XIth
XI International Myeloma
Myeloma Workshop
Workshop, Kos, June
June 28th
28 , 2007
Single vs. Double HDT in Multiple Myeloma
Hartmut Goldschmidt
Medizinische Klinik V, Universität Heidelberg
Nationales Centrum für Tumorerkrankungen Heidelberg
Single vs. double HDT in MM
Compar i
s on: HDT vs. CT
Trial
Number
CR Rate (%)
EFS (months)
OS (months)
Patients
(ASCT vs CC)
(ASCT vs CC)
(ASCT vs CC)
Attal et al. 1996
200
22 vs 5**
28 vs 18 **
57 vs 44**
(IFM90)
Fermand et al. 1999
190
n.d.
25 vs 19**
42 vs 45
(MAG91)
Child et al. 2003
401
44 vs 8**
31 vs 19**
54 vs 42**
(MRC7)
Palumbo et
et al
al, 2003
195
26 vs 7 **
28 vs 16**
16
58+ vs 43**
43
(IMMSG)
Bladé et al. 2003
164
30 vs 11**
42 vs 34**
65 vs 67
(PETHEMA)
Barlogie et al. 2006
516
11 vs 11
17* vs 14*
38* vs 38*
(USIG)
[Abr.: ASCT, autologous stem cell transplantation; CC, conventionel Chemotherapy; IFM, Inter Groupe Francophone du Myelome; MRC,
Medical Research Council; MAG,
;, Myelom
y
e Auto Greffe;
ÜETHEMA, Spanish Cooperative Group; USIG, US Inter Group; IMMSG, Italian Multiple Myeloma Study Group; CR, complete
Remission; EFS, event free survival; OS, over all survival; n.d., not done; *, 7 y EFS/OS, ** significant difference]
High-dose therapy in MM
ASCT: Current status Single HDT
ASCT is the standard
standard of care for
for younger (<
(< 60-
60 75
-
years) myeloma patients due to:
Improved CR, VGPR, PR
Improved EFS
Improved OS, if VGPR or CR is achieved
Low treatment related mortality (1- 5%)
Debate B. Barlogie vs. J.F. Fermand:
ASCT as an part of primar
pp
y therapy
py in myeloma
y
Single vs. double HDT in MM
ASCT: Current status Double HDT
Double HDT was evaluated in many prospective trials
(IFM, MAG, HOVON, Bologna, GMMG, DSMM) and is
considered the standard in several transplant centers and
study groups because of:
Further improvement of CR, VGPR, PR
Improvement of
of EFS
EFS (IFM, MAG,
MAG, HOVON,
HOVON, Bologna)
Bologna)
MEL 200-based tandem transplant is the
backbone of the Arkansas Total Therapy
regimens with potential cure
But: Prolonged OS
OS only in
in two
two (IFM, MAG) trials
Is Double HDT standard of care?
High-dose therapy in MM
Single versus Double HDT: Results EFS/OS
Author
n
median
Results
Follow-up
______________________________________________________
IFM 94
399
60
Better EFS* and OS*
HOVON
303
50
Better EFS**, OS =
Bologna
220
60
Better EFS*, OS =
MAG 95
227
73
Better EFS and OS
GMMG HD2
261
24
Better EFS***
* For Pts. with VGPR
VGPR ( CR)
n
d
an CR
CR
** For Pts. with CR
***3rd Analysis presented at Sydney
Single vs. double HDT in MM
Improvement of Remission-Status: HD1- Trial 1996-1999
nCR
n
n
High-dose therapy in MM
ASCT:
ASCT Double HDT Critical Po
P ints
Type
Type of high dose therapy
therapy (e.g. including
including TBI?)
Time between first and second HDT
Mi
Mai t
n enance versus no
i
ma t
n enance
Relapse therapy (second/third TPX), new drugs
High-dose therapy in MM
IFM 95
95 : SURV
SUR IV
V AL
IV
Arm B : Mel
Mel-200
Arm A : TBI
Moreau et al. Blood 1999
High-dose therapy in MM
IFM 94
94 : Overall Survival
Survival All Patients
Patients
P<0.01
DT
ST
Attal et al. NEJM 2003
High-dose therapy in MM
IFM 94 : Overall Survival if response
p
to 1st graft
g
< 90%
DT
p<0.001
ST
Attal et al. NEJM 2003
High-dose therapy in MM
IFM 94 : Overall Survival if response to 1st graft
pg
90 %
DT
ST
p= n.s.
Attal et al. NEJM 2003
High-dose therapy in MM
HOVON 24 : Event Free Survival
(A)
100
ge
75
a
logrank p=0.014
percent
50
logrank p=0.014
ulative
Cum
25
Double
N
E
Single
148
139
Single
Double
155
134
0
0
24
48
72
96
months
120
At risk:
Single 148
60
21
11
4
1
Double 155
74
44
23
12
2
Sonneveld et al. 2007 in press
High-dose therapy in MM
HOVON 24 : Overall Survival
(C)
100
75
logrank p=0.81
tagen
Single
n
perce
50
Double
ulativem
Cu
25
N
D
Single
148
105
Double
155
108
0
0
24
48
72
96
months
120
At risk:
Single 148
117
82
51
21
5
Double 155
109
81
57
23
3
Sonneveld et al. 2007 in press
High-dose therapy in MM
GMMG-HD2 trial
1999-2002
Randomisation I: VID vs. VAD
until CR or plateau, max. 6 cycles
>/= SD
SD VAD/VID
V
Randomisation II
HD-cyclophosphamide
(ifosfamide) + G-CSF
Leukapheresis
CD34+-selection optional
Cycle 1
One cycle
Melphalan
200 mg/m²
Cycle 2
+ PBSCT
PBSCT
Interferon
-
Interferon-
Single vs. double HDT in MM
GMMG-HD2: Patient characteristics
Single
Double
Number of Patients
178
180
Median Age [y
g[years]
55
56
Beta-2 MG [mg/l]
2.5
2.8
ALB [g/l]
[g/l]
40
39
HB [g/dl]
11.5
11.8
CRP [mg/dl]
6
5
Database 6/2007
Single vs. double HDT in MM
GMMG-
GMMG HD2: Number of Pa
P tients
a
Single TPX
Double TPX
Randomization
n=188
n= 197
N=385
-10
-17
-27
Evaluable
n=178
n=180
N=358
-12
-6
-18
Stem Cell Mob.
n=166
n=174
N 340
=
-10
-6
-16
TPX I
n=156
n=168
N=324
Refusal of 2nd
-75
TPX by 47 patients
TPX IIII
n=93
High-dose therapy in MM
ASCT: HD2 Points to consider
2nd TPX only in 52% of evaluable pts., 26% of
pts in Double TPX-Arm refused 2nd TPX, therefore
ITT and "per protocol" analyses
TRM Single HDT (2%) vs. Double TPX (2%/3%)
Time between Single HDT and Double HDT:
Median of 141d
Relapse therapy second/third TPX >20%
Tr
T eatment with new
new drugs > 40%
GMMG Single vs. Double HDT: EFS ITT
double
single
GMMG Single vs. Double HDT: EFS per protocol
double
single
GMMG Single vs. Double HDT: OS ITT
double
single
GMMG Single vs. Double HDT: OS per protocol
double
single
Single vs. double HDT in MM
GMMG HD2: Conclusions
The final analysis of the GMMG-HD2 study does not
show a benefit in terms of EFS or OS for pts. treated
with Double
Double HDT compared to pts. treated
treated with Single
Single
HDT
CR after HDT correlated with "good prognosis"
prognosis ,t
, here
there
is no difference in CR in both treatment arms (p=0.5)
We have to identify Pts. who significantl
yg
y benefit
from Double HDT
Single vs. double HDT in MM
EFS after HDT TT 2: 70 genes high risk model
Shaughnessy et al., Blood 2007
Single vs. double HDT in MM
EFS after HDT in predicted EC-groups HD and MPL data, n=100
.01
.80
12
12
12
EC1 1
. :
1: 11
1 q13+, CCND1
EC1.2: t(11;x), CCND1
60.
EC2.1: CCND2
tear
EC2.2: t(4;
(;14),
), CCND2, FGFR3
S
EF
.40
21
21
11
11
.20
l
p. r = 0 0008
.
17
22
22
p.cph = 0.0029
00.
0
3
6
9
12
15
18
21
24
27
30
33
36
Months
p.cph(1.1 vs. 2.2) = 0.00106
44
41
4
32
32
24
19
1
12
8
7
5
3
1
25
18
16
15
10
7
5
4
1
18
18
1
13
12
9
9
7
3
3
3
13
1
95
42
22
Hose et al., abstr. 74, ASH2004
Single vs. double HDT in MM
Dynamic magnetic resonance imaging (DMRI) in MM
before
f
a ter
Conclusion I: HDT in MM
ASCT:
HDT is the current standard of care
TBI (12Gy)
(12Gy) or BU 16 should be
be avoided and Mel
Mel
200 should be used
TRM is
is relatively
relatively low
low
Follow up for patients treated with HDT is partly
longer than 10 years late effects are known
Treatment time (Induction, SC-Mob, TPX) is mostly
shorter than one year
Conclusion II: HDT in MM
ASCT:
CR and VGPR correlate with better quality of life
CR and VGPR
VGPR achievement correlates
correlates with longer
longer
survival
Combination of
of new
new drugs with HDT induces more
and deeper CR => Cure?
Outside clinical trials, double transplantation
should be proposed to patients failing to achieve a
CR or VGPR after the first transplant
Single vs. double HDT in MM
Pa
P r
a ticipa
t
t
icipa ing
t
centers (n = 66)
Caritas-Krankenhaus Bad Mergentheim
Klinikum Fulda
Med. Klinik und Poliklinik Universität Mainz
HUMAINE-Klinikum Bad Saarow
Städt. Krankenhaus Gütersloh
III. Med. Klinik Univ. Mannheim
Md
Med. Ui
Universität
ität k
s li
kli i
n k
ik Vi
Virchow-Klinik
ikum Bl
Ber ilin
Kt
Ka h
th. Krank
h
en aus Hagen
Universitäts
Universität klinik Marburg
Krankenhaus Berlin-Neukölln
Allg. Krankenhaus Hamburg-Altona
Marinen Hospital Marl
Krankenanstalten Gilead Bielefeld
Universitätskrankenhaus Hamburg-Eppendorf
Kreiskrankenhaus Meißen
Med. Universitätsklinik Bochum
Ev. Krankenhaus Hamm
Medizinische Klinik Minden/Westf.
Med. Univ.
Univ -
. Klinik Bonn
St. Marien
Marien-Hosp
Hos ita
p
l
ita Hamm
Ham
Krankenhaus Maria Hilf Mönchengla
g dbach
Med.Univ.-Poliklinik Bonn
Städt. Krankenhaus Siloah Hannover
Dr.Grabenhorst Mönchengladbach
Zentralkrankenhaus St. Jürgen Straße Bremen
PD Dr. Rohrberg/Dr. Hurtz Halle
Städtische Kliniken Offenbach
Knappschaftskrankenhaus Bottrop
Med. Klinik und Poliklinik V, Univ. Heidelberg
Dr. Baldus Rüsselsheim
Med. Klinik Klinikum Chemnitz
Klinik für KMT Idar-Oberstein
Akad. Lehrkrankenhaus Saarbrücken
Karl-Thiem-Klinikum Cottbus
PD Dr. Ruffert/Dr. Hoffmann Jena
Nordwest-Krankenhaus Sande
Städt. Kliniken Darmstadt
Med. Klinik Westpfalz-Klinikum Kaiserslautern
Evang. Diakoniewerk Schwäbisch Hall
Städt. Klinikum Dessau
Med. Klinik St. Vincentius-Krankenhäuser Karlsruhe
Mutterhaus d. Borromäerinnen Trier
Knappschaftskrankenhaus Dortmund
Städtisches Klinikum Karlsruhe
KH der Barmherzigen Brüder Trier
Med. Klinik und Poliklinik I, Tech. Univ. Dresden
Klinikum Kassel
Klinik
ikum der Stadt Villingen-Sh
Schwen i
n ngen
St. Johannes-Hospital Duisburg
Klinik für Innere Medizin Universität Köln
Hanusch Krankenhaus Wien
Werdau Kliniken Duisburg
Klinikum Krefeld
Zentrum für KMT Wiesbaden
Med. Klinik Universitätsklinikum Essen
Städt. Krankenhaus Süd Lübeck
Med. Poliklinik Univ. Würzburg
Malteserkrankenha
an
us
kenha
Flensburg
Klinikum der Stadt Ludw
Lud igs
i
h
gs a
h fe
a n
fe
Med. Klinik
Klinik, Kliniken St. Antonius Wuppertal
Med. Klinik III, Universität Frankfurt
Medizinische Fakultät der Universität Magdeburg
Universitätsspital Zürich
Krankenhaus Nordwest Frankfurt
Krankenhaus Altstadt Magdeburg
Stadtspital Triemli Zürich
Vielen Dank!
Thank You!
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HS
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a
d
wen er
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Jens Hillengaß
Christof Scheid
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Ralph Naumann
Anthony D. Ho
M
t
on
lli
pe er
At
Anne t
tte Hä
Hä
l
ne
Dieter Huhn
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