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.
靶向免疫疗法组合，包括抗CD38单克隆抗体达雷妥尤单抗，在复发/难治性多发性骨髓瘤患者中已显示出良好疗效，显著延长了无进展生存期。然而，大部分患者仍不可避免地出现复发。为探究这一现象，我们对32例接受达雷妥尤单抗、来那度胺和地塞米松联合治疗的复发多发性骨髓瘤患者进行了研究。我们采用全基因组测序和流式细胞术对复发/难治性多发性骨髓瘤患者进行了整合分析。治疗前后的全基因组测序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和染色体碎裂的功能获得性结构变异。对31例患者每3个月采集一次直至疾病进展的202份血液样本进行流式细胞分析，揭示了显著影响临床结局的特定免疫变化。进展期患者随时间推移表现出CD38阳性自然杀伤细胞的显著耗竭、T细胞耗竭状态的持续存在以及调节性T细胞耗减程度的降低。这些发现强调了免疫组成及达雷妥尤单抗诱导的免疫变化在促进多发性骨髓瘤耐药中的作用。整合基因组学与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免疫微环境之间错综复杂的相互作用，正是这种相互作用导致了复发/难治性多发性骨髓瘤患者对达雷妥尤单抗联合疗法的耐药性。
肿瘤(癌症)患者之家