A Ph
Phase II
II PETHEMA Trial of Alternati
ting
Bortezomib and Dexamethasone as Induction
Regimen Prior
Prior Autologous Stem Cell
Transplantation in Younger Patients with
Multiple My
pyeloma: Efficacy and Clinical
Implications of Tumor Response Kinetics.
L. Rosiñol1, A. Oriol2, MºV.Mateos3, A. Sureda4, P. García-Sánchez5, N.
Gutiérrez3, A. Alegre6, J.J. Lahuerta7, J. de la Rubia8, C. Herrero9, X. Liu10, H.
Van de Velde10, J. San Miguel3, J. Bladé1.
1H. Clinic Barcelona, 2H. Germans Trias Pujol, 3H. Clinico Salamancam 4H Sant Pau
5H.Clinico Madrid 6La Princesa, 7H. 12 de Octubre, 8H. La Fe, 9Janssen Cilag Spain,
10Jonhson&Jonhson Pharmaceutical R&D, Beerse,Belgium and Raritan, USA
Bk
Back
d
groun
Dexamethasone-based combinations have been the standard
induction regimens for younger patients with multiple myeloma (MM)
during the last two decades.
Bortezomib alone or in association with dexamethasone has shown
significant activity in patients with both refractory/relapsed and newly
diagnosed MM.
The efficacy of bortezomib and dexamethasone administered on an
alternating basis has not been investigated.
Aims
Decrease toxicity
Assess the M-protein decrease with each
drug
Ed
End-Pit
Points
Primary end-points :
response rate
kinetics of
of response
response
Secondary end-points:
safety
stem cell collection
Response p
ppostransplant
Pt
Pa i
tients and Meth
thods (I)
(I)
n
Nº patients
40
Sex: M/F
18/22
Age,
g, yrs (median,ran
,
ge
g )
54(40.8-65.4)
Hb (g/L) (mean, SD)
98±35
Creatinine (mg/dL)(mean, SD)
1.1±0.2
Isotype: IgG / IgA / light chain
26/11
26/1 /3
1
Kappa/lambda
23/17
Extramedullary plasmacytomas
6
FISH analysis
Del Rb
11/34 (32%)
t(11;14)
6/34 (18%)
(4
t
14)
;
/34
5
(1
(1 %
5 )
%)
t(14;16)
2/34 (6%)
del 17p
3/34 (8%)
Pati
tients and Methods (II)
(II)
Schedule:
bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11
(cycles 1, 3, 5)
dexamethasone 40 mg p o
. . on days 1-
1 49
-4, -
9 12
-
and
17-20 (cycles 2, 4 and 6)
stem cell collection and high dose-therapy
intensification with
with MEL
MEL 200
-
.
Responses were evaluated by the EBMT criteria but
a VGPR category was included.
Stem cell mobilization was
was performed with G-
G CSF
-
alone.
Patients and Methods (III)
Statistical analysis on tumor response
yp
kinetics
Random effects model
model
Piecewise linear model
Results (I)
Response to treatment
Best response ever achieved
End of induction treatment
(n=40)
(n=40)
8%
3%
8%
12%
3%
13%
8%
17%
10%
8%
3%
17%
17%
42%
39%
ORR: 82.5%
ORR: 77.5%
CR
VGPR
PR
MR
Stable
Progression
Non-evaluable
Results (II)
Response to
to treatment
treatment according to
to
cytogenetic findings
90%
p=NS
pNS
90%
100%
93%
p=NS
78%
80%
90%
75%
70%
80%
70%
60%
60%
50%
50%
40%
40%
30%
30%
25%
22%
20%
20%
10%
7%
10%
10%
10%
0%
0%
Del Rb(+)
Del Rb(-)
IgH(+)
IgH(-)
Re
R s
e pons
s
e
pons
No
No re
r s
e pons
s
e
pons
Re
R s
e pons
s
e
pons
No
No re
r s
e pons
s
e
pons
Del Rb: 11/34 patients (32%)
IgH(+): 14/34 patients (43%)
Results (III)
Responses in patients with IgH translocations
70%
64%
IgH(+
IgH( ): 14/34 patients (43%)
60%
50%
CR
40%
PR
30%
MR
21%
Progression
20%
7%
7%
10%
0%
CR
PR
MR
Progression
t (11;14)
1
3
1
1
t (4;14)
3
2
t (14;16)
(14;16)
2
Other IgH(+)
1
Results (IV)
Tumor Response Kinetics
Decrease in serum M-protein
M-protein
p
Cycle
g/L
95% CI
Value
Estimate
Baseline
44 12
.
(36 3
. , 51 8)
.
Overall change (% of baseline)
-28.94 (66%)
(-37.0, -20.8)
<.0001
Incremental change by cycle (% of total change)
C1 (VEL) - Baseline
-10 32
.
(36%)
(-14 5
. , 60
-6. )
0)
< 0001
.
C2 (Dex) - C1 (VEL)
-13.90 (48%)
(-17.8, -9.9)
<.0001
C3 (VEL) - C2 (Dex)
-2.58 (9%)
(-4.6, -0.5)
0.0149
C4 (Dex) - C3 (VEL)
-30
3. 3(
03 10%)
(10%)
(-49
4.9, 11
-1. )
1)
0 0
. 031
0031
C5 (VEL) - C4 (Dex)
0.09 (<1%)
(-2.0, 2.1)
0.9274
C6 (Dex) - C5 (VEL)
0.81 (3%)
(-1.8, 3.4)
0.5341
VEL (C1 3
+
5
+ )
5) - Dex (C246
(C2+4+ )
6)
33
3. 1(
31 11
(1 %)
1%)
(-64
6.4, 13
13 0
. )
0)
0 4
. 891
4891
Results (V)
Tumor Response Kinetics
Decrease in Urine M-protein
M
ti
-protein
P
Cycle
g/24h
95% CI
Value
Estimate
Baseline
2.32
(0.5,
(, 4.0)
Overall change (% of baseline)
-1.79 (77%)
(-4.0, 0.4)
0.10
Incremental change by cycle (% of total change)
C1 (
C(VEL) -Baselin
ase
e:-
e
0.36
03 (
6(20%)
0%)
(-2.1, 1.3)
,3)
0.67
06
C2 (Dex) - C1 (VEL):
-1.11 (62%)
(-2.4, 0.2)
0.10
C3 (VEL) - C2 (Dex):
-0.04 (2%)
(-1.3, 1.3)
0.95
C4 (Dex) - C3 (VEL):
-00
0. 4(
04 2%)
(2%)
(-14
1.4, 13
1. )
3)
09
0. 5
95
C5 (VEL) - C4 (Dex):
-0.02 (2%)
(-1.5, 1.5)
0.96
C6 (Dex) - C5 (VEL):
-0.20 (11%)
(-2.1, 1.7)
0.83
VEL C1+C3+C5 - DEX C2+C4+C6
C2+C4+C6
09
0. 2(
92 51%)
(51%)
(-40
4.0, 59
5. )
9)
07
0. 1
71
60
80
A
B
70
50
60
40
in
50
in
e
e
ot
ot
-pr
-pr
30
M
40
M
rum
rum
e
e
S
S 30
20
20
10
10
0
0
C1
C2
C3
C4
C5
C6
End
C1
C2
C3
C4
C5
C6
End
50
C
40
A: response bortezomib and dexamethasone
(n=20)
ine 30
otr
B: response dexamethasone
dexamethasone
-p
M
(n=10)
m
ru 20
Se
C: response bortezomib
10
(n=3)
0
C1
C2
C3
C4
C5
C6
End
Results (VI)
Ti
Toxi i
c t
ity
100
80
60
15
60
5
(%)
40
35
Grade 3
2,5
45
20
Gra
Gr de 2
5
20
2,5
27,5
22,5
7,5
Grade 1
17,5
17,5
7,5
2,5
2,5
0
l
ia
ia
e
al
hy
in
an
u
ver
en
en
er
at
Sk
ti
g
p
p
h
p
s
ti
Li
s
a
to
te
F
y
tro
rip
ro
u
in
oc
Pe
ro
b
Ne
neu
m
ast
o
G
Thr
Results (VII)
Stem C l
e l
ll H
t
arves
CD34+ x106/Kg collected (median, range):
5.6 (1.5-17.8)
Nº apheresis (
p(median, range
g ):1 (1-3)
Results (VIII)
Response after HDT (+3 months)
ORR: 94%
6%
6%
6%
33%
33%
22%
(
36)
n=
CR
VGPR
PR
MR
Progression
Bortezomib and dexamethasone
as up-front therapy in MM
Post-tx
Response
CR
Regimen
Nº Pat
rate (%)
(%)
CR (%)
VGPR (%)
Jagannath et al,
B±Dex
40
94
6
-
-
2005
Ht
Harousseau et l
a ,
B + Dex#
48
74
21
33
21
2006
Present series
B / Dex
40
82
12.5
33
22
#Dex 40 mg, days 1-4,9-12 for cycles 1-2, days 1-4 for cycles 3-4
Defined as negative electrophoresis
Cl
Concl
i
us ons (I)
(I)
Bortezomib alternating with dexamethasone is a highly effective
regimen as up-front therapy in patients with MM.
The M-protein decrease is slightly higher with dexamethasone
than with bortezomib, although the difference is not statistically
significant.
Chromosome 13q deletions as well as t(4;14) and t(14;16) did
not have a negative impact on response.
Our results suggest an additive rather than a synergistic effect
between bortezomib and dexamethasone.
C
l
onc
i
us ons (II)
(II)
Very low toxicity profile.
El
Exce lll
t
en stem
ll
ce ht
harves i
ting.
The results of this trial
a support a short program of
alternating bortezomib and dexamethasone as an
effective and safe induction regimen for newly
diagnosed younger myeloma patients.