relapsed myeloma – sequencing...
TRANSCRIPT
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Relapsed Myeloma – Sequencing Treatments
Noopur Raje, MDDirector, Center for Multiple Myeloma
MGH Cancer Center
Professor of MedicineHarvard Medical School
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Disclosures
• Consultant /Advisory Board: Celgene, MilleniumTakeda, Amgen-Onyx, Novartis, Janssen, BMS
• Research Funding: Acetylon, Eli-Lilly, Astra Zeneca
• Steering Committee: Amgen, Eli-Lilly, Roche
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Learning Objectives:
• Summarize recent clinical advances in treatment of multiple myeloma
• Discuss novel treatment options
• Discuss factors which influence sequencing
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MultipleMyeloma• Secondmostcommonhematologicmalignancy• Estimatednewdiagnoses30,330;5yrsurvivalof47%• Diagnosis:
– Monoclonalimmunoglobulin– Bonemarrowplasmacytosis– Skeletallesions
CA:ACancerJournalforCliniciansVolume66,Issue6,pages443-459, 12SEP2016
AllCa =15,533,220BloodLymphoid Ca=136,960
Bone Marrow CD 138+ Kappa + t(11:14) GEP Mutational Profile
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FDA Approved Drugs
Panobinostat2015
Daratumumab2015
Lenalidomide2006
Pomalidomide2013
Melphalan2016
Carfilzomib20122015
Bortezomib20032005
Ixazomib2015
Elotuzumab2015
Thalidomide2006
DoxorubicinWith
Bortezomib2007
ImprovedDiagnosisandmonitoring
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Treatment Paradigm for Newly Diagnosed MM
Supportive Care
InductionTherapy
TransplantConsolidation
Maintenance
Treatment of
Relapsed disease
Transplant EligiblePatients
Transplant Ineligiblepatients Initial Therapy/ Maintenance
FirstLineTherapy
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Continuous Improvement in Response Seen With Combinations of Newer
Agents
StewartAKetal.Blood.2009;114:5436-5443.Jakubowiak Aetal.Blood.2012;120:1801-1809.
100
90
80
70
60
50
40
30
20
10
0TDVAD VTDRD CVDPAD CVRDRVD
CR/nCR
Response(%
)
InductionRegimenCRD
ORR VGPR
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RegistrationRVD1
Lenalidomide + Bortezomib + Dexamethasone
25mg/d(d1to14) 1.3mg/m2 (d1,4,8,11) 20mg/d(d1,2,4,5,8,9,11,12)
)
Randomization (stratified on ISS and FISH)
ArmA ArmB
RVD2and3
PBSCCollection(cyclophosphamide 3g/m2 andG-CSF)
10mcg/kg/d)ASCT
HDM200mg/m2RVD4to8
RVD4and5LenalidomideMaintenance
12months (10-15mg/d)
RVD2and3
PBSCCollection(cyclophosphamide 3g/m2 andG-CSF)
IFM2009:StudyDesign.
LenalidomideMaintenance12months (10-15mg/d)
Attal etal.ASH2015
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IFM 2009: Response and PFS
RVDarmN=350
TransplantarmN=350
p-value
CR 49% 59%
VGPR 29% 29% 0.02
PR 20% 11%
<PR 2% 1%
Atleast VGPR 78% 88% 0.001
Neg MRD by FCMn(%) 228(65%) 280(80%) 0.001
AttaletalAbstract391ASH2015
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P-value : p<0.0001
Negative (<10-6)
PositivePositive
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Patie
nts
with
out p
rogr
essi
on (%
)
51 51(0) 51(0) 51(0) 47(3) 36(9) 26(5) 6(9) 3(0)MRD positive80 80(0) 80(0) 80(0) 80(0) 73(3) 57(3) 33(5) 9(0)MRD neg (<10-6)
N at risk(events)
06
1218
2430
3642
48
Months since randomization
MRD at post-maintenance inCRpatients
375CR/sCR,only 131MRD
83%
30%
Avet-Loiseau etal.ASH2015
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Meta-AnalysisofLenalidomide MaintenanceafterASCT
CALGB100104(accrual8/2005–11/2009)
INDUCTIONASCT1:1RANDOMIZATION“NOEVIDENCEOFPD”Primary Endpoint:PFS
LENMNTCa
(n=231)PLACEBO(n=229)
CROSSOVER BEFOREPDALLOWED
CONTINUEDTREATMENT
IFM2005-02(accrual6/2006–8/2008)
INDUCTIONASCT1:1RANDOMIZATION“NOEVIDENCEOFPD”Primary Endpoint:PFS
LEN:2COURSES
LENMNTCa
(n=307)PLACEBO(n=307)
ALLTREATMENTDISCONTINUEDJan2011
CONTINUEDTREATMENTNOCROSSOVER
BEFOREPDALLOWED
INTERIMANNG
aStarting doseof10mg/dayondays1-28/28wasincreasedto15mg/dayiftoleratedandcontinueduntilPD.bPatientsreceived10mg/dayondays1-21/28untilPD.ASCT,autologousstemcelltransplant;LEN,lenalidomide;NDMM,newlydiagnosedmultiplemyeloma;MNTC,maintenance;MPR,melphalan,prednisone,andLen;PD,progressivedisease .
Dec2009 Jan2010
TargetpopulationofpatientswithNDMMwhoreceivedLENmaintenanceorplacebo/nomaintenanceafterASCT
AttaletalASCO2016McCarthyetalEHA2016
INTERIMANALYSISANDUNBLINDING
GIMEMA(RV-MM-PI-209)(accrual11/2007–7/2009)
MPR:6COURSES
LENMNTCb
(n=67)NOTREATMENT(n=68) LENMNTCbNO
TREATMENT
ASCT
CONTINUEDTREATMENT
CONTINUEDTREATMENT
PRIMARYANALYSIS
2× 2DESIGNLEN+DEX× 4INDUCTIONPrimary Endpoint:PFS
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OverallSurvival:MedianFollow-Upof80Months
0.00 10 20 30 40 50 60 70 80 90 100 110 120
0.2
0.4
0.6
0.8
1.0
Thereisa26%reduction inriskofdeath,representing anestimated2.5-yearincreaseinmediansurvivala
605 578 555 509 474 431 385 282 200 95 20 1 0604 569 542 505 458 425 350 271 174 71 10 0
Overall Survival, mos
Surv
ival
Pro
babi
lity
Patients at risk
7-yr OS
62%
50%N=1209 LENALIDOMIDE CONTROL
MedianOS(95%CI),mos
NE(NE-NE)
86.0(79.8-96.0)
HR(95%CI)P value
0.74 (0.62-0.89).001
aMedian forlenalidomide treatmentarmwasextrapolated tobe116months based onmedian of thecontrol armand HR(median, 86 months; HR=0.74). HR,hazardratio;NE,notestimable;OS,overallsurvival.
AttaletalASCO2016McCarthyetalEHA2016
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Cycle1CycleDay 18 152128
Cycle218 152128
Cycle318 152128
Cycle818 152128
Cycle918 152128
Lenalidomide Dailydose Dailydose Dailydose Dailydose Dailydose
Bortezomib xx x x xx x x xx x x xx x x xx x xDexamethasone dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd
Induction35-daycycle
Cycle1018 1521
Cycle1118 1521
Cycle1218 1521
Cycle1518 1521
Dailydose Dailydose Dailydose Dailydose
xx xx xx xx
CycleDayLenalidomide
Bortezomib
Consolidation28-daycycle
Cycle1618 1521
Cycle1718 1521
Cycle1818 1521
CycleN18 1521
Dailydose Dailydose Dailydose DailydoseCycleDayLenalidomide
Maintenance 28-daycycle
RVDLite forNonTransplantEligiblePatients
DosingRegimen
O'DonnellEetal. ASH2015.
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RVDLiteforNonTransplantEligiblePatients
O'DonnellEetal.submitted
PFS:35months OS:60%at35month f/u
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RVD +/- Transplant is standard
CyBorDex in some (renal failure)
KRD versus RVD is under investigation
Summary
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3 Drug Induction now STANDARD
Should we add a 4th drug?
EVOLUTION Trial: CRVD- NOT Better
Ongoing Phase II StudiesDara-IRDELO-RVDPano-RVDDara-KRD
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Myeloma: Scope of the Problem
• Mediantimetofirstrelapsewithcurrenttherapies:3-4yrs
KumarSK, etal.Leukemia.2014;28:1122-1128.
>100,000ptslivingwithmyelomaO
S(%)
Yrs
2006-2010
2001-2005
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 1 2 3 4 5 6
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Confronting Disease Relapse in Myeloma
KumarSK, etal.MayoClin Proc.2004;79:867-874.KumarSK, etal.Leukemia.2012;26:149-157.
Pts(%)
100
80
60
40
0
20
0 12 24 36 48 60
Mos
OSEFS
Events,n/N170/286217/286
Median,Mos(Range)9(7-11)5(4-6)
12
10
8
6
0
2
First Second Third Fourth Fifth Sixth
TreatmentRegimen
MedianRe
sponseDuration(M
os)
4
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SOME FACTS
• Although CR with MRD should be the goal of clinical trials, NOT all patients get there.
• Having some response translates into CBR
• DCR similarly translates into improved outcomes
• This translates into delayed TNT
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Questions to Ask
• Do I really need to treat this pt?
Biochemical Relapse versus Clinical Relapse
• Does the pt have new high-risk features?
Genotypic Evolution
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Altered Genes per PatientMutation Load by Disease StageClonal Evolution with Progression
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Additional Questions to Ask• What drugs have been used so far?
• Response to previous treatments
• How well is the patient?
• What are the associated co-morbidities?
• What are the pt’s goals/preferences?
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Challenges and Opportunities in Relapsed Myeloma
– Many new treatments available
– Initial treatment options are changing (LEN moving frontline)
– Use of continuous treatment means that patients are refractory at progression (LEN maintenance)
– Data supports triplet combinations of novel agents in early relapse (exposure to multiple novel agents occurs earlier)
– Data from pivotal trials is lagging behind clinical practice
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Selected phase III trials in relapsed disease
Name of trial No. prior lines Arm N PFS(months) ORR ≥VGP
R ≥CR
ENDEAVOR 1-3 Kd 464 18.7 77% 54% 13%Vd 465 9.4 63% 29% 6%
TOURMALINE-MM1 1-3 IRd 360 20.6 78% 48% 12%Rd 362 14.7 72% 39% 7%
ELOQUENT-2 1-3 Elo-Rd 321 19.4 79% 33% 4%Rd 325 14.9 66% 28% 7%
ASPIRE 1-3 KRd 396 26.3 87% 70% 32%Rd 396 17.6 67% 40% 9%
PANORAMA 1 1-3 Pano-Vd 387 11.99 61% 11%Vd 381 8.08 55% 6%
NIMBUS (MM-003) ≥2§ Pd 302 4.0 31% 6% 1%D 153 1.9 10% 1% 0%
CASTOR ≥1 Vd-dara 251 NE 82.9% 59.2% 19.2%
Vd 247 7.2 63.2% 29.1% 9%
POLLUX ≥1 Rd-dara 286 NE 93% 76% 43%Rd 283 18.4 76% 44% 19%
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POLLUXandCASTOR• Multicenter, randomized (1:1), open-label, active-controlled, phase 3 studies in ≥1 prior line of therapy for MM
DRd(n=286)D16mg/kgIV
Everyweek:Cycles1-2Every2weeks:Cycles3-6Every4weeksuntilPD
R25mgPO (similartoRd alone)d40mg
Rd(n=283)R25mgPO
Days1-21 of eachcycle untilPDd40mgweeklyuntilPD
RANDOMIZE
POLLUX
DVd(n=251)D16mg/kgIV
Everyweek:Cycles1-3Every3weeks:Cycles4-8Every4weeks:Cycles9+
V1.3mg/m2 SC(similartoVdalone)d20mg
Vd(n=247)V1.3mg/m2 SConDays1,4,8,and 11
for 8cyclesd20mg onDays1,2,4,5,8,9,11, and12for
8cycles
CASTOR
RANDOMIZE
MRDassessments§ Atsuspected CR§ 3& 6months afterCR
MRDassessments§ Atsuspected CR§ 6& 12months afterfirst studydose
Patientcharacteristics§ Median(range)priorlines:1(1-11)§ PriorV:84%§ PriorR:18%
Patientcharacteristics§ Median(range)priorlines:2(1-10)§ PriorV:66%§ PriorR:42%
Avet-Loiseau ASH2016,abstract246
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UpdatedPFS:POLLUXandCASTORPatie
ntssurvivingwithoutp
rogressio
n,%
0
20
40
60
80
100
0 3 6 9 12 18 21 27
PFS,months
2415
60%
22%
12-monthPFSa
Vd
DVd
0
20
40
60
80
100
0 3 6 9 12 15 18 24
PFS,months
21
Rd
DRd
18-monthPFSa
76%
49%
POLLUX CASTOR
Median(range)follow-up:13.0(0-21.3)months
Median(range)follow-up:17.3(0-24.5)months
Patie
ntssurvivingwithoutp
rogressio
n,%
§ MedianPFS– DRd:notreached;Rd:17.5months– HR:0.37(95%CI,0.28-0.50;P <0.0001)
§ MedianPFS– DVd:notreached;Vd:7.1months– HR:0.33(95%CI,0.26-0.43;P <0.0001)
Avet-Loiseau ASH2016,abstract246
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Ricolinostat in Combination with Lenalidomide and Dexamethasone
Omitfrom
Respo
nses-PR
u
Yeeetal,LancetOncol 2016
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SNaPshot Assay
Dias-SantagataD,etal.,Rapidtargetedmutationalanalysisofhumantumors:aclinicalplatformtoguidepersonalizedcancermedicine.EMBOMolMed.2010May;2(5):146-58,O’DonnellandRaje,CancerDiscovery2013
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BRAFc.1799T>A,p.V600E
Genomiccontrol Myeloma-GT
TrackingGeneticHetrogeneity
Lohr etal,submitted
BMandBloodBiopsies
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BASKETSTUDY:VEMURAFENIBforBRAFmutantMM
Trametinib+DabrafenibforBRAF/NRAS/KRASmutantMM
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Treatment Approach in Early Relapse
Early Relapse (1-3 prior lines)
Participate in clinical trials with Novel Agents
Imid- based regimen
PI- based regimen
Autologous Transplant
Long remission post 1st transplant (>18-24 months)
Transplant not part of primary therapy
Len-naïve/ sensitive
KRd, IRd, Rd-Elo
BTZ-naïve/ sensitive
Kd, KRd, IRd
ImmuneTherapy
Chemo Resistant
ElotuzumabDaratumumab
+/- Imid/PI
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Treatment approach in Rel and Ref MM≥ 3 Prior Lines and/ or double refractory
Participate in clinical trials with Novel Agents
Pom- dex Daratumumab Re-treatment
MM-003• Median no. of prior
treatments: 5 (1-14)• ORR/ CBR (%) 31/39• PFS: 4.0 mos• Median OS: 12.7
mos
SIRIUS Study• Median no. of prior
treatments: 5 (2-14)• ORR/ CBR (%) 31/36• PFS: 3.7 mos• Median OS: 17.5
mos
• Even if a patient has progressed on a certain agent, they may become sensitive due to re-emergence of drug sensitive clones
• Requires a combination approach
1) San Miguel et al, 2013, Lancet. 2) Lonial et al. 2016. Lancet.
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FDAAPPROVEDDRUGS
Panobinostat2015
Daratumumab2015
Lenalidomide2016
Pomalidomide2013
Melphalan2016
Carfilzomib20122015
Bortezomib20132015
Ixazomib2015
Elotuzumab2015
Thalidomide2016
ImprovedDiagnosisandMonitoring
DoxorubicinWith
Bortezomib2007
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• Ixazomib
• Oprozomib
• Marizomib
Oralproteasomeinhibitors
• Elotuzumab
• Daratumumab
• Isatuximab
Monoclonalantibodies
• Vermurafenib
• Afuresertib
• Dinaciclib
• PIM(LGH447)
• Trametinib
Kinaseinhibitors
• Panobinostat
• Ricolinostat
• ACY241
HDACi
• Venetoclax
• Selinexor
Novelmechanisms
• PDL-1/PD-1
• CAR-T
• BITE
Immuno-therapies
HDACi, histone deacetylase inhibitor
• CC-122
• CC-220
New
IMiDs
What is New in MM
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Venetoclax Background
§ BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival§ Venetoclax is a selective, orally available small molecule BCL-2 inhibitor1 and
bortezomib can indirectly inhibit MCL-1§ Venetoclax enhanced bortezomib activity in vitro and in vivo2
1.RobertsAWetal.NEJM20152.Punnoose Eetal.Mol CancerTher 2016
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Phase1Venetoclax forRRMM:responseandTTPinallpatientsandbyt(11;14)status
0
1 0
2 0
3 0
4 0
5 0
Pe
rce
nta
ge
of
Pa
tie
nts
sCR CR VGPR PR
A ll P a t ie n tsN = 6 6
t (1 1 ;1 4 )n = 3 0
O R R 2 1 %
O R R 4 0 %
n o n - t (1 1 ;1 4 )n = 3 6
O R R 6 %
6%
8%13%
4%
10%
13%
3%3%
3%
4%
Datacutoffof19Aug2016
KumarASH2016Abstract488
0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 40
2 5
5 0
7 5
1 0 0
M o n th s s in c e f irs t d o s e
% N
ot
Pro
gre
ss
ed
t (1 1 ;1 4 )n o n -t(1 1 ;1 4 )
N o . a t r is k 6 6 3 3 2 7 2 0 1 6 9 3 1 1 1 1 1N o . a t r is k 3 0 2 0 1 9 1 7 1 3 7 2 1 1 1 1 1N o . a t r is k 3 6 1 3 8 3 3 2 1
T im e to P ro g re s s io n
A ll P a tie n ts
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Boussiotis VA.NEngl JMed2016;375:1767-1778.
PD-1CHECKPOINTBLOCKADE
PD-1expressiono Activationo Exhaustiono AlterT/DCinteraction
PD-1Ligandexpressiono Immuneevasiono Proliferativeadvantageo Resistance
Investigatorshypothesizedthatinthesettingofimmunestimulatorypropertiesofpomalidomide;theblockadeofPD1-PD-L1mayrestoreMMspecificcytotoxicTcellsleadingtoclinicallyrelevantresponses.
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ChimericAntigenReceptor(CAR)Tcells
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An International, Randomized, Double Blind Trial Comparing Denosumab With Zoledronic Acid for the Treatment of Bone Disease in Patients With
Newly Diagnosed Multiple MyelomaDenosumab120mgSC
+PlaceboIVOver15minutesQ4W
(N=850)
ZoledronicAcid4mgIVOver
15minutesQ4W+
PlaceboSC(N=850)
Benefit:RiskPositive?
OfferedOpen-LabelDenosumabUpto
2Years
2-YearFollow-upforSurvival
Yes
No
Randomization(N=1700)
Stratified by:
• Anti-Myeloma Therapy:Novel Based (IMiDs, Proteasome Inhibitors) vs Non-Novel Based
• Planned Autologous PBSC Transplant:Yes/No
• Disease Stage:ISS 1, 2, or 3
• Previous SRE: Yes/No
• Region: Japan; Yes/No
676Events
1:1 DailySupplementsofCalciumand
VitaminD
*Perprotocol andZometa® label,IVproduct wasdoseadjusted forbaselinecreatinineclearanceandsubsequentdoseintervalsweredetermined byserumcreatinine levels.NoSCdoseadjustments wererequired.
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ResultsPrimaryEndpointMet:NoninferiorityforTimetoFirstOn-StudySkeletal-RelatedEvent
HR (95% CI) = 0.98 (0.85, 1.14); P=0.01 (Noninferiority)
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ResultsExploratory Endpoint: Progression-Free Survival
HR(95%CI)=0.82(0.68,0.99);P=0.036(Descriptive)
MedianDuration(95%CI),MonthsDenosumab - 46.09(34.30,NotEstimable)ZoledronicAcid - 35.38(30.19,NotEstimable)
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HowwouldIsequencetherapy?TransplantEligible
RVD/KRD-Transplant-maintenance
Pom Dex +PI
Dara+PI/IMiD
Cellulartherapy
ClinicalTrial
TransplantIneligible
RVDlite/RID
Pom/PI
Dara+PI/IMiD
Clinicaltrial
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CurrentUnderstanding
• Combinations will allow us to improve responses and cure a higher fraction of patients.
• Drugs with different MOA will overcome genetic heterogeneity
• High risk disease can be identified and specifically targeted
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• Aim for deep and durable response– MRD measurements insightful in clinical trials
• Continuous therapy improves outcome– Induction, upfront transplant and maintenance– Initial treatment for 12 months followed by maintenance
• Prognostic factors are evolving– High risk disease needs new drugs– Immuno-oncology will play an important role
• Tailor therapy for– Age and frailty– Renal impairment
• Supportive care– Bone health– Thromboprophylaxis– Infection
Take Home Points
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Acknowledgements
Our Patients