Mikulski Damian, Robak Paweł, Perdas Ewelina, Węgłowska Edyta, Łosiewicz Aleksandra, Dróżdż Izabela, Jarych Dariusz, Misiewicz Małgorzata, Szemraj Janusz, Fendler Wojciech, Robak Tadeusz
Department of Biostatistics and Translational Medicine, Medical University of Lodz, 93-215 Lodz, Poland.
Copernicus Memorial Hospital, 93-510 Lodz, Poland.
J Clin Med. 2021 Dec 26;11(1):112. doi: 10.3390/jcm11010112.
Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The present study examines the influence on progression-free survival (PFS) and overall survival (OS) by the serum levels of 27 selected cytokines in 61 newly diagnosed MM patients receiving first-line therapy with bortezomib-based regimens. The measurements were performed using a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay and a MAGPIX Multiplex Reader, based on the Bio-Plex 200 System (Bio-Rad). The following levels were determined: IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF. Most patients received a VCD chemotherapy regimen (bortezomib, cyclophosphamide, and dexamethasone). In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240-0.8291, = 0.0302) and ASCT (HR 0.3722, 95% CI: 0.1826-0.7585, = 0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046-0.438, = 0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471-9.949, = 0.0059), and two cytokine levels-IL-1Ra (HR 1.017, 95% CI: 1.004-1.030, = 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037-0.698, = 0.0147)-were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.
多发性骨髓瘤（MM）的特征是骨髓中克隆性浆细胞恶性增殖，伴有单克隆副蛋白升高、肾功能损害、高钙血症、溶骨性骨病变和贫血。免疫细胞及相关细胞因子在MM的生长、进展和播散中起重要作用。虽然一些细胞因子及其临床意义在MM生物学中已有充分描述，但其他一些细胞因子仍相对不为人知。本研究检测了61例接受基于硼替佐米方案一线治疗的新诊断MM患者血清中27种选定细胞因子水平对无进展生存期（PFS）和总生存期（OS）的影响。检测使用基于Bio-Plex 200系统（伯乐公司）的伯乐Bio-Plex Pro人细胞因子27联检测试剂盒和MAGPIX多通道检测仪进行。测定了以下细胞因子水平：白细胞介素-1β（IL-1β）、白细胞介素-1受体拮抗剂（IL-1Ra）、白细胞介素-2（IL-2）、白细胞介素-4（IL-4）、白细胞介素-5（IL-5）、白细胞介素-6（IL-6）、白细胞介素-7（IL-7）、白细胞介素-8（IL-8）、白细胞介素-9（IL-9）、白细胞介素-10（IL-10）、白细胞介素-12（IL-12）、白细胞介素-13（IL-13）、白细胞介素-15（IL-15）、白细胞介素-17（IL-17）、嗜酸性粒细胞趋化因子（Eotaxin）、成纤维细胞生长因子（FGF）、粒细胞集落刺激因子（G-CSF）、粒细胞-巨噬细胞集落刺激因子（GM-CSF）、干扰素-γ（IFN-γ）、干扰素诱导蛋白10（IP-10）、单核细胞趋化蛋白-1（MCP-1）、巨噬细胞炎性蛋白-1α（MIP-1α）、巨噬细胞炎性蛋白-1β（MIP-1β）、血小板衍生生长因子BB（PDGF-BB）、调节激活正常T细胞表达和分泌因子（RANTES）、肿瘤坏死因子-α（TNF-α）和血管内皮生长因子（VEGF）。大多数患者接受了VCD化疗方案（硼替佐米、环磷酰胺和地塞米松）。在最终的多变量模型中，IL-13细胞因子水平（风险比[HR]0.1411，95%置信区间[CI]：0.0240 - 0.8291，P = 0.0302）和自体干细胞移植（ASCT）（HR 0.3722，95% CI：0.1826 - 0.7585，P = 0.0065）对PFS有显著影响。此外，ASCT（HR 0.142，95% CI：0.046 - 0.438，P = 0.0007）、诊断时存在骨病（HR 3.826，95% CI：1.471 - 9.949，P = 0.0059）以及两种细胞因子水平——IL-1Ra（HR 1.017，95% CI：1.004 - 1.030，P = 0.0091）和IL-4（HR 0.161，95% CI：0.037 - 0.698，P = 0.0147）——是OS的独立预测因素。根据不同的细胞因子谱鉴定出了三组MM患者。总之，IL-13和IL-4的血清预处理水平分别是较好PFS和OS的预测指标，而IL-1Ra预处理水平对接受基于硼替佐米化疗的MM患者的OS有负面影响。细胞因子特征谱可能对接受硼替佐米治疗患者的预后有潜在影响。
