多發(fā)性骨髓瘤治療新進(jìn)展來(lái)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(guó)東部腫瘤協(xié)作組(ECOG)試驗(yàn)來(lái)那度胺+高劑量地塞米松(RD)

vs來(lái)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(shí)降低毒性主要終點(diǎn):4個(gè)周期后的總體緩解率(ORR)來(lái)那度胺+地塞米松治療NDMM:

ECOG研究–試驗(yàn)設(shè)計(jì)RajkumarSV,etal.LancetOncol.2010;11:29-37.4個(gè)周期b

適合移植的患者可接受SCT繼續(xù)治療直至疾病進(jìn)展來(lái)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(lái)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(jī)對(duì)照III期研究，入組時(shí)間2004.11-2006.4ECOG,EasternCooperativeOncologyGroup;NDMM,newlydiagnosedmultiplemyeloma.來(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn)–關(guān)鍵性入選標(biāo)準(zhǔn)既往未治療過(guò)的有癥狀的多發(fā)性骨髓瘤，骨髓漿細(xì)胞增多或活檢證實(shí)的漿細(xì)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(píng)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(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn)–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(wú)%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(lái)那度胺+地塞米松治療NDMM:

ECOGE4A03試驗(yàn)–4個(gè)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(gè)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(shí)間：1個(gè)月;中位緩解持續(xù)時(shí)間：RD21.4個(gè)月vs.Rd24.1個(gè)月來(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn)–跨組后，Rd仍較RD具有顯著PFS優(yōu)勢(shì)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(gè)月后)，基于Rd的1年OS率顯著優(yōu)勢(shì)(P=0.0002)，研究終止且RD組患者跨組至Rd組無(wú)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(lái)那度胺+地塞米松治療NDMM:

ECOGE4A03試驗(yàn)–跨組前，Rd較RD具有顯著OS優(yōu)勢(shì)RajkumarSV,etal.LancetOncol.2010;11:29-37.431例在完成4個(gè)周期RD/Rd誘導(dǎo)方案后存活的患者繼續(xù)原方案治療≥4個(gè)周期(n=248)4個(gè)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(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn)–界標(biāo)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(lái)那度胺治療兩者對(duì)患者生存的影響來(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn),界標(biāo)分析–后續(xù)治療能延緩疾病進(jìn)展誘導(dǎo)后治療2年P(guān)FS3年P(guān)FS3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P(guān)FS相似接受移植的患者，RD和Rd方案的2年P(guān)FS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P(guān)FS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(dǎo)方案后接受移植的患者的3年生存率達(dá)92%Rd/RD方案是非常有效的移植前誘導(dǎo)方案來(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn),界標(biāo)分析–3年生存率4個(gè)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(gè)療程后持續(xù)治療的患者的3年生存率優(yōu)于4個(gè)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(zhǎng)的生存期4個(gè)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(gè)療程后持續(xù)治療的患者(n=248)來(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn),界標(biāo)分析–持續(xù)治療的3年生存率更高≥3級(jí)不良事件RD,n(%)(n=223)Rd,n(%)(n=220)P值血液學(xué)貧血18(8)15(7)0.72血小板減少13(6)11(5)0.83中性粒細(xì)胞減少26(12)40(20)0.02非血液學(xué)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(wú)力25(11)9(4).01總結(jié)前4個(gè)月內(nèi)任何≥3級(jí)毒性反應(yīng)117(52)76(35).0001治療期間≥3級(jí)非血液學(xué)毒性反應(yīng)146(65)106(48).0002治療期間≥4級(jí)非血液學(xué)毒性反應(yīng)46(21)18(8).0002早期死亡(前4個(gè)月)12(5)1.003導(dǎo)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(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn)–Rd方案的安全性優(yōu)于RD*研究方案最初建議但不強(qiáng)制性應(yīng)用預(yù)防性抗血栓治療，在入組266例患者后，方案修訂為強(qiáng)制性預(yù)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(gè)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(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn)–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(shí)間:1個(gè)月中位PFS:25.3個(gè)月

vs19.1個(gè)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(jí)不良事件所有:35%vs52%(P=.0001)所有非血液學(xué)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(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn)–總結(jié)

來(lái)那度胺+地塞米松治療NDMM:

ECOG試驗(yàn)–總結(jié)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(shì)并未轉(zhuǎn)化為無(wú)進(jìn)展生存期和總生存期的優(yōu)勢(shì)。RD/Rd誘導(dǎo)后自體干細(xì)胞移植的3年OS可達(dá)92%，說(shuō)明RD/Rd方案是一個(gè)很好的移植前誘導(dǎo)治療的選擇RD/Rd持續(xù)治療能進(jìn)一步延緩疾病進(jìn)展，延長(zhǎng)患者生存GIMEMA研究

來(lái)那度胺+馬法蘭+強(qiáng)的松(MPR)

VS馬法蘭200mg/m2+SCT治療NDMMMPRvs.MEL200–試驗(yàn)設(shè)計(jì)觀察28天周期直至復(fù)發(fā)來(lái)那度胺

10mg/天,

D1-21第二次隨機(jī)化2個(gè)周期#馬法蘭:200mg/m2,

D-2SCT:D06個(gè)28天周期美法侖:0.18mg/kg/天,D1-4強(qiáng)的松:2mg/kg/d天D1-4來(lái)那度胺:

10mg/天,D1-21第一次隨機(jī)化#OnecourseMEL200ifpatientsachievesVGPRaftercycle1.DoR,緩解持續(xù)時(shí)間;OS,總生存;PFS,無(wú)進(jìn)展生存期;RR,緩解率.4個(gè)28天的周期來(lái)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(lái)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(diǎn):PFS,RR,DoR患者同時(shí)隨機(jī)接受阿司匹林或LMWH作為預(yù)防性抗血栓治療PalumboA,etal.Blood.2010;116(21):1471.[abstract3573].BoccadoroM,etal.ASCO2013abs8509MPRvs.MEL200–Rd誘導(dǎo)治療緩解率可達(dá)87%來(lái)那度胺聯(lián)合低劑量地塞米松作為誘導(dǎo)治療的CR+VGPR率達(dá)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(dǎo)方案的緩解率和耐受性環(huán)磷酰胺(4g/m2)作為干細(xì)胞動(dòng)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(xì)胞量:8.7×106CD34+cells/kg作為預(yù)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(jí)不良事件,%Rd(N=402)中性粒細(xì)胞缺乏8血小板減少3感染4皮膚毒性5DVT/PE2MPRvs.MEL200:首次隨機(jī)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(gè)28-天周期M:0.18mg/Kg/d,days1-4P:2mg/Kg/d,days1-4R:10mg/d,days1-21MEL200

2個(gè)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(xué)

中性粒細(xì)胞減少4983<.001

血小板減少983<.001非血液學(xué)

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(xué)和非血液學(xué)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(fēng)險(xiǎn)比;MEL200:大劑量美法侖后續(xù)ASCT;MPR:美法侖+強(qiáng)的松+來(lái)那度胺;OS:總生存;PFS:無(wú)進(jìn)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(shí)間：49個(gè)月MPRvs.MEL200:R維持治療vs.觀察R:來(lái)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(fù)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(shí)間：35個(gè)月MPRvs.MEL200:復(fù)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(jié)論盡管移植較MPR可以延遲患者的疾病進(jìn)展，但兩者的遠(yuǎn)期生存相當(dāng)。MPR作為鞏固治療的作用與移植相當(dāng)無(wú)論鞏固方案如何，來(lái)那度胺維持治療均可以顯著降低疾病進(jìn)展風(fēng)險(xiǎn)并延長(zhǎng)患者生存來(lái)那度胺治療不會(huì)導(dǎo)致疾病侵襲性更強(qiáng)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(xiàng)比較來(lái)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(jī)化、雙盲3期臨床試驗(yàn)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(yàn)設(shè)計(jì)與研究終點(diǎn)主要終點(diǎn):至疾病進(jìn)展時(shí)間TTP(從接受ASCT起至發(fā)生疾病進(jìn)展或死亡)次要終點(diǎn):總生存OS,移植后緩解率,長(zhǎng)期來(lái)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(lái)那度胺作為誘導(dǎo)治療對(duì)患者進(jìn)行分層分析來(lái)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(lái)那度胺較安慰劑具有壓倒性優(yōu)勢(shì)，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(lái)那度胺中位隨訪時(shí)間:18個(gè)月主要分析:數(shù)據(jù)截止日期:2011年10月31日中位隨訪時(shí)間:34個(gè)月長(zhǎng)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(shí)間:48個(gè)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(lái)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(dǎo)治療,含硼替佐米/來(lái)那度胺/沙利度胺*,%42/34/4440/35/45移植后D100時(shí)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(shí)間~48個(gè)月)中位TTP:50vs.27個(gè)月(P<0.001)中位OS:NRvs.73個(gè)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(shí)間~48個(gè)月)自安慰劑跨組至LEN組的中位時(shí)間：11個(gè)月跨組時(shí)間不影響來(lái)那度胺維持治療的OS優(yōu)勢(shì)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(lái)那度胺組中3-4級(jí)血液學(xué)不良反應(yīng)的報(bào)告率高于安慰劑組(P<0.001)因不良事件導(dǎo)致治療終止的發(fā)生頻率并不高：來(lái)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(jí)血液學(xué)不良事件?,n(%)來(lái)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(xì)胞減少104(45)34(15)0.001中性粒細(xì)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(xì)胞減少16(7)4(2)0.01貧血11(5)1(<1)0.006白細(xì)胞減少27(12)8(3)0.001CALGB100104:疾病進(jìn)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(shí)間(月)血液系統(tǒng)8+1=912-ALLAMLHLMDSNHL15+1110000011001032--6-實(shí)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(xì)胞癌

鱗狀細(xì)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(shí)間~48個(gè)月)LEN組的SPM累積發(fā)生率較高(P=0.034)安慰機(jī)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(shí)間~48個(gè)月)ITT分析:至發(fā)生SPM、PD或死亡時(shí)間安慰機(jī)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(gè)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(shí)間~48個(gè)月)來(lái)那度胺誘導(dǎo)-ASCT-來(lái)那度胺維持所達(dá)到的TTP優(yōu)于其他誘導(dǎo)/維持治療組合StratificationbyPriorLENUse中位TTP(月)PBO,nopriorLEN27PBO,priorLEN28LEN,nopriorLEN46LEN,priorLENNotreachedCALGB100104:TTP-誘導(dǎo)治療是否含來(lái)那度胺