Thalidomide/Dexamethasone (TD) vs.
Velcade/Thalidomide/Dexamethasone (VTD) vs.
VBMCP/VBAD/Velcade as Induction Regimens prior to
Autologous Stem Cell Transplantation (ASCT): Results of
a Prospective
p
Phase III PETHEMA/GEM Trial.
Laura Rosiñol, Mª Teresa Cibeira, Joaquín Martínez, Mª Victoria Mateos,
Mª José Terol, Javier de la Rubia, Luis Palomera, Felipe de Arriba, Albert
Oriol, Adrián Alegre, Joan Besalduch, Raquel de Paz, José García-
Laraña, Joaquín Díaz-Mediavilla, Anna Sureda, Juan J. Lahuerta, Jesús
F. San
San Miguel, Joan Bladé. Hospital Clínic, Barcelona, Spain,
On Behalf of PETHEMA/Spanish Myeloma Group.
Background
Autologous stem cell transplantation
p
(ASCT)
() has
become the standard of care in the up-front therapy
of younger patients with multiple myeloma.
The achievement of a complete remission (CR) post-
ASCT is the crucial step for long-
long lasting response
and prolonged survival.
The degree of tumor reduction achieved with the
induction pre-transplantation therapy is the key factor
for the post-
post transplant CR rate.
rate
Aim
To investigate the efficacy and safety of three
pre-transplant induction regimens:
VBMCP/VBAD + bortezomib
Thalidomide/dexamethasone (TD)
Bortezomib/thalidomide/dexamethasone (VTD)
GEM05MENOS65
De "novo" symptomatic MM <65 yrs
1st randomization
VBMCP/VBAD
THALIDOMIDE/
THAL/DEX*/
x 4
DEXAMETHASONE*
BORTEZOMIB**
BORTEZO
OOMIB**
(TD)
() x 6
(VTD) x 6
x 2
ASCT (MEL200)
2nd randomization
INTERFERON- 2b
THALIDOMIDE
THALIDOMIDE/BORTEZOMIB
*Thalidomide: 200 mg/day; Dexamethasone: 40 mg on days 1-4, 9-12
**Bortezomib: 1.3 mg/m2 on days 1,4,8, and 11
TD and VTD at 4 week-interval
End-points
Primary
Response rate
Secondary
Time to progression
Overall survival
Safety
Patients and Methods
Methods
Patients < 65 yrs-old with
with symptomatic MM
Response criteria:
criteria: EBMT (plus
(plus VGPR)
Sample size: 390 patients (130
(130 per arm)
Statistical methods: chi
chi-square, Kaplan
Kaplan and
Meier method, log-rank test.
GEM05MENOS65
De "novo" symptomatic MM <65 yrs
306 PTS INCLUDED
INCLUDED
(As of December 31, 2008)
VBMCP/VBAD
TD
VTD
+ Bortezomib
(N=104)
(N=102)
(N=100)
ASCT (MEL200)
218 evaluable post-ASCT
Patient Characteristics
Characteristics (I)
VBMCP/VBAD
TD
VTD
+Bortezomib
(n=104)
(n=102)
(n=100)
Age (median)
58
55
56
Gender (M/F)
47/53
54/50
55/47
M-protein type (%)
IgG
60
55
65
IgA
23
26
20
Light chain
16
16
10
IgD1
g
3
4
IgM
-
-
1
Patient Characteristics
Characteristics (II)
VBMCP/VBAD
TD
VTD
+ Bortezomib
(n=104)
()
(n=102)
()
(
100)
n=
Hb < 10 g/dL (%)
39
34
30
EMP* (%)
14
19
20
Poor cytogenetics (%):
20
20
25
t(4;14); t(14;16), del (17p)
(17p)
*EMP: extramedullary (soft-tissue) plasmacytomas
Patient Characteristics
Characteristics (III)
VBMCP/VBAD
TD
VTD
+ Bortezomib
(n=104)
(n=102)
(n=
(n 100)
Durie-Salmon (%)
I10
3
9
II
42
49
48
III
48
48
43
ISS (%)
I41
41
35
II
38
42
45
III
19
17
20
Results (I)
Rt
Response to Inducti
tion Th
Therapy
VBMCP/VBAD
Response
TD
VTD
+Bortezomib
(n=104)
(n=102)
(n=100)
CR (%)
23
14*
31*
CR+VGPR(%)
37**
28&
59&
CR+VGPR+PR (%)
71
62
82
SD (%)
14
16
9
PD (%)
15
22¶
8¶
*VTD vs. TD, p=0.004
&VTD
&
vs
vs. TD
TD, p<0
p<0.00001; VTD vs
vs. VBMCP/VBAD+bortezomib, p=0
p=0 003
.
VTD vs. TD, p=0.001
¶VTD vs. TD, p=0.005
Results (II). Response in patients with
td
extramedullllary plasmacytomas
PD in patients with and without EMP: 27% vs. 12%, p=0.01
VBMCP/VBAD
TD
VTD
+ Bortezomib
(n=20)
(n=21)
(n=14)
CR (%)
28
10*
10
38*
38
CR+VGPR (%)
35
20#
52#
CR+VGPR+PR (%)
71
45&
76&
SD (%)
-
15
10
PD (%)
29
40**
14**
*p=0.04
# p=0.03
&p=0.04 **p=0.06
Results (III). Response in patients with high-
risk cytogeneti
tics: t (4;14); t(14;16); del (17 )
p
VBMCP/VBAD
TD
VTD
+ Bortezomib
(n=19)
()
(n=19)
()
(
17)
n=
CR (%)
23*
-
42*
CR+VGPR (%)
(%)
23
26
58
CR+VGPR+PR (%)
59
47#
84#
SD (%)
18
15
5
PD (%)
23¶
37¶
-¶
*VTD vs. TD,p= 0.0031; VBMCP/VBAD+bortezomib vs TD, p=0.04
#VTD
#
vs
vs. TD
TD, p=0
p=0 01
.
¶VTD vs. TD, p=0.0034; VTD vs. VBMCP/VBAD+botezomib, p=0.04
Results (IV).
Adverse events / di
ti
scon
ti
nua ons
VBMCP/VBAD
TD
VTD
+ Bortezomib
(n=104)
(n=102)
(n=100)
()
AEs (grade 3-4) (%)
24
22
30
Di
ti
scon
ti
nua ons
33
8
due to toxicity (%)
Deaths during
35
3
induction (%)
Results (V).
(V). Grade 3 toxicity
toxicity
VBMCP/VBAD
TD
VTD
+ Bortezomib
(n=104)
(n=102)
(n=100)
Neutropenia (%)
17
8
7
Thrombocytopenia (%)
(%)
4
5
8
Thrombotic events (%)
3
8*
1*
Peripheral neuropathy (%)
0**
1**
14**
*VTD vs. TD, p=0.01
**VTD vs. TD, p=0.0003; VTD vs. VBMCP/VBAD+bortezomib, p<0.0001
Results (VI).
(VI). Response post-ASCT*
VBMCP/VBAD
TD
VTD
+ Bortezomib
(n=64)
(n=78)
(n=76)
CR (%)
49
37
52
VGPR (%)
16
27
26
PR (%)
30
28
18
MR+NR (%)
1
2
1
PD (%)
2
1
1
TRM (%)
1-
1
Non-evaluable (%)
1
5
1
*Patients in whom ASCT was performed
Results (VII). Pre- and post-ASCT CR
t
ra e
d
accor i
ding to the induction regimen
Pre-ASCT
Post-ASCT
VBMCP/VBAD
23
49
+ Bortezomib (%)
TD (%)
14
37
VTD (%)
()
31
52
Overall survival according to the
id
induction arm
1,0
0,9
VBMCP/VBAD+bortezomib
0,8
TD
gin 0,7
VTD
ivrvu
S 0,6
onti
por 0,5
or
Pev 0,4
tilaum 0,3
uC
0,2
p=NS
0,1
0,0
0
5
10
15
20
25
30
35
40
45
Months
TTP and PFS according to the
id
induction arm
TTP
PFS
1,0
1,0
0,9
0,9
0,8
0,8
g
g
in 0,7
in 0,7
iv
iv
rv
rv
u
u
S 0,6
S 0,6
n
n
tio
tio
or
or
0,5
0,5
rop
rop
P
P
e
e
0,4
0,4
tiv
tiv
la
la
u
u
m
m
0,3
0,3
Cu
Cu
0,2
0,2
p=0.05
0,1
0,1
p=0.012
0,0
0,0
0
5
10
15
20
25
30
35
40
45
0
5
10
15
20
25
30
35
40
45
Months
Months
VBMCP/VBAD+
VBMCP/VBAD bortezomib
TD
VTD
TTP and PFS according to the presence
of extramedullary plasmacytomas (EMP)
TTP
PFS
1,0
1,0
0,9
0,9
0,8
0,8
g
g
in 0,7
in 0,7
iv
iv
rv
rv
u
u
S 0,6
S 0,6
n
tion
tio
0,5
or 0,5
ropor
rop
Pe
P
e
e
0,4
tiv
0,4
tiv
lau
la
m
u
0,3
m 0,3
Cu
Cu
0,2
0,2
0,1
0,1
p=0.05
p=0.2
00
0,0
0,0
0
5
10
15
20
25
30
35
40
45
0
5
10
15
20
25
30
35
40
45
Months
Months
EMP
No EMP
TTP and PFS in patients with high-risk
cytogenetics: t (4;14);
(4;14); t(14;16); del
del (17p)
TTP
PFS
TTP
1,0
1,0
0,9
0,9
0,8
0,8
g
g
in 0,7
in 0,7
iv
iv
rv
rv
u
u
S 0,6
S 0,6
tion
tion
0,5
0,5
ropor
ropor
P
P
e
e
0,4
tiv
0,4
tiv
la
la
u
u
m
m
0,3
0,3
Cu
Cu
0,2
0,2
p=0.06
p=0.01
0,1
0,1
00
0,0
00
0,0
0
5
10
15
20
25
30
35
40
45
0
5
10
15
20
25
30
35
40
45
Months
Months
High-risk
Low-risk
Conclusions (I)
(I)
Induction with VTD resulted in higher response rate
and in a lower PD than induction with TD.
In patients with high-risk cytogenetics TD resulted in
a
significantly
lower
CR
rate
than
VBMCP/VBAD+bortezomib and VTD.
Patients with EMP had a higher progressive disease
rate and a shorter time to progression.
Conclusions (II)
(II)
With the current follow-up, there are no significant
differences in OS among the three groups. However,
TTP and PFS were significantly shorter with TD.
The incidence of AEs was not significantly different
among the three arms. However, thrombotic events
were significantly higher with TD and peripheral
neuropathy with VTD.
ASCT increased the CR rate in about 20% of patients
irrespective of the induction regimen used.
Acknowledgments
Investigators including patients in the Spanish Myeloma
Group's trials, and most of all, the patients!