Maintenance Therapy in Myeloma - Educational Concepts Group

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Maintenance Therapy in Myeloma - Educational Concepts Group

Lenalidomide


CALGB 100104A Phase III Randomized, Double-Blind Study ofMaintenance Therapy With Lenalidomide (CC5013) or Placebo Following Autologous StemCell Transplantation for Multiple MyelomaPhilip McCarthy, Roswell Park Cancer Institute, representing CALGB, ECOG,and BMT CTNMcCarthy PL, et al. J Clin Oncol. 2010;28(15S). Abstract 8017.


CALGB 100104 SchemaRegistrationRestagingDays 90-100RandomizationPlaceboS-D Stage 1-3, < 70 years> 2 cycles of inductionAttained SD or better 1 yr from start of therapy2 x 10 6 CD34 cells/kgMel 200ASCTCRPRSDLenalidomide10 mg/d with ↑↓(5-15 mg)Stratification based on diagnostic 2M and thalidomide and lenalidomide usedduring InductionMcCarthy PL, et al. J Clin Oncol. 2010;28(15S). Abstract 8017.


Grade 3-5 Adverse Events DuringMaintenance for 368 of 418Randomized PatientsLenalidomide n = 194 Placebo n = 174 P ValueN % N %Thrombocytopenia 23 12 6 3 = 0.01Neutropenia 83 42 13 7 < 0.0001Anemia 10 6 1 1 = 0.0028Fatigue 11 6 5 3 = 0.19Rash 9 5 3 2 = 0.12Diarrhea 8 4 5 3 = 0.52Febrile neutropenia 11 6 3 2 = 0.48Documented Infection 13 7 3 2 = 0.0313% (28 of 210) on lenalidomide and 2% on placebo (4 of 208) came off therapydue to AEs and 12% (26 of 210) on lenalidomide and 7% (14 of 208) on placebocame off therapy for other reasonsMcCarthy PL, et al. J Clin Oncol. 2010;28(15S). Abstract 8017.


Results• TTP was defined as disease progression or deathdue to any cause• TTP was calculated from day 0 of ASCT• Of 210 lenalidomide patients, 29 haveexperienced an event (progression or death)• Of 208 placebo patients, 58 have experienced anevent (P < 0.0001)• Estimated hazard ratio of .42, thus a 58%reduction in the risk of disease progression withlenalidomideMcCarthy PL, et al. J Clin Oncol. 2010;28(15S). Abstract 8017.


There is not long enough follow-up to determine ifthere is a difference in OS; 11 deaths inlenalidomide arm and 17 deaths in the placebo arm(P < 0.2)McCarthy PL, et al. J Clin Oncol. 2010;28(15S). Abstract 8017.


Conclusions• Maintenance therapy with lenalidomide when compared toplacebo will significantly prolong time to disease progression• Currently, there is no difference in OS at a median follow-up of 1year post-ASCT• Lenalidomide prolonged TTP within patient stratification by highand low β2M, and prior thalidomide or lenalidomide inductiontherapy• Lenalidomide maintenance produced some hematologic toxicity,but this was not severe with dropouts due to all AEs at 13%McCarthy PL, et al. J Clin Oncol. 2010;28(15S). Abstract 8017.


Lenalidomide Maintenance After AutologousTransplantation for Myeloma:First Interim Analysis of a ProspectiveRandomized Study of the IntergroupeFrancophone Du Myélome(IFM 2005-02 Trial)By Michel Attal, Gerald Marit, Denis Caillot, Thierry Facon, Philippe Moreau,Cyrille Hulin, Claire Mathiot, Hervé Avet-Loiseau, and Jean-Luc Harousseau forthe IFM*Attal M, et al. J Clin Oncol. 2010;28(15S). Abstract 8018.*IFM: Intergroupe Francophone du Myelome.


IFM 2005-02: Study DesignPhase III randomized, placebo-controlled trialN = 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008Patients < 65 years, with non-progressive disease, 6 months after ASCT in first-lineRandomization: stratified according to β2M, del13, VGPRArm A =Placebo(n = 307)Consolidation:Lenalidomide alone 25 mg/day p.o.days 1-21 of every 28 days for 2 monthsArm B =Lenalidomide(n = 307)until relapse10-15 mg/d untilrelapsePrimary endpoint: PFSSecondary endpoints: CR rate, TTP, OS, feasibility of long-term lenalidomideAttal M, et al. J Clin Oncol. 2010;28(15S). Abstract 8018.


IFM 2005-02 Trial: PatientCharacteristics (N = 614)Arm A (placebo)n = 307Arm B (Len)n = 307Age (years) 55 55Sex (male/female) 59% / 41% 55% / 45%ISSIIIIII36%25%39%30%24%46%β2M (≤ 3 / > 3) 33% / 67% 30% / 70%Del 13 (present / eval) 40% 42%t(4-14) (present / eval) 7% 11%Del 17 (present / eval) 5% 7%Attal M, et al. J Clin Oncol. 2010;28(15S). Abstract 8018.


IFM 2005-02 Trial: PatientCharacteristics (N = 614)Arm A (placebo)n = 307Arm B (Len)n = 307Induction regimenVADVel-DexOthers51%44%5%46%46%8%Number of transplants (1 / 2) 79% / 21% 79% / 21%VGPR post ASCT 58% 61%Interval diagnosis - randomization 10 m (8-12) 10 m (8-12)Interval transplant - consolidation 4 (3-5) 4 (3-5)Interval transplant - maintenance 6 (5-7) 6 (5-7)Attal M, et al. J Clin Oncol. 2010;28(15S). Abstract 8018.


IFM 2005-02: Response a DuringConsolidation (N = 572)PRE POST P value bCR (IF -) 13% 19% < 0.0001≥ VGPR 58% 68% < 0.0001aInternational Myeloma Workshop (IMW) Criteria b McNemar test.Attal M, et al. J Clin Oncol. 2010;28(15S). Abstract 8018.


IFM 2005-02: BestResponse a (N = 614)Arm A(n = 307)Arm B(n = 307) P valueCR (IF -) 22% 25% 0.4≥ VGPR 70% 77% 0.08aIMW Criteria.Attal M, et al. J Clin Oncol. 2010;28(15S). Abstract 8018.


IFM 2005-02: PFS FromRandomization.Arm An = 307Arm Bn = 307PProgression or Death 143 (47%) 77 (25%)Median PFS (m) 24 (21-27) NA3-year post randomizationPFS34% 68%Hazard Ratio 1 .46 < 10 -7Attal M, et al. J Clin Oncol. 2010;28(15S). Abstract 8018.


IFM 2005-02: PFS FromRandomization.00 .25 .50 .75 1.00P < 10 -70 6 12 18 24 30 36PlaceboLenalidomideAttal M, et al. J Clin Oncol. 2010;28(15S). Abstract 8018.


Disease ProgressionMPR vs MPR + MaintenanceLenalidomideCycles (28-day) 1-9 Cycles 10+UntreatedMM< 65 YearsN = 459RMPR-RM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day po, daysMPRM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day po, daysLenalidomide10 mg/day,days 1-21PlaceboSecondary ComparisonDouble-Blind Treatment PhasePalumbo A, et al. Blood. 2009;114(22). Abstract 613.Median follow-up: 9.4 months


Patients Without Event (%)MPR vs MPR-R, PFS Landmark AnalysisLandmark Analysis: PFS After Cycle 9100MPR-R vsMPR7550250HR = 0.314, P < 0.00010 5 10 15 20MonthsMedian follow-up: 21 monthsPalumbo A, et al. Blood. 2009;114(22). Abstract 613.Palumbo A, et al. European Hematology Association 15th Congress. 2010. Abstract 566.


MP vs MPR vs MPR-R, Phase IIIMPR-RN = 152MPRN = 153MPN = 154P(MPR-Rvs MP)ORR (> PR) 77% 68% 50% < 0.001CR 16% 11% 4% < 0.001> VGPR 32% 33% 12% < 0.001Median PFS NR 14.1 13.0 < 0.001months months2 year PFS 55% 24% 16% < 0.001Median follow-up: 24 monthsPalumbo A, et al. Blood. 2009;114(22). Abstract 613.Palumbo A, et al. 15th Congress of the European Hematology Association. 2010. Abstract 566.


MP vs MPR-R, ToxicityAdverse event MPR-R MPGrade 3 4 3 4Anemia 21% 3% 16% 1%Thrombocytopenia 25% 13% 10% 4%Neutropenia 35% 36% 22% 8%Febrile neutropenia 5% 2% 0% 0%Infections 9% 1% 8% 0%Fatigue 5% 0% 3% 0%Rash 4% 0% 1% 0%DVT / PE 2% 1% 1% 0%Peripheral % Patients neuropathy 0% 0% 0% 0%• ↑ Discontinuations with MPR-R (20% vs 8%)• ↑ G-CSF use with MPR-R (66% vs 31%)• ↑ Platelet transfusion (35% MPR-R vs 18% MP)Palumbo A, et al. European Hematology Association 15th Congress. 2010. Abstract 566.


Bortezomib


VMP vs VTP, Followed by VP or VTUntreatedMultipleMyeloma> 65 YearsN = 260InductionMelphalan: 9 mg/m 2 , d1-4, cycles 1-6Prednisone: 60 mg/m 2 , d1-4, cycles 1-6Bortezomib: 1.3 mg/m 2 , twice weekly, cycle 11.3 mg/m 2 , weekly, cycles 2-6Mateos MV, et al. Blood. 2009;114(22). Abstract 3.Mateos MV, et al. Blood. 2008;112(11). Abstract 651.RVMPBortezomibMelphalanPrednisone 1:1n = 130VTPBortezomibThalidomidePrednisonen = 130RRVPn = 87VTn = 91VPn = 87VTn = 91Maintenance (up to 3 years):Prednisone: 50 mg/m 2 every 48 hrsBortezomib: 1.3 mg/m 2 , d1, 4, 8, 11, every 3 monthsThalidomide: 50 mg daily


VMP vs VTP, Followed by VP or VT• CR (IF -) increased from 23% after induction to 42%in maintenance• Both maintenance regimens increased the CR rateResponse in MaintenanceVTn = 91VPn = 87CRIF- 44% 39%CRIF+ 15% 16%PFS from 2nd randomization Not reached 23 months2-year OS 2nd randomization 86% 81%Mateos MV, et al. Blood. 2009;114(22). Abstract 3.


Proportion Progression-FreeProportion Progression-FreePFS: VMP / VTP Stratified byVMPMaintenanceVTP1.01.00.80.80.60.60.40.40.2VT: Median not reachedVP: 32 monthsHR: 1.7; P = 0.10.2VT: Median not reachedVP: 26.5 monthsHR: 1.7; P = 0.10.00.05 10 15 20 25 30 35 405 10 15 20 25 30 35 40monthsMateos MV, et al. Blood. 2009;114(22). Abstract 3.months


VP vs VT: Maintenance ToxicityInductionVPn = 87VTn = 91Anemia 2% 2%Neutropenia 1% 3%Thrombocytopenia 1% 1%GI Toxicity 1% 4%Infections 1% 2%Cardiac 1% 2%Peripheral Neuropathy 2% 5%DVT / Thromboembolism 0% 1%Treatment discontinuation 5% 2%Deaths 1% 1%Mateos MV, et al. Blood. 2009;114(22). Abstract 3.


Bortezomib Consolidation After ASCT• Bortezomib-naïve patients were randomized 3 monthspost-ASCT to 21 weeks of bortezomib or control• ToxicityBortezomibn = 149Controln = 150CR / nCR month 3 20% 19% 0.9CR / nCR month 9 49.3% 33.3% 0.01Progression 6% 11.7% 0.08– > grade 3 neutropenia (22%), thrombocytopenia (9%), neurological pain(5%), sensory neuropathy (3%)PMellqvist U, et al. Blood. 2009:114(22). Abstract.


Thalidomide


Thal / Pamidronate vs Pamidronate vsMultipleMyeloma< 65 YearsVADInductionObservation1:1DoubleASCTN = 597ThalidomidePamidronaten = 201Pamidronaten = 196No Maintenancen = 200VAD: 0.4 mg vincristine/m 2 ; 9 mg doxorubicin/m 2 over 24 hrs x 4d; 40 mg dexamethasone, d1-4.Melphalan was given at 140 mg/m 2 before 1st SCT and 200 mg/m 2 before 2nd SCT.Pamidronate 90 mg IV at 4-wk intervals. Thalidomide 400 mg orally, dose reduction to a minimumof 50 mg.Attal M, et al. Blood. 2006;108:3290-3294.


Percent of PatientsPercent of Patients100908070605040302010Thal / Pamidronate Maintenance:EFS- Thalidomide+ ThalidomideP = 0.002Outcomes100908070605040302010P = 0.04OS- Thalidomide+ Thalidomide01 13 25 37 49Months From Randomization01 13 25 37 49Months From Enrollment+ Thalidomide - Thalidomide3-year OS 93% 87%4-year OS 87% 75%3-year EFS 52% 37%4-year EFS 36% 26%Attal M, et al. Blood. 2006;108:3290-3294.

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