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Current and future IFM trials
Michel Attal
For the IFM

Young patients

IFM-99: impact of overall response
after high-
high dose therrapy on EFS and OS
EFS
4-year OS
< PR: median 24 months
PR:
median 32 months
1.00
VGPR: median 36 months
1.00
CR:
median 42 months
ction
function
0.75
0.75
fun
utionb 05
0. 0
50
stribution
05
0. 0
50
p = 0.0003
di
distri
< PR: 65%
ival
0.25
p = 8 × 10-6
urvival
0.25
PR:
67%
S
PR:
VGPR: 76%
Surv
CR:
80%
0
0
0
500
1,000
1,500
2,000
0
500
1,000
1,500
2,000
Time (days)
Time (days)
Harousseau J-L, et al. Blood. 2006;108 [abstract 3077].

Current and Future IFM trials
·Current trials: New drugs in the HD strategy ?
Id
Ind
t
uc i
tion:
IFM 2005
2005--01
01
IFM 2007
200 -02
Conditioning regimen:
Pilot IFM 2007
Consolidation:
Pilot IFM 2008
Maintenance:
IFM 2005
2005--02
02
·Future trial: HDT in the era of New drugs?
IFM 2009

IFM 2005-01: Study Design
Primary analysis: post-induction response in VAD (A1+A2) vs Vel-Dex (B1+B2)
Randomization
stratified by beta 2m (>3mg/L vs 3mg/L) and 13 del (by FISH analysis)
A1
A2
B1
B2
VAD x 4
VAD x 4
Induction
Vel-Dex x 4
Vel-Dex x 4
DCEP x 2
Consolidation
DCEP x 2
Melphalan
Melphalan
Melphalan
Melphalan
200mg/m2
200mg/m2
Transplant 1
200mg/m2
200mg/m2
+A
+ SCT
ASCT
+A
+ SCT
ASCT
+A
+ SCT
ASCT
+A
+ SCT
ASCT
Second ASCT or RIC allo if <VGPR

Response To Induction
(Evaluablee Patients)
Patients)
VAD
VA
Vel
Ve -Dex
(A1+A2)
(B1+B2)
P value
N=210
N=214
CR
1.4%
6.1%
0.0109
CR+nCR
6.7%
15.4%
0.0035
> VGPR
15.7%
39.2%
< 0.0001
> PR
65.2%
81.8%
<.0001
MR+SD
27.6%
13.1%
PD
4.3%
4.7%
Death
2.9%
0.5%
Response after review by IRC

Response to First ASCT
Analysis on Evaaluable Patients
VAD
Vel-Dex
P value
(A1+A2)
(B1+B2)
N=
N 218
N=223
CR
8.7%
16.1%
0.016
CR + nCR
nCR
18.3%
35%
<0.0001
> VGPR
37.2%
54.3%
0.0003
> PR
77.1%
80.3%
NS
MR/SD/PD
3.7%
MR/SD/PD
2.7%
No ASCT
15.6%
11.7%

PFS (2 yr median
m
f--up)
up)
Vel-Dex
VAD
Median 28 m 2- yr PFS 60 %
Median NR 2 - yr PFS 69%
Months

Conclu
usions
Vel-
Vel Dex improves post-
post inductio
on and post-
post SCT CR rates
The better CR rate post SCT is associated with a longer PFS
Vel-Dex regimen is well tolerated except a high incidence of
peripheral neuropathy (all grades = 53%; grades 2 = 33%)
@Conclusion: Vel-Dex is a new standard for induction
@Logical next question:
question cou
uld a third drug improve VD?

IFM 2007
2007--02:
02: Study Design
Primary end point: post-induction CR after Vel-Dex vs VTD
Randomization
stratified by beta 2m (>3mg/L vs 3mg/L) and 13 del (by FISH analysis)
A
B
VD x 4
Indu
VD x 4
ction
VTD x 4
Melphalan
Melphalan
200mg/m2
Transplant
200mg/m2
+A
+ SCT
ASCT
+A
+ SCT
ASCT
Activated in 2/2008 and closed in 2/2009 : 200 patients

STUDY DESIGN
Open-label, multicenter, phase II study
in de 54 de novo MM pts < 65 y
pyrs
Primary endpoint: CR + VGPR rates at 3 mo post HDT
Secondary endpo
oint: safety profile
profile
HDM
PBSC
BB
B
B
-6
-3
-2
0
+1
+4
B= Bortezom
Bortezo ib 1mg / m2
HDM= Melpha
Melph lan 200 mg / m2

RESPONSE to INDUCTION
Induction therapy was not specified in the protocol and was
made on an individual-patient basis by the treating clinician
All patients (n=54)
VAD
Bor-Dex 2 lines
(n=29) (n=18)
(n=7)
CR
2 (3%)
0%
11%
0%
VGPR
17 (31%)
21%
56%
14%
PR
48 (89%)
90%
83%
100%
SD
6 (11%)
10%
17%
0%
IMWG criteria

RESPONSE to VEL-Mel +SCT
All pts
pts
VAD
Bor-Dex
2 lines
n=53
n=28
n=18
n=7
CR
18 (34%)
36%
39%
14%
> VGPR
37 (70%)
68%
72%
71%
> PR
50 (94%)
93%
100%
86%
SD
2(
2 4%)
(4%)
7%
0
0
PD
1 (2%)
0
0
14%
IMWG criteria

STEM CELLS and ENGRAFMENT
di
me an
range
PBSC infused, CD34 x106/kg
4
1,8 - 12
ANN< 500/mm3
7 d
4 - 15
Plat <50 G/L
8 d
3 - 31
Duration of hospitalization
19 d
14 - 29
Toxic death
0

CONCLUSIONS
Bor (1mg/m2x4) and HDM regimen is:
SAFE
EFFECTIVE: 70% VGPR post HDT
But :
is Bor + HDM > HDM ?

Bor + HDM > HDM ?
In order to address this issue we performed
p
a matched
case-controlled study:
Between our cohort and patie
ents of the IFM 2005-
2005 01 trial (VAD
or Vel/dex followed by HDM +SCT)
2 patients of the IFM 2005-
2005 01 trial were matched with 1 patient
of our cohort according to:

induction therapy (VAD orr Vel-
Vel Dex)
-

response after induction (VGPR or not)

age

MATCHED CASE-CONTROL STUDY :
Baseline Characteristics (2 for control / 1 for pilot)
Control 2005-01
Pilot Vel-Mel
N=92
N= 46
Age, median
57 y
58 y
ISS 1/2/3 (n)
43/31/18
23/11/12
Del 13q (n)
46
25
t(4;14) (n)
56
Del 17p (n)
12
2
VAD
56
VAD
28
Induction therapy (n)
BOR-DEX 36
BOR-DEX 18
Response after induction
induction
CR/VGPR/PR/SD (n)
4/28/48/12
2/14/24/6

MATCHED CASE-CONTROL STUDY:
Response to
to Mel
Mel 200 or Ve
Vel-Mel
Control (Mel 200)
Pilot Vel-Mel
n= 92
n= 46
CR
12 (13%)
17 (37%)
VGPR
53 (58%)
32 (70%)
PR
90 (98%)
44 (96%)
SD
2 (2%)
2 (4%)
Chi 2 =10,565 for CR vs Non CR

CONCLUSIONS
B(
Bor 1
(1
/ 2
mg/m x4)
d
an HDM (2200)
i
reg men is:
SAFE
EFFECTIVE: 70% VGPR post HDT
Bor + HDM > HDM in thi
this mathd
atched case
t
con
l
ro t
s d!
udy!
@ A Randomized stu
udy is warranted !

Pilot Study:I
: F
:IIFM 2008 (n=
(n 32)
Induction: VRD x 3
HD: Mel 200 + CSP
CS
Consolidation: VRD
Dx2
D x 2
Maintenance: Rev
Pi
Pr
P imary
i
d
en
i
po t
n :
t
Str CR (FC) before and after consolidation

IFM 99 02 : EFS from Diagnosis
Arm C
P P<
<
P 0<.0.01
003
01
003
Arm B
Arm A

IFM 99 02 : Overall Survival according to Thal
(Arm B versus Arm C).
Arm C
Arm B
P < 0.01

IFM 99 02 : EFS According to Response at Random
Response at
at Random
Random 90%
Response at
at Random
Random < 90%
Thal +
Thal +
Thal - (n = 391)
Thal -
NS
P < 0.0003
Thal -

IFM 2005
2005--02:
02: Lenalidomide as maintenance therapy After
ASCT ffor MM
M
MM
phase III randomized, placebo-controlled trial, From 7/ 2006 to 8/2008, 614 patients
Patients < 65 years, with non-progressive disease, 6 months after
ASCT in first line
Randomize
Consolidation
Lenalidomide 25 m
mg/day p.o., days 1-
1 21 of
every 28 days for 2 months
Lenalidomide
10 -15 mg/day p o
. .,
Pl
b
ace o
til
un
l
re apse
continuous dosing until
relapse
Primary end-
end point: time to relapse.
Secondary end-points: CR rate, PFS, OS, feasibility of long-term lenalidomide.
ASCT = autologous stem cell transplant.
IFM = Intergroupe Francophone du Myelome.

Current results and questions of the IFM trials (Young
Patients)
Induction regimen: VD
· 40% of VGPR after induction
·VTD (IFM 2007)? VRD (IFM 2008)?
Conditioning regimen: Vel/Mel
· 70% of VGPR after HDT
Consolidation post HDT:
Th
·
l
a : 10% f
o PR
PR
d
converte in VG
VG
GPR (IFM
(IFM 99)
·Rev (IFM 2005)? VRD (IFM 2008) ?
Maintenance:

·Thal prolongs EFS
·Rev (IFM
(IFM 2005)?
80% to 90% of VGPR can be achieved ! (sCR?)

New drug Regimen as initial therapy
Authors
Regimen
Regimen
N
CR
CR+
C
RR
EFS
Survival
Survival
VG
GPR
Rakjumar
Dex
Dex--T
T
102
8%
43%
4
69%
Median: 22 m
.
Rakjumar
dex
dex--R
R
190
42%
4
71%
Median: 23 m 87% at 24 m
Palumbo
MPT
MPT
129
15%
36%
3
76%
Median: 26 m 85% at 24 m
Facon
MPT
MPT
124
16%
50%
5
81%
Median: 28 m Median
Median 54 m
Palumbo
MPR
54
24%
448%
81%
87% at 16 m
.
San Miguel
MPV
336
35%
45%
4
82%
Median: 24 m 83% at 24 m
Richardson
VRD
68
68
37%
74%
7
98%
????

SCT versus VRD in young patients ?
SCT
VRD
RR
>
>90
9 %
> 90%
VGPR
800%
0
74%
Molecular CR
20
2 %
%?
?
PFS (med)
>
>55 year
yea s(TT
rs(TT22))
?
40 m (IF
FM 99)
99
The
ti
ques on h
s ould
ld be ask d
e !!!
d!!!

IFM 2009/ DFCI Trial
V
VRD x 3
SC collection
VRD x 5
Mel 200 + ASCT
VRD x 2
Rev 1 ye
year
Rev 1 ye
year
(HDM + ASCT at relapse)
Major question: Can early SCT prolong EFS of at least 9 months ? (886 patients).

Elderly patients

First line TT in elderly patients
We previously demonstrated that:
·Dex was not a standard
Dex < MP (IFM 95)
·HDT was not a standard
HDT < MPT (IFM 99)
·MPT was a standard
MPT > MP (IFM 99)
The current question:
Alkylating agents in the era of new drugs: MPT versus dex +
Rev

MPT vs Revlimid-low dose Dexamethasone in Newly
Diagnosed Myeloma P
Patients, Aged
Aged >65
>65 Years
Phase III international study / MM-020, IFM 2007-01, FIRST study
MPT
12 cycles M
MP at 6-
6 week interval + Thal at
aat
2200
00 mg/day
d ,
ay stopped at end of MP
1
Re
R v
e + low
low--dose
dose Dex.
N = 1590
Rev 25mg/da
25mg/d y
a ,
y days 11--21
21 ; Dex 40 mg/day,
mg/day
Primary
1
days 1,8,15, 22
endpoint:
18 cycles at 44--week
week interval
PFS
1
Re
R v
e + low
low--dose
dose Dex.
sam
sa e
m schedule as above
Given until
u
progessive disease