Presentation on theme: "Imedex 2-27-14 Frontline Therapy and Maintenance for Newly Diagnosed Multiple Myeloma Transplant eligible vs transplant ineligible Doublets vs triplets."— Presentation transcript:
1ImedexFrontline Therapy and Maintenance for Newly Diagnosed Multiple MyelomaTransplant eligible vs transplant ineligibleDoublets vs tripletsIntegrating Novel Agents into Frontline TherapyCarfilzomibElotuzumabPomalidomideOral PI’sMaintenance
5The Concept of Dividing Myeloma Patients into Transplant Eligible vs Transplant Ineligible Arguments for making this distinction:The use of melphalan impedes the ability to collect PBSC’sOlder patients cannot tolerate more aggressive regimensOlder patients don’t need to achieve a deeper response since they don’t have as long to live anywayArguments against making this distinction:More and more we have been able to collect stem cells after melphalanThere are data that older patients benefit just as much from deeper responses and would appreciate the added longevity (I would)Most US oncologists don’t use melphalan-based regimens anyway (prefer Vd and Rd)
7Prognostic effect of Patients in CR vs those in (nCR or VGPR or PR) vs those with (SD or PD) after HDT/ASCTMartinez-Lopez et al Blood. 2011;118(3):
8In non-transplant candidates, achievement of CR is also associated with improved PFS and OS Gay F et al. Blood. 2011;117:3025.Shouldn’t the achievement of deeper response be also a goal in non-transplant candidates?
9Frontline Therapy Transplant Eligible Patients Are Triplets the Standard of Care?
10Improving Response Rates with Combination Therapies 10
14Active treatment + PFS follow-up phase FIRST: Lenalidomide/Dexamethasone vs MPT in NDDM SCT-Ineligible PatientsActive treatment + PFS follow-up phasePhase IIIN = 1623Randomization 1:1:1Arm AContinuous RdLen + LoDex ContinuouslyLenalidomide 25 mg Days 1-21/28LoDex 40 mg Days 1, 8, 15, 22/28PD or unacceptable toxicitysubsequent anti-MM TxPD, OS, andLen + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28LoDex mg Days 1, 8, 15, 22/28Arm BRd18Mel + Pred + Thal 12 cycles (72 wks)Melphalan 0.25 mg/kg Days 1-4/42Prednisone mg/kg Days 1-4/42Thalidomide mg Days 1-42/42Arm CMPTPts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal 100 mg Days 1-42/42; Mel 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage.1. Facon T, et al. ASH Abstract Facon T, et al. Lancet. 2007;370: Hulin C, et al. J Clin Oncol. 2009;27:
15FIRST Trial: Progression-Free Survival 10080604020Median PFSRd (n = 535)25.5 mosRd18 (n = 541)20.7 mosMPT (n = 547)21.2 mosHR:Rd vs MPT: 0.72 (P = )Rd vs Rd18: 0.70 (P = )Rd18 vs MPT: 1.03 (P = )Patients (%)72 wks6121824303642485460Mos1. Facon T, et al. ASH Abstract 2. Reproduced with permission.
16Integrating Approved Newer Agents into Frontline Regimens Transplant Eligible
17Carfilzomib, Lenalidomide, dexamethasone (CRd) Treatment Schema InductionCRdMaintenanceLenalidomide(off protocol)Transplant-eligible and ineligible patientsLEN Cycles 25+CRd Cycles 1–4CRd Cycles 5–8CRd Cycles 9–24Until disease progression or unacceptable toxicityTransplant-eligible≥PRASCTStem cell collectionCycles 1–8CFZ mg/m2 Days 1–2, 8–9, 15–161LEN 25 mg Days 1–21DEX 40 mg weekly Cycles 1-4, 20 mg weekly Cycles 5–8Cycles 9–24CFZ on Days 1–2 and 15–16 onlyCFZ, LEN, DEX at last best tolerated dosesCycles 25+LEN at last best tolerated doseJakubowiak AJ, et al. Blood. 2012;120(9):
18CRd - Best Response (n=53)* †*ITT, including patients who discontinued treatment early (eg, proceed to transplant)†iCR is an estimate of MRD-negative disease (10 color flow), based on percentage of patients in sCR evaluated for MRD at 12 months (18 of 19) and at 22 months (22 of 24)Jakubowiak et al, ASCO 2013
19Progression-free Survival CRd – SurvivalProgression-free SurvivalOverall Survival24-month rate 98%24-month rate 94%N=53Median follow-up of 25 months (range 5-37)Patients receive 8 cycles of CRd Induction then 16 cycles of CRd maintenance then LEN maintenance until progressionJakubowiak et al, ASCO 2013
20CRd - Time to Response Jakubowiak et al, ASCO 2013 Median Time to Response, mo0.93.76.711.013.1Jakubowiak et al, ASCO 2013
21Integrating Approved Newer Agents into Frontline Regimens Transplant Ineligible Patients
22Carfilzomib, Melphalan, Prednisone (CMP) PFSMTD defined at CFZ 36 mg/m2Patients receive 9 cycles then stop treatment68 patients have been enrolled in Phase 1 +2Median age 72 years (61 – 86)High risk 17%After a median of 7 cycles (1 – 9)CR 6%VGPR 50%PR %SD 9%PD 0Median PFS = 22 monthsOS93.9%>VGPR 56%>PR 91%OS= 87%Median follow-up = 12 monthsMoreau et al, ASCO 2013, Courtesy P. Moreau
23Carfilzomib, Cyclophosphamide, dex (CCd) Time to Event Patients receive 9 cycles of CCD then CFZ maintenance until progressionPalumbo et al, ASH 2012, Courtesy A. Palumbo
25Ixazomib (weekly), Lenalidomide, dexamethasone Patients treated at RP2D (2.23 mg/m2 / 4.0 mg) ORR 94%ORR 95%ORR 90%≥VGPR49%≥VGPR58%≥VGPR58%%Of 3 response-evaluable patients who completed 12 cycles, 2 achieved CR and 1 VGPRKumar et al, ASH 2012, Courtesy S. Kumar
26Oprozomib (ONX 0912)Oprozomib (OPZ, formerly ONX 0912) is a structural analog of carfilzomib (CFZ)It is an orally bioavailable, next-generation PISimilar to CFZ, OPZ is a potent, selective, and irreversible proteasome inhibitorBeing evaluated in hematologic malignancies and solid tumorsSavona MR, et al. Blood. 2012;120. Abstract 203.
27Monoclonal antibodies Anti CS 1ElotuzumabAnti CD 38DaratumumabSAR
28Efficacy: Best Response Phase II (Study 1703) Elotuzumab 10 mg/kgElotuzumab 20 mg/kgTotalPatients, n363773ORR (≥PR), n (%)33 (92)28 (76)61 (84)CR/stringent CR, n (%)5 (14)4 (11)9 (12)VGPR, n (%)17 (47)13 (35)30 (41)PR, n (%)11 (31)11 (30)22 (30)<PR, n (%)3 (8)9 (24)12 (16)Overall median time to response: 1 mo (range, ); 1 new and 3 deepening responses were observed since the previous data cut (October, 2011)1Overall median time to best response: 2.5 mo (range, )Median duration of objective response: 15 mo1. Lonial S et al. Blood 2011;Abstract 30328
29Progression-free Survival from the Phase II Cohort 10 mg/kg (n=36): 33 mos (95% CI: NA)20 mg/kg (n=37): 18.6 mos (95% CI: )Total (n=73): 25.8 mos (95% CI: )In the 10 mg/kg cohort, median PFS was 33 months In the 20 mg/kg cohort, the median PFS was 18 monthsLonial et al, ASCO 2013
30Ongoing Studies with Elotuzumab PhaseTreatmentPrimary EndpointMM Patient PopulationELOQUENT - 1IIIRD +/– ElotuzumabPFSPreviously UntreatedELOQUENT - 2Relapsed or Refractory
31Daratumumab Phase I/II Maximal Change in Paraprotein *Data at baseline below limits for measurable diseaseResults are before database lock≤1 mg/kg2 mg/kg4 mg/kg8 mg/kg16 mg/kg
32% Change in Paraprotein SAR650984: Maximal Change in Paraprotein Myeloma Patients Treated at Doses of 1 mg/kg Q2W or Higher1501 mg/kg Q2W3 mg/kg Q2W1255 mg/kg Q2W10 mg/kg Q2W10010 mg/kg QW20 mg/kg Q2W755025% Change in Paraprotein-25-50-75-100One patient at 3.0 mg/kg and 20 mg/kg with 0% change; One patient at 20 mg/kg not evaluable
34Conventional Chemotherapy vs ASCT RANDOMIZED STUDIES Median OS Patients(n)AgeMedian Follow UpConventional ChemotherapyASCTIFM90200<657 y4457MAG9119055-6556 m5055MRC740342 m42PETHEMA*1646472*in patients responding to conventional chemotherapy1. Attal M et al. N Engl J Med. 1996;335: Fermand JP et al. J Clin Oncol. 2005;23: Child A et al. N Engl J Med. 2003;348: Blade J et al. Blood. 2005;106:3755.
35The Debate…ASCT: Up-Front or at Relapse Len-Bz-Dex ×3Len-Bz-Dex ×3Stem collectionStem collectionASCTLen-Bz-Dex ×5Len ×12m (IFM)Len until relpase (USLen-Bz-Dex ×2Len ×12m (IFM)Len until relapse (US)ASCT at relapseNCI Clinical Trial Identifier NCT
36Not as Simple as We Thought Maintenance TherapyNot as Simple as We Thought
37Post-Transplant Lenalidomide Maintenance CALGB 100104 Updated OSIncludes pts crossing overUpdated TTPEstimated HR=0.51(95% CI = 0.39 to 0.66),146 events on placebo104 events on lenalidomideAnalysis including placebo patients crossing over within 12 months of randomization on lenalidomide arm with a median follow-up of ~48 months. p= 0.003ITT Analysis with a median follow-up from transplant of ~48 months p<0.001 Median TTP: 50 months versus 27 months.Cut-off date January 7, 2013McCarthy, IMW Kyoto, April 2013
38CALGB 100104: Event-Free Survival & SPM Hematologic SPM: 8 (LEN; 3.5%) vs. 1 (PBO; 0.4%)Solid-tumor SPM: 10 (LEN; 4.3%) vs. 5 (PBO; 2.2%)ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; EFS: event-free survival; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; PBO: placebo; PD: progressive disease; SPM: second primary malignancy. McCarthy PL. N Engl J Med. 2012;366:
39IFM 2005-02: Progression-Free Survival ASCT: autologous stem cell transplant; β2-M: β2-microglobulin; del: deletion; HR: hazard ratio; IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; PBO: placebo; PFS: progression-free survival; VGPR: very good partial response. Attal M. N Engl J Med. 2012;366:
40IFM 2005-02: Overall Survival With a median follow-up of 45 months, no differences in OS has been observed across treatment arms4 year OS (post-randomization): 73% (LEN) vs. 75% (placebo)IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo. Attal M. N Engl J Med. 2012;366:
43IFM 2005-02: Event-Free Survival & SPM* Hematologic SPM: 13 (LEN) vs. 5 (placebo) (18 v 7)Solid tumor SPM: 10 (LEN) vs. 4 (placebo) (13 v 11)* Data as of Oct 2011, including events during consolidation and maintenance. EFS: event-free survival; IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; N/A: not applicable; PBO: placebo; PD: progressive disease; SPM: second primary malignancy. Attal M. N Engl J Med. 2012;366:
45Bortezomib Maintenance HOVON-65/GMMG-HD4 Trial PFSOSBortezomib was used both pre- and post-transplantBenefits mostly in patients with high risk diseaseSonneveld et al, J Clin Oncol 2012;30:
46MM-015: Study DesignDex: dexamethasone; ISS: International Staging System; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone- lenalidomide followed by lenalidomide maintenance; PBO: placebo; po: orally. Palumbo A. N Engl J Med. 2012;366:
47MM-015: Progression-Free Survival MPR-R significantly extended median PFS vs. MP and MPRHR: hazard ratio; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; N/A: not applicable; PFS: progression-free survival. Palumbo A. N Engl J Med. 2012;366:
48MM-015: Overall SurvivalThe number of deaths is low and comparable across treatment groupsHR: hazard ratio; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; N/A: not applicable; OS: overall survival. Palumbo A. N Engl J Med. 2012;366:
49Controversies in Maintenance Therapy Should everyone (anyone) receive it?Should everyone receive the same drug(s)?Lenalidomide?VRd for high risk? Who is high risk?What should be the duration of therapyIs there a way to measure this (MRD)?Does more therapy result in more SPM’s and less effect?Would some patients be better off with just “consolidation?”At least those of us who work in this area will not be at a loss for new studies.