要意义。© 2023. Springer Nature Limited.

In multiple myeloma spatial differences in the subclonal architecture, molecular signatures and composition of the microenvironment remain poorly characterized. To address this shortcoming, we perform multi-region sequencing on paired random bone marrow and focal lesion samples from 17 newly diagnosed patients. Using single-cell RNA- and ATAC-seq we find a median of 6 tumor subclones per patient and unique subclones in focal lesions. Genetically identical subclones display different levels of spatial transcriptional plasticity, including nearly identical profiles and pronounced heterogeneity at different sites, which can include differential expression of immunotherapy targets, such as CD20 and CD38. Macrophages are significantly depleted in the microenvironment of focal lesions. We observe proportional changes in the T-cell repertoire but no site-specific expansion of T-cell clones in intramedullary lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity in multiple myeloma with potential implications for models of cell-cell interactions and disease progression.© 2023. Springer Nature Limited.