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Multiple myeloma

ESMO/ACF Patient Guide Seriesbased on the ESMO Clinical Practice Guidelines


Multiplemyeloma:aguideforpatients-InformationbasedonESMOClinicalPracticeGuidelines-v.2017.1 Page1

ThisdocumentisprovidedbytheAnticancerFundwiththepermissionofESMO.The information in this document does not replace amedical consultation. It is for personal use only and cannot bemodified,reproducedordisseminatedinanywaywithoutwrittenpermissionfromESMOandtheAnticancerFund.

MULTIPLEMYELOMA:AGUIDEFORPATIENTS

PATIENTINFORMATIONBASEDONESMOCLINICALPRACTICEGUIDELINESThisguide forpatientshasbeenpreparedby theAnticancerFundasa service topatients, tohelppatients and their relativesbetterunderstand thenatureofmultiplemyelomaandappreciate thebesttreatmentchoicesavailableaccordingtothesubtypeofdisease.Werecommendthatpatientsask their doctors aboutwhat tests or types of treatments are needed for their type and stage ofdisease. The medical information described in this document is based on the clinical practiceguidelines of the European Society forMedicalOncology (ESMO) for themanagement ofmultiplemyeloma.ThisguideforpatientshasbeenproducedincollaborationwithESMOandisdisseminatedwith the permission of ESMO. It has been written by a medical doctor and reviewed by twooncologists from ESMO including the leading author of the clinical practice guidelines forprofessionals. It has also been reviewed by representatives from the European Oncology NursingSociety(EONS)andthepatientrepresentativefromESMO’sPatientAdvocatesWorkingGroup.MoreinformationabouttheAnticancerFund:www.anticancerfund.orgMoreinformationabouttheEuropeanSocietyforMedicalOncology:www.esmo.orgForwordsmarkedwithanasterisk,adefinitionisprovidedattheendofthedocument.



Tableofcontents

FactsheetaboutMultipleMyeloma.......................................................................................................3

DefinitionofMultipleMyeloma.............................................................................................................4

IsMultipleMyelomafrequent?..............................................................................................................5

WhatcausesMultipleMyeloma?...........................................................................................................6

HowisMultipleMyelomadiagnosed?...................................................................................................7

Whatisitimportanttoknowtogettheoptimaltreatment?................................................................9

Whatarethetreatmentoptions?........................................................................................................11

Whatarethepossiblesideeffectsofthetreatments?........................................................................15

Whathappensafterthetreatment?....................................................................................................17

Definitionsofdifficultwords................................................................................................................19

ThistextwaswrittenbyDrAlbertoMussetti(fortheAnticancerFund)andreviewedbyDrAnaUgarte(AnticancerFund),DrSvetlanaJezdic(ESMO),Prof.PhilippeMoreau(ESMO),Prof.ChristianBuske(ESMO),VanessaMarchesi,PhD(ESMO),ClaireBramley(ESMO),Prof.Jean-YvesDouillard(ESMO),AnitaMarguliesBSNRN(EONS),PatriciaBosman,MSc(EONS),AnandaPlate (ESMOPatientAdvocatesWorkingGroup;MyelomaPatients Europe),AlfonsoAguarón (MyelomaPatients Europe)andAnaVallejo(MyelomaPatientsEurope).



FACTSHEETABOUTMULTIPLEMYELOMADefinition:

- Multiplemyeloma is a cancer thatdevelops fromplasmacells*. Plasmacells area typeofwhitebloodcellmadeinthebonemarrow.Thesecellsarepartoftheimmunesystemandtheirfunctionistoproduceantibodies*whichprotectusfrominfections.

Diagnosis:- Specific symptoms* such as fatigue, more frequent infections, bone pain or spontaneous

fracturescanbepresentatdiagnosis.- Theteststhatarenecessarytomakeadiagnosisare:

o Detection of monoclonal protein* (an antibody* produced by plasma cells* inpatientswithmultiplemyeloma)inthebloodor24-hoururinesamples;

o Bonemarrowaspirate*orbiopsy* tomeasure thepercentageofmyelomacells inthebonemarrow;

o Evaluationofbonelesions*maybeperformedbyyourdoctor.Thiscanbedonebyeither a magnetic resonance imaging (MRI), a whole body low dose radiationcomputedtomography(CT)scan*orpositronemissiontomography(PET)*.

o Bloodteststoassesskidneyfunctionandlevelsofcalciumandhaemoglobin*.Treatment:

- Treatment is only required in case of symptomatic* disease (in the presence ofhypercalcemia*, kidney problems, anaemia*or bone lesions*) or high risk asymptomaticdisease*.

- Firstlinetreatmentisdividedintotwogroups:o Patientsingoodphysicalconditionwhoaresuitableforautologoustransplant*:4-6

cyclesofbortezomib*-basedchemotherapy*followedbyhighdosemelphalan*andautologoustransplant*aspartofdiseasereductionafterconsolidation*.

o Patients with significant comorbidities* or who are not physically fit enough toundergoautologoustransplant*: oralcombinationsofmelphalan*andprednisone*plusnewerdrugsarethestandardtreatmentsinthissetting.Inthiscasethereisnoneedforfurthertherapyaftertheendoftheplannedcyclesoftreatment.

- Relapsed*andrefractory*diseasetreatment:The choice of treatment depends on several parameters regarding the patient (age andhealth status) and previous therapies. Autologous transplant* can still be an option.Allogeneictransplant*shouldbecarriedoutonlyinthecontextofclinicaltrials.

- Enrolment in clinical trials is strongly recommended for both first line and subsequenttreatmentssincethereareseveralneweractivedrugscurrentlybeingtested.

Follow-up:- Sincemultiplemyeloma is characterisedby recurrent symptoms*,a long term follow-up is

necessarytodetectdiseaserelapse*asquicklyaspossibletoavoidorgandamage.- Bloodandurinetestsshouldbecarriedoutevery2-3months.Radiologicalexams*andbone

marrowexamination*shouldbedonewithindividualevaluation.- If themultiplemyeloma comesback, the goal is to obtain a further responseby choosing

betweendifferentavailabletherapies.



DEFINITIONOFMULTIPLEMYELOMAMultiplemyelomaisacancerofplasmacells*.Theseareatypeofwhitebloodcellwhichoriginateinthe bone marrow. The function of plasma cells* is to produce antibodies*. Antibodies* occurnaturally in our immune system and help protect us from infections caused by agents such asbacteria or viruses.When plasma cells* grow in an uncontrolledway it suppresses the growth ofotherbonemarrowcells.Thiscanleadtoconditionssuchasanaemia*,bleedingdisorders,infectionsandbonelesions*.Inmostcasesthereisalsoanabnormalproductionofnon-functionalantibodies*calledmonoclonalprotein*. Inmultiplemyelomaa largeamountofa single typeofabnormalantibody* isproducedwhichhasnousefulroleinthebody.Inmostcases,treatmentscaninducelongintervalswithoutanysymptoms*ofthediseaseallowingpatientstohaveagoodqualityoflife.Therefore,multiplemyelomacanbeconsideredasachroniccondition.

Illustrationofbonemarrowwhereplasmacells*aremade:normalplasmacells*andabnormalplasmacells*ofmultiplemyelomaareshown.



ISMULTIPLEMYELOMAFREQUENT?Multiplemyelomaisnotascommonasbreast,colon,lungorprostatecancerbutitisconsideredtobethesecondmostcommonbloodcancerafterNon-Hodgkinlymphomas*.Itsincidence*increaseswithage,thusitisconsideredadiseaseoftheelderly.Theprobability thataperson inEuropewilldevelopmultiplemyelomaduringhisorher lifetime is0.31%. Thismeans for example, in Europe, 4 to 6 caseswill be diagnosed among 100 000 peopleeveryyear.Theincidence*islowerforwomen.Medianageatdiagnosisis72years.IncidenceratesarehigherinpeopleofAfro-AmericanoriginandlowerinAsians.



WHATCAUSESMULTIPLEMYELOMA?Todaythecausesofmultiplemyelomaarenotclear.Someriskfactors*havebeenidentified.Ariskfactor* increases the chance of cancer occurring, but is neither necessary nor sufficient to causecancer.Ariskfactor*isnotacauseinitself.Some people with these risk factors* will never develop multiple myeloma and some peoplewithoutanyoftheseriskfactors*maydevelopmultiplemyeloma.Themainriskfactors*ofmultiplemyelomaare:

- Monoclonal Gammopathy of Uncertain Significance (MGUS): mostmultiple myelomas arise from a benign* condition known as MGUS.People affected by this condition have a little abnormal production ofmonoclonal protein* without any symptoms*. The majority of peoplewiththisconditionwillneverdevelopsymptomatic*multiplemyeloma.InmostcasesMGUSisdiscoveredbyaccidentduringroutinebloodtests.

- Older age: the chance of developing multiple myeloma increases with

age.

- Genetic predisposition: the incidence* of multiple myeloma is slightlydifferent between ethnicities. In addition, female sex is a modestprotectivefactorinmultiplemyeloma.

- Environmental factors: radiation exposure, benzene and insecticideshavebeenassociatedwithmultiplemyeloma.Theseassociationshaveaminorroleinthedevelopmentofmultiplemyeloma.

Besides the presence of MGUS and age, the evidence for all the other riskfactors*hasnotbeenproven.



HOWISMULTIPLEMYELOMADIAGNOSED?MultiplemyelomaoftenarisesfromMGUS.IfMGUSispresent,patientsaremonitoredbyadoctor.If MGUS progresses and develops into multiple myeloma prompt treatment can prevent thedevelopmentofdiseasesymptoms*.Symptoms*characterisingmultiplemyelomaSymptoms*causedbybonemarrowinfiltration:

− Fatigue: this is thephysical feelingofbeing tiredevenafter rest. It is related toanaemia*(lowlevelofhaemoglobin*)andtotheabnormalpresenceofmultiplemyelomainthebody.

− Bonepainandfractures:sometimesprogressivelyintensebonepainispresentwhichrarelyresponds to commonpainkillers. This pain is often felt in the spine, ribs or hip bones andcouldbearesultofbonefractures.

− Infections: infectionsmay occurmore frequently and these infectionsmay take longer tohealthaninthepastinthesameperson.Thisisrelatedtobothadecreasedwhitecellcountandtheabnormalfunctionofplasmacells*.

− Bleeding: rarely,abnormalbleedingmayoccur (forexample,whenbrushingyour teeth)oryou may notice that bruising or haematomas* occur more easily. This is related to lowplatelet* count and to abnormalities inmechanisms responsible for stopping the bleedingbecauseofmonoclonalprotein*intheblood.

Symptoms*orsignsrelatedtoexcessivemonoclonalprotein*production:

- Mildtoseverekidneyproblems:thisconditioniscausedbydirectdamagefrommonoclonalprotein*filteredbythekidneys.Usuallythisconditiondoesnotcausesymptoms*untilthedamageissevere.

- Amyloidosis*: this is caused by abnormal accumulation ofmonoclonal protein* in specificsitesofthebody(heart,kidneyetc.).Theabnormalstoresoftheproteincancausechronicinflammationandorgandamage.

- Peripheral neuropathy: this is a result of nerve damage caused by monoclonal protein*.Sensorydisturbances(tingling,alteredheatperceptioninhandsandfeetetc.)arethemostcommonsymptoms*.

Thediagnosisofmultiplemyelomaisbasedonthefollowingexaminations:Detectionofmonoclonalprotein*inthebloodor24-hoururinesamples:this isobtainedbyatestcalledproteinelectrophoresis*.Othertestsarethenperformed,suchasimmunofixation*(toidentifythetypesofmonoclonalprotein*present),andteststomeasurethelevelsofserumfreelightchain*.The percentage ofmyeloma cells in the bonemarrow is analysed using a bonemarrow aspirate*and/or biopsy*. Both procedures are minimally invasive, and last for about 10-15 minutes. Localanaesthesia* is used before the procedure and amild burning sensation should be expected. Thesamples obtained are necessary to quantify the percentage of plasma cells* present in the bonemarrowandtoperformgenetictests,suchasFluorescenceInsituHybridization(FISH)*.Thesetestsare helpful as they provide additional information on the prognosis* of the disease which isimportantsinceitcouldinfluencethechoiceoftreatment.



Evaluation of bone lesions*: a complete radiological skeletal bonescan is necessary to identify possible fractures or areas of diseaseinfiltration. Magnetic resonance imaging (MRI)* of the spine andpelvis ismoresensitivethanX-ray* indetectingbonelesions*.Thisis helpful to identify lesions when they are not yet causingsymptoms*. Awhole body low dose CT scan* or a PET scan*mayalsobeneededtoevaluatebonelesions*.Blood tests: completeblood cell count*, calcium, creatinine*, albumin*andbeta-2-microglobulin*levelsareallnecessarytoexamineifthediseaseissymptomatic*andforprognostic*reasons.

Thesetestsallowdifferentiationbetweenthreeconditions:MonoclonalGammopathyofUncertainSignificance (MGUS):abenign*conditionwhichrarely

developsintomultiplemyelomaandischaracterisedbyserummonoclonalprotein*<3g/dl;tumouralbonemarrowplasmacells*<10%;normalcalciumlevels,normalkidneyfunction*,normalhaemoglobin*levelsandnobonelesions*.

Asymptomatic* (smoldering) multiple myeloma: a pathologic condition which progresses tomultiplemyelomaata rateof10%per yearover the first5 years followingdiagnosis. It ischaracterised by serum monoclonal protein* >3g/dL or urinary monoclonal protein*>500mg/24hourand/ortumouralbonemarrowplasmacells*10-60%withoutanymultiplemyelomadefiningevents(listedinthetablebelow)oramyloidosis*.

Multiple myeloma: the symptomatic* condition which requires treatment. It has the samefeaturesof asymptomatic* (smoldering)multiplemyelomaplusmultiplemyelomadefiningevents(listedinthetablebelow).

Multiplemyelomadefiningevents DefinitionHypercalcemia* Serum calcium >1mg/dL higher than the upper limit of normal or

>11mg/dLKidneyproblems Creatinineclearance*<40mLperminorserumcreatinine*>2mg/dLAnaemia* Haemoglobin* value of >2g/dL below the lower limit of normal or

<10g/dLBonelesions* One or more bone lesions* on skeletal radiography, CT*, PET-CT* or

MRI*Bonemarrowplasmacells*excess Tumouralbonemarrowplasmacell*percentage>60%Veryhighserumfreelightchainratio*

Involved:uninvolvedserumfreelightchainratio*>100



WHATISITIMPORTANTTOKNOWTOGETTHEOPTIMALTREATMENT?Tochoosethebesttreatment,thedoctorneedstoconsidermanyaspects,takingintoaccountboththepatientandthemultiplemyeloma.Relevantinformationaboutthepatient

• General health status: this has to be evaluated with specific scoresrelatedtoyourdailyactivities.Thereareotherphysicalfactorsthatalsohavetobeevaluatedbeforestartingtreatment:1. heartfunction(electrocardiogram*andechocardiography*)2. respiratoryfunction(pulmonaryfunctiontests)3. liverandkidneyfunction(bloodtests)

• Personalmedical history: knowing relevant past or current health issues, such as previoussurgical procedures or chronic diseases (diabetes, atrial fibrillation, viral infections etc.), isnecessarytochoosethecorrecttreatment.

• Age: even if age itself should not be considered as theonly criterion to judge the generalstatusofapatient,therearestandardagelimitswhichareusedtodecideifapatientcouldbeeligibleforamoreintensivetherapy.Usually,beingyoungerthan65yearsallowspatientstoreceiveintensivetherapy,whilebeingolderthan70yearsexcludesthemfromthisoption.Forpeoplebetween65and70,thisdecisiondependsupontheirgeneralhealthstatus.

RelevantinformationaboutthemultiplemyelomaTreatmentformultiplemyelomaisnotnecessarywhentherearenosymptoms*.Disease staging* and cytogenetics* are not necessary for asymptomatic* (smoldering) multiplemyeloma.Staging*Informationaboutthestageofthediseaseisnecessarywhenmultiplemyelomaissymptomatic*andtreatmenthastobestarted.The information about stage is important to select the right treatment. The lower the stage, thebetter the prognosis*. The International Staging System (ISS) is a very helpful score used for thisdisease.Itreliesonlyontheserumlevelsofalbumin*andbeta-2-microglobulin*.

Stage DefinitionStageI Serumbeta-2-microgloblulin*<3.5mg/dlandserumalbumin*>3.5g/dlStageII NotstageIorIIIStageIII Serumbeta-2-microglobulin*>5.5mg/lCytogenetics*givesadditionalimportantinformationregardingprognosis*asitisknownthatsomegeneticabnormalitiesareassociatedwithapooreroutcome.



HowtomeasureresponsetotherapyTherapy efficacy is measured by reduction of monoclonal protein*, measured in blood serum orurine.Furthertests,e.g.bonemarrowevaluation*,maybedoneonanindividualbasisifyourdoctorthinkstheyarenecessaryorifyouareundergoingtreatmentaspartofaclinicaltrial.Typeofresponse DefinitionStringentcompleteresponse

Disappearanceofmonoclonalprotein*inserumorurine(immunofixation*negative,normalfreelightchainratio*,absenceoftumourplasmacells*inthebonemarrow)

Completeresponse Disappearanceofmonoclonalprotein*inserumand/orurine(immunofixation*negative,abnormalfreelightchainratio*,<5%plasmacells*inbonemarrow)

Verygoodpartialresponse

90%orgreaterreductioninserumproteinplusurineprotein<100mgper24horserumand/orurineproteindetectablebyimmunofixation*butnotwithelectrophoresis*

Partialresponse >50%reductionofserumproteinandreductionin24hurinaryproteinby>90%orto<200mgper24hInpatientswithoutmeasurableserumandurinemonoclonalprotein*levels,thedifferencebetweeninvolvedanduninvolvedfreelightchainlevels*canbeusedInpatientswithoutmeasurableserumandurinemonoclonalprotein*levelsandwithoutmeasurableinvolvedfreelightchainlevels*,bonemarrowplasma-cell*percentagecanbeusedAppearanceofanewbonelesion(s)*orincreaseofexistinglesion(s)ifthisistheonlymeasureofdisease

Minimalresponse Asforpartialremission*butserumorurineproteinreductioncomprisedbetween>25%but<49%

Stabledisease

Responsecriterianotfulfillingdefinitionofcompleteresponse,verygoodpartialresponse,partialresponse,minorresponse

Progressivedisease

AnyoneormoreofthefollowingcriteriaIncreaseof25%fromlowestconfirmedresponsevalueinoneormoreofthefollowingcriteria:Serummonoclonalprotein*orurinemonoclonalprotein*.Inpatientswithoutmeasurableserumandurinemonoclonalprotein*levels,thedifferencebetweeninvolvedanduninvolvedfreelightchainlevels*canbeusedInpatientswithoutmeasurableserumandurinemonoclonalprotein*levelsandwithoutmeasurableinvolvedfreelightchainlevels*,bonemarrowplasma-cell*percentagecanbeusedAppearanceofanewbonelesion(s)*orincreaseofexistinglesion(s)ifthisistheonlymeasureofdiseaseIncreaseincirculatingplasmacells*ifthisistheonlymeasureofdisease



WHATARETHETREATMENTOPTIONS?There are three questions to consider when selecting a treatment for multiplemyeloma:1) Is thedisease localised inonly oneplacewithout general involvementof thebones?2)Isthediseasesymptomatic*?3)Isautologousstemcelltransplantation*anoption?Answering these questions will help to decide which treatment to choose andwhenitshouldbestarted.1) Isthediseaselocalisedinonlyonesitewithoutgeneralinvolvementofthe

bones?In some rare cases, there is just one single localised site (for example, femoralbone lesion*) of the body affected by abnormal plasma cells*. In this scenario,whichiscalledsolitaryplasmocytoma,asystemictreatment*isnotrequired.Thetherapyofchoiceisradiotherapy*orsurgicalexcisionofthelesion.Thereafter,astrict follow-up is required since this condition often evolves into multiplemyeloma.2) Isthediseasesymptomatic*?Aresymptoms*present?Ifthediseaseisasymptomatic*(smolderingmyeloma),astrictfollow-up,usuallywithouttreatment,is required.Once there is evidenceofmultiple disease sites (diffusebonemarrow involvementormultiple bone lesions*), it is crucial tounderstand if there are signs and symptoms*of disease.Asystemictreatment*hastobestartedifthediseaseissymptomatic*.Thetreatmentwillusuallyincludetherapiesthat:

• treatmultiplemyelomasystemically(treatingmyelomacellsthroughoutthebody).• treat multiple myeloma locally (i.e. in specific sites of the body), such as surgery or

radiotherapy*ifsymptomatic*bonelesions*arepresent(e.g.backbonefractures).3) Isautologousstemcelltransplantation*anoption?Autologous stem cell transplantation* (with the patient’s own stem cells) gives the best diseaseresponseswhenincorporatedinthefirst-lineoftherapy.Evenifitisnowlesstoxicthaninthepast,this is reserved only for younger patients and those patients in good physical condition who cantolerate the side-effects of the procedure. Being older than 70 usually excludes patients fromundergoing stem cell transplantation. An exceptionmight bemade if an older patient is in goodphysical condition without other relevant health issues. This depends on an accurate clinicalevaluationofeachcase.Treatments listed below have their benefits, their risks and their contraindications. It isrecommendedthatyouaskyourdoctorabouttheexpectedbenefitsandrisksofeverytreatmentinorder tobe informedabout theconsequencesof the treatment. In caseswhere several treatmentoptionsareavailable,thechoiceshouldbediscussedaccordingtothebalancebetweenbenefitsandrisks.



First-linetreatmentplanforautologousstemcelltransplantation*candidatesPatients ingoodphysicalcondition(orthoseyoungerthan65)whoare candidates for autologous stem cell transplantation* usuallyreceive an induction treatment*. The aim of this is to reduce thedisease burden* before the transplantation. Once the diseaseburden*isreduced,thegoalistomaintainaresponseforaslongaspossiblewithanautologoustransplant*.Inductiontreatment*isusuallycomposedofathree-drugregimen:- Bortezomib*(V)/thalidomide*(T)/dexamethasone*(D)(VTD)- Bortezomib*(V)/cyclophosphamide*(C)/dexamethasone*(D)(VCD)- Bortezomib*(P)/doxorubicin*(A)/dexamethasone*(D)(PAD)- Lenalidomide* (R)/bortezomib* (V)/dexamethasone* (D) (RVD - this combination is not

approvedyetinEurope).Onetreatmentcycleusuallylasts21or28days.Responsetotreatmentisassessedbeforeeachcycle.The total number of cycles required to complete the induction treatment* ranges from 4 to 6,dependingonthetypeofresponse,therapyandyourhealthstatus.After the induction therapy*, a consolidation* phase is necessary to prolong the interval thatpatientsremainfreefromdisease.Inmultiplemyeloma,consolidation*isobtainedwithautologousstemcelltransplantation*.Thisprocessisprecededbythecollectionofautologous(ofthepatient)stem cells by a procedure called apheresis*. To stimulate the releaseof stem cells from thebonemarrow to thebloodstream, thepatient receivesa growth factor* (granulocyte-colony stimulatingfactor,G-CSF)aloneorincombinationwithchemotherapy*(cyclophosphamide*).Afterafewdays,whenthenumberofstemcellsrises,thepatientreceivestheapheresis*procedure.Thenumberofstemcellscanbedeterminedbymeansofbloodtests.Peripheralblood*isfilteredandstemcellsarecollected and frozen. Once the collection has been done and the patient has recovered from theprocedure,heorshecanbeadmittedfortheautologoustransplantation*.Thisprocedureconsistsofadministering high dose chemotherapy* (usually with a drug called melphalan*) followed byreinfusionofthepatients’ownstemcells.If the first transplantdoesnotgiveacompleteoralmostcomplete response,a secondautologoustransplantation*canbeperformedusuallywithin3-6monthsafterthefirst.Allogeneicstemcell transplantation*(fromadonor)shouldonlybecarriedout in thecontextofaclinicaltrial.First-linetreatmentplanforNONtransplantcandidatesPatientswho are not candidates for autologous stem cell transplantation* (70 years and older orpatientsinpoorphysicalcondition)areusuallytreatedwithathree-druginductionregimen.Frailerpatientscanbetreatedwithatwo-drugregimen.Threedrugregimens:

- Bortezomib*(V)/melphalan*(M)/prednisone*(P)(VMP)- Melphalan*(M)/prednisone*(P)/thalidomide*(T)(MPT)



Twodrugregimen:- Lenalidomide*(R)/dexamethasone*(D)(RD)- Bendamustine*/prednisone*- Melphalan*/prednisone*

Second-linetreatmentplanforrelapsed*orrefractory*diseaseParticipation inclinical trials shouldbeencouraged toallowpatients tobenefit fromnewdrugsorcombinationsofdrugswhicharecurrentlybeingtested.Considerations that should be taken into accountwhen choosing first-line treatment still apply tosecond-lineorsubsequenttherapies.Choicedependsonseveralfactorsregardingthepatient(age,healthstatus)andprevioustreatments(type,efficacy,tolerance).Thefollowingtherapiescanbeusedinthissetting:

- Lenalidomide*/dexamethasone*- Pomalidomide*/dexamethasone*:onlyforpatientswhohavealreadyfailed

onlenalidomide*andbortezomib*- Bortezomib* alone or in combination with dexamethasone* or pegilated

doxorubicin*- Carfilzomib*/lenalidomide*/dexamethasone*orcarfilzomib*/dexamethasone*- Ixazomib*/lenalidomide*/dexamethasone*: only for patients who have

alreadyfailedoneofprevioustherapies- Panobinostat*/bortezomib*/dexamethasone*: only for patients who have already failed on

bortezomib*andanimmunomodulatorydrug*(thalidomide*,lenalidomide*,pomalidomide*)- Elotuzumab*/lenalidomide*/dexamethasone*- Daratumumab* alone for patients who have already failed on proteasome inhibitors

(bortezomib*, carfilzomib*, ixazomib*) and immunomodulatory agents* (thalidomide*,lenalidomide*, pomalidomide*), and in combination with lenalidomide* anddexamethasone*, or bortezomib* and dexamethasone*, for the treatment of adult patientswithmultiplemyelomawhohavereceivedatleastonepriortherapy.

Autologous stem cell transplantation* could also be used in selected cases (in those with goodresponsetopreviousautologoustransplant*andwithdiseaseresponseoflongerthan2years).Allogeneicstemcell transplantation*(fromadonor)shouldbecarriedoutonly in thecontextofaclinicaltrial.TreatmentofmultiplemyelomacomplicationsItisveryimportantforthetreatmentofmultiplemyelomatocureitsorgan-relatedcomplications.Timingisfundamentaltopreventchronicorgandamageorlife-threateningevents.Impaired kidney function: almost fifty percent of patients affected by multiple myeloma haveimpairedkidneyfunction.Treatmentmayvarydependingonthegradeofkidneyimpairment.Alongwith systemic therapy*, oral and intravenous hydration* or even dialysis* could be part of thetreatment. It is fundamental to avoid the use of non-steroidal anti-inflammatory drugs, such asaspirinornimesulide,astheymaycausekidneydamage.



Bonepainorbonelesions*:bonedamageisfrequentinmultiplemyeloma.Itcanbeasymptomatic*or it may cause pain. In some cases, bone fractures can be the initial manifestation of multiplemyeloma and in this case an orthopaedic intervention is necessary. Besides surgical intervention,radiotherapy*canalsobeuseful.If bone lesions* are not present but there are early signs of bone erosion, a therapy with bonestrengthening drugs is suggested. Bisphosphonates* are the main drugs used for this purpose.Zoledronate*orpamidronate*aregivenbyintravenousinfusion.Thistreatmentshouldbedonefortwoyearsandinfectionsofthejawshouldbeexcludedbeforestartingthesedrugs.Increased blood calcium level: this is due to bone erosion. The extent of the increase can vary.Intravenousfluidsandbisphosphonates*arerequiredincaseofveryhighcalciumlevels.Anaemia*: this is related to low red blood cell count. There are several causes of anaemia* inmultiplemyeloma.Bonemarrow infiltrationbyabnormalplasmacells*and/or kidneydamagearethemostfrequentcauses.Bloodtransfusionscanbenecessaryinveryseverecases.Administrationof erythropoietin*, a drugwhich stimulates red blood cell production,may decrease the need fortransfusions.Infections:both chemotherapy* andmultiplemyeloma canweaken the immune system. For thisreason,yourdoctormaygiveyousomeanti-infectivedrugstopreventinfection.Incaseoffeverorothersignsofinfection,donothesitatetocontactyourdoctorasitcouldbeimportanttostartthecorrecttreatment.Theinfluenzavaccineishelpfulindecreasingtherateofrespiratoryinfection.Spinal cord compression: the cause of this complication is the presence of a localised mass(plasmocytoma)atbackbonelevelwhichcompressesthespine.Thiscanalsobecausedbybackbonefractures. Symptoms* are localised pain or nervous symptoms* such as tingling in the legs ormuscular weakness. You should seek medical attention immediately if you experience thesesymptoms* as this complication can lead to irreversible paralysis if not treated. Corticosteroids*,radiotherapy*orevensurgeryaretherapiesavailabletotreatthiscondition.



WHATARETHEPOSSIBLESIDEEFFECTSOFTHETREATMENTS?Side effects vary according to treatment type. A few of themost common side effects caused bymultiplemyelomatherapiesareasfollows:

- Appetiteloss:sometreatmentsmaycauseappetitelosswhichcanlastforafewdaysafterthe treatmentendsor sometimes longer. Try to eat smallermealsmoreoften thanusual,sincetheyareeasiertodigest.Avoidfatty foodsanddrinkplentyof liquids (approximately1.5-2L/day).

- Constipation: some drugs, such as thalidomide*, bortezomib* or dexamethasone*, cancauseconstipation.Thisisaverycommonsymptom*andyourdoctorcanprescribespecialmedication (laxatives) in case this occurs. It is very important to prevent constipation. Ifconstipation is present, drink plenty of liquids (2 litres/day of water/soda/tea etc.) andincludeexerciseinyourdailyroutine.

- Diarrhoea: this symptom* can be related to certain drugs, such as lenalidomide*, orbortezomib*, or to an unrelated infection. There are several remedies that can be useddependingonthecauseofthediarrhoea.Itisimportanttonotifyyourdoctorifthisoccurs.

- Hair loss: older chemotherapy* drugs can cause hair thinning or loss. Depending on thetherapy,itmaylastuntiltherapyiscompleted.Oncethetreatmentisfinished,yourhairwillgrowback.

- Infertility: Alkylating agents*, such as melphalan* (used for autologous transplantation*)

and cyclophosphamide* (used for stem cell collection), are more likely to cause this sideeffect. If you are taking thalidomide* or lenalidomide*, teratogenic* effectsmay occur. Ifyouareplanningtohavechildrenorthiscouldbeanoptioninyourfuture,remembertoaskyourdoctoraboutthisissue.Todaytherearesomewaystoreducethechanceofbecominginfertileandtocollectspermoreggsbeforestartingtreatment.

- Infections:virtuallyallchemotherapy*agentscan increasethe incidenceof infections.This

happensbecauseofareducednumberoralteredfunctionofwhitebloodcells.Thesecellsdefend our body from bacterial, viral or fungal infections. Bacterial infections and viralreactivationsarethemostcommon infectiouscomplicationsduringa treatmentand inthefollowingmonthsafteritiscompleted.Somedrugsareusuallyprescribedduringthisphaseto reduce the incidence* of this complication.Neutropenia* is a reduction of neutrophils,the fractionofwhiteblood cellswhose function is toprotectus frombacterial and fungalinfections.Ifyouhaveafeveroranyothersymptom*whileyouareneutropenic(withalownumber of neutrophils), it is important to contact a doctor as soon as possible since it ispossibletodevelopasevereinfectionrequiringhospitalization.Thereareafewtipstofollowtoreducethechancesofbecomingill:1)Avoidcrowdedplaces: thehigher thenumberofpeople, themore likely thechancesofbecomingill.Thisisespeciallytrueduringthefluseason(autumn/winter).2)Eathealthily:thismeansavoidingfoodsthatmaycarryinfections.Followstandardhygienerulesanddonoteatrawmeatorfish/seafoodorunpasteuriseddairyproducts.



3) Stay active: doing light physical activities, such as walking, can help you recover fromchemotherapy*-relatedfatigueanditwillkeepyourheart,lungsandmusclesingoodshape.Thisreducestheriskofinfectionandhelpsyourbodytocopewithstressfulconditions.

- Nauseaandvomiting:thissideeffectisusuallyrelatedtotraditionalchemotherapy*agents.Antiemeticagents*arecommonlyusedtopreventthissideeffect.Sometimes,ifpreventionisnotenough,otherdrugscanbeprescribedtotreatnauseaandvomiting.

- Peripheral neuropathy*: this is commonly related to bortezomib* and thalidomide*.Damage toperipheralnerves cancauseboth sensorydeficit (palmsand soles tingling)andpain.Thisdamageusuallyarisesgradually,startingwithfeetandhands.Itisimportanttotellyourdoctorifyouhaveanyofthesesymptoms*.Adjustingdrugdosageandhowthedrugisadministered (subcutaneous instead of intravenous bortezomib*) is usually sufficient toreduce or stop these symptoms*. There are a few drugs available to reduce peripheralneuropathy*.

- Thrombosis*: the risk of developing a blood clot is higher when thalidomide* orlenalidomide*arecombinedwithdexamethasone*.Swelling,painandoccurrenceofa redwarmareaaresignsandsymptoms*ofthrombosis*.Ifyounoticethisinyourarmsorlegs,contactyourdoctor immediately.Toreduce thechanceof thrombosis,aprophylaxis*withanti-coagulant drugs (heparin or low-dose aspirin) is usually prescribed and may berecommendedwhentheabovecombinationsareused.



WHATHAPPENSAFTERTHETREATMENT?Follow-upwithdoctorsIn patients withmultiplemyeloma, a long term follow-up is necessary to detect disease relapse*beforeitbecomessymptomatic*.Bloodtests,e.g.completebloodcellcount*,measurementsofcreatinine*andcalciumlevels,serumandurineelectrophoresis*and/orserum-freelightchainratio*determination,shouldbecarriedoutevery 2-3 months. Radiological exams* and bone marrow examination* may be done on anindividualbasis.BacktodailyactivitiesThe diagnosis of multiple myeloma may cause changes in yourdaily life and also in the daily activities of those close to you.Patientsupportgroupsmayhelpyoutocopewiththesechanges.It can be hard to live with the idea that multiple myeloma cancome back. Based on what is currently known, there are nospecific recommendations to decrease the risk of recurrence*aftercompletionoftreatment.Asaconsequenceofthetreatmentandthemultiplemyelomaitself,returntonormallifemaynotbeeasy for some people. Questions related to body-image, sexuality, fatigue, work, emotions orlifestylemaybeaconcernforyou.Discussingthesequestionswithrelatives,friends,otherpatientsordoctorsmaybehelpful.Patientsupportgroupsmayalsobeabletohelpbyprovidingadviceondealing with the effects of treatments. Psycho-oncologists or telephone information services andhelplinesareavailableinmanycountriestoprovideadditionalsupport.Whatifthemultiplemyelomacomesback?Ifthemultiplemyelomacomesbackthis iscalledarelapse*orrecurrence*.Treatmentinthiscasedependsontheageandhealthstatusofthepatientandpriortreatments.Therearecurrentlyseveraleffectivetherapiesavailableforrelapsed*multiplemyelomaanditisofutmostimportancetofindthemostappropriateoneintermsofefficacyandtoxicity.Moredrugsareexpectedtoarriveintoclinicalpracticeinthenextfewyears.Generally,thegoalofasecond-linetherapyformultiplemyelomaistoobtainasecondresponse,thelongerthebetter, inordertoofferthepatientanotherperiodoftimewithoutdiseasesymptoms*.Thiscouldbecomparedtotheconceptofachronicdisease,suchasdiabetesorhypertension,wheretheaimoftreatmentisnottocurethediseaseitselfbutitssymptoms*.Inbothcases,theaimistoallowthepatienttoliveanormallifeforaslongaspossible.



ShouldIconsiderclinicaltrials?Despite the best therapies that are currently available, themajority of patients will have diseaserelapse*afterfirst-linetreatment.Duringthelastfewyears,anincreasingnumberofnewdrugshavebeendevelopedandtestedworld-wide.Drugsproventobeeffectiveinlaboratoryexperimentsareeligibletobetestedinhumans, inwhat isknownasclinicaltrials.Notallclinicaltrialswillresult inbettertreatmentandmayshowthatthetreatmentbeingtestedisn’tasgoodasthosealreadyinuse.However,participatinginclinicaltrialsis importantasitgivespatientsaccesstodrugswhichwouldnototherwisebeavailableforanumberofyears.Itisimportanttotalkwithyourdoctoraboutthepossibilityofparticipatinginsuchaclinicaltrial.YoucanalsofindinformationaboutclinicaltrialsonInternet(clinicaltrials.gov,orclinicaltrialsregister.eu).



DEFINITIONSOFDIFFICULTWORDSAlbuminAtypeofproteinfoundinblood,eggwhite,milk,andothersubstances.AlkylatingagentAtypeofdrugthatisusedinthetreatmentofcancer.ItinterfereswithDNAandinhibitscellgrowth.Allogeneictransplant(transplantation)Aprocedure inwhichapersonreceivesstemcells (cells fromwhichallbloodcellsdevelop)fromageneticallysimilar,butnotidentical,donor.AmyloidosisAgroupofdiseasesinwhichproteinbuildsupincertainorgans(localisedamyloidosis)orthroughoutthe body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause),secondary(causedbyanotherdisease,includingsometypesofcancer,suchasmultiplemyeloma),orhereditary (passeddown fromparents to children).Manyorgans are affectedby amyloidosis. Theorgansaffectedmaydependontheform(primary,secondary,orhereditary)oftheamyloidosis.AnaemiaAconditioncharacterisedbytheshortageofredbloodcellsorhaemoglobin.Haemoglobinisthepartof the red blood cell that carries oxygen from the lungs to the whole body and in patients withanaemiathisprocessisdiminished.AnaesthesiaReversiblestateoflossofawarenessinwhichthepatientfeelsnopain,hasnonormalreflexes,andresponds less tostress. It is inducedartificiallybytheemploymentofcertainsubstancesknownasanaesthetics.Itcanbecompleteorpartialandallowspatientstoundergosurgery.Antibody/antibodiesAproteinmadebyplasmacells*(atypeofwhitebloodcell)inresponsetoanantigen(asubstancethat causes the body to make a specific immune response). Each antibody can bind to only onespecificantigen.Thepurposeofthisbindingistohelpdestroytheantigen.Someantibodiesdestroyantigensdirectly.Othersmakeiteasierforwhitebloodcellstodestroytheantigen.Anantibodyisatypeofimmunoglobulin*.AntiemeticagentAdrugthatpreventsorreducesnauseaandvomiting.ApheresisAprocedureinwhichbloodiscollected,partofthebloodsuchasplatelets*orwhitebloodcells istakenout,andtherestofthebloodisreturnedtothedonor.Alsocalledpheresis.AsymptomaticInadisease,thisistheabsenceofsymptoms*,suchaspain,orsubjectivemanifestationsoftheillness.



Autologoustransplant(transplantation)Autologousstemcell transplantation isaprocedure inwhichstemcells (cells fromwhichallbloodcells develop) are removed, stored, and later given back to the same person. Autologous bonemarrowtransplantationisaprocedureinwhichbonemarrowisremovedfromaperson,stored,andthengivenbacktothepersonafterintensivetreatment.BendamustineThe active ingredient in a drug that is used to treatmultiplemyeloma and other haematologicalmalignancies.BendamustinemaydamagetheDNAincancercellsandcausethemtodie.Itisatypeofalkylatingagent*andatypeofantimetabolite.BenignForatumour,benignmeansnotcancerous.Benigntumoursmaygrowlarger,butdonotspreadtootherpartsofthebody.Alsocallednon-malignant.

Beta-2-microglobulinA small protein normally found on the surface ofmany cells, including lymphocytes, and in smallamountsinthebloodandurine.Anincreasedamountinthebloodorurinemaybeasignofcertaindiseases,includingsometypesofcancersuchasmultiplemyelomaorlymphoma.BisphosphonatesDrugsor substancesused to treathypercalcemia*andbonepaincausedbysometypesofcancer.Forms of bisphosphonates are also used to treat osteoporosis and for bone imaging.Bisphosphonatesinhibitatypeofbonecellthatbreaksdownbone.Alsocalleddiphosphonate.Bonelesion(s)A bone lesion is an abnormality in the growth or structure of a bone. Bone lesion(s) may becancerousornon-cancerous.Bonelesionsresultindestructionofthebonesinpatientswithmultiplemyelomaandprimarilyaffectthespine,pelvisorribcage.Inpatientswithmultiplemyeloma,bonelesionsweakenthebone,causingpainandincreasingtheriskoffractures.BonemarrowaspirateBonemarrowaspirationremovesasmallamountofbonemarrowfluidandcellsthroughaneedleputintoabone.Thebonemarrowfluidandcellsarethenexaminedforproblemswithanyofthebloodcellsmadeinthebonemarrow.BonemarrowbiopsyAprocedure inwhichasmallsampleofbonewithbonemarrow inside it is removed,usually fromthe hip bone. A small area of skin and the surface of the bone underneath are numbedwith ananaesthetic.Thenaspecial,wideneedleispushedintotheboneandrotatedtoremoveasampleofbone with the bone marrow inside it. This procedure may be done at the same time as a bonemarrowaspiration.Theremovedcellsortissueswillbeexaminedbyapathologist.Thepathologistmay study the tissue under a microscope or perform other tests on the cells or tissue. Thepathologistwilldetermineifthebonemarrowisaffectedbyorisfreeofmyeloma.



Bonemarrow aspiration and biopsy. After a small area of skin is numbed, a Jamshidi needle (a long, hollow needle) isinserted into the patient's hip bone. Samples of blood, bone, and bonemarrow are removed for examination under amicroscope.Bonemarrowexamination/evaluationBonemarrowexaminationreferstothepathologicanalysis(evaluationofcellsandtissuesmadebyapathologistusingmicroscope)ofsamplesofbonemarrowobtainedbybonemarrowaspirationandbonemarrowbiopsy.BortezomibAdrugusedtotreatmultiplemyeloma.Itisalsousedtotreatmantlecelllymphomainpatientswhohavealreadyreceivedatleastoneothertypeoftreatmentandisbeingstudiedinthetreatmentofothertypesofcancer.Bortezomibblocksseveralmolecularpathwaysincellsandmaycausecancercellstodie.Itisatypeofproteasomeinhibitor-itblockstheactionofenzymescalledproteasomes,whichmayhelpkeepcancercellsfromgrowingandmaykillthem.CarfilzomibAdrugusedaloneorwithotherdrugstotreatmultiplemyelomathathasgottenworseorcomebackaftertreatmentwithotheranticancertherapy.Itisalsobeingstudiedinthetreatmentofothertypesof cancer. Carfilzomib is a type of proteasome inhibitor – it blocks the action of enzymes calledproteasomes,whichmayhelpkeepcancercellsfromgrowingandmaykillthem.ChemotherapyAtypeofcancertreatmentusingdrugsthatkillcancercellsand/or limit theirgrowth.Thesedrugsare usually administered to the patient by slow infusion into a vein but can also be administeredorally,bydirectinfusiontothelimborbyinfusiontotheliver,accordingtocancerlocation.



ComorbidityTheconditionofhavingtwoormorediseasesatthesametime.CompletebloodcellcountAcompleteblood cell count is abloodpanel requestedby adoctororothermedical professionalthatgives informationaboutthecells inapatient'sblood,suchasthecellcount foreachcell typeandtheconcentrationsofvariousproteinsandminerals.Thecellsthatcirculateinthebloodstreamaregenerallydividedintothreetypes:whitebloodcells(leukocytes),redbloodcells(erythrocytes),andplatelets* (thrombocytes).Abnormallyhighor low countsmay indicate thepresenceofmanyformsofdisease,andhencebloodcountsareamongthemostcommonlyperformedbloodtestsinmedicineastheycanprovideanoverviewofapatient'sgeneralhealthstatus.Computedtomography(CT)scanA form of radiography in which body organs are scanned with X-rays* and the results are puttogetherbyacomputertogeneratedetailedimagesofpartsofthebody.Adyemaybeinjectedintoa veinor swallowed tohelp the tissues andorgans showupmore clearly. Itmaybeused tohelpdiagnosedisease,plantreatment,orfindouthowwelltreatmentisworking.Consolidation(treatment)Treatment that is given after cancer has disappeared following the initial therapy. Consolidationtherapyisusedtokillanycancercellsthatmaybeleftinthebody.Itmayincluderadiationtherapy,astemcelltransplant,ortreatmentwithdrugsthatkillcancercells.CorticosteroidsAny steroid hormone made in the outer part of the adrenal gland. They are also made in thelaboratory. Corticosteroids have many different effects in the body and are used to treat manydifferentconditions.Theymaybeusedashormonereplacement,tosuppresstheimmunesystem*,and to treat some side effects of cancer and its treatment. Corticosteroids are also used to treatcertainlymphomasandlymphoidleukaemias.CreatinineA compound that is excreted from the body in urine. Creatinine levels are measured to monitorkidneyfunction.CreatinineclearanceThecreatinineclearancetesthelpsprovideinformationabouthowwellthekidneysareworking.Thetestcomparesthecreatinine*levelinurinewiththecreatinine*levelinblood.CyclophosphamideAdrugthatisusedtotreatmanytypesofcancerandisbeingstudiedinthetreatmentofothertypesof cancer. Cyclophosphamide attaches toDNAin cells and may kill cancer cells. It is a typeofalkylatingagent*.



CytogeneticsThe study of chromosomes, which are long strands of DNA and protein that containmost of thegeneticinformationinacell.Cytogeneticsinvolvestestingsamplesoftissue,blood,orbonemarrowin a laboratory to look for changes in chromosomes, including broken, missing, or extrachromosomes.Changes incertainchromosomesmaybeasignofageneticdiseaseorconditionorsome types of cancer. Cytogenetics may be used to help diagnose a disease or condition, plantreatment,orfindouthowwelltreatmentisworking.DaratumumabAdrugusedtotreatmultiplemyeloma.DaratumumabbindstoaproteincalledCD38,whichisfoundonsometypesof immunecellsandcancercells, includingmyelomacells.DaratumumabmayblockCD38andhelptheimmunesystemkillcancercells.Itisatypeofmonoclonalantibody.DexamethasoneA synthetic steroid (similar to steroid hormones produced naturally in the adrenal gland).Dexamethasoneisalsousedtotreatleukaemiaandlymphomaandmaybeusedtotreatsomeoftheproblemscausedbyothercancersandtheirtreatment.DialysisTheprocedureisusedtofilterthebloodwhenthekidneysarenotworkingproperlyandareunabletocompletethistask.DiseaseburdenThe total effect of a diseaseonan individual or on a society. In the contextof this guide, diseaseburdenreferstotheextentofmyelomaspread.DoxorubicinAdrugthatisusedtotreatmanytypesofcancerandisbeingstudiedinthetreatmentofothertypesofcancer.DoxorubicincomesfromthebacteriumStreptomycespeucetius.ItdamagesDNAandmaykillcancercells.Itisatypeofanthracyclineantitumourantibiotic.EchocardiographyAprocedurethatuseshigh-energysoundwaves(ultrasound)tolookattissuesandorgansinsidethechest.Echoesfromthesoundwavesformapictureofthesize,shape,andpositionoftheheartonacomputerscreen(echocardiogram).Thepicturescanalsoshowthepartsoftheinsideoftheheart,suchasthevalves,andthemotionoftheheartwhileitisbeating.Echocardiographymaybeusedtohelpdiagnoseheartproblemsanddamagetotheheartmuscle.Itmayalsobeusedtocheckforaninfectiononoraroundtheheartvalves,bloodclotsortumoursinsidetheheart,andfluidbuildupinthesacaroundtheheart.ElectrocardiogramA line graph that shows changes in the electrical activity of the heart over time. It ismade by aninstrumentcalledanelectrocardiograph.Thegraphcanshowifthereareabnormalconditions,suchasblockedarteries,changesinelectrolytes(particleswithelectricalcharges),andchangesinthewayelectricalcurrentspassthroughthehearttissue.AlsocalledECGandEKG.



ElectrophoresisA laboratory technique that uses an electric current to separate substances, such as proteins ornucleicacids.Thesizeandelectricalcharge(eitherpositiveornegative)ofasubstancedetermineshowfar itmoveswiththecurrent.Electrophoresismaybeusedtohelpdiagnosiscertaindiseases.Therearemanydifferenttypesofelectrophoresis.ElotuzumabAdrugusedtotreatmultiplemyeloma.Itisusedinpatientswhosecancerhasbeentreatedwithonetothreepreviousanticancertherapies.ElotuzumabbindstoaproteincalledCS1,whichisfoundonmyeloma cells and some typesof immune cells. ElotuzumabmayblockCS1 andhelp the immunesystemkillcancercells.Itisatypeofmonoclonalantibody.ErythropoietinAsubstancethatisnaturallyproducedbythekidneysandthatstimulatesthebonemarrowtomakeredbloodcells.Whenerythropoietin ismade in the laboratory, it is calledepoetinalfaorepoetinbeta.FluorescenceInsituHybridization(FISH)testA cytogenetic* technique that uses fluorescent probes to detect and localize the presence orabsenceofspecificDNAsequencesonchromosomes.Fluorescencemicroscopycanbeusedtofindoutwhere the fluorescentprobe isbound to the chromosomes. It canhelpdefine thepatternsofgeneexpressionwithincellsandtissues.GrowthfactorAsubstancemadebythebodythatregulatescelldivisionandcellsurvival.Somegrowthfactorsarealsoproducedinthelaboratoryandusedinbiologicaltherapy.HaemoglobinAproteininsideredbloodcellsthatcarriesoxygenfromthelungstotissuesandorgansinthebodyandcarriescarbondioxidebacktothelungs.Testingfortheamountofhaemoglobininthebloodisusually part of a complete blood cell test. It is used to check for conditions such as anaemia,dehydration,andmalnutrition.Haematoma(s)Apoolof clottedorpartially clottedblood in anorgan, tissue,orbody space,usually causedbyabrokenbloodvessel.HighriskdiseaseInmedicine,riskgroupsareusedtodescribepeoplewhoarealikeinimportantways.Forexample,patients with the same type of cancer may be divided into different risk groups that depend oncertain aspects of their disease. These risk groupsmaybebasedon thepatients’ chanceof beingcured (good versus poor) or the chance that their disease will come back (high versus low).Treatmentmaybebasedonwhichriskgroupapatientfallsinto.



HydrationAprocessofgivingfluidsneededbythebody.HypercalcemiaHigher than normal levels of calcium in the blood. Some types of cancer increase the risk ofhypercalcemia.ImmunesystemAcomplexnetworkofcells,tissues,organs,andthesubstancestheymakethathelpsthebodyfightinfectionsandotherdiseases.Theimmunesystemincludeswhitebloodcellsandorgansandtissuesof the lymph system, such as the thymus, spleen, tonsils, lymph nodes, lymph vessels, and bonemarrow.ImmunofixationImmunofixation is a technique that allows the detection and typing of monoclonal antibodies orimmunoglobulinsinserumorurine.Atypicalantibodyiscomposedoftwoimmunoglobulin*heavychains and two immunoglobulin* light chains. Immunofixation is important for the diagnosis andmonitoringofcertainbloodrelateddiseasessuchasmultiplemyeloma.ImmunoglobulinAproteinthatismadebyBcellsandplasmacells(typesofwhitebloodcells)andhelpsthebodyfightinfection. Some immunoglobulins may be found in higher than normal amounts in patients withcertain conditions or certain types of cancer, including multiple myeloma and Waldenstrommacroglobulinemia.Measuringtheamountofspecificimmunoglobulinsinthebloodandurinemayhelpdiagnosecanceror findouthowwell treatment isworkingor if cancerhascomeback.Someimmunoglobulinsmaybeusedastumourmarkers.AlsocalledIg.Immunomodulatorydrug(agent)Atherapeuticagentthatsuppresstheimmunesystem.IncidenceThenumberofnewcasesofadiseasediagnosedeachyear.InductiontreatmentThe first treatment given for a disease. It is often part of a standard set of treatments, such assurgeryfollowedbychemotherapyandradiation.Whenusedbyitself,inductiontherapyistheoneacceptedasthebesttreatment.If itdoesn’tcurethediseaseoritcausesseveresideeffects,othertreatmentsmaybeusedasasubstituteorinadditiontotheoneusedasinductiontherapy.IxazomibAdrugusedtotreatmultiplemyeloma. It isused inpatientswhohavereceivedat leastoneotheranticancer treatment. It is also being studied in the treatment of other types of cancer. Ixazomibblocks enzymes called proteasomes,whichmay help keep cancer cells from growing andmay killthem.Itisatypeofproteasomeinhibitor.



KidneyfunctionAtermusedtodescribehowwellthekidneyswork.Thekidneysremovewasteandextrawaterfromtheblood(asurine)andhelpkeepchemicals(suchassodium,potassium,andcalcium)balancedinthebody.Theyalsomakehormonesthathelpcontrolbloodpressureandstimulatebonemarrowtomakeredbloodcells.Alsocalledrenalfunction.LenalidomideAdrug that is similar to thalidomide*, and isused to treatmultiplemyelomaand certain typesofanaemia.Itisalsousedtotreatmantlecelllymphomathathascomebackorhasnotgottenbetterafterothertreatment. It isbeingstudied inthetreatmentofotherconditionsandtypesofcancer.Lenalidomide may help the immune system kill abnormal blood cells or cancer cells. It may alsopreventthegrowthofnewbloodvesselsthattumoursneedtogrow.Itisatypeofantiangiogenesisagentandatypeofimmunomodulatingagent*.Magneticresonanceimaging(MRI)Animagingtechniqueusedinmedicinethatusesmagneticresonance(magnetismandradiowaves)tocreateapictureoforgansandtissuesinsidethebody.Sometimes,afluidisinjectedthatenhancesthecontrastbetweendifferenttissuestomakestructuresmoreclearlyvisible.MelphalanAdrugused to treatmultiplemyeloma. It is alsobeing studied in the treatmentofother typesofcancer.MelphalanmaykillcancercellsbydamagingtheirDNAandstoppingthemfromdividing.Itisatypeofalkylatingagent*.MonoclonalGammopathyofUncertainSignificance(MGUS)Most multiple myelomas arise from a benign* condition known as Monoclonal Gammopathy ofUncertainSignificance(MGUS).Peopleaffectedbythisconditionhavealittleabnormalproductionofmonoclonalprotein*withoutanysymptoms*.Themajorityofpeoplewiththisconditionwillneverdevelop symptomatic* multiple myeloma. In most cases MGUS is discovered by accident duringroutinebloodtests.MonoclonalproteinAnantibodyfoundinunusuallylargeamountsinthebloodorurineofpeoplewithmultiplemyelomaandothertypesofplasmacell*tumours.AlsocalledMprotein.(Peripheral)neuropathyA nerve problem that causes pain, numbness, tingling, swelling, or muscle weakness in differentparts of the body. It usually begins in the hands or feet and gets worse over time. Peripheralneuropathymay be caused by cancer or cancer treatment, such as chemotherapy. Itmay also becausedbyphysical injury, infection,toxicsubstances,orconditionssuchasdiabetes,kidneyfailure,ormalnutrition.Alsocalledneuropathy.NeutropeniaAconditioninwhichthereisalower-than-normalnumberofneutrophils(atypeofwhitebloodcell).



Non-Hodgkinlymphoma(s)Any of a large group of cancers of lymphocytes (white blood cells). Non-Hodgkin lymphomas canoccuratanyageandareoftenmarkedbyenlargedlymphnodes,fever,andweight loss.Therearemanydifferenttypesofnon-Hodgkinlymphoma.Thesecanbedividedintoaggressive(fast-growing)and indolent (slow-growing) types formed from either B-cells or T-cells. B-cell non-HodgkinlymphomasincludeBurkittlymphoma,chroniclymphocyticleukaemia/smalllymphocyticlymphoma(CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma,precursor B-lymphoblastic lymphoma, and mantle cell lymphoma. T-cell non-Hodgkin lymphomasinclude mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblasticlymphoma.Lymphomasthatoccurafterabonemarroworstemcell transplantationareusuallyB-cellnon-Hodgkinlymphomas.Prognosis*andtreatmentdependonthestageandtypeofdisease.PamidronateAdrugusedtotreathypercalcemia(high levelsofcalciumintheblood)causedbycertaintypesofcancer.Itisalsousedwithotheranticancerdrugstotreatmultiplemyelomaandbreastcancerthathas spread to the bone and is used to treat Paget's disease of bone. Pamidronatemayhelp keepbone from breaking down and prevent the loss of calcium from the bones. It is a type ofbisphosphonate.PanobinostatAdrugusedwithbortezomibanddexamethasonetotreatmultiplemyeloma. It isused inpatientswhohavealreadybeentreatedwithbortezomibandanimmunomodulatingagent*.It isalsobeingstudiedinthetreatmentofothertypesofcancer.Panobinostatblockscertainenzymesneededforcells to grow and divide and may kill cancer cells. It may also prevent the growth of new bloodvessels that tumours need to grow. It is a type of histone deacetylase inhibitor and a type ofantiangiogenesisagent.PeripheralbloodBloodcirculatingthroughoutthebody.PeripheralneuropathyA nerve problem that causes pain, numbness, tingling, swelling, or muscle weakness in differentparts of the body. It usually begins in the hands or feet and gets worse over time. Peripheralneuropathymay be caused by cancer or cancer treatment, such as chemotherapy. Itmay also becausedbyphysical injury, infection,toxicsubstances,orconditionssuchasdiabetes,kidneyfailure,ormalnutrition.Alsocalledneuropathy.PlasmacellsPlasmacells,alsocalledplasmaBcells,plasmocytes,plasmacytes,arewhitebloodcellsthatsecretelargevolumesof antibodies. Theyare transportedby thebloodplasmaand the lymphatic system.Once released into the blood and lymph, these antibody molecules bind to the target antigen(foreign substance)and initiate itsneutralizationordestruction.Plasmacellsoriginate in thebonemarrowfromBcells.



PlateletSmallcellfragmentsthatplayafundamentalroleintheformationofbloodclots.Patientswithalowplateletcountareatriskofseverebleeding.Patientswithahighcountareatriskofthrombosis,theformationofbloodclotsthatcanblockbloodvesselsandresultinstrokeorothersevereconditions,andcanalsobeatriskofseverebleedingbecauseofplateletdysfunction.PomalidomideAdrug that is a formof thalidomide*, and is used to treatmultiplemyeloma that has not gottenbetterwithotheranticancerdrugs.Itisalsobeingstudiedinthetreatmentofothertypesofcancer.Pomalidomidemayhelptheimmunesystemkillcancercells.Itmayalsopreventthegrowthofnewblood vessels that tumoursneed to grow. It is a typeof immunomodulating agent* anda typeofantiangiogenesisagent.Positronemissiontomography(PET)scanA procedure inwhich a small amount of radioactive glucose (sugar) is injected into a vein, and ascannerisusedtomakedetailed,computerizedpicturesofareasinsidethebodywheretheglucoseistakenup.Becausecancercellsoftentakeupmoreglucosethannormalcells,thepicturescanbeusedtofindcancercellsinthebody.Positronemissiontomography-computedtomography(PET-CT)scanA procedure that combines the pictures from a positron emission tomography (PET) scan and acomputed tomography (CT) scan.ThePETandCT scansaredoneat the same timewith the samemachine.Thecombinedscansgivemoredetailedpicturesofareasinsidethebodythaneitherscangivesbyitself.APET-CTscanmaybeusedtohelpdiagnosediseases(suchascancer),plantreatment,orfindouthowwelltreatmentisworking.PrednisoneAdrugthat lessens inflammationandsuppresses immuneresponses. It isusedwithotherdrugstotreat leukaemia and lymphoma and other types of cancer. Prednisone is also used to treatmanyconditions,includingarthritis,certainskindiseases,allergies,lowlevelsofsomeadrenalhormones,lossofappetiteandanaemia*.Itisatherapeuticglucocorticoid.ProphylaxisAnattempttopreventdisease.PrognosisThelikelyoutcomeorcourseofadisease;thechanceofrecoveryorrecurrence*.PrognosticAsituationorcondition,oracharacteristicofapatient,thatcanbeusedtoestimatethechanceofrecoveryfromadiseaseorthechanceofthediseaserecurring(comingback).Radiologicalexam(s)Atestthatusesimagingtechnology(suchasradiography,ultrasound*,computedtomography*andnuclearmedicine) tovisualizeorgans, structuresand tissueswithin thebody tobothdiagnoseandtreatdiseases.



RadiotherapyAtherapyinwhichradiationisusedinthetreatmentofcancer.It isalwaysorientedtothespecificlocationofthecancer.RecurrenceCancerthathasrecurred(comeback),usuallyafteraperiodoftimeduringwhichthecancercouldnotbedetected.Thecancermaycomebacktothesameplaceastheoriginal(primary)tumourortoanotherplaceinthebody.Alsocalledrecurrentcancer.RefractorydiseaseCancer that does not respond to treatment. The cancer may be resistant at the beginning oftreatment or it may become resistant during treatment. Also called resistant disease or resistantcancer.Relapse(relapseddisease)Return of themanifestations of a disease after a period of improvement. In cancer, return of thecancerafteraremission*.RemissionAdecreaseinordisappearanceofsignsandsymptomsofcancer.Inpartialremission,some,butnotall,signsandsymptomsofcancerhavedisappeared.Incompleteremission,allsignsandsymptomsofcancerhavedisappeared,althoughcancermaystillbepresentinthebody.RiskfactorSomething that increases the chance of developing a disease. Some examples of risk factors forcancer are age, a family history of certain cancers, use of tobacco products, being exposed toradiationorcertainchemicals,infectionwithcertainvirusesorbacteria,andcertaingeneticchanges.SerumfreelightchainlevelImmunoglobulin*lightchainsthatarecirculatinginseruminafree(unbound)statearecalledfreelightchains.Usingabloodtesttomeasuretheserumleveloffreelightchainscanhelptodiagnoseandmonitormultiplemyelomaandrelateddisorders.Therearetwotypesofimmunoglobulin*lightchainproducedinhumans,designatedbytheGreekletterskappa(κ)andlambda(λ).SerumfreelightchainratioComparingtheratioofkappa(κ)freelightchainstolambda(λ)freelightchainsinthebloodagainstreference ranges indicates whether that personmay have a plasma cell tumour such asmultiplemyelomaorALamyloidosis*.StagingPerformingexamsandteststolearntheextentofthecancerwithinthebody,especiallywhetherthediseasehasspreadfromtheoriginalsitetootherpartsofthebody.Itisimportanttoknowthestageofthediseaseinordertoplanthebesttreatment.



SymptomAphysical ormental problem that a person experiences thatmay indicate a diseaseor condition.Symptomscannotbeseenanddonotshowuponmedical tests.Someexamplesofsymptomsareheadache,fatigue,nausea,andpain.SymptomaticHavingtodowithsymptoms,whicharesignsofaconditionordisease.Systemictreatment(therapy)Treatmentusingsubstancesthattravelthroughthebloodstream,reachingandaffectingcellsalloverthebody.TeratogenicA teratogen is a substance or process that causes birth defects. Teratogens include certain drugs(suchasthalidomide),infectionsandionizingradiation.ThalidomideAdrugusedtotreatmultiplemyeloma.Itisbeingstudiedinthetreatmentofothertypesofcancer.Thalidomidemayhelptheimmunesystemtokillcancercells.Itmayalsopreventthegrowthofnewblood vessels that tumours need to grow. It is a type of antiangiogenesis agent and a type ofimmunomodulatingagent*.ThrombosisTheformationorpresenceofathrombus(bloodclot)insideabloodvessel.UltrasoundAprocedurethatuseshigh-energysoundwavesto lookat tissuesandorgans insidethebody.Thesound waves make echoes that form pictures of the tissues and organs on a computer screen(sonogram).Ultrasoundmaybeusedtohelpdiagnosediseases,suchascancer.Itmayalsobeusedduringmedicalprocedures,suchasbiopsies.Alsocalledultrasonography.X-rayAtypeofradiationusedinthediagnosisandtreatmentofcancerandotherdiseases.Inlowdoses,X-raysareusedtodiagnosediseasesbymakingpicturesoftheinsideofthebody.Inhighdoses,X-raysareusedtotreatcancer.ZoledronateAdrugusedtotreatpatientswithhypercalcemia*(highbloodlevelsofcalcium)causedbycancer.Itisalsousedtogetherwithotherdrugstotreatmultiplemyelomaandtopreventbonefracturesandreducebonepain inpeoplewhohavecancer thathas spread to thebone. Itbelongs toa classofdrugcalledbisphosphonates*.

The ESMO / Anticancer Fund Guides for Patients are designed to assist patients, their relatives and caregivers to understand the nature of different types of cancer and evaluate the best available treatment choices. The medical information described in the Guides for Patients is based on the ESMO Clinical Practice Guidelines, which are designed to guide medical oncologists in the diagnosis, follow-up and treatment in different cancer types.These guides are produced by the Anticancer Fund in close collaboration with the ESMO Guidelines Working Group and the ESMO Patient Advocates Working Group.

For more information please visit www.esmo.org and www.anticancerfund.org


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