Multicenter, Randomized Trial in Newly Diagnosed
yg
Multiple Myeloma Patients Older than 65 years
(GEM05>65)
MV Mateos, A Oriol, J Martínez, MT Cibeira, R de Paz, MJ Terol, J García-Laraña,
E Bengoechea, R Martínez, A Martín, F de Arriba, L Palomera, JM Hernández,
JL Bello, ML Martín, Y González, JJ Lahuerta, J Bladé, JF San Miguel.
On behalf of Spanish Myeloma G(
Group (PETHEMA/G
/GEM)
Novel based-agents combinations for elderly MM patients
TTP
Study
Regimen
N
CR (IF-)
Overall Survival
PFS/EFS
Palumbo
MPT (T maint.)
129
16%
21.8m
NS (45m vs 47 6m
.
(Blood 2008)
MP (no maint.)
126
4%
14.5m
P=0.79)
Facon
MPT (72 weeks)
125
13%
27.5m
51.6m vs 33.2m
(Lancet 2007)
MP (72 weeks)
196
2%
17.8m
HR = 0.59, P=0.0006
Hulin
MPT (72 weeks)
113
7%
24.1m
45.3m vs 27.7m
(JCO 2009)
MP (72 weeks)
116
1%
19m
HR n/a, P=0.03
Wijermans
MPT (T maint.)
165
2%
13m
NS (37m vs 30m
(ASH 2008)
MP (no maint.)
maint.)
168
2%
10m
P=
P 0.16)
Gulbrandsen
MPT (T maint.)
363
6%
20m
NS (29m vs 33m
(EHA 2007)
MP (no maint.)
3%
18m
P=0.46)
Palumbo
LenMP (Phase I/II)
54
24%
1-y EFS: 92%
1-y OS: 100%
(JCO 2007)
Rajkumar
RD
445
13%
19m
1-y OS: 83% vs 94%
(Lancet Onc
Rd
10%
25m
In elderly patients
2009)
VMP (54 weeks)
344
30%
24.0m
NR vs 43 months
San Miguel
MP (54 weeks)
338
4%
16.6m
HR 0.653
(ASH 2009)
P=0.0008
(GEM05>65)
Rationale and key question
Phase I/II study: Bortezomib plus MP (VMP)
89% PR with 32% CR rate1
Median progression free survival (PFS) was 25 months2
Median OS was 50
50 months
months (vvs 29 months for historical
historical MP)
MP)
VMP was well tolerated: G3-4 Peripheral Neuropathy: 17%1,2
1Mateos et al. Blood 2006;108:2165-72; 2Mateos et al. Haematologica 2008;93:560-5.
Can we
we maintain the eff
ef ic
fic
cacy and reduce the
the toxicity
with a less intensive Bortezomib-based approach?
(GEM05>65)
Multicenter, Two-stage Randomized Trial in Newly
Diagnosed MM Patients Older than 65 Years
Bort/Mel/Pred
Bort/Thal/Pred
vs
Induction
(VMP)
(VTP)
Bort/Thal
Bort/Pred
Bort/Thal
Bort/Pred
Maintenance
(VT)
(VP)
(VT)
(VP)
(GEM05>65)
Primary Objectives
Induction
- Which is the best partner for bortezomib in induction: an
alkylating agent or an immunomodulator drug (VMP vs VTP) ?
To
To detect a difference of
of 15% in ORR (7
70%
70%
85%) and/or CR rate (20%
(20%
35%)
Maintenance
- Can we increase the depth of the response rate with a
favourable toxicity profile ?
To increase the CR rate by 15% (20-35%35-40%)
Sample size: 260 patients, using a significance level of 0,05 and a power of 80%
(GEM05>65)
Secondary Objectives
How do these results translate in terms of PFS/OS?
Can these combinations overcome the adverse
prognosis of high-
high risk cyto
ogenetic abnormalities?
abnormalities?
All data were monitored by an external CRO
(GEM05>65)
1st objective
To compare two induction regimens (VMP and VTP)
Which is the best partner for Bortezomib during the
induction therapy: an alkylating agent or an
immunomod
dulatory drug?
drug?
(GEM05>65)
Induction A: VMP (n:130)
· One-6k
6 weeks
l
cyc e
Day
1 2 3 4
8
11
22
25
29
32
3342
Bortezomib 1 3
. mg/m2
mg/m
R
est
Melphalan 9 mg/m2
peri
Prednisone 60 mg/m2
od
· Five-5 weeks cycles
Day
1 2 3 4
8
15
22 2335 Re
Bortezomib 1,3 mg/m2
st
Melphalan 9 mg/m2
period
Prednisone 60 mg/m2
31 weeks
(GEM05>65)
Induction B: VTP (n:130)
One-
One 6 weeks
weeks cycle
Day
1 2 3 4
8
11
15
22
25
29
32
3342
Bt
Bortezomib
ib 1 3
.
/ 2
mg/m
Rt
Rest period
Thalidomide
50 mg
100 mg
Prednisone 60 mg/m2
g
Five-5 weeks cycles
Day
1 2 3 4
8
15
22 2335
Bortezomib 1.3 mg/m2
Thalidomide
100 mg
Prednisone 60 mg/m2
31 weeks
Baseline patients' characteristics (n:260) (GEM05>65)
VMP
VTP
(n:130)
(n:130)
Male, %
53
47
Mean (Median) Age, yr
73 (65-83)
73 (65-86)
Age 75 yr (%)
32
36
IgG / IgA / light chain, %
62 / 28 / 9
55 / 32 / 12
ISS stage I / II / III, %
30 / 40 / 30
19 / 43 / 37
Beta2microglobulin
<2.5 / 2.5-5,5 / >5.5, %
22 / 49 / 29
13 / 53 / 34
Albumin < 3 5
. g/dL
g/dL, % (median)
43
52
PCsBM infiltration >35%, (%)
40
46
High-risk [t(4;14), t(14;16), del 17p]
Cytogenetic by FISH, (%)
14
7
No significant differences
(GEM05>65)
Efficacy: Response rate after induction therapy
(ITT
(
analy
anal sis
y
(y
in
i 260 patients
p
)
atients
p)
ORR: 80% vs 81%
60%
48%
50%
VMP
46%
VTP
40%
30%
27%
20%
20%
12%
10%
11%
10%
10%
8%
6%
0%
CRIF-
CRIF+
PRMRSD
Only 2 pts
yp
in each arm pro
p
gressed
g
during induction
*EBMT criteria
· Responses to VMP/VTP were rapid: Median time to achieve first response: 1.6 m
· Prolonged therapy improves the quality of response: Median time to achieve CR: VMP: 4.4 / VTP: 4.9 m
(GEM05>65)
VMP vs VTP: Toxicity profile (G3-4 AEs) (n:260)
VMP (n:130)
VTP (n:130)
Hematologic toxicity
- Anemia
15 (11%)
10 (8%)
pNS
- Neutropenia
51 (39%)
29 (22%)
p=0,008
- Th
b
rom
t
ocy
i
open a
35 (27%)
16 (12%)
p=0 0001
,
Non-hematologic toxicity
- GI toxicities
9 (7%)
()
2 (2%)
()
pN
p S
-PN
9 (5%)
12 (9%)
pNS
- Infections
9 (7%)
1 (<1%)
p=0,01
- DVT/Thromboembolism
1(<1%)
3 (2%)
pNS
- Cardiologic events*
-11 (8%)
p=0,001
Pts discontinuing due to SAEs, n (%)
(%)
15 (11%)
(1
22 (17%)
p=0 0
, 3
03
Deaths, n (%)
7* (5%)
7** (5%)
p NS
*5/7 in VMP: infections
**5/7 in VTP: cardiac complications
Safety profile: VMP vs VTP (n:260)
VMP (n:130)
VTP (n:130)
Related-
Related SAEs, n(
n %)
(%)
200 (15%)
(15%)
40 (30%)
p=00
p0, 1
01
Pts discontinuing due to SAEs, n (%)
15 (11%)
22 (17%)
p=0,03
Deaths, n (%)
7* (5%)
7** (5%)
p NS
Conclusions (I)
· Both induction regimens,
g, VMP and VTP resulted in similar efficacy in
terms of ORR (80 and 81%) and IF-CR rate (20% and 27%)
· VMP resulted in higher incidence of G3-4 infections that led to
discontinuation
or
death;
therefore
prophylactic
antibiotics
should be considered. The incidence of PN was 5%
· VTP resulted in higher incidence of SAEs that led to discontinuation
or deaths (cardiac events)
(GEM05>65)
2nd objective
To improve the response rate (CR) by the use of
maintenance therapy (VT or VP)
Expectation:
Expectation - by 15% in CR
R rate (20-35%
% 35-40%)
%
- Not increase o
of the toxicity
- VT > VP
(GEM05>65)
(GEM05>65)
Multicenter, Two-stage Randomized Trial in Newly
Diagnosed MM Patients Older than 65 Years
Bort/Mel/Pred
Bort/Thal/Pred
vs
Induction
(VMP)
(VTP)
Bort/Thal
Bort/Pred
Bort/Thal
Bort/Pred
Maintenance
(VT)
(VP)
(VT)
(VP)
VT
(GEM05>65)
(n=91)
Day
1
4
8
11
90
Bortezomib 1,3 mg/m2
mg/m
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
(GEM05>65)
Efficacy: Response rate to maintenance therapy (n=178)
CR (IF-) increased from 23% (after induction) up to 42% (maintenance)
CR/nCR: 59% vs 55%
60%
VT =91
50%
44%
44%
39%
39%
VP=87
40%
30%
20%
15%16%
10%
2% 1%
0%
CRIF-
CRIF+
PR
MR
*EBMT criteria
(GEM05>65)
VP vs VT: Toxicity profile (AEs) (n:178)
VP (n:87)
VT (n:91)
Hematologic toxicity (G1-2)
- Anemia
2 (2%)
2 (2%)
- Neutropenia
1 (1%)
3 (3%)
- Thrombocytopenia
1(
1 1%)
(1%)
1(
1 1%)
(1%)
Non-hematologic toxicity (G3-4)
- GI toxicities
1 (1%)
4 (4%)
-PN
2 (2%)
5 (5%)
- Infections
1 (1%)
2 (2%)
-DVT/Thromboembolism
-
1(1%)
- Cardiologic events*
1 (1%)
2 (2%)
-Patients discontinuing due to related-AEs
4+ (5%)
7++ (7%)
-Deaths
1 (1%)
1 (1%)
Conclusions (II)
· Both maintenance regimens, VT and VP were able to
increase
the
CR
rate,
without significant differences
between both arms
· Acceptable toxicity profile
(GEM05>65)
(GEM05>65)
3th
3
bj
o ective
How do
do these
these results tr
trranslate in
in terms
terms of
of time
to events data?
(GEM05>65)
Overall TTP/PFS/OS on ITT analysis (whole series)
Median follow-up: 24 m (12-43)
TTP
P
PFS
OS
1,0
1,0
1,0
0,8
0,8
0,8
0,6
0,6
0,6
0,4
0,4
0,4
3y
3 -
y TTP: 53%
Median PFS: 33 m
3y
3 -
y OS: 75%
0,2
0,2
0,2
0,0
0,0
0,0
0
5
10 15 20 25 30 35 40 45
0
5
10 15 20 25 30 35 40 45
0
5
10 15 20 25 30 35 40 4
Influence of induction regimens: VMP vs VTP (GEM05>65)
Survival from 1st randomization
Median follow-up: 24 m (12-43)
PFS
1,0
1,0
OS
08
0,8
0,8
0,6
0,6
0,4
0,4
VMP: 34 months
VMP: 3-
3 y OS:
OS: 80%
0,2
VTP: 23 months
0,2
VTP: 3-y OS: 64%
HR: 1.3; p=0.1
HR: 1.4; p=0.1
0,0
0,0
,
0
5
10
15
20
25
30
35
40
45
0
5
10
15
20
25
30
35
40
45
Influence of maintenance therapy: VT vs VP (GEM05>65)
Survival from 2nd randomization
Median follow-up: 15 m (3-34)
PFS
OS
1,0
1,0
0,8
0,8
0,6
0,6
0,4
0,4
VT: median not reached
VT: 2-y OS: 86%
0,2
VP: 23 months
0,2
VP: 2-y OS: 81%
HR: 1.7; p=0.05
HR: 1.1; p=0.7
0,0
0,0
0
5
10
15
20
25
30
35
0
5
10
15
20
25
30
35
(GEM05>65)
Patients receiving VMP/VTP as induction stratified
according to
to maintenance
maintenance treatment (VT vs VP)
VP
VMP
VTP
PFS
PFS
1,0
1,0
08
0,8
0,8
0,6
0,6
0,4
0,4
VT:
VT median
median not reached
VT:
VT median
median not reached
0,2
VP: 32 months
0,2
VP: 26,5 months
HR: 1.7; p=0.1
HR: 1.7; p=0.1
00
0,0
0,0
5
10
15
20
25
30
35
40
5
10
15
20
25
30
35
40
(GEM05>65)
Outcome of the four different cohorts (n: 178)
1,0
PFS
1,0
OS
0,8
Treat Group
0,8
VMP-VT
0,6
VMP-V
VP
06
0,6
VTP-VT
0,4
VTP-VP
0,4
VMP+VT: NR
VMP+VT: 88% at 2y
0,2
VMP+VP: 32 m
VTP+VP vs
0,2
VMP+VP: 88% at 2y
VTP+VT : NR
VMP+VT
HR 1.6, p=0.008
VTP+VT : 84% at 2y
VTP+VP :26.5 m
VTP+VP : 81% at
at 2y
2y
0,0
0,0
5
10
15
20
25
30
35
40
45
0
5
10
15
20
25
30
35
40
45
Cox regression analysis of PFS and OS with inverse probability weighting (p=0.8 for the
interaction term)
(GEM05>65)
4th
4
bj
o ective
Influence of
of high-
high risk cyttogenetic abnormalities
(VMP or VTP followed by VT or VP)
(GEM05>65)
Efficacy in high-risk cytogenetic abnormalities
Responses after induction therapy (VMP&VTP)
IF-CR
R
IF+CR
PR
Standard risk cytogenetic by FISH
(n=231)
()
23%
11%
48%
High-risk cytogenetic by FISH
(n=27)
29%
4%
41%
[t(4;14), t(14;16), del 17p]
Responses after maintenance therapy (VT&VP)
IF-
IF CR
R
IF+CR
PR
Standard risk cytogenetic by FISH
(n=157)
42%
17%
40%
High-risk cytogenetic by FISH
(n=21)
38%
5%
52%
[t(4;14), t(14;16), del 17p]
(GEM05>65)
Efficacy in high-risk cytogenetic abnormalities
F1
From 1st
d
ran
i
om
t
za ition
F2
From 2 d
n
d
ran
i
om
t
za ition
1,0
PFS
1,0
PFS
0,8
08
0,8
0,6
0,6
0,4
0,4
0,2
Standard risk: 55% at 2 y
0,2
Standard risk: 61% at 2 y
High-risk: 58% at 2 y
High-risk: 58% at 2 y
0,0
0,0
0
5 10 15 20 25 30 35 40 45 50
0
5
10
15
20
25
30
35
40
OS
1,0
OS
1,0
0,8
0,8
0,6
0,6
0,4
0,4
Standard risk: 77% at 2 y
0,2
0,2
Standard risk: 84% at 2 y
High-risk: 74% at 2 y
High-risk: 82% at 2 y
0,0
0,0
0
5
10 15 20 25 30 35 40 45 50
0
5
10
15
20
25
30
35
40
(GEM05>65)
Can novel agents inducce immunophenotypic
remissions?
Conventional
chemotherapy
followed
by
ASCT
induces
immunophenotypic
remissions
which
were
associatted
with
prolonged overall survival
Paiva B et al. Blood 2008;112 (10):4017-23
Survival according to MRD by Immunophenotyping in BM after
induction therapy (n=153)
TTP
OS
MRD negative (n=34)
100
100
Median: NR
MRD negative (n=34, 22%)
80
80
MRD positive (n= 119)
Median: NR
60
60
40
MRD positive
40
(n= 119)
Median: 31m
20
20
P < .001
P = .07
0
0
0
10
20
30
40
50
0
10
20
30
40
50
Months
Months
Impact on survival of the depth of response after induction
therapy (n=153)
Immunophenotypic
CR (IFx negative) (n=23)
nCR + PR (n=82)
< PR (n=15)
remii
ission (
33)
n=
TTP
OS
100
100
Median: NR
Median: NR
80
80
Median: NR
Median: NR
Median
60
: NR
60
Median: 33m
40
40
Median: 21m
20
20
P < .001
P = .27
0
0
0
10
20
30
40
50
0
10
20
30
40
50
Months
Months
(GEM05>65)
Conclusions
· Alkylating agents should remain as important drugs in the treatment
armamenti
tarium of elderlyuntt
treated eld
dl
derly MM patients
· The weekly shedule of Bort significantly reduced the incidence of PN
· Maintenance therapy wasableto increase the CR rate with a low toxicity
profile. VT was s
i
uper or in terms of TTE
Et
Events. Len shl
hou d
ld beex ld
plored
· The combination of VMP followed by V
VT is significantly superior to VTP/VP
·These novel Bort-based schemes appear to overcome the poor prognosis of
high-risk cytogenetic abnormalities
Acknowledgments
Investigators including patients in the Spanish Myeloma Group's
trials, and most of all, the patients!