以硼替佐米为基础的联合方案治疗114例初诊多发性骨髓瘤患者的周围神经病变分析

doi:10.16150/j.1671-2870.2017.05.008

摘要/Abstract

摘要： 目的：观察、分析初次诊断多发性骨髓瘤（multiple myeloma,MM）患者采用硼替佐米为基础的联合化疗方案治疗后其周围神经病变情况。方法：收集2008年9月至2017年5月在上海交通大学医学院附属瑞金医院、上海交通大学医学院附属医院瑞金北院、上海市北站医院及同济大学附属杨浦医院血液科接受硼替佐米为基础的化疗方案治疗的初诊为MM的114例患者。根据治疗效果分为3组,组①为完全缓解（complete remission, CR）患者+很好的部分缓解(very good partial response, VGPR) 患者,共60例;组②为部分缓解（partial remission, PR）患者,共20例;组③为疾病稳定（ stable disease, SD）患者+疾病进展（ progressive disease, PD）患者,共34例,统计患者接受4个疗程治疗后的周围神经病变发生、相关风险因素分析及后续改善情况。结果：周围神经病变的总体发生率为65.8%,组①发生神经病变者49例、组② 13例、组③ 13例。4个疗程中,若患者出现周围神经病变后则调整治疗方案,调整后的单个疗程的硼替佐米总剂量,利用Kruskal-Wallis秩和检验方法进行统计,发现组①、组②、组③的硼替佐米剂量差异有统计学意义（P=0.002）,不同疗效组间的周围神经病变程度差异存在统计学意义（P=0.042）;利用Spearman方法分析发现疗效与周围神经病变间呈负相关（r=-0.383,P=0.001）。Spearman法分析结果显示,MM患者疗效与初诊时β₂微球蛋白、乳酸脱氢酶水平呈负相关（r均<-0.3,P<0.05）;周围神经病变的出现与初诊时的白蛋白、β₂微球蛋白、血钙、血红蛋白、血小板、肌酐、乳酸脱氢酶、性别、年龄间无统计学相关性（r均<0.3,P>0.05）。加用维生素B₁₂治疗后,能够改善其周围神经病变（P=0.032）。结论：初治MM患者在采用硼替佐米为基础的方案治疗时早期出现神经病变,即预示其有较高的治疗反应率;该种周围神经病变的发生与白蛋白、β₂微球蛋白、血钙、血红蛋白、血小板、肌酐、乳酸脱氢酶、性别、年龄间均无相关性;在患者出现Ⅰ级神经病变时,可不调整剂量,加用维生素B₁₂即可继续标准剂量治疗。

关键词: 多发性骨髓瘤, 初次诊断, 硼替佐米, 疗效, 周围神经病变

Abstract: Objective: To investigate the occurrence and development of bortezomib-induced peripheral neuropathy in newly-diagnosed multiple myeloma (MM) patients. Methods: A total of 114 newly-diagnosed MM patients receiving bortezomib based therapeutic regimen at Ruijin Hospital, Ruijin Hospital Northern Branch, Shanghai North Station Hospital and Yangpu Hospital from September 2008 to May 2017 were enrolled. According to treatment response, patients were divided into three groups: Group 1, complete remission (CR) and very good partial response (VGPR), 60 cases; Group 2, partial remission (PR), 20 cases; Group 3, stable disease (SD） and progressive disease (PD), 34 cases. The incidence, influencing factors and subsequent improvement of peripheral neuropathy（PN）after 4 treatment cycles were analyzed. Results: The overall incidence of peripheral neuropathy was 65.8%; and there were 49 cases(43.0%) in group 1, 13 cases (11.4%) in group 2 and 13 cases (11.4%) in group 3. During the 4 treatment cycles, the dose of bortezomib would be regulated if peripheral neuropathy occurred. Dose of bortezomib was compared between 3 groups by using Kruskal-Wallis test, which revealed that there was significant difference in bortezomib dose and efficacy between the 3 groups (P<0.05）. Efficacy of bortezomib was negatively correlated with peripheral neuropathy. Univariate analysis showed that albumin, beta-2 microglobulin, calcium, hemoglobin, platelets, creatinine, lactate dehydrogenase,sex and age were not the risk factors for peripheral neuropathy (correlation coefficient <0.3）. Peripheral neuropathy could be ameliorated when patients were given Vitamin B₁₂ (P<0.05). Conclusions: For newly-daignosed MM patients, the occurrence of PN in the early treatment predicts a better treatment response to bortezomib based therapeutic regimen. Efficacy of bortezomib is negatively correlated with peripheral neuropathy in newly-diagnosed MM patients. The levels of albumin, beta-2 microglobulin, calcium, hemoglobin, platelets, creatinine, lactate dehydrogenase have no correlation with the incidence of peripheral neuropathy. The bortezomib-induced peripheral neuropathy could be reversible with the administration of Vitamin B₁₂.

Key words: Multiple myeloma, Newly diagnosed, Bortezomib, Efficacy, Peripheral neuropathy

中图分类号:

R551.3

曹亚峰, 王静, 顾俊, 陆弘逾, 许杰, 刘元坊, 王焰, 王瑾, 陈钰, 陈玉宝, 李佳明, 郝杰, 糜坚青, 陈梅. 以硼替佐米为基础的联合方案治疗114例初诊多发性骨髓瘤患者的周围神经病变分析[J]. 诊断学理论与实践, 2017, 16(05): 492-497.

CAO Yafeng, WANG Jing, GU Jun, LU Hongyu, XUN Jie, LIU Yuanfang, WANG Yan, WANG Jin, CHEN Yu, CHEN Yubao, LI Jiaming, HAO Jie, MI Jianqing, CHEN Mei. Analysis of peripheral neuropathy following treatment with bortezomib in 114 newly-diagnosed multiple myeloma patients[J]. Journal of Diagnostics Concepts & Practice, 2017, 16(05): 492-497.

参考文献

[1] Shen Y, Zhou X, Wang Z, et al.Coagulation profiles and thromboembolic events of bortezomib plus thalidomide and dexamethasone therapy in newly diagnosed multiple myeloma[J]. Leuk Res,2011,35(2):147-151.
[2] 陈灏珠. 实用内科学 (下册)[M]. 人民卫生出版社,2001:1884-1889.
[3] 赵冰冰, 王焰, 糜坚青, 等. 硼替佐米为主的化疗方案对改善初治多发性骨髓瘤患者生存的作用[J]. 上海交通大学学报 (医学版),2011,31(12):1793.
[4] Wang YM, Long H, Yang D, et al.Clinical efficacy of cellular immuotherapy combined with bortezomib for the treatment of patients with multiple myeloma[J]. Zhongguo Shi Yan Xue Ye Xue Za Zhi,2017,25(3):818-822.
[5] Bruna J, Udina E, Alé A, et al.Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice[J]. Exp Neurol,2010,223(2):599-608.
[6] 张之南, 沈悌. 血液病诊断及疗效标准[M]. 3版.北京:科学出版社,2007:232-235.
[7] US Department of Health and Human Services. Common terminology criteria for adverse events v4. 03[R]. 2010.
[8] Alsina M, Boyce B, Devlin RD, et al.Development of an in vivo model of human multiple myeloma bone disease[J]. Blood,1996,87(4):1495-1501.
[9] Mateos MV, Hernández JM, Hernández MT, et al.Bortezomib plus melphalan and prednisone in elderly untrea-ted patients with multiple myeloma: results of a multicen-ter phase 1/2 study[J]. Blood,2006,108(7):2165-2172.
[10] Ma MH, Yang HH, Parker K, et al.The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents[J]. Clin Cancer Res,2003,9(3):1136-1144.
[11] Mitsiades N, Mitsiades CS, Richardson PG, et al.The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications[J]. Blood,2003,101(6):2377-2380.
[12] Takamatsu Y.Management of proteasome inhibitor-induced peripheral neuropathy[J]. Nihon Rinsho,2015,73(1):137-141.
[13] Meregalli C, Carozzi VA, Sala B, et al.Bortezomib-induced peripheral neurotoxicity in human multiple myeloma-bearing mice[J]. J Biol Regul Homeost Agents,2015, 29(1):115-124.
[14] San Miguel JF, Schlag R, Khuageva NK, et al.Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma[J]. N Engl J Med,2008,359(9):906-917.
[15] Antoine JC, Camdessanché JP.Peripheral nervous system involvement in patients with cancer[J]. Lancet Neurol,2007,6(1):75-86.
[16] Corso A, Mangiacavalli S, Varettoni M, et al.Bortezomib-induced peripheral neuropathy in multiple myeloma: a comparison between previously treated and untreated patients[J]. Leuk Res,2010,34(4):471-474.
[17] Cho J, Kang D, Lee JY, et al.Impact of dose modification on intravenous bortezomib-induced peripheral neuropathy in multiple myeloma patients[J]. Support Care Cancer,2014,22(10):2669-2675.
[18] Dimopoulos MA, Mateos MV, Richardson PG, et al.Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study[J]. Eur J Haematol,2011,86(1):23-31.
[19] Bruna J, Udina E, Alé A, et al.Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice[J]. Exp Neurol,2010,223(2):599-608.
[20] Morawska M, Grzasko N, Kostyra M, et al.Therapy-rela-ted peripheral neuropathy in multiple myeloma patients[J]. Hematol Oncol,2015,33(4):113-119.
[21] 王焰, 张赟翔, 范青叶,等. 23例免疫球蛋白D型多发性骨髓瘤的临床诊治经验[J]. 内科理论与实践,2016, 11(3):165-169.
[22] Favis R, Sun Y, van de Velde H, et al. Genetic variation associated with bortezomib-induced peripheral neuropathy[J]. Pharmacogenet Genomics,2011,21(3):121-129.
[23] Yamamoto S, Kawashiri T, Higuchi H, et al.Behavioral and pharmacological characteristics of bortezomib-induced peripheral neuropathy in rats[J]. J Pharmacol Sci,2015,129(1):43-50.
[24] Cavaletti G, Gilardini A, Canta A, et al.Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat[J]. Exp Neurol,2007,204(1):317-325.
[25] Thawani SP, Tanji K, De Sousa EA, et al.Bortezomib-associated demyelinating neuropathy--clinical and pathologic features[J]. J Clin Neuromuscul Dis,2015,16(4):202-209.
[26] Quartu M, Carozzi VA, Dorsey SG, et al.Bortezomib treatment produces nocifensive behavior and changes in the expression of TRPV1, CGRP, and substance P in the rat DRG, spinal cord, and sciatic nerve[J]. Biomed Res Int,2014,2014:180428.
[27] Poruchynsky MS, Sackett DL, Robey RW, et al.Proteasome inhibitors increase tubulin polymerization and stabilization in tissue culture cells: a possible mechanism contributing to peripheral neuropathy and cellular toxicity following proteasome inhibition[J]. Cell Cycle,2008,7(7):940-949.
[28] Broyl A, Corthals SL, Jongen JL, et al.Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial[J]. Lancet Oncol,2010,11(11):1057-1065.
[29] Nasu S, Misawa S, Nakaseko C, et al.Bortezomib-induced neuropathy: axonal membrane depolarization precedes development of neuropathy[J]. Clin Neurophysiol,2014, 125(2):381-387.
[30] Broyl A, Corthals SL, Jongen JL, et al.Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial[J]. Lancet Oncol,2010,11(11):1057-1065.
[31] Campo C, da Silva Filho MI, Weinhold N, et al. Bortezomib-induced peripheral neuropathy: A genome-wide association study on multiple myeloma patients[J/OL]. Hematol Oncol.2017-03-20[2017-10-11].https://www.ncbi.nlm.nih.gov/pubmed/28317148.