Romano Alessandra, Parrinello Nunziatina Laura, Parisi Marina, Del Fabro Vittorio, Curtopelle Angelo, Leotta Salvatore, Conticello Concetta, Di Raimondo Francesco
Dipartimento di Chirurgia e Specialità Medico-Chirurgiche, Università degli Studi di Catania, 95123 Catania, Italy.
Division of Hematology, AOU "Policlinico-Vittorio Emanuele", 95123 Catania, Italy.
Biomedicines. 2021 Oct 13;9(10):1455. doi: 10.3390/biomedicines9101455.
Myeloid dysfunction is an emerging hallmark of microenvironment changes occurring in multiple myeloma (MM). Our previous work showed that FcγRI/CD64 overexpression in neutrophils of newly diagnosed MM patients is associated to inferior outcomes, reduced oxidative bursts and phagocytosis, with an increased risk of bacterial infections. Pomalidomide is a novel immune-modulatory drug approved for relapsed/refractory patients (RRMM), with drug-related neutropenia as major limitation to treatment. Herein, we describe a prospective analysis of 51 consecutive RRMM patients treated with pomalidomide and dexamethasone (PomDex) from March 2015 through December 2016, associated with secondary prophylaxis with filgrastim (G-CSF) in case of neutrophil count <1500 cells/μL. Neutrophil function was investigated by flow cytometry, including the phagocytosis, oxidative bursts, and median fluorescence intensity of FcγRI-CD64. Controls included a group of newly diagnosed symptomatic MM (NDMM), asymptomatic (smoldering myeloma, MGUS) and healthy subjects referred to our Center in the same time-frame. Compared to controls, RRMM neutrophils had higher expression of FcγRI/CD64 and lower phagocytic activity and oxidative bursts. We maintained median leukocyte counts higher than 3.5 × 10/L for 6 cycles, and median neutrophil counts higher than 1.5 × 10/L, with only 6 (11%) patients developing grade 3-4 infections, without pomalidomide dose reduction. After 4 cycles of PomDex, FcγRI/CD64 was further increased in neutrophils, and phagocytic activity and oxidative bursts recovered independently from filgrastim exposure and the quality of hematological responses. Similarly, in NDMM patients, lenalidomide but not bortezomib upregulated FcγRI/CD64 expression, improving phagocytic activity and oxidative bursta as tested in vitro. Our combined biological and clinical data provide new information on the ability of pomalidomide and lenalidomide to modulate the functional activity of neutrophils, despite their chronic activation due to FcγRI/CD64 overexpression.
髓系功能障碍是多发性骨髓瘤（MM）中微环境变化的一个新出现的标志。我们之前的研究表明，新诊断MM患者中性粒细胞中FcγRI/CD64的过表达与较差的预后、氧化爆发和吞噬作用降低以及细菌感染风险增加有关。泊马度胺是一种批准用于复发/难治性患者（RRMM）的新型免疫调节药物，药物相关的中性粒细胞减少是治疗的主要限制因素。在此，我们描述了对从2015年3月至2016年12月连续接受泊马度胺和地塞米松（PomDex）治疗的51例RRMM患者的前瞻性分析，在中性粒细胞计数<1500个细胞/μL时联合使用非格司亭（G-CSF）进行二级预防。通过流式细胞术研究中性粒细胞功能，包括吞噬作用、氧化爆发以及FcγRI-CD64的中位荧光强度。对照组包括同一时间段转诊至我们中心的一组新诊断的有症状MM（NDMM）、无症状（冒烟型骨髓瘤、意义未明的单克隆丙种球蛋白血症）和健康受试者。与对照组相比，RRMM中性粒细胞中FcγRI/CD64的表达更高，吞噬活性和氧化爆发更低。我们使白细胞计数中位数在6个周期内维持高于3.5×10⁹/L，中性粒细胞计数中位数维持高于1.5×10⁹/L，只有6例（11%）患者发生3-4级感染，且未降低泊马度胺剂量。在4个周期的PomDex治疗后，中性粒细胞中FcγRI/CD64进一步升高，吞噬活性和氧化爆发独立于非格司亭暴露和血液学反应质量而恢复。同样，在NDMM患者中，来那度胺而非硼替佐米上调FcγRI/CD64表达，如体外测试所示改善了吞噬活性和氧化爆发。我们的生物学和临床综合数据提供了关于泊马度胺和来那度胺调节中性粒细胞功能活性能力的新信息，尽管由于FcγRI/CD64过表达导致它们长期激活。
