Induction Therapy in Transplant Eligible MM 2 December Tontanai Numbenjapon, M.D.

Transcription

1 Induction Therapy in Transplant Eligible MM 2 December 2017 Tontanai Numbenjapon, M.D.

2 What we need from induction therapy in NDMM Depth of response: MRD-negative, scr, CR Longest response Acceptable toxicity Good quality of life

3 New treatment paradigm for transplant candidate MM NDMMtransplant candidate Induction regimen High dose melphalan and ASCT Post ASCT consolidation Post ASCT maintenance Maximize the depth of response Minimize the burden of the residual cells

4 Agents to make induction combination regimen for NDMM-transplant eligible 6 different classes of agents Sterioids Alkylators PIs: 2 nd generation-carfilzomib and ixazomib IMiDs: 3 rd generation-pomalidomide DACIs: panobinostat mabs: elotuzumab and daratumumab

5 Novel agent-based induction therapies for transplant eligible MM Combination Thalidomidebased Bortezomibbased Lenalidomidebased 2-drug TD VD Rd RD 3-drug TAD CTD PAD VCD RAD CRD PI + IMiD-based VTD VRD KRd/KTD Ixa-RD 4-drug VTDC RVCD VTD-Dara VRD-Elo

6 Efficacy of induction regimens

7 Role of ASCT in MM (non-novel agent era) Group/trial N Age (years) Median F/U CR rate (%) Median EFS (months) Median OS (months) CCT HDT CCT HDT CCT HDT IFM <65 7 years MAG months PATHEMA 164 <65 44 months Italian MMSG 195 <70 39 months MRC7 407 <65 42 months MAG years US S months J Clin Oncol 2011;29:

8 Response rate Meta-analysis: Bortezomib-based vs. nonbortezomib-based induction prior to ASCT Post-transplant (%) Bortezomib -based induction (n = 775) Non-bortezomib based induction (n = 772) OR 95%CI p CR+nCR <0.001 Response rate Bortezomibbased induction (n = 775) Nonbortezomib based induction (772) PFS, mos HR 95%CI p CR+nCR <0.001 Sonneveid et al. J Clin Oncol 2013;31:

9 Phase III VTD vs. TD: response and survival with ASCT and consolidation therapy

10 VCD vs. VTD induction: response IFM trial (prospective, intention-to-treat analysis) 1 VTD (4-cycles) VCD (4 cycles) P-value CR 13.0% 8.9% 0.22 VGPR 66.3% 56.2% 0.05 GIMEMA MMY-3006 and EMN-02 studies (retrospective, case-matched analysis) 2 VTD (4-cycles) VCD (4 cycles) P-value CR 13.0% 8.9% 0.22 VGPR 66.3% 56.2% 0.05 Moreau P, et al. Blood 2016;127: Cavo, et al. Leukemia 2015;29:

11 Evolving role of high-dose melphalan and ASCT in the era of novel agents and antibodies Novel agents Improved induction Improved consolidation Improved maintenance Early vs. late transplant Single vs. Tandem transplant Role of transplants in high-risk disease

12 Upfront ASCT vs. late ASCT Palumbo A, et al. N Engl J Med 2014;371:895.

13 RVd x 3 cycles Cyclophosphamide mobilization PBSC collection R maintenance R 10 mg/d x 3 months then titrate to 15 mg/d if tolerated cont. up to 1 year or until disease progression IFM 2009: Role of ASCT in novel agent era RVd (n=350) Five 21-day cycles V 1.3 mg/m 2 D1,4,8,11 R 25 mg D1-14 d 10 mg daily 3 weeks NDMM Age 65 years (n=700) R1:1 HDT-ASCT + RVd x 2 cycles (n=350) Melphalan 200 mg/m 2 ASCT 3 weeks Primary endpoint: Progression free survival Secondary endpoint: Response rate, time to disease progression, overall survival, adverse events Attal M, et al. N Engl J Med 2017;376:

14 Upfront ASCT is important in novel agent era RVD arm Transplant arm P value CR 49% 59% VGPR 29% 29% 0.02 PR 20% 11% At least VGPR 78% 88% Neg MRD by FCM 65% 80% y PFS 35% 47% HR: 0.69 ( ; P<0.001) 4-y OS 83% 86% HR: 1.2( ; P = NS) Attal M, et al. Blood 2015;126:391a Attal M, et al. N Eng J Med 2017;376: ç

15 Upfront ASCT is important in novel agent era PFS OS Attal M, et al. Blood 2015;126:391a Attal M, et al. N Eng J Med 2017;376: ç

16 First ASCT BMT CTN0702 StaMINA trial AM R maintenance R 10 mg/d for 3 years or until disease progression TAM Second ASCT Mel 200 mg/m 2 NDMM symptomatic Age 70 years, (n=758) Mel 200 mg/m 2 No improvement of PFS and OS using tandem ASCT or post ASCT consolidation over single ASCT R1:1:1 ACM Consolidation VRd x 4 cycles Median follow up from randomization: 38 months 38-month PFS: ACM 57% vs. TAM 56% vs. AM 52% Median OS not been reached; 38-month ACM 86% vs. TAM 82% vs. AM 83% Cumulative incidence of disease progression is not different **Addition of second ASCT or RVd consolidation was NOT superior to single ASCT followed by Lenalidomide maintenance** Blood 2016;128:LBA-1

17 With more effective induction, consolidation and maintenance, ASCT is still required Treatment arm Induction ASCT Consolidation Post maintenance VGPR CR CR VGPR CR VGPR CR ASCT 73% 16% 27% 91% 67% 94% 86% No ASCT 69% 18% 89% 34% 90% 59% Zimmerman T, et al. ASH abstract 675

18 Transplant increases MRD-neg CR

19 Autograft 1 vs. 2

20 EMN02/HO95 MM trial: study design Stratification: ISS I vs. II vs. III Randomization to VMP or HDM was 1:1 in centers with a fixed single ASCT policy Randomization to VMP or HDM-1 or HDM-2 was 1:1:1 in centers with a double ASCT policy Cavo M, et al. ASH abstract 673.

21 1192 pts eligible for randomization 1

22 1 transplant is essential but 2 transplants improve outcomes in HR-NDMM Cavo M, et al. ASH abstract 673. Sonneveid P, et al. ASH abstract 242.

23 Single vs. double ASCT for patients who failed CR after bortezomib-based induction regimens and had del(17p) and or t(4;14) Harousseau et al. JCO 2010;28: Cavo M, et al. Lancet 2010;376: Rosinof L, et al. Blood 2012;120: Cavo M, et al. ASH 2013 abstract 768

24 OS by study group and by treatment arm (single vs. double HDM/ASCT) HOVON PAD and VAD arms: single ASCT GMMG PAD and VAD arms: double ASCT PAD: single vs. double HDM/ASCT at 96 moths: 42% vs. 55% Cox all arms: HR: 0.71, 95% CI = ; P = Double ASCT subanalysis PFS at 5 years, % OS at 5 years, % FISH n Bor p standard Bor p Standard Del(17p) y/n 39/312 22% vs. 27% % vs. 24% 65% vs. 72% % vs. 66% Sonneveid P, et al. ASH 2015 abstract 27

25 Conclusions: Management of transplant candidate in the era of new drugs 3-drug combinations are recommended induction regimens, with the recent EMA-approval of VTD in this setting ASCT should remain as standard of care in 2017 in the frontline treatment of patients eligible for high-dose therapy Double tandem transplant is of use, particularly in high-risk patients? Conventional CR is inadequate to predict outcomes since in most of the cases may logs of residual tumor cells still persist MRD negativity should be the current treatment endpoint, but not in Thailand now Consideration of the whole treatment sequence, including induction regimen and post-asct therapy, will maximize the depth of response. 4-drug regimens may possibly be the next standard of care.