IFM phase III randomized trials
1990 - 2001
Pr Phili
Philippe Moreau,
University Hospital, Nantes, France
Older than 65
IFM 95-01 trial
488 patients, 65-75 years,
R
MP
M-dex
dex
dex-IFN
Facon et al, Blood 2006;107:1292
M-dex is not superior to MP
Morbidity associated with dex-based
regimens was significantly higher
infections, psychiatric,
psychiatric, diabetes...
Lancet 2007
MP vs MPThal vs high-dose therapy
prospective, randomized,
436 patients, 65-75 years
IFM 99-06
Newly diag
ygnosed MM 65-75 years
Arm A
Arm B
Arm C
VAD 1
MP 1
Arm A
+
VAD 2
Th lid
a
id
om e
MP 2
400 mg/day
MP 3
Cyclophosphamide 3g/m2
+G
+ G-CSF
+ PBSC harvest
MEL 100 mg/m2
mg/m
+ PBSC + G-CSF
MP 12
MEL 100 mg/m2
MEL 100 mg/m
+ PBSC + G-CSF
Facon et
et al
al ,
Lancet 2007
IFM 01/01 Study protocol
Newly diagnosed
diagnosed MM > 75 years
12 cycles MP every 6 weeks
Melphalan
0.2 mg/kg/d Day 1- 4
Prednisone
2 mg/kg/d Day 1- 4
Double Blind
Placebo
Thalidomide
2 caps 50 mg/d
2 caps 50 mg/d
72 weeks
72 weeks
Hulin et al, J Clin Oncol, in press
Progression-free survival
24.1 vs 18.5 months, p = 0.001
1,0
st 08
0,8
n
tieapgin 0,6
ivv
sur
of 0,4
n
rtio
poo
MP
Pr 0,2
MP+Thalidomide
0,0
0
6
12
18
24
30
36
42
48
54
Months
116
94
76
56
34
16
11
5
4
3
113
97
83
66
52
35
25
19
13
7
Overall survival
1,00
44 vs 29.1 months, p = 0.001
0,80
s
ntei
pat
0,60
ingiv
rvu
fso
0,40
n
tio
por
roP
MP
0,20
MP+Tha
P
lidomide
d
0,00
0
6
12
18
24
30
36
42
48
54
Mont
Mon hs
116
105
96
80
65
40
31
27
17
11
113
101
96
80
70
57
45
36
26
16
Cl
Concl i
us on: IFM99
IFM99 06
-
& IFM01
IFM01 01
-
- MP thal
-
should be
be considered
considered as standard
of care for patients > 65 years of age
- IFM99-06 pivotal trial for thalidomide
approval in combination with MP
Less than 65
N Engl
Engl J Med 1996
IFM90 trial
trial
IFM 90
200 patients < 65 years
HDM 140 + TBI / ABMT
CC
HDT
p
N=100
N=100
Response
p
14%
38%
< 0.001
(CR + VGPR)
Md
Me i
dian EFS
EFS
18 m
28 m
7-year EFS
8%
16%
< 0.01
Median OS
44 m
57 m
7-year OS
25%
43%
< 0.05
N Engl J Med 1996 ­ Attal et al
IFM90 trial
Conclusion: IFM90
ASCT should be recommended as part of
front-line therapy in patients < 65 years
Best conditioning regimen ?
IFM95-02 trial
IFM 95 TRIAL DESIGN
de novo MM
<6
< 5
65 y
VAD x 3
SC collection
if no progression
R
HDM 140 + TBI 8 Gy
HDM 200
N = 140
N = 142
IFM 95-02
RESULTS
HDM 200 is less toxic
- Si ifi
gn cant r d
e
i
uct on f
o i
t me to hematopoi i
et c recovery
-Significant reduction of PBSC and platelet
gp
transfusions
and iv ATB
- Significant reduction
reduction of hospitalisation
- Significant reduction of grade 3/4 mucositis
- 0/142 deaths vs 5/140 with HDM 140 + TBI
IFM 95-02 RESULTS
HDM 200 is at least as effective
No significant difference in response rate and
EFS
Better overall survival
Better salvage after relapse
IFM95-02 trial
Moreau et al, Blood 2002
Cl
Concl i
us on: IFM95
IFM95 02
-
Mel 200 should be considered as standard of
care prior to ASCT
IFM94 trial
N Engl J Med 2003
IFM 94 trial
Randomized at diagnosis
VAD x 4
Mel 140 + TBI 8 Gy
Mel 140
Mel 140 + TBI 8 Gy
200 patients
199 patients
IFM 94 : EFS
P < 0.03
B
A
IFM 94 : Overall survival
p < 0.01
B
A
IFM 94 : OS if response to 1st graft > 90 %
P = 0.7
B
A
IFM 94 : CONCLUSIONS
1 - Double transplantation significantly improves OS of MM
patients and could
could be recommended
r
for
for patients < 65
65 years
years
2 - Double transplantation should be recommended for patients
failing to achieve VGPR or CR after the 1st transplant.
IFM99 stratification : del13 , 2 > 3 mg/l
0-
0 1 Factor
Factor
2 Factors
VAD x 3
Mel 140 + PBSC
VAD x 3
M l
e 200 + PBSC
PBSC
Mel 200 + PBSC
IFM 99-
99 02
IFM 99-03
IFM 99-04
No maintenance,
HLA id sibling
No HLA id sibling
Pamidronate, or
Miniallo
Mel 220 + PBSC + anti IL6
Pamidronate
+ Thalidomide
IFM99-02
IFM 99-02
- Pi
Patients < 65 years, de novo
- 0 or 1 adverse prog
pgnostic factors (chr
(
13, 2 M)
VAD
VAD
VAD
HDM 140 + ASCT
HDM 200 + ASCT
Contro
Contr l
o
Pamidronate
Pamidr
arm A, 200 patients
Pamidronate
+ Thalidomide
arm B, 196 patients
arm C, 201 patients
IFM 99-02: Response Rate 90%.
Arm A
Arm B
Arm C
p
After VAD
15%
15%
16%
NS
At Random
45%
47%
50%
NS
After
55%
57%
68%
0.03
Random
IFM 99-02 : Event-Free-Survival.
ABC
p
Med
38 m
38 m
> 48 m
EFS
4-year
37%
35%
50%
0.003
EFS
IFM 99 02 : EFS According to del 13
Del 13 -
Del 13 +
Thal +
Thal +
Thal - (n = 391)
P = 0.001
NS
Thal -
Thal -
IFM 99-02 : EFS According to Response at Random
Response at Random 90%
Response at Random < 90%
Thal +
Thal +
Thal - (n = 391)
Thal -
NS
P < 0.0003
Thal -
Overall survival according to treatment arm
Attal, M. et al. Blood 2006;108:3289-3294
Cl
Concl i
us on: IFM99
IFM99 02
-
Thalidomide after ASCT : consolidation rather
than maintenance, and may improve OS
STUDY DESIGN
Enrollment IFM 9903 or 9904 : 284
FLOW CHART
CHAR
IFM 9903 : 65
IFM9904 : 219
VAD
Progr
Pr
ession
ogr
Infection
HDM200
Death
Rf
Refusal
Violation
Randomisation
53 (24%)
Feasibility 76%
(24%)
166
Arm A : HDM220
Arm B : HDM220+anti-IL6moAb
85
81
1.0
0.9
Event-
Event free
fr
survival
0.8
Arm A
0.7
Arm B
0.6
0.5
ival
0.4
Surv
of
p = .39
0.3
obability
0.2
Pr
0.1
0
0
12
2436
4860 months
Moreau et al, Blood 2006
1.0
Overall survival
0.9
Arm A
0.8
Arm B
07
0.7
0.6
0.5
val
Survi
0.4
of
p = .90
0.3
bability
Pro
0.2
0.1
0
0
122436
48
60
months
Moreau et al . Blood 2006
Cl
Concl i
us on: IFM99
IFM99 04
-
The addition of anti-IL6 moAb (+ mel 220)
does not improve the outcome of high-risk
patients
Enrollment IFM 9903 or 9904 : 284
FLOW CHART
CHAR
IFM 9903 : 65
IFM9904 : 219
VAD
46 completed
Auto/miniallo
HDM200
Randomisation
166
Arm A : HDM220
Arm B : HDM220+anti-IL6moAb
85
81
1.0
0.9
Median follow-up: 56 months
0.8
22 vs 19 months, p = 58
.
0.7
al 0.6
ivrvu
S 0.5
of
0.4
Probability
0.3
0.2
IFM99-03, 65 patients
0.1
IFM99-04, 219 patients
0
0
600
1200
1800
2400
3000
Et
Event fi
-free survival, i t
n
t
en t
-
tt
o-treat
1.0
Median follow-up: 56 months
0.9
Median follow-up: 56
0.9
48 vs 34 months,p
months,
months p = .07
0.8
0.7
06
0.
0 6
0.5
IFM99-04, 219 patients
0.4
0.3
0.2
IFM99-03, 65 patients
0.1
0 0
600
1200
1800
2400
3000
days
ay
Overall survival,
survival intent-to-treat
tr
Moreau et al, Blood 2008
1.0
Median follow
follow up:
-
56 months
0.9
57 vs 41 months, p = .08
0.8
0.7
0.6
IFM99-04, 166 patients
0.5
alvi
Surv
of
0.4
ty
Probabili
0.3
IFM99 03
- , 46
ti
pa
t
en s
0.2
0.1
0
0
600
1200
1800
2400
3000
OS, treatment
tr
completed
Cl
Concl i
us on: IFM99
IFM99 03
-
vs 99 04
-
In high-risk disease,
auto/mini-allo (fluda-bu-ATG)
is not superior to double ASCT (mel200
p(
/ mel220)
Conclusions : IFM trials
trials 1990
1990 2001
- MP Thal standard of care > 65 years
- ASCT > Conventional chemotherapy
- Mel 200 best conditioning regimen
- Double > single if response less VGPR
- Thalidomide consolidation post-ASCT
- Auto-miniallo < double auto in high-risk
26 in Belgium
145 in France
Lille-Boulogne-Dunkerque
Amiens-Compiègne
Rouen
Le Havre-Caen Paris & ReimsMetz-Nancy
IDF
Quimper-Brest-Rennes
Strasbourg
Vannes
Nantes
Angers Orléans
Chalon
Le Mans Tours
Dijon
Besançon
La Roche/Yon
7 in Switzerland
La Rochelle
Poitiers
Clermond
Grenoble-Lyon
Ferrand
Annecy
Bordeaux
Libourne
Avignon-Marseille
Toulouse
M
lli
Ni
Tarbes
Montpellier
ce