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HOVON 50 MM final analysis
A randomized phase III study on the effect of
Thalidomide combined
combined with Adriamycin
Adriamycin,
Dexamethasone and High Dose Melphalan in
patients with multiple myeloma
Henk Lokhorst & Pieter Sonneveld
Statistics: Bronno van der Holt

HOVON 50 Stage II/III MM, < 66 years
VAD (3x)
TAD (3x)
vs
Iv push
Thal 200 mg/daily
556 patients
Iv push
Thal 200 mg/daily
p
CAD +G
+ G-CSF
87%
Cyclo/adria/dex
HLA-id
RIC
Sib
HDM 1-2x
82%
N=109
20%
200mg/m2
Hovon 54
-IFN
Th
T alid
id
om e
34%
46%
Thrice/weekly
50 mg/daily

Patient characterist
stics
cs
· Age median
56 years (32-65)
· Male/female
60/40
· Salmon&Durie II/III
20/80
· ISS
I
52%
II/III
48%
Equally divided in both arms

Best response on
on protocl
protocl
A (VAD)
B (TAD)
p.
At least
PR
79 %
87%
<0.01
VGPR
54 %
65%
<0.01
CR
21 %
30%
0.03

Event Free Survival
EFS with censoring at RIC allo-SCT
Treatment arm
100
P<0.001
75
ntagee
perc
50
B:+Thal
ulativem
Cu
25
A:noThal
N
E
A:noThal
267
168
B:+Thal
269
134
Logrank P<.001
0
0
12
24
36
48
months 60
At risk:
A:noThal 267
138
84
44
15
3
B:+Thal 269
163
123
74
34
9
4 Jun 2008 - 17:11:36

Progr
og ession Free
ee Su
Survival
Progression free survival
Treatment arm
100
P<0.001
ge
75
a
percent
50
B:+Thal
tivea
A:noThal
Cumul
25
N
P
A:noThal
267
201
B:+
B: Thal
269
156
Logrank P<.001
0
0
12
24
36
48
months 60
At risk:
A:noThal 267
200
133
73
23
6
BT
B:+ h
Thal 269
213
162
95
42
11
4 Jun 2008 - 17:11:37

Survival
Overall survival
Treatment arm
100
P0
P=0 9
. 6
96
75
A:noThal
B:+Thal
ntagee
perc
50
ulativem
Cu
25
N
D
A:noThal
267
98
B:+Thal
269
101
Logrank P=.96
0
0
12
24
36
48
months 60
At risk:
A:noThal 267
227
204
151
65
20
B:+Thal 269
233
201
148
80
24
4 Jun 2008 - 17:11:38

Overall survival from progression/relapse
Treatment arm
Reduced OS from relapse after Thal exposure
100
ge
75
a
P=0 0
. 1
01
A:noThal
percente
50
v
B:+Thal
Cumulati
25
N
D
A:noThal
179
81
B:+Thal
133
79
Logrank P=.01
0
0
12
24
36
months 48
At risk:
A:noThal 179
108
57
25
3
B:+Thal 133
72
34
13
5
1 Dec 2008 - 09:26:52

Thalidomide and IFN compliance
· Induction
- Thalidomide full dose
58%
- Thalidomide modified
13%
- Thalidomide stopped
29%
· Maintenance started
IFN
Thal:
- 43%
67%
· Maintenance continued
IFN
Thal
- 12 months 23%
44%
- 24 months 15%
30%
- 36 months 11%
21%

Number (%) of patients with adverse events
CTC
d
gra e 3-4 during VAD/TAD
VAD/TAD cycles 1-3
Arm A: VAD (n=266 ) Arm B: TAD (n=268)
P
N%
N
%
N%
N
%
Any adverse event
131
41
179
65
0 .13
Cardiovascular
25
10
26
10
0 .72
Coagulation #
22
8
26
10
0.54
Constitutional
26
9
33
12
0.41
Metabolic
34
13
36
14
01
0. 6
16
Gastro-intestinal
14
5
31
12
0.23
Neurology CTC 3-4
19
8%
39
15%
0.09
Neurology CTC 2-4
73
29%
132
48%
0.04
# Patients received LMWH during thalidomide induction

DVT during first 12 months
Months 1st DVT - T0
Treatment arm
100
N DVT
A:noThal
268
33
B:+Thal
269
32
75
tage
percen
50
lativeu
Cum
25
A:noThal
B:+Thal
0
0
3
6
9
months 12
At risk:
A:noThal 268
236
220
213
202
B:+Thal 269
232
223
215
207

Adverse prognostic factors
Multivariate analysis
CR
EFS
PFS
OS
age
ns
ns
ns
ns
stage
ns
ns
ns
ns
LDH
0.9
0.00008
0.0001
0.00001
IgA
0.4
0.5
0.01
0.001

0.8
0.4
0.4
0.08
ISS II
0.6
0.4
0.8
0.1
ISS III
0.02
0.006
0.8
0.0005
Del 13
0.4
0.8
0.4
0.8
Thalidomide did not overcome unfavourable factors

Event free survival; RIC-allo censored
ISS
EFS depending on ISS
100
75
tage
I
t
P<0.001
II
percen
50
III
tive
Cumula
25
N
E
I
208
110
II
91
53
III
97
65
Logrank P<.001
0
0
12
24
36
48
months 60
At risk:
I 208
130
101
69
30
12
II 91
54
36
23
16
5
III 97
43
29
20
8
2
1 Dec 2008 - 09:26:52

Overall survival
ISS
OS depending on ISS
100
I
75
II
tage
III
percen
50
tive
P<0.001
Cumula
25
N
D
I
208
65
II
91
40
III
97
53
Logrank P<.001
0
0
12
24
36
48
months 60
At risk:
I 208
195
178
158
89
33
II 91
78
66
54
36
10
III 97
74
60
50
27
8
1 Dec 2008 - 09:32:45

Landmark analysis
best response achieved within 12 months
HOVON 50 MM: survival from 12 months after randomisation
EFSC: EFS, [mo] (censored at alloSCT) [start = 12 mo]
PFS: Progression free survival [m] [start = 12 mo]
Best response within 12 months
Best response within 12 months
100
100
75
75
age
age
cent
cent
per
50
per
50
ive
CR
ive
CR
VGPR
VGPR
Cumulat
25
Cumulat
25
N
F
N
F
PR
CR
EFS
PR
43
20
CR
43
20
EFS
PFS
VGPR
139
84
VGPR
139
87
PR
102
67
PR
102
71
0
0
0
12
24
36
48
months 60
0
12
24
36
48
months 60
At risk:
At risk:
CR 43
38
25
14
6
0
CR 43
38
25
14
6
0
VGPR 139
102
67
30
9
2
VGPR 139
104
69
31
9
2
PR 102
61
37
21
6
1
PR 102
64
38
21
6
1
25 Nov 2008 - 11:05:42
25 Nov 2008 - 11:05:43
OS: Overall survival [m] [start = 12 mo]
Best response within 12 months
100
CR
75
tage
cen
VGPR
per
50
tivea
PR
Cumul
25
N
F
CR
43
6
OS
VGPR
139
42
PR
102
38
0
0
12
24
36
48
months 60
At risk:
CR 43
42
37
26
10
0
VGPR 139
129
108
64
22
5
PR 102
90
76
47
15
3
25 Nov 2008 - 11:05:43

PFS by response
PFS from 12 months by response
Events/Patients
Statistics
HR & 95% CI
Reduction
Response
B:+Thal
A:noThal
(O-E)
Var.
(B:+Thal : A:noThal)
(SD)
Best response within 12 months
CR
13/30
7/13
-1.9
3.7
VGPR
45/84
42/55
-10.1
19.8
PR
24/43
47/59
-10.4
17.4
Total
82/157
96/127
-22.4
41.0
42%(9)
(52%)
(76%)
reduction
0
0.5
1.0
1.5
2
2P<0.001
B:+Thal
A:noThal
better
better
Also patients achieving a VGPR/CR
benefit from
from thalidomide
thalidomide maintenance
maintenance
with regard to PFS

Conclusions
· Thalidomide combined with intensive therapy
improves response, EFS
EFS, PFS but not OS
· Achievement of a CR is the most determinant factor
for prolonged PFS and OS.
improvement of CR is the ultimate goal
· The role of maintenance) of thalidomide (other novel
agents) is still debated

Most effective strategy of novel agents
combined with intensive therapy
therapy is
is to
to be
be
determined
· Focus on maximal induction + intensification only?
- combination of
of (all)
(all) novel agents ?
· Is their a role for post intensification therapy?
- only in patients not achieving CR (+VGPR)?
- short consolidation?
- (limited) maintenance?
maintenance?
Acknowledgements

Participating hospitals (48)
B-Leuven-Gasthuisberg
NL-Haarlem-Kennemer
NL-Af
Amersfoort-El
Eeml
d
an
NL-Heerlen-Atrium
NL-Amsterdam-AMC
NL-Hengelo-SZ Twente
NL-Amsterdam-AVL
NL-Leeuwarden-MC
NL-Amsterdam-OLVG
NL-Leiden-LUMC
NL-At
Amsterdam-Sl t
o ervaart
NL-Leidschendam-
NL-Amsterdam-VUMC
NL-Maastricht-AZM
NL-Apeldoorn-Gelre, Lukas
NL-Nieuwegein-Antonius Ng
NL-Arnhem-Rijnstate
NL-Nijmegen-Canisius
NL-Bd
Breda-A
h
mp i
hia, L
dijk
angen
NL-Nijmegen-Rd
Ra b
db
d
ou
NL-Breda-Amphia, Molengracht
NL-Roosendaal-Franciscus
NL-Brunssum-Atrium
NL-Rotterdam-Clara
NL-Delft-RdeGraaf
NL-Rotterdam-EMC
NL-Dl
De f
lfzijl
ijl-Dl
De f
lfzi h
c t
ht
NL-Rt
Ro t
tterdam-EMC D
i
an l
e
NL-Den Bosch-Bosch MC
NL-Rotterdam-Franciscus
NL-Den Bosch-Carolus
NL-Rotterdam-Zuider
NL-Den Haag-Leyenburg
NL-Sittard-Maasland
NL-Dt
Deventer-Zi k
e
h
en
i
u zen
NL-Utrecht-Di k
a onessen
NL-Dordrec-Schweitzer-Dortwijk
NL-Utrecht-UMCU
NL-Dordrech-Schweitzer-Amstelw
NL-Veldhoven-Maxima
NL-Eindhoven-Catharina
NL-Venlo-Vie Curie
NL-Enschede-MS Twente
NL-Zd
Zaandam-DH
De H
l
ee
NL-Gouda-Groene Hart
NL-Zwolle-Sophia
NL-Groningen-AZG
NL-Zwolle-Weezenlanden

Long term follow-up results of IFM99-
03 and IFM99
IFM99-04 comparing non
myeloablative allotransplantation with
autl
tologous transplantati
tion in hi
high-
risk de novo multiple myeloma
P.Moreau, F.Garban, M.Attal, M.Michallet, G.Marit, C.Hulin,
L.Benbou
Benboubker
b
, C Doyen
.
, M Mohty
.
, I Yakoub
.
-
Yakoub Agha, S L
. eyvraz
Leyvraz,
P.Casassus, H.Avet-Losieau, L.Garderet, C.Mathiot, J.L.Harousseau