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Multiple myeloma, 25 (45) years of progress…

The IFM experience in patients treated withfrontline ASCT

Philippe Moreau, Nantes

Shibata T.

Prolonged survival in a case of multiple myeloma treatedwith high‐dose of melphalan

Rinsho Ketsueki 1973;14:619‐625

McElwain TJ & Powles RLLancet 1983;ii:822‐824

High‐dose intravenous melphalan for plasma‐cellleukaemia and myeloma

9 patients, MM or plasma cell leukemia, refractory140 mg/m2 melphalan IV3 CR and 1 prolonged survival

proof of principle : dose / response

Efficacy of high‐dose melphalan in RRMM was confirmed

Barlogie et al, Blood 1988;72:215‐219

Lokhorst et al, J Clin Oncol 1992;10:47‐51

‐ High response rates‐ Prolonged neutropenia : 24 – 36 days‐ TRM : 10‐20%

High‐dose melphalan + GM‐CSF / G‐CSF

Barlogie et al, Blood 1990Moreau 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%)

Concept of ASCT was introduced to reduce TRM,

first in RRMM

Barlogie, Blood 1986;67:1298High‐dose melphalan with autologous bone marrowtransplantation for multiple myeloma

Harousseau, Br J Haematol 1987;67:493High‐dose melphalan and autologous bone marrowtransplantation in high‐risk multiple myeloma

mel200 or mel140 + TBI

response rate: 50 to 70% CR: 5 to 20% median OS: 3 years

Relapse  frontline setting, pilot trials

Cunningham JCO 1994mel200 + ABMT

Attal Blood 1992mel140 + TBI 8 Gy + ABMT

Fermand Blood 1993BCNU/VP16/Mel +/‐ Cy + TBI 10/12Gy + PBSC

Response rates : 75‐80% CR : 20 to 40%Median OS : 5 years TRM < 5%

IFM90 N Engl J Med 1996

IFM 90 (Attal et al, N Engl J Med 1996)

CCN=100

HDTN=100

p

Response(CR + VGPR)

Median EFS

7‐year EFS

Median OS

7‐year OS

14%

18 mo

8%

44 mo

25%

38%

28 mo

16%

57 mo

43%

<0.001

<0.01

<0.05

200 patients < 65 years HDM 140 + TBI / ABMT

N Engl J Med 1996 – Attal et al

IFM90 trial

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

CC vs ASCTRANDOMIZED STUDIES

IFM90(NEJM 96)

MRC7(NEJM 2003)

Italian MMSG(Blood 2004)

MAG91(JCO 2005)

US INTERGROUP(JCO 2006)

PETHEMA(Blood 2006)

Nb of pts

200

401

195

190

516

164

Age

< 65Med 57

< 65Med 55 

50‐70Med 63 

55‐65Med 61

< 70Med 54

< 65Med 56

CC

VMCP/VBAP

ABCM

MP

VMCP

VAD/VBMCP

VBMCP/VBAP

HDT

HDM140+ TBI

HDM200

HDM 100x2+ PBSC

HDM200 orHDM140 + Bu16

HDM +TBI

HDM140 + TBIOr HDM200

CC vs ASCTRANDOMIZED STUDIES

IFM90(NEJM 96)MRC7(NEJM 03)Italian MMSG(Blood 04)MAG 91(JCO 2005)PETHEMA(Blood 06)US Intergroup(JCO 06)

Nb of pts

200

401

194

190

164

516

Age

< 65

< 65

50‐70

55‐65

< 65

< 70

CR rate (%)

5 vs 22

8 vs 44

6 vs 25

‐

11 vs 30

15 vs 17

Median EFS (mo)

18 vs 28

19 vs 31

16 vs 28

19 vs 25

34 vs 42

21 vs 25

Median OS

44 vs 57

42 vs 54

43 vs 58

50 vs 55

67 vs 65

53 vs 62

RESULTS ACHIEVED WITH single ASCTin the 90’s

CR

VGPR

Median PFS

Median OS

ASCT

15‐25%

40‐50%

25‐35 months

55‐60 months

CC

< 10%

< 20%

15‐20 months

42‐60 months

IFM 95‐02

MM de novo< 66 years

VAD x 3

PBSCharvest

R

HDM 140 + TBI 8 gy                       HDM 200n = 140                             n = 142

Moreau et al, Blood 2002

IFM95‐02, Overall survival

IFM 94

N Engl J Med 2003

IFM 94

Randomization : single versus tandemVADVADVADVAD

Mel 140 + TBI

Mel 140Mel 140 + TBI

IFM 94 TRIALFEASIBILITY

Single ASCTN = 199

Double ASCTN = 200

HDM 140Toxic deathHDM 140 + TBIToxic death

‐‐

177 (85%)3

177 (88%)2

156 (78%)5

Attal, N Engl J Med 2003

IFM 94

Single TXN = 199

Double TXN = 200

p

EFSmedian6‐yr

OSmedian6‐yr

31 m19%

50 m26%

37 m28%

58 m46%

0.03

0.02

Attal, N Engl J Med 2003

IFM 94 : Overall survival

P < 0.01

B

A

Attal, N Engl J Med 2003

IFM 94 : OS if response to 1stgraft <90%

P < 0.001

A

B

Attal, N Engl J Med 2003

IFM 94 : OS if  response to 1st graft > 90 %

P = 0.7

B

A

SINGLE vs DOUBLE ASCTRANDOMIZED STUDIES

IFM 94(NEJM 03)

MAG 95(Kos 07)

Bologna(JCO 07)

GMMG(Kos 07)

Hovon(Haematologica 07)

Nb of pts

399

227

220

261

303

Age

< 61

< 56

< 61

< 66

< 66

Results

EFS and OS

EFS and OS

EFS

EFS

CR and EFS

‐ No plateau on survival curves

‐Major finding :importance of CR/VGPR after ASCT

Impact of CR + VGPR on outcome –IFM99 trials

Harousseau et al, J Clin Oncol 2009

Major importance of best responseafter induction therapy

Lahuerta, J. J. et al. J Clin Oncol; 26:5775‐5782 2008

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

How to improve the CR/VGPR rate?

Incorporation novel agents

< 65 years, de novo

Induction therapy ASCT

VAD Melphalan 200 mg/m2

(Melphalan) 200 mg/m2

< 65 years, de novo

Induction therapy ASCT

VAD Melphalan 200 mg/m2

(Melphalan) 200 mg/m2

Maintenance

Thalidomide

IFM 99‐02Patients < 66 years

VADVADVAD PBSC harvest

HDM 140 + ASCT

HDM 200 + ASCT

Controln = 200 Pamidronate

n = 196

Pamidronate+ Thalidomide

n = 201

Attal, M. et al. Blood 2006;108:3289‐3294

Overall survival according to treatment armwith thalidomide maintenance

4‐year OS : 87%

Randomized Studies on Post‐ASCT With Thalidomide

No Initial dose,mg

CR,%

EFS or PFS%

OS%

AttalBlood 2006BarlogieBlood 2008SpencerJCO2009LokhorstBlood 2010MorganBlood 2011

597

668

269

556

493

400

400

200

50

50

67 vs 55

62 vs 43

63 vs 40

66 vs 54

39 vs 34

3-year EFS52 vs 36

5-year EFS54 sv 44

3-year PFS42 vs 23

Median PFS34 vs 25 moMedian PFS30 vs 23 mo

4-year82 vs 708-year

57 vs 443-year

86 vs 75Median

73 vs 60 mo3-year

75 vs 80

< 65 years, de novo

Induction therapy ASCT

Revlimid 

VAD Melphalan 200 mg/m2

(Melphalan) 200 mg/m2

Maintenance

Thalidomide

IFM 2005‐02 : prospective randomizedMaintenance trial, using revlimid

IFM 2005‐02: lenalidomide maintenance after ASCT

Lenalidomide 10 ‐15 mg/d

Until progression

Patients < 65 y, non‐progressive or stable,     6 months post‐ASCT

Placebo until progression

Primary end‐point :  TTPSecondary end‐points: CR, PFS, OS, feasibility‐toxicity

Phase III prospective randomised, versus placebo

ConsolidationLenalidomide 25 mg/d, D1‐21, 28‐day cycle, 

during 2 cycles

Randomisation

IFM 2005‐02 : PFS from randomization

P < 10‐8

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42

Placebo Revlimid

P < 10 ‐8

Rev (n =307)

Placebo (n = 307)

Median follow up: 34 m post rando, 44 m post diag

Attal et al , N Engl J Med 2012

Lenalidomide maintenance: OS meta-analysisStudies included

Dex, dexamethasone; MPR, melphalan-prednisone-lenalidomide; Tx, treatment. Attal M, et al. Presented at ASCO 2016. J Clin Oncol. 2016;34 Suppl:abstract 8001.

CALGB 100104(accrual 8/2005–11/2009)

InductionASCT

1:1 randomization“No evidence of PD”

LEN(n = 231)

PLACEBO(n = 229)

Crossover before PD allowed

Continuedtreatment

IFM 2005-02(accrual 6/2006–8/2008)

InductionASCT

1:1 randomization“No evidence of PD”

LEN: 2 courses

LEN(n = 307)

PLACEBO(n = 307)

ALL treatment discontinued

Jan 2011

Continued treatmentNo crossover

before PD allowed

GIMEMA (RV-MM-PI-209)(accrual 11/2007–7/2009)

LEN (n = 67)

MPR: 6 courses

2 x 2 designLEN + DEX x 4

Induction

No treatment(n = 68)

LENNo Tx

Continued treatment

Continued treatment

ASCT

< 65 years, de novo

Induction therapy ASCT

Velcade‐Dex (IFM 2005‐01)

Revlimid IFM 2005‐02

VAD Melphalan 200 mg/m2

(Melphalan) 200 mg/m2

Maintenance

Thalidomide

Response To InductionEvaluable Patients

CR CR+nCR> VGPR> PRMR+SDPDDeath

VAD

N=218

1.4%  6.4% 15.1%62.8%26.6%4.1%2.8%

Vel‐Dex

N=223

5.8% 14.8%37.7%78.5%12.6%4.5%0.5%

P value

0.012 0.004

< 0.0001.0003

Harousseau et al, J Clin Oncol 2010

Response to First ASCTEvaluable Patients

CRCR + nCR> VGPR> PRMR/SD/PDNo ASCT

VAD

N=218

8.7%18.4%37.2%77.1%3.7%15.6%

Vel‐Dex

N=223

16.1%35%54.3%80.3%2.7%11.7%

P value

0.016<0.001<0.0010.401

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

< 65 years, de novo

Induction therapy ASCT

Velcade‐Dex (IFM 2005‐01)

Velcade‐Thal‐Dex (IFM 2007‐02)

Revlimid IFM 2005‐02

VAD Melphalan 200 mg/m2

(Melphalan) 200 mg/m2

Maintenance

Thalidomide

IFM 2007‐02

4 cycles followed by ASCT prepared by mel 200Disease response evaluation after 2 cycles & 4 cycles

VD (IFM 2005/01)                                   vTD

Vel 1.3mg/m2 d1,4,8,11    Vel 1mg/m2 d1,4,8,11Dex 40mg d1‐4,9‐12                     Thal 100mg/d Cycles 1 & 2                    Dex idemd1‐4, cycles 3 & 4

Moreau et al, Blood 2011

IFM2007‐ 02 / results induction phase

03/2008  01/2009, 205 patients < 65 years

Investigator‐based assessment

VD vTD%CR 12  14 p = 0.68% > VGPR 36 50 p = 0.047% > PR 81 91 p = 0.06Stable 12 5Prog 7 4

Response to ASCTIntent‐to‐treat analysis

CR

CR+nCR

≥ VGPR

≥ PR

VD

26%

47%

54%

84%

vTD

20%

60%

66 %

92%

P‐value

0.33

0.50

0.044

0.33

Moreau et al, Blood 2011

Peripheral Neuropathy(% of patients)

All grades

Grade >=2

Grade >=3

SAE leading to Tt discontinuation

VDN=102

63%

28%

6%

4%

vTDN=97

56%

16%

3%

0%

p. value

0.31

0.04

0.34

0.12

vTD : standard of care

< 65 years, de novo

Induction therapy ASCT

Velcade‐Dex (IFM 2005‐01)

Velcade‐Thal‐Dex (IFM 2007‐02 / IFM 2013‐04)

Revlimid IFM 2005‐02

VAD Melphalan 200 mg/m2

(Melphalan) 200 mg/m2

Maintenance

Thalidomide

VTDN = 169

VCDN = 169

P value

≥ CR

≥ VGPR

≥ PR

13.0%

66.3%

92.3%

8.9%

56.2%

83.4%

0.22

0.05

0.01

Intent-to-treat analysis

Response: centralized assessment (Dr Dejoie, Nantes), IMWG criteria 2011

VTD, n = 169Grade 3-4 %

VCD, n= 169Grade 3-4 %

p value

Any AesAnemiaNeutropeniaInfectionThrombocytopeniaThrombosisCardiac disordersCystitisGI symptomsPeriph. NeuropathyPN grade 2-4

63.94.118.97.74.71.81.20

5.37.721.9

68.29.533.110.110.61.80

0.63.52.912.9

0.400.05

0.0030.450.040.990.160.320.420.05

0.008

Toxicity

Toxicities assessed according to NCI CTCAE, version 4.0.

Leleu X, Moreau P. Leukemia 2013Apr5 [Epub ahead of print]

Retrospective trial217 patients

VTD – autovsVTD – auto ‐ VTD

CONSOLIDATION

RVDRichardson et al, Blood 2010, online 12  april

Up to eight 21‐day cycles

1  2        4  5               8  9          11 12         14                   

Lenalidomide

Bz Bz Bz Bz

Dex Dex Dex Dex

Phase II : Len 25, Btz 1.3, Dex : 20

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)

PFS according to receipt of ASCT

Receipt of ASCT did not affect 1‐yr PFS (P = .38)

< 66 years, de novoBest option ?

Induction therapy ASCT

VTD

VRDMelphalan 200 mg/m2

Maintenance

RevlimidVTD

VRD

Consolidation

< 65 years, de novoPilot trial, IFM 2008‐01

Induction therapy ASCT

VRD x 3 Melphalan 200 mg/m2

Maintenance

Lenalidomide

Consolidation

VRD x 2

Roussel et al. J Clin Oncol. 2014 Sep 1;32(25):2712‐7

RESPONSE RATES   (ITT)

after Induction after ASCT after Consolidationn % n % n %

sCR 4 13 8 26 12 38CR 3 10 3 10 3 10

CR+sCR 7 23 11 36 15 48VGPR 12 39 10 32 11 36

≥ VGPR 19 62 21 68 26 84PR 10 32 7 23 3 10

ORR 29 94 28 91 29 94SD 2 6 2 6 1 3

out of trial 0 1 3 1 3total 31 100 31 100 31 100

IFM DFCI 2009 Trial700 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

Attal et al,  N Engl J Med 2017

PROGRESSION‐FREE SURVIVAL

Attal et al,  N Engl J Med 2017

OVERALL SURVIVAL

IFM 2009: Best Response. 

RVD groupN=350

Transplant groupN=350

p‐value

CR 48%  59%

VGPR 29%  29% 0.004 

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

IFM 2009: PFS, Prognostic Factors.  Multivariate  Analysis 

aHR p‐value

Treatment arm (B/A) 0.80 0.02

ISS   II vs IIII vs I

1.33 1.45 

0.020.01

FISH (highrisk/standard) 2.22 <0.001

CR 0.58  <0.001

MRD (FCM) 0.39   <0.001

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

P-value : p<0.0001

Negative (<10-6)

Positive

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0P

atie

nts

with

out p

rogr

essi

on (%

)

159 159(0) 147(12) 132(15) 120(11) 94(22) 67(11) 22(17) 6(4)MRD positive87 87(0) 87(0) 85(2) 83(2) 74(6) 54(4) 31(3) 8(0)MRD neg (<10-6)

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at pre-maintenance

IFM 2009 trial – NGS premaintenanceAfter consolidation

Avet-Loiseau H et al. Oral presentation at ASH 2015 (Abstract 191).

P = 0.01

PFS according to normalization of PET-CT before maintenance therapy

Moreau et al. J Clin Oncol 2017, july 7

P = 0.03

OS according to normalization of PET-CT before maintenance therapy

Moreau et al. J Clin Oncol 2017, july 7

86 / 134 patients had also MRD evaluation pre-maintenance by CMF

PET-CTpos

PET-CTneg

MRDpos

11 20

MRDneg

14 41

Fisher exact test: p = 0.33McNemmar test: p = 0.39

Moreau et al. J Clin Oncol 2017

PFS for patients withnegative 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

100

75

50

25

0

15                     30 45 60 MONTHS

IFM 2009

IFM 2005

IFM 94

IFM 90

OVERALL SURVIVAL

Study Scheme

SCR

EEN

FOLL

OW

-UP

RA

ND

OM

IZE

VTD + DARAx 4 cycles

VTDx 4 cycles St

em c

ell m

obili

zatio

n/C

ondi

tioni

ng a

nd A

SCT

Induction

VTD + DARAx 2 cycles

VTDx 2 cycles

Consolidation

RA

ND

OM

IZE

DARA Q8W for 2 years

Observation

Maintenance

Part1 Part 2

≥PR

www.clinicaltrials.gov; NCT02541383

CASSIOPEIA trialPET / FLOW / NGS PET / FLOW / NGS

https://www.clinicaltrials.gov/ct2/show/NCT02541383

SC2

Slide 84

SC2 added refSakabedoyan, Caline [JACFR], 03/07/2017

IFM 2018

Risk‐adapted strategy and MRD based

High‐risk : 17p / R‐ISS3Vs standard risk

High risk :tandem ASCT + quadruplet induction and consolidationIncrease PFS by 30% versus IFM 2009

Standard risk : Quadruplet induction / ASCT Adapted versus non‐adapted strategy

Thank you