Frontline treatm
treat ent in patients
not eligible for
f
stem cell
transpla
antation
Thierry FACON
F
Lille
Lill U i
n vers
i
ity
i
H
Hi
osp
H
i
osp ta
i l,
l France
F
Dexamethasone-based regimens versus melphalan-prednisone for
elderly multiple myeloma patients ineligible for high-dose therapy
T.Facon et al. Blood 2006,107,1292-98
1.0
1.0
08
0.8
08
0.8
0.6
0.6
0.4
Proportion
Proportion
0.4
0.2
0.2
0.0
0.0
0
12 24 36 48 60 72 84 96 108
0
12243648
60728496
Time from inclusion (month)
Time from inclusion (month)
Progression-free
Tr
T eatment
O/N
Survival time
tim
Tr
T eatment
O/N
survival time
tim
median±se (month)
median±se (month)
MP
106/122
34.0 ± 3.6
MP
120/122
21.1 ± 1.7
M + DEX
97/118
39.6 ± 3.1
M + DEX
112/118
22.9 ± 2.0
DEX
110/127
33.4 ± 2.0
DEX
123/127
12.2 ± 1.0
DEX + IFN
102/121
32.0 ± 5.3
DEX + IFN
118/121
1
15 2
. ± 27
2.7
MP vs MPT in Newly Diagnosed
Myeloma Patients, Aged 60
60--85
85 Years
GIME
GIM MA Tr
T ial Design
Previously
Standard MP
6 cours
untreated
u
patients
es
s
at 44--week
week intervals
Primary
1
with MM
endp
end oint
p
:
Median age, 72
response
years
and EFS
1
MPT Arm
(N = 255)
()
MP + Thal aat 100 mg/day,
mg/day continuously
Palumbo A et al. Lancet 2006; 367:825-831.
MPT vs MP in Elderly Patients with Multiple Myeloma:
Event
Event--Free
Free Survival and Overall Survival
MP vs MPT vs Mel 100 in Newly Diagnosed
Myeloma Patients
Patients, Aged 65 75
-
Years
IFM 99-06 Trial Design
Standard MP
12 coursees at 6-
6 week intervals
Newly
3
diagnosed MM
MPT Arm
patients; age
age
Primary
2
MP + Th
T al
h at MTD but 400
65-75 years
endpoint:
mg/day,
mg/day s
(N = 447)
topped
s
at end of MP
overall survival
2
Mel
M 100 x 2 Arm
VAD
V
x 2;
2 cyclophosphamide
3g
3 /
3g m
g/m2
m ;
2 Mel
M
Mel 100 mg/m2
mg/m
Facon et al. J Clin Oncol. 2006;24(18S):245. ASCO Abstract 1
MP vs MPT or Mel 100
10 in Newly Diagnosed,
Elderly,
Elderly MM
M
MM
MPat
a i
t e
i n
e ts
t
Patients*
s
1.0
PFS
MPT
1.0
OS
MP
Mel 100
0.8
0.8
0.6
0.6
portion
ortion
o 04
p
0.4
Pr
0.4
Pro
0.2
0.2
0.0
0.0
0
12
24
36
48
60
72
0
12
24
36
48
60
72
Time From Inclusion (mos)
Time From Inclusion (mos)
Treatment
PFS (mos)
P Value
OS (mos)
P Value
CR
> 90%
> 50%
MP
17.1
32.2
2%
8%
40%
< 0.001
0.001
MPT
27.6
53.6
16%
50%
81%
Mel 100
19.4
0.001
38.6
0.004
17%
43%
73%
*Date of analysis Oct.8,2005 ; median follow-up time (± SEM) = 32.2 ± 1.8 months; P < 0.0001.
Facon et al. J Clin Oncol. 2006;24(18S):245. ASCO Abstract 1
MP vs MPT vs Mel 100 in Newly Diagnosed Myeloma Patients
IFM 99
99--06,
06, updated analysis Jan.8,2007, median FU = 51.5mo.
PFS
OS
Treatment
O/N+
PFS time
Treatment
O/N+
OS time
median ± se
median ± se
(month)
(month)
MP
171/196
17.8 ± 1.4
MP
128/196
33.2 ± 3.2
MP-T
92/125
27.5 ± 2.1
MP-T
62/125
51.6 ± 4.5
MEL100
110/126
19.4 ± 1.0
MEL100
78/126
38.3 ± 2.7
ts
patien
1
1
MP-T vs MP, P<0.0001
MP-T vs MP, P=0.0006
iving 0.8
MP-T vs MEL100, P<0.0002
0.8
MP-T vs MEL100, P=0.02
surv
atients
e
p
0.6
ing 0.6
iv
on-fre
surv
0.4
0.4
of
rogressi
n
p
o
0.2
0.2
of
Proporti
0
0
0
1224
3648
6072
0
12
24
36
4860
7284
Proportion
Time from randomization (month)
Time from randomization (month)
O/N+: number of progressions or deaths / number of patients at randomization
MP vs MPT in Newly
e
Diagnosed
Myeloma Patients
Patientss,
s Aged
Aged >75
>
>75 Years
IFM 01
01 01
-
Tri l
a D i
es gn
MP
M + placebo
M=
M 02
=
M0.
M0 22mg/kg/d,
2mg/kg/d days 1-
1 4
12 course
cours s
e at 66--week
week intervals
Newly
1
diagnosed MM
Primary endpoint:
endpoint:
patients; age
overall survival
>75 years
1
(N = 200)
MPT Arm
MP + Thal at
a 1100
00 mg/day,
mg/day stopped
at end of MP
Hulin et al. J Clin Oncol. 2007;25(18S):441s. ASCO Abstract 8001
MPT vs MP in Elderly Patients with Multiple Myeloma:
Progression-Free Survival (PF
FS) and
and Overall Survival
S
Survival (OS)
200 Pts, Median follow
follo --up
up time = 24 months
PFS
OS
ction 1.00
1.00
n
MPT
n
MPT
ction
Median = 24.1 months
Median = 45.3 months
Fu 0.75
Fun 0.75
ribution 05
0. 0
50
bution 05
0. 0
50
Dist
MP
Distri
0.25
MP
0.25
Median = 19 months
Median = 27.7 months
urvival
rvival
S 0.00
u 0.00
S
0
10
2030
40
5060
010
20
30
40
50
60
Time from randomization (months)
Time from randomization (months)
Log-Rank test p=0.001
Log-Rank test p=0.05
Conclusions / MP
MP--T
T
·
Three randomized studies (IFM 99-06, IFM 01-01, and GIMEMA) show the
superiority of MP-T in the treatment of newly diagnosed elderly patients
with MM
·
The superiority of MP-T over MP was demonstrated based on
response,including
including CR rate, and PFS
PFS
S in
in all
all studies
·
In the IFM studies, the PFS advantage observed with MP-T translated into a
OS advantage.
g MP-T was also found to be superior
p
to MEL100 in the IFM
99-06 study
·
MP-T toxicity was acceptable but higher than the MP toxicity
·
MP-T could be the reference treatment for all newly diagnosed MM patients
ineligible for HDT
MP
MP--V: resp
res onse rates
Response after
Best response
1 cycle of MP-V
median 7 cycles (29)
70% ORR
89% ORR
70%
62 %
70%
60%
60%
50%
50%
43% CR + nCR
45%
40%
40%
32%
30%
24 %
30%
20%
20%
11%
11%
10%
6%
6%
10%
2%
0%
0%
C R IF - C R IF +
P R
M R
S D
CR I F - C R I F +
P R
S D
Mateos et al. Blood 2006;108:216572
MP
MP--V:
V Efficacy in terms of survival
Ti
T me to Progression
Overall survival
1,0
1,0
MP-V: 85%
Median MP-
MP V:
V: 272m
27.2 m
0,8
0,8
P=0.001
P=0.0001
0,6
0,6
0,4
Median MP: 20 m
0,4
MP: 49%
0,2
0,2
0,0
0,0
0
5
10
15
20
25
30
35
0
10
20
30
40
Median follow-up: 26 months (1538)
Mateos et al. EHA 2007 (abstract 404)
Conclusions / MP-V
High efficacy of MP-V:
- 43% CR/nCR (32% CR IF-)
- Response is not influenced by cytogenetic abnormalities
Survival:
- Md
Me i
dian PFS
PFS = 27
27 mo.
- Longer PFS and OS as compared to historical MP controls
- Neither age
age nor cytogenetics abnorrmalities influenced
influenced TTP
Toxicity:
- Higher in >75 y
- Significantly decreased after the third cycle
Formed the
the basis for
for the international
international ra
raandomized phase 3 VISTA
VIST study
Mateos et al. EHA 2007 (abstract 404)
MP plus Lenalidomide in
i newly diagnosed MM
Patients
- N=54
- Median age 71
71 (57
(57 77)
- 13q-: 38%
Treatment
- Induction therapy: Mel 0.180.25 mg/kg
Prednisone 2 mg/kg,
Lenalid
domide 5-
5 10 mg/day
Nine 46-week cycles
- Maintenance therapy: Lenalidomide 10 mg/day
Results
- MTD: Mel
Mel 0.18
18 mg/kg
mg/kg + Le
Leenalidomide 10
10 mg/day
mg/day
- Responses data (n=21)
Palumbo et al. EHA2007 (abstract 402)
Response MP
P--R
R vs MP
MP--T
T
MP
MP--R
R
70
70
MP
MP--T
T
Cohort 3 (0.18
(0.18--10)
10)
Best Response
Bt
Best Response
129*
n=
60
60
n=21
50
50
48%
37%
40
40
40
33
patients
patients
30
pfp
30
of
24
24
of
%
19
%o%
21
20
20
16
10
8
10
55
00
0
0
C R
VG PR
PR
M R
SD
PD
C R
VG PR
PR
M R
SD
PD
*Historical control Palumbo
Palumbo et al, Lancet 2006
5.4% of response not available
Conclusions / MP-R
High efficacy of MP-R
- 24% CR,
-48% CR+VGPR
-No PD
Survival
- EFS = 75% at 2 years
- OS 100% at 1 year, 91% at 2 years
- EFS is not influenced by cytogenetic abnormalities
To
T xicity
o
- Early deaths 0%
- Grade 3-4 Toxicity
Neutropenia
52.4%
Thromb
bocytopenia 23.8%
Anemia
4.8%
Cutaneous Toxicity 9.5%
Infectio
ons
9.5%
Formed the basis for the international randomized phase 3 CELGENE
MM015 study
Palumbo et al. EHA2007 (abstract 402)
MP + novel agen
e ts: study results
MP
MP--T
T
MP
M --T
T
MP
MP--R
R
MP
MP--V
V
(n=124)
(n=129)
(n=21 [MTD])
[MTD])
(n=60)
Facon et al.
Palumbo et al.
Palumbo et al.
Mateos et al.
Age (%, >75 years)
0
25%
6%
47%
Efficacy
CR + PR
76%
76%
81%
88%
CR
13%
16%
24%
32%
EFS
28m
54% at 24m
75% at 24m
27m
Palumbo et al. Lancet 2006; 367:82531
Palumbo et al. EHA2007 (abstract 402)
Facon et al. ASCO 2006 (abstract 1) Updated
Mateos et al. EHA 2007 (abstract 404)
MP + novel agents / Toxicity
Toxicit
MP-T
MP
P-T
MP-R
MP-V
(n=124)
(n=129)
(n=53)
(n=60)
Facon et al.
Palumbo et al.
Palumbo et al.
Mateos et al.
Toxicity (grade 3/4, %)
Infections
17
1011
16
Neutropenia
41
22
67
43
DVT
12
125
0
Neuropathy
6
8
0
17
Palumbo et al. Lancet 2006;367:82531
Palumbo et al. ASH 2006 (abstract 800)
Facon et al. ASCO 2006 (abstract 1)
Mateos et al. Blood 2006;108:216572
Lenalidomide plus high
high--do
d se
o
Dexamethasone versus
Lenalidomide plus low
low--dose
dose Dex
De amethasone
x
in newly diagnosed
patients
p
m
myeloma
myy
Rajkumar et al. Blood 2006 (abs.799)
b
& JCO 2007 (abs.8025)
ECOG E
E4A03 Trial
Trial Design
Rev.
Rev + high
high--dose
dose Dex
x 4 cycles (cycle length : 28 d)
Rev.
Rev 25
2 mg/d, days 11--21
21
Dex. 40 mg/d,
g
days 11--4,
4, 99--12,
12, 17
17--20
20
Newly
1
diagnosed MM
Primary objective:
patients
response rate and
(N = 445)
1
toxicity
Rev.
Rev + low
low--dose
dose Dex
x 4 cycles
Rev.
Rev 25
2 mg/d, days 11--21
21
Dex. 40 mg/d,
m
days 1, 8, 15, 22
Thalidomide plus dexamethasone salvage therapy for non-responders
One year
-
Survival R
Rate,
Rate Age 65 years
N
Events
Survival Probability
(95%CI)
Len-High Dex
119
18
0.83
(0.76, 0.90)
Len-Low Dex
114
6
0.94
(0 89
. , 0 99)
.
Overall Survival (m
(months)
onths :
) Age
g
)g 65
Rd
RD
One
One--year
year Survival rate in Newly Diagnosed MM Trials / elderly pts
1-yr
Study
Age
Phase
N
Regimen
Survival
Ref
rate
Palumbo
Median=72
III
124
MP-T
87%~
Lancet 06
E4A03 Arm A
> 65
III
119
Len + high-dose dex
83%
ASCO 2007
Facon
Median=70
III
129
MP-T
87.5%
ASCO 2006
Mateos
Median=74
I/II
60
MP-V
87%~
EHA 2007
E4A03 Arm B
> 65
III
114
Len + high-dose dex
94%
ASCO 2007
Palumbo
Median=71
I/II
21
MP-R
100%
EHA 2007
MPT vs Revlimid
Revlimid--low
low dose Dexamethasone in Newly
Diagnosed Myeloma Pa
P
Paatients, Aged
A
Aged >65 Years
Phase III international study
IFM 20007-01 Tri l
a D i
es gn
MPT Arm (reference)
9 cycles MP + Thal at
at 200
2
mg/day,
mg/day
stopped at end of MP
Newly
1
diagnosed MM
Rev + low-dose Dex.
patients; age
Rev 25mg/day, days 1-21; Dex 40 mg/day,
Primary
1
>65 years
days 1,8, 15, 22
endpoint:
(N = 1500)
12 cycles at 4-week interval
PFS
1
Rev + low-dose Dex.
same schedule as above
with Rev. until progression
Conclu
Concl sions
· Novel agents are changing the scenario in elderly
· MP-T
- has
has been shown to
to be
be su
superior over MP and MEL100
MEL100
· Initial results suggest a high efficacy for MP-V, MP-R, and Rev.
low-
low dose
-
Dex
Dex
· Response rates with novel agents in elderly patients are
comparable to previous outcom
mes with ASCT
ASCT in
in younger
younger
patients
· Open questions
- How to reduce toxicity
- Prognostic factors (cytogenetics)
- How to
to delay
delay relapse
Need for new first
first--lin
line regimens for elderly
ti
pa en
ti
ts
t wit
iitth myeloma
l
·
Autologous transplant has become the standard of care for young MM
ti
pa
t
en s
·
More than 50% of all patients with MM will not receive a transplant
Almost half of MM patients are
e aged
aged >70
>70 years
Some young patients are not transplant candidates due to co-
morbidities
·
Melphalan and prednisone combination
Response rate: 4060%, CR rare, PFS: 18m, OS: 3 years
There is an urgent need for more active therapies for elderly patients
Reece Hematology (Am Soc Hematol Educ Program) 2005:3539
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