-
摘要: 多发性骨髓瘤目前仍是一种无法治愈的血液恶性肿瘤，以蛋白酶体抑制剂、免疫调节剂为代表的新药治疗使多发性骨髓瘤的预后明显改善，但残存的骨髓瘤干细胞在药物的压力选择下会发生克隆演化，导致耐药，复发难治不可避免，预后极差。在免疫治疗时代，以CD38单抗、靶向BCMA为代表的抗原嵌合受体T细胞、抗体药物偶联物、双特异性抗体为代表的免疫治疗已经证实能明显改善复发难治骨髓瘤的预后，成为多发性骨髓瘤治疗方面的研究热点，本文将对新的免疫治疗研究进展进行综述。Abstract: Multiple myeloma is still an incurable hematologic malignant tumor, and the prognosis of multiple myeloma has been significantly improved by the new drug treatment represented by proteasome inhibitors and immunomodulators. However, the residual myeloma stem cells will undergo clonal evolution under the pressure of drug selection, resulting in drug resistance, refractory recurrence and extremely poor prognosis. In the era of immunotherapy, immunotherapy represented by CD38 monoclonal antibody, chimeric antigen receptor T cells targeting BCMA, antibody drug conjugate and bisspecific antibody has been proven to significantly improve the prognosis of relapsed refractory myeloma, and has become a research hotspot in the treatment of multiple myeloma. This paper will review the progress of new immunotherapy research.
-
-
表 1 单克隆抗体临床试验数据
名称 靶点 试验名称及阶段 纳入人数 既往治疗线数 缓解率 无进展生存 不良反应 TAK-079 CD38 NCT02219256Ⅰ期NCT03499280Ⅰ/Ⅱa期 34 4(2~12) RP2(600 mg)，ORR 33%(n=9)临床试验正在进行 NR* 疲劳21%，贫血18%，中性粒细胞减少18%，白细胞减少15%；唯一与药物相关的严重不良反应为3级憩室炎 SAR442085 CD38 临床前研究阶段 VIS832 CD138 临床前研究阶段 R8H283 CD98 临床前研究阶段 *NR：临床上未达到预期结果。 
下载: 导出CSV
表 2 ADC临床试验数据
名称 靶点 化学毒物 试验名称及阶段 纳入人数 既往治疗线数 缓解率 无进展生存 不良反应 MDI2228 BCMA tesirine NCT03489525Ⅰ期 82 2~11 ORR 61%，≥VGPR率24% 未报道 畏光53.7%，血小板减少31.7%，皮疹29.3% HDP-101 BCMA α-天蒿素 NCT04879043Ⅰ/Ⅱa期 临床试验正在进行
下载: 导出CSV
表 3 双特异性抗体临床试验数据
名称 靶点 试验名称及阶段 纳入人数 既往治疗线数 缓解率 无进展生存/月 疗效持续时间/月 不良反应 ABBV-383(TNB-383B) BCMA×CD3 NCT03933735Ⅰ期 124 5 ORR 57%(n=122，所有剂量)，≥VGPR率43%；≥60 mg剂量队列(n=49)中ORR和≥VGPR率分别为59%和39%；≥40 mg剂量队列(n=79)中ORR和≥VGPR率分别为68%和54% NR* NR* 中性粒细胞减少37%，贫血29%；CRS 57%(3/4级3%)；疲劳30% Cevostamab FcRH5×CD3 NCT03275103Ⅰ期 160 6 160 mg剂量水平ORR 54.5%；90 mg剂量水平ORR 36.7% 未报道 15.6(95%CI6.4~21.6) CRS 80% Talquetamab(JNJ-64407-564) GPRC5D×CD3 NCT03399799Ⅰ期 78 5.5(2~14) 405 μg/kg组ORR 70%，≥VGPR率57% 未报道 NR* 中性粒细胞减少67%(3/4级53%)；CRS 77%(3/4级3.3%)；皮肤相关和指甲疾病83%，皮肤去角质37% 800 μg/kg组ORR 64%，≥VGPR率52% 中性粒细胞减少36%(3/4级23%)；CRS 80%，无3/4级；皮肤及指甲疾病75%，皮肤去角质39% RO7297089 BCMA×CD16A NCT04434469Ⅰ期 21 8(2~11) ORR NR*达VGPR 1例 NR* NR* 贫血52.4%，输注相关反应47.6%，背痛23.8%，ALT升高19%，血小板减少19% CTX-8573 BCMA×NKp30 临床前研究阶段 IBI379 BCMA×CD3 临床前研究阶段 *NR：临床上未达到预期结果。
下载: 导出CSV
表 4 CAR-T细胞疗法临床试验数据
名称 靶点 试验名称阶段 纳入人数 既往治疗线数 缓解率 无进展生存 不良反应 CT103A(IBI326) BCMA NCT05066646Ⅰ/Ⅱ期 79 5(3~23) ORR 94.9%，≥CR率68.4%，MRD(-)CR率100% 所有队列的PFS尚未达到；在既往CAR-T患者中为7.5个月(95%CI 2.9~未达到) ≥3级93.7%：中性粒细胞减少82.3%，血小板减少59.5%，淋巴细胞减少58.2%；CRS 94.9% C-CAR088 BCMA NCT03815383
NCT03751293
NCT04295018
NCT04322292
Ⅰ期31 4 ORR 96.4%(n=28)，≥CR率57.1%，MRD(-)CR率93.7% NR* CRS 93.5%，3例(9.6%)发生3级CRS，1例(3.2%)出现1级神经毒性 Decartes-08 BCMA NCT04816526Ⅱ期 临床试验正在进行 *NR：临床上未达到预期结果。
下载: 导出CSV
-
[1] Lopes R, Caetano J, Ferreira B, et al. The Immune Microenvironment in Multiple Myeloma: Friend or Foe?[J]. Cancers, 2021, 13(4): 625. doi: 10.3390/cancers13040625
[2] Leblay N, Maity R, Hasan F, et al. Deregulation of Adaptive T Cell Immunity in Multiple Myeloma: Insights Into Mechanisms and Therapeutic Opportunities[J]. Front Oncol, 2020, 10: 636. doi: 10.3389/fonc.2020.00636
[3] Ho M, Goh CY, Patel A, et al. Role of the Bone Marrow Milieu in Multiple Myeloma Progression and Therapeutic Resistance[J]. Clin Lymphoma Myeloma Leuk, 2020, 20(10): 752-768. doi: 10.1016/j.clml.2020.05.026
[4] Korver W, Carsillo M, Yuan J, et al. A Reduction in B, T, and Natural Killer Cells Expressing CD38 by TAK-079 Inhibits the Induction and Progression of Collagen-Induced Arthritis in Cynomolgus Monkeys[J]. Pharmacol Exp Ther, 2019, 370(2): 182-196. doi: 10.1124/jpet.119.256602
[5] Krishnan AY, Patel KK, Hari P, et al. A phase Ib study of TAK-079, an investigational anti-CD38 monoclonal antibody(mAb)in patients with relapsed/refractory multiple myeloma(RRMM): Preliminary results[J]. J Clin Oncol, 2020, 38(15_suppl): 8539. doi: 10.1200/JCO.2020.38.15_suppl.8539
[6] Kassem S, Diallo BK, El-Murr N, et al. SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma[J]. Blood, 2022, 139(8): 1160-1176. doi: 10.1182/blood.2021012448
[7] Yu Teng, Chaganty B, Lin L, et al. A Novel CD138-Targeting Monoclonal Antibody Induces Potent Myeloma Killing and Further Synergizes with IMiDs or Bortezomib in in Vitro and In Vivo Preclinical Models of Human Multiple Myeloma[J]. Blood, 2020, 136(Supplement 1): 30-31.
[8] Hasegawa K, Ikeda S, Yaga M, et al. Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain[J]. Sci Transl Med, 2022, 14(632): eaax7706. doi: 10.1126/scitranslmed.aax7706
[9] Offidani M, Corvatta L, Morè S, et al. Belantamab Mafodotin for the Treatment of Multiple Myeloma: An Overview of the Clinical Efficacy and Safety[J]. Drug Des Devel Ther, 2021, 15: 2401-2415. doi: 10.2147/DDDT.S267404
[10] Xing L, Lin L, Yu T, et al. Anti-Bcma PBD MEDI2228 Combats Drug Resistance and Synergizes with Bortezomib and Inhibitors to DNA Damage Response in Multiple Myeloma[J]. Blood, 2019, 134(Supplement_1): 1817. doi: 10.1182/blood-2019-127163
[11] Xing L, Lin L, Yu T, et al. A novel BCMA PBD-ADC with ATM/ATR/WEE1 inhibitors or bortezomib induce synergistic lethality in multiple myeloma[J]. Leukemia, 2020, 34(8): 2150. doi: 10.1038/s41375-020-0745-9
[12] Xing L, Wang S, Liu J, et al. BCMA-Specific ADC MEDI2228 and Daratumumab Induce Synergistic Myeloma Cytotoxicity via IFN-Driven Immune Responses and Enhanced CD38 Expression[J]. Clin Cancer Res, 2021, 27(19): 5376-5388. doi: 10.1158/1078-0432.CCR-21-1621
[13] Strassz A, Raab MS, Orlowski RZ, et al. A First in Human Study Planned to Evaluate Hdp-101, an Anti-BCMA Amanitin Antibody-Drug Conjugate with a New Payload and a New Mode of Action, in Multiple Myeloma[J]. Blood, 2020, 136(Supplement 1): 34.
[14] Pahl A, Lutz C, Hechler T, et al. Amanitins and their development as apayload for antibody-drug conjugates[J]. Drug Discov Today Technol, 2018, 30: 85-89. doi: 10.1016/j.ddtec.2018.08.005
[15] Figueroa-Vazquez V, Ko J, Breunig C, et al. HDP-101, an Anti-BCMA Antibody-Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells[J]. Mol Cancer Ther, 2021, 20(2): 367-378. doi: 10.1158/1535-7163.MCT-20-0287
[16] Ravi G, Costa LJ. Bispecific T-cell engagers for treatment of multiple myeloma[J]. Am J Hematol, 2023, 98 Suppl 2: S13-S21.
[17] Kumar S, D'Souza A, Shah N, et al. A Phase 1 First-in-Human Study of Tnb-383B, a BCMA×CD3 Bispecific T-Cell Redirecting Antibody, in Patients with Relapsed/Refractory Multiple Myeloma[J]. Blood, 2021, 138(Supplement 1): 900. doi: 10.1182/blood-2021-150757
[18] D'Souza A, Shah N, Rodriguez C, et al. A Phase Ⅰ First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen×CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma[J]. J Clin Oncol, 2022, 40(31): 3576-3586. doi: 10.1200/JCO.22.01504
[19] Fei K, Ni H, Zhu M, et al. IBI379, a novel B cell maturation antigen/CD3 bispecific T-cell engager, displays high antitumor efficacy in preclinical models of multiple myeloma[J]. Cancer Lett, 2022, 536: 215663. doi: 10.1016/j.canlet.2022.215663
[20] Nakamura R, Lear S, Wilson D, et al. Early Pharmacodynamic Changes in T-Cell Activation, Proliferation, and Cytokine Production Confirm the Mode of Action of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma[J]. Blood, 2020, 136(Supplement 1): 14-15.
[21] Trudel S, Cohen AD, Krishnan AY, et al. Cevostamab Monotherapy Continues to Show Clinically Meaningful Activity and Manageable Safety in Patients with Heavily Pre-Treated Relapsed/Refractory Multiple Myeloma(RRMM): Updated Results from an Ongoing Phase Ⅰ Study[J]. Blood, 2021, 138(Supplement 1): 157. doi: 10.1182/blood-2021-147983
[22] Cohen AD, Harrison SJ, Krishnan A, et al. Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma[J]. Blood, 2020, 136(Supplement 1): 42-43.
[23] Verkleij CPM, Broekmans MEC, van Duin M, et al. Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma[J]. Blood Adv, 2021, 5(8): 2196-2215. doi: 10.1182/bloodadvances.2020003805
[24] Minnema MC, Krishnan AY, Berdeja JG, et al. Efficacy and safety of talquetamab, a G protein-coupled receptor family C group 5 member D×CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma(RRMM): Updated results from MonumenTAL-1[J]. J Clin Oncol, 2022, 40(16_suppl): 8015. doi: 10.1200/JCO.2022.40.16_suppl.8015
[25] Demaria O, Gauthier L, Debroas G, et al. Natural killer cell engagers in cancer immunotherapy: Next generation of immuno-oncology treatments[J]. Eur J Immunol, 2021, 51(8): 1934-1942. doi: 10.1002/eji.202048953
[26] Kakiuchi-Kiyota S, Ross T, Wallweber HA, et al. A BCMA/CD16A bispecific innate cell engager for the treatment of multiple myeloma[J]. Leukemia, 2022, 36(4): 1006-1014. doi: 10.1038/s41375-021-01478-w
[27] Plesner T, Harrison SJ, Quach H, et al. A Phase Ⅰ Study of RO7297089, a B-Cell Maturation Antigen(BCMA)-CD16a Bispecific Antibody in Patients with Relapsed/Refractory Multiple Myeloma(RRMM)[J]. Blood, 2021, 138(Supplement 1): 2755. doi: 10.1182/blood-2021-147418
[28] Yoon JW, Guzman W, Oliphant A, et al. CTX-8573, an Innate-Cell Engager Targeting BCMA, is a Highly Potent Multispecific Antibody for the Treatment of Multiple Myeloma[J]. Blood, 2019, 134(Supplement_1): 3182. doi: 10.1182/blood-2019-128749
[29] Zhao WH, Wang BY, Chen LJ, et al. Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China(LEGEND-2)[J]. J Hematol Oncol, 2022, 15(1): 86. doi: 10.1186/s13045-022-01301-8
[30] Mi JQ, Zhao W, Jing H, et al. Phase Ⅱ, Open-Label Study of Ciltacabtagene Autoleucel, an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor-T-Cell Therapy, in Chinese Patients With Relapsed/Refractory Multiple Myeloma(CARTIFAN-1)[J]. J Clin Oncol, 2023, 41(6): 1275-1284. doi: 10.1200/JCO.22.00690
[31] 梅恒, 李成功, 胡豫, 等. 嵌合抗原受体T细胞疗法在难治/复发多发性骨髓瘤中的研究进展[J]. 临床血液学杂志, 2020, 33(7): 441-445. doi: 10.13201/j.issn.1004-2806.2020.07.001 https://lcxy.whuhzzs.com/article/doi/10.13201/j.issn.1004-2806.2022.05.018
[32] 韩为东, 张亚晶. CAR-T细胞治疗淋巴瘤——我们仍然在路上[J]. 临床血液学杂志, 2022, 35(9): 612-615. https://lcxy.whuhzzs.com/article/doi/10.13201/j.issn.1004-2806.2022.09.002
[33] 董斐斐, 傅维佳, 秦永文, 等. 嵌合抗原受体T细胞治疗的心血管毒性[J]. 临床心血管病杂志, 2020, 36(1): 83-85. https://www.cnki.com.cn/Article/CJFDTOTAL-LCXB202001019.htm
[34] 茆诗源, 马瑞聪, 聂山林, 等. CART细胞治疗患者住院期间心血管不良事件发生的危险因素分析[J]. 临床心血管病杂志, 2021, 37(12): 1106-1111. doi: 10.13201/j.issn.1001-1439.2021.12.008
[35] Wang D, Wang J, Hu G, et al. A phase 1 study of a novel fully human BCMA-targeting CAR(CT103A) in patients with relapsed/refractory multiple myeloma[J]. Blood, 2021, 137(21): 2890-2901. doi: 10.1182/blood.2020008936
[36] Li C, Wang D, Song Y, et al. Updated phase 1/2 data of safety and efficacy of CT103A, fully human BCMA-directed CAR-T cells, in relapsed/refractory multiple myeloma[C]. 2022 EHA Congress, 2022, Abstract S187.
[37] Qu X, An G, Sui W, et al. Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma[J]. J Immunother Cancer, 2022, 10(9): e005145. doi: 10.1136/jitc-2022-005145
[38] Lin L, Cho SF, Xing L, et al. Preclinical evaluation of CD8+ anti-BCMA mRNA CAR T-cells for treatment of multiple myeloma[J]. Leukemia, 2021, 35(3): 752-763. doi: 10.1038/s41375-020-0951-5
[39] Lu H, Zhao X, Li Z, et al. From CAR-T Cells to CAR-NK Cells: A Developing Immunotherapy Methodsfor Hematological Malignancies[J]. Front Oncol, 2021, 11: 720501. doi: 10.3389/fonc.2021.720501
[40] Forero JV, Moreno Cortes F, Robledo JEG, et al. Preclinical NK Cell Platform for CAR Directed Therapies: Functional and Phenotypic Comparison Using a Rechallenge Cytotoxicity Assay[J]. Blood, 2021, 138(Supplement 1): 4805. doi: 10.1182/blood-2021-154176
[41] Goodridge JP, Bjordahl R, Mahmood S, et al. FT576 path to first-of-kind clinical trial: translation of a versatile multi-antigen specific off-the-shelf NK cell for treatment of multiple myeloma[J]. Cancer Res, 2021, 81(13_Supplement): 1550. doi: 10.1158/1538-7445.AM2021-1550
[42] Goodridge JP, Bjordahl R, Mahmood S, et al. FT576: Multi-Specific Off-the-Shelf CAR-NK Cell Therapy Engineered for Enhanced Persistence, Avoidance of Self-Fratricide and Optimized Mab Combination Therapy to Prevent Antigenic Escape and Elicit a Deep and Durable Response in Multiple Myeloma[J]. Blood, 2020, 136(Supplement 1): 4-5.
-
| 引用本文: |
季嘉敏, 赵万红. 多发性骨髓瘤免疫治疗进展[J]. 临床血液学杂志, 2023, 36(9): 680-687. doi: 10.13201/j.issn.1004-2806.2023.09.014
|
| Citation: |
JI Jiamin, ZHAO Wanhong. Advances in immunotherapy for multiple myeloma[J]. J Clin Hematol, 2023, 36(9): 680-687. doi: 10.13201/j.issn.1004-2806.2023.09.014
|