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First analysis of HOVON-65/GMMG-HD4 randomized
phase III trial comparing Bortezomib, Adriamycine,
D
t
exame h
thasone (PA
(P D)
AD) vs VAD as i d
n
t
uc ition t
t
rea
t
men
prior to High Dose Melphalan (HDM) in patients with
multiple my
pyeloma (MM
(
).
)
Sonneveld P, Goldschmidt H, van der Holt B, el Jarari L, Bertsch U,
Salwender H, Zweegman S, Vellenga E, Raymakers R, Schubert J,
Blau W, Jie A, Beverloo B, Hose D, van de Velde H, Schaafsma
MR, Kersten MJ, Delforge M, de Weerdt O, van der Griend R,
Wijermans PW, Martin H, Lokhorst HM for the Dutch-Belgian
HOVON group and the German GMMG
GMMG group

Disclosures
P. Sonneveld
Advisory Board Jansen-Cilag
H. Goldschmidt
Advisory Board Jansen-Cilag
H. van de Velde
Employee Jansen-Cilag

Study objectives
· The HOVON65 GMMG-HD4 randomised phase III trial was
designed to assess the efficacy (CR+VGPR) of Bortezomib as
induction treatment prior to
to high
high-dose therapy
therapy and
· To investigate the efficacy of Bortezomib as maintenance
treatment compared
p
to Thalidomide
· Correlative studies were planned to investigate the relevance of
prognostic subgroups in patients treated with Bortezomib
· Here we present the first i.t.t. interim analysis on the response
data for the initial 300 out of 825 registered patients.

HOVON 65/GMMG-HD4
R
Randomization
3 x VAD
3 x Bort-AD
Iv push
d 1,4,8,11
CAD
CAD
Stem cell collection
Cyclo/adria/dex
Cyclo/adria/dex
HDM
HDM
Auto PBSCT
200mg/m2
200mg/m2
HLA-id Sib
NonmyeloST
200 G
c y
Thalidomide
Bortezomib
Maintenance/
50 mg/daily
2x /month

Schedule of PAD (3 cycles)
Dose/day
Route
Days
Bortezomib
1.3 mg/m2
i.v. rapid infusion
all cycles:
Days
1,4,8,11
Doxorubicin
9 mg/m2
mg/m
i.v. rapid infusion
infusion
all cycles:
cycles:
1, 2, 3, 4
Dexamethasone
40 mg
p.o.
all cycles:
1- 4,
9- 12,
17-
17 20

Study Endpoints
Primary endpoints
· Progression-free
g
survival
Secondary endpoints
· Response after Induction
Induction, HDM and overall
overall (CR
(CR, VGPR, PR)
· OS from registration
· Toxicity
· PFS from HDM
Response
p
criteria
· EBMT criteria as per protocol (start 2005)
· CR as in EBMT
· nCR : CR, immunofixation unknown/positive
· VGPR as in IMWG criteria

Inclusion/exclusion criteria
Inclusion criteria
· Multiple Myeloma stage II/III, A+B, all ISS stages
· Age 18-
18 65 yr
· WHO performance 0 3
· Newly diagnosed
Exclusion criteria
· AL Amyloidosis
· Non-secretory MM
· Neuropathy CTC grade 2-4
· Severe concomittant
concomittant disease

Study conduct
· Cooperative trial by the Dutch-Belgium HOVON Myeloma Working Party
& th
the German M l
u ti
lti l
p e M l
ye oma Group GMMG b
d
ase on a common
protocol, study rules and data flow.
· The HOVON65/GMMG
HOVON65/GMMG-HD4 randomised phase III trial was
was performed
according to the newly defined European Law GCP regulations in 2005
· Including:
HOVON initiated and sponsored the trial
On site center monitoring
European Good Clinical Practice regulations applied
Drug accountability program
program
Data Safety Monitoring Board
Timely data management for AE, SAE and SUSAR reporting
All data analysis and evaluation at HOVON DC for HOVON & GMMG

Accrual

Patient characteristics
VAD
PAD
Patients #
150
150
M/F
90/60
89/61
Median age yr
56
57
Stage II/III %
32/11
32/1 8
1
29/121
A/B %
128/22
136/14
ISS I/II/III %
54/19/28
59/22/19
IA
IgA %
21
24
IgG %
60
62
LCD %
18
14

Patient characteristics
VAD
PAD
Patients #
150
150
M/F
90/60
89/61
Median age
Well yr
balanced for the
56
stratification
57
factors
Stage II/III %
32/11
32/1 8
1
29/121
Beta-2-Microglobulin and Salmon-Durie stage
A/B %
128/22
136/14
ISS I/II/III %
and 1 HDM
54/19/28
(HOVON) or 2 HDM
59/22/19
(GMMG)
IA
IgA %
21
24
IgG %
60
62
LCD %
18
14

Patient flow
VAD
PAD

Pre & Post-ASCT Response with
VAD vs Bortezomib-AD (PAD) induction
VAD
PAD
P value
CR/nCR %
1
5
> VGPR
15
42
< 0.000001
> PR
59
83
0.000014

Pre & Post-ASCT Response with
VAD vs Bortezomib-AD (PAD) induction
VAD
PAD
P value
CR/nCR %
1
5
> VGPR
15
42
< 0.000001
> PR
59
83
0.000014
HDM-SCT
HDM-SCT
CR/nCR %
9
23
0.0015
> VGPR
50
80
0.0019
80
> PR
80
93
0.0021

Stem Cell Collection
ITT population
VAD
PAD
N = 150
N = 150
Mobilization: Cyclo 4 g/m2 + G-CSF
Median No. CD34+ (x106/kg)
9.26
10.48
Range
(4.10-37.60)
(4.00-37.00)
Median no. apheresis
1 (1-4)
1 (1-5)
Time to succesful apheresis
110
111
(days)
H. Goldschmidt ASH 2008 abstract
#3470

Adverse events during Induction
VAD
PAD
N / %
N / %
Any AE, n (%)
122 / 82
129 / 87
Grade 3, n (%)
79 / 53
88 / 59
Gd
Grade 4(
4, n %)
(%)
18 / 12
12
32 / 21
21
SAE, n (%)
53 / 35
67 / 45
AE leading to study drug
5/3
5 / 3
9/6
9 / 6
discontinuation, n (%)
AE leading to death, n (%)
6 / 4
3 / 2

Hematologic toxicity/Infections grade 2-4
VAD
PAD
Infections gr 2-4
%
%
Any
42
54
Pulmonary
17
21
ENT
6
4
GI
6
7
GU
5
4
FUO
4
7
HZV
2
3
No difference in trombocytopenia, anemia, leukocytopenia

Non Hematologic Toxicity grade 2-4
VAD
PAD
%
%
P
Fatigue
26
29
Rash
11
13
GI symptoms
yp
30
38
PNP
-Gr 2
17
13
- G3
Gr +4
3+4
4
16
0.003
Cardiac
6
6
HZV
1
7
VTE
3
4

Dose adherence of Bortezomib
100%
90%
80%
other
ot
70%
Interrupted/not given
s
60%
reduced & delayed
ient
50%
pat ents
reduc
r
ed
educ
dose
dos
40%
100 % & delayed
pati
30%
100 % dose
20%
10%
0%
PAD 1
PAD 2
PAD 3

Reasons to go off protocol
VAD
VAD/HDM
PAD
PAD/HDM
%%
%%
Excessive toxicity
3
1
6
9
Nt
Not l
e ili i
g bl
ible FT
FT
0
1
0
3
Progression/
02
01
Relapse
Intercurrent death
3
2
0
No compliance
2
2
1
1
Other
2
4
1
2
Allo
6
8
Cumulative
10
26
10
34
88 % of VAD and 87 % of PAD patients received HDM/ASCT

FISH
VAD
PAD
PR
VGPR
PR
VGPR
%
%
%
Del 13/13q Yes
Ye
46
85
48
96
64
N=220
No
54
76
40
89
56
t(4;14)
Yes 20
76
29
96
57
N=146
No
80
93
71
92
67
No effect of FISH 13q and t(4;14) on response in
patients treated with PAD

Conclusions
· PAD is a safe and effective induction regimen
g
· 80 % of patients can complete 3 cycles without dose
reduction
· 42 % of patients achieves at least VGPR after 3 PAD
cycles
· 80 % of
of patients achieves
achieves at
at least
least VGPR
VGPR after
after PAD
PAD
followed by HDM+ASCT
· PAD improves CR & VGPR significantly compared with
VAD after induction and after HDM+ASCT
· Stem cell apheresis is succesful in all PAD treated
patients
· 87 % of patients achieve HDM/ASCT

Acknowledgements
Janssen-Cilag Orthobiotech
Contactgroep
gp Kahler en
Waldenström Patiënten
www.kahler.nl

Bortezomib feasibility (%)
IFM
H65
ASH
ASH
2008
2008
VD
PAD
n
239
150
SAE
34
41
PNP total
25
23
PNP 3+4
2
16
Discontinue B
6
10
(n)CR % I/HDM
15/40
5/23
> VGPR I/HDM
39/61
42/71