Maintenance treatment with Thalidomide
and Pamidronate after autologous stem cell
transplantation for Myeloma.
A prospective, randomized trial of the Intergroupe
Francophone du Myélome: Second analysis of
the IFM 99 02 Trial.
Michel Attal for the IFM.
Sydney 2005

IFM 90 : Survival 60 years
HDT
CC

CC versus HDT: Overall Survival
HD regimen
CC
HDT
p. Value
IFM90
Mel+TBI 8Gy
44
57
0.03
MRC7
Mel
42
54
< 0.001
IMMSG
Mel
43
58+
0.0008
MAG91
Mel+BU
45
42
NS
PETHEMA
Mel+TBI 12Gy
67
65
NS
USIG
Mel+TBI 12Gy
53
58
NS
Mel Without TBI should be the preparative regimen!!!

IFM 94 : Overall Survival
OS if response to 1stgraft < 90%
ALL PATIENTS
P<0.01
P<0.001
A
B
DT
OS if response to 1st graft 90 %
ST

INDICATIONS FOR BLOOD AND MARROW
TRANSPLANTATION IN NORTH AMERICA
2002
4,500
Allogeneic (Total N = 7,200)
4,000
Autologous (Total N = 10,500)
3,500
3,000
2,500
2,000
1,500
TRANSPLANTS
1,000
500
0
NHL
AML Hodgkin ALL
MDS /
CML
CLL
Breast
Multiple
Other
Non-
Disease
Other
Neuroblastoma
Cancer
Myeloma
Cancer Malignant
Leukemia
Disease

IFM 99 02 Trial
· HDT (single / tandem) is the recommended treatment for
young patients with myeloma.
· However, no plateau on EFS curves and 7-year EFS = 15-20%
· Effective maintenance therapy is required after HDT !!
· The IFM 99 02 was design to evaluate the impact of :
-Thalidomide on the duration of response after HDT
and
-Pamidronate on the incidence of bone events after HDT

IFM 99 02 : Inclusion criteria
· Stages I (1 bone lesion), II, III.
· Patients aged under 65 years.
· No prior treatment for MM.
· 0 or 1 adverse factor ( 13, ß2m>3)

IFM 99 02 : Study Design
Inclusion: 13 ; ß2m
(0 or 1 Factor)
· VAD x 3
· Mel-140 + PBSC
· Mel 200 + PBSC
Randomization
No maintenance
Pamidronate
Pamidronate + Thal

IFM 99 02: Treatment Arms
Randomization:
(3 months after the 2d transplant,
no progression)
· Arm A : no maintenance
· Arm B : Pamidronate 90 mg / month
· Arm C : Thalidomide 100 mg / d + Pamidronate

The IFM 99 02 trial: Second analysis
· 74 centres (Belgian, French, Swiss).
· Activation : April 2000.
· End of enrolment : October 2003.
· Nb of enrolled patients : 780.
· Nb of randomized patients : 588 (75%).
·Date of analysis : October 2004.
·Median Follow-up:
-From Inclusion: 30 m
-From Randomization: 17 m

IFM 99 : Patient flow (04/2000 to 10/2003)
IFM 99 Registration : 1019 patients
* ß2m 3 and 13
:273 (27 %)
* ß2m 3 and 13 :211 (21%)
* ß2m > 3 and 13 :269 (26 %)
* ß2m > 3 and 13 :
229 (22 %)
* FISH not informative :
37
(4 %)
0-1 Factor: IFM 99 02
2 Factors : IFM 99 03 / 04
780 patients (77%)
239 patients (23%)

IFM 9902 : Patient flow (0 - 1 Factor)
Inclusions = 780
On therapy = 94
Exclusions = 97
Randomizations = 588 (75 %)
Arm A = 197
Arm B = 194
Arm C = 197

IFM 99 02: Patient characteristics
Arm A
Arm B
Arm C
p
Age
59
55
59
NS
Stage III DS
69%
72%
70%
NS
IgG isotype
62%
65%
60%
NS
del 13 +
30%
28%
29%
NS
ß2m > 3 mg/l
33%
36%
36%
NS
LDH (IU)
315
320
310
NS
CRP (mg/l)
9.5
11
13
NS

IFM 99 02: Patient characteristics
Arm A
Arm B
Arm C
p
· - Random
11 m
10 m
10 m
NS
· Response
14%
18%
14%
NS
to VAD 90%
· Response at
44%
51%
48%
NS
Random 90%

IFM 99 02 : PFS from Random.
Arm A
Arm B
Arm C
p
Progression
25%
24%
15%
0.04
Median PFS
27 m
28 m
> 38 m
3-year PFS
34%
37%
56%
0.01

IFM 99 02 : PFS from Random
Arm C
Arm A
Arm B
P < 0.01

IFM 99 02 : PFS According to Thalidomide
120
100
80
60
Thal + (n = 197)
40
Thal - (n = 391)
20
P < 0.002
0
1
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
41
43

IFM 99 02 : PFS According to Thalidomide
O Factor
1 Factor
Thal +
Thal +
Thal -
P < 0.1
P < 0.002
Thal -
Thal - (n = 391)

IFM 99 02 : PFS According to Thalidomide
Response at Random 90%
Response at Random < 90%
Thal +
Thal +
Thal +
Thal
Thal - -
Thal -
P < 0.002
P < 0.1 Thal - (n = 391)
P = 0.05
P < 0.1

IFM 99 02 : Risk of Bone Events.
Arm A
Arm B
Arm C
p
*Bone Events
14%
8%
7%
0.1
*3-year risk
65%
26%
24%
0.04
of Bone Events

IFM 99 02 : Risk of Bone Events
Arm A
P < 0.04
Arm B
Arm C

IFM 99 02 : Risk of Bone Events
Pamidronate - (n = 194)
P < 0.03
Pamidronate + (n = 385)

IFM 99 02 : Overall Survival from randomisation
(Analysis: 10-2004).
Arm A
Arm B
Arm C
p
*Deaths
5%
8%
7%
NS
*3-year OS
83%
78%
78%
NS

IFM 99 02 : Overall Survival from randomisation

IFM 99 02 : Prognostic factors for EFS among
randomized patients
Multivariate analysis
p
* Age
NS
* Albumin (35 / >35)
NS
* CRP
NS
* LDH
NS
* Del 13
0.02
* ß2-m (3 / >3)
0.001
* Response at Random (<90% / 90%)
0.001
* Treatment arm (Thal + / -)
0.02

IFM 99 02 : EFS according to ß2-m and 13
among randomized patients.
120
100
80
60
ß2- and 13-
· ß2m ; p = 0.001 (
/
)
ß2- and 13+
40
· 13 ; p = 0.02 (
/
)
20
ß2+ and 13-
0
1
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
41
43
45
47
49
51
53
55
57

IFM 99 02 : Conclusions of this second analysis
· Intermediate analysis with a short follow-up of 3 years from
diagnosis.
· Maintenance therapy with THAL is feasible after HDT.
· Maintenance therapy with THAL may prolong the duration of
response.
· Maintenance therapy with Pamidronate may decrease the
incidence of bone events after HDT.
· A longer follow-up is required to appreciate the impact on OS.

The IFM Board

Document Outline