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Dott.ssa Giulia Rivoli Ospedale Policlinico S. Martino Università di Genova MGUS E MIELOMA MULTIPLO: UPDATE DIAGNOSTICO- TERAPEUTICO
Dott.ssa Giulia Rivoli
Ospedale Policlinico S. Martino Università di Genova
MGUS E MIELOMA MULTIPLO: UPDATE DIAGNOSTICO-
TERAPEUTICO
MGUS MIELOMASMOLDERING MIELOMASINTOMATICOComponentemonoclonalesierica<3g/dl(30g/L)
Componentemonoclonalesierica≥3g/dl(30g/L)
Componentemonoclonalesierica/urinariadiqualsiasientità
Infiltratoplasmacellularemidollare<10%
Infiltratoplasmacellularemidollare≥10%
Infiltratoplasmacellularemidollare/plasmocitomaassociatoaSintomid’organo(CRAB:hyperCalcemia,Renalfailure,Anemia,Boneinvolvement)
Nosintomid’organo(CRAB+nuovicriteri)
Nosintomid’organo(CRAB+nuovicriteri)
Infiltratomidollare≥60%
sFLC(catenacoinvolta/noncoinvolta)ratio>100(selivellosiericocatenacoinvolta>100mg/L)
1opiùlesionifocalididimensione>5mmallaRMN
CRITERIDIAGNOSTICIMGUS/MM
IMWG updated criteria for the diagnosis of multiple myeloma; Rajkumar et al, Lancet 2014
CRITERISTRATIFICAZIONEPROGNOSTICASMM(MAYOCLINIC2018)
FATTORIDIRISCHIO
INFILTRATOPCMIDOLLARE(BMPC>20%)
ENTITA’DELLACM(>2g/dL)
ALTERAZIONEDELRAPPORTOκ/λ(FLCratio>20)
• Nessunfattore:lowrisk• 1fattore:intermediaterisk• ≥2fattori:highrisk
Lakshmanetal,BloodCancerJournal(2018)8:59;DOI10.1038/s41408-018-0077.4
EstimatedmedianTTP:• Low-risk109.8months• Intermediate-risk67.8months• Highrisk29.2months(p < 0.0001)
FIG5.Kaplan-Meierestimatesofprogression-freesurvivalbytreatmentarmwithinMayo2018risksubgroup:(A)highrisk,(B)intermediaterisk,and(C)lowrisk.
Publishedin:SagarLonial;SusannaJacobus;RafaelFonseca;MatthiasWeiss;ShajiKumar;RobertZ.Orlowski;JonathanL.Kaufman;AbdulraheemM.Yacoub;FrancisK.Buadi;TimothyO’Brien;JeffreyV.Matous;DanielM.Anderson;RobertV.Emmons;AnujMahindra;LynneI.Wagner;MadhavV.Dhodapkar;S.VincentRajkumar;JournalofClinicalOncologyAheadofPrintDOI:10.1200/JCO.19.01740Copyright©2019AmericanSocietyofClinicalOncology
LENALIDOMIDEVSOBSERVATIONINSMOLDERINGMM
• 182pazienticondiagnosidiintermediate/highriskSMMentroiprecedenti60mesi
• Esclusipazienticoncriterislim-CRAB
• Earlytherapyperhigh-riskSMM,definiticoncriteriMayo2018
IMWGCONSENSUSRECOMMENDATIONSONIMAGINGINMONOCLONALPLASMACELLDISORDERS
IMWGconsensusrecommendationsonimaginginmonoclonalplasmacelldisorders;LancetOncol2019;20:e302-12
MGUSHighrisk(Mayocriteria)non
Ig-MMGUS:• WholebodyTC(WBCT)SeWBCTnondisponibile:
• RXscheletroconvenzionale• RMN(wholebodyoppure
colonnaebacino)
Nonraccomandatofollow-upperiodico
SMOLDERINGMM• NONraccomandatarxscheletroconvenzionale• WBCTprimascelta
• SenegativaRMN(wholebodyoppurecolonnae
bacino)• PET/TCutilizzabileseRMN
nondisponibile/fattibileFollow-upannualeperalmeno
5anni
IMWGCONSENSUSRECOMMENDATIONSONIMAGINGINMONOCLONALPLASMACELLDISORDERS
IMWGconsensusrecommendationsonimaginginmonoclonalplasmacelldisorders;LancetOncol2019;20:e302-12
MMALLADIAGNOSI:
• WBCT:primasceltaperidentificareevalutarelesioniosteolitiche
• SeWBCTnegativaeassenzadialtrieventimieloma-definentiWBRMN(ocolonna+bacino);necessarioescluderelapresenzadilesionifocalicomeeventimieloma-definenti
• PET/CTpuòsostituireRMN;neitrialscliniciusatapercrearebaselinenecessarioperilmonitoraggiodellarispostasuccessiva
MONITORAGGIORISPOSTAEFOLLOW-UP
• Indaginedaripetereinbasealladisponibilitàdelbaseline
• NuovefratturenonnecessariamentesegnidiPD,specieseremissionebiochimica
• SelesioniresiduePET/TCdopoterapia,raccomandatoFUannuale
PAZIENTICONNUOVADIAGNOSIMM(NDMM)ELEGGIBILIADASCT
Gayetal,EMNguidelinesHaematologica2018
PAZIENTICONNUOVADIAGNOSIMM(NDMM)ELEGGIBILIADASCT:INDUZIONE
TreatmentofMultipleMyeloma:ASCOandCCOJointClinicalPracticeGuidelineSummaryJosephMikhael,NofisatIsmaila,andTomMartinJournalofOncologyPractice201915:5,279-286*terapienonapprovateinItalianelsettingNDMMTE
RECOMMENDATION:atleast3to4cyclesofinductiontherapyincludinganimmumodulatorydrug(IMID),proteasomeinhibitor(PI)andsteroidsare
advisedpriortostemcellcollection
• ConfrontoVTDvsVCD*eKRD*vsKCD*
• Significativoaumentodellaprobabilitàdiottenere≥VGPRneigruppiIMID/PI
• StudioFORTE:quotadiMRDnegsuperioreperKRDvsKCD
• SeIMIDnondisponibile,ciclofosfamidepuòessereunaccettabilesostituto
PAZIENTICONNUOVADIAGNOSIMM(NDMM)ELEGGIBILIADASCT:ASCT
RECOMMENDATIONS:Upfronttransplantshouldbeofferedtoalltransplanteligiblepatients.
DelayedinitialSCTmaybeconsideredinselectedpatients
TandemASCTshouldnotberoutinelyrecommended
• STAMINAtrial(MTCTN0702):nondifferenzeinterminidiPFStrasingoloedoppioASCTperpazientitrattaticonVRDinduzione-consolidamento,seguitidaRmantenimento• EMN02:miglioramentoPFSeOSa3annicontandemASCTnelsottogruppoaltorischiocitogenetico
TreatmentofMultipleMyeloma:ASCOandCCOJointClinicalPracticeGuidelineSummaryJosephMikhael,NofisatIsmaila,andTomMartinJournalofOncologyPractice201915:5,279-286
PAZIENTICONNUOVADIAGNOSIMM(NDMM)ELEGGIBILIADASCT:tandemASCT;EMN02
AnalysisofEMN02/HO95study:ASCT-1vs2inNDMM3-yearsPFS73%vs64%(ASCT-2vsASCT-1respectively)p=0.043-yearsOS89%vs82%(ASCT-2vsASCT-1respectively)p=0.01,BenefitretainedinHRgroupsCavoetal,ABSTRACT401,ASH2017
PAZIENTICONNUOVADIAGNOSIMM(NDMM)ELEGGIBILIADASCT:ASCT
RECOMMENDATIONS:Upfronttransplantshouldbeofferedtoalltransplanteligiblepatients.
DelayedinitialSCTmaybeconsideredinselectedpatients
TandemASCTshouldnotberoutinelyrecommended
• STAMINAtrial(MTCTN0702):nondifferenzeinterminidiPFStrasingoloedoppioASCTperpazientitrattaticonVRDinduzione-consolidamento,seguitidaRmantenimento• EMN02:miglioramentoPFSeOSa3annicontandemASCTnelsottogruppoaltorischiocitogeneticoUpfronttandemASCTmaybeconsideredinselectedhighriskpatientsor
thosewithsuboptimalresponsetofirsttransplant
TreatmentofMultipleMyeloma:ASCOandCCOJointClinicalPracticeGuidelineSummaryJosephMikhael,NofisatIsmaila,andTomMartinJournalofOncologyPractice201915:5,279-286
PAZIENTICONNUOVADIAGNOSIMM(NDMM)ELEGGIBILIADASCT:MANTENIMENTO
RECOMMENDATIONS:
Lenalidomidemaintenancetherapyshouldberoutinelyofferedtostandardriskpatientsstartingatapproximatelyday90-110at10to15mgdailyuntil
progression.
Aminimumof2yearsofmaintenancetherapyisassociatedwithimprovedsurvival,andeffortstomantaintherapyforatleastthisdurationare
recommended
Forhigh-riskpatients,maintenancetherapywithaPIwithorwithoutlenalidomidemaybeconsidered*
TreatmentofMultipleMyeloma:ASCOandCCOJointClinicalPracticeGuidelineSummaryJosephMikhael,NofisatIsmaila,andTomMartinJournalofOncologyPractice201915:5,279-286*terapiadimantenimentoconPInonapprovatainItalia
PAZIENTICONNUOVADIAGNOSIMM(NDMM)ELEGGIBILIADASCT:MANTENIMENTO
LenalidomideMaintenanceAfterASCTinNDMM:AMeta-Analysis;McCarthyetal,JCO2017
NDMMNONELEGGIBILEADAUTOTRAPIANTO:TERAPIADIILINEA
MMalladiagnosiNONeleggibileadASCT:
MPV(melphalan,prednisonebortezomib)inlabel,6-9cicli
RD(lenalidomide,desametasone):daottobre2016inbaseairisultati
dellostudioFIRST,finoaPD/tossicitàinaccettabile
CRITERIDACONSIDERAREPERLASCELTADELTRATTAMENTO:
Ø Comorbidità(NP)Ø Caratteristichedellamalattiaalla
diagnosiØ InsufficienzarenaleØ Rischiocitogenetico
NDMMNONELEGGIBILEADASCTINTERMEDIATE/FRAIL:INDIVIDUALIZZAZIONEDELTRATTAMENTO
Caratteristiche Trattamento
Noinsufficienzarenale(IR) Lenalidomide-based
Nonmalattiaaggressiva
Presenzadineuropatiaperiferica
Difficoltàdiaccessoalcentro
PresenzadiIR Bortezomib-based
Malattiaaggressiva
Malattiaextramidollare
Possibilitàdiaccessoalcentro
How I treat fragile myeloma patients, Larocca A, Palumbo A, Blood 2015. Optimizing treatment in elderly patients with NDMM, Palumbo et al, JCO 2016
Laroccaetal,ASH2017:impactofBortezomiborLenalidomide-basedinductiontreatmentonhighriskcytogenetic(del(17p),t(4;14),t(14;16))transplantineligiblepatientswith
NDMM
902ptswithavailablecytogeneticanalysis;27%highrisk,73%standardriskcytogeneticHRgroup:significantadvantageforBORTgroupintermsofPFSandOS
(p=.02and.04respectively)
NDMMNONELEGGIBILEADASCTINTERMEDIATE/FRAIL:INDIVIDUALIZZAZIONEDELTRATTAMENTO
LENALIDOMIDEANDLOW-DOSEDEXAMETHASONE(RD)VERSUSBORTEZOMIB,MELPHALAN,PREDNISONE(VMP)INELDERLYNEWLYDIAGNOSEDMULTIPLE
MYELOMAPATIENTS:ACOMPARISONOFTWOPROSPECTIVETRIALS
Lenalidomide and low‐dose dexamethasone (Rd) versus bortezomib, melphalan, prednisone (VMP) in elderly newly diagnosed multiple myeloma patients: A comparison of two prospective trials, Volume: 92, Issue: 3, Pages: 244-250, First published: 22 December 2016, DOI: (10.1002/ajh.24621)
• VMP:maggiorerapiditàdiriduzionedeltumorburden
• RD:laminorerapiditàdiriduzionedeltumorburdenècompensataattraversolasommistrazioneincontinuo
LENALIDOMIDEANDLOW-DOSEDEXAMETHASONE(RD)VERSUSBORTEZOMIB,MELPHALAN,PREDNISONE(VMP)INELDERLYNEWLYDIAGNOSEDMULTIPLE
MYELOMAPATIENTS:ACOMPARISONOFTWOPROSPECTIVETRIALS
Lenalidomide and low‐dose dexamethasone (Rd) versus bortezomib, melphalan, prednisone (VMP) in elderly newly diagnosed multiple myeloma patients: A comparison of two prospective trials, Volume: 92, Issue: 3, Pages: 244-250, First published: 22 December 2016, DOI: (10.1002/ajh.24621)
• VMP:capacitàdisuperamentodell’impattoprognosticonegativolegatoall’altorischiocitogenetico
PAZIENTICONMMRECIDIVATO-REFRATTARIO(RRMM):RACCOMANDAZIONI
Treatmentofbiochemicallyrelapsedmyelomashouldbeindividualized
Allclinicallyrelapsedpatientswithsymptomsduetomyelomashouldbetreatedimmediately
Triplettherapyshouldbeadministeredonfirstrelapse,thoughthepatient’s
toleranceforincreasedtoxicityshouldbeconsidered
ASCT,ifnotreceivedafterprimaryinductiontherapy,shouldbeofferedtotransplanteligiblepatientswithrelapsedMMifPFSafterfirsttransplantis
18monthsorgreater
TreatmentofMultipleMyeloma:ASCOandCCOJointClinicalPracticeGuidelineSummaryJosephMikhael,NofisatIsmaila,andTomMartinJournalofOncologyPractice201915:5,279-286
PAZIENTICONMMRECIDIVATO-REFRATTARIO(RRMM):RACCOMANDAZIONI
Quandoiniziareiltrattamento:
• Età(frailtyscore),comorbiditàetossicitàresidue
• Rischiocitogenetico• Cineticadiraddoppiamento
dellacomponentemonoclonale
Sceltadeltrattamento:
• EfficaciainterminidiPFS/OS• Terapieprecedentieduratadi
risposta• Safety:tossicitàditrattamenti
precedenti/comorbidità• Modalitàdisomministrazione,
numerodiaccessialcentro,impattosuQOL
• Costi
Treatmentofbiochemicallyrelapsedmyelomashouldbeindividualized
TreatmentofMultipleMyeloma:ASCOandCCOJointClinicalPracticeGuidelineSummaryJosephMikhael,NofisatIsmaila,andTomMartinJournalofOncologyPractice201915:5,279-286
REGIMIBASATISUPIsØ VDBortezomib-DesametasoneØ KDCarfilzomib-desametasoneØ V-DOX/PADBortezomib-Doxorubicinaliposomialepegilata±dexØ BVDBortezomib-Bendamustine-DesametasoneØ DARA-VD:Daratumumab-Bortezomib-desametasone
REGIMIBASATISUIMIDsØ RD:Lenalidomide-DesametasoneØ ElO-RD:elotuzumab-lenalidomide-desametasoneØ DARA-RD:Daratumumab-Lenalidomide-desametasone
COMBINAZIONIPIs-IMIDsØ KRDcarfilzomib-lenalidomide-desametasoneØ IRDixazomib-lenalidomide-desametasone(subordinatoadHR
citogeneticoinIrecidiva)
MMRECIDIVATOOREFRATTARIO–REGIMIUTILIZZABILIINIRECIDIVA
Regime Standardrisk Highrisk Del17p t(4;14) ORRMedianPFS
KRDvsRD 29.6vs19.5months(HR=0.66)
23.1vs13.9months(HR=0.70)
24.5vs11.1months(HR=NA)
23.1vs16.7months(HR=NA)
87,1%vs66,7%
Elo-RDvsRD 19.4vs14.9months(HR=0.70)ITTpopulation
21.2vs14.9months(HR=0.70)
15.8vs5.5months(HR=0.52)
79%vs66%
IRDvsRD 20.6vs15.6months(HR=0.64)
21.4vs9.7(HR=0.54)
21.4vs9.7(HR=0.59)
18.5vs12(HR=0.64)
78%vs72%
DARA-RDvsRDPOLLUX
NRvs17 93%VS76%(CR55%vs23%)
DARA-VDvsVD 16,7vs7 85%vs63%
MMRICADUTO/REFRATTARIO:COMBINAZIONI
AvetLoiseauHetal,Blood2016;DimopoulosMAetal,ASH2015;Moreauetal,NEJM2016;AvetLoiseauetal,Blood2017;Dimopoulosetal,NEJM,2016;MeletiosetalUpdatedanalysisofPOLLUX,Haematologica2018;Palumboetal,NEJM,2016;SpenceretalUpdatedanalysisofCASTOR,Haematologica2018
Ø Pomalidomide-Desametasone:indicazioneperpazienticonRRMM,già
trattaticonBortezomibeLenalidomide
Ø DaratumumabsingleagentdisponibileinRRMMconterapieprecedenticheabbianoinclusoalmenounPIeunIMIDeprogressionedellamalattiadurantel'ultimaterapia
Ø KDCarfilzomib-desametasone
MMRICADUTO/REFRATTARIO:OLTRELAIRECIDIVA
PROSPETTIVEFUTURE
NDMMELEGGIBILEADASCT• CASSIOPEIAtrial:Dara-VTDvsVTD(induzione-ASCT-consolidamento-
mantenimento)• FORTEtrial:induzioneKCD/KRD+/-ASCT,consolidamento-mantenimento
NDMMNONELEGGIBILEADASCT• MAYAtrial:Dara-RDvsRD• VRDlite• ALCYONEtrial:Dara-VMPvsVMP
IMMUNOTERAPIA• CAR-T:antiBCMA,dualtargetBCMA/CD38…• BITE:BCMA/CD3
CLINICAEMATOLOGICAProf.R.M.Lemoli
Prof.M.CeaDr.ssaA.Cagnetta
Dr.M.Miglino
Dr.M.ClavioDr.F.Ballerini
Dr.ssaM.BergamaschiDr.F.Guolo
RINGRAZIAMENTI
