尽管治疗效果有所改善，但在接受包含达雷妥尤单抗（一种针对 CD38 的单克隆抗体）的治疗方案的新诊断多发性骨髓瘤患者中，40% 的患者病情过早进展。通过整合使用卡非佐米、来那度胺和地塞米松与达拉妥尤单抗 (NCT03290950) 的前期 2 期试验的肿瘤全基因组和微环境单细胞 RNA 测序，我们展示了不同的基因组驱动因素（包括高 APOBEC 突变活性、IKZF3 和 RPL5 缺失以及 8q 增益）如何影响临床结果。此外，在卡非佐米、来那度胺和地塞米松与达雷妥尤单抗治疗八个周期之前和之后进行的配对骨髓谱评估显示，治疗前自然杀伤细胞的数量、治疗前高 T 细胞受体多样性、持续免疫激活的消失（即即 B 细胞和 T 细胞）和单核细胞随时间的扩张都预示着持续的微小残留病阴性。总体而言，这项研究提供了强有力的证据，证明肿瘤细胞和免疫微环境之间存在复杂的相互作用，可以预测接受含有抗 CD38 抗体的高效组合治疗的新诊断多发性骨髓瘤患者的临床结果和治疗反应深度。© 2023。作者获得 Springer Nature America, Inc. 的独家许可。

Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.