Article(id=1207314223613452328, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1207314214872518754, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2025.04.06, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1707235200000, receivedDateStr=2024-02-07, revisedDate=null, revisedDateStr=null, acceptedDate=1739462400000, acceptedDateStr=2025-02-14, onlineDate=1765775741723, onlineDateStr=2025-12-15, pubDate=1745510400000, pubDateStr=2025-04-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765775741723, onlineIssueDateStr=2025-12-15, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765775741723, creator=13701087609, updateTime=1765775741723, updator=13701087609, issue=Issue{id=1207314214872518754, tenantId=1146029695717560320, journalId=1205117082300743687, year='2025', volume='44', issue='4', pageStart='241', pageEnd='320', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=1, specialIssue=0, createTime=1765775739638, creator=13701087609, updateTime=1765775882010, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1207314812124635584, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1207314214872518754, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1207314812124635585, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1207314214872518754, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=272, endPage=277, ext={EN=ArticleExt(id=1207314224116768812, articleId=1207314223613452328, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Clinical observation of bendamustine combined with chemotherapy for relapsed and refractory multiple myeloma, columnId=1207314218647392369, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Original Article, runingTitle=null, highlight=null, articleAbstract=

AIM To observe the efficacy and safety of bendamustine combined with chemotherapy for relapsed and refractory multiple myeloma(RRMM). METHODS A retrospective analysis was conducted on 32 RRMM patients treated with bendamustine combined with chemotherapy in the Department of Hematology and Oncology, Shijingshan Campus of Beijing Chaoyang Hospital, Capital Medical University from August 2019 to September 2022. The efficacy, adverse reactions and survival conditions were observed. RESULTS Thirty-two patients completed 3(1, 8) treatment courses. The overall response rate(ORR) was 38%(11/29) for 29 patients who completed ≥2 treatment courses, and the ORR was 73%(11/15)for 15 patients who completed≥4 treatment courses. The ORR was 26%(5/19) for 19 patients with extramedullary diseases,and the disease control rate was 53% (10/19). The estimated median progression-free survival was 11 months, and the estimated median overall survival was 25 months for the 32 RRMM patients. Sixteen patients experienced adverse reactions of decreased white blood cell count with the grade from 1 to 3. CONCLUSION Bendamustine combined with chemotherapy has the advantages of good therapeutic response and good tolerance in the treatment of RRMM, and can be used as one of the treatment options for RRMM patients, especially for those with extramedullary diseases.

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目的 观察苯达莫司汀联合化疗治疗复发或难治性多发性骨髓瘤(RRMM)的疗效及安全性。方法 回顾性分析2019年8月—2022年9月在首都医科大学附属北京朝阳医院石景山院区血液与肿瘤科使用苯达莫司汀联合化疗治疗的RRMM患者32例,观察其疗效、不良反应及生存情况。结果 32例患者完成了3(1,8)个疗程。29例完成了≥2个疗程的患者客观缓解率(ORR)为38%(11/29),15例完成了≥4个疗程的患者ORR为73%(11/15)。19例伴髓外病变的患者ORR为26%(5/19),疾病控制率为53%(10/19)。32例RRMM患者的预计中位无进展生存期为11个月,预计中位总生存期为25个月。16例患者出现白细胞计数减少的不良反应,但均为1~3级。结论 苯达莫司汀联合化疗治疗RRMM具有治疗反应好、耐受性良好等优点,可作为RRMM患者的治疗方案选择之一,尤其是针对伴发髓外病变的RRMM患者。

, correspAuthors=null, authorNote=null, correspAuthorsNote=
李新
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汤然,男,主治医师,硕士,主要从事多发性骨髓瘤的研究,E-mail:

李新,女,主任医师,博士,主要从事多发性骨髓瘤的研究,E-mail:

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汤然,男,主治医师,硕士,主要从事多发性骨髓瘤的研究,E-mail:

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汤然,男,主治医师,硕士,主要从事多发性骨髓瘤的研究,E-mail:

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Haematologica, 2015,100(2): e56-e59., articleTitle=PhaseⅡ study of bendamustine, bortezomib and dexamethasone as second-line treatment for elderly patients with multiple myeloma: the intergroupe francophone du myelome 2009-01 trial, refAbstract=null), Reference(id=1207314239916712372, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223613452328, doi=null, pmid=null, pmcid=null, year=2024, volume=38, issue=6, pageStart=1323, pageEnd=1333, url=null, language=null, rfNumber=[15], rfOrder=14, authorNames=JELINEK T, ZIHALA D, SEVCIKOVA T, journalName=Leukemia, refType=null, unstructuredReference=JELINEK T, ZIHALA D, SEVCIKOVA T, et al. Beyond the marrow:insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors[J]. 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Blood Cancer J, 2018, 8(8): 71., articleTitle=Bendamustine,pomalidomide, and dexamethasone for relapsed and/or refractory multiple myeloma, refAbstract=null), Reference(id=1207314240113844664, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223613452328, doi=null, pmid=null, pmcid=null, year=2018, volume=36, issue=null, pageStart=8019, pageEnd=null, url=null, language=null, rfNumber=[17], rfOrder=16, authorNames=GRAMATZKI M, GUENTHER A, OFFIDANI M, journalName=J Clin Oncol, refType=null, unstructuredReference=GRAMATZKI M, GUENTHER A, OFFIDANI M, et al. Carfilzomib,bendamustine, and dexamethasone (KBd) in advanced multiple myeloma: the EMN09-trial[J]. 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项目数值
年龄/岁60.00±1.55
性别/例(%)男性22(69)
女性10(31)
骨髓中异常浆细胞比例/%27.50(6.50,80.80)
血清指标血钙/mmol·L-12.17(2.02,2.45)
血肌酐/μmol·L-177.70(68.08,106.43)
β2微球蛋白/mg·L-14.41(3.84,9.18)
白蛋白/g·L-133.10(27.70,37.40)
乳酸脱氢酶/U·L-1197.70(164.00,240.40)
M蛋白类型/例(%)IgG型17(53)
IgA型6(19)
Kappa轻链型6(19)
Lambda轻链型2(6)
不分泌型1(3)
临床首发症状/例(%)腰骶部疼痛16(50)
胸背部疼痛11(34)
乏力伴双下肢水肿3(9)
发热2(6)
Durie-Salmon分期/例(%)ⅢA期29(91)
ⅢB期3(9)
国际预后分期/例(%)Ⅱ期17(53)
Ⅲ期15(47)
红细胞沉降率/mm·h-1125.00(60.00,140.00)
血常规指标血红蛋白/g·L-192.94±4.76
白细胞计数/×109·L-14.20(3.70,6.80)
血小板计数/×109·L-1140.00±15.10
FISH检测(n=23)/例(%)IgH基因位点缺失3(13)
1q21(+)12(52)
TP53(+)3(13)
t(14;16)4(17)
t (14;20)1(4)
t(4;14)3(13)
13q缺失2(9)
t(4;11)1(4)
t(11;14)1(4)
阴性5(22)
既往化疗线数4(2,6)
), ArticleFig(id=1207314237341409664, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223613452328, language=CN, label=表1, caption=

32例RRMM患者的基线临床特征

, figureFileSmall=null, figureFileBig=null, tableContent=
项目数值
年龄/岁60.00±1.55
性别/例(%)男性22(69)
女性10(31)
骨髓中异常浆细胞比例/%27.50(6.50,80.80)
血清指标血钙/mmol·L-12.17(2.02,2.45)
血肌酐/μmol·L-177.70(68.08,106.43)
β2微球蛋白/mg·L-14.41(3.84,9.18)
白蛋白/g·L-133.10(27.70,37.40)
乳酸脱氢酶/U·L-1197.70(164.00,240.40)
M蛋白类型/例(%)IgG型17(53)
IgA型6(19)
Kappa轻链型6(19)
Lambda轻链型2(6)
不分泌型1(3)
临床首发症状/例(%)腰骶部疼痛16(50)
胸背部疼痛11(34)
乏力伴双下肢水肿3(9)
发热2(6)
Durie-Salmon分期/例(%)ⅢA期29(91)
ⅢB期3(9)
国际预后分期/例(%)Ⅱ期17(53)
Ⅲ期15(47)
红细胞沉降率/mm·h-1125.00(60.00,140.00)
血常规指标血红蛋白/g·L-192.94±4.76
白细胞计数/×109·L-14.20(3.70,6.80)
血小板计数/×109·L-1140.00±15.10
FISH检测(n=23)/例(%)IgH基因位点缺失3(13)
1q21(+)12(52)
TP53(+)3(13)
t(14;16)4(17)
t (14;20)1(4)
t(4;14)3(13)
13q缺失2(9)
t(4;11)1(4)
t(11;14)1(4)
阴性5(22)
既往化疗线数4(2,6)
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苯达莫司汀联合化疗治疗复发或难治性多发性骨髓瘤的临床观察
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汤然 1 , 郭彩虹 2 , 张佳佳 1 , 申曼 1 , 詹晓凯 1 , 范斯斌 1 , 赵凤仪 1 , 黄仲夏 1 , 李新 1
中国新药与临床杂志 | 论著 2025,44(4): 272-277
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中国新药与临床杂志 | 论著 2025, 44(4): 272-277
苯达莫司汀联合化疗治疗复发或难治性多发性骨髓瘤的临床观察
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汤然1 , 郭彩虹2, 张佳佳1, 申曼1, 詹晓凯1, 范斯斌1, 赵凤仪1, 黄仲夏1, 李新1
作者信息
  • 1.首都医科大学附属北京朝阳医院石景山院区 血液与肿瘤科,北京 100043
  • 2.北京大兴区人民医院 肿瘤内科,北京 102600
  • 汤然,男,主治医师,硕士,主要从事多发性骨髓瘤的研究,E-mail:

    李新,女,主任医师,博士,主要从事多发性骨髓瘤的研究,E-mail:

通讯作者:

李新
Clinical observation of bendamustine combined with chemotherapy for relapsed and refractory multiple myeloma
Ran TANG1 , Cai-hong GUO2, Jia-jia ZHANG1, Man SHEN1, Xiao-kai ZHAN1, Si-bin FAN1, Feng-yi ZHAO1, Zhong-xia HUANG1, Xin LI1
Affiliations
  • 1. Department of Hematology and Oncology, Shijingshan Campus of Beijing Chaoyang Hospital, Capital Medical University,BEIJING 100043, China
  • 2. Department of Oncology, Beijing Daxing District People’s Hospital, BEIJING 102600, China
出版时间: 2025-04-25 doi: 10.14109/j.cnki.xyylc.2025.04.06
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目的 观察苯达莫司汀联合化疗治疗复发或难治性多发性骨髓瘤(RRMM)的疗效及安全性。方法 回顾性分析2019年8月—2022年9月在首都医科大学附属北京朝阳医院石景山院区血液与肿瘤科使用苯达莫司汀联合化疗治疗的RRMM患者32例,观察其疗效、不良反应及生存情况。结果 32例患者完成了3(1,8)个疗程。29例完成了≥2个疗程的患者客观缓解率(ORR)为38%(11/29),15例完成了≥4个疗程的患者ORR为73%(11/15)。19例伴髓外病变的患者ORR为26%(5/19),疾病控制率为53%(10/19)。32例RRMM患者的预计中位无进展生存期为11个月,预计中位总生存期为25个月。16例患者出现白细胞计数减少的不良反应,但均为1~3级。结论 苯达莫司汀联合化疗治疗RRMM具有治疗反应好、耐受性良好等优点,可作为RRMM患者的治疗方案选择之一,尤其是针对伴发髓外病变的RRMM患者。

苯达莫司汀  /  多发性骨髓瘤  /  复发或难治  /  髓外病变  /  回顾性研究

AIM To observe the efficacy and safety of bendamustine combined with chemotherapy for relapsed and refractory multiple myeloma(RRMM). METHODS A retrospective analysis was conducted on 32 RRMM patients treated with bendamustine combined with chemotherapy in the Department of Hematology and Oncology, Shijingshan Campus of Beijing Chaoyang Hospital, Capital Medical University from August 2019 to September 2022. The efficacy, adverse reactions and survival conditions were observed. RESULTS Thirty-two patients completed 3(1, 8) treatment courses. The overall response rate(ORR) was 38%(11/29) for 29 patients who completed ≥2 treatment courses, and the ORR was 73%(11/15)for 15 patients who completed≥4 treatment courses. The ORR was 26%(5/19) for 19 patients with extramedullary diseases,and the disease control rate was 53% (10/19). The estimated median progression-free survival was 11 months, and the estimated median overall survival was 25 months for the 32 RRMM patients. Sixteen patients experienced adverse reactions of decreased white blood cell count with the grade from 1 to 3. CONCLUSION Bendamustine combined with chemotherapy has the advantages of good therapeutic response and good tolerance in the treatment of RRMM, and can be used as one of the treatment options for RRMM patients, especially for those with extramedullary diseases.

bendamustine  /  multiple myeloma  /  relapsed or refractory  /  extramedullary disease  /  retrospective study
汤然, 郭彩虹, 张佳佳, 申曼, 詹晓凯, 范斯斌, 赵凤仪, 黄仲夏, 李新. 苯达莫司汀联合化疗治疗复发或难治性多发性骨髓瘤的临床观察. 中国新药与临床杂志, 2025 , 44 (4) : 272 -277 . DOI: 10.14109/j.cnki.xyylc.2025.04.06
Ran TANG, Cai-hong GUO, Jia-jia ZHANG, Man SHEN, Xiao-kai ZHAN, Si-bin FAN, Feng-yi ZHAO, Zhong-xia HUANG, Xin LI. Clinical observation of bendamustine combined with chemotherapy for relapsed and refractory multiple myeloma[J]. Chinese Journal of New Drugs and Clinical Remedies, 2025 , 44 (4) : 272 -277 . DOI: 10.14109/j.cnki.xyylc.2025.04.06
多发性骨髓瘤(multiple myeloma,MM)是易发生于中老年的血液系统浆细胞肿瘤。随着人口老龄化的加剧,近年来MM的发病率逐渐升高。MM主要表现为骨髓浆细胞异常增生,伴单克隆免疫球蛋白(immunoglobulin,Ig)或轻链异常分泌,进而引起贫血、骨破坏、肾损害、感染等。硼替佐米、来那度胺、苯达莫司汀、卡非佐米及CD38单抗类药物的应用,使得MM患者的生存期有所延长,但MM易复发、不可治愈,如何优化治疗方案仍需进一步探讨。
苯达莫司汀是兼具烷化剂功能和抗代谢功能的双功能氮芥衍生物,早在2008年就被美国食品药品管理局(FDA)批准用于治疗利妥昔单抗耐药的惰性非霍奇金淋巴瘤和慢性淋巴细胞白血病[1],后被美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)指南推荐可用于治疗复发或难治性多发性骨髓瘤(relapsed and refractory multiple myeloma,RRMM)和新诊断华氏巨球蛋白血症(Waldenstrom’s macroglo-bulinemia,WM)[2, 3]。苯达莫司汀于2018年在我国获批上市,2021年被NCCN指南推荐用于治疗RRMM,为我国RRMM患者提供了一个可选择的治疗药物。目前,苯达莫司汀在我国治疗RRMM的真实世界研究仍然较少,为此,本研究回顾性分析了本院应用苯达莫司汀治疗的32例RRMM患者的临床资料,以期为RRMM的治疗提供参考。
选取2019年8月—2022年9月在北京朝阳医院石景山院区血液与肿瘤科采用苯达莫司汀为主要方案治疗的32例RRMM患者作为研究对象。随访时间截至2022年12月9日。
MM的诊断标准、难治/复发标准和治疗反应标准参考国际骨髓瘤工作组(International Myeloma Working Group,IMWG)的指南及2021年版NCCN指南进行[4, 5]。MM的诊断标准:骨髓中克隆性浆细胞比例>10%,且存在血钙升高(血钙>2.75 mmol·L-1)、肾损害(血肌酐>177 μmol·L-1或肌酐清除率<40 mL·min-1)、贫血(血红蛋白<10 g·dL-1)和骨损害(溶骨性骨质破坏或病理性骨折)等症状之一。治疗反应标准参考2016 IMWG疗效标准,治疗过程中或治疗结束后60 d内疾病进展(progressive disease,PD)定义为难治。符合以下1项或多项定义为复发:(1)出现新的骨病变或者软组织浆细胞瘤(骨质疏松性骨折除外);(2)已有的浆细胞瘤或骨病变增加,可测量病变最大垂直径乘积之和增加50%且最大垂直径绝对值≥1 cm;(3)高钙血症(血钙>2.75 mmol·L-1);(4)血红蛋白下降≥20 g·L-1(与治疗或非MM因素无关);(5)从MM治疗开始,血肌酐上升≥176.8 μmol·L-1(2 mg·dL-1)并且与MM相关;(6)血清M蛋白相关的高黏血症。
32例患者既往均应用过硼替佐米治疗,其中29例患者既往接受过来那度胺治疗。32例患者中,有14例接受了BRD方案,即苯达莫司汀+来那度胺(25 mg,qod,d1~d21)+地塞米松(20 mg,d1~d4);13例接受了BPD方案,即苯达莫司汀+硼替佐米(1.3 mg·m-2,d1、d4、d8、d11)+地塞米松(20 mg,d1、d4、d8、d11);2例患者接受了苯达莫司汀+达雷妥尤单抗(16 mg·kg-1,d1、d8、d15、d22)+地塞米松(20 mg,d1、d8、d15、d22)方案;此外,各有1例患者分别接受了苯达莫司汀+地塞米松(20 mg,d1~d4)方案,苯达莫司汀+依托泊苷(0.1 g,d1、d2)+长春地辛(4 mg,d1)+地塞米松(20 mg,d1~d4)方案,苯达莫司汀+卡非佐米(27 mg·m-2,d1、d2、d8、d9、d15、d16)+地塞米松(20 mg,d1、d2、d8、d9、d15、d16)方案。所有方案中的苯达莫司汀用药剂量均为60 mg·m-2,d1、d2。所有方案均为每28 d为一个疗程,治疗至PD、死亡或随访截止。
通过检测血、尿M蛋白定量,骨髓克隆性浆细胞比例,血钙水平及全身骨骼影像检查进行疗效评价,疗效评价标准参照IMWG的评价标准,分为严格意义的完全缓解(stringent complete response,sCR)、完全缓解(complete response,CR)、非常好的部分缓解(very good partial response,VGPR)、部分缓解(partial response,PR)、微小缓解(minimal response,MR)、疾病稳定(stable disease,SD)和PD。采用磁共振成像或电子计算机断层扫描检查评价髓外病变(extramedullary disease,EMD)发生情况。分别于第1、2、4、6、8疗程结束时评价疗效。客观缓解率(ORR)=(PR例数+VGPR例数+CR例数+sCR例数)/总例数×100%。疾病控制率=(CR例数+VGPR例数+PR例数+SD例数)/总例数×100%。
比较不同治疗线数组(分为≥3线组和<3线组)及苯达莫司汀不同疗程组(分为≥3个疗程组和1~2个疗程组)患者间的生存差异。其中,总生存期(overall survival,OS)为患者使用苯达莫司汀化疗至死亡或随访结束的时间,无进展生存期(progression free survival,PFS)为从应用苯达莫司汀化疗至患者出现PD的时间。
参照美国国家癌症研究所常见不良事件评价标准(CTCAE)第5版判断不良反应。
查阅患者的门诊或住院病历,若末次记录后的3~6个月未看到患者复诊或再住院,则进行电话随访。随访主要内容为患者的生存状态,若患者已故,需记录死亡时间。
采用SPSS 24.0统计软件进行统计学分析,计数资料以例(%)表示;采用Shapiro-Wilk法检验计量资料的正态性,符合正态分布的数据用描述,并进行t检验;不符合正态分布的数据用MQ25Q75)描述。用非参数检验分析各组患者间的生存差异。绘制Kaplan-Meier曲线分析患者生存情况。以P<0.05为差异有显著意义。
32例患者的中位随访时间为13(3~27)个月。其中,男性22例,女性10例;年龄42~80岁。32例患者的M蛋白主要为IgG型和IgA型,均为Durie-Salmon分期Ⅲ期患者。32例RRMM患者的临床首发症状为骨痛,主要以腰骶部、胸背部骨痛为主(27例,84%),其次是乏力伴双下肢水肿(3例,9%)和发热(2例,6%);此外,还有20例患者合并病理性骨折,1例合并淀粉样变性。23例进行了荧光原位杂交技术(fluorescence in situ hybridization,FISH)遗传学检测的患者中,FISH结果阴性5例;18例(78%)FISH检测异常患者中,IgH基因位点缺失3例,剩余15例FISH检测异常均为MM合并EMD患者,包括1q21(+)12例、TP53(+)3例、t(14;16)4例、t(14;20)1例、t(4;14)3例、13q缺失2例、t(4;11)1例、t(11;14)1例,其中8例患者为细胞遗传学高危患者。既往中位化疗线数4(2,6)线。患者的基线临床特征见表1
32例患者中,有19例(59%)RRMM患者伴EMD,其中7例EMD为初诊时伴发,12例为复发时伴发,髓外包块常见发生部位包括头部3例(16%)、胸壁2例(11%)、胸椎6例(32%)、腰椎5例(26%)、骨盆3例(16%)、椎管内2例(11%);其中16例患者存在骨旁EMD,3例患者为软组织EMD。
32例患者完成苯达莫司汀化疗的中位疗程数为3(1,8)个。3例患者仅完成1个疗程,其中2例死亡,1例仍在随访中,疗效为SD;29例患者完成了至少2个疗程的化疗,2个疗程后评价疗效,结果为1例CR,11例PR,10例SD,7例PD;15例患者完成了至少4个疗程的化疗,4个疗程后评价疗效,结果为1例CR,10例PR,3例SD,1例PD;3例患者完成了至少6个疗程的化疗,6个疗程后评价疗效,结果为1例PR,1例VGPR,1例PD;1例患者完成了8个疗程的治疗,8个疗程后,达VGPR。随访截止时,除3例仅治疗了1个疗程的患者外,29例RRMM患者应用苯达莫司汀治疗后的最终ORR为38%(11/29),其中,CR1例,VGPR 1例,PR 9例,SD 6例,PD 12例;值得一提的是,其中用药4个疗程及以上的患者评估疗效,ORR为73%(11/15)。
32例RRMM患者的预计中位PFS为11个月(图1),预计中位OS为25个月(图2)。
32例RRMM患者中有20例为应用苯达莫司汀治疗前已行3线及以上化疗复发的患者,其预计中位PFS为11个月,中位OS为25个月;12例3线以下复发的患者,尚未观察到有50%的患者出现PD或死亡,因此无法计算中位PFS和OS(图3图4),两组比较均无显著差异(P>0.05)。32例RRMM患者中有20例完成了≥3个疗程的化疗,12例患者完成了1~2个疗程的化疗,两组的预计中位PFS分别为21个月和2个月(P<0.001)(图5),预计中位OS分别为28个月和8个月(P=0.02)(图6),两组比较均有显著差异。
32例患者中死亡10例(31%),其中8例因PD死亡,另外2例因非MM的原因死亡(分别因心脏衰竭和肺癌而死亡)。
截至本研究最后一次随访,19例RRMM伴EMD的患者中,1例VGPR,4例PR,5例SD,9例PD,ORR为26%(5/19),疾病控制率为53%(10/19)。
参照CTCAE第5版进行安全性评价,32例患者发生的非血液学不良反应中,乏力(14/32,44%)、食欲不振(11/32,34%)是最常见的不良反应症状,均较轻微,均为1~2级。血液学不良反应方面,有16例患者(16/32,50%)出现白细胞计数减少,其中1级10例(31%),2级4例(13%),3级2例(6%);2例患者(2/32,6%)的血红蛋白下降超过1 g·dL-1;8例患者(8/32,25%)的血小板减少,其中1级2例,2级1例,3级5例,但8例患者中有3例患者治疗前血小板就低于正常值,均不需要输注血小板;2例患者(2/32,6%)出现腹泻,均为2级。
MM是一种常见的浆细胞恶性肿瘤,近年来新型药物和嵌合抗原受体T细胞(CAR-T)等免疫治疗的应用,使其缓解率显著提高,生存期较前延长,但MM最终仍会复发而产生耐药,成为RRMM,且有6%~20%的MM患者复发时合并EMD。目前,MM仍是不可治愈的疾病之一,多线治疗后仍复发且伴EMD的RRMM患者,往往因为对多种靶向药物耐药,其治疗面临着巨大挑战。
苯达莫司汀是一个含有类嘌呤苯并咪唑环的双功能氮芥衍生物。氮芥及其衍生物可形成亲电的碱性基团,可与富电子的亲核基团形成共价键,造成DNA链间交联,也会使DNA和蛋白之间,以及蛋白和蛋白之间产生交联,这种共价联结打乱了DNA和蛋白的功能,从而通过多种途径导致肿瘤细胞死亡,发挥抗肿瘤作用;同时,苯达莫司汀可以通过激活碱基切除的DNA修复途径来表现细胞毒性。多项临床试验显示其在B细胞恶性肿瘤中具有较高效能,且与其他烷化剂的交叉耐药性较低[6]
2021年NCCN发布的指南推荐苯达莫司汀可用于治疗RRMM。此外,多项研究支持苯达莫司汀可以与免疫调节剂、硼替佐米等药物联合治疗MM[7-11]。MEY等[12]报道了苯达莫司汀、来那度胺和地塞米松联合治疗50例RRMM患者的疗效,苯达莫司汀剂量为75 mg·m-2,d1、d2,以28 d为一疗程,中位疗程为6(4, 9)个,结果ORR为89%,中位PFS为18.6个月。POZZI等[13]报道了苯达莫司汀与来那度胺、地塞米松治疗38例RRMM患者的疗效,苯达莫司汀剂量为40 mg·m-2,d1、d2,以28 d为一疗程,化疗6个疗程后,ORR为48%,中位PFS为10个月。RODON等[14]报道了苯达莫司汀与硼替佐米、地塞米松联合治疗73例RRMM患者的疗效,苯达莫司汀的剂量为70 mg·m-2,d1、d8,以28 d为一疗程,中位疗程为7(1,12)个,结果,ORR为58%,中位PFS为10.8个月。可见,苯达莫司汀的疗效可能与剂量及联合使用的药物有关,但仍需通过进一步研究证实。
本研究中,32例RRMM既往中位化疗线数在4线以上,应用苯达莫司汀(60 mg·m-2,d1、d2)联合硼替佐米/来那度胺与地塞米松治疗后的预期中位PFS为11个月,29例患者完成了至少2个疗程的化疗,截止到随访日期,最终ORR为38%,与文献报道的疗效相似。从治疗线数来看,32例RRMM患者中,有20例为接受了3线及以上化疗后复发的患者,12例为接受了3线以下化疗后复发的患者,两组的预计PFS和OS比较,均无显著差异,考虑可能与本研究病例数较少及随访时间较短相关。从疗程来看,完成了≥3个疗程和仅完成了1~2个疗程患者的PFS分别为21个月和2个月,预计中位OS分别为28个月和8个月,两组比较有显著差异,表明疗程越长,疗效越好。随访截止时,29例完成了≥2个疗程的RRMM患者最终ORR为38%(11/29),15例用药≥4个疗程的患者ORR为73%(11/15)。因此,笔者建议,患者如果没有出现PD,可考虑使用苯达莫司汀化疗4个疗程以上,以取得更好的疗效。
32例RRMM中有19例合并了EMD,治疗后的疾病控制率为53%(10/19)。由于EMD的疗效很难达到CR,有的病灶即使已经没有活性了,但仍然存在,而患者的临床症状是稳定的,所以此类患者治疗后的疾病控制率较为满意。本研究中,有1例患者右侧下颌支及下颌角的EMD在使用苯达莫司汀化疗后明显缩小,疼痛缓解较快,且持续18个月无复发。此外,15例MM合并EMD患者中有12例1q21阳性,有研究表明初治MM患者中1q21 gain/amp和KRAS的突变组合预示着EMD发生的风险更高[15]。故初治患者FISH检查存在1q21阳性时,临床应在其髓外病变方面给予更多关注。
苯达莫司汀还可以与泊马度胺、地塞米松联合。SIVARAJ等[16]报道了38例RRMM患者使用苯达莫司汀(120 mg·m-2,d1,以28 d为一疗程)的疗效,中位疗程为7(1,31)个,ORR为61%,中位PFS为9.6个月。GRAMATZKI等[17]报道,苯达莫司汀(70 mg/m2,d1、d8,以28 d为一疗程)与卡非佐米、地塞米松联合治疗对硼替佐米、来那度胺双耐药的RRMM患者63例,治疗8个疗程后,ORR为51%,中位PFS为11.6个月。可见,临床在化疗方案的选择上也可以尝试应用苯达莫司汀联合既往未曾使用过的泊马度胺或卡非佐米治疗。
本研究中,苯达莫司汀的剂量是每疗程120 mg·m-2,治疗的主要血液学不良反应是白细胞计数降低,发生率为50%(16/32),但3级以上的仅为2例(6%),无4级不良反应,且无患者需要输注血小板,表明应用苯达莫司汀60 mg·m-2,d1、d2的联合治疗方案对于RRMM患者是相对安全的。
综上所述,苯达莫司汀治疗RRMM具有疗效好、患者耐受性良好等优点,可作为该类患者合理有效的治疗方案选择之一,在伴发EMD的RRMM患者中,苯达莫司汀也可取得一定的疗效。目前,以苯达莫司汀为基础的RRMM治疗方案仍在不断研究与改良。随着真实世界研究的不断总结,相信苯达莫司汀可以为RRMM及伴发EMD患者带来更多获益。
  • 北京市石景山区卫生与健康委员会医学重点学科建设项目(石卫健医发〔2021〕2号)
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2025年第44卷第4期
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doi: 10.14109/j.cnki.xyylc.2025.04.06
  • 接收时间:2024-02-07
  • 首发时间:2025-12-15
  • 出版时间:2025-04-25
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  • 收稿日期:2024-02-07
  • 录用日期:2025-02-14
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北京市石景山区卫生与健康委员会医学重点学科建设项目(石卫健医发〔2021〕2号)
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    1.首都医科大学附属北京朝阳医院石景山院区 血液与肿瘤科,北京 100043
    2.北京大兴区人民医院 肿瘤内科,北京 102600

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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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