The MMRF CoMMpass StudySM · there were an estimated 30,330 new cases of myeloma in the United States in 2016, representing 1.8% of all new cancer cases.3 Myeloma is estimated to

themmrf.org

The MMRF CoMMpass StudySM

in ContextA Look at the Past, Present, and Future

of Multiple Myeloma Research

81445CoMMpassWhitePaper

2

TableofContents

GeneralOverview.........................................................................................................................................3

MultipleMyelomaResearchFoundation:WhoWeAre..............................................................................4

MultipleMyeloma:DiseaseBackground......................................................................................................4

EmergingFocusonPrecisionMedicine........................................................................................................7

MultipleMyelomaPrecisionMedicineModel.............................................................................................7

TheDataBank..............................................................................................................................................8

MultipleMyelomaGenomicsInitiative(MMGI).......................................................................................8

TheMMRFCoMMpassStudySM..............................................................................................................11

StudyDesignandImplementation.....................................................................................................11

WhatWeHaveLearnedSoFarFromCoMMpass..............................................................................12

WhatWeExpecttoLearnFromCoMMpass.....................................................................................16

TheLearningNetwork................................................................................................................................17

ResearcherandCoMMunityGatewayWebPortals...............................................................................17

MyelomaDiseaseModel........................................................................................................................18

TranslationalNetwork............................................................................................................................18

TheClinic....................................................................................................................................................19

MultipleMyelomaResearchConsortium...............................................................................................19

NextStepsfortheCoMMpassStudyandforMMResearch......................................................................20

Glossary/AcronymList................................................................................................................................22

References..................................................................................................................................................24

21

23


3

GeneralOverview

Despitetheenormoustreatmentadvancesmadeinthepastfewyears,multiplemyeloma(MM),a

hematologicmalignancyofplasmacellsinthebonemarrow,remainsanincurabledisease,andmost

patientswilleventuallyrelapse,withlimitedoptionsandpoorprognosis.TheMultipleMyeloma

ResearchFoundation(MMRF)hasbeenworkingtirelesslytoacceleratethepaceofMMresearch.The

MMRFisfacilitatingprecisionmedicinethroughacomprehensiveend-to-endmodelthatbeginswith

generatinggenomicandclinicaldataandleadseventuallytotestingtargetedtherapiesinpatientswith

MM.

ThiswhitepaperwillexplainthecomponentsoftheMMRF’sprecisionmedicinemodel–TheDataBank,

TheLearningNetwork,andTheClinic–withafocusonthecornerstoneCoMMpassStudySM,thefirst

large-scale,longitudinalstudyinMMtoattempttoidentifygenomicdriversofdiseaseatdiagnosisand

otherimportanttimepoints.Designedtobeaccessibletoabroadaudience,thiswhitepaperdescribes

keyfeaturesoftheCoMMpassStudyandalsoprovidescontextarounditsdevelopment,includinga

briefdiseasebackground,previousMMRFeffortsthathelpedpavethewayforthislandmarkstudy,and

whatthefuturemayholdforpatientswithMMaswellasclinicians.


4

MultipleMyelomaResearchFoundation:WhoWeAre

TheMMRFwasestablishedin1998asa501(c)(3)non-profitorganizationbyidenticaltwinsistersKathy

GiustiandKarenAndrewssoonafterKathywasdiagnosedwithmultiplemyeloma(see

www.themmrf.org).ThemissionoftheMMRFistohelpacceleratethepaceofdevelopingtreatments

forMM,withtheultimategoaloffindingacureforthedisease.TheMMRFbelievesthatopen,rapid

communicationofscientificfindingsisessentialfortimelyinnovation.The“standard”practiceof

keepingdatadecentralizedandprivate,whileperhapsbenefitingindividualresearchersorcompanies,

ultimatelyservestoslowthepaceofresearchtothedetrimentofpatientswithMMinurgentneedof

newtreatmentoptions.EspeciallyinrareandcomplexcancerssuchasMM,collaborationanddata

sharingareessentialinordertomakemeaningfulprogress.

MultipleMyeloma:DiseaseBackground

Myelomaisatypeofhematologicmalignancy(bloodcancer)inwhichabnormalplasmacells(white

bloodcellsthatproduceantibodies)areoverproducedinthebonemarrow,crowdingoutnormal

plasmacellsthathelpfightinfection.Myelomaisoftenfoundinmultipleplacesinthebodyandreferred

toasMM;inrarecases,myelomaisfoundinoneplaceinthebodyandreferredtoassolitarymyeloma.

ThemalignantplasmacellsproducedinMMmakemonoclonalproteins(Mproteins),abnormal

antibodiesthatcancollectinblood,urine,andorgans,ultimatelycausingbonedamage,kidneyfailure,

andimpairedimmunesystemfunction.AhighlevelofMproteininthebloodisconsideredthehallmark

characteristicofMM.Multiplemyelomacanbeginasanon-cancerousconditioncalledmonoclonal

gammopathyofunknownsignificance(MGUS),whichcanthenprogresstoasymptomatic(smoldering)

oractivemyeloma(Figure1).1


5

Figure1.ProgressionofMultipleMyeloma

CRABcriteria=hyperCalcemia,Renalfailure,AnemiaandBonelesionscriteria(measureofendorgandamage);CT=computerizedtomographyscan;M=monoclonalproteins;MDE=myeloma-definingevents;MRI=magneticresonanceimaging;PC=monoclonalmalignantplasmacells;SFLC=serumfreelightchain.

RepublishedwithpermissionoftheAmericanSocietyofHematology,from“HowItreatsmolderingmultiplemyeloma,”GhobrialIMandLandgrenO,Blood124(23),©2014;permissionconveyedthroughCopyrightClearanceCenter,Inc.

MMisahighlyheterogeneousdisease,withacomplexandincompletelyunderstoodmolecular

pathogenesis.Notonlydoesmyelomadifferfromonepatienttoanother,withupto10different

subtypesidentified,butmoreoveragivenindividualonaveragehasfourslightlydifferentformsofthe

disease(clones)thatevolvewithdiseasestageandthetreatmentstowhichthatpersonisexposed.2

AccordingtotheNationalCancerInstitute’sSurveillance,Epidemiology,andEndResults(SEER)Program,

therewereanestimated30,330newcasesofmyelomaintheUnitedStatesin2016,representing1.8%

ofallnewcancercases.3Myelomaisestimatedtohavebeenresponsibleforapproximately12,650

deathsin2016,or2.1%ofallcancerdeaths.Themedianageatmyelomadiagnosisis69years,andthe

diseaseismorecommoninmenthanwomenandamongindividualsofAfricandescent.

MGUS MyelomaSmoldering Myeloma• M spike <3 gm/dL• PC <10%• No CRAB criteria

• M spike <3 g/dL• Or urinary M protein >500mg/ 24 hrs and/or• PC ≥10%• No CRAB criteria

• Any M spike or urinary M protein• PC ≥10% or plasmacytoma• CRAB criteria• New criteria of MDE including clonal plasma cells ≥60, involved/ uninvolved SFLC >100, 2 or more focal lesion on MRI or CT

MMcells

Cell dissemination and metastasis

Bloodvessel


6

ThetreatmentofMMhasundergonerapidandunprecedentedchangeinthepastfewyears.

Chemotherapy,stemcelltransplant,andradiationtherapyremainstandardtreatmentoptions;

however,aplethoraofnewtreatmentshasemergedoverthepastdecade.In2015alone,fourdrugs

wereapprovedintherelapsed/refractorysetting,includingthehistonedeacetylaseinhibitor

panobinostat(Farydak®),theoralproteasomeinhibitorixazomib(Ninlaro®),andthemonoclonal

antibodiesdaratumumab(Darzalex™)andelotuzumab(Empliciti™).Thecombinationoflenalidomide

(Revlimid®)plusdexamethasoneinthesettingofnewlydiagnosedMMalsowasapprovedin2015.

TheseandotherrecentdrugapprovalsmeanthattreatmentchoicesforMMaremorecomplexbutalso

potentiallymorebeneficial.

Asformanydiseases,thereisnoone-size-fits-allapproachinthetreatmentofMM.Giventheunique

characteristicsofindividualpatients,includingfactorssuchasgenomicprofile,age,performancestatus,

andstageofdisease,treatmentshouldideallybetailoredtomatcheachpatient’sneeds.Cliniciansand

patientsfacewhatmightbeseenasadauntingchallengeindeterminingthecorrecttreatmentpath,

includinghowtoappropriatelysequencetherapies,andwhenandhowtocombinetherapiesfora

maximalclinicalrisk-to-benefitratio.TheapprovalofnewtherapiesmeansthattheMMtreatment

landscapeisconstantlyundergoingrefinement.

Despitethesubstantialprogressmadeinrecentyears,mostpatientswithMMwilleventuallyrelapseon

theircurrenttherapyandhavelimitedsubsequenttreatmentoptionsandpoorprognosis.Therelative

rarityofMMandtheheterogeneityofthediseasecomplicatetheabilitytodesignadequatelysized

clinicaltrials.Newstrategiesareneededthatenabletheconductofadequatelysizedclinicaltrials,

optimizetheutilizationofexistingclinicaldata,facilitatethedevelopmentoftargetedtherapy,andhelp

informcliniciansandpatientsaboutthemostappropriatetreatmentpath.


7

EmergingFocusonPrecisionMedicine

ChallengessuchasthosefacedinMMhaveledtotheemergenceofthefieldofprecisionmedicine.In

2015,PresidentObamalaunchedthePrecisionMedicineInitiative,withthegoalofacceleratinganew

eraofmedicinethatdeliverstherighttreatmentattherighttimetotherightperson,takinginto

accountanindividual’shealthhistory,genes,environment(s),andlifestyles.MMRFFounderKathyGiusti

–inrecognitionoftheMMRF’slongstandingleadershipinprecisionmedicine–wasappointedtothe

WhiteHousePrecisionMedicineWorkingGroup,whichismadeupofkeyleadersinresearch,science,

technology,epidemiology,investment,policy,andpatientadvocacy.

Theemergenceofprecisionmedicinecoincideswithastrongtrendtowardpatientsasactive

participants,ratherthanaspassivesubjects,intheclinicaldecision-makingprocess.Increasingpatients’

knowledgeoftheiruniquediseasecharacteristicsanddiseasejourneywillhelptofurtherstrengthenthe

roleofprecisionmedicineinthefuture.

MultipleMyelomaPrecisionMedicineModel

In2011,severalyearspriortotheObama-ledinitiative,theMMRFlauncheditsownPrecisionMedicine

ModelwiththeCoMMpassStudyasitscornerstone.TheMMRFhasdevelopedanend-to-endsystemto

accelerateprecisionmedicineincancerwiththefollowingthreecomponents:TheDataBank,The

LearningNetwork,andTheClinic.Thesecomponentsrepresenttheprocessbywhichgenomicandother

dataaregenerated,madepublic,analyzed,and–insomecases–utilizedinclinicaltrials.

THEPATIENT

THEDATABANK

THELEARNINGNETWORK

THECLINIC

Data generation & integration Collaboration and discovery Accelerating trials

MMGI

CoMMpass

Registry

Gateways

Myeloma Disease Model

Translational Network

MMRC

- Molecularly targeted therapies

- Immune therapies

- Novel therapies


7




















7




















8

TheDataBank

TheDataBankrepresentsthedatageneration,aggregation,andintegrationcomponentoftheMMRF’s

PrecisionMedicineModel.ExamplesofDataBankinitiatives,whicharedescribedbelow,includethe

MultipleMyelomaGenomicsInitiative(MMGI)andtheongoingCoMMpassStudy.Patientsserveasan

integralpartofTheDataBankthroughthedonationoftheirpersonaldata,includingbonemarrowand

bloodsampleresults,qualityoflifedata,andmanyotherclinicalparameters.

MultipleMyelomaGenomicsInitiative(MMGI)

In2005,theMMRFlaunchedtheMMGI,aprogressivegenome-mappingprogram.TheMMGIwas

formedasacollaborationbetweentheMMRF,anacademicpartner(BroadInstituteofMITand

Harvard),andanon-profitpartner(TranslationalGenomicsResearchInstitute;TGen).Priortothe

MMGI,therewaslimitedunderstandingofthebiologyofMMandaneedfornewdrugtargets.In2009,

theMMGIbecamethefirstefforttosequencetheMMtumorgenomeinitsentirety,animportantfirst

stepintheidentificationofgenesandmolecularpathwaysthatplayaroleintheonsetandprogression

THEPATIENT

THEDATABANK

THELEARNINGNETWORK

THECLINIC


MMGI

CoMMpass

Registry

Gateways



MMRC


- Immune therapies

- Novel therapies

THE

PATIENT

THE

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Data generation &

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Accelerating trials

MM

GI

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Myelom

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Translational Netw

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8

TheDataBank














8

TheDataBank














9

ofMM(Table1).TheMMGIhassinceprofiledmorethan200myelomapatientsamplesinavarietyof

genomicanalyses.Afree,web-baseddataportal,calledtheMultipleMyelomaGenomicsPortal

(MMGP),wasdevelopedinconjunctionwiththeMMGItoserveasarepositoryofmetadataand

analysisresults.TheMMGPrepresentedthefirstwell-developed,centralizedrepositoryofMMgenomic

information.Todate,theportalhasthousandsofregisteredusers,provingthefeasibilityandutilityof

suchaweb-based,open-accesssite.

Table1.GeneticMutationsIdentifiedviatheMMGI*

Mutation %ofpatients

KRASandNRAS 40BRAF 8CDKN2CandCCND1 18PI3K/Akt 5FGFR3 5IGF-1RandALK 5IDH1/2 5MyD88 3Others 11*ThesemutationsandtheirfrequencieshavebeensubsequentlyconfirmedintheCoMMpassstudy.ALK=anaplasticlymphomakinase;BRAF=B-Rafproto-oncogene,serine/threoninekinase;CCND1=cyclinD1;CDKN2C=cyclin-dependentkinase4inhibitorC;FGFR3=fibroblastgrowthfactorreceptor3;IDH1/2=isocitratedehydrogenase1/2;IGF-1R=insulin-likegrowthfactor-1receptor;KRAS=V-Ki-ras2Kirstenratsarcomaviraloncogenehomolog;MyD88=myeloiddifferentiationprimaryresponsegene88;NRAS=neuroblastomaRASviraloncogenehomolog;PI3K/Akt=phosphatidylinositol-4,5-bisphosphate3-kinase/proteinkinaseB.

OneofthesuccessstoriesoftheMMGIandtheassociatedMMGPconcernstheBRAFgenemutation,

whichhasmovedthroughTheDataBankandTheLearningNetworkandsoonwillbestudiedinThe

CliniccomponentoftheMMRFPrecisionMedicineModel.Reportedin2011,theidentificationofthe

BRAFmutationviagenome-mappingrepresentedapossibleactionabletargetforBRAFmutation-

positiveMMpatients.4ThisfindingwassubsequentlyconfirmedintheCoMMpassstudy.Furtherpre-

clinicalworkidentifiedotheralterationsinthesamepathwaythatsuggestedthatacombined

therapeuticapproach,onethatincludesadditionaldrugtargetsasidefromBRAF,mightbeoptimalin


9


















9


















9


















10

someMMpatientswithBRAFmutations.2AclinicaltrialiscurrentlybeingdesignedtotesttheBRAF

inhibitor,vemurafenib,intheBRAFmutation-positiveMMindication.

ASH=AmericanSocietyofHematology.

TheworkbytheMMGIhashelpedtoincreasetheunderstandingofthegenomicprofileofMMandthe

heterogeneityofthedisease.However,thegenomicinformationgeneratedbythisinitiativeislimited

bythefactthatitprovidesonly“snapshots”atsingletimepointsofthediseaseinvariouspatients.

DuringthecourseoftheMMGI,cliniciansandresearcherscametounderstandthatwhatwasneededto

furthertheunderstandingofthebiologybehinddiseaseprogressionwasalongitudinalstudythat

followedpatientsthroughtheirentirejourneywiththedisease.Aprospectivelydesignedlongitudinal

studysuchasthiswouldenableamoredetailedunderstandingofthechangesthatoccurthroughthe

courseofMMandtheclonalheterogeneityofthedisease.


10












BRAF: DISCOVERY TO CLINIC

2011 2011 2012 2014 Today

Identify BRAFmutation:38 genomes

Chapman et al.Nature. 2011;471: 467-72.

Clinicians begintrials with BRAFinhibitorvemurafenib

Clinicalresponsesobserved andreported at ASH

203 genomessequenced

Several otheractionable targetsidentified

Lohr et al.Cancer Cell. 2014;25: 91-101.

Initiatingcombinationdrug trials


10













10













11

TheMMRFCoMMpassStudySM

LeveragingtheirexperienceandfindingsfromtheMMGI,theMMRFhelpedtolaunchtheCoMMpass

Study([Relating]ClinicalOutcomesinMultipleMyelomatoPersonalAssessmentofGeneticProfiles)in

2011.CoMMpassisthefirstlarge-scale,longitudinalstudyinMMfocusedondiseaseprogressionand

responsetotreatmentbasedonpatients’genomicormolecularprofiles(Clinicaltrials.govidentification

number:NCT01454297).

StudyDesignandImplementation

CoMMpassisaprospective,longitudinal,observationalstudyinnewlydiagnosedsymptomaticpatients

withMM.Nowclosedtoenrollment,patientswereincludedwhowere18yearsorolderandwhowere

candidatesforanimmunomodulatorydrug(e.g.,lenalidomide[Revlimid®],pomalidomide[Pomalyst®],

orthalidomide[Thalomid®])and/oraproteasomeinhibitor(e.g.,bortezomib[Velcade®]orcarfilzomib

[Kyprolis®])aspartoftheirinitialtreatmentregimen.Inadditiontotherapywithanimmunomodulatory

drugand/orproteasomeinhibitor,patientsreceivedacorticosteroidsuchasdexamethasone(dex)and,

insomecases,achemotherapyagentsuchascyclophosphamide.Initialtherapycouldbeadministered

indoubletcombinationssuchasRevlimid®-dexorVelcade®-dex;ortripletcombinationssuchas

Revlimid®-Velcade®-dexorVelcade®-cyclophosphamide-dex.

In2015,CoMMpassreacheditstargetenrollmentof1,000MMpatients,aremarkableachievementina

relativelyrarediseaseandatestamenttothecommitmentofpatientstohelpadvancethefieldofMM.

CoMMpassinvolvesanactiveassessmentschedule,includingbonemarrowsamplesatbaseline,at

responsetotreatment,andatrelapse.Eachpatientisfollowedforuptoeightyears.Preplannedinterim

analysesoccureverysixmonths.

Executingproperlyonsuchanambitiousinitiativeneedsmultipleplayers.CoMMpassisamulti-site,

multi-nationalstudyinvolvingnon-profit,industry,andacademicpartners.Approximately90


12

communityandacademiccancercentersfromacrossNorthAmericaandEuropeareparticipatinginthe

study.Providingfinancialandscientificsupport,industrypartnersincludeTakedaPharmaceuticalsCo.

Ltd(formerlyMillenniumPharmaceuticals,Inc.);Amgen,Inc.(formerlyOnyxPharmaceuticals,Inc.);

JanssenPharmaceuticals,Inc.;andBristol-MyersSquibbCo.OthercollaboratorsincludeTGen,GNS

Healthcare,SpectrumHealthHospitals,theDepartmentofVeteransAffairs,theUSOncologyNetwork,

andtheVanAndelResearchInstitute.Afteraninitialperiodofprioritizedaccess,participating

institutionshaveagreedtogiveupintellectualpropertyandpatentrightsonthedatatothepublic

domain.Creatinganintellectualproperty-freezonehasallowedthesevariousconstituentsto

collaboratemaximallyondataanalysisandsharinginitiatives,unhinderedbytheusualconcernsaround

protectingone’swork–essentiallybreakingdownthedatasilosthatimpederesearchtodayand

acceleratingthepaceofresearchinordertobringnewtreatmentstopatientsasquicklyaspossible.

WhatWeHaveLearnedSoFarFromCoMMpass

Duetoregularinterimanalyses,importantfindingshavebeguntoemergefromCoMMpass.Baseline

characteristicsoftheCoMMpasspopulation(Figure2)5showbroadrepresentationandareconsistent

withcharacteristicsofMMpatientsinthegeneralpopulation.Basedontheseventhinterimanalysis

(IA7),theaverageagewas64yearsandthemajorityofparticipantsweremalesofnon-Hispanic/non-

Latinodescent.Approximately18%ofCoMMpasspatientsself-reportedasAfricanAmerican,an

importantfeature,giventhehigherincidenceofpersonsofAfricandescentintheMMpopulation

comparedtothegeneralpopulation.3GenomicalterationsthatwerefirstobservedbyMMGIhavebeen

confirmedbyCoMMpass(Table1).


13

Figure2.CoMMpassDemographicsAreinLineWithWhatIsSeenintheBroaderPopulationofMMPatients,inParticulartheAfricanAmericanContribution

AttheannualmeetingoftheAmericanSocietyofHematology(ASH)in2015,sevenCoMMpass-related

abstractswerepresented,basedontheIA7dataonarangeoftopicssuchasinitiatingtrunkmutations

anddistinctmolecularsubtypes,symptomburdeninolderpatientswithMM,andassociationsbetween

performancestatusandhealth-relatedqualityoflife(Table2).6-12InanabstractbyManojlovicetal.,

AfricanAmericanswerereportedtobenomorestatisticallylikelytohaveahigh-riskmutationburden

thanpersonsofEuropeandescent.6

3

CoMMpass - Demographics

CoMMpass demographics are in line with what is seen in the broader population of MM patients, in particular the African-American contribution


13

Figure2.CoMMpassDemographicsAreinLineWithWhatIsSeenintheBroaderPopulationofMMPatients,inParticulartheAfricanAmericanContribution

AttheannualmeetingoftheAmericanSocietyofHematology(ASH)in2015,sevenCoMMpass-related

abstractswerepresented,basedontheIA7dataonarangeoftopicssuchasinitiatingtrunkmutations

anddistinctmolecularsubtypes,symptomburdeninolderpatientswithMM,andassociationsbetween

performancestatusandhealth-relatedqualityoflife(Table2).6-12InanabstractbyManojlovicetal.,

AfricanAmericanswerereportedtobenomorestatisticallylikelytohaveahigh-riskmutationburden

thanpersonsofEuropeandescent.6


14

Table2.CoMMpass-RelatedAbstractsPresentedatASHMeeting2015

Authors Institution Title

Fiala,etal.7 WashingtonUniversitySchoolofMedicine

TheAssociationBetweenPerformanceStatusandHealth-RelatedQualityofLife

Fiala,etal.8 WashingtonUniversitySchoolofMedicine

TheAssociationofInternationalStagingSystem(ISS)StagewithDiseaseandSymptomBurdeninPatientswithNewlyDiagnosedMultipleMyeloma

Gruber,etal.9 GNSHealthcare(A) InvestigationofMechanismsofResponseinMultipleMyelomaViaBayesianCausalInference:AnEarlyAnalysisoftheCoMMpassStudyData

Keats,etal.10 TranslationalGenomicsResearchInstitute(TGEN)(A)

IdentificationofInitiatingTrunkMutationsandDistinctMolecularSubtypes:AnInterimAnalysisoftheMMRFCoMMpassStudy

Keller,etal.11 WashingtonUniversitySchoolofMedicine

PresentingCharacteristicsandSymptomBurdenofNewlyDiagnosedOlderMultipleMyelomaPatientsintheCoMMpassStudy

Lagana,etal.12 IcahnSchoolofMedicineatMountSinai

TowardsaNetwork-BasedMolecularTaxonomyofNewlyDiagnosedMultipleMyeloma

Manojlovic,etal.6

TGEN(A) In-DepthMolecularProfilingofMultipleMyelomainAfricanAmericans

(A)=MMRFcollaborator;ASH=AmericanSocietyofHematology.

OtherpreliminaryfindingsfromIA7demonstrateimprovedprogression-freesurvivalwithtriplettherapy

versusdoublettherapy(Figure3).9,10,13Researchalsoindicatesimprovedprogression-freesurvivalwith

triplettherapyfollowedbystemcelltransplantcomparedtotriplettherapyalone(Figure4).9,13Given

thepreliminarynatureofthesefindings,furtherworkmustbedonetoconfirmtheresultsandshare

themwiththeresearchcommunity.Eventually,thesedatawillhelpcontributetoaclearertreatment

pathwayforeachMMpatientbasedonthecharacteristicsofhisorherdisease.


15

Figure3.Progression-FreeSurvival(FirstPD)byFirst-LineTherapyClassification(in>3%ofPatients)

Bortezomib-basedtriplettherapyispredominantlybortezomib-lenalidomide-dexamethasone.Bortezomib-baseddoublettherapyincludedbortezomibplusdexamethasone.IMID/carfilzomib-basedtriplettherapyincludedtheimmunomodulatorydrug(IMID)lenalidomidepluscarfilzomibplusdexamethasone.IMID-baseddoublettherapyincludedlenalidomideplusdexamethasone.PD=progressivedisease.

1.0

Bortezomib-based TRIPLET Bortezomib-based DOUBLETIMID/Carfilzomib-based TRIPLETIMID-based DOUBLET

MMRF CoMMpass – IA7Progression-free Survival (First PD)

By First-line Therapy Classification (in >3% of patients)

0.8

Prop

ortio

n of

Pat

ient

s

Time (months)

0.6

0.4

0.2

0.0

0 4 8 12 16 20 24 28 32 36 40


15

Figure3.Progression-FreeSurvival(FirstPD)byFirst-LineTherapyClassification(in>3%ofPatients)

Bortezomib-basedtriplettherapyispredominantlybortezomib-lenalidomide-dexamethasone.Bortezomib-baseddoublettherapyincludedbortezomibplusdexamethasone.IMID/carfilzomib-basedtriplettherapyincludedtheimmunomodulatorydrug(IMID)lenalidomidepluscarfilzomibplusdexamethasone.IMID-baseddoublettherapyincludedlenalidomideplusdexamethasone.PD=progressivedisease.


16

Figure4.Progression-FreeSurvivalWithorWithoutTransplant

Seefootnotesinpreviousfigureforbortezomib-orcarfilzomib-basedtripletcombinations.

WhatWeExpecttoLearnFromCoMMpass

AstheCoMMpassdatacontinuetomature,itistheMMRF’sintentthatthefindingswillhelptoanswer

someofthequestionsmostimportanttopatients,including:Ismygenomicprofilepredictive?Howis

mydiseasedoing?ShouldIbeonthreedrugs?ShouldIhaveatransplant?IfandwhenIrelapse,what

shouldIbethinkingabout?Similarlyforclinicians,CoMMpasswillhopefullybegintoanswerquestions

suchas:HowandwhenshouldIcombinetherapies?HowshouldIsequencetherapy?Whichclinicaland

genomicvariablespredicttreatmentresponse?Whatistheroleofmaintenancetherapywhenthe

patientisexperiencingacompleteresponsetotherapy?

CoMMpassmayalsoeventuallyhelpustounderstandtheroleofminimalresidualdisease(MRD),or

low-leveldiseaseoccurringduringaperiodofremission.Effortsarecurrentlyunderwaytoimprovethe

abilitytodetectandquantifyMRDinordertomoreaccuratelyassessresponsetotreatment,thereby

1

0.8

Prop

ortio

n of

Pat

ient

s

Days in Study

0.6

0.4

0.2

00

Group Hazard Ratio p-value

Triplet with transplant 0.3558

Triplet w/o transplant 1.6321

<.0001

0.0005

200 400 600 800 1,000 1,200

MMRF CoMMpass - IA7Progression-free Survival

With or Without Transplant


17

enablingmoreappropriateandtimelytreatmentdecisions.Researchersarecomparingtheeffectiveness

ofmeasuringMRDusingflowcytometryversusnext-generationsequencing,aswellasevaluatingthe

potentialformeasuringcirculatingmyelomatumorcellsinthebloodversusneedingabonemarrow

biopsy.

TheLearningNetwork

TheLearningNetworkencompassesinitiativesdesignedtosharedataandfacilitatecollaborationand

discovery,suchastheGatewaywebportalsandtheMyelomaDiseaseModeldescribedbelow.

Translationalresearchinitiatives,alsoapartofTheLearningNetwork,helpbringpotentialtherapies

from“benchtobedside”bytestingtheoreticaldiscoveriesgeneratedinTheDataBankstageina

laboratorysettingpriortotestinginhumans.

ResearcherandCoMMunityGatewayWebPortals

TheResearcherGatewaywaslaunchedin2013asanopen-accessresearchportalservingasadata

repositoryforCoMMpassandothergenomicand/orclinicalstudies.BuildingontheMMRF’sexperience

withtheMMGP,theResearcherGatewayisdesignedtohaveauser-friendlyinterfacethatenables

cliniciansandresearcherstoviewdatasetsandenterqueries.Thewebportalhousesgenomic,clinical,

andoutcomesdatainoneeasilyaccessiblelocation.Patientdataarede-identifiedtoprotectpatient

privacyandallowresearcherstoextractonlythespecificinformationinwhichtheyareinterested.

TheCoMMunityGatewayenablesCoMMpassStudyparticipantsandotherMMpatientstoconnectwith

eachother,basedontheirsubtypeandspecificdiseasecharacteristics(see

THEPATIENT

THEDATABANK

THELEARNINGNETWORK

THECLINIC


MMGI

CoMMpass

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Gateways



MMRC


- Immune therapies

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THE

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k

MM

RC

- M

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ular

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erap

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- Im

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biopsy.

TheLearningNetwork
















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https://community.themmrf.org/).ThewebportalalsoallowsMMpatientstobematchedwithongoing

clinicaltrialsaccordingtotheiruniqueprofileandtreatmentneeds.

MyelomaDiseaseModel

OnenotablecollaborationfortheMMRFiswithGNSHealthcare,aleadingprecisionmedicinecompany

thatappliescausalmachinelearningtechnologytomatchhealthinterventionstoindividualpatients.

UsingdatageneratedbyCoMMpass,theMMRF/GNSHealthcarepartnership,alsotermedtheMyeloma

DiseaseModel,isidentifyingpotentialdriversofclinicaloutcomesandtheirassociatedmolecular

pathways.Interimresultshaverecentlybeenpresented.9

TranslationalNetwork

TheMMRFrecentlyestablishedandsupportsatransformativeMMRFTranslationalNetworkof

Excellence,whichisfocusedonthemostpromisingresearchonnovelpreclinicalmodelsfornewtargets

anddrugvalidation,immunebiology,immunetherapeutics,andMRDinmyelomaandmyeloma-related

diseases.Thisgroundbreakinginitiativehasbeenmadepossibleduetodecade-longeffortsbythe

MMRFtogenerateassetsandcreateahighlyintegratedclinicalconsortiumnecessaryforsuchatask.

Inahighlycollaborativemanner,the4to6leadingacademiccentersinvolvedintheTranslational

NetworkofExcellencewilluseandsharetheircuttingedgetechnologies,platforms,andtoolsto

accomplishtheambitiousgoalofrapidlyadvancingscientificfindingstotheclinic.DuetotheMMRF’s

commitmenttotransparency,datageneratedthroughthiseffortwillbemadefreelyavailablethrough

theMMRFscientificportals,andcelllines/modelsandothertoolscouldbeobtainedthroughadditional

resourceswithinthenetwork.ThehopeisthattheMMRFTranslationalNetworkofExcellencewillbe

thecatalystneededtosparkessentialandremarkableprogressformyelomapatientsandcouldserveas

amodelforothercancers.


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biopsy.

TheLearningNetwork
















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MyelomaDiseaseModel





















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MyelomaDiseaseModel





















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MyelomaDiseaseModel





















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MyelomaDiseaseModel





















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TheClinic

TheClinicrepresentstheclinicaltrialcomponentofthemodelinwhichinvestigationaltherapies,

generatedfromdiscoveriesmadeinTheDataBankandTheLearningNetwork,aretestedinpatients

withMMfortheirsafety,efficacy,andfeasibilityasreal-worldtreatmentoptions.

MultipleMyelomaResearchConsortium

ThedesignandimplementationoftheseclinicaltrialswouldbeperformedinpartbytheMultiple

MyelomaResearchConsortium(MMRC),whichwascreatedbytheMMRFin2004toacceleratethe

launchandcompletionofPhase1and2studiesofnovelagentsandcombinations.TheMMRC–

comprisedof22centersintheUSandCanada–employsauniquecollaborativemodel,bringing

togetheracademicresearchcentersandindustrypartnersinorderthatnewtreatmentscanbebrought

topatientsasquicklyaspossible.Over70MMRC-facilitatedtrialshavebeenlaunchedtodatetotest

molecularlytargetedtherapies,immunetherapies,andothernoveltherapies(Figure5).Precision

medicineisnotjustaboutmolecularlytargetedtreatments;immuneandnovelagentswilllikelybe

neededincombinationformany/allpatients,anditisimportanttohavearobustportfoliosothatthere

aretrialsforeverypatient/subtype.Giventhisbroadandextensiveexperience,theMMRCisideally

positionedtoserveinthePrecisionMedicineModelastheumbrellaorganizationtorapidlytestideas

andhypothesesintargetedpopulationsastheyemergefromTheDataBankandTheLearningNetwork.

THEPATIENT

THEDATABANK

THELEARNINGNETWORK

THECLINIC


MMGI

CoMMpass

Registry

Gateways



MMRC


- Immune therapies

- Novel therapies

THE

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ORKTH

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Figure5.MMRCTrialPipeline

ALK=anaplasticlymphomakinase;BTK=Bruton’styrosinekinase;CAR=chimericantigenreceptor;CDK=cyclin-dependentkinase;CRM1=chromosomalmaintenance1;FGFR3=fibroblastgrowthfactorreceptor3;HDAC=histonedeacetylaseinhibitors;HSP90=heatshockprotein90;IDH1/2=isocitratedehydrogenase1/2;IGF-1=insulin-likegrowthfactor-1;KSP=kinesinspindleprotein;PD-1=programmeddeathreceptor1;PDL-1=programmeddeathligand1.

NextStepsfortheCoMMpassStudyandforMMResearch

TheongoingCoMMpassStudy,representingthecornerstoneoftheMMRF’sPrecisionMedicineModel,

hasalreadyprovidedvaluableinsightsintotopicssuchasthediversebaselinecharacteristicsofnewly

diagnosedMMpatients,theeffectivenessoftripletversusdoublettherapy,andtheimportanceofstem

celltransplantation.Asthedatacontinuetomature,patientsandclinicianswillbebetterabletoanswer

keyquestionsintheclinicaldecision-makingprocess,suchashowandwhentocombinetherapyandto

sequencetherapy.Inaddition,thegenomicandclinicaldatageneratedfromCoMMpasswillenhance


20











21

theunderstandingofunderlyingdiseasemechanismsandhowtheychangeovertime,helptoidentify

newdrugtargets,andallowexplorationoftheinterplayoftargetedtherapyandimmunetherapy,

amongotherfactors.CoMMpassprovidesaroadmapforthefutureofMMtreatment.Theultimate

goalisforallpatientswithMMtohavegenomicandimmuneprofilinginorderforthemtogetthebest

possibletreatmentfortheirparticulardisease.

TheMMRF’sPrecisionMedicineModelenablesacomprehensiveend-to-endapproachthatstartswith

datagenerationandintegrationinTheDataBank,collaborationanddiscoveryinTheLearningNetwork,

andacceleratedclinicaltrialsinTheClinic.ThePrecisionMedicineModel,withanemphasisonopen-

accessdatasharingandanalysisandmulti-stakeholderinvolvement,providesaninvaluabletemplate

thatcouldbeappliedtootherdiseasestates,particularlyrareorheterogeneousdiseaseswheredata

andpatientsarescarce.

ThroughthecollaborativeandintegratedapproachofthePrecisionMedicineModel,theMMRF

representsanewandexcitingerainmedicine,onethatfocusesonimprovingthelivesofpatientsas

quicklyandefficientlyaspossible.


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Glossary/AcronymList

Antibody=alarge,Y-shapedproteinusedbytheimmunesystemtoidentifyandneutralizepathogens

CoMMpassStudy=ClinicalOutcomesinMultipleMyelomatoPersonalAssessmentofGeneticProfiles

study;alarge-scale,longitudinalstudyinitiatedin2011tounderstandmoleculardriversofMMat

diagnosisandatotherkeytimepoints

CoMMunityGateway=webportalforCoMMpasspatientsandotherpatientswithMMtosharetheir

journeyandbematchedwithclinicaltrials

IA7=theseventhinterimanalysisoftheCoMMpassStudy

Mproteins=abnormalantibodiesthatcancollectinblood,urine,andorgans,ultimatelycausingbone

damage,kidneyfailure,andimpairedimmunesystemfunction

MM=multiplemyeloma;atypeofbloodcancer,orhematologicmalignancy,inwhichabnormalplasma

cellsareoverproducedinthebonemarrow

MMGI=MultipleMyelomaGenomicsInstitute

MMGP=MultipleMyelomaGenomicsPortal

MMRC=MultipleMyelomaResearchConsortium

MMRF=MultipleMyelomaResearchFoundation

MRD=Minimalresidualdisease

Plasmacell=atypeofwhitebloodcellthatproduceantibodies

ResearcherGateway=anopen-accessresearchportalservingasadatarepositoryforCoMMpassand

otherMM-relatedstudies

SEER=Surveillance,Epidemiology,andEndResults(aUSNationalCancerInstituteprogram)81445CoMMpassWhitePaper

23

Whitebloodcells=cellsoftheimmunesysteminvolvedinfightinginfection


24

References

1. GhobrialIM,LandgrenO.HowItreatsmolderingmultiplemyeloma.Blood.2014;124(23):3380-

3388.

2. LohrJG,StojanovP,CarterSL,etal.Widespreadgeneticheterogeneityinmultiplemyeloma:

implicationsfortargetedtherapy.CancerCell.2014;25(1):91-101.

3. NationalCancerInstituteSEERProgram.SEERstatfactsheets:myeloma.Availableat:

http://seer.cancer.gov/statfacts/html/mulmy.html.AccessedMay25,2016.

4. ChapmanMA,LawrenceMS,KeatsJJ,etal.Initialgenomesequencingandanalysisofmultiple

myeloma.Nature.2011;471(7339):467-472.

5. MultipleMyelomaResearchFoundation.ResearcherGateway:ExploreIA7:Demographics

Analysis.Availableat:https://research.themmrf.org/rp/explore.AccessedJune14,2016.

6. ManojlovicZ,ChristoffersonA,LegendreC,etal.In-depthmolecularprofilingofmultiple

myelomainAfrican-Americans[abstract].Blood.2015;126(23):2973.

7. FialaMA,KellerJ,SladeM,etal.Theassociationbetweenperformancestatusandhealth-

relatedqualityoflife[abstract].Blood.2015;126(23):3312.

8. FialaMA,SladeM,KellerJ,etal.TheassociationofInternationalStagingSystem(ISS)stagewith

diseaseandsymptomburdeninpatientswithnewlydiagnosedmultiplemyeloma[abstract].

Blood.2015;126(23):2115.

9. GruberF,HayeteB,KeatsJJ,etal.Investigationofmechanismsofresponseinmultiplemyeloma

viaBayesiancausalinference:anearlyanalysisoftheCoMMpassstudydata[abstract].Blood.

2015;126(23):1794.

10.KeatsJJ,SpeyerG,LegendreC,etal.Identificationofinitiatingtrunkmutationsanddistinct

molecularsubtypes:aninterimanalysisoftheMMRFCoMMpassStudy[abstract].Blood.

2015;126(23):722.


23

Whitebloodcells=cellsoftheimmunesysteminvolvedinfightinginfection


24

References

1. GhobrialIM,LandgrenO.HowItreatsmolderingmultiplemyeloma.Blood.2014;124(23):3380-

3388.

2. LohrJG,StojanovP,CarterSL,etal.Widespreadgeneticheterogeneityinmultiplemyeloma:

implicationsfortargetedtherapy.CancerCell.2014;25(1):91-101.

3. NationalCancerInstituteSEERProgram.SEERstatfactsheets:myeloma.Availableat:

http://seer.cancer.gov/statfacts/html/mulmy.html.AccessedMay25,2016.

4. ChapmanMA,LawrenceMS,KeatsJJ,etal.Initialgenomesequencingandanalysisofmultiple

myeloma.Nature.2011;471(7339):467-472.

5. MultipleMyelomaResearchFoundation.ResearcherGateway:ExploreIA7:Demographics

Analysis.Availableat:https://research.themmrf.org/rp/explore.AccessedJune14,2016.

6. ManojlovicZ,ChristoffersonA,LegendreC,etal.In-depthmolecularprofilingofmultiple

myelomainAfrican-Americans[abstract].Blood.2015;126(23):2973.

7. FialaMA,KellerJ,SladeM,etal.Theassociationbetweenperformancestatusandhealth-

relatedqualityoflife[abstract].Blood.2015;126(23):3312.

8. FialaMA,SladeM,KellerJ,etal.TheassociationofInternationalStagingSystem(ISS)stagewith

diseaseandsymptomburdeninpatientswithnewlydiagnosedmultiplemyeloma[abstract].

Blood.2015;126(23):2115.

9. GruberF,HayeteB,KeatsJJ,etal.Investigationofmechanismsofresponseinmultiplemyeloma

viaBayesiancausalinference:anearlyanalysisoftheCoMMpassstudydata[abstract].Blood.

2015;126(23):1794.

10.KeatsJJ,SpeyerG,LegendreC,etal.Identificationofinitiatingtrunkmutationsanddistinct

molecularsubtypes:aninterimanalysisoftheMMRFCoMMpassStudy[abstract].Blood.

2015;126(23):722.


25

11.KellerJ,FialaMA,SladeM,etal.Presentingcharacteristicsandsymptomburdenofnewly

diagnosedoldermultiplemyelomapatientsintheCoMMpassstudy[abstract].Blood.

2015;126(23):3307.

12.LaganaA,ReadheadB,PerumalD,etal.Towardsanetwork-basedmoleculartaxonomyofnewly

diagnosedmultiplemyeloma[abstract].Blood.2015;126(23):840.

13.GiustiK.TheMMRFPrecisionMedicineModel.Availableat:

http://www.themmrf.org/pmwc2016.AccessedApril19,2016.

Multiple Myeloma Research Foundation383 Main Avenue, 5th Floor

Norwalk, CT 06851203.229.0464themmrf.org

Documents

The MMRF CoMMpass StudySM · there were an estimated 30,330 new cases of myeloma in the United States in 2016, representing 1.8% of all new cancer cases.3 Myeloma is estimated to