多发性骨髓瘤的新药研发与治疗现状

邓书会; 安刚; 邱录贵

doi:10.3969/j.issn.1000-8179.2020.22.061

多发性骨髓瘤的新药研发与治疗现状

doi: 10.3969/j.issn.1000-8179.2020.22.061

中国医学科学院血液病医院(中国医学科学院血液学研究所), 实验血液学国家重点实验室, 国家血液系统疾病临床医学研究中心(天津市 300020)

基金项目:

国家自然科学基金重点项目 81630007

国家自然科学基金国际（地区）合作与交流项目 81920108006

详细信息

作者简介:
邓书会专业方向为多发性骨髓瘤及淋巴瘤的诊治。E-mail:dengshuhui@ihcams.ac.cn

邱录贵中国医学科学院北京协和医学院二级教授，主任医师，博士研究生导师。现任中国医学科学院血液病医院淋巴肿瘤中心主任，天津市脐带血造血干细胞库主任。兼任国际骨髓瘤工作组专家委员会成员、中国抗癌协会血液肿瘤专业委员会主委、中国临床肿瘤学会淋巴瘤研究联盟副主席、中国医师协会整合血液专业委员会副主任委员、中国医药教育协会血液学专业委员会副主任委员、天津市抗癌协会血液肿瘤专业委员会主任委员、中国医药生物技术协会精准医疗分会常务委员等。担任Blood Advances及《中华血液学杂志》等期刊编委/常务编委。主要研究方向为淋巴肿瘤的分子遗传与发病机制和有效治疗策略，干细胞工程。发表论文450余篇，其中SCI收录120余篇

通讯作者:
邱录贵 qiulg@ihcams.ac.cn

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出版历程
- 收稿日期: 2020-08-24
- 刊出日期: 2020-12-26

Development and application of new drugs and therapies for multiple myeloma

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Tianjin 300020, China

Funds:

the Key Program of National Natural Science Foundation of China 81630007

the International Cooperation and Exchange of the National Natural Science Foundation of China 81920108006

More Information

Corresponding author: Lugui Qiu; E-mail:qiulg@ihcams.ac.cn

摘要

摘要: 近20年来，多发性骨髓瘤（multiple myeloma，MM）治疗领域出现了划时代的进步。随着免疫调节剂（immunomodulatory drugs，IMiDs）、蛋白酶体抑制剂（proteasome inhibitors，PIs）的出现和普及，患者的治疗疗效明显提高，生存期显著延长，上述两类药物以及自体造血干细胞移植（autologous stem cell transplantation，ASCT）已成为MM治疗的基石。同时，新的药物仍在不断涌现。如新一代的IMiDs、PIs，抗体类药物及其衍生药物及小分子靶向性治疗药物，还出现了嵌合抗原受体T细胞免疫治疗（chimeric antigen receptor T-cell immunotherapy，CAR-T）等手段。上述治疗在MM中均显示出良好的前景。本文旨在对MM领域新药的研发和应用进行综述。
- 多发性骨髓瘤 /
- 新药 /
- 治疗 /
- CAR-T
Abstract: The treatment for patients of multiple myeloma (MM) has significantly improved over the past 20 years. With the introduction of immunomodulatory drugs (IMiDS) and proteasome inhibitors (PIs), the response rate and survival of patients with MM have remarkably increased. Currently, IMiDS, PIs, and autologous stem cell transplantation (ASCT) have become the cornerstone of MM treatment. However, numerous new treatments, such as the next generation of IMiDS and PIs, antibody drugs and their derivatives, smallmolecule-targeted therapy drugs, chimeric antigen receptor T-cell immunotherapy (CAR-T), and other cell therapies, are emerging. These treatments have shown promising prospects in treating MM. In this study, we aim to review the development and application of these highly appealing new drugs and therapies for MM.
- multiple myeloma (MM) /
- new drug /
- therapy /
- chimeric antigen receptor T-cell immunotherapy (CAR-T)

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参考文献(40)

[1]	Tai YT, Anderson KC. B cell maturation antigen (BCMA)-based immunotherapy for multiple myeloma[J]. Expert Opin Biol Ther, 2019, 19(11):1143-1156. doi: 10.1080/14712598.2019.1641196
[2]	Ghosh A, Mailankody S, Giralt SA, et al. CAR T cell therapy for multiple myeloma:where are we now and where are we headed[J]? Leuk Lymphoma, 2018, 59(9):2056-2067. doi: 10.1080/10428194.2017.1393668
[3]	Morandi F, Horenstein AL, Costa F, et al. CD38:A target for immunotherapeutic approaches in multiple myeloma[J]. Front Immunol, 2018, 9:2722. doi: 10.3389/fimmu.2018.02722
[4]	Kriegsmann K, Dingeldein M, Cremer M, et al. Cell-based immunotherapy approaches for multiple myeloma[J]. Br J Cancer, 2019, 120(1):38-44. doi: 10.1038/s41416-018-0346-9
[5]	Rosenblatt J, Avigan D. Cellular Immunotherapy for multiple myeloma[J]. Cancer J, 2019, 25(1):38-44. doi: 10.1097/PPO.0000000000000356
[6]	Wu C, Zhang L, Brockman QR, et al. Chimeric antigen receptor T cell therapies for multiple myeloma[J]. J Hematol Oncol, 2019, 12(1):120. doi: 10.1186/s13045-019-0823-5
[7]	Nooka AK, Kaufman JL, Hofmeister CC, et al. Daratumumab in multiple myeloma[J]. Cancer, 2019, 125(14):2364-2382. doi: 10.1002/cncr.32065
[8]	Giuliani N, Malavasi F. Editorial:immunotherapy in multiple myeloma[J]. Front Immunol, 2019, 10:1945. doi: 10.3389/fimmu.2019.01945
[9]	Tamura H, Ishibashi M, Sunakawa M, et al. Immunotherapy for multiple myeloma[J]. Cancers (Basel), 2019, 11(12):91.
[10]	Chim CS, Kumar SK, Orlowski RZ, et al. Management of relapsed and refractory multiple myeloma:novel agents, antibodies, immunotherapies and beyond[J]. Leukemia, 2018, 32(2):252-262. doi: 10.1038/leu.2017.329
[11]	Giuliani N, Accardi F, Marchica V, et al. Novel targets for the treatment of relapsing multiple myeloma[J]. Expert Rev Hematol, 2019, 12(7):481-496. doi: 10.1080/17474086.2019.1624158
[12]	Fouquet G, Bories C, Guidez S, et al. Pomalidomide for multiple myeloma[J]. Expert Rev Hematol, 2014, 7(6):719-731. doi: 10.1586/17474086.2014.966074
[13]	Miguel JS, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003):a randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2013, 14(11):1055-1066. doi: 10.1016/S1470-2045(13)70380-2
[14]	Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma[J]. Blood, 2017, 130(8):974-981. doi: 10.1182/blood-2017-05-785246
[15]	Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus Pomalidomide and dexamethasone for multiple myeloma[J]. N Engl J Med, 2018, 379(19):1811-1822. doi: 10.1056/NEJMoa1805762
[16]	Mateos MV, Blacklock H, Schjesvold F, et al. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183):a randomised, openlabel, phase 3 trial[J]. Lancet Haematol, 2019, 6(9):e459-e469. doi: 10.1016/S2352-3026(19)30110-3
[17]	Badros A, Hyjek E, Ma N, et al. Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma[J]. Blood, 2017, 130(10):1189-1197. doi: 10.1182/blood-2017-03-775122
[18]	Richardson PG, Oriol A, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM):a randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2019, 20(6):781-794. doi: 10.1016/S1470-2045(19)30152-4
[19]	Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR):a randomised, phase 3, open-label, multicentre study[J]. Lancet Oncol, 2016, 17(1):27-38. doi: 10.1016/S1470-2045(15)00464-7
[20]	Dimopoulos M, Siegel D, White DJ, et al. Carfilzomib vs bortezomib in patients with multiple myeloma and renal failure:a subgroup analysis of ENDEAVOR[J]. Blood, 2019, 133(2):147-155. doi: 10.1182/blood-2018-06-860015
[21]	Dimopoulos MA, Stewart AK, Masszi T, et al. Carfilzomib-lenalidomidedexamethasone vs lenalidomide-dexamethasone in relapsed multiple myeloma by previous treatment[J]. Blood Cancer J, 2017, 7(4):e554. doi: 10.1038/bcj.2017.31
[22]	Stewart AK, Dimopoulos MA, Masszi T, et al. Health-related quality-oflife results from the open-label, randomized, phase Ⅲ ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma[J]. J Clin Oncol, 2016, 34(32):3921-3930. doi: 10.1200/JCO.2016.66.9648
[23]	Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma[J]. J Clin Oncol, 2018, 36(8):728-734. doi: 10.1200/JCO.2017.76.5032
[24]	Facon T, Lee JH, Moreau P, et al. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma[J]. Blood, 2019, 133(18):1953-1963. doi: 10.1182/blood-2018-09-874396
[25]	Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma[J]. N Engl J Med, 2018, 378(6):518-528. doi: 10.1056/NEJMoa1714678
[26]	Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma[J]. N Engl J Med, 2019, 380(22):2104-2115. doi: 10.1056/NEJMoa1817249
[27]	Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE):a randomised, open-label, phase 3 trial[J]. Lancet, 2020, 395(10218):132-141. doi: 10.1016/S0140-6736(19)32956-3
[28]	Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA):a randomised, open-label, phase 3 study[J]. Lancet, 2019, 394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1
[29]	Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma:the GRIFFIN trial[J]. Blood, 2020, 136(8):936-945. doi: 10.1182/blood.2020005288
[30]	Caraccio C, Krishna S, Phillips DJ, et al. Bispecific antibodies for multiple myeloma:a review of targets, drugs, clinical trials, and future directions[J]. Front Immunol, 2020.[Epub ahead of print].
[31]	Giuliani N, Accardi F, Marchica V, et al. Novel targets for the treatment of relapsing multiple myeloma[J]. Expert Rev Hematol, 2019, 12(7):481-496. doi: 10.1080/17474086.2019.1624158
[32]	Panowski SH, Kuo TC, Zhang Y, et al. Preclinical efficacy and safety comparison of CD3 bispecific and ADC modalities targeting BCMA for the treatment of multiple myeloma[J]. Mol Cancer Ther, 2019, 18(11):2008-2020. doi: 10.1158/1535-7163.MCT-19-0007
[33]	Zuch DZC, Fajardo F, Zhong W, et al. Targeting multiple myeloma with AMG 424, a novel anti-CD38/CD3 bispecific T-cell-recruiting antibody optimized for cytotoxicity and cytokine release[J]. Clin Cancer Res, 2019, 25(13):3921-3933. doi: 10.1158/1078-0432.CCR-18-2752
[34]	Bruins W, Zweegman S, Mutis T, et al. Targeted therapy with immunoconjugates for multiple myeloma[J]. Front Immunol, 2020.[Epub ahead of print].
[35]	Trudel S, Lendvai N, Popat R, et al. Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159):a dose escalation and expansion phase 1 trial[J]. Lancet Oncol, 2018, 19(12):1641-1653. doi: 10.1016/S1470-2045(18)30576-X
[36]	Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma[J]. Blood, 2017, 130(24):2594-2602. doi: 10.1182/blood-2017-06-793869
[37]	Jhaveri KD, Wanchoo R. Selinexor for refractory multiple myeloma[J]. N Engl J Med, 2019, 381(20):1977. doi: 10.1056/NEJMc1912625
[38]	Stirrups R. Selinexor-dexamethasone for refractory multiple myeloma[J]. Lancet Oncol, 2019, 20(10):e560. doi: 10.1016/S1470-2045(19)30566-2
[39]	Basali D, Chakraborty R, Rybicki L, et al. Real-world data on safety and efficacy of venetoclax-based regimens in relapsed/refractory t(11;14) multiple myeloma[J]. Br J Haematol, 2020, 189(6):1136-1140. doi: 10.1111/bjh.16454
[40]	Vaxman I, Sidiqi MH, Gertz M. Venetoclax for the treatment of multiple myeloma[J]. Expert Rev Hematol, 2018, 11(12):915-920. doi: 10.1080/17474086.2018.1548931