Final results of the IFM 99-04 protocol :
double transplant +/- anti-IL6 monoclonal
antibody
in high-risk de novo multiple myeloma
P.Moreau, C.Hullin, F.Garban, T.Facon, M.Attal,
L.Benboubker, G.Marit, J.G.Fuzibet, C.Doyen, L.Voillat,
C.Berthou, P.Casassus, M.Monconduit, M.Michallet,
A.Najman, J.J.Sotto, R.Bataille, Hervé Avet-Loiseau,
J.L.Harousseau

Overall survival according to the number of
unfavorable prognostic factors (2m 2.5 mg/L, 13)
Survival
1.0
0.8
# factors
O/N
Survival time
(month)
0.6
0
2/22
> 111.
1
29/55
47.3 ± 4.6
2
22/33
25.3 ± 3.2
0.4
0.2
P < .0001
0.0
0
12
2436
4860
728496
time from diagnosis (months)
Facon et al , Blood 2001

de novo MM, < 65 years
2M > 3 mg/L and 13
VAD x 4
Stem cell collection
HDM 200
If HLA-sibling available
No donor available
Mini-allo
HDM 220 +/- anti-IL6
Bu-Fluda-ATG
IFM9903 trial
IFM9904 trial

Rationale
HDM220 +/- anti-IL-6 moAb

Moreau et al, Br J Haematol 1996;95:527
Melphalan mg/l
14
12
10
HDM 220
8
6
4
HDM 200
2
HDM 140
Hours
0
0.5
1
2
3
4
5

Moreau et al, Bone Marrow Transplant
1999;23:1003
Melphalan 220 mg/m2 + PBSCT in 27 pts
with advanced multiple myeloma
Response rate : 87.5%

Murine anti-IL-6 moAb, B-E8
Klein et al Blood 1991;78:1198
Bataille et al Blood 1995;86:685
feasible without toxicity
suppress the proliferation of
myeloma cells in vivo

BE-8 : anti-iL-6-mAb (Diaclone Research / OPI France)
100mg 50mg
50mg
50mg
HDM 220
ASCT
DXM 40mg
40mg
40mg 40mg
G-CSF
Day
-6
-5
-4
-3
-2
-1
0
7

Enrollment IFM 9903 or 9904 : 284 patients
IFM 9903 : 64
IFM9904 : 220
VAD
Progression
Infection
HDM200
Death
Refusal
Violation
Randomisation
54 (24%)
166
Arm A : HDM220
Arm B : HDM220 + anti-IL6 moAb
85
81

1.0
0.9
0.8
Median : 39 months
0.7
l
0.6
0.5
Surviva
of
0.4
ity
0.3
babil
Pro
0.2
0.1
0
012
24
36
48
60
Overall survival from diagnosis : 220 patients
Intent-to-treat

1.0
0.9
Median 30 months
0.8
0.7
0.6
l
0.5
Surviva
0.4
of
ity
0.3
babil
0.2
Pro
0.1
0
0
1224
36
4860
Event-free survival from diagnosis : 220 patients
intent-to-treat

Non randomised, n = 54 (24%)
- Toxic death VAD :
6
- Toxic death HDM200 :
2
- Protocol violation :
5
- Refusal :
10
- Progressive disease :
17
- No graft :
1
- Cardiac :
2
- Pulmonary :
2
- Infection :
4
-Other :
5

1.0
0.9
p < .0001
0.8
0.7
l
0.6
0.5
Surviva
of
0.4
ity
0.3
babil
Pro
0.2
0.1
0
0
1224
3648
60
Overall survival : randomised (166 pts)
vs non randomised (54 pts)

1.0
0.9
p < .0001
0.8
0.7
l
0.6
0.5
Surviva
of
0.4
ity
0.3
babil
Pro
0.2
0.1
0
0
12
2436
4860
EFS randomised (166 patients)
vs non randomised (54 patients)

1.0
0.9
0.8
Median 47 months
0.7
0.6
l
0.5
Surviva
0.4
of
ity
0.3
babil
0.2
Pro
0.1
0
0
1224
36
4860
Overall survival : 166 patients

1.0
0.9
0.8
Median : 33 months
0.7
0.6
l
0.5
Surviva
0.4
of
ity
0.3
babil
0.2
Pro
0.1
0
012
24
36
48
60
Event-free survival : 166 patients

Arm A
Arm B
p
n = 85
n = 81
Age at diagnosis
56 (34-65)
58 (28-65)
0.053
Sex (M/F)
41 / 44
47 / 34
0.28
Isotype (G/A/BJ)
45/23/17
42/24/15
0.93
Stage (I/II/III)
1/9/75
0/10/71
0.98
Beta2mic
4.6 (3-28.5)
4.8 (3-37.2)
0.35
Albumin
9.5 (5.1-14.7)
10.2 (4.7-14.4)
0.14
Platelets
216 (60-462)
204 (84-469)
0.63
Hb
38 (22.5-54)
37 (16.2-52)
0.62
Ca
2.42 (1.96-4.5)
2.42 (1.87-4.03)
0.85
CRP
7 (1-244)
5 (1-137)
0.22

1.0
p = .53
0.9
0.8
0.7
Arm B
l
0.6
0.5
Surviva
of
0.4
ity
Arm A
0.3
babil
Pro
0.2
0.1
0
0
1224
364860
Survival : arm A vs arm B

1.0
0.9
0.8
p = .59
0.7
l
0.6
0.5
Surviva
of
0.4
Arm B
ity
0.3
babil
Pro
0.2
Arm A
0.1
0
012
24
36
48
60
Event-free survival : arm A vs arm B

Response
VAD
ASCT n°1
Arm A
Arm B
HDM
HDM
HDM
p
200
220
220 + moAb
CR (%)
4
14
31
35
0.84
VGPR
12
20
19
18
0.93
PR
48
54
46
38
0.46
Stable
20
8
2
5
0.45
Progressive
12
2
1
2
0.96
Death
4
2
1
2
0.96

Conclusions IFM99-04
- The combination of anti-IL6 moAB +
HDM220 is not superior to HDM220 alone
- The survival rates after tandem transplant
HDM200 / HDM220 in this high-risk group
are « encouraging »

Comparison IFM 99-03 (Dr Sotto/Dr Garban)
vs IFM 99-04

Enrollment IFM 9903 or 9904 : 284 patients
IFM 9903 : 64
IFM9904 : 220
n = 18
Progression
Refusal
Infection
Randomisation : 166
Miniallo performed : 46
76%
71%

IFM99-03 vs 99-04 : Initial characteristics
IFM99-03
IFM99-04
p
N = 64
N = 220
Age at diagnosis
53 (36-65)
57 (28-65)
0.004
Sex (M/F)
31/33
115/105
0.69
Beta2-mic
4.1 (3.1-16.6)
5 (3.1-39.4)
0.024
Albumin
38 (27-60)
37.9 (16.2-59)
0.46
Hemoglobin
97 (52-135)
98 (47-147)
0.79
Ca
2.4 (1.4-3.9)
2.4 (1.9-5.4)
0.37
t(11;14) Y/No/missing
10/33/21
21/124/75
0.35
t(4;14) Y/No/missing
16/27/21
26/116/78
0.54

1.0
0.9
p = .34
0.8
0.7
0.6
9904
0.5
l
9903
0.4
Surviva
of
ity
0.3
babil
0.2
Pro
0.1
0
012
24
36
48
60
SURVIVAL Intent-to-treat : 64 vs 220 patients
IFM9903 vs 9904

1.0
0.9
p = .70
0.8
0.7
9904
0.6
0.5
l
0.4
Surviva
of
9903
ity
0.3
babil
0.2
Pro
0.1
0
012
24
36
48
60
EFS intent-to treat : 64 vs 220 patients
IFM9903 vs 9904

1.0
0.9
p = .49
0.8
0.7
9904
0.6
l
0.5
0.4
Surviva
9903
of
ity
0.3
babil
0.2
Pro
0.1
0
0
12
243648
60
EFS 166 vs 46 patients
IFM9904 vs 9903

1.0
0.9
P = .09
0.8
0.7
0.6
Tandem auto
l
0.5
0.4
Surviva
of
ity
0.3
9903
babil
0.2
Pro
0.1
0
012
24
36
48
60
Survival 166 vs 46 patients
IFM9904 vs 9903

1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
010
20
30
40
50
Chronic GVHd

Conclusion IFM99-03 vs IFM99-04
In patients with high-risk de novo MM,
autologous + miniallogeneic SCT
is not superior to tandem autologous SCT

Document Outline