Transcript
Announcer:
You’relisteningtoReachMD. This medical industry feature titled, DARZALEX® (daratumumab) in Combination With Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma: 5-Year Update of the MAIA Study, is brought to you by Janssen Pharmaceuticals, Inc.
Here’syourhost,Dr Charles Turck.
Host:
This is ReachMD. I’m Dr Charles Turck, and today, we’re joined by Dr Noa Biran, who is an Associate Professor of Medicine at the Department of Medicine at the Hackensack Meridian School of Medicine. Dr Biran ishere to talk us through the results from the phase 3 MAIA study, which show the addition of DARZALEX® (or daratumumab) to lenalidomide and dexamethasone resulted in a statistically significant progression-free survival benefit over lenalidomide and dexamethasone inpatients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant and were treated until diseaseprogression,onlyaftertheprimary3-yearanalysis.Furthermore,additionalfollow-updatawasrecentlypublishedforthe5-year analysis.
Dr Turck:
Dr Biran let’s dive right in and talk about patients that are ineligible for transplant. What do we need to know about selecting the righttreatment upfront?
DrBiran:
So as we know, for most patients, the course of disease with multiple myeloma is characterized by multiple relapses.Witheachsuccessive line oftherapy,attritionratesincrease.
A retrospective analysis published by Fonseca et al of 3 US databases, the OPTUM™ Commercial Claims database, the OPTUM™ElectronicMedicalRecordsdatabase,andtheSurveillance,Epidemiology,andEndResults-MedicareLinkeddatabase,lookedatpatientswithnewlydiagnosedmultiple myelomawhodidnot receivestemcelltransplant atany time duringfollow-up.
Foreachlineoftherapy,theproportionofpatientsreceivingasubsequentlineoftherapydecreasedbyapproximately50%.
So based on this, we know that it can be particularly important to select an effective treatment option in the frontline setting forpatientswhoarenoteligibleforatransplant astherearefeweropportunitiestotreatwithprovenregimenswitheachsuccessivelineoftherapy.
Dr Turck:
Dr Biran, as we know, when it comes to newly diagnosed patients with multiple myeloma who are ineligible for transplant, theMAIA trial supports the use of DARZALEX® (or daratumumab) in combination with lenalidomide and dexamethasone, or DRd. So, let’s get a betterunderstanding of this treatment option.
Butbeforewediveintoourdiscussion,let’sfirstreviewthecontraindications,warnings,andprecautionsforDARZALEX®.
Announcer:
DARZALEX®(daratumumab)isindicatedforthetreatmentofadultpatientswithmultiplemyeloma:
•In combination with lenalidomide and dexamethasone in newly diagnosed patients who areineligible for autologous stem cell transplant and in patients with relapsed or refractory multiplemyelomawhohavereceivedatleast onepriortherapy
•Incombinationwithbortezomib,melphalan,andprednisoneinnewlydiagnosedpatientswhoareineligible forautologous stemcelltransplant
•Incombinationwithbortezomib,thalidomide,anddexamethasoneinnewlydiagnosedpatientswhoareeligibleforautologousstemcell transplant
•Incombinationwithbortezomibanddexamethasoneinpatientswhohavereceivedatleastonepriortherapy
•Incombinationwithcarfilzomibanddexamethasoneinpatientswith relapsedorrefractorymultiplemyelomawhohavereceivedonetothree priorlines oftherapy
•Incombinationwithpomalidomide anddexamethasoneinpatientswhohavereceivedatleasttwopriortherapies includinglenalidomideandaproteasomeinhibitor
•As monotherapy in patients who have received at least three prior lines of therapy including aproteasomeinhibitor(PI)andanimmunomodulatoryagent orwhoaredouble-refractory toaPIand animmunomodulatoryagent
Dr. Turck:
Now Dr Biran, could you please tell us a little bit about DARZALEX® and DRd?
Dr Biran:
Certainly. DARZALEX® is an anti-CD38 antibody that is now approved across multiple lines of therapy in multiple myeloma, including 3 frontline regimens. As you mentioned, DRd is approved in newly diagnosed patients with multiple myeloma who are ineligible for transplant.
Dr Turck:
Now, let’s dig a little deeper into the MAIA trial, which supports the use of frontline therapy with DRd in transplant ineligiblepatients. The 5-year follow-up data, as presented at the European Hematology Association (or EHA) 26th Annual Congress in 2021, showed theimpactofaddingDARZALEX®toRdonoverallsurvival.Couldyoubriefly describetheMAIAstudyandwhatmakesitimportant?
Dr Biran:
Of course. So, the MAIA study established the efficacy and safety of DARZALEX® plus Rd in newly diagnosed, transplant-ineligible multiple myeloma. It is a phase 3, open-label, randomized, active-controlled trial in 737 patients with newly diagnosed,transplant-ineligiblemultiple myeloma.
In this study, key inclusion criteria included an Eastern Cooperative Oncology Group performance status of 0 to 2 and a creatinine clearanceof30mL/min orhigher.
Patients were randomized, 1:1, to receive either DRd or Rd. In the interventional arm, patients received DARZALEX® 16 mg per kg byintravenous infusion, weekly for Cycles 1 through 2, every 2 weeks for Cycles 3 through 6, and every 4 weeks for Cycles 7 andbeyond, in combination with oral lenalidomide 25 mg daily on Days 1 through 21 and oral dexamethasone 40 mg weekly (or a reduced dose of 20 mg/week for patients >75 years of age or with a body mass index <18.5). The active control arm consisted of orallenalidomide25mgdailyonDays1 through21 andoraldexamethasone40mgweekly(orareduceddoseof20mg/weekforpatients >75 years of age or with a body mass index <18.5). Patients in both arms continued treatment until either their disease progressed orunacceptabletoxicity occurred.
Theprimaryendpointwasprogression-freesurvival. And key secondary endpoints included complete response or better, very good partial response or better, rate of minimal residualdisease,orMRD, negativity,overall responserate,overallsurvival,andsafety.
The demographic and clinical characteristics of the two groups were similar at baseline: the median age for both arms was 73 years (range,45-90); themajority ofpatientswere White,about92%;and52% weremale.
Now, given all of this information, we know that the MAIA trial is important because it examined the combination of DARZALEX® with acurrentstandardofcare.Italsoenrolledanolder patientpopulation,ofwhich44%wereover theageof75.
Dr Turck:
As you previously mentioned, the primary endpoint of the MAIA study was progression-free survival, or PFS. With that in mind,whatcanyou tell usabouttheefficacyofDARZALEX®plusRd?
Dr Biran: Yes, so based on International Myeloma Working Group (IMWG) criteria, the primary endpoint was PFS, defined as time from randomizationto either disease progressionor death, whichever occurredfirst.
Keepinmindthatintheprimaryanalysisatamedianfollow-upofapproximately30months,themediandurationoftreatmentwas25.3 monthsin theDRdarmand21.3monthsinthe Rdarm.
PatientsintheDARZALEX®plusRdarmdemonstratedasignificantimprovementinPFScomparedwithpatientsintheRdarm.This translated to a 44% reduction in the risk of disease progression or death with the DRd combination versus Rd alone (hazard ratio[HR]=0.56;95% confidence interval[CI], ranging 0.43-0.73,P<0.0001).
And at 30 months, about 70.6% (95% CI, 65-75.4) of patients showed no disease progression in the DRd arm compared with 55.6%(with a 95%CI, ranging 49.5-61.3)ofpatientsinthe Rdarm.
As we mentioned earlier, we now have the 5-year follow-up of efficacy and safety data from the MAIA trial that was presented at the2021 EHA Annual Congress. Data on overall survival in the MAIA trial was presented for the first time at this meeting. Patientsin bothtreatmentarmswere treateduntildiseaseprogression.
Overall survival was a secondary endpoint of the MAIA study. After almost 5 years of follow-up, 66% of patients were still alive with DRd (95% CI, ranging 61-71) versus just 53% with Rd (95% CI, ranging 47-59) alone. This translated into a 32% reduction in the risk ofdeathwithDRdversus Rd alone(HR=0.68; with a 95%CI, ranging 0.53-0.86, and P=0.0013).
Now let’s look at progression-free survival. The 60-month progression-free survival rate was 52.5% in the DRd arm versus 28.7% in theRd arm. This represented a 47% reduction in the risk of disease progression or death with DRd versus Rd alone. The medianprogression-free survival was not reached in the DRd arm versus 34.4 months in the Rd arm (HR=0.53; with a 95% CI, ranging 0.43-0.66).Please keep in mind that the 60-month analyses are not included in the FDA-approved Prescribing Information. The 60-month progression-free survival resultswerenotadjustedformultiple comparisons,andnoconclusionsshouldbedrawn.
Dr Turck:
WhatabouttheresponseratesevaluatedintheMAIAtrial?Couldyoutellusalittlebitaboutthosefindings?
Dr Biran:
Yes, absolutely. In the primary analysis of the MAIA trial, with a follow-up time of approximately 30 months, the DRd armshowed a significant improvement in response rate at 93% compared with 81% in the Rd arm, with a P-value of less than 0.0001.
Now, when we look at the depth of response, nearly twice as many patients achieved a complete response or stringent completeresponse,48% withDRdversus25%withRdalone, after amedianfollow-upof30 months.
Another secondary endpoint we should keep in mind was the assessment of MRD, which was evaluated at a threshold of 1 tumor cell per10to thenegative5cells inthebonemarrow.
Consistentwiththehigherratesofcompleteorstringentcompleteresponse,theMRDnegativityratewasgreaterwithDRdat24%versus7% in the Rd arm.
Dr. Turck:
It’s very encouraging to see the efficacy results in the MAIA trial. Dr Biran, let’s take a look at the safety profile of DARZALEX® plusRd. What are some of the most common and serious adverse reactions observed in this study? And were there any new safety signals detected afterthe 5-year follow-up?
Dr Biran:
In the first analysis at a median treatment duration of 25.3 months, the most frequent adverse reactions occurring in 20% or greater were infusion-related reactions, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia,pyrexia, upper respiratory tract infections, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy,dyspnea, and cough. Adverse reactions that occurred with a frequency between 10 and 20%, and with at least a 5% greater frequency in the DRd arm, were headache, urinary tract infection, hyperglycemia, hypocalcemia, vomiting, chills, paresthesia, andhypertension.
Seriousadversereactionswitha2%greaterincidenceintheDRdarmcomparedwiththeRdarmwerepneumonia,bronchitis,and dehydration.
Patients also experienced treatment-emergent hematologic laboratory abnormalities from baseline in both arms. Except for anemia,which showed a lower incidence in the DRd arm, about 47%, when compared with the Rd arm, with an incidence rate of 57%,allotherhematologicabnormalities weremoreprevalentintheDRdarmcomparedwiththeRdarm:neutropenia(91%vs77%), leukopenia(90% vs 82%), lymphopenia (84%vs 75%),andthrombocytopenia (67% vs 58%).
Dr. Turck:
We’ve certainly covered a lot of information, so I’d like to thank Dr Noa Biran for taking us through the MAIA trial andproviding her insights on the impact of DARZALEX® plus Rd in patients with newly diagnosed multiple myeloma who are ineligible for transplant.
Thankyou,DrBiranforthisinsightfuldiscussion.
Dr. Biran:
My pleasure. It was nice to be here. Thank you.
Dr Turck:
Nowbeforeweclose,let’sreviewsomeimportantsafetyinformationforDARZALEX®.
Announcer:
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
DARZALEX® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylacticreactions)todaratumumaboranyofthecomponents oftheformulation.
WARNINGSANDPRECAUTIONS
Infusion-RelatedReactions
DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions.These reactions can be life-threatening, and fatal outcomes have been reported. In clinical trials(monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with theWeek1(16mg/kg)infusion,2%withtheWeek2infusion,andcumulatively 6%withsubsequentinfusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequentinfusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurredduring infusion or within 4 hours of completing DARZALEX®. Severe reactions have occurred, includingbronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonaryedema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closureglaucoma.Signs andsymptomsmayinclude respiratorysymptoms,suchasnasalcongestion,cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms werewheezing,allergicrhinitis,pyrexia,chestdiscomfort,pruritus,hypotension,andblurredvision.
WhenDARZALEX®dosingwasinterruptedinthe settingofASCT(CASSIOPEIA)foramedianof
3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX® following ASCT were consistent in terms of symptoms and severity (Grade 3 or4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS,patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 ofWeek1,4%onDay2ofWeek1,and8%withsubsequentinfusions.
Pre-medicatepatientswithantihistamines,antipyretics,andcorticosteroids.Frequentlymonitorpatientsduring the entire infusion. Interrupt DARZALEX®infusion for reactions of any severity and institutemedical management as needed. Permanently discontinue DARZALEX®therapy if an anaphylacticreaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. ForpatientswithGrade1,2,or3reactions,reducetheinfusionratewhen re-startingthe infusion.
To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patientsfollowing DARZALEX® infusions. Patients with a history of chronic obstructive pulmonary disease mayrequireadditionalpost-infusionmedicationstomanagerespiratorycomplications.Considerprescribingshort- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructivepulmonary disease.
Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due tociliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred withDARZALEX®infusion. If ocular symptoms occur, interrupt DARZALEX®infusion and seek immediateophthalmologicevaluationprior torestartingDARZALEX®.
InterferenceWithSerologicalTesting
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test(indirectCoombstest).Daratumumab-mediated positiveindirectantiglobulintest maypersistforupto 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection ofantibodiestominorantigensinthepatient’sserum.Thedeterminationofapatient’sABOandRhbloodtype is not impacted. Notify blood transfusion centers of this interference with serological testing andinform blood banks that a patient has received DARZALEX®. Type and screen patients prior to startingDARZALEX®.
NeutropeniaandThrombocytopenia
DARZALEX® may increase neutropenia and thrombocytopenia induced by background therapy. Monitorcomplete blood cell counts periodically during treatment according to manufacturer’s prescribinginformation for background therapies. Monitor patients with neutropenia for signs of infection. ConsiderwithholdingDARZALEX®untilrecoveryofneutrophilsorfor recoveryofplatelets.
InterferenceWithDeterminationofCompleteResponse
DaratumumabisahumanimmunoglobulinG(IgG)kappa monoclonalantibodythatcanbedetectedonboth the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinicalmonitoring of endogenous M-protein. This interference can impact the determination of completeresponseand ofdisease progressionin some patientswith IgGkappamyeloma protein.
Embryo-FetalToxicity
Based on the mechanism of action, DARZALEX® can cause fetal harm when administered to a pregnantwoman. DARZALEX®may cause depletion of fetal immune cells and decreased bone density. Advisepregnantwomenofthe potentialrisktoafetus. Advise femaleswithreproductivepotentialtouseeffectivecontraception duringtreatmentwithDARZALEX®and for3monthsafterthe lastdose.
The combination of DARZALEX®with lenalidomide, pomalidomide, or thalidomide is contraindicated inpregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects anddeathoftheunbornchild.Refertothelenalidomide,pomalidomide,orthalidomideprescribinginformationonuseduringpregnancy.
ADVERSEREACTIONS
The most frequently reported adverse reactions (incidence ≥20%) were upper respiratory infection,neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheralsensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. Themost common hematologic laboratory abnormalities (≥40%) with DARZALEX®are neutropenia,lymphopenia,thrombocytopenia,leukopenia,andanemia.
Dr Turck:
Thankyou, DrBiranandlisteners.
PleaseseethefullPrescribingInformationforDARZALEX®availableviathepodcasthostpageoratwww.darzalexhcp.com.
AnnouncerClose:
This program was sponsored by Janssen Pharmaceuticals, Inc. Ifyoumissedanypartofthisdiscussion,visitreachmd.com/industry-feature.ThisisReachMD.BePartoftheKnowledge.
