Single vs double intensive therapy in
untreated Multiple Myeloma:
updated analysis of the prospective phase III
HOVON 24 study
the HOVON group, the Netherlands
Updated analysis of HOVON 24 trial
Study objectives
To investigate whether a second intensive treatment with
myelo-ablative therapy and autologous stem cell
transplantation would improve the outcome in previously
untreated Multiple Myeloma
Primary endpoints: EFS, OS and Quality of Life
Other endpoints : Response, PFS, TTP
To investigate prospectively the effect of allogeneic
transplantation in first line treatment of Multiple Myeloma
Registration
HOVON 24
3-4 VAD push
Allo-SCT if HLA-id
sibling
R
Cyclophosphamide
Cyclophosphamide
4g/m2 + G-CSF
4g/ m2 + G-CSF
Melphalan
Melphalan
140mg/m2 (2 x 70)
140mg/m2 (2 x 70)
Cy/TBI + ASCT
Interferon 3*106 IU
s.c 3x/week
Interferon 3* 106 IU
s.c. 3x/week
Updated analysis of HOVON 24 trial
Accrual: November 1995 - March 2000
453 patients included
60 proceeded to Allo-SCT
303 randomized
Median follow up 68 months
156/453 patients alive
Analysis 17th March 2005
Unfavourable clinical prognostic variables
Single
Double
Patients
148
155
Age > 50
72 %
77 %
M> 3
37 %
45 %
2
Stage III
75 %
76 %
LDH > N
16 %
15 %
Cytogenetics 1997-2000 (n=169)
NN
63 %
63 %
AN/AA
37 %
37 %
PR + CR (ITT) on protocol
Single
Double
Patients
148
155
After VAD
63 %
62 %
All treatment
PR + CR
86 %90 %p=0.22
CR
13 %
28 %
p=0.002
Effect of time of PR and CR
TTP from PR, [mo]
TTP indicator
PR reached after
CR reached after
100
100
N
p
N
p
VAD
279
192
VAD/IDM
44
24
later
81
69
later/FU
61
29
Logrank P=.02
Logrank P=.54
later
75
75
later/FU
VAD
percentage
50
percentage
50
VAD/IDM
lativeu
lativeu
mu
m
p=0.02
u
C
25
C
25
0
0
0
24
48
months 72
0
24
48
months 72
At risk:
At risk:
VAD 279
136
57
17
VAD/IDM 44
22
15
5
later 81
38
14
2
later/FU 61
21
9
1
Overall survival
Overall survival
PR reached after
CR reached after
100
100
75
75
VAD/IDM
percentage
50
later
percentage
50
later/FU
lativeu
VAD
lativeu
mu
mu
C
25
C
25
N
d
N
d
VAD
279
176
VAD/IDM
44
24
later
81
46
later/FU
61
28
Logrank P=.52
Logrank P=.72
0
0
0
24
48
months 72
0
24
48
months 72
At risk:
At risk:
VAD 279
197
126
37
VAD/IDM 44
28
21
8
later 81
58
37
10
later/FU 61
34
16
2
Results of treatment at 60 months (%)
Single
Double
logrank
OS
47
43
NS
EFS
10
20
0.014
PFS
10
22
0.032
TTP
87
74
0.001
Survival by treatment arm
Overall survival
Event free survival
Treatment arm randomised
Treatment arm randomised
100
100
Single
75
75
p=0.014
centage
centage
Double
per
50
per
50
Double
umulative
mulative
25
u
25
C
N
F
C
N
F
IFN-a
148
86
IFN-a
148
137
PB/AuBMT
155
95
PB/AuBMT
155
126
Single
Logrank P=.39
Logrank P=.01
0
0
0
24
48
72
months 96
0
24
48
72
months 96
At risk:
At risk:
IFN-a 148
117
80
23
4
IFN-a 148
60
20
5
0
PB/AuBMT 155
108
73
26
4
PB/AuBMT 155
73
37
13
2
Progression free survival
Time to progression from randomization, [mo] - 2
Treatment arm randomised
Treatment arm randomised
100
100
N
F
IFN-a
148
125
PB/AuBMT
155
102
Single
Logrank P<.001
75
75
centage
p=0.032
centage
Double
per
50
per
50
Double
mulative
p=0.001
u
mulative
25
u
25
C
N
F
C
IFN-a
127
116
Single
PB/AuBMT
140
111
Logrank P=.03
0
0
0
24
48
72
months 96
0
24
48
72
months 96
At risk:
At risk:
IFN-a 127
59
20
4
0
IFN-a 148
71
23
7
0
PB/AuBMT 140
71
36
13
1
PB/AuBMT 155
84
43
13
2
Salvage treatment with high-dose therapy at
progression
Single
Double
Patients (#)
148
155
Progression (#)
112
106
HDM/ASCT salvage
41 %
7 %
Quality of Life at 12 months (EORTC QLQ-C30)
Single
Double
p
Overall QOL
78
65
<0.05
Social
95
73
<0.01
Functioning
77
53
<0.05
Role Functioning
22
46
<0.01
Fatigue
21
42
<0.05
Pain
3
25
<0.05
Hazard ratios by Cox regression multivariate analysis
intention to treat in randomized patients (p< 0.05)
OS
EFS
PFS
TTP
Double treatment
-
0.70
0.73
0.62
Stage 3
2.16
Hb > 6.2 mmol/L
0.68
0.70
0.71
LDH > n
1.70
1.95
2.06
2.03
Age
1.03
1.02
2M > 3.0
1.57
1.38
1.49
IgA
1.64
1.60
Plasmablastic MM
1.39
1.43
Subgroup analysis in patients with abnormal karyotype:
1q/1p
Overall survival
Event free survival
Chrom. 1 abnormality
Chrom. 1 abnormality
100
100
no
P<0.001
75
75
centage
centage
P<0.001
yes
per
50
per
50
no
umulative
mulative
25
u
25
C
N
F
C
N
F
yes
no
123
57
no
123
99
yes
28
26
yes
28
28
Logrank P<.001
Logrank P<.001
0
0
0
24
48
72
months 96
0
24
48
72
months 96
At risk:
At risk:
no 123
97
77
20
3
no 123
66
30
5
0
yes 28
15
8
0
0
yes 28
8
0
0
0
Progression free survival
TTP from start VAD, [mo] - 1
Chrom. 1 abnormality
Chrom. 1 abnormality
100
100
N
F
no
123
75
yes
28
25
yes
Logrank P<.001
75
75
P<0.001
centage
centage
no
per
50
per
50
no
P<0.001
mulativeu
mulative
25
u
25
C
yes
N
F
C
no
100
76
yes
22
22
Logrank P<.001
0
0
0
24
48
72
months 96
0
24
48
72
months 96
At risk:
At risk:
no 100
57
27
2
0
no 123
81
38
7
0
yes 22
5
0
0
0
yes 28
8
0
0
0
Survival by 2M and 1p/q
Overall survival
Event free survival
Number of risk factors B2M>3 and chrom. 1 abn.
Number of risk factors B2M>3 and chrom. 1 abn.
100
100
0 factors
N
F
0 factors
53
39
1 factor
60
51
p<0.001
2 factors
16
16
75
75
1 factor
centage
centage
0 factors
p<0.001
per
50
per
50
2 factors
1 factor
umulative
25
mulativeu
25
C
N
F
C
0 factors
53
20
2 factors
1 factor
60
35
2 factors
16
15
0
0
0
24
48
72
months 96
0
24
48
72
months 96
At risk:
At risk:
0 factors 53
47
40
16
2
0 factors 53
35
18
5
0
1 factor 60
41
27
0
0
1 factor 60
25
9
0
0
2 factors 16
6
4
0
0
2 factors 16
4
0
0
0
Progression free survival
TTP from start VAD, [mo] - 1
Number of risk factors B2M>3 and chrom. 1 abn.
Number of risk factors B2M>3 and chrom. 1 abn.
100
100
N
F
0 factors
44
30
2 factors
1 factor
48
39
2 factors
11
11
75
75
centage
0 factors
centage
1 factor
p<0.001
per
50
per
50
p<0.001
1 factor
0 factors
mulativeu
25
mulativeu
25
C
C
N
F
2 factors
0 factors
53
34
1 factor
60
34
2 factors
16
14
0
0
0
24
48
72
months 96
0
24
48
72
months 96
At risk:
At risk:
0 factors 44
32
17
2
0
0 factors 53
41
22
6
0
1 factor 48
19
7
0
0
1 factor 60
31
12
0
0
2 factors 11
3
0
0
0
2 factors 16
4
0
0
0
Survival by 2M, 1p/q and del13/13q-
Overall survival
Event free survival
Number of risk factors B2M>3, chrom.13 and chrom.1
Number of risk factors B2M>3, chrom.13 and chrom.1
100
100
0 factors
N
F
0 factors
49
35
p<0.001
1 factor
57
48
2-3 factors
22
22
75
75
1 factor
centage
centage
0 factors
p<0.001
per
50
2-3 factors
per
50
1 factor
umulative
25
mulativeu
25
C
N
F
C
0 factors
49
19
2-3 factors
1 factor
57
30
2-3 factors
22
20
0
0
0
24
48
72
months 96
0
24
48
72
months 96
At risk:
At risk:
0 factors 49
44
37
16
2
0 factors 49
32
18
5
0
1 factor 57
40
29
0
0
1 factor 57
27
9
0
0
2-3 factors 22
10
5
0
0
2-3 factors 22
5
0
0
0
Progression free survival
TTP from start VAD, [mo] - 1
Number of risk factors B2M>3, chrom.13 and chrom.1
Number of risk factors B2M>3, chrom.13 and chrom.1
100
100
2-3 factors
N
F
0 factors
40
26
1 factor
47
38
2-3 factors
15
15
75
75
0 factors
p<0.001
centage
centage
1 factor
per
50
per
50
1 factor
p<0.001
mulativeu
25
2-3 factors
mulativeu
25
C
C
N
F
0 factors
0 factors
49
30
1 factor
57
32
2-3 factors
22
20
0
0
0
24
48
72
months 96
0
24
48
72
months 96
At risk:
At risk:
0 factors 40
30
17
2
0
0 factors 49
38
22
6
0
1 factor 47
20
7
0
0
1 factor 57
33
12
0
0
2-3 factors 15
4
0
0
0
2-3 factors 22
5
0
0
0
Multiple factors contributing to variations in drug responses
Analysis of genetic SNP polymorphisms:
role for toxicity and treatment outcome
Subgroup analysis for 207/303 patients with available material
Analysis of genes involved in cellular protection and xenobiotics
Here report of CYP3A4, CYP 3A5*3 and GSTP1
gene
site
mutation
function
GSTP1
exon 5
IleVal
reduces GSH
CYP3A4-V
promotor
290 AG
increased activity
CYP3A5*3
SNP exon 3
alt. splicing
no activity
gene
substrate
ww/wm/mm (%)
GSTP-1
Mel, Cyclo, TBI
30 / 45 / 25
CYP3A4-V
VA(D), Cyclo
90 / 2 / 8
CYP 3A5*3
VA(D), Cyclo, (MEL)
1 / 13 / 86
RFLP-PCR CYP3A5*3
Interpretation:
148 + 20 bp = wt/wt
168 bp = mt/mt
168 + 148 + 20 bp = heterozygous
125 bp = internal control
M
W
M
Patient samples
W
W
M
300
300
PCR Product
250
250
293
200
168
200
150
148
168
125
150
148
100
125
100
50
50
20
20
Analysis of genetic polymorphisms:
role for toxicity and treatment outcome
Any toxicity WHO 2 (%)
Gene
ww
wm
mm
p-value
CYP3A4-V
na
na
na
-
CYP 3A5*3
na
64
84
0.048
GSTP-1 Ile/Val
34
36
11
0.003
PR or CR on protocol (%)
ww
wm
mm
p-value
CYP3A4-V
82
100
ns
CYP 3A5*3
na
84
81
ns
GSTP-1 Ile/Val
92
80
70
0.017
GSTP1 Ile Val
Event free survival
Progression free survival
100
100
75
I1e/I1e
75
Val/I1e
Val/I1e
Val/Val
percentage
50
percentage
50
I1e/I1e
Val/Val
lativeu
lativeu
mu
mu
C
25
N
e
C
25
N
p
I1e/I1e
59
54
I1e/I1e
54
49
Val/I1e
87
75
Val/I1e
70
58
Val/Val
47
42
Val/Val
33
28
Logrank P=.23
Logrank P=.35
0
0
0
12
24
36
48
months 60
0
12
24
36
48
months 60
At risk:
At risk:
I1e/I1e 59
50
31
22
12
7
I1e/I1e 54
45
26
19
11
6
Val/I1e 87
64
49
33
20
13
Val/I1e 70
58
45
29
19
11
Val/Val 47
31
19
12
6
4
Val/Val 33
26
18
10
5
3
Time to progression
Overall survival
100
100
N
p
I1e/I1e
59
40
Val/I1e
87
61
Val/Val
47
36
Logrank P=.12
75
75
I1e/I1e
Val/Val
Val/I1e
percentage
50
I1e/I1e
percentage
50
Val/I1e
Val/Val
lativeu
lativeu
mu
mu
C
25
C
25
N
d
I1e/I1e
59
38
Val/I1e
87
53
Val/Val
47
33
Logrank P=.26
0
0
0
12
24
36
48
months 60
0
12
24
36
48
months 60
At risk:
At risk:
I1e/I1e 59
53
33
22
12
7
I1e/I1e 59
56
44
41
32
20
Val/I1e 87
77
61
42
24
13
Val/I1e 87
79
67
59
48
30
Val/Val 47
36
22
15
9
6
Val/Val 47
38
31
24
22
12
Cyp 3A5*3 SNP
Event free survival
Progression free survival
100
100
P=0.07
75
75
percentage
50
percentage
50
lativeu
lativeu
mu
mu
C
25
mm
mm
C
25
N
e
N
p
ww/wm
25
23
ww/wm
ww/wm
21
19
ww/wm
mm
175
153
mm
141
119
Logrank P=.19
Logrank P=.07
0
0
0
12
24
36
48
months 60
0
12
24
36
48
months 60
At risk:
At risk:
ww/wm 25
19
13
4
2
1
ww/wm 21
17
10
2
2
1
mm 175
130
88
64
37
25
mm 141
116
80
57
34
21
Time to progression
Overall survival
100
100
N
p
ww/wm
25
17
ww/wm
mm
175
122
Logrank P=.06
P=0.02
75
75
mm
percentage
mm
50
percentage
50
lativeu
lativeu
P=0.06
mu
mu
C
25
C
25
ww/wm
N
d
ww/wm
25
20
mm
175
107
Logrank P=.02
0
0
0
12
24
36
48
months 60
0
12
24
36
48
months 60
At risk:
At risk:
ww/wm 25
19
13
4
2
1
ww/wm 25
21
15
14
10
3
mm 175
153
106
76
44
27
mm 175
157
131
114
95
62
Conclusions (1)
Myelo-ablative therapy with stem cell rescue added to intensive therapy
when applied in previously untreated multiple myeloma results in a
higher CR rate and a better EFS, PFS and TTP due to a lower relapse
rate.
As yet, this effect is not achieved for overall survival, and the beneficial
effect cannot be demonstrated in subgroups of patients.
High serum 2M combined with the presence or absence of
del 13/13q- and 1p/q deletions are powerful instruments to predict
prognosis.
Allogeneic transplantation with myelo-ablative conditioning does not
improve prognosis over double intensive treatment
Conclusions (2)
Pharmacogenomic analysis reveals that patients with homozygous
mutations Cyp3A5*3 have a significantly better overall survival and
more toxicity (cyclophosphamide, doxorubicin, melphalan ?)
Cyp 3A4-V mutations are rare and do not have an effect on survival
outcome
Patients with GSTP1 Val/Val homozygous mutations have less toxicity
and a lower response rate, and no significant difference of survival
(melphalan, cyclophosphamide)
Further analyses of genetic polymorphisms are warranted for
Clinicians
Laboratory
P Sonneveld
B. Beverloo
CM Segeren
E. Kamst
E Vellenga
Y de Knegt
AJ Croockewit
R van Schaik
GEG Verhoef
JJ Cornelissen
MR Schaafsma
Datamanagement & Statistics
MHJ van Oers
PW Weijermans
PHM Westveer
WE Fibbe
MMC Steijaert
S Wittebol
B van der Holt
HC Schouten
M van Marwijk Kooy
DH Biesma
JW Baars
HM Lokhorst
Thank you for organizing the workshop in this beautiful
country
Results of upfront allogeneic transplantation
100
75
percentage
50
OS
TRM
Cumulative
25
prog/oth
0
0
24
48
72
96
months
Duration of IFN maintenance
Treatment arm randomised
100
75
percentage
50
Single
25
Cumulative
N
F
IFN-a
102
99
Double
PB/AuBMT
84
78
Logrank P=.37
0
0
12
24
36
48 months 60
At risk:
IFN-a 102
51
33
15
6
2
PB/AuBMT 84
32
17
11
8
4
HOVON 50 study of Thalidomide in High-dose treatment in
Multiple Myeloma (2000-2004)
1050 patients accrued
Set of 600 patients
available for validation
Analysis planned 2005-
2006
Genes of interest:
Metabolism
DNA repair
Signalling pathways
Bone disease
Trombosis
HOVON 65 trial of Bortezomib in High-dose treatment of
Multiple Myeloma (2005-2007)
Randomize
Prospective analysis of
Induction
Induction
prognostic factors related
3 x VAD
Bor/Adria/Dexa
q 21 days
(PAD) q 21 days
to gene expression by
CAD + G-CSF
CAD + G-CSF
micro-array (Affy)
Stemcell collection
Stemcel col ection
Allo-SCT if
Allo-SCT if
Focus on both disease
HLA-id donor
HDM 200
HDM 200
HLA-id donor
once (good risk)
once (good risk)
related and host related
twice (poor risk)
twice (poor risk)
genes
Maintenance
Maintenance
with Thalidomide
with Bortezomib
50 mg/day
2 / month
800 patients accrual in 30
for 2 years
for 2 years
months
Analysis planned 2006-
2008