多發(fā)性骨髓瘤治療進展

多發(fā)性骨髓瘤治療新進展來那度胺在初治、鞏固及維持方案中

的臨床研究匯總多發(fā)性骨髓瘤治療策略初始治療鞏固治療維持治療挽救治療鞏固/維持/持續(xù)治療支持治療適宜移植的患者不適宜移植的患者ECOGE4A03GIMEMAFIRST(MM020)CALGB100104MM009/010/021美國東部腫瘤協(xié)作組(ECOG)試驗來那度胺+高劑量地塞米松(RD)

vs來那度胺+低劑量地塞米松(Rd)治療NDMMaBasedonthesuperiorityoftheRdregimen,thestudywasstoppedatamedianfollow-up

of12.5monthsandpatientsintheRDarmcrossedovertoRdtherapy.bEvery28days;N=445.ECOG,EasternCooperativeOncologyGroup;NDMM,newlydiagnosedmultiplemyeloma;ORR,overallresponserate;SCT,stemcelltransplant.目的:降低地塞米松劑量能否在保持有效性的同時降低毒性主要終點:4個周期后的總體緩解率(ORR)來那度胺+地塞米松治療NDMM:

ECOG研究–試驗設計RajkumarSV,etal.LancetOncol.2010;11:29-37.4個周期b

適合移植的患者可接受SCT繼續(xù)治療直至疾病進展來那度胺+高劑量地塞米松(RD)a

Len:25mg/天,第1-21天Dex:40mg/天,第1-4,9-12,17-20天

(n=223)來那度胺+低劑量地塞米松(Rd)Len:25mg/天,第1-21天Dex:40mg/天,第1,8,15,22天

(n=222)雙盲隨機對照III期研究，入組時間2004.11-2006.4ECOG,EasternCooperativeOncologyGroup;NDMM,newlydiagnosedmultiplemyeloma.來那度胺+地塞米松治療NDMM:

ECOG試驗–關鍵性入選標準既往未治療過的有癥狀的多發(fā)性骨髓瘤，骨髓漿細胞增多或活檢證實的漿細胞瘤血清單克隆蛋白>1.0g/dL和/或尿單克隆蛋白≥200mg/天ECOG體能狀態(tài)評分≤2合格的肝腎功能合格的血常規(guī)血紅蛋白

>7g/dLRajkumarSV,etal.LancetOncol.2010;11:29-37.來那度胺+地塞米松治療NDMM:

ECOG試驗–兩組間患者基線特征均衡特征RD

(n=223)Rd

(n=222)中位年齡,歲(范圍)66(36-87)65(35-85)ECOG0/1/2,%44/47/950/41/9ISS分期I/II/III33/41/2633/42/25骨病,有/無%67/3357/43血紅蛋白≤110g/l/＞110g/l,%54/4650/50血清肌酐濃度,＞15mg/l/≤15mg/l,%14/8614/86白蛋白,g/l(范圍)35(4-52)36(19-51)β2-微球蛋白,mg/l(范圍)3.8(0.8-29.7)3.5(0.6-64.4)RajkumarSV,etal.LancetOncol.2010;11:29-37.來那度胺+地塞米松治療NDMM:

ECOGE4A03試驗–4個周期后的總體緩解率RD優(yōu)于RdP=0.008P＜0.0001RajkumarSV,etal.LancetOncol.2010;11:29-37.中位隨訪35.8個月后，RD方案的最佳總緩解率(≥PR)和CR+VGPR率仍顯著優(yōu)于Rd方案(P=0.009,0.04)中位起效時間：1個月;中位緩解持續(xù)時間：RD21.4個月vs.Rd24.1個月來那度胺+地塞米松治療NDMM:

ECOG試驗–跨組后，Rd仍較RD具有顯著PFS優(yōu)勢ECOG,EasternCooperativeOncologyGroup;NDMM,newlydiagnosedmultiplemyeloma;Rd,lenalidomide,low-dosedexamethasone;RD,lenalidomide,high-dosedexamethasone.RajkumarSV,etal.LancetOncol.2010;11:29-37.2007年3月(中位隨訪12.5個月后)，基于Rd的1年OS率顯著優(yōu)勢(P=0.0002)，研究終止且RD組患者跨組至Rd組無論患者年齡大小，Rd組患者的1年生存率顯著優(yōu)于RD組<65歲：98%vs91%;P=.01≥65歲：94%vs83%;P=.004來那度胺+地塞米松治療NDMM:

ECOGE4A03試驗–跨組前，Rd較RD具有顯著OS優(yōu)勢RajkumarSV,etal.LancetOncol.2010;11:29-37.431例在完成4個周期RD/Rd誘導方案后存活的患者繼續(xù)原方案治療≥4個周期(n=248)4個周期后退出治療(n=183)移植(n=90)中位年齡:57歲未接受移植(n=93)中位年齡:69歲RD(n=108)

中位年齡:65歲Rd(n=140)中位年齡:66歲來那度胺+地塞米松治療NDMM:

ECOG試驗–界標分析ECOG,EasternCooperativeOncologyGroup;NDMM,newlydiagnosedmultiplemyeloma;Rd,lenalidomide,low-dosedexamethasone;RD,lenalidomide,high-dosedexamethasone;SCT,stemcelltransplant.RajkumarSV,etal.LancetOncol.2010;11:29-37.目的:比較移植和持續(xù)來那度胺治療兩者對患者生存的影響來那度胺+地塞米松治療NDMM:

ECOG試驗,界標分析–后續(xù)治療能延緩疾病進展誘導后治療2年PFS3年PFS3年OS退出研究(n=93)25%NR55%SCT(n=90)63%-65%NR92%持續(xù)治療(n=248)RD(n=108)Rd(n=140)NRNRNRNR46%50%79%NRNR持續(xù)接受RD和Rd方案的患者的3年PFS相似接受移植的患者，RD和Rd方案的2年PFS相似(63%vs.65%)退出研究但未接受移植的患者，RD和Rd方案的2年PFS均僅有25%aStudywashaltedatamedianfollow-upof12.5months,whenpatientscrossedoverfromRDtoRd.ECOG,EasternCooperativeOncologyGroup;NDMM,newlydiagnosedmultiplemyeloma;

NR,notreported;OS,overallsurvival;PFS,progression-freesurvival;Rd,lenalidomide,low-dosedexamethasone;RD,lenalidomide,high-dosedexamethasone,SCT,stemcelltransplant.RajkumarSV,etal.LancetOncol.2010;11:29-37.aOverallsurvivaldidnotdifferbetweenpatientswhoreceivedRDandRdinductiontherapy.ECOG,EasternCooperativeOncologyGroup;Len+Dex,lenalidomide,dexamethasone;

NDMM,newlydiagnosedmultiplemyeloma;SCT,stemcelltransplant.1.RajkumarSV,etal.LancetOncol.2010;11:29-37.2.HarousseauJL,etal.JClinOncol2010;28:4621-29.3.CavoM,etal.Lancet2010;376:2075–2085.Len+Dex誘導方案后接受移植的患者的3年生存率達92%Rd/RD方案是非常有效的移植前誘導方案來那度胺+地塞米松治療NDMM:

ECOG試驗,界標分析–3年生存率4個療程后接受SCT的患者(n=90)Ref方案病例數(shù)3年-OSHarousseau2VDvs.VAD240vs.24281%vs.77%Cavo3VTDvs.TD236vs.23886%vs.84%Rajkumar1Rdvs.RD222vs.22392%4個療程后持續(xù)治療的患者的3年生存率優(yōu)于4個療程后終止治療的患者，分別為79%vs.55%持續(xù)Len+Dex方案治療可獲得更長的生存期4個療程后退出研究的患者(n=93)aOverallsurvivaldidnotdifferbetweenpatientswhoreceivedRDandRdinductiontherapy.ECOG,EasternCooperativeOncologyGroup;Len+Dex,lenalidomide,dexamethasone;

NDMM,newlydiagnosedmultiplemyeloma;SCT,stemcelltransplant.RajkumarSV,etal.LancetOncol.2010;11:29-37.4個療程后持續(xù)治療的患者(n=248)來那度胺+地塞米松治療NDMM:

ECOG試驗,界標分析–持續(xù)治療的3年生存率更高≥3級不良事件RD,n(%)(n=223)Rd,n(%)(n=220)P值血液學貧血18(8)15(7)0.72血小板減少13(6)11(5)0.83中性粒細胞減少26(12)40(20)0.02非血液學深靜脈血栓/肺栓塞*57(26)27(12).0003感染/肺炎35(16)20(9).04高血糖25(11)14(6).09乏力33(15)20(9).08神經(jīng)病變5(2)4(2).1非神經(jīng)源性無力25(11)9(4).01總結前4個月內(nèi)任何≥3級毒性反應117(52)76(35).0001治療期間≥3級非血液學毒性反應146(65)106(48).0002治療期間≥4級非血液學毒性反應46(21)18(8).0002早期死亡(前4個月)12(5)1.003導致治療終止的AE56(27)37(19)DVT,deepveinthrombosis;ECOG,EasternCooperativeOncologyGroup;

NDMM,newlydiagnosedmultiplemyeloma;PE,pulmonaryembolism;

Rd,lenalidomide,low-dosedexamethasone;RD,lenalidomide,high-dosedexamethasone.RajkumarSV,etal.LancetOncol.2010;11:29-37.來那度胺+地塞米松治療NDMM:

ECOG試驗–Rd方案的安全性優(yōu)于RD*研究方案最初建議但不強制性應用預防性抗血栓治療，在入組266例患者后，方案修訂為強制性預防性抗血栓治療變量RD,%(n=223)Rd,%(n=220)a第1-4周期209總體2612bRD組中發(fā)生深靜脈血栓或肺栓塞(DVT/PE)的患者人數(shù)顯著多于Rd組靜脈血栓栓塞(VTE)事件主要發(fā)生在前4個治療周期RajkumarSV,etal.LancetOncol.2010;11:29-37.aDataunavailablefor2patientsb

P=.0003.

DVT,deepveinthrombosis;ECOG,EasternCooperativeOncologyGroup;NDMM,newlydiagnosedmultiplemyeloma;PE,pulmonaryembolism;Rd,lenalidomide,low-dosedexamethasone;RD,lenalidomide,high-dosedexamethasone;VTE,venousthromboembolism.來那度胺+地塞米松治療NDMM:

ECOG試驗–深靜脈血栓+肺栓塞的發(fā)生率

有效性(RdvsRD)總緩解率(ORR):70%vs81%(P=.009)≥VGPR率:40%vs50%;P=.040中位起效時間:1個月中位PFS:25.3個月

vs19.1個月(P=.026)1年OS:96%vs87%(P=.0002)<65歲:98%vs91%(P=.01)≥65歲:94%vs83%(P=.004)安全性

(RdvsRD)≥3級不良事件所有:35%vs52%(P=.0001)所有非血液學不良事件:48%vs65%(P=.0002)深靜脈血栓或肺栓塞(DVT/PE):12%vs26%(P=.0003)DVT,deepveinthrombosis;ECOG,EasternCooperativeOncologyGroup;NDMM,newlydiagnosedmultiplemyeloma;ORR,overallresponserate;OS,overallsurvival;PE,pulmonaryembolism;PFS,progression-freesurvival;Rd,lenalidomide,low-dosedexamethasone;RD,lenalidomide,high-dosedexamethasone;VGPR,verygoodpartialresponse;VTE,venousthromboembolism.RajkumarSV,etal.LancetOncol.2010;11:29-37.來那度胺+地塞米松治療NDMM:

ECOG試驗–總結

來那度胺+地塞米松治療NDMM:

ECOG試驗–總結盡管RD方案具有較高的緩解率，但由于其較大的毒性和較高的早期死亡率，緩解率的優(yōu)勢并未轉化為無進展生存期和總生存期的優(yōu)勢。RD/Rd誘導后自體干細胞移植的3年OS可達92%，說明RD/Rd方案是一個很好的移植前誘導治療的選擇RD/Rd持續(xù)治療能進一步延緩疾病進展，延長患者生存GIMEMA研究

來那度胺+馬法蘭+強的松(MPR)

VS馬法蘭200mg/m2+SCT治療NDMMMPRvs.MEL200–試驗設計觀察28天周期直至復發(fā)來那度胺

10mg/天,

D1-21第二次隨機化2個周期#馬法蘭:200mg/m2,

D-2SCT:D06個28天周期美法侖:0.18mg/kg/天,D1-4強的松:2mg/kg/d天D1-4來那度胺:

10mg/天,D1-21第一次隨機化#OnecourseMEL200ifpatientsachievesVGPRaftercycle1.DoR,緩解持續(xù)時間;OS,總生存;PFS,無進展生存期;RR,緩解率.4個28天的周期來那度胺:25mg/天,D1-D21

地塞米松:40mg/天,D1,D8,D15,D222007年11月-2009年7月,共納入來自62家中心的402例患者(＜65歲,適宜移植的新診斷多發(fā)性骨髓瘤患者)主要研究終點:PFS,RR,DoR患者同時隨機接受阿司匹林或LMWH作為預防性抗血栓治療PalumboA,etal.Blood.2010;116(21):1471.[abstract3573].BoccadoroM,etal.ASCO2013abs8509MPRvs.MEL200–Rd誘導治療緩解率可達87%來那度胺聯(lián)合低劑量地塞米松作為誘導治療的CR+VGPR率達52%CR,completeresponse;MEL200,melphalan200mg/m2withstemcellsupport;MPR,melphalan,prednisone,lenalidomide;NDMM,newlydiagnosedmultiplemyeloma;PD,progressivedisease;PR,partialresponse;Rd,lenalidomide,low-dosedexamethasone;SD,stabledisease;VGPR,verygoodpartialresponse.PalumboA,etal.Blood.2010;116(21):1471.[abstract3573].Rd誘導方案的緩解率和耐受性環(huán)磷酰胺(4g/m2)作為干細胞動員方案的成功率高(n=331)91%的患者成功采集≥4×106CD34+cells/kg中位采集干細胞量:8.7×106CD34+cells/kg作為預防性抗血栓治療，LMWH和阿司匹林分別有1.3%和2.3%的VTE發(fā)生率AE,adverseevent;CR,completeresponse;CY,cyclophosphamide;DVT,deepveinthrombosis;LMWH,lowmolecularweightheparin;ORR,overallresponserate;PE,pulmonaryembolism;PR,partialresponse;Rd,lenalidomide,low-dosedexamethasone;VGPR,verygoodpartialresponse;VTE,venousthromboembolism.BoccadoroM,etal.JClinOncol.2011;29(15s):abstract8020[posterpresentation].?級不良事件,%Rd(N=402)中性粒細胞缺乏8血小板減少3感染4皮膚毒性5DVT/PE2MPRvs.MEL200:首次隨機化M:melphalan;P,prednisone;R:lenalidomide;MEL200:melphalan200mg/m2.BoccadoroM,etal.Melphalan/prednisone/lenalidomide(MPR)versushigh-dosemelphalanandautologoustransplantation(MEL200)pluslenalidomidemaintenanceornomaintenanceinnewlydiagnosedmultiplemyeloma(MM)patients.Oralpresentedat:AmericanSocietyofClinicalOncology.2013;May31-June4;Chicago,Illinois.MPR6個28-天周期M:0.18mg/Kg/d,days1-4P:2mg/Kg/d,days1-4R:10mg/d,days1-21MEL200

2個周期M:200mg/m2day-2Stemcellsupportday0RANDOMIZATION1°MPRvs.MEL200:兩組間患者基線特征均衡Del:deletion;ISS:InternationalStagingSystem;MEL200:high-dosemelphalanandASCT;MPR:melphalan,prednisone,lenalidomide;NA:notavailable;

t:translocation.BoccadoroM,etal.Melphalan/prednisone/lenalidomide(MPR)versushigh-dosemelphalanandautologoustransplantation(MEL200)pluslenalidomidemaintenanceornomaintenanceinnewlydiagnosedmultiplemyeloma(MM)patients.Oralpresentedat:AmericanSocietyofClinicalOncology.2013;May31-June4;Chicago,Illinois.MPR

(N=202)MEL200

(N=200)中位年齡(歲)5858ISS分期I40%47%II37%29%III23%24%染色體異常t(4;14)16%13%t(14;16)6%4%del1717%13%NA25%31%CR,completeresponse;MEL200,melphalan200mg/m2withstemcellsupport;MPR,melphalan,prednisone,lenalidomide;NDMM,newlydiagnosedmultiplemyeloma;OS,overallsurvival;PD,progressivedisease;PFS,progression-freesurvival;PR,partialresponse;SD,stabledisease;VGPR,verygoodpartialresponse.MPRvs.MEL200：兩組間緩解率和緩解水平相近PalumboA,etal.Blood.2010;116(21):1471.[abstract3573].不良事件,%MPR

(n=117)MEL200

(n=122)P值血液學

中性粒細胞減少4983<.001

血小板減少983<.001非血液學

全身性118<.001

感染018<.001

胃腸道021<.001因AE中斷治療24NSAE,adverseevent;MEL200,melphalan200mg/m2withstemcellsupport;

MPR,melphalan,prednisone,lenalidomide;NDSMM,newlydiagnosedmultiple

myeloma;NS,notsignificant.接受MPR鞏固治療的患者血液學和非血液學毒性均較低PalumboA,etal.Blood.2010;116(21):1471.[abstract3573].MPRvs.MEL200–鞏固治療安全性MPRvs.MEL200:PFS&OS(update);HR:風險比;MEL200:大劑量美法侖后續(xù)ASCT;MPR:美法侖+強的松+來那度胺;OS:總生存;PFS:無進展生存期.BoccadoroM,etal.Melphalan/prednisone/lenalidomide(MPR)versushigh-dosemelphalanandautologoustransplantation(MEL200)pluslenalidomidemaintenanceornomaintenanceinnewlydiagnosedmultiplemyeloma(MM)patients.Oralpresentedat:AmericanSocietyofClinicalOncology.2013;May31-June4;Chicago,Illinois.中位隨訪時間：49個月MPRvs.MEL200:R維持治療vs.觀察R:來那度胺.BoccadoroM,etal.Melphalan/prednisone/lenalidomide(MPR)versushigh-dosemelphalanandautologoustransplantation(MEL200)pluslenalidomidemaintenanceornomaintenanceinnewlydiagnosedmultiplemyeloma(MM)patients.Oralpresentedat:AmericanSocietyofClinicalOncology.2013;May31-June4;Chicago,Illinois.RANDOMIZATION2°觀察維持治療28-天周期直至復發(fā)R:10mg/day,days1-21MPRvs.MEL200:患者基線特征Del:deletion;ISS:InternationalStagingSystem;Maint:maintenance;NA:notavailable;

R:lenalidomide;t:translocation.BoccadoroM,etal.Melphalan/prednisone/lenalidomide(MPR)versushigh-dosemelphalanandautologoustransplantation(MEL200)pluslenalidomidemaintenanceornomaintenanceinnewlydiagnosedmultiplemyeloma(MM)patients.Oralpresentedat:AmericanSocietyofClinicalOncology.2013;May31-June4;Chicago,Illinois.R維持

(N=198)觀察

(N=204)中位年齡(歲)5758ISS分期I49%46%II27%30%III34%24%染色體異常t(4;14)11%10%t(14;16)4%3%del178%13%NA26%29%MPRvs.MEL200:R維持治療vs.觀察CI:confidenceinterval;HR:hazardratio;Maint:maintenance;OS:overallsurvival;PFS:progression-freesurvival;R:lenalidomide.BoccadoroM,etal.Melphalan/prednisone/lenalidomide(MPR)versushigh-dosemelphalanandautologoustransplantation(MEL200)pluslenalidomidemaintenanceornomaintenanceinnewlydiagnosedmultiplemyeloma(MM)patients.Oralpresentedat:AmericanSocietyofClinicalOncology.2013;May31-June4;Chicago,Illinois.中位隨訪時間：35個月MPRvs.MEL200:復發(fā)后OSCI:confidenceinterval;HR:hazardratio;Maint:maintenance;MEL200:high-dosemelphalanandautologousstemcelltransplant;MPR:melphalan,prednisone,lenalidomide;R:lenalidomide.BoccadoroM,etal.Melphalan/prednisone/lenalidomide(MPR)versushigh-dosemelphalanandautologoustransplantation(MEL200)pluslenalidomidemaintenanceornomaintenanceinnewlydiagnosedmultiplemyeloma(MM)patients.Oralpresentedat:AmericanSocietyofClinicalOncology.2013;May31-June4;Chicago,Illinois.MPRvs.MEL200:維持治療安全性DVT:deepvenousthrombosis;SPMs:secondprimarymalignancies.BoccadoroM,etal.Melphalan/prednisone/lenalidomide(MPR)versushigh-dosemelphalanandautologoustransplantation(MEL200)pluslenalidomidemaintenanceornomaintenanceinnewlydiagnosedmultiplemyeloma(MM)patients.Oralpresentedat:AmericanSocietyofClinicalOncology.2013;May31-June4;Chicago,Illinois.MPRvs.MEL200:結論盡管移植較MPR可以延遲患者的疾病進展，但兩者的遠期生存相當。MPR作為鞏固治療的作用與移植相當無論鞏固方案如何，來那度胺維持治療均可以顯著降低疾病進展風險并延長患者生存來那度胺治療不會導致疾病侵襲性更強Maint:maintenance;MEL200:high-dosemelphalanandautologousstemcelltransplant;MPR:melphalan,prednisone,lenalidomide;OS:overallsurvival;

PFS:progression-freesurvival;R:lenalidomide.BoccadoroM,etal.Melphalan/prednisone/lenalidomide(MPR)versushigh-dosemelphalanandautologoustransplantation(MEL200)pluslenalidomidemaintenanceornomaintenanceinnewlydiagnosedmultiplemyeloma(MM)patients.Oralpresentedat:AmericanSocietyofClinicalOncology.2013;May31-June4;Chicago,Illinois.CALGB100104:

一項比較來那度胺與安慰劑作為多發(fā)性骨髓瘤患者ASCT后維持治療的隨機化、雙盲3期臨床試驗McCarthyP.,etalMcCarthyPL.NEnglJMed.2012;366:1770-1781.CALGB100104:參與研究單位CelgeneCorp.DataonFile.全美范圍內(nèi)，研究共納入460例患者R1:1CR,PR,

MR,SDCALGB100104:試驗設計與研究終點主要終點:至疾病進展時間TTP(從接受ASCT起至發(fā)生疾病進展或死亡)次要終點:總生存OS,移植后緩解率,長期來那度胺治療的可行性*Allpatientsreceivedthromboprophylaxis;?

LENdoseadjustmentsbetween5-15mgpermitted.ASCT:autologousstemcelltransplant;β2-M:β2-microglobulin;CALGB:CancerandLeukemiaGroupB;CR:completeresponse;LEN:lenalidomide;MEL200:melphalan200mg/m2;MR:minimalresponse;OS:overallsurvival;PD:progressivedisease;PR:partialresponse;R:randomization;SD:stabledisease;THAL:thalidomide;TTP:timetoprogression;Tx:treatment.McCarthyPL.NEnglJMed.2012;366:1770-1781.安慰劑(n=229)MEL200ASCTN=460年齡≤70歲距離首次治療≤1年根據(jù)β2-M水平、是否接受沙利度胺和來那度胺作為誘導治療對患者進行分層分析來那度胺

10mg/天?(n=231)維持治療*再分期

(≤100天)CALGB100104:隨訪和交叉初步分析:數(shù)據(jù)截止日期:2009年12月17日鑒于來那度胺較安慰劑具有壓倒性優(yōu)勢，研究揭盲128例符合要求的安慰劑組患者中86例(67%)患者交叉跨組接受來那度胺中位隨訪時間:18個月主要分析:數(shù)據(jù)截止日期:2011年10月31日中位隨訪時間:34個月長期隨訪后分析:數(shù)據(jù)截止日期:2011年10月31日中位隨訪時間:48個月CALGB:CancerandLeukemiaGroupB;LEN:lenalidomide.CALGB100104:患者特征組間患者特征均衡*Ptscouldhavereceivedinductiontherapiescontainingacombinationoftheseagents.ASCT:autologousstemcelltransplant;β2-M:β2-microglobulin;BORT:bortezomib;ISS:InternationalStagingSystem;LEN:lenalidomide;

THAL:thalidomide.McCarthyPL.NEnglJMed.2012;366:1770-1781.特征來那度胺

(n=231)安慰劑

(n=229)中位年齡,歲(范圍)59(29-71)58(40-71)男性,%5256β2-M≤2.5mg/L/>2.5mg/L/缺失,%74/22/571/24/5ISS分期I/II/III/missing,%77/5/2/1774/7/1/17誘導治療,含硼替佐米/來那度胺/沙利度胺*,%42/34/4440/35/45移植后D100時的療效,n(%)完全緩解CR67(29)79(34)部分緩解PR115(50)109(48)微小緩解MR11(5)5(2)疾病穩(wěn)定SD38(16)32(14)CALGB100104:UpdatedTTP&OS(ITT)數(shù)據(jù)截止日期:2013年1月7日(中位自移植后隨訪時間~48個月)中位TTP:50vs.27個月(P<0.001)中位OS:NRvs.73個月(P=0.008)AHCT:autologoushematopoieticstemcelltransplant;CI:confidenceinterval;HR:hazardratio;ITT:intent-to-treat;NR:notreached;OS:overallsurvival;TTP:timetoprogression.McCarthyP,OwzarK,HofmeisterC,etal.Secondprimarymalignancies,progressionandoverallsurvivalduringlenalidomidemaintenancetherapyformultiplemyelomapatients.Adaptedfromtheoralpresentationat:14thInternationalMyelomaWorkshop.2013;April3-7;Kyoto,Japan.CALGB100104:UpdatedOSWithCrossover數(shù)據(jù)截止日期:2013年1月7日(中位自移植后隨訪時間~48個月)自安慰劑跨組至LEN組的中位時間：11個月跨組時間不影響來那度胺維持治療的OS優(yōu)勢AHCT:autologoushematopoieticstemcelltransplant;CI:confidenceinterval;HR:hazardratio;LEN:lenalidomide;OS:overallsurvival;PBO:placebo;ppt:patient.McCarthyP,OwzarK,HofmeisterC,etal.Secondprimarymalignancies,progressionandoverallsurvivalduringlenalidomidemaintenancetherapyformultiplemyelomapatients.Adaptedfromtheoralpresentationat:14thInternationalMyelomaWorkshop.2013;April3-7;Kyoto,Japan.來那度胺組中3-4級血液學不良反應的報告率高于安慰劑組(P<0.001)因不良事件導致治療終止的發(fā)生頻率并不高：來那度胺組合安慰劑組分別為10%和1%CALGB100104:不良事件**ThroughFeb2012.?

Occurringin5timesmoreineitherstudygroup.AE:adverseevent;CALGB:CancerandLeukemiaGroupB;GR:grade;LEN:lenalidomide;PBO:placebo.McCarthyPL.NEnglJMed.2012;366:1770-1781.3-4級血液學不良事件?,n(%)來那度胺

(n=231)安慰劑(n=229)P值任何事件110(48)39(17)<0.001中性粒細胞減少104(45)34(15)0.001中性粒細胞減少性發(fā)熱13(6)3(1)0.019血小板減少32(14)11(5)0.001淋巴細胞減少16(7)4(2)0.01貧血11(5)1(<1)0.006白細胞減少27(12)8(3)0.001CALGB100104:疾病進展前的SPM(Updated)ALL:acutelymphocyticleukemia;AML:acutemyeloidleukemia;GI:gastrointestinal;HL:Hodgkinlymphoma;LEN:lenalidomide;MDS:myelodysplasticsyndrome;NHL:non-Hodgkinlymphoma;PBO:placebo;PD:progressivedisease;SC:skincancer;SPM:secondprimarymalignancy.McCarthyP,OwzarK,HofmeisterC,etal.Secondprimarymalignancies,progressionandoverallsurvivalduringlenalidomidemaintenancetherapyformultiplemyelomapatients.Adaptedfromtheoralpresentationat:14thInternationalMyelomaWorkshop.2013;April3-7;Kyoto,Japan.數(shù)據(jù)截止日期:2013年1月7日;SPMLENPBOPBO跨組至LEN跨組至LEN的時間(月)血液系統(tǒng)8+1=912-ALLAMLHLMDSNHL15+1110000011001032--6-實體瘤1051乳腺癌類癌腦癌消化道腫瘤婦科黑色素瘤前列腺甲狀腺癌腎癌301211110010112000000000001--------14非侵襲性皮膚癌4+3=731基底細胞癌

鱗狀細胞癌2+321201-4CALGB100104:SPM,PD,Death的累積發(fā)生率(Updated)AHCT:autologoushematopoieticstemcelltransplant;LEN:lenalidomide;PBO:placebo;PD:progressivedisease;SPM:secondprimarymalignancy.McCarthyP,OwzarK,HofmeisterC,etal.Secondprimarymalignancies,progressionandoverallsurvivalduringlenalidomidemaintenancetherapyformultiplemyelomapatients.Adaptedfromtheoralpresentationat:14thInternationalMyelomaWorkshop.2013;April3-7;Kyoto,Japan.數(shù)據(jù)截止日期:2013年1月7日(中位自移植后隨訪時間~48個月)LEN組的SPM累積發(fā)生率較高(P=0.034)安慰機組PD(P=0.004)和死亡(P<0.001)的累積發(fā)生率較高CALGB100104:EFS–UpdatedAHCT:autologousstemcelltransplant;CI:confidenceinterval;EFS:event-freesurvival;HR:hazardratio;ITT:intent-to-treat;LEN:lenalidomide;PBO:placebo;pts:patients;SPM:secondprimarymalignancy.McCarthyP,OwzarK,HofmeisterC,etal.Secondprimarymalignancies,progressionandoverallsurvivalduringlenalidomidemaintenancetherapyformultiplemyelomapatients.Adaptedfromtheoralpresentationat:14thInternationalMyelomaWorkshop.2013;April3-7;Kyoto,Japan.數(shù)據(jù)截止日期:2013年1月7日(中位自移植后隨訪時間~48個月)ITT分析:至發(fā)生SPM、PD或死亡時間安慰機組和LEN組分別有66%(151/229)和49%(113/231)的患者發(fā)生事件中位EFS:27vs.47個月(P<0.001)ProbabilityTimesinceAHCT(months)AHCT:autologoushematopoieticstemcelltransplant;LEN:lenalidomide;PBO:placebo;TTP:timetoprogression.McCarthyP,OwzarK,HofmeisterC,etal.Secondprimarymalignancies,progressionandoverallsurvivalduringlenalidomidemaintenancetherapyformultiplemyelomapatients.Adaptedfromtheoralpresentationat:14thInternationalMyelomaWorkshop.2013;April3-7;Kyoto,Japan.數(shù)據(jù)截止日期:2013年1月7日(中位自移植后隨訪時間~48個月)來那度胺誘導-ASCT-來那度胺維持所達到的TTP優(yōu)于其他誘導/維持治療組合StratificationbyPriorLENUse中位TTP(月)PBO,nopriorLEN27PBO,priorLEN28LEN,nopriorLEN46LEN,priorLENNotreachedCALGB100104:TTP-誘導治療是否含來那度胺