来那度胺联合硼替佐米和地塞米松治疗多发性骨髓瘤的疗效

doi:10.11958/20250356

摘要/Abstract

摘要：

目的探讨来那度胺联合硼替佐米和地塞米松治疗多发性骨髓瘤（MM）的疗效及对热休克蛋白90（HSP90）mRNA、miR-28-5p、抗酒石酸酸性磷酸酶5b（TRACP-5b）、高迁移率族蛋白B1（HMGB1）的影响。方法选取80例初诊MM患者，根据治疗方式的不同将患者分为二联组（40例，硼替佐米和地塞米松治疗）和三联组（40例，硼替佐米、地塞米松联合来那度胺治疗）。实时荧光定量聚合酶链反应检测HSP90 mRNA、miR-28-5p水平。酶联免疫吸附试验检测TRACP-5b、HMGB1水平。比较2组临床疗效，治疗前后HSP90 mRNA、miR-28-5p、TRACP-5b、HMGB1水平，免疫细胞功能、肾功能指标和不良反应发生率。结果三联组总有效率高于二联组（92.50% vs. 75.00%，P<0.05）。与治疗前相比，治疗后2组HSP90 mRNA、TRACP-5b、血肌酐、尿素氮水平降低，且三联组低于二联组；2组miR-28-5p、HMGB1、CD4⁺、CD3⁺、CD4⁺/CD8⁺水平升高，且三联组水平高于二联组（P<0.05）。2组不良反应发生率比较差异无统计学意义。结论来那度胺联合硼替佐米和地塞米松治疗MM临床疗效显著，安全可靠。

关键词: 多发性骨髓瘤, 来那度胺, 硼替佐米, 地塞米松, HSP90热休克蛋白质类, HMGB1蛋白质, miR-28-5p, 抗酒石酸酸性磷酸酶5b

Abstract:

Objective To investigate the efficacy of lenalidomide combined with bortezomib and dexamethasone in the treatment of multiple myeloma (MM) and their effects on heat shock protein 90 (HSP90) mRNA, miR-28-5p, anti-tartrate acid phosphatase 5b (TRACP-5b) and high mobility group protein B1 (HMGB1). Methods Eighty patients with newly diagnosed MM were selected and divided into the two-combination group (40 patients treated with bortezomib and dexamethasone) and the three-combination group (40 patients treated with bortezomib and dexamethasone combined with lenalidomide) according to the treatment modalities. Real-time fluorescence quantitative polymerase chain reaction was used to detect HSP90 mRNA and miR-28-5p levels. Enzyme-linked immunosorbent assay was used to detect TRACP-5b and HMGB1 levels. The clinical efficacy of the 2 groups was compared. Levels of HSP90 mRNA, miR-28-5p, TRACP-5b, HMGB1, the immune cell function, renal function indexes and the incidence of adverse reactions were compared before and after treatment. Results The total effective rate of the three-combination group was higher than that of the two-combination groups (92.50% vs. 75.00%, P<0.05). Compared with the pretreatment, the levels of HSP90 mRNA, TRACP-5b, blood creatinine (SCr), and urea nitrogen (BUN) decreased in the 2 groups after treatment, and which was lower in the three-combination group than that in the two-combination groups. The levels of miR-28-5p, HMGB1, CD4⁺, CD3⁺ and CD4⁺/CD8⁺ were elevated in the 2 groups, and the levels were higher in the three-combination group than those in the two-combination group (P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups. Conclusion Lenalidomide combined with bortezomib and dexamethasone is clinically effective, safe and reliable in the treatment of MM.

Key words: multiple myeloma, lenalidomide, bortezomib, dexamethasone, HSP90 heat-shock proteins, HMGB1 protein, miR-28-5p, tartrate resistant acid phosphatase 5b isoenzyme

中图分类号:

R733.3

图/表 7

参考文献 26

[1]	LIU J, DU F, CHEN C, et al. CircRNA ITCH increases bortezomib sensitivity through regulating the miR-615-3p/PRKCD axis in multiple myeloma[J]. Life Sci, 2020,262:118506. doi:10.1016/j.lfs.2020.118506.
[2]	刘荟敏, 许旋旋, 王远丽, 等. CircBACH1调节miR-140-5p/MDM2轴对多发性骨髓瘤细胞增殖、凋亡和化疗敏感性的影响[J]. 天津医药, 2023, 51(11):1170-1175.
	LIU H M, XU X X, WANG Y L, et al. Impacts of CircBACH1 on proliferation,apoptosis and chemosensitivity of multiple myeloma cells by regulating miR-140-5p/MDM2 axis[J]. Tianjin Med J, 2023, 51(11):1170-1175. doi:10.11958/20230126.
[3]	SIEGEL R L, MILLER K D, FUCHS H E, et al. Cancer Statistics,2021[J]. CA Cancer J Clin, 2021, 71(1):7-33. doi:10.3322/caac.21654.
[4]	JURCZYSZYN A, WASZCZUK-GAJDA A, CASTILLO J J, et al. Primary refractory multiple myeloma:a real-world experience with 85 cases[J]. Leuk Lymphoma, 2020, 61(12):2868-2875. doi:10.1080/10428194.2020.1788014.
[5]	FAN H, WANG W, ZHANG Y, et al. Current treatment paradigm and survival outcomes among patients with newly diagnosed multiple myeloma in China:a retrospective multicenter study[J]. Cancer Biol Med, 2023, 20(1):77-87. doi:10.20892/j.issn.2095-3941.2022.0612.
[6]	CHANUKUPPA V, MORE T H, TAUNK K, et al. Serum metabolomic alterations in multiple myeloma revealed by targeted and untargeted metabolomics approaches:a pilot study[J]. RSC Adv, 2019, 9(51):29522-29532. doi:10.1039/c9ra04458b.
[7]	王佳, 李晓红, 李静, 等. 补肾化浊法联合硼替佐米联合地塞米松方案治疗多发性骨髓瘤的疗效观察[J]. 广西医学, 2021, 43(23):2824-2828.
	WANG J, LI X H, LI J, et al. Therapeutic efficacy of tonifying kidney and resolving turbidity therapy combined with bortezomib plus dexamethasone regimen on multiple myeloma[J]. Guangxi Medical Journal, 2021, 43(23):2824-2828. doi:10.11675/j.issn.0253-4304.2021.23.12.
[8]	李青青, 梁立新, 令狐锐, 等. 不同剂量来那度胺治疗初诊中晚期多发性骨髓瘤疗效分析[J]. 临床研究, 2024, 32(12):70-73.
	LI Q Q, LIANG L X, LINGHU R, et al. Efficacy analysis of different doses of lenalidomide in the treatment of newly diagnosed advanced multiple myeloma[J]. Clinical Research, 2024, 32(12):70-73. doi:10.12385/j.issn.2096-1278(2024)12-0070-04.
[9]	罗曼, 胡莉文, 古学奎, 等. 来那度胺长期维持治疗对多发性骨髓瘤患者的临床疗效和预后评估[J]. 中国实验血液学杂志, 2021, 29(2):540-546.
	LUO M, HU L W, GU X K, et al. Evaluation of the clinical efficacy and prognosis of long-term maintenance lenalidomide therapy in patients with multiple myeloma[J]. Journal of Experimental Hematology, 2021, 29(2):540-546. doi:10.19746/j.cnki.issn1009-2137.2021.02.037.
[10]	李永莉, 傅琼瑶, 赵莲, 等. 多发性骨髓瘤患者血清HSP90 mRNA、β2-MG的表达水平及其与患者预后的关系[J]. 现代肿瘤医学, 2023, 31(10):1875-1879.
	LI Y L, FU Q Y, ZHAO L, et al. The expression levels of serum HSP90 mRNA and β 2-MG in patients with multiple myeloma and their relationship with patient prognosis[J]. Journal of Modern Oncology, 2023, 31(10):1875-1879. doi:10.3969/j.issn.1672-4992.2023.10.019.
[11]	李超, 杨如玉, 段丽娟. 血清miR-28-5p、HMGB1表达与多发性骨髓瘤患者病理特征及预后的关系[J]. 分子诊断与治疗杂志, 2023, 15(3):392-395,400.
	LI C, YANG R Y, DUAN L J. The relationship between serum miR-28-5p, HMGB1 expression and pathological characteristics and prognosis of multiple myeloma patients[J]. Journal of Molecular Diagnostics and Therapy, 2023, 15(3):392-395,400. doi:10.3969/j.issn.1674-6929.2023.03.009.
[12]	范小红, 王雪莲, 孟亚红. 血清MIP-1α、TRACP-5b和骨硬化蛋白水平在多发性骨髓瘤病情和预后中的临床价值[J]. 检验医学与临床, 2023, 20(2):150-154,159.
	FAN X H, WANG X L, MENG Y H. The clinical value of serum MIP-1 α,TRACP-5b,and osteopontin levels in the condition and prognosis of multiple myeloma[J]. Laboratory Medicine and Clinic, 2023, 20(2):150-154,159. doi:10.3969/j.issn.1672-9455.2023.02.002.
[13]	中国医师协会血液科医师分会, 中华医学会血液学分会, 中国医师协会多发性骨髓瘤专业委员会. 中国多发性骨髓瘤诊治指南(2017年修订)[J]. 中华内科杂志, 2017, 56(11):866-870.
	Chinese Hematology Association, Chinese Society of Hematology, Chinese Myeloma Committee-Chinese Hematology Association. The guidelines for the diagnosis and management of multiple myeloma in China(2017 revision)[J]. Chinese Journal of Internal Medicine, 2017, 56(11):866-870. doi:10.3760/cma.j.issn.0578-1426.2017.11.021.
[14]	KUMAR S, PAIVA B, ANDERSON K C, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma[J]. Lancet Oncol, 2016, 17(8):e328-e346. doi:10.1016/S1470- 2045(16)30206-6.
[15]	付彬, 刘萍, 关建民. 硼替佐米每周一次用药方案治疗初治多发性骨髓瘤效果观察[J]. 白血病·淋巴瘤, 2020, 29(4):236-239.
	FU B, LIU P, GUAN J M. Efficacy observation of bortezomib once-weekly therapy for newly diagnosed multiple myeloma[J]. Journal of Leukemia and Lymphoma, 2020, 29(4):236-239. doi:10.3760/cma.j.cn115356-20190820-00161.
[16]	顾小慧, 尹淑荣, 赵凤晓, 等. 硼替佐米联合来那度胺、地塞米松治疗多发性骨髓瘤的疗效观察[J]. 航空航天医学杂志, 2020, 31(11):1353-1354.
	GU X H, YIN S R, ZHAO F X, et al. Curative effect of bortezomib combined with lenalidomide and dexamethasone in the treatment of multiple myeloma[J]. Journal of Aerospace Medicine, 2020, 31(11):1353-1354. doi:10.3969/j.issn.2095-1434.2020.11.039.
[17]	DUTTA D, LIU J, WEN K, et al. BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy,overcomes resistance, and modulates the immune microenvironment in multiple myeloma[J]. Blood Cancer J, 2023, 13(1):184. doi:10.1038/s41408-023-00955-y.
[18]	胡晓丽. 硼替佐米联合地塞米松及来那度胺治疗多发性骨髓瘤的疗效及安全性[J]. 临床研究, 2023, 31(5):72-75.
	HU X L. Efficacy and safety of bortezomib combined with dexamethasone and lenalidomide in the treatment of multiple myeloma[J]. Clinical Research, 2023, 31(5):72-75. doi:10.12385/j.issn.2096-1278(2023)05-0072-04.
[19]	毛沛沛, 杨琛. 硼替佐米联合地塞米松、来那度胺化疗方案治疗多发性骨髓瘤的疗效和安全性评价[J]. 实用癌症杂志, 2023, 38(3):502-506.
	MAO P P, YANG C. Efficacy and safety evaluation of bortezomib combined with dexamethasone and lenalidomide chemotherapy regimen in the treatment of multiple myeloma[J]. The Practical Journal of Cancer, 2023, 38(3):502-506. doi:10.3969/j.issn.1001-5930.2023.03.039.
[20]	许伟, 丁现超. 伊沙佐米联合来那度胺及地塞米松治疗复发难治性多发性骨髓瘤的疗效与安全性[J]. 临床药物治疗杂志, 2022, 20(10):44-48.
	XU W, DING X C. Efficacy and safety of ixazomib combined with lenalidomide and dexamethasone in the treatment of relapsed and refractory multiple myeloma[J]. Clinical Medication Journal, 2022, 20(10):44-48. doi:10.3969/j.issn.1672-3384.2022.10.008.
[21]	LI Z, WONG K Y, CHAN G C, et al. Epigenetic silencing of LPP/miR-28 in multiple myeloma[J]. J Clin Pathol, 2018, 71(3):253-258. doi:10.1136/jclinpath-2017-204501.
[22]	YUAN S, LIU Z, XU Z, et al. High mobility group box 1(HMGB1):a pivotal regulator of hematopoietic malignancies[J]. J Hematol Oncol, 2020, 13(1):91. doi:10.1186/s13045-020-00920-3.
[23]	吴顺泉, 陈惠君, 战榕. 热休克蛋白90在多发性骨髓瘤患者中的表达及临床意义[J]. 中国实验血液学杂志, 2021, 29(2):525-529.
	WU S Q, CHEN H J, ZHAN R. Expression and clinical significance of heat shock protein 90 in multiple myeloma patients[J]. Journal of Experimental Hematology, 2021, 29(2):525-529. doi:10.19746/j.cnki.issn1009-2137.2021.02.034.
[24]	CZERWIŃSKA-LEDWIG O, ŻYCHOWSKA M, JURCZYSZYN A, et al. The impact of a 6-week nordic walking training cycle and a 14-hour intermittent fasting on disease activity markers and serum levels of wnt pathway-associated proteins in patients with multiple myeloma[J]. J Clin Med, 2024, 13(10):2771. doi:10.3390/jcm13102771.
[25]	曹慧, 黄来全, 汪琼, 等. 来那度胺联合硼替佐米,地塞米松治疗多发性骨髓瘤的效果及对免疫功能的影响研究[J]. 中国医药导报, 2024, 21(8):119-122.
	CAO H, HUANG L Q, WANG Q, et al. Study on the effect of Lenalidomide combined with Bortezomib and Dexamethasone in the treatment of multiple myeloma and its effect on immune function[J]. China Medical Herald, 2024, 21(8):119-122. doi:10.20047/j.issn1673-7210.2024.08.28.
[26]	王珂, 杜恒飞. 来那度胺联合硼替佐米和地塞米松治疗多发性骨髓瘤的疗效观察[J]. 中国肿瘤临床与康复, 2022, 29(5):585-588.
	WANG K, DU H F. Efficacy of lenalidomide combined with bortezomib and dexamethasone in the treatment of multiple myeloma[J]. Chinese Journal of Clinical Oncology and Rehabilitation, 2022, 29(5):585-588. doi:10.13455/j.cnki.cjcor.2022.05.18.

基因	引物序列（5'→3'）	产物大小/bp
HSP90 mRNA	上游：GTCTGCGTATCCGAAAGCAAG	2 568
HSP90 mRNA	下游：CTGAGGGGTGGGGATGATGTC	2 568
miR-28-5p	上游：GGCGTGAGGCTGAGGCTA	47
miR-28-5p	下游：ATGGCTGAGCGAAATTGCGGAC	47
U6	上游：CTCGCTTCGGCAGCACA	150
U6	下游：AACGCTTCACGAATTTGCGT	150

基因	引物序列（5'→3'）	产物大小/bp
HSP90 mRNA	上游：GTCTGCGTATCCGAAAGCAAG	2 568
HSP90 mRNA	下游：CTGAGGGGTGGGGATGATGTC	2 568
miR-28-5p	上游：GGCGTGAGGCTGAGGCTA	47
miR-28-5p	下游：ATGGCTGAGCGAAATTGCGGAC	47
U6	上游：CTCGCTTCGGCAGCACA	150
U6	下游：AACGCTTCACGAATTTGCGT	150

组别	性别（男/女）	年龄/ 岁	病程/ 年	D-S分期（Ⅱ期/Ⅲ期）	ISS分期（Ⅱ期/Ⅲ期）
二联组	21/19	57.61±6.07	2.63±0.37	4/36	10/30
三联组	23/17	57.33±6.25	2.73±0.40	3/37	9/31
t或χ²	0.202	0.272	1.594	0.157	0.069

组别	性别（男/女）	年龄/ 岁	病程/ 年	D-S分期（Ⅱ期/Ⅲ期）	ISS分期（Ⅱ期/Ⅲ期）
二联组	21/19	57.61±6.07	2.63±0.37	4/36	10/30
三联组	23/17	57.33±6.25	2.73±0.40	3/37	9/31
t或χ²	0.202	0.272	1.594	0.157	0.069

组别	n	完全缓解	非常好的部分缓解	部分缓解	病情稳定	病情进展	总有效
二联组	40	2（5.00）	11（27.50）	17（42.50）	7（17.50）	3（7.50）	30（75.00）
三联组	40	5（12.50）	13（32.50）	19（47.50）	2（5.00）	1（2.50）	37（92.50）
χ²							4.501^＊