Precursor states of multiple myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, monoclonal gammopathy of unknown significance and smoldering MM, to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find that natural killer cell abundance is frequently increased in the early stages and associated with altered chemokine receptor expression. As early as smoldering MM, we show loss of granzyme K⁺ memory cytotoxic T cells and show their critical role in MM immunosurveillance in mouse models. Finally, we report major histocompatibility complex class II dysregulation in CD14⁺ monocytes, which results in T-cell suppression in vitro. These results provide a comprehensive map of immune changes at play over the evolution of premalignant MM, which will help develop strategies for immune-based patient stratification.

多发性骨髓瘤 (MM) 的前体状态及其原生肿瘤微环境需要深入的分子表征，以更好地对处于危险中的患者进行分层和治疗。使用从前体阶段、未知意义的单克隆丙种球蛋白病和冒烟的 MM 到成熟的 MM 以及健康供体的骨髓细胞的单细胞 RNA 测序，我们展示了患者进展过程中的早期免疫变化。我们发现自然杀伤细胞丰度在早期阶段经常增加，并且与趋化因子受体表达的改变有关。早在阴燃的 MM 中，我们就显示出颗粒酶 K ⁺记忆细胞毒性 T 细胞的丢失，并在小鼠模型中显示它们在 MM 免疫监视中的关键作用。最后，我们报告了 CD14 ^{+中的主要组织相容性复合体 II 类失调}单核细胞，这导致体外 T 细胞抑制。这些结果提供了一个全面的免疫变化图谱，反映了癌前 MM 的演变过程，这将有助于制定基于免疫的患者分层策略。