1、复发难治MM联合用药方案-过去与未来a Lenalidomide and/or thalidomide.BORT,bortezomib;EFS,event-free survival;OS,overall survivalKumar SK,et al.Leukemia.2012;26:149157.回回顾顾性分析：晚期性分析：晚期RRMM的的预预后后Median EFS:5 months(46)Median OS:9 months10008040200601224364860MonthsPercentage For patients(N=286)refractory to BORT and r
2、elapsed/refractory or ineligible for immunomodulatory drugsa Median OS was 12 months for patients receiving at least one treatment,and 3 months for patients receiving no treatmentAdapted from Greaves MF,Malley CC.Nature.2012;481:306-313.骨髓瘤克隆演骨髓瘤克隆演变变：治治疗对疗对复复发时发时克隆构成的影响克隆构成的影响Subclones with unique
3、genotype/”driver”mutationsEcosystem 1Single founder cell(stem or progenitor)Ecosystem 3Ecosystem 5Selective pressuresRelapseEcosystem 4PCLMMMGUSDiffuseFocalEcosystem 2EMMTreatmentGI,gastrointestinal;IV,intravenous;PS,performance status;SC,subcutaneous;VTE,venous thromboembolism.RRMM治治疗疗的考的考虑虑因素因素初始治
4、疗方案 免疫调节剂 蛋白酶体抑制剂 烷化剂 地塞米松初始治疗疗效 缓解程度 PFS患者/疾病特征 年龄，体能状况，并发症 侵袭性 vs 非侵袭性复发 难治性疾病 骨病 骨髓储备 肾功能状况 治疗相关的不良反应 (周围神经病变，VTE,胃肠道毒性)复发的评价临临床床 疾病相关疾病相关复复发发程度程度局限性局限性/侵侵袭袭性性脊椎脊椎压缩压缩性骨折性骨折髓外病髓外病变变/浆细浆细胞白血病胞白血病 患者相关患者相关体能状况体能状况 治治疗疗相关相关既往治既往治疗疗和反和反应应既往既往缓缓解持解持续时间续时间毒性毒性-血球血球计计数数-肾肾功能功能-外周神外周神经经炎炎-VTEs 淀粉淀粉样变样变性性
5、分子学分子学 细细胞胞遗传遗传学学中期分裂相中期分裂相 复复杂杂核型核型FISH-1q+,17p-局灶性局灶性损损害害活活检检 Tidal clone status相同克隆相同克隆新突新突变变-Nature-Actionable-Y/N原克隆原克隆-突突变变状状态态-Actionable-Y/N 骨髓瘤和基骨髓瘤和基质质的的GEP特征特征新药方案治疗复发/难治MM的III期临床汇总：EMA获批的方案1.Weber DM,et al.N Engl J Med.2007;357(21):2133-2142.2.Dimopoulos M,et al.N Engl J Med.2007;357(21)
6、:2123-2132.3.Richardson PG,et al.Blood.2007;110(10):3557-3560.4.Orlowski RZ,et al.J Clin Oncol.2007;25(25):3892-3901.5.Dimopoulos MA,et al.Leukemia.2009;23(11):2147-2152.RegimenTrial ORR,%CR or nCR,%VGPR,%PFS or TTPMed,mo.Med OS,monthsLen/DexMM-00916124NE 13.4385Len/Dex MM-01026025NEVelAPEX34315NE63
7、0Vel/DoxMMY-300144413279NECR,complete response;Dex,dexamethasone;Dox,pegylated liposomal doxorubicin;Len,lenalidomide;nCR,near CR;NE,not evaluable;ORR,overall response;OS,overall survival;PFS,progression-free survival;TTP,time to progression;Vel,bortezomib;VGPR,very good partial responseMM-009 and M
8、M-010:CR or VGPR achieved in 114 of 353 patients treated with Lenalidomide+DexContinuing Lenalidomide+Dex treatment results in additional late CR or VGPRHarousseau JL,et al.Haematologica.2010;95:1738-44.Patients achieving CR/VGPR 82%had PR at first evaluationPatients achieving PR as initial response
9、 50.5%achieved CR/VGPRPatients achieving PR by cycle 4 43%achieved CR/VGPRPatients achieving PR by cycle 6 38%achieved CR/VGPRPatients with CR or VGPR(%)Treatment cycle来那度胺+地塞米松持续治疗提高了缓解质量 RD 方案在RRMM患者中有效 -无论年龄和肾功能状况 -无论既往是否接受过移植或沙利度胺治疗 RD 在以下情况下使用更优：-早期，首次复发使用-持续治疗，以提高缓解质量并延长PFS和OS-肾功能不全的患者使用适合的起始剂
10、量 RD 方案安全-并没有增加SPM的发生率 RD 方案是复发/难治MM的标准治疗方案来那度胺+地塞米松在RRMM中的应用来那度胺和硼替佐米用于RRMM的三药/四药联合方案RegimenN(Evaluable)ResponsesToxicitiesVMPT13023%PR 43%CR/VGPRPNVMDT262 66%PR 40%CR/VGPRG34 myelosuppression,infections,PNVCD350 82%PRG34 myelosuppression,infections,PNVMD45334%CR/nCR G34 TCP,infections,neutropenia,
11、PNRVD562 64%PR 25%nCR/CRG3/4 myelosuppression;DVT 2 patientsG3 PN 2 patientsRCD621 14%VGPR 5%CRNeutropenia,DVT 3 patientsPAD764 25%VGPR 67%PRG34 myelosuppression,infections,GI disturbances,PNDVT,deep vein thrombosis;GI,gastrointestinal;nCR,near CR;PN,peripheral neuropathy;TCP,thrombocytopenia;VGPR,v
12、ery good PR1.Palumbo A,et al.Blood.2007;109(7):2767-2772.2.Terpos E,et al.Leukemia 2008;22(12):2247-2256.3.Kropff M,et al.B J Haematol.2007;138(3):330-337.4.Popat R,et al.Br J Haematol.2009;144(6):887-894.5.Richardson P,et al.Haematologica.2011;96(suppl 1):Abstract P-250.6.Morgan GJ,et al.Br J Haema
13、tol.2007;137(3):268-269.7.Palumbo A,et al.Ann Oncol.2008;19(6):1160-1165.复发MM的治疗路径At relapseSwitch if:Short remissionLong-term treatmentUpfront toxicitiesRetreatment if:Long remission Short upfront treatment No toxicity upfrontIntensification:Increase dose2 drug vs 3 drug based and moreNCCN guidelin
14、es.Available at:www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf.Accessed December 2010.Adapted from:Ludwig H,et al.Oncologist.2012;17:592-606.首次复发的治疗选择 Retreatment with bortezomib after frontline bortezomib only if no PN,or if patient has recovered from PN and there is no other therapeutic
15、alternativeAdapted from:Ludwig H,et al.Oncologist.2012;17:592-606.Frontline therapy successful?Repeat or change frontline treatment?Long remission No toxicity concerns from first-line treatment Short remission Toxicity concern from previous line Bortezomib-based,e.g.Bortezomib+/-Dex Bortezomib/PLD*V
16、TD VCD PADYesSwitch drug class after:Repeat treatment after:Frontline consisted ofConsider SCTPre-transplant inductionBortezomib-based regimen,e.g.VMP or VDIMiD-based regimen,e.g.CTD,MPT,RD,or Rd IMiD-based,e.g.Lenalidomide+Dex*CRD Thal/Dex CTDUse novel agentBortezomib-basedIMiD-basedInvestigational
17、 agentsNo*Data available from phase 3 randomized clinical trials.荟萃分析:硼替佐米再治疗纳入23 项研究(n=1051)荟萃分析纳入的临床研究信息 联合方案 硼替佐米 地塞米松:4 studies 硼替佐米+联合方案:19 studies 对于硼替佐米难治或非难治 11 项研究包括了硼替佐米难治患者 6 项研究未包括硼替佐米难治患者 6 项研究硼替佐米难治患者信息缺失Knopf et al.IMW 2013(Abstract P-228),poster presentation.合并的加权平均ORR、TTP和OSKnopf et
18、 al.IMW 2013(Abstract P-228),poster presentationStadtmauer EA,et al.Eur J Haematol.2009;82:426-32.来那度胺+地塞米松用于首次复发MM患者的TTP和OS更长1 prior therapy(Lenalidomide+Dex),median TTP 17.1 months 2 prior therapies(Lenalidomide+Dex),median TTP 10.6 monthsp=0.026p=0.0410255075100Patients(%)Time to progression(mont
19、hs)01020301 prior therapy(Lenalidomide+Dex),median OS 42.0 months 2 prior therapies(Lenalidomide+Dex),median OS 35.8 months0255075100Patients(%)Overall survival(months)020408060MM-009 and MM-010:pooled analysisMM-009：接受过硼替佐米治疗的来那度胺+地塞米松方案缓解率Overall response rate,%Dex(n=176)Len+Dex(n=177)pTotal popul
20、ation19.961.0 0.001Prior bortezomib10.068.4 0.001No prior bortezomib21.260.1 65 岁的老年患者岁的老年患者 (p=0.001)Kumar SK,et al.Blood.2012;120:abstract 3972.Updated data presented at ASH 2012.生存生存2001200520062010p中位中位 OS,年年4.6NR0.0011-年年 OS,%8390预预期期5-年年 OS,%总总体患者体患者4866 65 岁岁31560.001 65 岁岁6373NS0123451.00.80.60.40.20Proportion survivingFollow-up from diagnosis(years)诊断时间20062010诊断时间 20012005复发难治MM联合用药方案:过去与未来Thierry FACONProfessor of HematologyService des Maladies du SangUniversity of LilleLille,France
