Reduced-
Reduced dose bortezomib plus
plus thalidomide
thalidomide plus
plus
dexamethasone (vTD) ) is superior to bortezomib
plus dexamethasone (VD) as induction treatment
prior to autologous stem-cell transplantation
(ASCT) in newly diagnosed multiple myeloma
(MM):
lt
resu s f
o IFM2007
IFM2007-02 prospective
randomized study.
P.Moreau, H.Avet-Loiseau, T.Facon, M.Atttal, C.Doyen, C.Hulin, G.Marit
L.Garderet, M.Tiab,
M.Tiab, B.Pégourié, G.Lepeu,
G.Lepeu, A.M.Stoppa,
A.M.Stoppa, M.Michallet,C.Aranjo
M.Michallet,C.Aranjo
D.Caillot, M.O.Petillon, C.Mathiot, J-Y Mary, J.L.Harousseau
Rationale (1)
- IFM 2005-01 trial:
Vel-dex (VD) > VAD in terms of CR + VGPR rates before
and after ASCT, better PFS in VD arm
Harousseau et al, J Clin Oncol 2010, in press
- GIMEMA 26866138-MMY-3006 trial :
VTD > TD in terms of CR + VGPR rates before and after
ASCT, better PFS
PFS in the VTD
VTD arm
Cavo et al, ASH 2009
Need for a randomized trial comparing VD vs VTD
Rationale (2)
- Grade 3 / 4 neuropathy rates:
7% in VD arm of 2005-01
9% in VTD arm of Gimema
14% in VTD
VTD arm of Pethema
Rd
Reduced doses f
o Velcade 1
/
mg m2
Reduced doses of Thalidomide : 100 mg/day
IFM 2007-02, study design
Newly diagnosed
yg
myeloma
y
up to 65 years
y
of age
g
Stratification by 2mic and del 13 (FISH)
R
VD (IFM 2005/01)
TD
v
Four 21D cycles
Four 21D cycles
Ve
Vel13m
l 1.3
g/m2
mg/m2 d1481
d1,4,8, 1
11
Vel 1 mg/m2d
mg/m2 1481
d1,4,8, 1
11
Dex 40mg d1-4,9-12
Thal 100 mg/d
Cycles 1 & 2
Dex idem
d1-4, cycles 3 & 4
increased up to 1.3 & 200mg/day
if response < PR after 2 cycles
+ LMWH
VD vs vTD : IFM2007-02
Pi
Primary end
it
-point
CR rate (IF < 0)
() after 4 cycles
y
of
Vel Dex or vTD
Secondary end-points
Statistical hypothesis
CR + VGPR
VGPR after
after induction
induction
7% CR with VD (IFM 2005-01
CR, CR + VGPR after ASCT
22% CR with vTD
Safety
5%, 90%, bilateral
Incidence and
and severity of
of neuropathy
neuropathy
99 pts per
per arm
Response Assessment
- After cycle 2 and 4, and 1-3 months after ASCT
IMWG
if
un orm criteria ( l
p us n-CR)
- Centralized analysis of blood and urine, electrophoresis and of
immunofixation (H
(H. Avet
A
-Loiseau, Nantes)
- Data monitoring by external CRO
- Intent-to-treat analysis
- All patient withdrawals prior to evaluation were considered
fi
fa lilures.
- For post-ASCT assessment patients who did not undergo ASCT
were considered failures
Patients' characteristics
VD
vTD
p value
n = 99
n = 100
Age
g median
57
58
0.28
Gender (M/F)
60 / 39
55 / 45
0.42
ISS 3
22
23
0.82
Beta2mic median
36
3.6
38
3.8
09
0. 9
99
Albumin median
36.9
35.7
0.77
Del 13 (FISH)
45%
48%
0.67
t(4;14)
9%
15%
0.23
Del17p
7%
12%
0.16
Del 17p or t(4;14)
16%
27%
0.079
Creatinine (M/L) median
88
88
0.68
Response after 2 cycles
py
, intent-to-treat
VD
vTD
pa
p v l
al e
u
>PR
78%
90%
0.008
> VGPR
20%
22%
0.77
CR + nCR
nCR
16%
15%
09
0. 5
95
CR
6%
4%
07
0. 1
71
Response after 4 cycles, intent-to-treat
VDvTD
p value
> PR
81%
90%
0.079
> VGPR
35%
51%
0.037
CR + nCR
nCR
22%
32%
0.104
CR
12%
13%
07
0. 4
74
Response after ASCT, intent-to-treat
VD
vTD
p value
N= 99
N = 100
> PR
84%
90%
0.23
> VGPR
59%
73%
0.037
CR + nCR
54%
61%
0.35
CR
33%
30%
06
0. 5
65
VD vs VTD
VD
VD
VTD
VTD
vTD
4 cycles
4 cycles
6 cycles 3 cycles
4 Cycles
2005-01
2007-02
Rosinol
Cavo
2007-02
N = 223
N = 99
N = 102
N = 226
N = 100
Post-induction
CR
6
12
30
21
13
CR + nCR
nCR
15
22
40
33
32
VGPR
38
35
59
61
51
Post-ASCT
CR
16
33
49
43
30
CR + nCR
35
54
64
55
61
VGPR
54
59
78
76
73
Stem cell collection
VD
vTD
p value
Nb of apheresis
2
2.5
< 0.001
median
Nb CD34+ (106/kg)
7.4
6.4
0.0014
Md
Me i
dian
G-
G CSF priming
priming alone failure,
6%
21%
0 003
.
cyclophosphamide mobilization
Failure of collection
1%
2%
ASCT, prepared by mel 200
VD
vTD
p value
N = 90
N = 92
Days, hospitalization
19
18
0.04
median
Days, neutrophils < 103/L
6
7
0.03
median
Days, platelets < 50 103/L
7
6.5
0.87
median
Ti
Toxic d
t
ea h
th
0
0
Toxicity during induction
VD
vTD
p value
Nb f
o Ad
Adverse events
974
886
Patients with at
at least
least 1 AE
99%
99%
09
0. 7
97
Grade > 3
37%
43%
0.38
AE leading to study
4%
0%
0.05
discontinuation
Toxicity ­ Grade 3 / 4 (%)
VD
vTD
p value
Ai
Anemia
2
2
09
0. 6
96
Thrombocytopenia
0
1
0.28
Infections
0
2
0.24
Thrombosis
1
1
0.97
Herpes zoster
1
2
0.53
Fatigue
6
7
07
0. 0
70
GI symptoms
2
3
0.61
Peripheral neuropathy (%)
VD
vTD
p value
All grades
63
55
0.24
Gd
Grade > 2
28
15
00
0. 3
03
Grade > 3
6
3
03
0. 4
34
SAE leading to treatment
4
0
0.12
discontinuation
Conclusions
- vTD more effective than VD : CR/VGPR rate superior both after
induction and after ASCT
(primary objective : CR rate after induction is similar)
- Decreasing the doses of V and T does not impair
gp
efficacy
- Stem cell collection after G-CSF priming alone: significantly inferior
after vTD
vTD : cyclophosphamide required
- Incidence of grade 3 / 4 AE : very low
- Incidence of grade 2 / 3 peripheral neuropathy dramatically reduced
This new triple combination vTD is superior to VD with a
good efficacy/toxicity ratio
International
XIIIth
XIII
Wo
W rkshop
o
on
Multiple Myeloma
PARIS, may 2011
Inside the
Carrousel du Louvre
Organizing committee:
Thierry Facon
Jean-Paul Fermand
Philippe Moreau