Velcade-Dexamethasone versus VAD
as Induction Treatment Prior to ASCT
in Newly Diagnosed MM. Updated
Rl
Resu t
lt
f
so th
the IFM2005/01
IFM2005/01 Trial.
JL Harousseau, C. Mathiot, M. Attal, G. Marit, D.
Caillot, C. Hulin, T. Facon, I. Webb, H. Avet-
Loiseau, P. Moreau
Moreau
Intergroupe Francophone du Myélome
Disclosures for
for Jean-Luc Harousseau
In compliance with ACCME policy, ASH requires the
the following disclosures to the activity audience:
audience
Research Support/P.I.
N/A
California
Employee
N/A
Francisco,
Consultant
N/A
San
Major Stockholder
N/A
Meeting
Honoraria
N/A
nnualA
Speakers Bureau/Scientific
ASH
Celgene, Johnson & Johnson
th
Advisory Board
50
Presentation includes discussion of the following off-label use of a drug or medical
device: N/A
Introduction
In the context of ASCT, CR+VGPR achievement is associated with
improved PFS and OS
Increasing CR+VGPR rate following induction could improve the
overall CR+VGPR rate
rate
VAD has been the standard induction therapy but results in < 10%
CR rate
Preliminary results of the IFM 2005-01 trial have shown a higher
CR/nCR/VGPR rate with Vel-Dex compared to VAD both after
induction and after ASCT (ASCO 2008)
However there were two limitations at the time of this presentation:
- Investigators' assessment only
- Due to a short follow-up, no difference in OS or even PFS
Study Design
Primary analysis: post-induction CR+nCR in VAD (A1+A2) vs Vel-Dex (B1+B2)
Randomization
stratified by 2-microglobulin level (>3mg/L vs 3mg/L) and presence of chromosome 13
abnormalities (by FISH analysis)
A1
A2
B1
B2
VAD x 4
VAD x 4
Induction
Vel-Dex x 4
Vel-Dex x 4
DCEP x 2
Consolidation
DCEP x 2
Melphalan
Melphalan
Melphalan
Melphalan
200mg/m2
200mg/m2
Transplant 1
200mg/m2
200mg/m2
+A
+ SCT
ASCT
+A
+ SCT
ASCT
+A
+ SCT
ASCT
+A
+ SCT
ASCT
Second ASCT or RIC allo if <VGPR
Study Design
VAD regimen (28-da
g(
y cycle
yy
):
)
Vincristine 0.4 mg/m2 and doxorubicin 9 mg/m2, days 14
continuous infusion
Dexamethasone 40 mg, days 14 (cy
(ycles 14), and days 912, 17
20 (cycles 12 only)
Vel-Dex regimen (21-day cycle):
Bt
Bortezomib
ib 1 3
.
/ 2
mg/m , d1
days 1, 4, 8,
d
an 11
11
Dexamethasone 40 mg, days 14 (cycles 14), and days 912
(cycles 12 only)
DCEP regimen (28-day cycle):
Dexamethasone 40 mg, days 14
Cyclophosphamide 15 mg/m2
mg/m , etoposide 400 mg/m2
mg/m , and
cisplatinum 10 mg/m2, days 14 continuous infusion
Baseline Patient Demographics and
Disease Characteristics
July 2005 January 2007 = 482 patients
yp
have been enrolled
VAD
Vel-Dex
(A1+A2)
(B1+B2)
P value
N=242
N=240
Male, %
52 5
.
57 9
.
02
0. 3
23
Mean (Median) Age, yr
55.8 (57.1)
55.4 (57.2)
0.53
ISS stage III, %
22.3
21.7
0.73
2m > 3 mg/L, %
57 9
.
57 1
.
08
0. 6
86
Chr 13 del by FISH, %
43
42
0.92
t(4;14) and/or del(17p), %
12
17
0.14
Mean (Median) Hb
Hb, g/dL
g/dL
10 9
. (10
(10 8)
.
10 9
. (10
(10 9)
.
09
0. 7
97
Mean (Median) Cr, mol/L
100.6 (87)
106.3 (87)
0.32
Mean (Median) Calcium, mol/L
2.4 (2.3)
2.4 (2.4)
0.25
Response To Induction
Evaluable Patients
Patients
VAD
VA
Vel
Ve -Dex
(A1+A2)
(B1+B2)
P value
N=210
N=214
CR
1%
6%
0.0109
CR+nCR
7%
15%
0.0035
> VGPR
16%
39%
< 0.0001
> PR
65%
82%
<.0001
MR+SD
28%
13%
PD
4%
5%
Death
3%
0.5%
Response by IRC assessment
Impact of ISS on Post-Induction
Responses
VAD
Vel-Dex
(A1+A2)
(B1+B2)
P value
ISS 1
n=97
n=102
CR+n-CR
11%
16%
0.325
VGPR
21%
37%
0.01
ISS 2
n=82
n=81
CR+n-CR
5%
15%
0.043
VGPR
13%
36%
0.001
ISS 3
n=54
n=52
CR+n-CR
0%
14%
0.006
VGPR
7%
40%
<0.0001
Impact of Cytogenetics on Post-Induction
Responses (VGPR)
VAD
Vel-Dex
(A1+A2)
(B1+
(B1 B2)
P value
(A1+A2)
B2)
Chr 13 (by FISH)
deletion
n=103
n=
n 101
deletion
n=103
15%
47%
< 0.0001
normal/NE
n=139
n=139
15%
30%
0.003
15%
2M>3/13
n=65
n=63
15%
43%
0.0006
15%
t(4;14) and/or (17p)
yes
n=29
n=40
40%
00
0. 4
17%
04
normal/NE
n=213
n=200
15%
37%
<0.0001
Response To DCEP Consolidation
Evaluable Population
Population
VGPR
35
VG
CR+n-CR
32%
30
28%
25
P=0.37
14%
17%
20
15
10
14%
15%
P=0.72
72
5
0
A1+B1
A2+B2
- DCEP
+ DCEP
N=222
N=219
Response to First ASCT
ASCT Actually Performed
VAD
VA
Vel
Ve -Dex
(A1+A2)
(B1+B2)
N=184
N=197
P value
[84%]
[88%]
CR
10%
18%
0.019
CR + nCR
22%
40%
0.0001
> VGPR
44%
61%
0.0007
PR
91%
91%
NS
Pts needing
47%
34%
a 2nd
2 ASCT
Response to First ASCT
Evaluable Patients
Patients
VAD
VA
Vel
Ve -Dex
P value
(A1+A2)
(B1+B2)
N=213
N=212
CR
9%
17%
0.016
CR + nCR
nCR
19%
37%
<0 0001
.
> VGPR
38%
57%
0.0003
> PR
79%
84%
NS
MR/SD/PD
4%
3%
No ASCT
17%
13%
Best Response
Including 2nd
2
ASCT
VAD
Vel
Ve Dex
-
P value
CR+nCR
32%
39%
< 0.0001
VGPR
47%
68%
< 0.0001
Progression-Free Survival
2 yr
-
median follow up
-
100
Vel-Dex: 71 events
80
Median NR; 2-yr PFS 69%
ate
60
estim
eier
VAD:
V
101 events
40
Median: 28 months; 2-yr PFS 60%
aplan-MK 20
Vel-Dex (B1+B2)
VAD (A1+A2)
P-value (log-rank) = 0.0115
0 0 2 4 6 8 10121416 18 20222426 28 30 32 34 36 38 40
Time (months)
Overall Survival
2 yr
-
median follow up
-
Vel-Dex: 29 deaths
100
2yr OS: 90%
80
VAD: 33 deaths
ate
2yr OS: 88%
a
y
60
estim
eier
40
aplan-MK 20
Vel-Dex (B1+B2)
(B1+B2)
VAD (A1+A2)
P-value (log-rank) = 0.4689
0 0 2 4 6 8 10121416 18 20222426 28 30 32 34 36 38 40
Time (months)
Stem Cell Collection
VAD
Vel-Dex
N = 242
N = 240
After one mobilization (G-CSF alone):
Mean number of apheresis
1.62
2.04
Median No. CD34+ (x106
(x10 /kg)
6
83
8. 6
36
68
6. 0
80
Patients with > 2.106/kg
98%
96%
Patients with < 5.106/kg
10%
22.5%
Patients needing 2nd mobilization
12%
24%
Toxicities During
During Induction
Induction
VAD
Vel-Dex
N = 239
N = 239
Any AE, n (%)
219 (92%)
231 (97%)
Grade 3, n (%)
110 (46%)
112 (47%)
Grade 4n
4, n (%)
(%)
37 (16%)
27 (11%)
(1
SAE, n (%)
81 (34%)
65 (27%)
AE leading to
to study
study drug
discontinuation, n (%)
12 (5%)
15 (6.3%)
AE leading to death, n (%)
7 (3%)
()
2 (1%)
()
Hematologic Toxicity
During Induction
VAD
Vel-Dex
N=239
N=238
Gr 1-4
Gr 3-4
Gr 1-4
Gr 3-4
Anemia
21%
9%*
16%
4%*
Neutropenia
14%*
10%*
8%*
5%*
Thrombocytopenia
5%*
1%
11%*
3%
Infections
38%*
12%
48%*
9%
Herpes Zoster
2%*
-
9%*
-
Thrombosis
12%*
5%*
5%*
2%*
* P < 0.05
Non Hematologic Toxicity
During Induction
VAD
Vl
Vel D
- ex
Gr 1-4
N = 239
N = 238
Fatigue
21%
28%
Rash
9%
12%
GI symptoms
31%
27%
Cardiac disorders
6%
6%
Pt
Pneumopa h
thy
6%
3%
Peripheral Neuropathy
Induction+DCEP+ASCT 1
VAD
Vel
Ve Dex
-
P value
N = 239
N = 238
All grades
28%
46%
<0.0001
Grade 1
19%
28%
00
0. 2
02
Grade 2
8%
18%
0.002
Grades 3-
3 4
2%
7%
0.008
· No significant difference
difference between
between Vel
Ve Dex+DCEP
-
and
and Vel
Ve -
Dex: Grades 2-4: 37.5% vs 28.5%
Conclusions (1)
Vel-Dex significantly
gy improved
p
both post-induction
p
and
post-ASCT CR/nCR and VGPR rates vs VAD (ITT)
- Post-ASCT VGPR rate is comparable to those achieved after
doubl
ble ASCT
ASCT (57%)
(57%)
- The number of patients needing a 2nd ASCT is reduced
- Vel-
Vel Dex is
is equally
equally effective in
in patients
patients with
with poor-
poor risk MM (ISS 3;
poor-risk cytogenetic abnormalities)
DCEP consolidation did not have a significant impact on
response rates (ITT)
The better response after induction treatment with Vel-
Dex translated into significantly longer PFS
Conclusions (2)
In the Vel Dex arm stem cell collection yield was 2106
In the Vel-Dex arm stem cell collection yield was 2.10
CD34+/kg in 96% of patients
Vel-Dex regimen was well tolerated except
gp a high
g
incidence of Grade 2-3 peripheral neuropathy
Vel-Dex should now be considered the standard
induction treatment prior to
to ASCT
ASCT to
to which
which other
regimens including novel agents should be compared
Triple combinations with lower doses of VELCADE
might be as effective and better tolerated
Ongoing randomized IFM-2007-02 trial is
is evaluating Vel-Dex
versus Vel-Thal-Dex with Vel 1.0 mg/m2 and Thal 100 mg/d
Acknowledgments
CHU Nantes
- Maëlle Ningre
Project Manager
- Tanguy Roman
Data Managers
- Nicolas Pontoizeau
- JM Nguyen
- Christelle Volteau
Biostatistics
- Lucie Planche
- Anne Chiffoleau
Pharmacovigilance
IFM
- Claire Mathiot
- Philippe Moreau
- Herve Avet-Loiseau
- IFM investigators and CRA
Millennium: The Takeda Oncology Company
- Iain Webb
- Dixie Esseltine
Acknowledgments
Progression-Free Survival
Impact of CR or VGPR prior to
to ASCT
ASCT
Median not reached
32 events
Median not reached
41 events
P=0.0337
VGPR
after ASCT1/ASCT2
after induction/consolidation
months
Study Design
Stem cell collection:
Mobilization with G-CSF 10g/kg for 6 days after
cycle 3 of induction
If collection not adequate, second mobilization
with cyclophosphamide 3 g/m2 and G-CSF 5
g/kg
gg after cycle
y
4
Target collection: 5 x 106 CD34+ cells/kg, to
enable double transplantation, if required
Response To DCEP Consolidation
Evaluable Population
Population
VGPR
35
VG
CR+n-CR
32%
30
28%
25
P=0.37
14%
17%
20
15
10
14%
15%
P=0.72
72
5
0
A1+B1
A2+B2
- DCEP
+ DCEP
N=222
N=219