Multiple myeloma, 25 (45) years of progress. The IFM experience in patients treated with frontline ASCT. Philippe Moreau, Nantes

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1 Multiple myeloma, 25 (45) years of progress The IFM experience in patients treated with frontline ASCT Philippe Moreau, Nantes

2 Shibata T. Prolonged survival in a case of multiple myeloma treated with high dose of melphalan Rinsho Ketsueki 1973;14:

3 McElwain TJ & Powles RL Lancet 1983;ii: High dose intravenous melphalan for plasma cell leukaemia and myeloma 9 patients, MM or plasma cell leukemia, refractory 140 mg/m2 melphalan IV 3 CR and 1 prolonged survival proof of principle : dose / response

4 Efficacy of high dose melphalan in RRMM was confirmed Barlogie et al, Blood 1988;72: Lokhorst et al, J Clin Oncol 1992;10:47 51 High response rates Prolonged neutropenia : days TRM : 10 20%

5 High dose melphalan + GM CSF / G CSF Barlogie et al, Blood 1990 Moreau et al, J Clin Oncol 1997 duration of neutropenia was reduced (23 vs 29 days) duration of hospitalization was reduced (32 vs 38 days) but TRM remained high (10%)

6 Concept of ASCT was introduced to reduce TRM, first in RRMM

7 Barlogie, Blood 1986;67:1298 High dose melphalan with autologous bone marrow transplantation for multiple myeloma Harousseau, Br J Haematol 1987;67:493 High dose melphalan and autologous bone marrow transplantation in high risk multiple myeloma mel200 or mel140 + TBI response rate: 50 to 70% CR: 5 to 20% median OS: 3 years

8 Relapse frontline setting, pilot trials Cunningham JCO 1994 mel200 + ABMT Attal Blood 1992 mel140 + TBI 8 Gy + ABMT Fermand Blood 1993 BCNU/VP16/Mel +/ Cy + TBI 10/12Gy + PBSC Response rates : 75 80% CR : 20 to 40% Median OS : 5 years TRM < 5%

9 IFM90 N Engl J Med 1996

10 IFM 90 (Attal et al, N Engl J Med 1996) 200 patients <65 years HDM TBI / ABMT CC HDT p N=100 N=100 Response 14% 38% <0.001 (CR + VGPR) Median EFS 18 mo 28 mo 7 year EFS 8% 16% <0.01 Median OS 44 mo 57 mo 7 year OS 25% 43% <0.05

11 N Engl J Med 1996 Attal et al IFM90 trial

12 Child et al, New Engl J Med 2003;348:1875

13 CC vs ASCT RANDOMIZED STUDIES Nb of pts Age CC HDT IFM90 (NEJM 96) 200 <65 Med 57 VMCP/VBAP HDM140 + TBI MRC7 (NEJM 2003) 401 <65 Med 55 ABCM HDM200 Italian MMSG (Blood 2004) Med 63 MP HDM 100x2 + PBSC MAG91 (JCO 2005) Med 61 VMCP HDM200 or HDM140 + Bu16 US INTERGROUP (JCO 2006) 516 < 70 Med 54 VAD/VBMCP HDM +TBI PETHEMA (Blood 2006) 164 < 65 Med 56 VBMCP/VBAP HDM140 + TBI Or HDM200

14 CC vs ASCT RANDOMIZED STUDIES Nb of pts Age CR rate (%) Median EFS (mo) Median OS IFM90 (NEJM 96) MRC7 (NEJM 03) Italian MMSG (Blood 04) MAG 91 (JCO 2005) PETHEMA (Blood 06) US Intergroup (JCO 06) <65 < <65 < 70 5 vs 22 8 vs 44 6 vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs 62

15 RESULTS ACHIEVED WITH single ASCT in the 90 s ASCT CC CR VGPR Median PFS Median OS 15 25% 40 50% months months < 10% < 20% months months

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17 IFM MM de novo < 66 years VAD x 3 PBSC harvest R HDM TBI 8 gy HDM 200 n = 140 n = 142

18 Moreau et al, Blood 2002 IFM95 02, Overall survival

19 IFM 94 N Engl J Med 2003

20 IFM 94 Randomization : single versus tandem VAD VAD VAD VAD Mel TBI Mel 140 Mel TBI

21 Attal, N Engl J Med 2003 IFM 94 TRIAL FEASIBILITY HDM 140 Toxic death HDM TBI Toxic death Single ASCT N = (85%) 3 Double ASCT N = (88%) (78%) 5

22 IFM 94 Single TX Double TX p N = 199 N = 200 EFS median 31 m 37 m yr 19% 28% OS median 50 m 58 m yr 26% 46% Attal, N Engl J Med 2003

23 IFM 94 : Overall survival Attal, N Engl J Med 2003 P < 0.01 B A

24 IFM 94 : OS if response to 1 st graft <90% Attal, N Engl J Med 2003 P < B A

25 IFM 94 : OS if response to 1 st graft > 90 % P = 0.7 B A

26 SINGLE vs DOUBLE ASCT RANDOMIZED STUDIES Nb of pts Age Results IFM 94 (NEJM 03) 399 < 61 EFS and OS MAG 95 (Kos 07) 227 < 56 EFS and OS Bologna (JCO 07) 220 < 61 EFS GMMG (Kos 07) 261 < 66 EFS Hovon 303 (Haematologica 07) < 66 CR and EFS

27 No plateau on survival curves Major finding : importance of CR/VGPR after ASCT

28 Impact of CR + VGPR on outcome IFM99 trials Harousseau et al, J Clin Oncol 2009

29 Major importance of best response after induction therapy

30 Influence of response obtained after induction therapy on (A) event free survival (EFS) and (B) overall survival (OS); influence of response obtained after high dose therapy plus autologous stem cell transplantation on (C) EFS and (D) OS Lahuerta, J. J. et al. J Clin Oncol; 26:

31 How to improve the CR/VGPR rate? Incorporation novel agents

32 < 65 years, de novo Induction therapy ASCT VAD Melphalan 200 mg/m 2 (Melphalan) 200 mg/m 2

33 < 65 years, de novo Induction therapy ASCT Maintenance VAD Melphalan 200 mg/m 2 (Melphalan) 200 mg/m 2 Thalidomide

34 IFM Patients <66 years VAD VAD VAD PBSC harvest HDM ASCT Control n = 200 HDM ASCT Pamidronate n = 196 Pamidronate + Thalidomide n = 201

35 Overall survival according to treatment arm with thalidomide maintenance 4 year OS : 87% Attal, M. et al. Blood 2006;108:

36 Randomized Studies on Post ASCT With Thalidomide No Initial dose,mg CR, % EFS or PFS % OS % Attal vs 55 3-year EFS 4-year Blood vs vs 70 Barlogie vs 43 5-year EFS 8-year Blood sv vs 44 Spencer vs 40 3-year PFS 3-year JCO vs vs 75 Lokhorst vs 54 Median PFS Median Blood vs 25 mo 73 vs 60 mo Morgan vs 34 Median PFS 3-year Blood vs 23 mo 75 vs 80

37 < 65 years, de novo Induction therapy ASCT Maintenance VAD Melphalan (Melphalan) 200 mg/m mg/m 2 Thalidomide Revlimid IFM : prospective randomized Maintenance trial, using revlimid

38 IFM : lenalidomide maintenance after ASCT Phase III prospective randomised, versus placebo Patients < 65 y, non progressive or stable, 6 months post ASCT Randomisation Consolidation Lenalidomide 25 mg/d, D1 21, 28 day cycle, during 2 cycles Lenalidomide mg/d Until progression Placebo until progression Primary end point : TTP Secondary end points: CR, PFS, OS, feasibility toxicity

39 IFM : PFS from randomization Rev (n =307) P < 10 8 Placebo (n = 307) P < 10 8 Median follow up: 34 m post rando, 44 m post diag Placebo Revlimid Attal et al, N Engl J Med 2012

40 Lenalidomide maintenance: OS meta-analysis Studies included CALGB (accrual 8/ /2009) IFM (accrual 6/2006 8/2008) GIMEMA (RV-MM-PI-209) (accrual 11/2007 7/2009) Induction ASCT 1:1 randomization No evidence of PD Induction ASCT 1:1 randomization No evidence of PD 2 x 2 design LEN + DEX x 4 Induction ASCT MPR: 6 courses LEN: 2 courses PLACEBO (n = 229) LEN (n = 231) PLACEBO (n = 307) LEN (n = 307) No treatment (n = 68) LEN (n = 67) No Tx LEN Crossover before PD allowed Continued treatment No crossover before PD allowed Continued treatment Continued treatment Continued treatment ALL treatment discontinued Jan 2011 Dex, dexamethasone; MPR, melphalan-prednisone-lenalidomide; Tx, treatment. Attal M, et al. Presented at ASCO J Clin Oncol. 2016;34 Suppl:abstract 8001.

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43 < 65 years, de novo Induction therapy ASCT Maintenance VAD Melphalan (Melphalan) 200 mg/m mg/m 2 Thalidomide Velcade Dex (IFM ) Revlimid IFM

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45 Response To Induction Evaluable Patients VAD Vel Dex P value N=218 N=223 CR 1.4% 5.8% CR+nCR 6.4% 14.8% >VGPR 15.1% 37.7% < >PR 62.8% 78.5%.0003 MR+SD 26.6% 12.6% PD 4.1% 4.5% Death 2.8% 0.5% Harousseau et al, J Clin Oncol 2010

46 Response to First ASCT Evaluable Patients VAD Vel Dex P value N=218 N=223 CR CR + ncr >VGPR >PR MR/SD/PD No ASCT 8.7% 18.4% 37.2% 77.1% 3.7% 15.6% 16.1% 35% 54.3% 80.3% 2.7% 11.7% <0.001 <

47 Event free survival, intent to treat (f up 36 months)

48 < 65 years, de novo Induction therapy ASCT Maintenance VAD Melphalan (Melphalan) 200 mg/m mg/m 2 Thalidomide Velcade Dex (IFM ) Velcade Thal Dex (IFM ) Revlimid IFM

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50 IFM cycles followed by ASCT prepared by mel 200 Disease response evaluation after 2 cycles & 4 cycles VD (IFM 2005/01) vtd Vel 1.3mg/m2 d1,4,8,11 Dex 40mg d1 4,9 12 Cycles 1 & 2 d1 4, cycles 3 & 4 Vel 1mg/m2 d1,4,8,11 Thal 100mg/d Dex idem Moreau et al, Blood 2011

51 IFM / results induction phase 03/ /2009, 205 patients < 65 years Investigator based assessment VD vtd %CR p = 0.68 % > VGPR p = % >PR p = 0.06 Stable 12 5 Prog 7 4

52 Response to ASCT Intent to treat analysis VD vtd P value CR 26% 20% 0.33 CR+nCR 47% 60% 0.50 VGPR 54% 66 % PR 84% 92% 0.33 Moreau et al, Blood 2011

53 Peripheral Neuropathy (% of patients) VD N=102 vtd N=97 p. value All grades 63% 56% 0.31 Grade >=2 28% 16% 0.04 Grade >=3 6% 3% 0.34 SAE leading to Tt discontinuation 4% 0% 0.12 vtd : standard of care

54 < 65 years, de novo Induction therapy ASCT Maintenance VAD Melphalan (Melphalan) 200 mg/m mg/m 2 Thalidomide Velcade Dex (IFM ) Velcade Thal Dex (IFM / IFM ) Revlimid IFM

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56 Intent-to-treat analysis VTD VCD P value N = 169 N = 169 CR 13.0% 8.9% 0.22 VGPR 66.3% 56.2% 0.05 PR 92.3% 83.4% 0.01 Response: centralized assessment (Dr Dejoie, Nantes), IMWG criteria 2011

57 Toxicity VTD, n = 169 VCD, n= 169 p value Grade 3-4 % Grade 3-4 % Any Aes Anemia Neutropenia Infection Thrombocytopenia Thrombosis Cardiac disorders Cystitis GI symptoms Periph. Neuropathy PN grade Toxicities assessed according to NCI CTCAE, version 4.0.

58 CONSOLIDATION Retrospective trial 217 patients VTD auto vs VTD auto VTD Leleu X, Moreau P. Leukemia 2013Apr5 [Epub ahead of print]

59 RVD Richardson et al, Blood 2010, online 12 april Up to eight 21 day cycles Bz Bz Bz Bz Dex Dex Dex Dex Lenalidomide Phase II : Len 25, Btz 1.3, Dex : 20

60 Best response to treatment overall and in the phase II population Response, n (%) All pts (N=66) Phase II (N=35) CR 19 (29) 13 (37) ncr 7 (11) 7 (20) VGPR 18 (27) 6 (17) PR 22 (33) 9 (26) CR+nCR 26 (39) 20 (57) CR+nCR+VGPR 44 (67) 26 (74) At least PR 66 (100) 35 (100)

61 PFS according to receipt of ASCT Receipt of ASCT did not affect 1 yr PFS (P =.38)

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64 < 66 years, de novo Best option? Induction therapy ASCT Consolidation Maintenance VTD VRD Melphalan 200 mg/m 2 VTD VRD Revlimid

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66 < 65 years, de novo Pilot trial, IFM Induction therapy ASCT Consolidation Maintenance VRD x 3 Melphalan 200 mg/m 2 VRD x 2 Lenalidomide Roussel et al. J Clin Oncol Sep 1;32(25):2712 7

67 RESPONSE RATES (ITT) after Induction after ASCT after Consolidation n % n % n % scr CR CR+sCR VGPR VGPR PR ORR SD out of trial total

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69 IFM DFCI 2009 Trial 700 patients < 66y, Newly diagnosed symptomatic MM 3 RVD 5 RVD MEL200 + ASCT 2 RVD 12 months Lenalidomide maintenance Attal et al, New Engl J Med 2017

70 PROGRESSION FREE SURVIVAL Attal et al, N Engl J Med 2017

71 OVERALL SURVIVAL Attal et al, N Engl J Med 2017

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73 IFM 2009: Best Response. RVD group N=350 Transplant group N=350 p value CR 48% 59% VGPR 29% 29% PR 20% 11% <PR 3% 2% At least VGPR 77% 88% <0.001 MRD neg by FCM, n (%) 171/265 (65%) 220/278 (80%) <0.001

74 IFM 2009: PFS, Prognostic Factors. Multivariate Analysis ahr p value Treatment arm (B/A) ISS II vs I III vs I FISH (high risk/standard) 2.22 <0.001 CR 0.58 <0.001 MRD (FCM) 0.39 <0.001

75 IFM/DFCI 2009: OS according to MRD (FCM) (9/2015).

76 IFM 2009 trial NGS premaintenance After consolidation 1.0 MRD at pre-maintenance Patients without progression (%) P-value : p< Negative (<10-6) Positive 0.0 N at risk (events) MRD neg (<10-6 ) MRD positive (0) 87 (0) 87 (2) 85 (2) 83 (6) 74 (4) 54 (3) 31 (0) (0) 159 (12) 147 (15) 132 (11) 120 (22) 94 (11) 67 (17) 22 (4) 6 30 Months since randomization Avet-Loiseau H et al. Oral presentation at ASH 2015 (Abstract 191).

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78 PFS according to normalization of PET-CT before maintenance therapy P = 0.01 Moreau et al. J Clin Oncol 2017, july 7

79 OS according to normalization of PET-CT before maintenance therapy P = 0.03 Moreau et al. J Clin Oncol 2017, july 7

80 86 / 134 patients had also MRD evaluation pre-maintenance by CMF PET-CT pos PET-CT neg MRD pos MRD neg Fisher exact test: p = 0.33 McNemmar test: p = 0.39 Moreau et al. J Clin Oncol 2017

81 PFS for patients with negative PET-CT and negative MRD by flow (47.7% of patients) pre-maintenance vs others, p = 0.05 Moreau et al. J Clin Oncol 2017

82 100 OVERALL SURVIVAL 75 IFM 2009 IFM IFM IFM MONTHS

83 Study Scheme

84 SC2 PET / FLOW / NGS CASSIOPEIA trial PET / FLOW / NGS Induction Consolidation Maintenance SCREEN RANDOMIZE VTD + DARA x 4 cycles VTD x 4 cycles Stem cell mobilization/ Conditioning and ASCT VTD + DARA x 2 cycles VTD x 2 cycles PR RANDOMIZE DARA Q8W for 2 years FOLLOW-UP Observation Part1 Part NCT

85 Slide 84 SC2 added ref Sakabedoyan, Caline [JACFR], 03/07/2017

86 IFM 2018 Risk adapted strategy and MRD based High risk : 17p / R ISS3 Vs standard risk High risk : tandem ASCT + quadruplet induction and consolidation Increase PFS by 30% versus IFM 2009 Standard risk : Quadruplet induction / ASCT Adapted versus non adapted strategy

87 Thank you

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