Presentation on theme: "Heinz Ludwig Department of Medicine I"— Presentation transcript:
1What we know about myeloma in elderly patients from trials and observational studies? Heinz LudwigDepartment of Medicine ICenter for Oncology, Hematology and Palliative CareWilhelminenhospital, Vienna, Austria
2Goals of therapy in elderly patients Rapid symptom controlOptimal quality of lifeFew and acceptable side effectsBest possible quality of responseLong PFSLong OSCure ?
3Drug combinations for elderly patients Possible options1-drug*2 - drugs3- drugs4 - drugsDexBendamustine+PMPTVMPTThalVDVMPMP*CTDThal-DexVTDL-ldDex*only exceptional casesMost commonly used combinations contain 2-3 drugs
4The variation in biological fitness in a specific age cohort increases Characteristics of the Elderly Patient Chronological age does not necessarily correlate with biological ageAll three individuals are 70 years oldFit Minor morbidity significant morbidityThe variation in biological fitness in a specific age cohort increaseswith rising age, but the ‚biology‘ of myeloma cells does not vary with age
5further dose reduction Treatment of patients with multiple myeloma not eligible for transplantationAssess frailityFitUnfitFrailFull goSlow goVery slow go2 or 3 drug regimenreduce dose2 (3) drug regimenfurther dose reductionMP, CTX-PVD, Ld
6Instruments for assessing fraility and allocation to treatment groups FitUnfitFrailAge <80 yrFit >80 yrUnfit >80 yrADL 6IADL 8Charlson 0ADL 5IADL 6-7Charlson 1ADL ≤4IADL ≤5Charlson ≥2Go-goModerate-goSlow-goFull-dose regimensDose level 0Reduced-dose regimensDose level -1Reduced-dosePalliative approachDose level -2AssessAgeADLIADLCharlsoncomorbidityscorePalumbo A et al. IMW 2013
7Adaptation of dose according to risk factors AgentDose level 0Dose level-1Dose level - 2Dexamethasone40 mg20 mg10 mgMelphalan0.25 mg/kg or 9 mg/m20.18 mg/kg or 7.5 mg/m20.13 mg/kg or 5 mg/m2Thalidomide100 mg50 mg50 mg/qodLenalidomide25 mg15 mgBortezomib1.3 mg twice weekly, sc1.3 mg weekly, sc1.0 mg weekly,scPrednisone60 mg/m230 mg/m215 mg/m2CyclophosphamidePalumbo et al.,BLOOD 2011
8Comorbidities relevant for treatment selection in myeloma PolyneuropathyAvoid bortezomib (or use once weekly sc)Renal impairmentConsider dose adaptations when using lenalidomideBone marrow insufficiencyCareful dosing of cytoreductive drugs, consider single agent dexamethasoneCardiac arrhythmias/dysfunctionCave: Thalidomide & high dose dexamethasoneImmune systemCareful dosing of cytoreductive drugsDiabetesCave: high dose dexamethasoneCognitive function/complianceConsider iv regimens
9Higher risk of mortality in patients ≥ 75 years of age Retrospective meta-analysis of 4 EU phase III trials (N = 1,435) with MP, MPT, VMP, and VMPTMedian follow up 33 monthsMedian OS in total population 50 monthsEstimated 3-year OS 68% in patients < 75 years of age vs 57% in patients ≥ 75 years of age (HR 1.44, CI , p < 0.001)HR (95% CI)p valueAll1.44 (1.20–0.72)< 0.001MP1.21 (0.90–1.64)0.21MPT1.12 (0.81–1.56)0.49VMP1.62 (1.04–2.52)0.03VTP/VMPT3.02 (1.86–4.90)0.1110Higher mortality in patients < 75 years of ageHigher mortality in patients ≥ 75 years of ageBringhen S, et al. Haematologica. 2013;98:980-7.
10Age and Organ Damage Correlate with Poor OS: Meta-analysis of 4 Randomized Trials n=1435 (≥ 65 yrs ): MPT vs MP, VMP vs MP, VMP vs VMPT-VTBringhen et al. Haematologica 2013;98(6):
11*Meta-analysis of the 6 trials: PFS () OS Phase III studies incorporating novel agents in the non-transplant settingNew RegimenComparatorOutcomeMPT (6 Trials)*vs.MPMPT PFS 5/6, OS 2/6CTDaCTDa ORRVMPVMP PFS, OSVMPT VT PFS. OSVMP VT or VPVDT VT or VPnsMPR RMPRor MP PFSLDLdLd PFS, OSLD continousLd x 18, vs MPT x 12Ld cont PFS, OS*Meta-analysis of the 6 trials: PFS () OS
12HR=0.67 in favor of MPT, p<0.0001 MPT vs MP: Meta-analysis of 1685 individual-patient data of 6 randomized trials0.00.20.40.60.81.0Survival proportion12243648monthsMPMPTMedian 14.9 mos( )Median 20.3 mos( )HR=0.67 in favor of MPT, p<0.0001PFSOS0.00.20.40.60.81.012243648monthsMedian 32.7 mos( )Median 39.3 mos( )HR=0.83 in favor of MPT, p=0.005*MPTMP*Cox model for treatment, with analysis stratified by study using a random effects (frailty) modelFayers et al. Blood 2011, accepted for publication 30 May 2011
13MPT: Pros and Cons Pros Cons Survival benefit Thalidomide toxicity Oral regimenNot expensiveConsThalidomide toxicitySuboptimal in cytogenetic high risk groupShorter survival after relapse
14MP vs. VMP (VISTA) Final updated OS analysis Median follow-up 60.1 months31% reduced risk of death100908070605040302010Median OS benefit: 13.3 months5-year OS rates: 46.0% vs 34.4%Patients alive (%)Group N Event Median HR (95% CI) P-valueMVMP (0.567, 0.852)Time (months)San Miguel et al. JCO 2013
15Overall survival in different subgroups: VMP vs. MP San Miguel et al., JCO 2013
16VMP induced CR is associated with improved outcome Time to progressionTime to next therapyTreatment-free intervalOverall survivalHarousseau JL et al., BLOOD 2010
17VD vs. VTD vs. VMP followed by bortezomib maintenance therapy Para-meterVDVTDVMP>VGPR36%44%40%ORR68%78%71%PNP G3-415%26%20%PFS (mos)13.818.417.3Niesvitzky R. et al., BLOO,
18Global QoL during VD, VTD and VMP induction therapyVD vs. VTD or VMP: shorter PFS, similar OS, better toleranceNiesvizky R et al., ASH 2011
1914/04/2017Treatment scheduleMedian age 71 y; 30% >75 y; Median KPS 80%; 63% IgG; 33% B2M > % albumin < 35 g/L19
20PFS and OS: VMP vs VMPT –VT Progression free survival Overall survivallandmark analysisPalumbo A et al. ASH 2012
22Overall survival from relapse Palumbo et al. ASH 2012 (Abstract 200)
23VMPT-VT versus VMP in newly diagnosed elderly patients Significant OS benefit in patients< 75 years of age (none in pts > 75 years)With stage ISS 1-2 (tendency for OS in stage ISS 3)With CR (none in pts with VGPR/PR)Benefit in ‚good risk‘ patients with CR onlyGrade 3- 4 adverse events during VT maintenancePN 7%Hematological toxicity 5%Infection 3%Discontinuation due to AEs 12%Palumbo et al. ASH 2012 (Abstract 200), oral presentation
24How to reduce toxicity of Bortezomib and and maintain efficacy? Bortezomib once weeklylonger duration of therapysimilar cumulative dosesimilar efficacyless toxicty (G3/4 neurotoxicity)Bortezomib subcutaneously10 times lower serum peak concentrationsimilar area under the curveless neurotoxicity
25- MPR-R vs. MPR vs. MP (MM015 trial) RANDOMIZATION • Stratified by age (<75 years vs > 75 years) and stage (ISS I/II vs III)ISS, International Staging System; MP,melphalan, prednisone; MPR,, prednisone,lenalidomide; MPRR,withmaintenance; PBO, placebo.MPM:0.18 mg/kg, days 14P:2 mg/kg, days 1PBO:days 121MPRR:10 mg/daypo, days 1PlaceboRRANDOMIZATIONDouble-blind Treatment PhaseDiseaseProgressionMaintenanceLenalidomide(25 mg/day)+/DexamethasoneOpenLabelExtension PhaseCycles (28day) 19Cycles 10+N = 459, 82 centers in Europe, Australia, and IsraelMPR-R vs. MPR vs. MP (MM015 trial)Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of continuous lenalidomide treatment (melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance [MPR-R]) vs fixed-duration regimens of melphalan and prednisone (MP) or melphalan, prednisone, and lenalidomide (MPR)459 patients were recruited at 82 centers in Europe, Australia, and Israel between February 2007 and September 2008Approximately 50% of patients had stage III disease, and the median age was 71 years (MPR-R and MPR arms) and 72 years (MP arm)Patients were randomly assigned to receive MP (n = 154), MPR (n = 153), or MPR-R (n = 152)Patients could elect to receive open-label lenalidomide (25 mg/day) ± dexamethasone following disease progressionThe primary analysis was MPR-R versus MP and the primary endpoint was progression-free survival (PFS)The study was not powered to compare MPR-R vs MPRFollowing a pre-planned interim analysis at 50% information, an independent data-monitoring committee confirmed the superiority of MPR-R over MP at extending PFSThe cutoff for these data was April 15, 2009, allowing for a median follow-up of 9.4 months for PFSA second pre-planned interim analysis at 70% information was conducted for data on December 1, 2009, allowing for a median follow-up period of 21 months for PFSReferencePalumbo A, Delforge M, Catalano J, et al. A phase III study to determine the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients ≥ 65 years with newly diagnosed multiple myeloma (NDMM): continuous use of lenalidomide vs fixed-duration regimen. Blood. 2010;116: [abstract 622].
26Progression-free and overall survival HR, hazard ratio; MP,melphalan, prednisone; MPR,, prednisone,lenalidomide; MPR-R,withmaintenance; OS, overall survival; PFS, progressionfree survival; TTP, time to progression.ProgressionFree and Overall SurvivalAll Patients•TTP HR advantages were similar: MPRR vs MP = 0.337; MPR vs MP = 0.826Time (Months)Patients (%)HR 0.395P< .001HR 0.796= .13510203040255075100Median PFSMPRR31 months14 monthsMP13 months604year OS59%58%HR 0.898P =.579HR 1.089= .648Progression-free and overall survival
27PFS and OS with MPR-R and MPR patients aged 65-75 years
28FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs MPT (IFM 07-01; MM-020) Centres in EU, Switzerland, APAC, USA, and CanadaRANDOMIZATIONRd (28-day cycle; until disease progression)Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22Inclusion criteriaN = 1,623Previously untreated MMAge 65 years or not eligible for a transplantNo neuropathy of grade > 2Rd (28-day cycle; up to 18 cycles)Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22MPT (6-week cycle; up to 12 cycles )Melphalan* 0.25 mg/kg/day, days 1–4 Prednisone 2.0 mg/kg/day, days 1–4 Thalidomide* 200 mg/dayPrimary end-point: PFS*In patients aged > 75 years: Dex 20 mg/day, melphalan 0.20 mg/kg/day, thalidomide 100 mg/dayNCT Available from:282828
29What is the optimal duration of first line therapy? Trials & duration of therapy (months)VMP (Vista)12MPT trials6-18.5CTDa6-9MPR-R9, R untill PDVMPT-VT12.5, VT maintenance: 2 yearsLD (MM20)Continously until PD/intoleranceDuration of therapy: minimally 6, maximally 12 monthsMost experts recommend ≈ 9 months
30Outcome with novel combinations CR rate (%)Median PFS (months)Median OS (months)MP1,2rare11–20BP2-14*32MPT31020.339CTDa41333VMP53021.7–27.456.4MPR-R63159% (4-yr OS)VMP-VT/VP7423558% (5-yr OS)VMPT-VT8,935.359.3% (5-yr OS)LD continuous10≥PR 75% vs. 62%28% ↓ risk for PD22% ↓ risk for death1MTCG. J Clin Oncol 1998;16(12):2Ludwig et al., BLOOD 20092Pönisch et al. J Cancer Res Clin Oncol. 2006;132:3Fayers et al. Blood 2011; 118(5):4Morgan et al. Blood 2011;118:1231-85San Miguel et al. JCO 2013; 31(4):6Palumbo et al. N Engl J Med 2012;366(19):7Mateos et al. Blood 2012; 120:8Palumbo et al. ASH 2012 (Abstract 200), oral presentation9Palumbo et al. ASH 2011 (Abstract 653), oral presentation10Facon et al. ASH 2013 (Abstract 2), oral presentation
31Hematologic CR correlates with long PFS and OS in elderly patients treated with novel agents Retrospective analysis: 3 randomized European trials of GIMEMA and HOVON groups (N=1175)First-line treatmentMP (n=332), MPT (n=332), VMP (n=257), VMPT-VT (n=254)Significant benefit also seen when analysis is restricted to patients >75 years oldPFSOSCRCRVGPRProbabilityVGPRProbabilityPRPRP<0.001P<0.001Gay et al. Blood 2011; 117(11):
32Immunophenotypc CR correlates with OS GEM2005 >65y 100PFSImmunophenotypic CR 90% at 3y“Stringent CR” 38% at 3yConventional CR 57% at 3yPR (≥70% reduction) 28% at 3y80604020Paiva et al; J Clin Oncol. 2011;29(12):
33Cytogenetic abnormalities are a major prognostic factor in elderly patients with MM: IFM experience 1,890 patients (median age 72, range 66–94), including 1,095 patientswith updated data on treatment modalities and survivalOS according to t(4:14)OS according to del(17p)0.501.000.750.250.000.501.000.750.250.00p < 10.4p < 10.6Probability of OSProbability of OSt(4:14) negt(4:14) posdel(17p) < 60del(17p) ≥ 601234512345Time (years)Time (years)Whatever the treatment, t(4;14) and del(17p) were associated with shorter PFS and OS; similar results were achieved in the subgroup of 335 patients > 75 years1. Avet-Loiseau H, et al. J Clin Oncol (22): Hulin et al. Blood 2012:[abstract 204].
34The challenge of high-risk CA [t(4;14), del(17p), t(14;16)] in NDMM elderly patients StudyNo of pts with high-risk CAOutcome of high-risk CA patientsMPT/MP1NRCTDa/MP1(MRC Myeloma IX)CTDa does not overcome the effect of high-risk CA and is not significantly better than MP in high-risk CARD/Rd2 (E4A03)212y OS=76% for high-risk CA vs 91%VMP/MP3 (VISTA)46Absence of OS benefit, median OS 44.1mo. VMP vs 50.6 mo., MPVMP/VTP – VT/VP4(GEM-05)44Adverse prognosis of both t(4;14) and del (17p) regardless of induction and maintenance. Median OS t(4;14)=29 mo., del(17p) = 27mo.First generation novel agents only partly overcome the negative prognosisof high-risk CA in newly diagnosed elderly patients with MM1. Bergsagel PL, et al. Blood. 2013;121: Rajkumar SV, et al. Lancet Oncol. 2010;11: San Miguel J, et al. J Clin Oncol. 2013;31: Mateos MV, et al. Blood. 2011;118:
35Maintenance studies - summary Thalidomide PFSno improvement in OS Reduced OS after relapseNegative impact on high risk ptsClinical practicerecommendations50 mg for ≈ 12 mos may be consideredLenalidomideincreased risk for SPMBortezomib-thalidomideTendency for PFS and OS but not significant superior over VP
36Summary: Treatment results in elderly patients MPT, PFS, +/- OS, can be toxic in elderly ptsVMP, PFS OS, may induce severe PNPLd, PFS, OS, low dose Dex recommendedThal-Dex, an option for fit ptsCTDa vs MP, overall response rate, CR, VGPRBendamustine-Pred, approved for first line TXThalidomide maintenance PFS, but not OSMPR with Lenalidomide maintenance PFS, but not OSVT maintenance not significantly better than VP
37The natural course of multiple myeloma Maintenance
38Treatment of relapsed/refractory MM General considerations Components of initial therapyAlkylating-basedDexamethasone-basedIMiD-basedBortezomib-basedEfficacy of initial therapyQuality of responseTolerance of tretamentDuration of resposePatient status and type of relapseAge, performance status, glucose metabolismAggressive vs non-aggressive relapseBone marrow reserveRenal function impairmentPre-existing peripheral neuropathyOral vs. iv therapyIMiD, immunomodulatory derivative; MM, multiple myeloma
39IMiD based frontline TX Treatment of Relapsed/Refractory MyelomaFrontline Therapy successful?Yes NoLong duration of response Select other TX (Class switch)Yes NoRepeat first line TX Select other TXBortezomib based frontline TX:IMiD based frontline TXPomalidomideIMiD-basedTDMPTCTDRd(MPR)Old TypeMPDCEPM-100 +ASCTBort-basedVDVMPVTDLudwig et al.The Oncologist2011
40Retreatment with bortezomib: a meta-analysis including 23 studies 23 trials, 1051 patientsPatients refractory or not refractory to bortezomib11 studies including bortezomib-refractory pts6 studies excluding bortezomib-refractory pts6 studies missing information on bortezomib-refractory ptsCombinationsBortezomib ± Dex: 4 studiesBortezomib + combination therapy: 19 studiesKnopf et al. IMW 2013 (Abstract P-228), poster presentation
41Results of meta-analysis of retreatement with bortezomib in different risk groups VariableORRTTP (months)OS (months)Relapsed57%8.519.7Relapsed/>refractory19%5.920.4≤ 4 prior TX lines43%8.213.3> 4 prior TX lines29%7.120.0Boz + Dex51%7.919.2Combination36%16.2Pooled analysis8.4Knopf et al., IMW 2013
42Carfilzomib a second generation proteasome inhibitor
43Single agent Carfilzomib in relapsed/refractory patients Progressive disease at enrollment, Relapsed from 2 prior TX lines, Must include bortezomibMust include thalidomide or lenalidomide, Refractory to last lineResponse categoryAll patients(n=267)High risk cytogenetics(n=71)CR0.4%VGPR5.1%4.2%PR18.3%25.4%MR13.2%ORR37%29.5%PFS(median)3.7 mos3.6 mosDOR (median)7.8 mos6.9 mosSiegel D et al., BLOOD 2012
44Pomalidomide + LoDex vs HiDex (MM-003): Phase III Trial Design Stratified by age (≤ 75 vs > 75 yrs), number of previous treatments (2 vs > 2), disease population (refractory vs relapsed/refractory vs intolerant/refractory)28-day cyclesPOM + LoDex Pomalidomide 4 mg on Days Dexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1, 8, 15, 22 (n = 302)Follow-up for OS and SPM until 5 yrs Post enrollmentUntil PD*Patients with relapsed/refractory myeloma (N = 455)DOR, duration of response; DVT, deep venous thrombosis; LoDex, low-dose dexamethasone; HiDex, high-dose dexamethasone; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; POM, pomalidomide; SPM, second primary malignancies.HiDex Dexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1-4, 9-12, (n = 153)Companion trial MM-003C: Pomalidomide 21/28 daysUntil PD*Primary endpoint: PFSSecondary endpoints: OS, ORR, DOR, safety*Independently adjudicated in real time.Thromboprophylaxis indicated for patients receiving pomalidomide or with history of DVT.San Miguel JF, et al. ASCO Abstract 8510.
45Pomalidomide + LoDex vs HiDex: Key Criteria for Pts With Relapsed/Refractory MM All patientsRefractory to last therapy≥ 2 previous therapies≥ 2 consecutive cycles of lenalidomide and bortezomib (alone or in combination) or adequate previous alkylator therapyFailed bortezomib and lenalidomideProgression within 60 days; PR with progression within 6 mos, and/or bortezomib intolerant after ≥ 2 cycles and achieving ≤ MRRefractory or relapsed/refractoryPrimary refractory (never achieved better than PD to any therapy) or relapsed and refractory (relapsed after having ≥ SD for ≥ 2 cycles of therapy to ≥ 1 previous regimen and then developed PD ≤ 60 days of completing their last treatment)LoDex, low-dose dexamethasone; HiDex, high-dose dexamethasone; MR, molecular response; PD, progressive disease; PR, partial response, SD, stable disease.San Miguel JF, et al. ASCO Abstract 8510.
46Pomalidomide + LoDex vs HiDex (MM-003) PFS (ITT Population)OS (ITT Population)MosMosSan Miguel JF, et al. ASCO Abstract 8510.
47Pomalidomide + LoDex vs HiDex Adverse Events (MM-003) AE, %POM + LoDex(n = 300)HiDex(n = 150)Grade 3/4 hematologic AEsNeutropenia4816Anemia3337Thrombocytopenia2226Grade 3/4 nonhematologic AEsInfections3024Pneumonia138Bone pain75Fatigue6Asthenia4Grade 3/4 AEs of interestDVT/PE1Peripheral neuropathy*Discontinuation due to AEs910AEs, adverse events; DVT, deep vein thrombosis; HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; OS, overall survival; PE, pulmonary embolism; PFS, progression-free survival; POM, pomalidomide.*Includes hyperesthesia, peripheral sensory neuropathy, paraesthesia, hypoesthesia, and polyneuropathy.San Miguel JF, et al. ASCO Abstract 8510.
48Zoledronic Acid vs Clodronate in Newly Diagnosed MM: SREs Significantly reduced incidence of SREs* with zoledronic acid vs clodronateRegardless of presence of bone lesions at baselineHR: 0.74 (P = .0004)40CLO35.3%3027.0%Patients With an SRE (%)ZOL2010HR, hazard ratio; SRE, skeletal-related event6121824303642Time From Randomization (Mos)Patients at Risk, nZOL98166350639028420113897CLO97962946533725617311274*SREs defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic bone lesions.Morgan GJ, et al. ASH Abstract 311.48
49Planned and/or ongoing studies VD vs VTD vs VMP + V maintenance (UPFRONT study)VRd vs Rd + Rd maintenance (SWOG S0777)Rd vs MPT vs Rd + Rd maintenance (MM20/IM(FIRST trial)Rd vs MPR vs CRP + maintenance R vs RP (EMNTG)MPT+T vs MPR+R (HOVON 87-NMSG 18, ECOG EA1A06)CTDa vs RCD +/- R maintenance (MRC Myeloma XI)VP vs VMP vs VCP + VP maintenance (EMNTG)Carfilzomib + MP (CARMYSAP trial): ORR of 92% (40% VGPR). EHA 2012MLN9708 plus LD and MLN9708 plus MP: EHA 2012Rd vs MEL140 (DSMM XIII)Pomalidomide + Dex vs Dexamethasone: MM 005Alternating treatment with different regimens: VMP and RD (PETHEMA/GEM) Bortezomib + Bendamustine + Prednisone (PETHEMA/GEM)
51Recommendations for clinical practice Assesscomorbiditiesdegree of functional impairmentSelect most appropriate drug regimenAdapt dose if requiredConsider the increased risk of infections within first weeks/months of therapyOptimize supportive careAntibiotics, antivirals, growth factors, anti-thrombotics
52Thank you for your attention The future looks bright for elderlymyeloma patientsThank you for your attention