IS DOUBLE ASCT THE STANDARD
OF CARE ?
- Single vs double ASCT
- Which patients benefit more from double ASCT ?
- Integrating novel therapies in the double ASCT
paradigm
IFM 94 : EFS
p < 0.03
median
30 months
median
25 months
20%
B
A: single transplant (N=199)
A
B: double transplant (N=200)
10%
IFM 94 : OVERALL SURVIVAL
p< 0.01
42%
B
A
21%
A: single transplant (N=199)
B: double transplant (N=200)
SINGLE vs DOUBLE ASCT
RANDOMIZED STUDIES
Nb of pts
Age
Results
IFM 94
399
< 61
EFS and OS
(NEJM 03)
MAG 95
227
< 56
No difference
(Turin 04)
Bologna
220
< 61
EFS
(ASH 04)
GMMG
261
< 66
EFS
(Turin 04)
Hovon
303
< 66
CR and EFS
(ASH 04)
SINGLE vs DOUBLE ASCT
- Long follow-up is needed before drawing definite
Conclusions (IFM 94, Hovon)
- Current results are in favor of double ASCT
(IFM 94, better EFS in 3 out of 4 studies)
Impact of DOSE-INTENSITY
- However the improvement is modest
7-year EFS is only 20% in the IFM94 trial
Risk-adapted Strategy (IFM 99 trials)
IFM99 : FACTORS : 13 , 2 > 3 mg/l
0-1 Factor
2 Factors
VAD x 3
VAD x 3
Mel 140 + PBSC
Mel 200 + PBSC
Mel 200 + PBSC
IFM 99-02
IFM 99-03
IFM 99-04
No maintenance
HLA id sibling
No HLA id sibling
Pamidronate
Non myeloablative
Mel 200 + PBSC + anti IL6
Pamidronate
Allo BMT
+ Thalidomide
PBSC collection : IFM 99-01
Cyclo (4g/m²)
+ G-CSF
SCF
+ G-CSF
IFM 99-02 : OVERALL SURVIVAL FROM
RANDOMISATION
IFM 99-04
1.0
0.9
0.8
0.7
median : 39 months
0.6
0.5
OS
survie
0.4
de
ité
0.3
babil
median : 30 months
0.2
Pro
0.1
EFS
0
012
24
36
48
60
DOUBLE ASCT WITH MORE INTENSIVE 2ND
HDT IMPROVES THE OUTCOME OF POOR-RISK MM
Historical Comparison
EFS
OS
1.0
1.0
0.8
med 33
0.8
0.6
166 PTS
0.6
med 47
0.4
0.4
166 PTS
med 25
0.2
med 15
0.2
33 PTS
33 PTS
0.0
0.0
0
12
2436486
0
012
2 728
43
4
64860
728496
(month)
(month)
EFS INTENT-TO-TREAT :
IFM 99-03 VS 99-04
0.9
p = 0.70
0.8
0.7
99-04 N=220
0.6
0.5
l
0.4
Surviva
99-03 N=64
of
ity
0.3
babil
0.2
Pro
0.1
0
012
24
36
48
60
SURVIVAL INTENT-TO-TREAT :
IFM 99-03 VS IFM 99-04
1.0
0.9
p = 0.34
0.8
0.7
0.6
99-04 N=222
0.5
l
99-03 N=64
0.4
Survivaof
ity
0.3
babil
0.2
Pro
0.1
0
012
24
36
48
60
IS DOUBLE ASCT THE STANDARD
OF CARE ?
- Single vs double ASCT
- Which patients benefit more from double ASCT ?
- Integrating novel therapy in the double ASCT
paradigm
WHICH PATIENTS BENEFIT MORE
FROM DOUBLE ASCT ?
Arkansas experience
- Patients without any adverse prognostic
factor enjoy durable remission
- Patients with adverse prognostic factors (2m
or LDH, genetic abnormalities) have a
poor outcome despite tandem ASCT
IFM 94 trial
- Double ASCT > single ASCT in different
prognostic subgroups (2m, LDH) although
the difference is not significant (small
numbers)
ONLY FACTOR PREDICTING THE IMPACT
OF THE 2nd ASCT : RESULT OF THE FIRST
(n=46)
(n=128)
B
B
A
(n=81)
A
P = 0.7
P < 0.001
(n=84)
FISH ANALYSIS OF IFM 99 TRIALS
PRELIMINARY RESULTS
Hervé Avet-Loiseau (Nantes)
1082 registered patients
983 analysed
Ficoll + CD138 purification
Del (13) = 965 pts
ploidy = 658 pts (2/3 probes)
t(11;14) = 760 pts
c-myc = 576 pts
t(4;14) =
727 pts
del(17) = 526 pts
t(11;14)
t(11;14)=1 (153 patients)
t(11;14)=1 (570 patients)
p=0.15
t(11;14)=1 (153 patients)
t(11;14)=1 (570 patients)
p=0.22
Del(13)
del (13) = 0
(483 patients)
del(13) =1 (436 patients)
p=4.10-6
del(13) = 0 (483 patients)
del(13) =1 (436 patients)
p=6.10-6
CORRELATIONS BETWEEN
CYTOGENETIC ABNORMALITIES
del(13) in 84% of t(4;14)
77% of del(17p)
14% are t(4;14) and del(17p)
t(4;14)
t(4;14)=0 (593 patients)
t(4;14)=1 (97 patients)
p=10-7
t(4;14)=0 (593 patients)
t(4;14)=1 (97 patients)
p=10-7
IS DOUBLE ASCT THE STANDARD
OF CARE ?
- Single vs double ASCT
- Which patients benefit more from double ASCT ?
- Integrating novel therapies in the double ASCT
paradigm
INTEGRATING NOVEL THERAPIES IN
THE DOUBLE ASCT PARADIGM
Novel Agents INSTEAD of double AT (older
patients)
COMBINED with double ASCT
Before AT
to increase the overall CR/VGPR rate
or to decrease the number of patients who
need a 2nd AT (if CR/VGPR achieved after
one)
After AT to maintain Remission
RESPONSE TO TREATMENT
IN THE IFM 99-06 TRIAL
% of patients (at 12 months)
Category of response
MP
MP-T
MEL100
Complete response
3
14
18
90%
8
51
39
50%
34
84
71
NOVEL AGENTS AS PART
OF INDUCTION TREATMENT
-Thalidomide based programs
· Thal / Dex
·Thal / Chemo (DT Pace, Arkansas)
· Revlimid / Dex (Rajkumar ASH 2004)
- Velcade - Based programs
·Vel / Dex
· Vel / Chemo
- Thalidomide + Velcade
·VTD (Alexanian ASH 2004)
·TT3 (Barlogie ASH 2004)
IFM 2005-01
Patients wiht newly diagnosed MM < 65 y.o.
R
A1
A2
B1
B2
N
VAD
Vel/Dex
VAD
Vel/Dex
OI
VAD
Vel/Dex
VAD
Vel/Dex
TC
VAD
Vel/Dex
VAD
Vel/Dex
U
VAD*
Vel/Dex*
VAD*
Vel/Dex*
DNI
1st ASCT
1st ASCT
DCEP
DCEP
.L
DCEP
DCEP
OSNO
1st ASCT
1st ASCT
C
2nd ASCT if < 90% reduction of the M-component within 3 months
* SC collection
IFM 99-02 : PFS FROM RANDOM
Arm C
Arm A
Arm B
P < 0.01
IFM 99-02
DOUBLE ASCT FOR STANDARD RISK MM
3-yr PFS 56%
3-yr OS 78%
Progression-free survival according to the number of
unfavorable factors (2m > 2.5 mg/L, 13)
Progression-free
survival
1.0
Progression-free
# factors
O/N
survival time
median ± se (m)
0
11/22
37.0 ± 9.5
0.8
1
41/55
26.7 ± 3.8
2
28/33
15.2 ± 2.0
0.6
0.4
0.2
P < .0001
0.0
0
12
24364860
7284
time from diagnosis (month)
IFM 99 02 : EFS ACCORDING TO ß2-m AND 13
AMONG RANDOMIZED PATIENTS
120
100
80
60
ß2- and 13-
· ß2m ; p = 0.001 (
/
)
40· 13 ; p = 0.02 (
/
)
ß2- and 13+
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 99-04 SURVIE GLOBALE :
RANDOMISES (166 pts) VS NON RANDOMISES (54 pts)
1.0
0.9
p < .0001
0.8
0.7
0.6
ival
0.5
surv
of
0.4
ity
0.3
babil
Pro
0.2
0.1
00
12
24
36
48
60
IFM 99-03 / 99-04
IN POOR RISK MM
1.0
0.9
p = 0.70 0.9
p = 0.34
0.8
0.8
0.7
99-04 N=220
0.7
0.6
l
99-04 N=222
l 0.6
0.5
0.5
Surviva
Surviva
of 0.4
99-03 N=64
of
ity
99-03 N=64
0.4
ity
0.3
babil
0.3
babil
Pro 0.2
Pro 0.2
0.1
0.1
0
0
012
24
36
48
60
012
24
36
48
60
EFS
SV
INTEGRATING NOVEL THERAPIES IN
THE DOUBLE ASCT PARADIGM
- Instead of double ASCT
Novel agents
- Combined with double ASCT
IFM 99-02
- Patients < 65 years
- 0 or 1 adverse prognostic factors (chr 13, 2 M)
VAD
VAD
VAD
SC collection
HDM 140 + AT
HDM 200 + AT
Control
Pamidronate
Pamidronate
+ Thalidomide
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
SINGLE VS DOUBLE
Nb pts
F-up
CR rate
EFS
TTP
OS
Cavo*
228
54 (med)
35 vs 48
0.001
0.0001 NS
(o.p. 536)
Sonneveld
303
56 (med)
0.002
0.016
0.001
NS
(p. 940)
Einsele**
198
< 4A
NS
NS
-
-
(o.p. 537)
* Double > single in patients who do not reach CR after one
** Intensified conditioning regimen in the single AT arm
(TBI + Bu + Cy)
SINGLE VS DOUBLE ASCT
RANDOMIZED STUDIES
MEDIAN EFS
Med F-up
Single
Double
p. value
IFM 94
75 m
25
30
0.03
MAG 95
53 m
31
33
NS
Bologna
3 y
21.5
31
0.02
GMMG
23
NR
0.03
Hovon
56 m
20
22
0.016
IFM 99-03 / 99-04
- < 65 years
- 2 mic > 3 mg/l + 13 (FISH)
VAD x 3
SC collection
HDM200
+ ASCT
HLA id sibling
No HLA id sibling
IFM 99-03
IFM 99-04
ATG + Bu + F
HDM 220 + Anti IL6
Allo BMT
Auto SCT
IFM 99-04
RESPONSE RATE
90%
91%
100
70%
80
59%
60
40
36%
33%
20
16%
14%
4%
PR
0
VGPR
VAD
HDM 200
HDM 220
CR
N = 129
N = 116
N = 100
4 TD
1 TD
3 TD
IFM 99-03 vs 99-04
EFS (intention to treat)
1.0
0.9
197 vs 58 patients
0.8
0.7
l
0.6
0.5
Survivaof 0.4
ity
99/04
0.3
babil
Pro
0.2
p = 0.78
99/03
0.1
00
1224
364860
IFM 99-03 vs 99-04
Survival (intention to treat)
197 vs 58 patients
1.0
0.9
0.8
0.7
l
0.6
99/04
0.5
Survivaof
0.4
ity
p = 0.40
99/03
0.3
babil
Pro
0.2
0.1
0
0
12
24
364860
SINGLE VS DOUBLE ASCT
RANDOMIZED STUDIES
MEDIAN OS
Med F-up
Single
Double
p. value
IFM 94
75 m
48
58
0.01
MAG 95
53 m
49
73
0.14
Bologna
3 y
56
60
NS
Hovon
56 m
55
50
NS
IFM 99-04 : SURVIE GLOBALE A PARTIR DU DG : 220 PTS
INTENTION DE TRAITEMENT
1.0
0.9
0.8
Médiane : 39 mois
0.7
0.6
ival
0.5
surv
of
0.4
ity
0.3
babil
Pro
0.2
0.1
0012
24
36
48
60
TOTAL THERAPY II
4 phases of treatment
- intensive induction treatment (VAD, DCEP, CAD,
DCEP) + THAL (role of Thal still unknown )
- double ASCT (HDM 200)
- consolidation CT (DCEP / CAD)
- maintenance treatment (IFN + Dex)
TOTAL THERAPY II
- Preliminary Results (Barlogie, ASH 2003)
· 462 pts enrolled prior to 7/02 compared to 231 pts
treated with total therapy I
· CR and near CR 66% vs 43% (p < 0.001)
· 4-yr EFS 62%
· 4-yr OS 69%
- Comparison with total therapy I
Significant improvement of EFS and OS specially in
the group of patients without cytogenetic
abnormalities (2/3 of the pts)
TT3
Barlogie (ASH 2004)
VTD + PACE x 2
2 ASCT
- 57 patients
- 26% > near CR after cycle 2
- Myelosuppression most common side effect
- SC collection possible
IFM 99-02 : PATIENT FLOW (0-1 FACTOR)
Inclusions = 780
On therapy = 94
Exclusions = 97
Randomisations = 588 (75 %)
Arm A = 197
Arm B = 194
Arm C = 197
SURVIE GLOBALE : RANDOMISES (166 pts)
VS NON RANDOMISES (54 pts)
1.0
0.9
p < 0.0001
0.8
0.7
0.6
ival
0.5
surv
of
0.4
ity
0.3
babil
Pro
0.2
0.1
00
1224
3648
60
1.0
0.9
0.8
Médiane : 33 mois
0.7
0.6
ival
0.5
surv
0.4
of
ity
0.3
babil
Pro
0.2
0.1
0
012
24
36
48
60
Survie sans évènement : 166 patients
IFM 99-04 vs 99-03
EFS - TREATMENT ACTUALLY RECEIVED
1.0
0.9
p = 0.49
0.8
0.7
99-04 N=166
0.6
l
0.5
0.4
Surviva
99-03 N=46
of
ity
0.3
babil
0.2
Pro
0.1
0
0
12
243648
60
IFM 99-03 vs 99-04
SURVIVAL TREATMENT ACTUALLY RECEIVED
1.0
0.9
p = 0.09
0.8
0.7
Tandem auto N=166
0.6
l
0.5
0.4
Survivaof
ity
0.3
99-03 N=46
babil
0.2
Pro
0.1
0
012
24
36
48
60
IFM 99-03 : INCIDENCE CHRONIC GVHd
1.0
0.9
0.8
0.7
0.6
0.5
lure
Fai
0.4
of
ity
0.3
babil
Pro
0.2
46 patients
0.1
0
0
10
2030
4050
LONG-TERM RESULTS OF HDT
SINGLE CENTER EXPERIENCE
- 127 pts with a minimum follow-up time of 6 years
(85-95)
- 12-y OS 25%
12-y EFS 3%
- Prognostic factors association with a better
outcome - age < 55 A
- 2mic < 3 mg/l
- completion of 2nd transplant
- Patients with all favorable parameters (25% of
this group) have a 48% 10-yr OS
Moreau Leukemia 2002
FISH ANALYSIS
Moreau Blood 2002
168 patients
86 single ASCT
72 double ASCT
10 allo ASCT
117 IgH rearrangements (70%)
t(4;14)
22 (13%)
t(14;16)
4 (2%)
t(11;14)
26 (15.5%)
ch13 abnormalities
76 (45%)
Significant association between t(4;14) and ch13 abn (82%)
DOUBLE INTENSIVE THERAPY
- 97 pts (44 rel/ref MM, 53 newly diagnosed)
- 1st course = HDM 140 mg/m² without hematopoietic
support
- 2nd course
HDM 140 mg/m² + TBI
only 38/69 pts responding to the 1st
course due to severe myelosuppression
after the 1st
- 11/22 PR
CR after the 2nd course
(Blood 1992)
THE IMPACT OF DOUBLE TRANSPLANTATION
ON CR RATE
- Feasibility of double transplants thanks to the use of
growth factors and PBSC ( Vesole Blood 1994)
- CR rate increased from 24% after the first
transplantation to 43% after the second (Vesole Blood
1996)
CR 43 %
12
61
83
PR 38 %
53
84
1
TX
2nd
NR 19 %
53
14
2
Post
NR = 118
PR = 159
CR = 86
32 %
44 %
24 %
Post 1st TX
IFM 94 TRIAL
RESPONSE RATE
Single TX
Double TX
N = 199
N = 200
HDM 140
Response
-
77
CR
-
15
CR + VGPR
-
26
HDM 140 + TBI
Response
84
89
CR
34
35
CR + VGPR
42
p=0.15
50
IFM 94
Newly diagnosed patients < 60 years
First randomisation : single versus double
VAD
VAD
VAD
Second randomisation : BM versus PBSC
VAD
VAD
VAD
VAD
Mel (140) + TBI
Mel (140) + PBSC
Mel (140) + TBI
BM
PBSC
BM
PBSC
SINGLE VS DOUBLE ASCT
RANDOMIZED STUDIES
Nb of pts
Age
Single
Double
HDM140 +TBI
HDM280 + TBI
IFM 94
399
<61
(NEJM 03)
HDM280+VP16+TBI*
MAG95
227
<56
Multidrug +TBI
(Turin 04)
HDM320+BU12
Bologna
220
<61
HDM200
(Turin 04)
HDM200
HDM400
GMMG
261
<66
(Turin 04)
HDM140+CY120+TBI
Hovon
303
<66
HDM70x2
(Turin 04)
TBI + Bu +Cy
HDM 400
Einsele
198
<61
(ASH 04)
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
median ± se (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
24364860
728496
time from diagnosis (month)
TOXIC DEATHS
VAD
ASCT1
ASCT2
IFM 94
4
15
2
N =
IFM 99-03
4
2
3
N =
Hovon
NA
1.3*
3.9
TT2
2
1
2**
* Devided into 2 courses of HDM 70/m²
** with non TBI - regimen
Document Outline