Relapsed Myeloma – Sequencing Treatmentsdistribute.cmetoronto.ca.s3.amazonaws.com/MED1707/0815... · 2017-05-18 · Overall Survival: Median Follow-Up of 80 Months 0.0 0 10 20 30

Relapsed Myeloma – Sequencing Treatments

Noopur Raje, MDDirector, Center for Multiple Myeloma

MGH Cancer Center

Professor of MedicineHarvard Medical School

Disclosures

• Consultant /Advisory Board: Celgene, MilleniumTakeda, Amgen-Onyx, Novartis, Janssen, BMS

• Research Funding: Acetylon, Eli-Lilly, Astra Zeneca

• Steering Committee: Amgen, Eli-Lilly, Roche

Learning Objectives:

• Summarize recent clinical advances in treatment of multiple myeloma

• Discuss novel treatment options

• Discuss factors which influence sequencing

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

FDA Approved Drugs

Panobinostat2015

Daratumumab2015

Lenalidomide2006

Pomalidomide2013

Melphalan2016

Carfilzomib20122015

Bortezomib20032005

Ixazomib2015

Elotuzumab2015

Thalidomide2006

DoxorubicinWith

Bortezomib2007

ImprovedDiagnosisandmonitoring

Treatment Paradigm for Newly Diagnosed MM

Supportive Care

InductionTherapy

TransplantConsolidation

Maintenance

Treatment of

Relapsed disease

Transplant EligiblePatients

Transplant Ineligiblepatients Initial Therapy/ Maintenance

FirstLineTherapy

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

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

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

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

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

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

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.

RVDLiteforNonTransplantEligiblePatients

O'DonnellEetal.submitted

PFS:35months OS:60%at35month f/u

RVD +/- Transplant is standard

CyBorDex in some (renal failure)

KRD versus RVD is under investigation

Summary

3 Drug Induction now STANDARD

Should we add a 4th drug?

EVOLUTION Trial: CRVD- NOT Better

Ongoing Phase II StudiesDara-IRDELO-RVDPano-RVDDara-KRD

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

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

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

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

Altered Genes per PatientMutation Load by Disease StageClonal Evolution with Progression

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?

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

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%

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

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

Ricolinostat in Combination with Lenalidomide and Dexamethasone

Omitfrom

Respo

nses-PR

u

Yeeetal,LancetOncol 2016

SNaPshot Assay

Dias-SantagataD,etal.,Rapidtargetedmutationalanalysisofhumantumors:aclinicalplatformtoguidepersonalizedcancermedicine.EMBOMolMed.2010May;2(5):146-58,O’DonnellandRaje,CancerDiscovery2013

BRAFc.1799T>A,p.V600E

Genomiccontrol Myeloma-GT

TrackingGeneticHetrogeneity

Lohr etal,submitted

BMandBloodBiopsies

BASKETSTUDY:VEMURAFENIBforBRAFmutantMM

Trametinib+DabrafenibforBRAF/NRAS/KRASmutantMM

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

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.

FDAAPPROVEDDRUGS

Panobinostat2015

Daratumumab2015

Lenalidomide2016

Pomalidomide2013

Melphalan2016

Carfilzomib20122015

Bortezomib20132015

Ixazomib2015

Elotuzumab2015

Thalidomide2016

ImprovedDiagnosisandMonitoring

DoxorubicinWith

Bortezomib2007

• 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

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

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

Boussiotis VA.NEngl JMed2016;375:1767-1778.

PD-1CHECKPOINTBLOCKADE

PD-1expressiono Activationo Exhaustiono AlterT/DCinteraction

PD-1Ligandexpressiono Immuneevasiono Proliferativeadvantageo Resistance

Investigatorshypothesizedthatinthesettingofimmunestimulatorypropertiesofpomalidomide;theblockadeofPD1-PD-L1mayrestoreMMspecificcytotoxicTcellsleadingtoclinicallyrelevantresponses.

ChimericAntigenReceptor(CAR)Tcells

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.

ResultsPrimaryEndpointMet:NoninferiorityforTimetoFirstOn-StudySkeletal-RelatedEvent

HR (95% CI) = 0.98 (0.85, 1.14); P=0.01 (Noninferiority)

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)

HowwouldIsequencetherapy?TransplantEligible

RVD/KRD-Transplant-maintenance

Pom Dex +PI

Dara+PI/IMiD

Cellulartherapy

ClinicalTrial

TransplantIneligible

RVDlite/RID

Pom/PI

Dara+PI/IMiD

Clinicaltrial

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

• 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

Acknowledgements

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