Bristol Myers Squibb, Summit, New Jersey.
University of Calgary, Calgary, Alberta, Canada.
Clin Cancer Res. 2020 Nov 15;26(22):5895-5902. doi: 10.1158/1078-0432.CCR-20-1781. Epub 2020 Sep 14.
Addition of daratumumab to pomalidomide and low-dose dexamethasone (LoDEX) is a safe and effective combination for relapsed/refractory multiple myeloma treatment. We sought to better understand immune combinational benefit of pomalidomide and daratumumab with LoDEX.
Immunophenotypic changes were analyzed in peripheral blood from longitudinal sampling of patients treated with this triplet regimen from cohort B of the CC4047-MM-014 phase II trial (NCT01946477).
Consistent with the daratumumab mechanism, treatment led to decreased natural killer (NK) and B cells. In contrast, pronounced increases occurred in activated and proliferating NK and T cells, appreciably in CD8 T cells, along with reduction in naïve and expansion of effector memory compartments. Timing of T-cell changes correlated with pomalidomide dosing schedule. Enhanced activation/differentiation did not result in increased exhausted T-cell phenotypes or increases in regulatory T cells. Similar immune enhancements were also observed in patients previously refractory to lenalidomide.
These data support a potential mechanism for enhanced immune-mediated cytotoxicity in which daratumumab-mediated NK-cell diminution is partially offset by pomalidomide effects on the remaining NK-cell pool. Furthermore, daratumumab antimyeloma activity and elimination of CD38 T cells (regulatory/activated) provide a rationale for therapeutic combination with direct tumoricidal activity and immunomodulation of pomalidomide-directed T-cell enhancements. These data highlight enhancements in immune subpopulations for the combination of daratumumab with pomalidomide and potentially with next-generation cereblon-targeting agents.
达雷妥尤单抗联合泊马度胺和低剂量地塞米松（LoDEX）治疗复发性/难治性多发性骨髓瘤是一种安全有效的联合治疗方法。我们旨在更好地了解泊马度胺和达雷妥尤单抗联合 LoDEX 的免疫联合获益。
对来自 CC4047-MM-014 期 II 试验队列 B 中接受该三联方案治疗的患者进行纵向采样的外周血进行免疫表型变化分析（NCT01946477）。
与达雷妥尤单抗的作用机制一致，治疗导致自然杀伤（NK）细胞和 B 细胞减少。相比之下，激活和增殖的 NK 和 T 细胞显著增加，CD8 T 细胞明显增加，同时幼稚细胞减少，效应记忆细胞群扩张。T 细胞变化的时间与泊马度胺的给药方案相关。增强的激活/分化不会导致耗尽的 T 细胞表型增加或调节性 T 细胞增加。在先前对来那度胺耐药的患者中也观察到类似的免疫增强。
这些数据支持一种潜在的免疫介导的细胞毒性增强机制，其中达雷妥尤单抗介导的 NK 细胞减少部分被泊马度胺对剩余 NK 细胞池的作用所抵消。此外，达雷妥尤单抗的抗骨髓瘤活性和消除 CD38 T 细胞（调节/激活）为与具有直接细胞毒性活性和泊马度胺靶向 T 细胞增强的免疫调节作用的药物联合治疗提供了依据。这些数据突出了达雷妥尤单抗联合泊马度胺联合治疗的免疫亚群增强，并且可能与下一代 cereblon 靶向药物联合治疗。
