MM-Paris 2011.04.29UF
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Allogeneic stem cell transplantation for
High-Risk Myeloma
Hermann Einsele
Medizinische Klinik und Poliklinik II
Universitätsklinikum Würzburg
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Allo-SCT for MM
· Is there a GvM Effect ?
· Curative Treatment Option ?
· Allogeneic SCT as front-line therapy
(comparison to autologous SCT)?
for high risk disease
· Strategies to improve Allo-SCT
Reduce TRM
Increase GvM
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MM-Paris 2011.04.29UF
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Allo-SCT for MM
· Is there a GvM Effect ?
· Curative Treatment Option ?
· Allogeneic SCT as front-line therapy
(comparison to autologous SCT)?
for high risk disease
· Strategies to improve Allo-SCT
Reduce TRM
Increase GvM
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Graft-versus Myeloma Effect
Tricot et al. 1996
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MM-Paris 2011.04.29UF
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Allo-SCT for MM
· Is there a GvM Effect ?
· Curative Treatment Option ?
· Allogeneic SCT as front-line therapy
(comparison to autologous SCT)?
for high risk disease
· Strategies to improve Allo-SCT
Reduce TRM
Increase GvM
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Allogeneic Stem cell transplantation for MM
Response Quality correlates with OS
Progression depending on Response Quality
Response Quality
PCR-
PCR+
Status
CCR
94%
54%
Progress
6%
46%
Corradini et al, Blood 2003
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MM-Paris 2011.04.29UF
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Allo-SCT for MM
· Is there a GvM Effect ?
· Curative Treatment Option ?
· Allogeneic SCT as front-line therapy
(comparison to autologous SCT)?
for high risk disease
· Strategies to improve Allo-SCT
Reduce TRM
Increase GvM
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Tandem-Melphalan vs. Auto/Mini-Allo SCT
for High Risk Myeloma IFM 99-03/04
VAD x 4
Cy 4g/m²
1.
Only High Risk Patients
(13q deletion+ß m>3mg/l)
2
Mel 200 + Auto SCT
2. Suboptimal Conditioning
(High dose ATG-GvM?)
HLA-id. Sib.
no
yes
Mel 220
Flu/Bu 8+ATG
+ Auto-SCT
+ Allo-SCT
(n=105)
(n=45)
Moreau P. et al. for IFM 99, BLOOD 2006
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Tandem-Melphalan vs. Auto/Mini-Allo SCT
for High Risk Myeloma
Results
Tandem-Mel
Auto-allo-SCT
p
(n=85)
(n=81)
CR-Rate after 2nd SCT
31%
35%
0.62
TRM
5%
10.9%
0.51
Median OS at 41 Mo
46%
51%
0.90
Overall Survival
Moreau P. et al. for IFM 99, BLOOD 2006/2008
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Allogeneic SCT for young patients with newly
diagnosed MM (all patients no risk group)
VAD x 3
1.
Conditioning in Auto-Arm
Cy 4g/m²
Suboptimal (Mel 100 in
20 patients, additional
Mel 200 + Auto SCT
patients received 140
instead of 200 mg/m²)
HLA-id. Sib.
no
yes
Mel 100-200
200 cGy
+ Auto-SCT
+ Allo-SCT
(n=59)
(n=60)
Bruno et al., NEJM, 2007
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Tandem-HD-Melphalan vs. Auto-Allo-SCT
for Patients with newly diagnosed MM
Results
Tandem-Mel
Auto-allo-SCT
p
(n=46)
(n=58)
CR-Rate after 2nd SCT
26%
55%
0.004
TRM after 2 years
2%
10%
> 0.05
Acute GvHD-Rate (°II - IV)
n.a.
43%
n.a.
Relapse mortality
43%
7%
<0.001
Median OS at 46 Mo
58 Mo
not reached
0.03
In this study neither 13q del nor ß m impacted on
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outcome of Allo-SCT
Bruno et al., NEJM, 2007
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PETHEMA study
Newly diagnosed MM, age 65 yrs.
6x VMCP/VBAP
Mel 200+ASCT
(n=752)
CR/nCR n=402, 53%
<PR, n=70, 9%
PR, but CR/nCR
(n=280)
no 2nd SCT, n=170
Genetic Randomisation
n=110
HLA-id sib no
HLA-id sib yes
2nd ASCT
RIC-Allo
CVB/Mel 200
Flu-Mel 140
n=85
n=25
Rosinol L et al., Blood 2008
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PETHEMA study
Newly diagnosed MM, age 65 yrs.#
Progression Free Survival
P=0.08
Allo/Auto
PFS not reached
Tandem-Auto
PFS 31mo.
Progression-free survival
Rosinol L et al., Blood 2008
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Tandem autologous/reduced-intensity allogeneic stem cell
transplantation versus autologous transplantation in
myeloma long term follow up.
Björkstrand Bo et al. JCO 2011
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Auto/RIC-allo versus Auto in Myeloma
Non-Relapse Mortality since 1st transplant
·Constant difference: p=0.0001 (Gray
test)
·At 24 mns: 12% (CI: 7% - 20%)
·Auto+All
o
·Auto
·At 24 mns: 3% (CI: 2% - 6%)
only
·Auto (N=249)
194
123
96
58
27
8
2
·Auto+allo (N=109)
80
57
46
34
19
11
3
Björkstrand Bo et al. JCO 2011
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Auto/RIC-allo versus Auto in Myeloma
Progression Free Survival since 1st transplant
·Reduction of risk in time: p=0.0012 (Cox)
·Auto+All
·At 60 mns: 35% (CI: 27% - 45%)
o
·At 60 mns: 18% (CI: 13% - 24%) ·Auto
only
·Auto (N=249)
194
123
96
58
27
8
2
·Auto+allo (N=109)
80
57
46
34
19
11
3
Björkstrand Bo et al. JCO 2011
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Tandem Autologous(ASCT) / Allogeneic Reduced Intensity
Conditioning Transplantation (RIC) with Identical Sibling Donor
Versus ASCT in Previously Untreated Multiple Myeloma (MM):
Outcome (Med. Follow-up 60 mo.)
RIC-Allo
Tandem-Auto
p
(n=88)
(n=104)
CR rate
51%
43%
n.s.
5 yrs Progression Rate
45%
77%
p<0.05
5 yrs PFS
35%
18%
P=0.001
Subgroup del13
31%
11%
P=0.002
5 yrs OS
63%
60%
n.s.
Subgroup del13
70%
53%
n.s.
Björkstrand Bo et al. JCO 2011
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Risk-stratified DSMM V trial
Enrolment into high-risk group, n = 199
AD
AD = Adriamycin/dex
AD
IEV = Ifosfamide/epirucin/etoposide
AD
Flu/Mel = Fludarabine, melphalan
AD
IEV
HD-Mel 200
mg/m²
high risk:
standard
13q
risk
Conditioning regimen Flu/Mel:
HLA-identical donor?
HD-Mel 200
Fludarabine 30 mg/m² iv; d -5, -4, -3
mg/m²
Melphalan 140 mg/m² iv; d-2
no
ATMRD
MUD
R
G* 10 mg/KG BW iv; d -3, -2, -1
Allogeneic SCT d0
HD-Mel 200
IFN-
Allo-SCT (Flu/Mel)
PEG-IFN
mg/m²
* only MUD
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MM-Paris 2011.04.29UF
Patient characteristics
Subjects positive for del13q14 on central molecular cytogenetics
Variable
Tandem-Mel
Auto/allo-SCT
n=73
n=126
Median age (range) [years]
56 (30-60)
52 (34-60)
Gender distribution (female/male) [%]
45/55
48/52
Durie&Salmon Stages [%]
-II
25.1
19.8
- III
75.3
80.2
Type of MM [n (%)]
-IgG
39 (53.4)
61 (48.4)
-IgA
18 (24.7)
36 (28.6)
- Light chain
15 (20.6)
28 (22.2)
- Not known
1 (1.4)
1 (0.8)
LDH > Upper limit of normal [%]
20.0
19.5
Elevated serum creatinine [%]
24.7
22.2
Median serum -2-microglobulin, (range) [g/dl]
3.3 (0.6-10.5)
2.9 (0.3-32.0)
Central cytogenetic analysis for all patients in addition
to del 13q (FISH)
Dr Peter Liebisch/Dr Christian Langer/Prof. Dr H. Döhner / Ulm
17p13 Deletion
t (4;14) Translocation
t (4;16) Translocation
t (11;14) Translocation
1q21.2 Gain
11q22.3 Gain
11q25 Gain
22q11 Deletion
1p22 Deletion
9q34.2 Gain
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Response Rate/Qualitiy in High Risk patients
Response 12 months after end of therapy according to treatment arm
p=.003
60
59
Tandem-Mel
Auto/allo-SCT
]
50
54
[%
ects
40
32
subj
ng
30
32
20
Respondi
10
14
0
10
1
9
0
CR
PR
MR
SD
PD
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High Risk Patients
Survival for subjects after auto/allo-SCT in relation to donor type
Matched unrelated donor (n=70)
Matched related donor (n=56)
p=.93
Treatment-related mortality for tandem-Mel at 2 years: 3/73 (4.1 %)
Treatment-related mortality for auto/allo-SCT at 2 years: 15/126 (11.9%)
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MM-Paris 2011.04.29UF
DSMM V Study High Risk Arm
PFS after 1st Auto-SCT
Median PFS 34 mo.
Median PFS 23 mo.
P = 0.022 HR 0.64 (CI 0.44 0.94)
C. Meisner 2011
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Patients with LDH benefit from Auto/Allo-SCT
p=0.005
HR 0.32 (CI 0.15 0.71)
Kaplan-Meier-curves Study Arms C and D for PFS
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Patients with a del 17p13 benefit from
Auto/Allo-SCT
Median PFS > 22 mo.
p=0.001
Median PFS = 6 mo.
(HR 0.13 CI 0.04-0.45)
Kaplan-Meier-curves Study Arms C and D for PFS
Alvares CL et al.
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Patients with 17p13-del benefit from Auto/Allo-SCT
p=0.0023
HR 0.26, CI 0.08-0.83
Kaplan-Meier-curves Study Arms C and D for PFS
Alvares CL et al.
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DSMM XII-Study
* if patient`s choice and if HLA-
matched donor available
with 146 patients included
no therapy-related mortality
Knop ,ASH 2010
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Conclusions
1. Allogeneic SCT is a treatment option for
high risk MM patients
2. Superiority of allogeneic SCT vs Auto-SCT in
high risk patients demonstrated in 3/5 studies
number of high risk patients limited, no novel agents
included in any of these studies
3. TRM after allografting for MM significant reduced
4. High relapse/progression rate also after allo-SCT
- modulate GvM (vaccination/ adoptive cell therapy)
- post-allo consolidation/maintenance
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Allogeneic Stem Cell Transplant versus Tandem
High-Dose Melphalan for Front-Line Treatment of
Deletion 13q14 Myeloma
An Interim Analysis of the German DSMM V Trial
S Knop, P Liebisch, H Hebart, E Holler, M Engelhardt,
RC Bargou, B Metzner, D Peest, W Aulitzky, C Straka,
H Wandt, O Sezer, M Hentrich, H Ostermann, C Peschel,
G Hess, B Hertenstein, M Freund, M Kropff, HH Wolf,
W Jung, N Frickhofen, G Maschmeyer, HG Mergenthaler,
E Heidemann, N Kröger, C Engel, L Kanz, C Meisner, and H Einsele
... 50 dsmm centers
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· rostock · greifswald
· lübeck
Chair
· 2 x hamburg
Hermann Einsele, MD, Würzburg
· oldenburg
Christian Straka, MD, Berg
· bremen
· berlin
Coordinating secretary
·
·
potsdam
hannover
Stefan Knop, MD, Würzburg
· munster
· magdeburg
· wuppertal
· goslar
·
Study coordination
·
göttingen
duisburg · dortmund
· halle/saale
· essen
Carmen Wesemeier, MD, Würzburg
· eisenach
Martina Haase, Würzburg
· cologne
Mareike Väthröder, Würzburg
Martina Gropengießer, Würzburg
· frankfurt
Biostatistics & data management
· wiesbaden
· trier
· mainz
Christoph Meisner, PhD, Tübingen
· kaiserslautern
würzburg
· homburg
Imma Fischer, PhD, Tübingen
· saarbrücken
· bad friedrichshall · erlangen
Birgit Baumann, MD, Tübingen
· nuremberg
· ludwigsburg
· 3 x stuttgart
· tübingen
· ulm · augsburg
dsmm
· offenburg
· 5 x munich
· freiburg
doing studies on multiple
· kempten
myeloma
vienna
merano
bolzano
graz
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Thank you for your attention!
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