Venetoclax治疗多发性骨髓瘤的研究进展
Research Progress of Venetoclax for the Treatment of Multiple Myeloma
DOI: 10.12677/ACM.2022.127911, PDF,   
作者: 夏静静, 罗 伟*：青海大学附属医院血液科，青海 西宁
关键词: 多发性骨髓瘤；维奈克拉Bcl-2；Multiple Myeloma； Venetoclax Bcl-2
摘要: 尽管近年来多发性骨髓瘤在治疗方面取得了很大的进展，但对于大多数患者来说，这种疾病仍无法治愈。抗凋亡蛋白的过表达是癌症的标志，有利于肿瘤细胞存活和对治疗的抵抗。口服药物Venetoclax是第一种Bcl-2特异性BH3拟生物。在多发性骨髓瘤中，对Venetoclax的体外敏感性主要存在于t (11;14)易位中。1期临床试验证实了Venetoclax单药或联合用药治疗多发性骨髓瘤t (11;14)易位的疗效。并证实与蛋白酶体抑制剂联合用于复发难治性多发性骨髓中的有效性，并与t (11;14)易位无关，且多项2期及3期临床试验正在进行中。本文描述目前关于Venetoclax治疗多发性骨髓瘤的知识，总结Venetoclax在多发性骨髓瘤治疗中的作用机制、毒性特征和已发表的数据，从而推动该领域向个性化治疗骨髓瘤的方向发展。
Abstract: Although multiple myeloma has made great strides in treatment in recent years, for most patients, the disease remains incurable. Overexpression of anti-apoptotic proteins is a marker of cancer, fa-voring tumor cell survival and resistance to treatment. The oral drug Venetoclax is the first Bcl-2 specific BH3 mimetic. In multiple myeloma, in vitro sensitivity to Venetoclax is predominantly pre-sent in t (11;14) Translocation. Phase 1 clinical trials confirmed the efficacy of Venettoclax in the treatment of multiple myeloma t (11;14) translocations, and confirmed effectiveness in combina-tion with proteasome inhibitors in relapsing refractory multiple bone marrow, and t (11;14) Trans-location is independent, and a number of Phase 2 and Phase 3 clinical trials are underway. This ar-ticle describes the current knowledge about Venetoclax in the treatment of multiple myeloma, summarizes the mechanism of action, toxicity characteristics and published data of Venettoclax in the treatment of multiple myeloma, and thus promotes the development of this field in the direc-tion of personalized treatment of myeloma.
文章引用：夏静静, 罗伟. Venetoclax治疗多发性骨髓瘤的研究进展[J]. 临床医学进展, 2022, 12(7): 6303-6310. https://doi.org/10.12677/ACM.2022.127911

参考文献

[1] Turesson, I., Bjorkholm, M., Blimark, C.H., Kristinsson, S., Velez, R. and Landgren, O. (2018) Rapidly Changing My-eloma Epidemiology in the General Population: Increased Incidence, Older Patients, and Longer Survival. European Journal of Haematology. [Google Scholar] [CrossRef] [PubMed]
[2] Ramasamy, K., Gay, F., Weisel, K., Zweegman, S., Mateos, M.V. and Richardson, P. (2021) Improving Outcomes for Patients with Relapsed Multiple Myeloma: Chal-lenges and Considerations of Current and Emerging Treatment Options. Blood Reviews, 49, Article ID: 100808. [Google Scholar] [CrossRef] [PubMed]
[3] Touzeau, C., Moreau, P. and Dumontet, C. (2017) Monoclonal Antibody Therapy in Multiple Myeloma. Leukemia, 31, 1039-1047. [Google Scholar] [CrossRef] [PubMed]
[4] Vaxman, I., Sidiqi, M.H. and Gertz, M. (2018) Venetoclax for the Treat-ment of Multiple Myeloma. Expert Review of Hematology, 11, 915-920. [Google Scholar] [CrossRef] [PubMed]
[5] Wu, H., Zhang, H., He, H.Y., et al. (2017) Cytogenetic Ab-normalities and Prognosis of 532 Patients with Multiple Myeloma. The Journal Covers All Aspects of Hematology, 38, 739-743.
[6] Wong, K.Y. and Chim, C.S. (2020) Venetoclax, Bortezomib and S63845, an MCL1 Inhibitor, in Multiple Myeloma. Journal of Pharmacy and Pharmacology, 72, 728-737. [Google Scholar] [CrossRef] [PubMed]
[7] Basali, D., Chakraborty, R., Rybicki, L., et al. (2020) Real-World Data on Safety and Efficacy of Venetoclax-Based Regimens in Relapsed/Refractory t(11;14) Multiple Myeloma. British Journal of Haematology, 189, 1136-1140. [Google Scholar] [CrossRef] [PubMed]
[8] Costa, L.J., Davies, F.E., Monohan, G.P., et al. (2021) Phase 2 Study of Venetoclax plus Carfilzomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. Blood Ad-vances, 5, 3748-3759. [Google Scholar] [CrossRef] [PubMed]
[9] Ashkenazi, A., Fairbrother, W.J., Leverson, J.D. and Souers, A.J. (2017) From Basic Apoptosis Discoveries to Advanced Selective BCL-2 Family Inhibitors. Nature Reviews Drug Discovery, 16, 273-284. [Google Scholar] [CrossRef] [PubMed]
[10] Kumar, S., Kaufman, J.L., Gasparetto, C., et al. (2017) Efficacy of Ve-netoclax as Targeted Therapy for Relapsed/ Refractory t(11;14) Multiple Myeloma. Blood, 130, 2401-2409. [Google Scholar] [CrossRef] [PubMed]
[11] Maples, K.T., Nooka, A.K., Gupta, V., et al. (2021) Natural History of Multiple Myeloma Patients Refractory to Venetoclax: A Single Center Experience. The American Journal of Hematology, 96, E68-E71. [Google Scholar] [CrossRef] [PubMed]
[12] Nahi, H., Kashif, M., Klimkowska, M., et al. (2021) Low Dose Venetoclax as a Single Agent Treatment of Plasma Cell Malignancies Harboring t(11;14). The American Journal of Hematology, 96, 925-933. [Google Scholar] [CrossRef] [PubMed]
[13] Seymour, J.F., Kipps, T.J., Eichhorst, B., et al. (2018) Veneto-clax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. The New England Journal of Medicine, 378, 1107-1120. [Google Scholar] [CrossRef] 
[14] Di Nardo, C.D., Pratz, K., Pullarkat, V., et al. (2019) Venetoclax Combined with Decitabine or Azacitidine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia. Blood, 133, 7-17. [Google Scholar] [CrossRef] [PubMed]
[15] Wei, A.H., Strickland, S.A., Hou, J.Z., et al. (2019) Veneto-clax Combined with Low-Dose Cytarabine for Previously Untreated Patients with Acute Myeloid Leukemia: Results from a Phase Ib/II Study. Journal of Clinical Oncology, 37, 1277-1284. [Google Scholar] [CrossRef] 
[16] Green, D.R. and Llambi, F. (2015) Cell Death Signaling. Cold Spring Harbor Perspectives in Biology, 7, a006080. [Google Scholar] [CrossRef] [PubMed]
[17] Kale, J., Osterlund, E.J. and Andrews, D.W. (2018) BCL-2 Fam-ily Proteins: Changing Partners in the Dance towards Death. Cell Death & Differentiation, 25, 65-80. [Google Scholar] [CrossRef] [PubMed]
[18] Moreau, P., Chanan-Khan, A., Roberts, A.W., et al. (2017) Promising Efficacy and Acceptable Safety of Venetoclax plus Bortezomib and Dexamethasone in Relapsed/Refractory MM. Blood, 130, 2392-2400. [Google Scholar] [CrossRef] [PubMed]
[19] Matulis, S.M., Gupta, V.A., Nooka, A.K., et al. (2016) Dex-amethasone Treatment Promotes Bcl-2 Dependence in Multiple Myeloma Resulting in Sensitivity to Venetoclax. Leuke-mia, 30, 1086-1093. [Google Scholar] [CrossRef] [PubMed]
[20] Touzeau, C., Dousset, C., Le Gouill, S., et al. (2014) The Bcl-2 Specific BH3 Mimetic ABT-199: A Promising Targeted Therapy for t(11;14) Multiple Myeloma. Leukemia, 28, 210-212. [Google Scholar] [CrossRef] [PubMed]
[21] Touzeau, C., Le Gouill, S., Mahé, B., et al. (2017) Deep and Sustained Response after Venetoclax Therapy in a Patient with Very Advanced Refractory Myeloma with Translocation t(11;14). Haematologica, 102, e112-e114. [Google Scholar] [CrossRef] [PubMed]
[22] Kambhampati, S., Galligan, D., Huang, C.Y., et al. (2020) A Single-Center Retrospective Cohort Analysis of Venetoclax in Relapsed/Refractory Multiple Myeloma. Leukemia & Lymphoma, 61, 1211-1219. [Google Scholar] [CrossRef] [PubMed]
[23] Roberts, A.W., Davids, M.S., Pagel, J.M., et al. (2016) Tar-geting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. The New England Journal of Medicine, 374, 311-322. [Google Scholar] [CrossRef] 
[24] Jelinek, T., Popkova, T., Duras, J., et al. (2020) Veneto-clax plus Bortezomib and Dexamethasone in Heavily Pretreated End-Stage Myeloma Patients without t(11;14): A Re-al-World Cohort. Hematological Oncology, 38, 412-414. [Google Scholar] [CrossRef] [PubMed]
[25] Kumar, S.K., Harrison, S.J., Cavo, M., et al. (2020) Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma (BELLINI): A Randomised, Double-Blind, Multicentre, Phase 3 Trial. The Lancet Oncology, 21, 1630-1642. [Google Scholar] [CrossRef] 
[26] Boccon-Gibod, C., Talbot, A., Le Bras, F., et al. (2020) Car-filzomib, Venetoclax and Dexamethasone for Relapsed/ Refractory Multiple Myeloma. British Journal of Haematology, 189, e73-e76. [Google Scholar] [CrossRef] [PubMed]
[27] Bahlis, N.J., Baz, R., Harrison, S.J., et al. (2021) Phase I Study of Venetoclax plus Daratumumab and Dexamethasone, with or without Bortezomib, in Patients with Relapsed or Refractory Multiple Myeloma with and without t(11;14). Journal of Clinical Oncology, 39, 3602-3612. [Google Scholar] [CrossRef] 
[28] Sidiqi, M.H., Al Saleh, A.S., Kumar, S.K., et al. (2021) Venetoclax for the Treatment of Multiple Myeloma: Outcomes Outside of Clinical Trials. The American Journal of Hematology, 96, 1131-1136. [Google Scholar] [CrossRef] [PubMed]
[29] Seymour, J.F., Ma, S., Brander, D.M., et al. (2017) Venetoclax plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukaemia: A Phase 1b Study. The Lancet Oncology, 18, 230-240. [Google Scholar] [CrossRef] 
[30] Coiffier, B., Altman, A., Pui, C.H., Younes, A. and Cairo, M.S. (2008) Guidelines for the Management of Pediatric and Adult Tumor Lysis Syndrome: An Evidence-Based Re-view. Journal of Clinical Oncology, 26, 2767-2778. [Google Scholar] [CrossRef] 
[31] Motoyama, N., Kimura, T., Takahashi, T., Watanabe, T. and Nakano, T. (1999) Bcl-x Prevents Apoptotic Cell Death of both Primitive and Definitive Erythrocytes at the End of Mat-uration. Journal of Experimental Medicine, 189, 1691-1698. [Google Scholar] [CrossRef] [PubMed]
[32] Zhang, H., Nimmer, P.M., Tahir, S.K., et al. (2007) Bcl-2 Family Proteins Are Essential for Platelet Survival. Cell Death & Dif-ferentiation, 14, 943-951. [Google Scholar] [CrossRef] [PubMed]

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