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中华移植杂志(电子版) ›› 2021, Vol. 15 ›› Issue (02) : 93 -100. doi: 10.3877/cma.j.issn.1674-3903.2021.02.006

论著

自体造血干细胞移植治疗髓外多发性骨髓瘤疗效分析
何静松1, 张恩帆1, 赵毅1, 杨杨1, 何冬花1, 韩晓雁1, 郑高锋1, 陈晶晶2, 罗依1, 施继敏1, 黄河1, 蔡真1,†()   
  1. 1. 310003　杭州，浙江大学医学院附属第一医院血液科&骨髓移植中心
    2. 310003　杭州，浙江大学医学院附属第一医院静脉用药调配中心
  • 收稿日期:2021-02-22 出版日期:2021-04-25
  • 通信作者: 蔡真
  • 基金资助:
    国家自然科学基金(81800201，81800202，81872322); 国家科技重大专项"重大新药开发"(2018ZX09733-003)

Efficacy of autologous hematopoietic stem cell transplantation in the treatment of extramedullary multiple myeloma

Jingsong He1, Enfan Zhang1, Yi Zhao1, Yang Yang1, Donghua He1, Xiaoyan Han1, Gaofeng Zheng1, Jingjing Chen2, Yi Luo1, Jimin Shi1, He Huang1, Zhen Cai1,†()   

  1. 1. Department of Hematology and Bone Marrow Transplantation, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
    2. Intravenous Drug Dispensing Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
  • Received:2021-02-22 Published:2021-04-25
  • Corresponding author: Zhen Cai
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引用本文：

何静松, 张恩帆, 赵毅, 杨杨, 何冬花, 韩晓雁, 郑高锋, 陈晶晶, 罗依, 施继敏, 黄河, 蔡真. 自体造血干细胞移植治疗髓外多发性骨髓瘤疗效分析[J]. 中华移植杂志(电子版), 2021, 15(02): 93-100.

Jingsong He, Enfan Zhang, Yi Zhao, Yang Yang, Donghua He, Xiaoyan Han, Gaofeng Zheng, Jingjing Chen, Yi Luo, Jimin Shi, He Huang, Zhen Cai. Efficacy of autologous hematopoietic stem cell transplantation in the treatment of extramedullary multiple myeloma[J]. Chinese Journal of Transplantation(Electronic Edition), 2021, 15(02): 93-100.

目的

探究自体造血干细胞移植(ASCT)治疗初发髓外多发性骨髓瘤(EMM)的疗效及其对生存的影响。

方法

回顾性分析2013年5月至2019年9月在浙江大学医学院附属第一医院确诊为EMM且适合接受ASCT的55例患者临床资料。55例EMM患者均接受以硼替佐米为基础的诱导治疗方案。根据患者是否接受ASCT为巩固治疗将其分为ASCT组(14例)和非ASCT组(41例)。采用国际骨髓瘤工作组制订的疗效评定标准评估疗效，包括完全缓解、非常好的部分缓解、部分缓解、疾病稳定和疾病进展。ASCT组和非ASCT组间非正态分布计量资料比较采用Mann-Whitney U检验；两组间计数资料比较采用卡方检验或Fisher确切概率法。采用Kaplan-Meier法绘制两组患者生存曲线，并采用log-rank检验进行比较。采用Cox比例风险模型进行影响EMM患者无进展生存(PFS)和总生存(OS)的单因素和多因素分析。P<0.05为差异有统计学意义。

结果

55例EMM患者中位年龄57岁(31～65岁)，其中骨相关髓外病变49例，骨外髓外病变6例。巩固治疗前ASCT组和非ASCT组患者疗效差异无统计学意义(χ2＝2.808, P>0.05)；巩固治疗后两组患者疗效差异有统计学意义(χ2＝6.946, P<0.05)。截至2020年6月30日，ASCT组患者中位PFS为46.0个月(95%CI: 29.0～63.1), 1、3和5年PFS率分别为92.3%、60.2%和30.1%；非ASCT组患者中位PFS为18.8个月(95%CI: 11.3～26.3), 1、3和5年PFS率分别为72.5%、36.3%和24.2%，两组患者PFS差异无统计学意义(P均>0.05)。ASCT组患者中位OS为未达到，1、3和5年OS率均为100%；非ASCT组患者中位OS为43.6个月(95%CI: 38.9～57.5), 1、3和5年OS率分别为87.8%、60.3%和48.4%，两组患者OS差异有统计学意义(χ2＝5.838, P<0.05)。Cox比例风险模型多因素分析结果表明：EMM类型和ASCT是影响EMM患者PFS的独立危险因素(HR＝4.11和2.81, P均<0.05)；EMM类型是影响EMM患者OS的独立危险因素(HR＝5.23，P<0.05)。

结论

ASCT可明显改善以硼替佐米为诱导治疗的初发EMM患者预后，且是影响EMM患者PFS的独立危险因素；EMM类型是影响初发EMM患者PFS和OS预后的独立危险因素，但仍需扩大样本量并进行前瞻性研究以进一步确证。

关键词: 髓外多发性骨髓瘤, 自体造血干细胞移植, 硼替佐米
Objective

To study the effect of autologous hematopoietic stem cell transplantation (ASCT) as a consolidation therapy for newly diagnosed extramedullary multiple myeloma (EMM) and its effect on survival.

Methods

The clinical features, treatment, efficacy and survival of 55 patients with newly diagnosed EMM who were eligible for ASCT from May 2013 to September 2019 in the First Affiliated Hospital, School of Medicine, Zhejiang University, were retrospectively analyzed. All the EMM patients received bortezomib-based induction therapy regimen and were divided into ASCT group (n=14) and no ASCT group (n=41) according to whether or not the ASCT was performed as a consolidation therapy. The evaluative criterias set down by International Myeloma Working Group were used to evaluate the curative effect including complete remission, very good partial response, partial response, stable disease and progressive disease. The abnormal distribution measurement data between ASCT group and no ASCT group were compared by Mann-Whitney U test, and the enumeration data between the 2 groups were compared with chi-square test and Fisher exact probality test. The Kaplan-Meier method was used to draw the survival curve of the 2 groups and the log-rank test was used to compare. The Cox proportional hazard model was used to analyse the influence factors of progress free survive (PFS) and overall survival (OS). P<0.05 was considered statistically significant.

Results

The median age of the 55 EMM patients were 57 years old (31-65 years old). There were 49 cases of extramedullary-bone related and 6 cases of extramedullary-extraosseous. The difference of the curative effect after consolidation therapy between ASCT group and no ASCT group after consolidation therapy had no statistical significance (χ2=2.808, P>0.05), but the difference of the curative effect between the 2 groups was statistically significant (χ2=6.946, P<0.05). The EMM patients were followed until June 30, 2020, and the median PFS of ASCT group were 46.0 months (95%CI: 29.0-63.1), and the PFS rates of 1, 3, 5 year were 92.3%, 60.2% and 30.1%; the median PFS of no ASCT group were 18.8 months (95%CI: 11.3-26.3), and the 1, 3, 5 year PFS rates of patients were 72.5%, 36.3% and 24.2%, and the PFS rates between the 2 groups had no statistical significance (all P>0.05). The median OS of ASCT were not reached by the end of follow-up, and the 1, 3, 5 year OS rate of patients were all 100%; the median OS of no ASCT were 43.6 months (95%CI: 38.9-57.5), and the 1, 3, 5 year OS rates of patients were 87.8%, 60.3% and 48.4%, and the OS between the 2 groups had statistical significance (χ2=5.838, P<0.05). The result of multivariate analysis indicated that the EMM type and ASCT were independent factors of PFS in newly diagnosed EMM patients (HR=4.11 and 2.81, all P<0.05); and the EMM type was an independent risk factor of OS in neuly diagnosed EMM patients (HR=5.23, P<0.05).

Conclusions

ASCT can significantly improve the PFS and OS of newly diagnosed EMM patients treated with bortezomib, and it is an independent prognostic factor for PFS. The type of EMM is the independent prognostic factors for PFS and OS of newly diagnosed patients with EMM. However, it still necessary to expand the cases and conduct prospective studies to further confirm.

Key words: Extramedullary multiple myeloma, Autologous hematopoietic stem cell transplantation, Bortezomib
表1 ASCT组和非ASCT组EMM患者基线资料比较
项目 AST组(n＝14) 非ASCT组(n＝41) Z/χ2值 P值
年龄[岁，M(Min，Max)] 53( 39～ 64) 57( 31～　 65) 1.761 >0.05
性别(例，男/女) 8/6 24/17 0.008 >0.05
M蛋白类型(例)     1.147 >0.05
  IgA 4 8    
  IgG 5 16    
  IgD 2 5    
  轻链 3 11    
  双表型 0 1    
Durie-Salmon分期(例)     0.562 >0.05
  1+2+3A期 14 37    
  3B期 0 4    
ISS分期(例)     0.477 >0.05
  1+2期 12 30    
  3期 2 11    
血清肌酐[μmol/L，M(Min，Max)] 78( 52～123) 77( 39～ 310) 0.562 >0.05
骨髓浆细胞[%，M(Min，Max)] 20( 10～ 60) 27( 10～ 　74) 0.841 >0.05
血清LDH[U/L，M(Min，Max)] 176(117～351) 185(109～5 785) 0.184 >0.05
血红蛋白[g/L，M(Min，Max)] 110( 65～145) 108( 75～ 144) 0.577 >0.05
血小板[109/L，M(Min，Max)] 180(125～286) 179( 75～ 469) 0.090 >0.05
EMM类型(例)     1.000 >0.05
  EM-B 13 36    
  EM-E 1 5    
化疗方案(例)     0.688 >0.05
  PD方案 0 1    
  PAD方案 6 17    
  PCD方案 7 21    
  PTD方案 1 2    
表2 ASCT组和非ASCT组EMM患者巩固治疗前后疗效比较[例(%)]
组别 例数 巩固治疗前疗效 巩固治疗后疗效
<PR PR ≥VGPR <PR PR ≥VGPR
ASCT组 14 1(7.1%) 3(21.4%) 10(71.4%) 0 1( 7.1%) 13(92.9%)
非ASCT组 41 4(9.8%) 18(43.9%) 19(46.3%) 2(4.9%) 15(36.6%) 24(58.5%)
χ2值 - 2.808 6.946
P值 - >0.05 <0.05
图1 ASCT组和非ASCT组患者生存曲线
表3 EMM患者PFS和OS影响因素Cox比例风险模型单因素分析
变量 例数 PFS OS
HR值(95%CI) P值 HR值(95%CI) P值
性别   1.19(0.57～ 2.50) >0.05 1.43(0.54～　 3.81) >0.05
  女 23        
  男 32        
年龄(岁)   1.53(0.73～ 3.21) >0.05 1.04(0.39～　 2.81) >0.05
  ≤57 31        
  >57 24        
M蛋白类型   2.30(0.98～ 5.40) >0.05 1.40(0.40～　 4.95) >0.05
  非IgD 48        
  IgD 7        
Durie-Salmon分期   1.94(0.67～ 5.60) >0.05 1.64(0.37～　 7.21) >0.05
  1+2+3A期 51        
  3B期 4        
ISS分期   2.09(0.93～ 4.68) >0.05 3.27(1.21～　 8.84) <0.05
  1+2期 42        
  3期 13        
R-ISS分期   1.92(0.76～ 4.81) >0.05 3.84(1.36～　 10.84) >0.05
  1+2期 41        
  3期 9        
血红蛋白(g/L)   1.34(0.65～ 2.78) >0.05 2.56(0.95～　 6.90) >0.05
  ≥100 36        
  <100 19        
血小板计数(109/L)   1.34(0.65～ 2.78) >0.05 2.56(0.95～　 6.90) >0.05
  ≥150 21        
  <150 34        
骨髓浆细胞比例(%)   1.37(0.64～ 2.92) >0.05 2.32(0.84～　 6.41) >0.05
  ≤30 35        
  >30 20        
血清肌酐(μmol/L)   1.94(0.67～ 5.60) >0.05 1.64(0.37～　 7.21) >0.05
  ≤177 51        
  >177 4        
血清LDH(U/L)   2.80(1.29～ 6.09) <0.05 4.71(1.72～　 12.91) <0.05
  ≤250 41        
  >250 14        
C反应蛋白(g/L)   1.00(0.41～ 2.47) >0.05 1.58(0.50～　 4.98) >0.05
  ≤8 12        
  >8 39        
EMM类型   4.02(1.35～11.99) <0.05 8.27(2.63～ 　26.05) <0.05
  EM-B 49        
  EM-E 6        
ASCT   2.27(0.87～ 5.98) >0.05 32.83(0.30～3 605.60) >0.05
  接受 14        
  未接受 41        
巩固治疗后效果   1.55(0.75～ 3.21) >0.05 2.08(0.78～　 5.56) >0.05
  ≥VGPR 37        
  <VGPR 18        
表4 EMM患者PFS影响因素Cox比例风险模型多因素分析
变量 例数 HR值(95%CI) P值
M蛋白类型      
  非IgD 48 2.44(0.98～ 6.10) >0.05
  IgD 7
ISS分期      
  1+2期 42 1.50(0.66～ 3.44) >0.05
  3期 13
血清LDH(U/L)      
  ≤250 41 1.92(0.83～ 4.44) >0.05
  >250 14
EMM类型      
  EM-B 49 4.11(1.28～13.23) <0.05
  EM-E 6
ASCT      
  接受 14 2.81(1.03～ 7.67) <0.05
  未接受 41
表5 EMM患者OS影响因素Cox比例风险模型多因素分析
变量 例数 HR值(95%CI) P值
ISS分期      
  1+2期 42 2.65(0.80～ 8.84) >0.05
  3期 13
血小板计数(109/L)      
  ≥150 21 1.22(0.37～ 3.99) >0.05
  <150 34
骨髓浆细胞比例(%)      
  ≤30 35 1.58(0.48～ 5.16) >0.05
  >30 20
EMM类型      
  EM-B 49 5.23(1.40～19.49) <0.05
  EM-E 6
血清LDH(U/L)      
  ≤250 14 3.01(1.00～ 9.28) >0.05
  >250 41
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