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Journal of Southern Medical University logoLink to Journal of Southern Medical University
. 2021 Aug 31;41(9):1420–1425. [Article in Chinese] doi: 10.12122/j.issn.1673-4254.2021.09.19

自体造血干细胞移植可改善多发性骨髓瘤患者的临床状态

Autologous stem cell transplantation improves outcomes of patients with multiple myeloma receiving proteasome inhibitors and lenalidomide treatment

Xueqin NING 1, Xiaolei WEI 1, Xutao GUO 1, Qi WEI 1, Fen HUANG 1, Zhiping FAN 1, Na XU 1, Jing SUN 1, Ru FENG 1, Qifa LIU 1, Yongqiang WEI 1,*
PMCID: PMC8526324  PMID: 34658359

Abstract

Objective

To evaluate the effect of autologous stem cell transplantation (ASCT) on treatment response and survival outcomes in patients with newly diagnosed multiple myeloma (MM) receiving treatments with proteasome inhibitors and lenalidomide.

Methods

We retrospectively collected the clinical data of newly diagnosed MM patients, who were eligible for ASCT and received proteasome inhibitors or lenalidomide-based treatment in our hospital from January, 2015 to December, 2019. The patients were divided into transplantation group and non-transplantation group, and in transplantation group, the patients received 4 to 6 courses of induction therapy with proteasome inhibitors or lenalidomide before ASCT, while those in the non-transplantation group received more than 8 courses of induction and consolidation therapy with proteasome inhibitors or lenalidomide-based regimens. The therapeutic efficacy and survival outcomes of the patinets were compared between the two groups.

Results

A total of 105 patients were enrolled in the study, including 48 (45.7%) in transplantation group and 57 (54.3%) in non-transplantation group. The two groups were matched for gender, age and treatment response after 4 courses of induction therapy (P > 0.05). The rate of optimal response before relapse differed significantly between the two groups (P=0.000), and the patients receiving ASCT had significantly higher rates of complete response (85.4% vs 54.4%, P= 0.001) and very good partial response or better (95.8% vs 73.7%, P=0.002) than those without ASCT. At the end of follow-up, the median progression-free survival in the transplantation group was not reached, as compared with 29 months in the nontransplantation group (P=0.013). The median overall survival (OS) in the two groups was not reached, but the OS was better in the transplant group than in the non-transplant group (P=0.022).

Conclusion

ASCT can further improve the depth of remission and survival outcomes in patients with newly diagnosed MM receiving treatments with proteasome inhibitors and lenalidomide.

Keywords: multiple myeloma, proteasome inhibitor, lenalidomide, autologous stem cell transplantation

多发性骨髓瘤（MM）是一种起源于骨髓的异质性恶性浆细胞疾病[1]，随着医疗水平的进步，MM的治疗方案也随之发生改变，早期MM的治疗以单纯的化疗为主，继而发现化疗联合自体造血干细胞移植（ASCT）较单纯的化疗能改善患者的生存，奠定了ASCT在年龄≤65岁初诊MM患者一线治疗中的地位[2, 3]。近20年来，随着免疫调节剂和蛋白酶体抑制剂等药物的应用，患者的缓解深度得到提高，生存时间明显延长，5年的生存率达50% [4, 5]，这同时使得ASCT在初发MM患者的一线治疗中的地位受到质疑，随后的前瞻性研究结果表明免疫调节剂及蛋白酶体抑制剂联合ASCT相较于单纯的免疫调节剂及蛋白酶体抑制剂为基础的治疗可以进一步延长患者的无进展生存期（PFS），但是否可以延长患者总生存期（OS），不同临床试验的结果不尽一致[6, 7]。Remes等[8]回顾性的研究表明，免疫调节剂及蛋白酶体抑制剂联合ASCT相较于单纯的免疫调节剂及蛋白酶体抑制剂为基础的治疗能进一步改善患者的PFS及OS，但在该研究中，未移植组中部分患者未接受8疗程以上的治疗，且两组患者巩固治疗后均未行维持治疗。中国最新多发性骨髓瘤诊治指南对于不适合移植或适合移植拒绝移植的患者，推荐8~12疗程的治疗，随后进入维持治疗，维持治疗能进一步提高患者的缓解程度，改善患者的生存[9, 10]。国内对于ASCT在MM治疗中的作用的文献报道主要集中于分析接受ASCT单队列患者的疗效及预后，没有将患者分为移植组与未移植组进行两队列的比较，且分析时纳入了接受以蒽环类为主传统化疗的患者[11, 12]。目前国内外缺乏回顾性的研究比较在临床工作中，适合移植患者接受免疫调节剂及蛋白酶体抑制剂联合ASCT治疗与仅接受8疗程以上的免疫调节剂及蛋白酶体抑制剂为基础治疗的疗效及生存差异。本文回顾性的分析了我们中心初发MM患者接受新药（本文特指蛋白酶体抑制剂和免疫调节剂来那度胺）诱导治疗后序贯ASCT与仅接受8疗程以上新药治疗的两组患者的缓解深度和生存差异，旨在分析ASCT在新药治疗时代的临床价值。

1. 资料和方法

1.1. 患者

收集从2015年1月~2019年12月就诊南方医科大学南方医院满足以下条件的患者：（1）初发的符合国际骨髓瘤工作组（IMWG）症状性多发性骨髓瘤的诊断标准的[13]；（2）适合移植的[14]：即年龄≤65岁、ECOG评分≤1分等、脏器功能良好的患者；（3）诱导及巩固治疗全程接受蛋白酶体抑制剂和或来那度胺为基础的治疗，按照患者是否在4~6疗程治疗后接受自体干细胞移植分为移植组和未移植组，未移植组纳入接受8疗程以上诱导和巩固治疗的患者，包括在8疗程治疗治疗结束前进展的患者。该研究方案得到了我们医院的伦理机构委员会的批准。

1.2. 分期、疗效及生存

按照传统的Durie-Salmon（DS）分期系统及国际分期系统（ISS）进行分期[15, 16]，根据IMWG标准[17]进行疗效评价，治疗反应分为CR（完全缓解）、VGPR（非常好的部分缓解）、PR（部分缓解）、SD（疾病稳定）和PD（疾病进展）。PFS定义为从开始治疗到疾病进展或死亡的时间，而不考虑死亡原因；OS定义为从治疗开始到因任何原因死亡的时间。末次随访时间为2020年12月31日。

1.3. 治疗方案

根据NCCN指南[18]，诊断后开始一线诱导治疗，诱导方案以蛋白酶体抑制剂或来那度胺为基础，具体包括VCD（硼替佐米+环磷酰胺+地塞米松）、VTD（硼替佐米+沙利度胺+地塞米松）、VRD/IRD（硼替佐米/伊沙佐米+来那度胺+地塞米松）、PAD（硼替佐米+阿霉素+地塞米松）、VD/ID（硼替佐米/伊沙佐米+地塞米松）。4疗程诱导化疗后，移植组进行外周血干细胞动员、采集，动员方案包括：VCAD（硼替佐米+环磷酰胺+阿霉素+地塞米松）、大剂量环磷酰胺及普乐沙福联合粒细胞集落刺激因子（G-CSF），采集4.0×106/kg以上CD34+细胞，外周干细胞采集后再巩固0~2疗程以确保所有患者接受ASCT前达到PR及以上疗效，移植预处理方案以马法兰为主，移植后再巩固0~4疗程；未移植组4疗程诱导化疗后，对于疗效≥PR患者，继续原方案或同类方案巩固4疗程以上，对于疗效< PR的患者，继续原方案或改为含新药的二线方案，在8疗程结束前进展的患者，后续方案改为二线化疗或加入临床试验。两组患者诱导及巩固治疗后进入蛋白酶体抑制剂或免疫调节剂的维持治疗[19]。

1.4. 统计分析

应用SPSS 22.0进行数据处理和统计学分析，计数资料用百分率表示，组间比较行χ2检验或Fisher确切概率法，等级资料行Mann-Whitney U检验；计量资料用中位数（范围）表示，计量资料的比较先进行Levene方差齐性检验，方差齐时采用独立样本t检验，方差不齐时，采用矫正的t检验。采用K-M法绘制生存曲线，并行Log-rank检验；采用GraphPad Prism 8进行分析作图；以双侧P < 0.05为差异具有统计学意义。

2. 结果

2.1. 基线资料

总共105例患者纳入研究，4~6疗程治疗后序贯ASCT的48例（45.7%），拒绝ASCT接受8疗程以上治疗的57例（54.3%），包括4例在完成第5~8疗程治疗后进展的患者。移植组与未移植组的的男女比为0.9和1.2（P=0.509）、中位年龄为54岁和57岁（P=0.065）；移植组与未移植组中分别有47例（97.9%）和55例（96.5%）有ISS分期，两组患者在ISS分期（P=0.978）及DS分期（P=0.631）方面无统计学差异（表 1）。

1.

两组患者的基线资料、治疗方案及4疗程后的疗效等资料

Baseline clinical data, treatment and response after 4 courses of treatment in the two groups

Parameters ASCT (n=48) Non-ASCT (n=57) Statistic P
ASCT: Autologous stem cell transplantation; ISS: International staging system; BMPC: Bone marrow plasma cells; VCD: Bortezomib+cyclophosphamide+dexamethasone; IMiDs: Immunomodulatory drugs; PI: Proteasome inhibitor; CR: Complete response; VGPR: Very good partial response; PR: Partial response; SD: Stable disease.
Male/female 23/25 31/26 χ2=0.437 0.509
Age (year) 54 (38-65) 57 (35-65) t=-1.862 0.065
ISS stage
Ⅰ/Ⅱ/Ⅲ		 47 (97.9%)
8/17/22		 55 (96.5)
9/21/25		 Z=-0.044 0.978
Durie-salmon Ⅰ/Ⅱ/Ⅲ 6/6/36 8/4/45 t=0.921 0.631
Cr > 177 μmol/L 7 (14.6) 10 (17.5) χ2=0.197 0.657
BMPC % 31 (0.5-96) 26(1-84) t=0.734 0.465
Induction regimen 48(100) 57 (100)
  VCD 22 (45.8) 30 (52.6)
  Triplet IMiD+PI 12 (25.0) 8 (14.0) χ2=2.364 0.500
  Change regimen 9(18.8) 14 (24.6)
  Others 5 (10.4) 5 (8.8)
Efficacy after 4 cycles induction 48(100) 55 (96.5) Z=-0.741 0.459
  CR 14 (29.2) 13 (23.6)
  VGPR 13 (27.1) 15 (27.3)
  PR 19 (39.6) 23 (41.8)
  SD+PD 2 (4.2) 4 (7.3)
  CR+VGPR 27 (56.3) 28 (50.9) χ2=0.294 0.588
Treatment cycles 6(4-10) 9(4-14) t=-6.113 0.001
Maintenance received 45 (93.8) 49 (86.0) χ2=1.684 0.194
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2.2. 治疗及动员方案

移植组与未移植组中分别有22例（45.8%）和30例（52.6%）接受VCD方案、12例（25.0%）和8例（14.0%）接受含免疫调节剂（IMiDs）联合蛋白酶体抑制剂（PI）三药方案、9例（18.8%）和14例（24.6%）因不能耐受VTD、PAD方案或因肾功能改善更换为含来那度胺的三药方案或两药方案进行诱导治疗，两组患者在诱导治疗方案方面类似（P=0.500）。移植组的中位化疗疗程数为6（4-10），其中5例（10.4%）患者4疗程诱导治疗后序贯ASCT，移植后未行巩固化疗。未移植组的中位疗程数为9（4-14），包括4例（7.0%）在完成第5~8疗程治疗后进展的患者，未移植组的中位疗程数明显多于未移植组（P < 0.001）。移植组和未移植组分别有45例（93.8%）和患者49例（86.0%）接受了维持治疗，两组患者在接受维持治疗的人数上类似（P=0.194，表 1）。在48例移植患者中，有14例（29.2%）接受VCAD联合G-CSF、19例（39.6%）接受大剂量CTX联合G-CSF及15例（31.3%）接受G-CSF联合普乐沙福的方案进行动员；其中有45例（93.8%）患者接受马法兰进行移植前预处理，3例（6.3%）接受环磷酰胺+依托泊苷+白消安进行移植前预处理；移植相关死亡率为零。

2.3. 疗效及生存

未移植组2例（3.5%）轻链型患者在4疗程后未进行疗效评估，两组患者在4疗程诱导治疗后的缓解程度（P=0.459）及CR+VGPR率（56.3% vs 50.1%，P=0.588）方面无统计学差异。两组患者在随访截止时，在首次复发前获得过的最佳缓解程度有统计学差异（P=0.000），移植组获得CR（85.4% vs 54.4%，P=0.001））和VGPR及以上疗效（95.8% vs 73.7%，P=0.002）的患者比例明显高于未移植组（表 2）。在接受移植的48例患者中，移植后达到CR（58.3% vs 29.2%，P=0.004）及VGPR以上疗效（79.2% vs 56.3%，P=0.016）的患者比例明显高于移植前（表 3）。在截止随访时，未移植组与移植组的中位随访时间分别为33月、24月，未移植组的中位PFS相较于移植组的中位PFS（mPFS）为29月vs未达到（P= 0.013），未移植组与移植组2年的PFS分别为61.0%、89.2%；两组患者的中位OS（mOS）均未达到，但移植组的OS优于未移植组（P=0.022），未移植组与移植组的2年OS分别为87.5%、97.7%（图 1）。

2.

两组患者在首次复发前获得过的最佳疗效

Best treatment response before the first relapse in the two groups

Factors ASCT (n=48) Non-ASCT (n=57) Statistic P
Best response during treatment 48(100) 57 (100) Z=-3.557 0.001
  CR 41 (85.4) 31 (54.4)
  VGPR 5 (10.4) 11 (19.3)
  PR 2 (4.2) 13 (22.8)
  SD 0 2 (3.5)
  CR 41 (85.4) 31 (54.4) χ2=11.642 0.001
  VGPR+CR 46 (95.8) 42 (73.7) χ2=9.421 0.002
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3.

移植组48例患者在移植前后的疗效对比

Treatment responses before and after transplantation in the 48 patients undergoing ASCT

Items CR VGPR PR CR+VGPR ORR (%)
ORR: Overall response rate.
Before ASCT 14 (29.2) 13 (27.1) 19 (39.6) 27 (56.3) 46 (95.8)
After ASCT 28 (58.3) 10 (20.8) 9 (18.8) 38 (79.2) 47 (97.9)
Statistic 8.296 - - 5.765 0.000
P 0.004 - - 0.016 1.000
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1.

1

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移植组及未移植组两组患者的生存

Progression-free survival (A) and overall survival (B) of patients in the transplantation group and non-transplantation group.

3. 讨论

MM是浆细胞恶性增殖性疾病，以骨髓中克隆性浆细胞异常增生，并以分泌单克隆免疫球蛋白或其片段（M蛋白）导致脏器功能障碍为特征[13]。初诊MM治疗的目的是最大程度地清除产生M蛋白的克隆性浆细胞，达到深度的缓解状态以改善患者的生存质量及生存时间。以往多发性骨髓瘤的治疗主要依靠如马法兰、阿霉素等传统的化疗药物，患者5年生存率为25~35% [4, 20, 21]。20世纪80年代ASCT开始用于MM的治疗，MRCMM Ⅶ和IFM90等研究证实传统化疗联合ASCT能进一步提高多发性骨髓瘤患者缓解深度，改善患者的生存，使中位OS和中位无事件生存时间（EFS）均延长约12月，确定了了ASCT作为65岁以下初发MM患者的标准一线治疗方案的地位[3, 22]。

近20年来，多发性骨髓瘤的治疗已经进入免疫调节剂、蛋白酶体抑制剂等新药治疗时代，相较于传统的化疗，新药的应用明显提高了患者的缓解程度、改善了患者的生存[23, 24]。随着来那度胺、硼替佐米两大抗骨髓瘤基石药物在临床的广泛应用，MM患者5年的生存率提高到约50%[4]，与此同时自体干细胞移植在新诊断多发性骨髓瘤一线治疗中的地位受到质疑。2017年发表在新英格兰杂志的VRD与VRD序贯自体干细胞移植的头对头研究表明VRD联合ASCT可以进一步提高MM患者的缓解深度及PFS，但OS无明显获益（P=0.87）[7]。

我们报道的移植组与未移植组患者在整个治疗过程中获得VGPR以上疗效分别为95.8%和73.7%（P=0.002），该结果与Attal等[7]报道的3疗程VRD诱导治疗后加或不加ASCT再衔接维持治疗的研究结果相一致（移植组vs未移植：88% vs 77%，P=0.001），但我们报道的移植组患者达VGPR及以上疗效较Attal等报道的高，可能与本研究中移植组所有患者在移植前均接受4疗程以上的诱导治疗、56.3%的患者在移植前达VGPR及以上疗效（后者为47%）、79.2%的患者这在移植后达VGPR及以上疗效（后者为70%）及样本量较少有关[7]。

在本研究中移植组的mPFS未达到，未移植组中的mPFS为29月，低于SWOG S0777研究中VRD方案的mPFS 43月[25]，但高于报道的VCD方案的mPFS 12个月[26]，这可能与本研究中未移植组中57.9%患者采用的VCD方案，24.6%患者在治疗中更换治疗方案（大多数因不能耐受VTD或PAD方案更换成VRD的三药方案）有关，显示了两种新药的方案相较于含一种新药的方案能进一步延长患者的PFS [26]，也间接支持了VRD方案成为初发MM各大指南推荐的首选标准治疗方案[27]。截止随访时，两组患者的中位OS均未达到，但移植组的OS优于未移植组（P=0.022），与Remes等[8]报道的真实世界中移植组患者的OS优于未移植患者的结果相一致。在本研究中，移植组与未移植组2年的PFS分别为81.1%和57.4%、2年的OS分别为97.7%和87.5%，与Richardson等报道的VRD序贯移植组患者18月的PFS、OS分别为75%、95%的生存相似[28]，表明较高的生存与患者在首次复发前获得过的VGPR及以上疗效更高比例有关，尽管MM到目前为止仍是不可治愈的疾病，但患者的缓解程度与生存时间密切相关，达到VGPR及以上疗效患者的PFS和OS都明显长于仅达到PR的患者[29-31]。

目前对于适合移植的初发MM患者，推荐治疗选择为诱导治疗后序贯ASCT，拒绝ASCT的患者推荐接受8~12疗程的诱导治疗，随后进入维持治疗阶段[18]。我们回顾性地对比了我们单中心适合移植患者在新药方案诱导治疗后序贯ASCT及接受8疗程以上新药治疗的两组患者，结果表明，诱导治疗后序贯自体干细胞移植比单纯接受8疗程以上新药治疗可获得的缓解深度及生存更佳。我们的研究结果表明，蛋白酶体抑制剂及来那度胺诱导治疗后序贯ASCT能进一步提高多发性骨髓瘤患者的缓解深度及改善患者的生存。

Biography

宁雪琴，在读硕士研究生，E-mial: 904158664@qq.com

Funding Statement

广东省自然科学基金（2018A030313083）

Contributor Information

宁 雪琴 (Xueqin NING), Email: 904158664@qq.com.

魏 永强 (Yongqiang WEI), Email: wyq1973@163.com.

References

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