多发性骨髓瘤免疫麻痹的研究现状

doi:10.12092/j.issn.1009-2501.2026.04.016

摘要/Abstract

摘要：

多发性骨髓瘤（multiple myeloma，MM）具有高复发率，疾病进展的原因之一是肿瘤微环境的变化以及免疫细胞功能障碍，导致肿瘤特异性免疫力丧失。免疫麻痹是MM患者中的一种常见现象，其特征是一种或多种未受累多克隆免疫球蛋白受抑制。在意义未明单克隆免疫球蛋白增多症和冒烟型骨髓瘤中，免疫麻痹的出现被视为易进展成症状性MM的高危因素之一。MM患者感染风险增加也与免疫麻痹相关。近年来，初诊MM患者免疫麻痹的预后价值已被报道，但其是否能作为一个良好的预后指标仍存在争议。了解MM患者免疫麻痹的病理生理机制对疾病的影响及管理至关重要，也为MM预后分层研究提供一个方向。

关键词: 多发性骨髓瘤, 免疫麻痹, 预后, 感染

Abstract:

Multiple myeloma (MM) is associated with a high rate of disease recurrence, and one of the reasons for disease progression is changes in the tumor microenvironment and immune cell dysfunction, which leads to the loss of tumor-specific immunity. Immunoparesis is a common phenomenon in MM patients and is characterized by suppression of one or more uninvolved polyclonal immunoglobulins. In monoclonal gammopathy of undetermined significance and smoldering multiple myeloma, the presence of immunoparesis is considered to be one of the risk factors for progression to symptomatic MM. The increased risk of infection in MM patients has also been associated with immunoparesis. In recent years, the prognostic value of immunoparesis in patients with first diagnosis of MM has been reported, but whether it is a good prognostic indicator remains controversial. Understanding the pathophysiological mechanisms of immunoparesis in MM patients, the impact on the disease, and management is crucial to provide a direction for MM prognostic research.

Key words: multiple myeloma, immunoparesis, prognosis, infection

中图分类号:

R553

曾茜敏, 赵洁珺, 席亚明. 多发性骨髓瘤免疫麻痹的研究现状[J]. 中国临床药理学与治疗学, 2026, 31(4): 561-567.

Qianmin ZENG, Jiejun ZHAO, Yaming XI. Research status of immunoparesis in multiple myeloma[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(4): 561-567.

图/表 2

参考文献 43

1	Siwakoti A, Khadka S, Grimshaw AA, et al. Association between immunoparesis and treatment outcomes of patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis[J]. Clin Lymphoma Myeloma Leuk, 2024, 24 (11): e870- e877. doi: 10.1016/j.clml.2024.07.008
2	Swamydas M, Murphy EV, Ignatz-Hoover JJ, et al. Deciphering mechanisms of immune escape to inform immunotherapeutic strategies in multiple myeloma[J]. J Hematol Oncol, 2022, 15 (1): 17. doi: 10.1186/s13045-022-01234-2
3	Všianská P, Říhová L, Varmužová T, et al. Analysis of B-cell subpopulations in monoclonal gammopathies[J]. Clin Lymphoma Myeloma Leuk, 2015, 15 (4): e61- 71. doi: 10.1016/j.clml.2014.12.003
4	Chen Y, Chen Z, Cao J, et al. Severe and continuous immunoparesis during induction or maintenance therapy in nontransplant patients with multiple myeloma is a sign of poor prognosis[J]. Hematology, 2024, 29 (1): 2329378. doi: 10.1080/16078454.2024.2329378
5	Sørrig R, Klausen TW, Salomo M, et al. Immunoparesis in newly diagnosed Multiple Myeloma patients: Effects on overall survival and progression free survival in the Danish population[J]. PloS one, 2017, 12 (12): e0188988. doi: 10.1371/journal.pone.0188988
6	Lei A, Liao X, Zhu P, et al. The significance of autologous hematopoietic stem cell transplantation on immunoglobulin reconstitution and prognosis in elderly patients with multiple myeloma[J]. Hematology, 2023, 28 (1): 2255800. doi: 10.1080/16078454.2023.2255800
7	Liu JC, Zhang K, Zhang X, et al. Immunoglobulin class-switch recombination: mechanism, regulation, and related diseases[J]. MedComm, 2024, 5 (8): e662. doi: 10.1002/mco2.662
8	Walker BA, Wardell CP, Johnson DC, et al. Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells[J]. Blood, 2013, 121 (17): 3413- 3419. doi: 10.1182/blood-2012-12-471888
9	Plano F, Corsale AM, Gigliotta E, et al. Monoclonal gammopathies and the bone marrow microenvironment: from bench to bedside and then back again[J]. Hematol Rep, 2023, 15 (1): 23- 49. doi: 10.3390/hematolrep15010004
10	Russell BM, Avigan DE. Immune dysregulation in multiple myeloma: the current and future role of cell-based immunotherapy[J]. Int J Hematol, 2023, 117 (5): 652- 659. doi: 10.1007/s12185-023-03579-x
11	Kubicki T, Dytfeld D, Wróbel T, et al. Polyclonal immunoglobulin recovery in patients with newly diagnosed myeloma receiving maintenance therapy after autologous haematopoietic stem cell transplantation with either carfilzomib, lenalidomide and dexamethasone or lenalidomide alone: subanalysis of the randomized phase 3 ATLAS trial[J]. Br J Haematol, 2023, 203 (5): 792- 802. doi: 10.1111/bjh.19097
12	Zelle-Rieser C, Thangavadivel S, Biedermann R, et al. T cells in multiple myeloma display features of exhaustion and senescence at the tumor site[J]. J Hematol Oncol, 2016, 9 (1): 116. doi: 10.1186/s13045-016-0345-3
13	Leone P, Solimando AG, Malerba E, et al. Actors on the scene: immune cells in the myeloma niche[J]. Front Oncol, 2020, 10, 599098. doi: 10.3389/fonc.2020.599098
14	Chen H, Wang X, Wang Y, et al. What happens to regulatory T cells in multiple myeloma[J]. Cell Death Discov, 2023, 9 (1): 468. doi: 10.1038/s41420-023-01765-8
15	Sammartano V, Franceschini M, Fredducci S, et al. Anti-BCMA novel therapies for multiple myeloma[J]. Cancer Drug Resist, 2023, 6 (1): 169- 181. doi: 10.20517/cdr.2022.138
16	Shah N, Mustafa SS, Vinh DC. Management of secondary immunodeficiency in hematological malignancies in the era of modern oncology[J]. Crit Rev Oncol Hematol, 2023, 181, 103896. doi: 10.1016/j.critrevonc.2022.103896
17	Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management[J]. Blood, 2016, 127 (26): 3321- 3330. doi: 10.1182/blood-2016-04-703751
18	Wudhikarn K, Perales MA. Infectious complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy[J]. Bone Marrow Transplant, 2022, 57 (10): 1477- 1488. doi: 10.1038/s41409-022-01756-w
19	Josyula S, Pont MJ, Dasgupta S, et al. Pathogen-specific humoral immunity and infections in B cell maturation antigen-directed chimeric antigen receptor T cell therapy recipients with multiple myeloma [J]. Transpl Cell Ther, 2022, 28(6): 304. e301-304. e309.
20	Kampouri E, Walti CS, Gauthier J, et al. Managing hypogammaglobulinemia in patients treated with CAR-T-cell therapy: key points for clinicians[J]. Expert Rev Hematol, 2022, 15 (4): 305- 320. doi: 10.1080/17474086.2022.2063833
21	Rögnvaldsson S, Love TJ, Thorsteinsdottir S, et al. Correction: iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies[J]. Blood Cancer J, 2023, 13 (1): 39.
22	Visram A, Rajkumar SV, Kapoor P, et al. Assessing the prognostic utility of smoldering multiple myeloma risk stratification scores applied serially post diagnosis[J]. Blood Cancer J, 2021, 11 (11): 186. doi: 10.1038/s41408-021-00569-2
23	Giralt S, Jolles S, Kerre T, et al. Recommendations for management of secondary antibody deficiency in multiple myeloma[J]. Clin Lymphoma Myeloma Leuk, 2023, 23 (10): 719- 732. doi: 10.1016/j.clml.2023.05.008
24	Pérez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells[J]. Blood, 2007, 110 (7): 2586- 2592. doi: 10.1182/blood-2007-05-088443
25	Sørrig R, Klausen TW, Salomo M, et al. Smoldering multiple myeloma risk factors for progression: a danish population-based cohort study[J]. Eur J Haematol, 2016, 97 (3): 303- 309. doi: 10.1111/ejh.12728
26	肖辉建, 王秋菊, 吴双, 等. 骨髓浆细胞形态分型与单克隆性的相关性及其对高危冒烟型骨髓瘤的诊断价值[J]. 中国实验血液学杂志, 2024, 32 (4): 1146- 1151. doi: 10.19746/j.cnki.issn1009-2137.2024.04.026
27	Dávila J, González-Calle V, Escalante F, et al. Recovery of polyclonal immunoglobulins during treatment in patients ineligible for autologous stem-cell transplantation is a prognostic marker of longer progression-free survival and overall survival[J]. Br J Haematol, 2022, 198 (2): 278- 287. doi: 10.1111/bjh.18182
28	Geng C, Yang G, Wang H, et al. Deep and partial immunoparesis is a poor prognostic factor for newly diagnosed multiple myeloma patients[J]. Leuk Lymphoma, 2021, 62 (4): 883- 890. doi: 10.1080/10428194.2020.1855345
29	Lakhwani S, Mateos MV, Martínez-López J, et al. Immunoparesis recovery in newly diagnosed transplant ineligible multiple myeloma patients, an independent prognostic factor that complements minimal residual disease[J]. Ann Hematol, 2024, 103 (12): 5651- 5661. doi: 10.1007/s00277-024-06031-0
30	Wei M, Guo H, Liu S, et al. Combined immune score predicts the prognosis of newly diagnosed multiple myeloma patients in the bortezomib-based therapy era[J]. Medicine, 2021, 100 (41): e27521. doi: 10.1097/MD.0000000000027521
31	Richter J, Davids MS, Anderson-Smits C, et al. Burden of infection in patients with and without secondary immunodeficiency disease following diagnosis of a mature B cell malignancy[J]. Clin Lymphoma Myeloma Leuk, 2024, 24 (8): 553- 563. doi: 10.1016/j.clml.2024.04.002
32	Zhang M, Cheng Q, Zhao F, et al. Development of a nomogram prognostic model for early Grade ≥ 3 infection in newly diagnosed multiple myeloma based on immunoparesis[J]. Int Immunopharmacol, 2024, 126, 111277. doi: 10.1016/j.intimp.2023.111277
33	Kambhampati S, Sheng Y, Huang CY, et al. Infectious complications in patients with relapsed refractory multiple myeloma after BCMA CAR T-cell therapy[J]. Blood Adv, 2022, 6 (7): 2045- 2054. doi: 10.1182/bloodadvances.2020004079
34	Busca A, Cattaneo C, De Carolis E, et al. Considerations on antimicrobial prophylaxis in patients with lymphoproliferative diseases: A SEIFEM group position paper[J]. Crit Rev Oncol Hematol, 2021, 158, 103203. doi: 10.1016/j.critrevonc.2020.103203
35	Mohyuddin GR, Aziz M, McClune B, et al. Antibiotic prophylaxis for patients with newly diagnosed multiple myeloma: systematic review and meta-analysis[J]. Eur J Haematol, 2020, 104 (5): 420- 426. doi: 10.1111/ejh.13374
36	Danieli MG, Antonelli E, Auria S, et al. Low-dose intravenous immunoglobulin (IVIg) in different immune-mediated conditions[J]. Autoimmun Rev, 2023, 22 (11): 103451. doi: 10.1016/j.autrev.2023.103451
37	Chai KL, Wong J, Weinkove R, et al. Interventions to reduce infections in patients with hematological malignancies: a systematic review and meta-analysis[J]. Blood Adv, 2023, 7 (1): 20- 31. doi: 10.1182/bloodadvances.2022008073
38	Chai KL, Wellard C, Thao L, et al. Variation in immunoglobulin use and impact on survival in myeloma[J]. EJ Haem, 2024, 5 (4): 690- 697. doi: 10.1002/jha2.938
39	Lancman G, Parsa K, Kotlarz K, et al. IVIg use associated with ten-fold reduction of serious infections in multiple myeloma patients treated with anti-BCMA bispecific antibodies[J]. Blood Cancer Discov, 2023, 4 (6): 440- 451. doi: 10.1158/2643-3230.BCD-23-0049
40	Sim BZ, Longhitano A, Er J, et al. Infectious complications of bispecific antibody therapy in patients with multiple myeloma[J]. Blood Cancer J, 2023, 13 (1): 34. doi: 10.1038/s41408-023-00808-8
41	Crassini K, Gibson J. Pathogenesis and management of immune dysfunction secondary to B cell haematological malignancies[J]. Intern Med J, 2024, 54 (1): 16- 25. doi: 10.1111/imj.16279
42	Saltarella I, Altamura C, Solimando AG, et al. Immunoglobulin replacement therapy: insights into multiple myeloma management[J]. Cancers (Basel), 2024, 16 (18): 3190. doi: 10.3390/cancers16183190
43	Onishi A, Matsumura-Kimoto Y, Mizutani S, et al. Negative impact of immunoparesis in response to anti-SARS-CoV-2 mRNA vaccination of patients with multiple myeloma[J]. Int J Hematol, 2024, 119 (1): 50- 61. doi: 10.1007/s12185-023-03680-1

Author	Number of patients	Immunoparesis(%)	Prognostic significance of immunoparesis
Sorrig et al^[5]	2558 NDMM patients	2253(90%)	IP had no independent significant effect on OS (P = 0.12; HR 0.9 [0.7-1.0]). Qualitative IP was near significant riskfactor for PFS (P=0.054；HR 1.2[1.0-1.4]) and either 25%, 50% or 75% reduction in uninvolved immunoglobulin levels was all independent effect on PFS
Lakhwani et al^[29]	113 newly diagnosed transplant-ineligible patients	104(92%)	Patients who had IP at diagnosis and recovered it during or after treatment had longer OS ( P=0.007; HR 0.40[0.20-0.80]) and PFS (P<0.001;HR 0.32[0.19-0.52])
Chen et al^[4]	142 patients with MM	125(88%)	Severe and continuous IP ( at least two uninvolved Igs were suppressed continuously) was independent effect on OS (P=0.017; HR 1.275[1.044-1.556]) and PFS (P<0.001; HR 1.449[1.233-1.702])
Geng et al^[28]	287 NDMM patients	265(92.3%) 70% severe IP 80.8% partial IP	Severe (one of uninvolved immunoglobulins was below 50% the lower limit of normal ranges) and partial IP (suppression of at least two uninvolved immunoglobulins) were independently associated with shorter OS (P=0.040; HR 1.7[1.0-2.8]) and PFS (P=0.037; HR 1.7[1.0-2.9])
Lei et al^[6]	93 patients with MM who underwent ASCT	-	Patients who recovered from IP within 12 months after ASCT had longer OS (P<0.001) and PFS (P= 0.001)
Davila et al^[27]	431 transplant-ineligible patients with MM	350(81.2%)	IP was associated with a shorter OS (P=0.057; HR 0.746[0.551-1.010]) and PFS (P=0.066; HR 0.775[0.590-1.018]). Patients recovering from IP had longer OS (P=0.011; HR 0.678 [0.503-0.913]) and PFS (P=0.018; HR 0.703[0.526-0.941])

Author	Number of patients	Immunoparesis(%)	Prognostic significance of immunoparesis
Sorrig et al^[5]	2558 NDMM patients	2253(90%)	IP had no independent significant effect on OS (P = 0.12; HR 0.9 [0.7-1.0]). Qualitative IP was near significant riskfactor for PFS (P=0.054；HR 1.2[1.0-1.4]) and either 25%, 50% or 75% reduction in uninvolved immunoglobulin levels was all independent effect on PFS
Lakhwani et al^[29]	113 newly diagnosed transplant-ineligible patients	104(92%)	Patients who had IP at diagnosis and recovered it during or after treatment had longer OS ( P=0.007; HR 0.40[0.20-0.80]) and PFS (P<0.001;HR 0.32[0.19-0.52])
Chen et al^[4]	142 patients with MM	125(88%)	Severe and continuous IP ( at least two uninvolved Igs were suppressed continuously) was independent effect on OS (P=0.017; HR 1.275[1.044-1.556]) and PFS (P<0.001; HR 1.449[1.233-1.702])
Geng et al^[28]	287 NDMM patients	265(92.3%) 70% severe IP 80.8% partial IP	Severe (one of uninvolved immunoglobulins was below 50% the lower limit of normal ranges) and partial IP (suppression of at least two uninvolved immunoglobulins) were independently associated with shorter OS (P=0.040; HR 1.7[1.0-2.8]) and PFS (P=0.037; HR 1.7[1.0-2.9])
Lei et al^[6]	93 patients with MM who underwent ASCT	-	Patients who recovered from IP within 12 months after ASCT had longer OS (P<0.001) and PFS (P= 0.001)
Davila et al^[27]	431 transplant-ineligible patients with MM	350(81.2%)	IP was associated with a shorter OS (P=0.057; HR 0.746[0.551-1.010]) and PFS (P=0.066; HR 0.775[0.590-1.018]). Patients recovering from IP had longer OS (P=0.011; HR 0.678 [0.503-0.913]) and PFS (P=0.018; HR 0.703[0.526-0.941])

[1]	俞家旺, 李国梅, 黄昌保, 唐宁, 鲁卫华, 周锋. 皖南地区急性有机磷农药中毒患者预后预测的Nomogram模型研究[J]. 中国临床药理学与治疗学, 2026, 31(4): 460-466.
[2]	贺寿艳, 刘敏俊, 万聪, 谭布珍. PARP抑制剂治疗子宫内膜癌的研究进展[J]. 中国临床药理学与治疗学, 2026, 31(4): 536-542.
[3]	胡静, 张迪, 程二林. TLR-9（1237 T/C）基因多态性对糖尿病足患者复发感染的影响[J]. 中国临床药理学与治疗学, 2025, 30(7): 950-960.
[4]	丁勤, 杨汝薇, 张声南, 阳国平, 裴奇. 时间-事件分析在评价抗多重耐药革兰阴性菌感染药物疗效中的应用[J]. 中国临床药理学与治疗学, 2025, 30(7): 998-1008.
[5]	许婷婷, 汪万杰, 鲍静, 夏瑞祥. NLRC4介导的炎症小体通路与多发性骨髓瘤的关系及治疗前景[J]. 中国临床药理学与治疗学, 2025, 30(4): 501-508.
[6]	纪昊雨, 秦立龙, 查磊, 王寒黎, 程玉生. 酪氨酸磷酸酶Shp2与急性肺损伤[J]. 中国临床药理学与治疗学, 2025, 30(10): 1436-1440.
[7]	王文娟, 路佩源, 杨晓彤, 陈莉, 赵银枝, 袁媛. 美罗培南基于TDM个体化治疗重症感染患者的研究应用[J]. 中国临床药理学与治疗学, 2024, 29(12): 1329-1336.
[8]	王梦娇, 高超, 王涛, 张倩, 文娟, 吕冬梅, 胡丽丽. CDA C435T基因多态性显著延长吉西他滨治疗晚期非小细胞肺癌远期疗效[J]. 中国临床药理学与治疗学, 2024, 29(12): 1337-1343.
[9]	韦汝华, 曹雯, 陆雅婷, 蒙明薇, 李菊满, 秦艳娥, 蓝晓步, 莫凯. 中枢性神经系统感染患者美罗培南血药浓度达标情况及影响因素分析[J]. 中国临床药理学与治疗学, 2024, 29(10): 1146-1151.
[10]	石大伟, 郑晓永, 靳晓丹, 赵晓曼, 陈杰, 杜幸军. XPC基因多态性rs2228001对接受卡培他滨为基础辅助化疗的结直肠癌患者预后的影响[J]. 中国临床药理学与治疗学, 2023, 28(4): 391-399.
[11]	朱瑞芳, 郭东凯, 智慧, 江翊国, 张悦翎, 钱晓萍, 季士亮. ROS-NF-κB-p38MAPK通路探索榄香烯联合硼替佐米抗多发性骨髓瘤的机制研究[J]. 中国临床药理学与治疗学, 2023, 28(11): 1219-1226.
[12]	黄凯歌, 许勤华, 王伟. 血糖、血钙对急性重症胰腺炎患者预后影响的交互作用及预测效能研究[J]. 中国临床药理学与治疗学, 2023, 28(11): 1227-1234.
[13]	吴莉莉, 梁至, 黄思咏, 王妍. 肾功能亢进对感染性心内膜炎患者万古霉素药动学的影响及有效性与安全性研究[J]. 中国临床药理学与治疗学, 2023, 28(10): 1139-1145.
[14]	黄小明, 杜野, 林少明, 沈观乐. 呼吸道微生态对晚期非小细胞肺癌患者接受PD-1抑制剂单药治疗疗效影响的探索性研究[J]. 中国临床药理学与治疗学, 2023, 28(1): 66-74.
[15]	段圆圆, 李子坚. Ciltacabtagene autoleucel——治疗复发难治性多发性骨髓瘤的靶向BCMA CAR-T细胞新型疗法[J]. 中国临床药理学与治疗学, 2022, 27(10): 1145-1154.