多发性髓治疗课件

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1、多发性骨髓瘤的诊断治疗多发性骨髓瘤的诊断治疗MM的定义的定义 多发性骨髓瘤（多发性骨髓瘤（Multiple Myeloma Multiple Myeloma ，MMMM）是）是一种恶性浆细胞克隆性增生的肿瘤。因恶性浆细一种恶性浆细胞克隆性增生的肿瘤。因恶性浆细胞增殖导致的一系列临床表现：骨髓中恶性浆细胞增殖导致的一系列临床表现：骨髓中恶性浆细胞增多，血清或尿中见单克隆球蛋白，骨质破坏，胞增多，血清或尿中见单克隆球蛋白，骨质破坏，髓外浆细胞瘤，肾功能衰竭，终末期可见造血功髓外浆细胞瘤，肾功能衰竭，终末期可见造血功能衰竭：贫血、白细胞减少、血小板减少。能衰竭：贫血、白细胞减少、血小板减少。 MM流

2、行病学流行病学n n约占血液系统恶性肿瘤10%，恶性肿瘤的1% ，发病率有增加趋势，美国NCI数据：1994年新诊MM约12000例，2011年约20520例 ；n n好发于老年人，随着年龄的增长，MM的发病率增加 ；n n2011年美国NCI统计数据显示：MM发病中位年龄为男性62岁（70%70岁），女性61岁（79%70岁） 不同年龄段的不同年龄段的不同年龄段的不同年龄段的MMMM患者比例患者比例患者比例患者比例MM常见临床表现常见临床表现n n骨痛；n n贫血；n n感染发热；n n肾功能异常；n n高钙血症；n n其他：出凝血异常、高粘滞血症、淀粉样边等。MM的诊断的诊断初诊多发性骨髓

3、瘤诊断检查指标初诊多发性骨髓瘤诊断检查指标 必备指标必备指标示病情选做指标示病情选做指标血常规血常规生化常规（含肝肾功能、生化常规（含肝肾功能、LDHLDH、钙离子等）、钙离子等）血清血清2-2-微球蛋白微球蛋白血清游离轻链血清游离轻链血清免疫球蛋白定量血清免疫球蛋白定量血清蛋白电泳血清蛋白电泳血清免疫固定电泳血清免疫固定电泳MRIMRICTCTPET/CTPET/CT2424小时尿蛋白定量小时尿蛋白定量尿蛋白电泳尿蛋白电泳尿免疫固定电泳尿免疫固定电泳 髓外浆细胞瘤的组织活检髓外浆细胞瘤的组织活检骨密度检测骨密度检测浆细胞标记指数浆细胞标记指数骨骼检查骨骼检查骨髓及脂肪垫的淀粉染色骨髓及脂肪垫

4、的淀粉染色单侧骨髓穿刺单侧骨髓穿刺+ +活检活检骨髓细胞流式细胞仪检测骨髓细胞流式细胞仪检测细胞遗传学检查细胞遗传学检查FISHFISH检测：检测：del 13del 13，del del 17p1317p13，t(4;14)t(4;14)，t(11;14)t(11;14)，t(14;16)t(14;16)，1q211q21扩扩增增血液粘滞度检查血液粘滞度检查HLAHLA分型分型 白蛋白 1 2 血清蛋白电泳脊柱MRI，T2压脂象MM诊断标准诊断标准n n血清或尿有血清或尿有MM蛋白（除外无分泌型）；蛋白（除外无分泌型）；n n骨髓有克隆性浆细胞增生或活检证实为浆细胞瘤；骨髓有克隆性浆细胞增生

5、或活检证实为浆细胞瘤；n n有浆细胞增殖导致的器官或组织损伤的证据：有浆细胞增殖导致的器官或组织损伤的证据： 高钙血症：血清钙高钙血症：血清钙 11.5g/dl11.5g/dl； 肾功能损害：血清肌酐肾功能损害：血清肌酐1.73mmol/L(1.73mmol/L(2mg/dl)2mg/dl)或或肌酐清除率肌酐清除率40mL/min40mL/min； 贫血：血红蛋白贫血：血红蛋白10g/dl10g/dl，或小于正常值，或小于正常值2g2g； 骨骼病变：溶骨性病变、严重的骨质疏松或病理骨骼病变：溶骨性病变、严重的骨质疏松或病理性骨折。性骨折。 冒烟型冒烟型MM诊断标准诊断标准n n血清M蛋白（Ig

6、G或IgA型）30g/L有或没有骨髓克隆性浆细胞10；n n无浆细胞增殖导致器官或组织损伤表现如：高钙血症，肾功能损害，贫血，骨骼病变等。 鉴别诊断鉴别诊断不明原因的单克隆球蛋白增高症（MGUS）： 1、血清M蛋白30g/L； 2、骨髓克隆性浆细胞10%； 3、无浆细胞增殖导致器官或组织损伤表现；如为IgM型MGUS则无贫血、高粘滞血症及其他临床症状并排除淋巴增殖性疾病。MM分型分型n n按浆细胞分泌的免疫球蛋白类型将MM分为：IgG型、IgA型、IgM型、IgD型、IgE型、轻链型、轻链型、无分泌型及多克隆型 。MM分期分期n nDurie-Salmon 分期系统；n n国际分期系统（Int

7、ernational Staging System，ISS） 。DurieDurie-Salmon -Salmon 分期分期分期分期 分期分期分期指标分期指标 期期1 1、血红蛋白、血红蛋白100g/L100g/L；2 2、血清钙正常或、血清钙正常或 12mg/dL12mg/dL；3 3、骨、骨X-X-线正常或仅有孤立性浆细胞瘤；线正常或仅有孤立性浆细胞瘤；4 4、血清、血清MM蛋白含量低：蛋白含量低：IgGIgG50g/L50g/L，IgAIgA30g/L30g/L；5 5、尿轻链蛋白、尿轻链蛋白4g/24h4g/24h。 期期介于介于 期和期和期之间期之间期期1 1、血红蛋白、血红蛋白85

8、g/L85g/L；2 2、血清钙、血清钙12mg/dL12mg/dL；3 3、广泛性溶骨性病变；、广泛性溶骨性病变；4 4、血清、血清MM蛋白含量高：蛋白含量高：IgGIgG70g/L70g/L，IgAIgA50g/L 50g/L ；5 5、尿轻链蛋白、尿轻链蛋白12g/24h12g/24h。国际分期系统（国际分期系统（国际分期系统（国际分期系统（International Staging SystemInternational Staging System，ISSISS） 分期分期特点特点中位生存（月）中位生存（月）I I血清血清 2- 2- 微球蛋白微球蛋白 3.5 mg/L3.5 mg/

9、L血清白蛋白血清白蛋白 3.5 3.5 g/dLg/dL6262II II介于介于I I期和期和 IIIIII期之间期之间4444IIIIII血清血清 2- 2- 微球蛋白微球蛋白 5.5 mg/L5.5 mg/L2929亚型亚型n nA A 肾功能正常（血清肌酐肾功能正常（血清肌酐2.0mg/dL2.0mg/dL）n nB B 肾功能异常（血清肌酐肾功能异常（血清肌酐2.0mg/dL2.0mg/dL） MM分子遗传学预后指标分子遗传学预后指标 分组分组指标指标标危标危多倍体多倍体t t（1111；1414）t t（6 6；1414）中危中危t t（4 4；1414）1313号染色体缺失或低二

10、倍体号染色体缺失或低二倍体高危高危17p-17p-t t（1414；1616）t t（1414；2020）高危基因谱表达高危基因谱表达IMWG的多发性骨髓瘤的疗效评价标准的多发性骨髓瘤的疗效评价标准 类别类别评价标准评价标准分子学完全缓解分子学完全缓解CRCR加加ASO-PCRASO-PCR（等位基因特异性寡核苷（等位基因特异性寡核苷PCR PCR ）阴性）阴性严格意义的完全缓解严格意义的完全缓解（sCRsCR） 在在CRCR基础上满足以下条件：基础上满足以下条件：1 1、FLCFLC率正常；率正常；2 2、免疫组化或免疫荧光检测骨髓中无克隆性浆细胞。、免疫组化或免疫荧光检测骨髓中无克隆性浆细

11、胞。 完全缓解（完全缓解（CRCR）1 1、血清和尿的免疫固定电泳阴性；、血清和尿的免疫固定电泳阴性；2 2、软组织浆细胞瘤消失；、软组织浆细胞瘤消失；3 3、骨髓浆细胞、骨髓浆细胞 5%5%。接近接近CRCR（nCRnCR）1 1、血清和尿的免疫固定电泳阳性；、血清和尿的免疫固定电泳阳性；2 2、软组织浆细胞瘤消失；、软组织浆细胞瘤消失；3 3、骨髓浆细胞、骨髓浆细胞 5%5%。IMWG的多发性骨髓瘤的疗效评价标准的多发性骨髓瘤的疗效评价标准 类别类别评价标准评价标准非常好的部分缓解非常好的部分缓解（VGPRVGPR）血清、尿蛋白电泳阴性但血清、尿的免疫固定电泳血清、尿蛋白电泳阴性但血清、尿

12、的免疫固定电泳阳性；或阳性；或血清血清MM蛋白较前减少蛋白较前减少 90%90%；或；或血清血清MM蛋白明显减少伴尿蛋白明显减少伴尿MM蛋白蛋白100mg/24h100mg/24h。 部分缓解（部分缓解（PRPR） 1 1、血清、血清MM蛋白减少蛋白减少 50%50%，并且，并且2424小时尿小时尿MM蛋白减蛋白减少少 90%90%或或2424小时尿蛋白小时尿蛋白200mg200mg；2 2、无可测量的血清及尿的、无可测量的血清及尿的MM蛋白，则用异常蛋白，则用异常FLCFLC水水平下降平下降 50%50%作为评价标准；作为评价标准；3 3、无可测量的血清及尿的、无可测量的血清及尿的MM蛋白，

13、则用浆细胞减蛋白，则用浆细胞减少少 50%50%作为评价标准但要求治疗前骨髓浆细作为评价标准但要求治疗前骨髓浆细胞比例胞比例 30%30%；4 4、同时软组织浆细胞瘤缩小、同时软组织浆细胞瘤缩小 50%50%。IMWG的多发性骨髓瘤的疗效评价标准的多发性骨髓瘤的疗效评价标准 类别类别评价标准评价标准稳定（稳定（stable diseasestable disease，SDSD） 未达未达CRCR、VGPRVGPR、PRPR及及PDPD标准。标准。 进展进展（PDPD） 达到以下达到以下1 1个以上条件：个以上条件：1 1、血清、血清MM蛋白较基线水平增加蛋白较基线水平增加 25%25%或或MM

14、蛋蛋白绝对值增加白绝对值增加 0.5g/dL0.5g/dL；2 2、尿、尿MM蛋白较基线水平增加蛋白较基线水平增加 25%25%或或MM蛋白蛋白绝对值增加绝对值增加 200mg/24h200mg/24h；3 3、无可测量的血清及尿的、无可测量的血清及尿的MM蛋白，则蛋白，则FLCFLC较基线水平增加较基线水平增加 25%25%或绝对值增加或绝对值增加10mg/dL10mg/dL；4 4、骨髓浆细胞比例、骨髓浆细胞比例 10%10%；5 5、有新的骨骼病变或软组织肿瘤出现，或、有新的骨骼病变或软组织肿瘤出现，或原病灶较基线增大；原病灶较基线增大；6 6、浆细胞增殖导致的高钙血症（纠正的血、浆细胞

15、增殖导致的高钙血症（纠正的血清钙清钙11.5mg/dL11.5mg/dL或或2.65mmol/L2.65mmol/L。MM治疗治疗1956Light chain types (later termed kappa and lambda) recognizedMMMM诊断治疗发展史诊断治疗发展史Durie-Salmon staging system19831975Autologous transplantation 20052005Cytogenetic classificationInternational staging system19471939UrethaneSerum protein

16、 spike identified18951928First large case series of myelomaDescription of plasma cells18441845Abnormal urine protein, later termed Bence Jones proteinFirst documented case18451844Steel and quinineRhubarb and orange peel19621958MelphalanCorticosteroids1999Thalidomide20022002BortezomibLenalidomide1840

17、 1850 1860 1870 1880 1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010HSP-90 inhibitorsHDAC inhibitorsPomalidomideCarfilzomibReprinted from Kyle RA and Rajkumar SV. Blood. 2008;111:2962-2972.MM治疗常用药物治疗常用药物n n传统化疗药物：传统化疗药物： 马法兰（马法兰（MM） 环磷酰胺（环磷酰胺（C C） 阿霉素：吡柔吡星（阿霉素：吡柔吡星（A A） 脂质体阿霉素（脂质体阿霉

18、素（D D） 糖皮质激素（糖皮质激素（D D、P P）n n新药：新药： 免疫调节剂：沙利度胺（免疫调节剂：沙利度胺（T T） 雷那度胺（雷那度胺（R R） 蛋白酶体抑制剂：硼替唑咪（蛋白酶体抑制剂：硼替唑咪（V V）MM治疗常用化疗方案治疗常用化疗方案n n传统方案：MP、VAD、DVDn n含新药方案： VD、VTD、PAD、VDD、VRD、VCD； RD/Rd、TD、TAD、CTD； VMP、VMPT、MPT、MPR；不同时代不同时代不同时代不同时代MM治疗的疗效治疗的疗效Reprinted from Kumar SK et al. Blood. 2008;111:2516-2520.S

19、urvival20406080100 120 1400Time (months)1971-761977-821983-881989-941994-002001-06Overall survival from diagnosis1.00.80.60.40.20.0含新药方案与传统化疗方案疗效比较含新药方案与传统化疗方案疗效比较作者作者方案方案病例病例数数总有效率总有效率（%）CR+VGPCR+VGPR R（%）PRPR（%）m-m-PFSPFS（mm）3y-3y-OSOS（%）m-m-OSOS（mm）Palumbo Palumbo A et alA et alMPMPMPTMPT12912912

20、612647.647.676.076.07.27.227.927.92y-EFS2y-EFS27%27%54%54%P=0.0006P=0.000664648080P=0.19P=0.19454547.647.6Facon Facon Laurel Laurel 20072007MPMPMPTMPT 2 21313p=0.0008p=0.0008353576 76 p p0.00010.0001181827.527.5p p0.00010.0001333351.5 51.5 p=0.006p=0.006Hulin Hulin JCO 2009JCO 2009MPT MPT MPMP7 7 1

21、1p p0.0010.00162623131p p0.0010.001242418.518.5p p0.0010.00144442929p p= =0.0280.028HarousseaHarousseau u JL et al JL et alMPMPVMPVMP33733733133135357171P P0.0010.0018 84141P P0.0010.00115.215.221.721.7P P0.0010.001545468.568.5P P0.0010.0014343NRNRP P0.0010.001MM治疗常用药物的常见毒性治疗常用药物的常见毒性药物药物毒性毒性马法兰马法兰延

22、迟性的骨髓抑制延迟性的骨髓抑制 ，损伤干细胞，损伤干细胞阿霉素阿霉素骨髓抑制、心脏毒性骨髓抑制、心脏毒性沙利度胺沙利度胺嗜睡、乏力、血栓形成、皮疹、神经嗜睡、乏力、血栓形成、皮疹、神经系统毒性系统毒性与地塞米松联合血栓与地塞米松联合血栓及肺栓塞的风险增高及肺栓塞的风险增高 雷那度胺雷那度胺骨髓抑制骨髓抑制 、嗜睡、乏力、血栓形成、嗜睡、乏力、血栓形成硼替唑咪硼替唑咪乏力、腹泻、乏力、腹泻、血小板减少、神经毒性血小板减少、神经毒性、白细胞减少白细胞减少 与与T T联用神经毒加重联用神经毒加重初诊初诊MM的治疗的治疗n n拟行HDT+Auto-SCT ： 年龄65岁； 没有严重并发症或合并疾病 n

23、 n不行HDT+Auto-SCT： 年龄65岁 *Preferred Regimens (all category 1 or 2A)Other Regimens (all category 2B)Transplant eligibleBortezomib/dexamethasone Bortezomib/cyclophosphamide/dexamethasone (category 2A)Bortezomib/doxorubicin/dexamethasoneBortezomib/lenalidomide/dexamethasone Bortezomib/thalidomide/dexame

24、thasone Lenalidomide/dexamethasone DexamethasoneLiposomal doxorubicin/vincristine/dexamethasoneThalidomide/dexamethasoneNon-transplantBortezomib/dexamethasone (category 2A)Lenalidomide/low-dose dexamethasone Melphalan/prednisone/bortezomibMelphalan/prednisone/lenalidomide Melphalan/prednisone/thalid

25、omideDexamethasoneLiposomal doxorubicin/vincristine/dexamethasoneMelphalan/prednisoneThalidomide/dexamethasoneVincristine/doxorubicin/dexamethasoneCategory 1: High-level evidence (eg, phase III controlled trial); categories 2A and B: Lower levels of clinical evidence, but there is NCCN consensus tha

26、t the intervention is appropriate. Table from NCCN Clinical Practice Guidelines: Multiple Myeloma (V.1.2012). Available at: http:/www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf.NCCN：Current Standards for Primary TherapyBortezomib-based regimens are widely preferred in Europe regardless of

27、transplant statusBortezomib-based regimens are widely preferred in Europe regardless of transplant statusBoth bortezomib and IMIDs have been effectively combined with melphalan and prednisone combinations to improve outcomes in nontransplant-eligible Both bortezomib and IMIDs have been effectively c

28、ombined with melphalan and prednisone combinations to improve outcomes in nontransplant-eligible patients patients 29拟行拟行HDT+Auto-SCT患者的治疗患者的治疗诱导缓解化疗三药方案 两药方案VCD VDPAD TDVRD RD/RdVTDCTDTAD VAD（DVD） CR或VGPR继续原方案化疗4-6疗程PR可继续原方案化疗或更换方案以获得更好的缓解无效或PD单次或双次HDT+ASCTCR、VGPR或PRPD临床研究Auto-SCTAllo-SCT维持治疗：沙利度胺，

29、雷那度胺或硼替唑咪巩固化疗治疗策略诱导缓解化疗n n诱导缓解化疗的目的：诱导缓解化疗的目的： 1 1、尽快达到最佳疗效：达到、尽快达到最佳疗效：达到VGPR, nCR, CR 水平 ； 2 2、迅速逆转疾病相关并发症：高钙血症，肾功、迅速逆转疾病相关并发症：高钙血症，肾功能衰竭，贫血等；能衰竭，贫血等； 3 3、改善疾病症状；、改善疾病症状； 4 4、成功收集干细胞，减少干细胞损伤；、成功收集干细胞，减少干细胞损伤；n n含新药方案疗效优于传统方案；含新药方案疗效优于传统方案；n n疗程数：疗程数：4-64-6疗程；疗程；标准剂量化疗与标准剂量化疗与标准剂量化疗与标准剂量化疗与HDTHDT治疗

30、初诊治疗初诊治疗初诊治疗初诊MMMM的随机对照研究的随机对照研究的随机对照研究的随机对照研究 作者作者方案方案病例数病例数CRCR（%）mEFSmEFSmOSmOSAttalAttal et al et al化疗化疗HDTHDT1001001001005a5a222218a18a272737a37a5252FermandFermand et et al.al.化疗化疗HDTHDT9696949418.7a18.7a24.324.350.4b50.4b55.355.3Blade et al. Blade et al. 化疗化疗HDTHDT8383818111 a11 a303034.3a 34.

31、3a 42.542.566.9b66.9b67.467.4Child et al. Child et al. 化疗化疗HDTHDT2002002012018.5 a8.5 a444419.6 a19.6 a31.631.642.3 a42.3 a54.854.8BarlogieBarlogie et et al. al. 化疗化疗HDTHDT25525526126115 b15 b171721 b21 b252553 b53 b5858a: a: 有显著差异；有显著差异；b b：无显著差异：无显著差异在新药治疗在新药治疗MM的时代的时代HDT的作用？的作用？含新药方案与传统方案疗效比较含新药方

32、案与传统方案疗效比较作者作者方案方案病例数病例数RRRR（%）CR+VGPRCR+VGPR（%）m-m-PFSPFS（mm）3y-3y-OSOS（%）m-m-OSOS（mm）SonneveldSonneveld P P et alet alPADPADVADVAD37137137337390%90%83% 83% P=0.002 P=0.002 31311515 P .001 P .00135352828P=0.002P=0.002NANA51512121P .001P .001CavoCavo M et al M et alTD TD VTDVTD23823823623679799393P

33、.001P .00128286262P .001P .0014040NR NR P=0.006P=0.00684848686NRNRNRNRHarousseauHarousseau JL et alJL et alVADVADVDVD24224224024063637979P .001P .001232358.358.3P .001P 70702727171751513333FaconFacon T, et al. T, et al. Lancet. Lancet. 2007; 2007; 370:1209-1218.370:1209-1218.MP-Thalidomide (MPT) MP-

34、Thalidomide (MPT) *Significant difference between arms.Thal/Dex vs MP as induction.非移植患者含新药方案与传统化疗方案非移植患者含新药方案与传统化疗方案疗效比较疗效比较作者作者方案方案病例病例数数总有效率总有效率（%）CR+VGPCR+VGPR R（%）PRPR（%）m-m-PFSPFS（mm）3y-3y-OSOS（%）m-m-OSOS（mm）Palumbo Palumbo A et alA et alMPMPMPTMPT12912912612647.647.676.076.07.27.227.927.92y-E

35、FS2y-EFS27%27%54%54%P=0.0006P=0.000664648080P=0.19P=0.19454547.647.6Facon Facon Laurel Laurel 20072007MPMPMPTMPT 2 21313p=0.0008p=0.0008353576 76 p p0.00010.0001181827.527.5p p0.00010.0001333351.5 51.5 p=0.006p=0.006Hulin Hulin JCO 2009JCO 2009MPT MPT MPMP7 7 1 1p p0.0010.00162623131p p0.0010.001242

36、418.518.5p p0.0010.00144442929p p= =0.0280.028Meta-analysis of six phase 3 trials of thalidomideMP (MPT) vs MP1Median OS: 39.3 vs 32.7 months (6.6-month benefit), HR 0.83, 17% reduced risk of death非移植患者含新药方案与传统化疗方案非移植患者含新药方案与传统化疗方案疗效比较疗效比较作者作者方案方案病例病例数数总有效总有效率（率（%）CR+VGPCR+VGPR R（%）m-m-PFSPFS（mm）3y-

37、3y-OSOS（%）m-m-OSOS（mm）HarousseaHarousseau u JL et al JL et alMPMPVMPVMP33733733133135357171P P0.0010.0018 84141P P0.0010.00115.215.221.721.7P P0.0010.001545468.568.5P P0.0010.0014343NRNRP P0.0010.001Palumbo Palumbo A et alA et alVMPVMPVMPTVMPT25325325025081818989P=0.01P=0.0150505959P=0.03P=0.0327.42

38、7.4NRNR87878989P=0.77P=0.77NRNRNRNRMateosMateos MV et alMV et alVMPVMPVTPVTP130130130130202028283434252574746565RajkumarRajkumar et alet alRDRDRdRd22322322222282827070P=0.007P=0.00752524242P=0.006P=0.00619.119.125.325.3P=0.026P=0.0262y-OS2y-OS75758787P=0.006P=0.006NRNRNRNRVISTA: VELCADE as initial s

39、tandard therapy in multiple VISTA: VELCADE as initial standard therapy in multiple myelomamyeloma: Assessment with : Assessment with melphalanmelphalan and prednisone and prednisoneRandomized, international, phase III trial of VMP vs MP in previously untreated patients with symptomatic MM who were n

40、ot candidates for HDT-ASCT due to age (65 yrs) or co-morbid conditionsVMPCycles 1 - 4Bortezomib 1.3 mg/m2 IV: days 1, 4, 8, 11, 22, 25, 29, 32Melphalan 9 mg/m2 and prednisone 60 mg/m2: days 1-4Cycles 5 - 9Bortezomib 1.3 mg/m2 IV: days 1, 8, 22, 29Melphalan 9 mg/m2 and prednisone 60 mg/m2: days 1-4MP

41、Cycles 1 - 9 Melphalan 9 mg/m2 and prednisone 60 mg/m2: days 1-4RANDOMIZE9 x 6-week cycles (54 weeks) in both armsPrimary end point: TTPSecondary end points: CR rate, ORR, time to response, DOR, time to next therapy (TNT), OS, QoL (PRO)San Miguel JF, et al. N Engl J Med. 2008;359:906-917.VISTA: Fina

42、l updated OS analysisVISTA: Final updated OS analysis31% reduced risk of death with VMP31% reduced risk of death with VMPMedian follow-up 60.1 monthsSan Miguel JF, et al. Blood. 2011;118. Abstract 476.1. Fayers PM, et al. Blood. 2011;118:1239- 1247.Median OS benefit: 13.3 months5-year OS rates: 46.0

43、% vs 34.4%GroupNEventMedianOSHR (95% CI)P valueMP33821143.1VMP34417656.4 0.695 (0.567, 0.852)0.0004LenalidomideLenalidomide-MP: MM-015Stratified by age ( 75 Stratified by age ( 75 vsvs 75 years) and stage (ISS I/II 75 years) and stage (ISS I/II vsvs III) III)Primary comparison: MPR-R Primary compari

44、son: MPR-R vsvs MP MPMPM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4PBO: days 1-21MPRM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day po, days 1-21PlaceboPlaceboMPR-RM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day PO, days 1-21RANDOMIZATIONDouble-Blind Treatment PhaseDiseaseProgressionM

45、aintenanceLenalidomide (25 mg/day) +/- DexamethasoneOpen-Label Extension PhaseLenalidomide10 mg/daydays 1-21Cycles (28-day) 1-9Cycles 10+MM-015: Updated results for patients 65 to 75 yearsMM-015: Updated results for patients 65 to 75 yearsMedian follow-up 30 monthsMedian follow-up 30 monthsMPR-RMPR-

46、RMPRMPRMPMPOverall no. of ptsOverall no. of pts152152153153154154No. of pts 65-75 No. of pts 65-75 yearsyears116116116116116116ORRORR79.3%79.3%73.3%73.3%47.4%47.4% VGPRVGPR35.3%35.3%35.3%35.3%11.2%11.2%Median PFSMedian PFS31 months31 monthsp p0.0010.00115 months15 monthsp p0.0010.00112 months12 mont

47、hsP=0.009Data from Palumbo A, et al. Blood. 2011;118. Abstract 475.非移植患者非移植患者T维持治疗维持治疗临床研究临床研究作者作者发表年限发表年限病例病例数数方案方案治疗时间治疗时间PFS/EFSPFS/EFS(%)(%)OS(%)OS(%)复发后复发后生存生存GIMEMAGIMEMAPalumbo et Palumbo et al al200820083313316565岁岁MPT+T 100mg/dMPT+T 100mg/dMP+MP+观察观察至进展至进展中位中位-*-*22m22m14.5m14.5mm-OSm-OS45m

48、45m48m48mm-OS*m-OS*11.5m11.5m24m24mGEMGSGEMGSLudwig et Ludwig et al al201020101281286565岁岁干扰素干扰素+T 200mg/d+T 200mg/d干扰素干扰素至进展至进展中位中位-*-*28m28m13m13mm-OSm-OS53m53m51m51mm-OSm-OS8m8m25m25mMRC MRC myeloma myeloma Morgan Morgan et al 2012et al 20123273276565岁岁T 100mg/dT 100mg/d观察观察至进展至进展中位中位-*-*11m11m9m

49、9mm-OSm-OS38m38m39m39mm-OSm-OS21m21m26m26m非移植患者非移植患者R维持治疗维持治疗临床研究临床研究作者作者发表年限发表年限病例病例数数方案方案治疗时间治疗时间PFS/EFSPFS/EFS(%)(%)OS(%)OS(%)复发后复发后生存生存MM 015MM 015Palumbo Palumbo et alet al201120114994996565岁岁MPR+R MPR+R 10mg/dd1-2810mg/dd1-28MPRMPR或或MP+MP+观察观察至进展至进展中位中位-*-*31m31m14/13m14/13m3y-OS3y-OS73%73%65%

50、65%NANAMaintenance therapy with bortezomib plus thalidomide (VT) Maintenance therapy with bortezomib plus thalidomide (VT) or bortezomib plus prednisone (VP) in elderly myeloma or bortezomib plus prednisone (VP) in elderly myeloma patients included in the patients included in the GEM2005MAS65GEM2005

51、MAS65 trial trialMateos MV, et al. Presented at ASH 2011. Abstract 477. 260260例例 6565岁初诊岁初诊MMMM患者，随机接受患者，随机接受6 6疗程疗程VMPVMP或或VTPVTP方案化疗方案化疗,178,178例例患者再次随机进行患者再次随机进行VTVT或或VPVP维持治疗维持治疗. . 硼替唑咪硼替唑咪1.3mg/m2 d1,4,8,111.3mg/m2 d1,4,8,11每每3 3个月个月 强的松强的松 50mg50mg隔日隔日 沙利度胺沙利度胺 50mg/d 350mg/d 3年年Efficacy: Res

52、ponse rate to maintenance therapy (n = Efficacy: Response rate to maintenance therapy (n = 178)178)PremaintenancePremaintenanceVTVT(n: 91)(n: 91)VPVP(n:87)(n:87)IF-negative CR, %IF-negative CR, %24 24 46463939IF-positive CR, %IF-positive CR, %10 10 10101111Partial response %Partial response %47 47 3

53、9394747Minor response, %Minor response, %8 83 31 1Stable disease, %Stable disease, %10101 11 1No significant differences between VT/VP.CR = complete response; IF = immnofixation (assessment of M protein)Data from Mateos MV, et al. Presented at ASH 2011. Abstract 477.After a median of 20 months of ma

54、intenance therapy (range, 1-36 months)CR (IF-negative) increased from 24% (after induction) up to 42% (maintenance)Outcome according to maintenance armOutcome according to maintenance armMedian PFSVT: 39 m VP: 32 mP = 0.1Median follow-up: 46 m (range,17-67 months)VT: Not reached5-y OS: 69% VP: 60 mP

55、 = 0.1Median OSMateos MV, et al. Presented at ASH 2011. Abstract 477.*Preferred RegimensOther RegimensBortezomib (category 2A)Lenalidomide (category 2A)Thalidomide (category 1)Interferon (category 2B)Steroids (category 2B)Thalidomide/prednisone (category 2B)Category 1: High-level evidence (eg, phase

56、 III controlled trial); categories 2A and B: Lower levels of clinical evidence, but there is NCCN consensus that the intervention is appropriate. Table from NCCN Clinical Practice Guidelines: Multiple Myeloma (V.1.2012). Available at: http:/www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf.NC

57、CN NCCN 指南对指南对指南对指南对MMMM维持治疗的推荐维持治疗的推荐维持治疗的推荐维持治疗的推荐Overall, maintenance therapy improves cancer-related outcomesOverall, maintenance therapy improves cancer-related outcomesBortezomib and IMIDs are usedBortezomib and IMIDs are used67维持治疗方案维持治疗方案药物药物剂量剂量持续时间持续时间沙利度胺沙利度胺100-200mg/d100-200mg/d至进展？至进展？

58、雷那度胺雷那度胺10-15mg/d10-15mg/d1-21-2年？年？至进展？至进展？硼替唑咪硼替唑咪1.3mg/m2/2w1.3mg/m2/2w1.3mg/m2 d1,4,8,11/3m1.3mg/m2 d1,4,8,11/3m？维持治疗需关注的两个问题维持治疗需关注的两个问题n n诱发多药耐药细胞株的产生；n n诱发第二肿瘤。 所以维持治疗的最佳用药剂量及持续时间有待进一步证实。老年老年MM治疗小结治疗小结n n新诊断老年MM治疗首选：含新药方案n nVMP，MPT，Rd等，RR、CR、VGPR率及PFS/OS均优于MP方案n n 但含新药方案与MP方案比较，严重的治疗相关事件增加根据年

59、龄及化疗毒性推荐的剂量减低方案根据年龄及化疗毒性推荐的剂量减低方案 药物药物65657575岁岁7575岁岁进一步减低剂量进一步减低剂量地塞米松地塞米松40mg/40mg/周周20mg/20mg/周周10mg/10mg/周周马法兰马法兰0.25mg/kg d10.25mg/kg d14 40.18mg/kg d10.18mg/kg d14 40.13mg/kg d10.13mg/kg d14 4沙利度胺沙利度胺200mg/200mg/天天100mg/100mg/天天50mg/50mg/天天雷那度胺雷那度胺+ +地塞米松地塞米松25mg/25mg/天天 d1d1212115mg/15mg/天天

60、d1d1212110mg/10mg/天天 d1d12121雷那度胺雷那度胺+ +马法马法兰兰+ +强的松强的松10mg/10mg/天天 d1d121215mg/5mg/天天 d1d1212125mg25mg隔日隔日 d1d12121硼替唑咪硼替唑咪1.3mg/m21.3mg/m2 每周每周2 2次次1.3mg/m2 1.3mg/m2 每周每周1 1次次1.0mg/m2 1.0mg/m2 每周每周1 1次次新药治疗新药治疗新药治疗新药治疗 MM的常见毒副反应的常见毒副反应 Richardson PG, et al. Oncologist. 2007;12:664-684.AgentAgentPe

61、ripheral Peripheral NeuropathyNeuropathyThrombosisThrombosisMyelosuppressionMyelosuppressionThalidomideThalidomideYesYesYesYesNoNoLenalidomideLenalidomideNoNoYesYesYesYes(Dose-dependent)(Dose-dependent)BortezomibBortezomibYesYesNoNoYes Yes (Transient)(Transient)Delforge M, et al. Lancet Oncol. 2010;

62、 11:1086:1095RichardsonP, et al. Leukemia 2011, 23 Dec Epub ahead of printAgentAgentPredominant TypePredominant TypeReversibilityReversibilityBortezomibBortezomib感感感感觉觉可逆可逆可逆可逆ThalidomideThalidomide感感感感觉觉运运运运动动/ /轴轴突突突突不可逆不可逆不可逆不可逆? ?新药治疗新药治疗新药治疗新药治疗 MM的常见毒副反应的常见毒副反应Peripheral Neuropathy: Management

63、 Through Dose Peripheral Neuropathy: Management Through Dose Modification of Modification of BortezomibBortezomib1. Velcade package insert. Cambridge, MA; Millennium Pharmaceuticals, Inc.; 2011; 2. Richardson P, et al Leukemia 2011, 23 Dic Epub ahead of printCompany-recommendedCompany-recommendedNew

64、 proposed guidelineNew proposed guidelineGrade 1Grade 1No actionNo actionReduce dose by 1 level or Reduce dose by 1 level or change to once-weeklychange to once-weeklyGrade 1 (pain)/2Grade 1 (pain)/2Reduce to 1 mg/mReduce to 1 mg/m2 2 On twice-weekly: reduce dose On twice-weekly: reduce dose by 1 le

65、vel or change to once-by 1 level or change to once-weekly weekly On once-weekly: reduce dose On once-weekly: reduce dose by 1 level or temporary by 1 level or temporary discontinuation discontinuationGrade 2 (pain)/3Grade 2 (pain)/3Withhold until symptoms resolve; Withhold until symptoms resolve; re

66、start with 0.7 mg/mrestart with 0.7 mg/m2 2 and change and change treatment schedule to once weeklytreatment schedule to once weeklyDiscontinueDiscontinueGrade 4Grade 4DiscontinueDiscontinueDiscontinueDiscontinueOnce-weekly administration of Once-weekly administration of bortezomibStudy Study detail

67、sdetailsEfficacyEfficacySensory PNSensory PNDiscontiDiscontinued nued due to due to PNPNDiscontiDiscontinued due nued due to to AEsAEs overalloverallORRORRCRCRMediaMedian PFSn PFS3-yr 3-yr OSOSAll All gradegrades sGraGrade de 3/43/4VMP with twice-weekly VMP with twice-weekly bortezomibbortezomib adm

68、inistration administrationVISTAVISTA1-3,71-3,771%71%30%30%21.7m21.7m68.5%68.5%47%47%13%13%14%*14%*34%34%VMP with once-weekly VMP with once-weekly bortezomibbortezomib administration administrationGIMEMAGIMEMA4,5,74,5,7 79%79%23%23%27m27m87%87%22%22%2%2%4%4%17%17%PETHEMA/GPETHEMA/GEMEM6,76,780%80%20%

69、20%34m34m74%74%n/an/a7%7%n/an/a12%12% Discontinuations due to SAEs.1. San Miguel JF, et al. N Engl J Med. 2008; 359: 906-917; 2. San Miguel JF, et al. N Engl J Med. 2008; 359: 906-917. (Suppl App); 3. Mateos MV, et al. J Clin Oncol. 2010;28: 2259-2266;4. Palumbo A, et al. J Clin Oncol. 2010;28: 5101

70、-5109; 5. Bringhen S, et al. Blood. 2010; 116: 4745-4753; 6. Mateos MV, et al. Lancet Oncol. 2010;11: 934-941;7. Mateos MV, et al. Haematologica. 2011; 96 (s1):S81. Abstract P-175, Poster presentation at IMW 2011.*3% discontinued VMP; 11% selectively discontinued bortezomib due to PN.Peripheral Neur

71、opathy: Management Through Dose Peripheral Neuropathy: Management Through Dose Modification of ThalidomideModification of Thalidomide1. Mileshkin L et al, J Clin Oncol 2006; 24: 4507-45142. Mohty B et al, Haematologica 2010; 95: 311-319Grade 1Grade 1No actionNo actionGrade 2Grade 2Reduce dose of 50%

72、Reduce dose of 50%Grade 3Grade 3Discontinue and restart Discontinue and restart at reduce dose of 50% at reduce dose of 50% if improvement to if improvement to grade 1grade 1Grade 4Grade 4DiscontinueDiscontinueMyelosuppressionMyelosuppression: Management Through Dose ModificationLenalidomide1n nDisc

73、ontinue therapy when platelets fall to Discontinue therapy when platelets fall to 30,000/L30,000/Ln nRestart at 15 mg daily when platelets return to Restart at 15 mg daily when platelets return to 30,000/L30,000/Ln nDiscontinue therapy for each subsequent drop to Discontinue therapy for each subsequ

74、ent drop to 30,000/L30,000/Ln nResume at 5 mg less than previous dose until platelets Resume at 5 mg less than previous dose until platelets return to 30,000/Lreturn to 30,000/L Revlimid package insert. Summit, NJ: Celgene Corporation; 2010; Bortezomibn nTransient thrombocytopenian nGrade 1-3: admin

75、ister full dose; support with platelet infusion if necessaryn nGrade 3/4: withhold until recovery; restart at 25% reduced doseMyelosuppressionMyelosuppression: Management Through Dose Modification1、 Velcade package insert. Cambridge, MA; Millennium Pharmaceuticals, Inc.; 2011; 2、 Colson K, et al. Cl

76、in J Oncol Nurs. 2004;8:473-480; 3、 Lonial S, et al. Blood. 2005;106:3777- 3784.粒细胞减少的剂量调整粒细胞减少的剂量调整雷那度胺，硼替唑咪： 1、1-2度粒细胞减少在支持治疗下不用调整剂量； 2、4度粒细胞减少或3度粒细胞减少伴感染性发热，减量2550%。 化疗导致的贫血化疗导致的贫血雷那度胺、硼替唑咪： 血红蛋白10g/dL，减量2550%。 肾功能不全时剂量调整肾功能不全时剂量调整n n雷那度胺： 根据肌酐清除率调整剂量：3060ml/min，10mg/天；30ml/min不需透析者15mg隔日一次；30ml/

77、min需透析者5mg/日透析后服。 拟行Auto-SCT的初诊MM患者高危初诊MM按分子遗传分层治疗策略中危标危VRD4疗程Rd4疗程VCD4疗程ASCT；如果未达CR或VGPR第二次ASCTASCT；如果未达CR或VGPR第二次ASCT早期ASCT延迟ASCT硼替唑咪方案维持硼替唑咪方案维持2年如果未达CR或VGPRR维持在ASCT前可用Rd维持治疗不行Auto-SCT的初诊MM患者高危初诊MM按分子遗传分层治疗策略中危标危VRD1年Rd1年VCD1年硼替唑咪维持硼替唑咪方案维持2年雷那度胺维持冒烟型冒烟型MM是否需要马上治疗？是否需要马上治疗？ NCCN Guidelines推荐：SMM诊

78、断后可以先观察3-6个月或进入临床研究。 Median follow-up: 32 months (range 12 - 49)Lenalidomide + dexMedian TTP: NR9 Progressions (15%) 5 pts: early disc followed by PD 4 pts: symptomatic PDNo treatmentMedian TTP: 23 m37 Progressions (59%) 20 patients: bone disease 7 patients: renal failureHR: 6.0; 95% IC (2.912.6); P

79、 2 therapy linesSchedule: Bort 1.3 mg/m2 Days 1, 4, 8, 11 + Vor 400 mg/d Days 1-14, 21-day cycles; pts w PD allowed to add DexRefractory to: Bort = 100%, 1 IMID = 87%, 2 IMIDs = 40%Median # of cycles: 4 (1 to 26); 27% completed 8 cycles; treatment discontinuation: 20%ORR17%CBR31%Median PFS3.1 months

80、Median OS11.2 monthsSide effectsGI tract088: Vorinostat + Bortezomib in RRMM - Randomized Phase III Trialn = 637 MM patients; median age, 61 years ( 65 years = 37%); 1 to 3 prior lines (20% prior Bort)Treatment (21-day cycles): Bort 1.3 mg/m2 Days 1, 4, 8, 11 Vor 400 mg/d Days 1-14Vor + BortPlacebo

81、+ BortP ValueORR, CBR56%, 71%41%, 54% 0.0001Risk of progression23% reduced0.01Median PFS7.63 months6.83 months0.01OSNot reached28.1 monthsNSSide effectsWell tolerated; thrombocytopenia, diarrhea, nausa, vomitingHDAC-Inhibition: Vorinostat - Vantage 095 + 088 ResultsVorinostat at lower doses (300 mg)

82、 better tolerated98Progression-Free Survival and Overall SurvivalDimopoulos MA, et al. ASH 2011; Abstract 811 (oral).EventsMedian PFS (95% CI)HR (95% CI)P ValueBort + Vorinostat201/3177.63 months (6.9-8.4)0.774 (0.64-0.94)0.01Bort + Placebo216/3206.83 months (5.7-7.7)EventsMedian OS (95% CI)HR (95%

83、CI)P ValueBort + Vorinostat71/317NA0.86 (0.62-1.18)0.35Bort + Placebo80/32028.1 months (28.1-NA)*ORR20 mg00442.4%20/27 mga00323.7%m-OS 15.6m 004 52.2%TTP 8.3mPX-171-0031: n=266, 80%Relapsed after Btz and Len/Thal + refractory to last regimenPX-171-0042,3: n=129，Btz-nave，Relapsed after 1 to 3 previou

84、s linesa First cycle: 20 mg IV QD 2 for 3 weeks (28-day cycle); subsequently, 27 mg.Data from: 1. diCapua Siegel DS, et al. ASH 2010; Abstract 985; 2. Vij R, et al. ASCO 2010; Abstract 8000; 3. Vij R, et al. ASH 2011; Abstract 813.ORR PR Activity of Carfilzomib in Relapsed/Refractory MM100Activity o

85、f Carfilzomib in Newly Diagnosed MM 期临床试验，期临床试验，n=53n=53，方案：，方案：CRdCRd，4949例患者完例患者完成成4 4个疗程，个疗程，CR 67%CR 67%，sCR45%sCR45%。其中完成。其中完成8 8个疗程个疗程的的3636例患者中例患者中nCR78%nCR78%，sCR61% sCR61% 。 24m PFS 92%24m PFS 92%。 2012-7-202012-7-20，FDAFDA批准上市批准上市*nPopulationDose PR PFS/TTP/DORLacy1-36062% previous IMIDs2

86、mg (1-28)65%PFS 13 mo1. Lacy MQ, et al. JCO. 2009;27:5008-5014; 2. Mikhael JR, et al. ASH 2011; Abstract 2942; 3. Lacy MQ, et al. ASH 2011; Abstract 3963; 4. Lacy MQ, et al. Leukemia. 2010;24:1934-1939; 5. Leleu X, et al. ASH 2011; Abstract 812; 6. Lacy MQ, et al. Blood. 2011;118:2970-2975; 7. Richa

87、rdson PG, et al. ASH 2011; Abstract 634; 8. Weber D, et al. NEJM. 2007;357:2133-2142 (Updated; Weber D, et al. ASH 2007; Abstract 412); 9. Dimopoulos M, et al. NEJM. 2007; 357:2123-2132 (Updated; Weber DM, et al. ASH 2007; Abstract 412).Activity of Pomalidomide + DexamethasoneLacy3,434Len refractory

88、 2 mg (1-28)32%PFS 4.7 moLacy360Len refractory4 mg (1-28)37%PFS 7.9 moLeleu584Len and Btz refractory 4 mg (1-21)35%TTP 9.2 mo4 mg (1-28)34%TTP 7.3 moLacy3,670Len and Btz refractory2 mg (1-28)26%PFS 6.5 mo4 mg (1-28)29%PFS 3.3 moRichardson7113Previous Len and Btz.refractory to last line 4 mg (1-21)34

89、%PFS 4.7 mo102双磷酸盐在双磷酸盐在MM治疗的应用治疗的应用*MRC Myeloma IXTrial DesignIntensiveClodronateCVADZoledronic acidCVADClodronateC-TDZoledronic acidC-TDMEL-200ASCTThal+ThalNon-IntensiveClodronateMPZoledronic acidMPClodronateC-TDaZoledronic acidC-TDaMaxResponseThal+ThalPrimary endpoints: PFS, OS, ResponseSecondary

90、 endpoints: SREs (time to first SRE, SRE incidence), Safety, and QoLZoledronic acid (4 mg IV q 3-4 wk); Clodronate (1,600 mg/d PO)CVAD = cyclophosphamide (500 mg PO days 1, 8, and 15), vincristine (0.4 mg/d IV days 1-4), doxorubicin (9 mg/m2/d days 1-4), dexamethasone (40 mg/d PO days 1-4, 12-15 q 3

91、 wk); C-TD = cyclophosphamide (500 mg PO days 1, 8, and 15), thalidomide (100-200 mg/d), dexamethasone (40 mg/d PO days 1-4, 12-15 q 3 wk); C-TDa = C-TD except thalidomide 50-200 mg/d, dexamethasone 20 mg/d days 1-4, 15-18 q 4 wk; MP = melphalan (7 mg/m2), prednisolone (40 mg) PO for 4 days; Thal =

92、thalidomide (50-100 mg/d); PFS = progression-free survival; PO = oral; OS = overall survival, SRE = skeletal-related event; QoL = quality of life.Morgan G, et al. ASCO 2010. Abstract 8021. ISRCTN68454111N = 1,960 中位随访中位随访3.7yRANDOMISATIONRANDOMISATIONRANDOMISATIONRANDOMISATIONTreatment continued unt

93、il disease progression104*ZOL OS and PFS vs CLOCLO = clodronate; OS = overall survival; PFS = progression-free survival; SRE = skeletal-related event; ZOL = zoledronic acid.a Time to first SRE was included as a time-dependent covariate in an exploratory Cox model examining OS.Morgan GJ, et al. ASH 2

94、010. Abstract 311. RiskReductionHazard Ratio (ZOL versus CLO)00.20.40.60.811.21.41.61.82P Value.01780.85015%In favour of ZOLIn favour of CLO (adjusted for SRE)a.01180.84216%OS (overall).017912%0.883PFS (overall) ZOL CLO PZOL CLO PmOSmOS 51m 46m .03 51m 46m .03mPFSmPFS 19m 18m .01 19m 18m .01105 唑来磷酸

95、组骨事件发生率明显减少（27% vs 35%）,PFS和OS明显延长（19.5 个月vs 17.5个月）和（50个月 vs 44.5个月）。 不同机构推荐的双磷酸盐用法不同机构推荐的双磷酸盐用法 ASCOASCO2 2年，每次使用帕米磷酸和唑来磷酸前需年，每次使用帕米磷酸和唑来磷酸前需检测血肌酐。检测血肌酐。IMWGIMWGCRCR或或VGPRVGPR后持续后持续1 1年；未达年；未达VGPRVGPR或有或有活动性骨病的持续活动性骨病的持续2 2年，年，2 2年后视病情决定年后视病情决定是否用药。是否用药。MayoMayo2 2年，年，2 2年后持续年后持续CRCR或稳定停药；如疾病或稳定停药；如疾病活动再用活动再用3 3个月。个月。NCCNNCCN推荐用于活动性推荐用于活动性MMMM，需监测肾功能及注，需监测肾功能及注意下颌骨坏死的发生。意下颌骨坏死的发生。其他常见并发症治疗其他常见并发症治疗n n疼痛n n高钙血症n n贫血n n肾功能衰竭n n骨骼破坏谢谢 谢！谢！