Targeted immunotherapy combinations, including the anti-CD38 monoclonal antibody (MoAb) daratumumab, have shown promising results in patients with relapsed/refractory multiple myeloma (RRMM), leading to a considerable increase in progression-free survival. However, a large fraction of patients inevitably relapse. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676). We conducted an integrated analysis using whole-genome sequencing (WGS) and flow cytometry in patients with RRMM. WGS before and after treatment pinpointed genomic drivers associated with early progression, including RPL5 loss, APOBEC mutagenesis, and gain of function structural variants involving MYC and chromothripsis. Flow cytometry on 202 blood samples, collected every 3 months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38-positive NK cells, persistence of T-cell exhaustion, and reduced depletion of regulatory T cells over time. These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns. Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd in patients with RRMM.

靶向免疫治疗组合，包括抗 CD38 单克隆抗体 （MoAb） daratumumab，已在复发/难治性多发性骨髓瘤 （RRMM） 患者中显示出有希望的结果，导致无进展生存期显着增加。然而，很大一部分患者不可避免地会复发。为了了解这一点，我们调查了 32 例接受达雷妥尤单抗、来那度胺和地塞米松治疗的复发性 MM 患者 （Dara-Rd;NCT03848676）。我们使用全基因组测序 （WGS） 和流式细胞术对 RRMM 患者进行了综合分析。治疗前后的 WGS 确定了与早期进展相关的基因组驱动因素，包括 RPL5 缺失、APOBEC 诱变以及涉及 MYC 和染色体裂解的功能获得结构变异。对 202 份血液样本进行流式细胞术，每 3 个月收集一次，直至 31 名患者进展，揭示了显着影响临床结果的不同免疫变化。进展患者表现出 CD38 阳性 NK 细胞的显著耗竭、T 细胞耗竭的持续性以及随着时间的推移调节性 T 细胞耗竭减少。这些发现强调了免疫成分和 daratumumab 诱导的免疫变化在促进 MM 耐药性方面的影响。整合基因组学和流式细胞术揭示了不良基因组特征与免疫模式之间的关联。总体而言，本研究揭示了基因组复杂性与驱动 RRMM 患者对 Dara-Rd 耐药性的免疫微环境之间错综复杂的相互作用。