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AdditionofIxazomibtoLenalidomide/DexamethasoneImprovesProgression-FreeSurvivalinRelapsed/RefractoryMultipleMyeloma

Moreauetalfoundthataddingtheoralproteasomeinhibitorixazomib(Ninlaro)tolenalidomide(Revlimid)anddexamethasonesignificantlyprolongedprogression-freesurvivalamongpatientswithrelapsed,refractory,orrelapsedandrefractorymultiplemyeloma.TheyreportedthefindingsfromthephaseIIITOURMALINE-MM1trialinTheNewEnglandJournalofMedicine.ThetrialsupportedtherecentU.S.FoodandDrugAdmiNISTration(FDA)approvalofixazomibinpreviouslytreatedmultiplemyeloma,makingitthefirstapprovedoralproteasomeinhibitor.

StudyDetails

Inthedouble-blindtrial,722patientsfrom147sitesin26countrieswererandomizedbetweenAugust2012andMay272014toreceiveixazomib(n=360)orplacebo(n=362)pluslenalidomideanddexamethasone.Treatmentconsistedof28-daycyclesoforalixazomibat4mgorplaceboondays1,8,and15;orallenalidomideat25mgondays1through21(10mginthosewithcreatinineclearance≤60or≤50mL/min/1.73m2accordingtolocalprescribinginformation);andoraldexamethasoneat40mgondays1,8,15,and22.Theprimaryendpointwasprogression-freesurvival.

Fortheixazomibvsplacebogroups,medianagewas66yearsinboth(53%vs51%>65years);58%vs56%weremale;86%vs83%werewhite;EasternCooperativeOncologyGroupperformancestatuswas0or1in95%vs93%;InternationalStagingSystem(ISS)stagewasIin63%vs64%,IIin25%vs24%,andIIIin12%inboth;78%vs72%hadcreatinineclearance≥60mL/min/1.73m2;55%vs60%hadstandard-and21%vs17%hadhigh-riskcytogenetics;numberofpriortherapieswas1in62%vs60%,2in27%vs31%,and3in11%vs9%;59%vs55%hadpriorstemcelltransplantation;diseasecategorywasrelapsedin77%inboth,refractoryin12%vs11%,relapsedandrefractoryin11%vs12%,andprimaryrefractoryin7%vs6%;priorproteasomeinhibitortherapywasbortezomib(Velcade)in69%inbothandcarfilzomib(Kyprolis)in<1%vs1%,with1%vs2%ofpatientshavingdiseaserefractorytopriortreatment;andpriorimmunomodulatorytherapywaslenalidomidein54%vs56%andthalidomide(Thalomid)in44%vs47%,with21%vs25%havingdiseaserefractorytopriortherapy.

ImprovedProgression-FreeSurvival

Aftermedianfollow-upof14.7months,medianprogression-freesurvivalwas20.6monthsintheixazomibgroupvs14.7monthsintheplacebogroup(hazardratio[HR]=0.74,P=.01).Benefitofixazomibwasconsistentacrossprespecifiedsubgroups,includingpoor-prognosissubgroupssuchasthosewithhigh-riskcytogenetics(24.1vs9.7months,HR=0.54),ISSstageIIIdisease(18.4vs10.1months,HR=0.72),thoseaged>75years(18.5vs13.1months,HR=0.87),andthosewhohadreceivedtwo(17.5vs14.1months,HR=0.75)orthree(notestimablevs10.2months,HR=0.37)priortherapies.

Overallresponserateswere78%vs72%,withtheratesofcompleteresponseplusverygoodpartialresponseof48%vs39%.Mediantimetoresponsewas1.1vs1.9months.Mediandurationofresponsewas20.5vs15.0months.Atmedianfollow-upofapproximately23months,medianoverallsurvivalhadnotbeenreachedineithergroup.

AdverseEvents

Adverseeventsof≥grade3occurredin74%oftheixazomibgroupvs69%oftheplacebogroup,withthemostcommonintheixazomibgroupbeingneutropenia(23%vs24%)andthrombocytopenia(19%vs9%).Rashofanygradewasmorecommonintheixazomibgroup(36%vs23%),asweregastrointestinaladverseevents(mostlylowgrade);22%ofixazomibpatientsand19%ofplacebopatientsreceivedantidiarrhealagents,and21%and13%receivedantiemeticdrugs.Peripheralneuropathyofanygradeoccurredin27%vs22%(grade3in2%ineach).

Seriousadverseeventsoccurredin47%vs49%.Adverseeventsledtodosereductionofanydrugin56%vs50%,discontinuationofanydrugin25%vs20%,anddiscontinuationofthestudyregimenin17%vs14%.Deathoccurredduringthestudyperiodin4%vs6%.

Theinvestigatorsconcluded:“Theadditionofixazomibtoaregimenoflenalidomideanddexamethasonewasassociatedwithsignificantlylongerprogression-freesurvival;theadditionaltoxiceffectswiththisall-oralregimenwerelimited.”