Microsoft PowerPoint - MateosMaintenance15nov2011

Maintenance therapy with Bortezomib plus
Thalidomide (VT) or Bortezomib plus Prednisone
(VP) in elderly Myeloma patients included in the
GEM2005MAS65 spanish randomized trial
MV Mateos, A Oriol, J Martínez, AI Teruel, E Bengoechea, M Pérez, J López, J Díaz-Mediavilla, JM
Hernández, Y González, Joan Blade, Juan-Jose Lahuerta, and Jesús F. San Miguel
On behalf of Spanish Myeloma Group (PETHEMA/GEM)
Maintenance treatment in non-transplant setting:
Thalidomide
Median
Median
Median OS
follow-up
PFS
Reference
(months)
(months)
(months)
MPT + T vs
21.8
45.1
MP
38
Palumbo A. Blood 2008
14.5
47.6
MPT + T vs
*p=0.05
39
13
40*
Wijermans A. JCO 2010
MP
9
31
MPT + T vs
29
Waage A. Blood 2010
MP
-
20
18
33
CTDa/MP + T
Thal maintenance improves
CTD/MP
38
PFS with
Morgan G. Blood 2011
no OS advantage
Thal-IFN vs
27.7
52.6
IFN*
35
Ludwig H. Haematol 2010
13.2
51.4
*Thal/Dex vs MP as induction
1

Maintenance treatment in non-transplant setting:
Lenalidomide
Median
Median
Median OS
follow-up
PFS
Reference
(months)
(months)
(months)
MPR + R vs
31
MPR vs
21
14
NR
Palumbo A. ASH 2010
MP
13 *p<0.0001
MPR
Lenalidomide Continuous Therapy
100
MPR-R
75
MPR
(%)
50
HR 0.314
P < .001
Patients 25
Cycle 10
0 0
5
10
15
20
25
30
Time (months)
Maintenance treatment in non-transplant setting:
Bortezomib
Landmark
Median
Median
Median OS
follow-up
PFS
Analysis
Reference
52
(months)
% Reduced
(months)
Ri
(months) sk of Progression
VMPT-VT vs
*p<0.0001
VMP
NR
Palumbo A. ASH 2010
Median
GIMEMA)
32
37
maintenance
27
duration: 18 months
VMPT
VT Continuous Therapy
1.00
) 0.75
(%
ts
VMPT-VT
0.50
Patien
HR 0.48
P < 0.0001
0.25
HR 0.48, p < 0.0001
VMP
0.00
0
102
1
0
02
30
3
405
4
0
05
Time (m
( o
m nt
o hs
nt
)
hs
2

Rationale for the use of maintenance
Treatment initiation
Progression
MR
PR
VGPR/ nCR
CR
sCR
Molecular/Flow CR
Time
The objective of maintenance treatment would be to maintain the response
or to improve its quality, in order to prolong the PFS and finally, the OS.
Study design and aim
Series of 260 elderly untreated MM patients included in the GEM2005
spanish trial
Induction
Bort/Mel/Pred
Bort/Thal/Pred
vs
(6 cycles)
(VMP)
(VTP)
Bort/Thal
Bort/Pred
Bort/Thal
Bort/Pred
Maintenance
(VT)
(VP)
(VT)
(VP)
No significant differences in ORR between VMP and VTP
(80% and 81%), and CR rate (20% and 27%)
Mateos et al. Lancet Oncology 2010; 10(11): 934-41
3

Study design and aim
·
Can maintenance therapy upgrade the response rate
with a favourable toxicity profile?
·
What is the benefit in terms of PFS/OS?
Maintenance therapy (n:178)
VT (n=91)
Day
1
4
8
11
90
Bortezomib 1,3 mg/m2

Rest period
· Thalidomide, 50 mg daily up to 3 years
VP (n=87)
Day
1
4
8
11
90
Bortezomib 1,3 mg/m2

Rest period
· Prednisone, 50 mg every 48 h up to 3 years
Bortezomib was administered every 3 months up to 3 years
4

Baseline patients' characteristics (n:178)
VT
VP
(n:91)
(n:87)
Male, %
53
47
Mean (Median) Age, yr
71 (66-82)
72 (65-84)
Age 75 yr (%)
32
36
IgG / IgA / light chain, %
62 / 28 / 9
55 / 32 / 12
ISS stage I / II / III, %
30 / 41 / 29
28 / 41 / 30
Beta2microglobulin
mean,
3.7 mg/dL
3.8mg/dL
Induction group
VMP, %
52%
51%
VTP, %
48%
49%
High-risk [t(4;14), t(14;16), del 17p]
cytogenetic by FISH, (%)
17%
15%
No significant differences
Efficacy: Response rate to maintenance therapy
(n=178)
After a median of 20 months of maintenance therapy (1-36)
CR (IF-) increased from 24% (after induction) up to 42% (maintenance)
Pre-
VT
VP
maintenance
(n: 91)
(n:87)
IF-CR
24 %
46 %
39 %
IF+CR, %
10 %
10 %
11 %
PR, %
47 %
39 %
47 %
MR, %
8 %3 %1 %
SD, %
10 %
1 %
1 %
Not significant differences between VT/VP
5

Efficacy: Response rate to maintenance therapy
(n=178)
After a median of 20 months of maintenance therapy (1-36)
CR (IF-) increased from 24% (after induction) up to 42% (maintenance)
Pre-
VT
VP
maintenance
(n: 91)
(n:87)
IF-CR
24 %
46 %
39 %
IF+CR, %
10 %
10 %
11 %
PR, %
47 %
39 %
47 %
MR, %
8 %3 %1 %
SD, %
10 %
1 %
1 %
Not significant differences between VT/VP
Efficacy: Response rate to maintenance therapy by
induction arm (n=178)
VT
VP
(n: 91)
(n:87)
VMP (n:47)
VTP(n:44)
VMP(n:44)
VTP(n:43)
IF-CR
38%
53%
41%
37%
53%
58%
50%
49%
IF+CR
15%
5%
11%
11%
PR
40%
37%
45%
49%
MR
4%
2%
2%
-
SD
-2%
-
2%
Not significant differences
Median time to improvement of response: 2 months (1-31)
6

VP vs VT: Toxicity profile (AEs) (n:178)
VT (n:91)
VP (n:87)
Hematologic
toxicity, n(%)
Grade 1-2 Grade 3-4 Grade 1-2
Grade 3-4
Anemia
-
-
1(1%)
-
Thrombocytopenia
2 (2%)
-
-
-
Neutropenia
3 (3%)
1 (1%)
-
-
VP vs VT: Toxicity profile (AEs) (n:178)
VT (n:91)
VP (n:87)
Non-Hematologic
Grade 3-4
Grade 3-4
toxicity, n(%)
Astenia
2 (2%)
-
Skin Rash
-
-
G-I symptoms
4 (4%)
1 (1%)
Infections
-
-
Thrombotic events
-
-
PN
9 (9%)**
3 (3%)**
-Emergent PN
1pt
-
-Worsened PN
8pts
3pts
Cardiac events*
2 (2%)
1 (1%)
*Cardiac events: Tachycardia (1), Hearth atack (2)
7

VP vs VT: Toxicity profile (n:178)
VT (n:91)
VP (n:87)
Discontinuations,n (%)
52 (57%)
51 (59%)
Disease Progression
32 (35%)
40(46%)
Toxicity
12* (13%)
8* (9%)
Others
6 (7%)
2(3%)
- SPM*
3pts
1pt
Discontinuations due to toxicity: Peripheral neuropathy and cardiac toxicity
SPM: Second primary malignancies
VP vs VT: Toxicity profile (n:178)
VT (n:91)
VP (n:87)
Discontinuations, n(%)
52 (57%)
51 (59%)
Disease Progression
32 (35%)
40(46%)
Toxicity
12* (13%)
8* (9%)
Others
6 (7%)
2(3%)
-SMP
3pts
1pt
Deaths, n(%)
24 (26%)
30 (35%)
Disease Progression
19 (20%)
26(30%)
Toxicity
5 (6%)
4 (5%)
Discontinuations due to toxicity: Peripheral neuropathy and cardiac toxicity
8

PFS according to maintenance arm (n: 178 pts)
Median follow-up: 46 m (17-67)
PFS
1.0
0.8
VT: 39 m
pts
of
0.6
0.4
VP: 32m
Proportion
0.2
p=0.1
0.0
0
10
20
30
40
50
60
Time in months from 1st randomization
PFS was not influenced by the previous induction regimen: VMP/VTP
OS according to maintenance arm (n: 178 pts)
Median follow-up: 46 m (17-67)
OS
1.0
VT: Not reached
5-y OS: 69%
0.8
pts
of
0.6
VP: 60m
0.4
Proportion
0.2
p=0.1
0.0
0
10
20
30
40
50
60
Time in months from 1st randomization
9

OS according to maintenance therapy
by induction arm (n: 178 pts)
Median follow-up: 46 m (17-67)
VT
VP
1.0
1.0
VMP->VT
VMP->VP
0.8
0.8
pts
of 0.6
VTP->VT
0.6
VTP->VP
0.4
0.4
Proportion
0.2
0.2
0.0
0.0
0
10
20
30
40
50
60
10
20
30
40
50
60
Time in months from 1st randomization
Time in months from 1st randomization
Efficacy according to cytogenetic abnormalities by
FISH after maintenance (n:139)
t (4;14) ±
Standard-risk
High-risk
t (14;16) ±
(n:111)
(n:28, 20%)
del(17p)
IF-CR
45%
40%
IF+CR
13%
11%
PR
38%
50%
Not significant differences between VT/VP as maintenance regimen
10

Outcome according to cytogenetic abnormalities:
influence of maintenance
Median follow-up: 46 m (17-67)
PFS
OS
1.0
Standard risk: 39m
1.0
Standard risk: NR
0.8
0.8
0.6
p=0.01
0.6
p=0.002
0.4
High risk: 26m
0.4
High risk: 50m
0.2
0.2
HR: 1.8, 95% IC: 1.1-2.9
HR: 2.7, 95% IC: 1.4-5.1
0.0
0.0
0
5
10
15
20
25
30
35
40
45
50
0
10
20
30
40
50
60
Time in months
Not significant differences between VT/VP as maintenance regimen
Conclusions
· Maintenance therapy with VT or VP improved the ORR and CR rate
after soft induction therapy
· No significant differences were observed between both maintenance
arms, with a trend to better outcome for VT
· Toxicity profile was acceptable, slightly higher for VT arm
· Both maintenance regimens don't overcome the poor prognosis of
high-risk CA
· These bortezomib-based maintenance regimens represent an
attractive platform for further optimization
11

Acknowledgments
Investigators including cases in trials of the Spanish
Myeloma Group, and most of all, the patients!
12