Induction Therapy: Have a Plan Sagar Lonial, MD Professor, Winship Cancer Institute Director of Translational Research, B-cell Malignancy Program Disclosures Consulting fees from: Bristol-Myers Squibb, Celgene, Millennium, Novartis, Sanofi, and Onyx 1
Topics When to treat? Smoldering vs Symptomatic Risk stratification Choice of Induction regimen Role of HDT Role of consolidation/maintenance Criteria for Diagnosis of Myeloma SMM Active MM MGUS • ≥ 3 g M spike • ≥ 10% plasma cells • < 3 g M spike • < 10% plasma cells • ≥ 10% plasma cells • M spike + AND AND No anemia, bone lesions, Anemia, bone lesions, high calcium, or normal calcium, and abnormal kidney function kidney function MGUS = monoclonal gammopathy of unknown significance; SMM = smoldering multiple myeloma. Kyle et al, 2009. 2
Smoldering Multiple Myeloma 27% will convert in 15 years Roughly 2% per year Kyle R et al. N Engl J Med 2007;356:2582-2590 Free Light is Useful for Risk Assessment in AMM Dispenzeri et al Blood 2008 3
Schedule of therapy (n:126 pts) Treatment arm Control arm (n = 60) (n = 66) Lenalidomide 25 mg/daily during 21d every 28 d Induction Therapeutic abstention Dexamethasone Nine 4-week cycles 20 mg D1-D4 and D12-D15 every 28 d Lenalidomide Therapeutic abstention Maintenance 10 mg/daily during 21 d every month* Ammendment on August 2011: Stop treatment at 2 years of treatment * Low-dose Dex will be added at the moment of biological progression PFS for Early treatment Mateos et al, NEJM 2013 4
OS from study entry Mateos et al, NEJM 2013 Challenges to Adoption Not clear these patients were truly smoldering (bone disease) Method for identifying these patients not standardized (minimal overlap methods) New definition of Smoldering coming from the IMWG soon 5
Freelight Ratio >100 predicts risk Larsen et al, Leukemia 2013 Plasma cells can predict for Progression Kastritis et al, Leukemia 2013 6
ECOG/SWOG: Phase III – Asymptomatic ECOG/SWOG: Phase III – Asymptomatic Myeloma*(PI: SL) Myeloma*(PI: SL) Lenalidomide vs. observation Lenalidomide vs. observation No Dex to isolate the effect of len R A CR/PR/ CR/PR/ Continue therapy Continue therapy N Lenalidomide Lenalidomide Stable Stable till prog. or toxicity till prog. or toxicity D O M IZ A Prog. Prog. TI Observation Observation Off Rx Off Rx anytime anytime O N Control/standard arm Overall Survival - Multiple Myeloma Patients (1980-1992) 7
The Good News Kumar SK, et al. Blood. 2008 Outcomes for patients are clearly improved The use of HDT or melphaln based novel agent inductions have doubled median survival for nearly all patients PETHEMA Cure with old Drugs Functional cure? Martinez-Lopez et al, Blood 2011 8
What is the Current state of the Art? Induction for younger patients – 3 drug induction followed by auto transplant in first response (Cavo et al) – Maintenance therapy post auto transplant (Attal, McCarthy, Palumbo) – Maximize duration of first response (Palumbo) – Goals of treatment now include trying to achieve MRD negativity (San Miguel/Paiva) Phase III Trials: Novel Agent Induction for Transplantation-Eligible Patients ≥ VGPR, % Trial Regimens n After After First After Induction ASCT Maintenance VTD x 3 241 62 79 Cavo [1] TD 239 28 58 VD x 4 223 37.7 54.3 IFM 2005-01 [2] VAD 218 15.1 37.2 HOVON-65/ PAD x 3 371 42 62 GMMG-HD4 [3] VAD 373 14 36 CR rate improved TV by 23% (TV), PETHEMA/GEM [4] 74 T 11% (T), 19% a2-IFN (a2-IFN) VTD 130 60 PETHEMA/GEM [5] TD 127 29 VMBCP/VBAD/B 129 36 RD 445 50 E4A03 [6] Rd 422 40 1. Cavo M, et al. Lancet. 2011;376:2075-2085. 2. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629. 3. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. 4. Rosiñol L, et al. ASH 2011. Abstract 3962. 5. Rosiñol L, et al. Blood. 2012;120:1589-1596. 6. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. 9
Early Phase Studies: Novel Regimens for Induction for Transplantation-Eligible Pts Phase Regimens ≥ VGPR, % Survival (N) Bortezomib/lenalidomide/ I/II 18-mo PFS: 75% 67 (after induction) Dexamethasone (RVD) [5] (n = 66) (with or without ASCT) 87 (after induction) [3] Carfilzomib/lenalidomide/ I/II 88 (after induction) [4] 12-mo PFS: 97% [2] Dexamethasone (CRD) [2,3,4] (n = 53) 24-mo PFS: 92% [2] rapid /deep responses improved with time 64 (after induction) Carfilzomib/thalidomide/ II 71 (after ASCT) Dexamethasone (CTD) [1] (n = 70) 84 (after consolidation) 60 (ITT) Bortezomib/cyclophosphamide/ II 67 (if completed all 4 cycles) dexamethasone (CyBorD) [6] (n = 63) Similar activity with weekly or twice weekly dosing Ixazomib/lenalidomide/ I/II 70 (after induction) dexamethasone [7] (n = 62) 1. Sonneveld P, et al. ASH 2013 (abstract 688). 2. Jakubowiak A, et al. Blood. 2012;120:1801-9. 3. Jasielec J, et al. ASH 2013 (abstract 3220). 4. Korde N, et al. ASH. 2013 (abstract 538). 5. Richardson, PG et al. Blood. 2010;116:679. 6. Reeder CB, et al. Blood. 2010;115:3416-3417. 7. Richardson PG, et al. ASH 2013. Abstract 535. Role and Timing of HDT Optimal induction is a Key Is the role of HDT waning? Does timing matter? What is the impact of MRD 10
Getting to Minimal Residual Disease (MRD): New Definitions for CR Newly diagnosed 1 × 10 12 S.S. Patient Disease burden CR 1 × 10 8 Stringent CR Antibodies MRD Maintenance Therapy 1 × 10 4 Molecular/Flow CR ?Cure? 0.0 Distribution of high risk features Flowchart for patients RVD induction (222 pts) Early ASCT Delayed ASCT (138 pts) (84 pts) Lenalidomide RVD Observation HDT ‐ ASCT maintenance maintenance (16 pts) (65 pts) (3 pts) Lenalidomide Bortezomib RVD Observation maintenance maintenance maintenance (57 pts) HDT ‐ ASCT at relapse (28 pts) (60 pts) (6 pts) (15 pts) Nooka et al ASCO 2013 11
Progression Free Survival – entire cohort Nooka et al ASCO 2013 Overall Survival – entire cohort Nooka et al ASCO 2013 12
Treatment schedule 402 patients (younger than 65 years) randomized from 62 centers Patients: Symptomatic disease, organ damage, measurable disease 1 ° 2 ° MPR R six 28-day courses R NO M: 0.18 mg/Kg/d, days 1-4 A A MAINTENANCE P: 2 mg/Kg/d, days 1-4 N N R: 10 mg/d, days 1-21 D D Rd* O O four 28-day courses M M R: 25 mg/d, days 1-21 I I d: 40 mg/d, days Z Z 1,8,15,22 A A T T MEL200 MAINTENANCE I I two courses 28-day courses until relapse O M: 200 mg/m2 day -2 O R: 10 mg/day, days 1-21 Stem cell support day 0 N N *Thromboprophylaxis randomization: aspirin vs low molecular weight heparin R, lenalidomide; d, low-dose dexamethasone; M, melphalan; P, prednisone; MEL200, melphalan 200 mg/m 2 MPR vs MEL200 1 ° MPR R six 28-day courses A M: 0.18 mg/Kg/d, days 1-4 N P: 2 mg/Kg/d, days 1-4 D R: 10 mg/d, days 1-21 O M I Z A MEL200 T two courses I M: 200 mg/m2 day -2 O Stem cell support day 0 N M, melphalan; P, prednisone; R, lenalidomide; MEL200, melphalan 200 mg/m 2 13
MPR vs MEL200 Overall survival Progression-free survival Median PFS 5-year OS MPR 24 months MPR 62% MEL200 38 months 100 MEL200 71% 100 Difference in Outcomes is accounted for by 75 75 MRD negativity 50 50 HR 1.69 HR 1.25 25 25 P <.0001 P =.27 0 0 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Months Months MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m 2 R maintenance vs No maintenance 2 ° R NO A MAINTENANCE N D O M I Z MAINTENANCE A 28-day courses until T relapse I R: 10 mg/day, days 1-21 O N R, lenalidomide 14
R maintenance vs No maintenance Overall survival Progression-free survival 48% reduced risk of progression 38% reduced risk of death Median PFS 5-year OS R maint. 75% R maint. 37 months 100 100 No maint. 58% No maint. 26 months 75 75 50 50 25 HR 0.52 HR 0.62 25 P <.0001 P =.02 0 0 0 0 10 20 30 40 50 60 70 10 20 30 40 50 60 70 Months Months o s R, lenalidomide MPR vs MEL200 vs MPR-R vs MEL200-R Progression-free survival Overall survival 100 100 MEL200-R 75 75 MPR-R MEL200 MPR 50 50 MEL200-R MEL200 25 25 MPR-R MPR 0 0 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Months Months MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m 2 ; R, lenalidomide maintenance 15
Phase III Maintenance Studies – Transplant Eligible Patients Trial N Regimen Outcomes Maintenance lenalidomide vs placebo 4-yr PFS: IFM 2005-02 [1] 614 following first or second ASCT 60% vs 33% Maintenance lenalidomide vs placebo after Median TTP: CALGB 100104 [2] 460 ASCT 46 vs 27 mos Median PFS (R vs no R): MPR + maintenance lenalidomide vs MPR vs 37 vs 26 mos RV-MM-PI-209 [3] 402 MEL200 + maintenance lenalidomide vs 5-Yr OS (R vs no R): MEL200 75 vs 58 mos Median PFS: VAD vs PAD followed by HD melphalan and 28 vs 35 mos HOVON-65 [4] 827 ASCT, then thalidomide or bortezomib as CR/nCR: maintenance 15% vs 31% ≥ nCR: Nordic MSG 15 [5] 370 Bortezomib x 21 wks vs no maintenance 45% vs 35% 1. Attal M, et al. N Engl J Med. 2012;366:1782-1791. 2. McCarthy PL, et al. N Engl J Med. 2012;366:1770- 1781. 4. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. 5. Mellqvist UH, et al. Blood. 2013;121:4647-4654. Progression Free Survival from IFM pilot RVD Induction HDT RVD consolidation Len maintenance Roussel et al, JCO 2014 16
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