Dose-reduced Allogeneic
Stem Cell Transplantation
in Multiple Myeloma
Nicolaus M. Kröger MD
Francis A. Ayuk MD
Acknowledgement
Bone Marrow Transplantation University Hospital
Hamburg/Germany
A.R. Zander
B. Fehse
H. Kabisch
A. Badbaran
R. Erttmann
M. Zagrivnaja
H. Schieder
L. Fang
H.Renges
A. Lange
N. Fehse
M. Lioznov
J. Panse
T. Binder
N. Stute
Acknowledgement
Germany
Spain
J. Perez-Simon
Salamanca
H.G. Sayer
Jena
R. Martino
Barcelona
R. Schwerdtfeger
Wiesbaden
A. Alegre
Madrid
M. Kiehl
Idar-Oberstein
J. Beyer
Marburg
A. de Leon
Jerez
J. Tomus
Madrid
USA
J. San Miguel
Salamanca
H. Klingemann, H. Myint
Chicago
United Kingdom
Israel
B. Shaw
London
D. Marks
Bristol
A. Nagler, A. Shimoni
Tel Hashomer
K. Peggs
London
Supported by German Krebshilfe and Roggenbuck-Foundation
Allogeneic SCT for Multiple Myeloma
in Europe (EBMT)
400
Allo SCT
300
RIC
200
100
unrelated
1997
1998
1999
2000
2001
2002
Dose-reduced Melphalan/Fludarabin
in Multiple Myeloma
1. Salvage therapy: For patients
with relapse to autograft (n = 73)
Strategy
2. Auto-allo tandem approach mainly
for newly diagnosed pts (n = 57)
Dose-reduced Melphalan/Fludarabin
in Multiple Myeloma
Melphalan
100-140 mg/m²
Fludarabin 30mg/m² ATG*
SCT
CSA day100/180
-7
-6
-5
-4
-3
-2
-1
0
+1
+3
+6
day
MTX 10 mg/m²
*optional in MRD
Allografting after melphalan/fludarabine
(n=120)
· median age: 52 yrs (34-65)
· Previous high-dose regimen
none:
n = 24
one:
n = 83
two:
n = 12
· Relapse after autograft: n = 58
· Donor: related: n = 85
unrelated: n = 35
· Status at transplantation:
Chemosensitive: n = 74
Chemorefractory: n = 46
Allografting after melphalan/fludarabine
Results
· TRM:
at 1 year: 18% (95% CI: 12-38%)
· Response: CR: 49%
PR: 38%
MR/SD: 9%
PD: 5%
· 2 yr OS:
59% (95% CI: 29-89%)
· 2 yr PFS:
39% (95% CI: 29-49%)
· 2 yr Relapse: 43% (95% CI: 33-57%)
Overall survival after allografting
1.0
.9
No relapse to
prior HD
.8
.7
.6
.5
Relapse to
.4
prior HD
.3
.2
.1
0.0
0
12
24
36
Progression-free survival for Deletion 13
relapse to HD-therapy
No relapse to HD-therapy
1,0
1,0
without deletion 13
without deletion 13
with deletion 13
with deletion 13
0,8
survival
0,8
e-free
0,6
0,6
iseasdfo
0,4
0,4
0,2
0,2
probability
p=0.05
0,0
0,0
0
200
400
600
800
1000
0
500
1000
1500
days after transplantation
Prognostic factors after allografting:
Multivariate Analysis
Relapse to prior high- p-value
Chronic
p-value
dose therapy
GvHD
OS
HR 2.69
(95% CI)
(1.35 5.35)
0.005
EFS
HR 3.11
(95% CI)
(1.77 5.46)
< 0.001
Relapse
HR 4.14
HR 0.37
(95% CI)
(2.04 8.38)
< 0.001
(0.16 0.89) p = 0.02
TRM
HR 2.80
(95% CI)
(1.16 6.74)
0.02
Dose-reduced Melphalan/Fludarabin
in Multiple Myeloma
1. Salvage therapy: For patients
with relapse to autograft
Strategy
2. Auto-allo tandem approach mainly
for newly diagnosed pts
Multiple Myeloma II/III
+ HLA-compatible Donor (18 - 65 y.)
Induction or salvage chemotherapy
Melphalan 200 mg/m2
Autologous PBSC
Fludarabin 5 x 30 mg/m2
Melphalan 100-140 mg/m2
ATG 3 x 10-20 mg/kg KG
Allogeneic PBSC
DLI persistent disease/relapse
Kröger et al., Blood 2002
Patients
· 57 pts have completed autologous and allogeneic
transplantation.
· Median age:
51 years (r: 31-64)
· Male/female:
38/19
Cytogenetic (FISH) n=40: normal n= 16
Del 13 n= 24
· Med. ß
mg/dl (r,1
2microgl.:
2.9 mg/dl
-12.4)
· Median follow up:
16 months (r, 2- 46)
Allogeneic transplantation
· Interval between autologous and allogeneic
transplantation: 124 days (r: 39 to 223)
· HLA-type: matched related
n = 24
mismatched related
n = 2
matched unrelated
n = 29
mismatched unrelated n = 2
· Stem cell source: PBSC
n = 55 (96%)
BM
n = 2 (4%)
Allogeneic transplantation
Disease-status at allogeneic SCT
CR
n= 3 (6%)
PR
n= 37 (78%)
MR n= 1 (2%)
NC
n= 2 (4%)
PD
n= 4 (8%)
Relapsed to any chemotherapy n=9
(incl. to HD-therapy (n=4))
No relapse to any chemotherapy n= 48
Remission after allograft
· CR
55%
· PR
27%
· NC
5%
· PD
3%
Graft-versus-Host disease
· Acute GvHD:
II-IV:
n = 20 (35%)
III/IV:
n = 4 (7%)
· chronic GvHD: lim:
n = 10 (22%)
(n=46)
ext:
n = 4 (9%)
Treatment-related mortality
transplant-related mortality
1,0
0,8
Day 100 TRM: 11% (95% CI: 2-20)
0,6
1-year TRM: 17%
(95% CI: 7-27)
0,4
0,2
0,0
0
500
1000
1500
days after transplantation
Treatment-related mortality
transplant-related mortality
1,0
unrelated donor n=31
0,8
related donor
n=26
0,6
0,4
0,2
0,0
0
500
1000
1500
days after transplantation
Update auto-allo tandem transplantation
probability of overall survival
1,0
0,8
68% (95% CI: 55-81%)
0,6
0,4
0,2
0,0
0
500
1000
1500
days after transplantation
Update auto-allo tandem transplantation
probability of overall survival
1,0
0,8
0,6
0,4
0,2
unrelated donor n=31
related donor
n=26
0,0
0
500
1000
1500
days after transplantation
Update auto-allo tandem transplantation
probability of disease-free survival
1,0
0,8
0,6
42% (95%CI:24-60%)
60%)
0,4
0,2
0,0
0
500
1000
1500
days after transplantation
Update auto-allo tandem transplantation
probability of disease-free survival
without relapse to chemotherapy n= 48
1,0
with relapse to chemotherapy
n= 9
0,8
0,6
0,4
0,2
p< 0.001
0,0
0
500
1000
1500
days after transplantation
Update auto-allo tandem transplantation
relapse
1,0
unrelated donor
related donor
0,8
0,6
0,4
0,2
0,0
0
500
1000
1500
days after transplantation
ATG vs Campath an unrelated SCT in
Multiple Myeloma
Clinical trial Committee of the British Society of Blood and Marrow
Transplantation and the German Cooperative Transplant Group
Melphalan
140 mg/m²
ATG
Fludarabin
SCT
CSA day +180
20mg/kg
-7
-6
-5
-4
-3
-2
-1
0
+1
+3
+6
day
MTX
20 mg 20 mg 20 mg 20 mg 20 mg
10 mg/m²
Alemtuzumab
ATG vs Alemtuzumab: Results
ATG
CAMPATH
p
Number of patients
n = 48
n = 25
Leukocyte > 1 x 109/l
15 (range, 10 23)
13 (range, 3 22)
0.003
Platelets < 20 x 109/l
19 (range, 9 43)
13 (range, 9 23)
0.002
PR / CR after allograft
95 %
90 %
0.4
CR after allograft
51 %
19 %
0.01
Acute GvHD grade II IV
n = 22 (47 %)
n = 6 (24 %)
0.06
Acute GvHD grade III IV
n = 6 (13 %)
n = 0
0.06
Chronic GvHD
n = 13 (33 %)
n = 5 (25 %)
0.5
CMV-reactivation
n = 16 (47 %)
n = 12 (100 %)
0.001
Cumulative incidence of
21 % (95% CI: 12-
29 % (95% CI: 15-
0.7
treatment-related mortality (1 y)
37%)
55%)
53 %
45 %
Estimated overall survival (2 yrs)
0.5
(95% CI: 38-74%)
(95% CI: 27-73%)
ATG vs Campath in pts without any relapse to prior
chemotherapy at time of MUD SCT in myeloma
Campath n=9
ATG n=17
100
100
OS (days)
PFS (days)
80
80
60
60
40
40
20
20
0
0
0
200 400 600 800 1000 1200
0
200 400 600 800 1000 1200
100
100
TRM
Relapse incidence
80
80
60
60
40
40
20
20
p=.006
0
0
0
200 400 600 800 1000 1200
0
200 400 600 800 1000 1200
KIR-Ligand mismatch and outcome after
unrelated SCT in multiple myeloma
KIR-Ligand mismatch +(n=9)
OS (days)
No KIR-Ligand mismatch(n=48)
100
100
PFS (days)
80
80
60
60
40
40
20
20
0
0
0
200 400 600 800 1000 1200
0
200 400 600 800 1000 1200
100
100
TRM
Relapse incidence
80
80
60
60
40
40
p=0.04
20
20
0
0
0
200 400 600 800 1000 1200
0
200 400 600 800 1000 1200
Donor-Lymphocyte Infusion
GvHD after DLI: II - IV:n = 7 (30%)
III / IV:n = 2 (9%)
Response: 38%
1,0
CR:n = 3;PR:n = 5
0,8
0,6
unrelated n=10
0,4
p=0,01
0,2
related
n=11
0,0
0
50
100
150
days
Ayuk et al., Leukemia 2004
Thalidomide and DLI
Treatment plan
Thalidomide 100 mg
14 days
DLI: 1 x 106 CD3+/kg (MUD)
or: 5 x 106 CD3+/kg (related)
No response:
escalating Thalidomide (200 300 400 mg)
And/or: further DLI
Kröger et al, Blood 2004
Thalidomide and DLI
· n = 18
· Median age: 53 years (range 31 - 64)
· Prior autograft:
n = 17
single:
n = 12
tandem:
n = 5
· Allograft:
n = 18
RIC
n = 17
standard:
n = 1
· MUD:
n = 9
Related:
n = 9
· Study inclusion:
progessive disease n = 9
residual disease and failure to DLI: n = 9
Thalidomide and DLI
Response rate
CR:
6/18
33%
PR:
4/18
22%
67% (ORR)
MR:
2/18
12%
SD/NC:
5/18
28%
PD:
1/18
5%
Med. time to response: 108 days (36 266)
Thalidomide and DLI
· Acute GvHD:
I - II
n = 2 (11%)
II - IV:
none
· cGvHD
(n = 16)
limited:
6/16 (38%)
(4 pts had lim. cGvHD prior treatment
without worsening after Thal + DLI)
Only 2/16 pts: de novo lim. cGvHD (13%)
Dose-reduced Melphalan/Fludarabin
in Multiple Myeloma
Conclusions
1. Treatment related mortality is relatively low
after dose-reduced allograft with Mel/Flu
2. Unrelated SCT is feasible with no higher TRM
if performed at an early stage of disease
3. Transplantation should be performed at an
early stage of the disease
Dose-reduced Melphalan/Fludarabin
in Multiple Myeloma
4. DLI is effective in relapsed patients.
5. Thalidomide + DLI enhances remission rates
without severe GvHD
What is the Role of Reduced Intensity
Allogeneic Stem Cell Transplantation?
We see dose reduced allografting as part of a
broad treatment strategy including
autologous Transplantation, DLI, Thalidomide,
Velcade, Revlimid and other emerging drugs.
Dose-reduced Melphalan/Fludarabin
in Multiple Myeloma
Thank you !!
Dose-reduced Melphalan/Fludarabin
in Multiple Myeloma
Thank you !!
Dose-reduced Melphalan/Fludarabin
in Multiple Myeloma
Thank you !!
Engraftment after
allogeneic transplantation
· No graft failure
· Leucocyte > 1/nl: 16 days (r: 6-23)
· Platelets > 20/nl: 17 days (r: 8-33)
German Study-Group Multiple Myeloma
(DSMM)
Diagnose
Induktion (4x ID)
Mobilisierung
High-risk
Low-risk
Del 13
1x Mel 200
no Del 13
Biological randomisation
2nd Mel 200
HLA-id. Donor
Randomisation
yes
no
Mini-Allo
2nd Mel 200
Maintenance
Maintenance
Autologous transplantation
(Melphalan 200 mg/m²)
· Median transplanted cell dose:
4.2 x 106/kg CD34+ cells (r: 1.3 11)
· Engraftment:
Leucocyte > 1/nl: 12 days (r: 9 - 17)
Platelets > 20/nl: 14 days (r: 4 - 25)
Treatment of minimal residual disease
Auto-allo tandem protocol
Complete remission
Minimal residual disease (PCR)
No
Yes
Cure?
Relapse?
Molecular residual disease after allogeneic
stem cell transplantation
Treatment of residual disease after allografting:
1. Donor lymphocyte infusion
Thalidomide plus DLI
2. Myeloma specific T-Cells (mHA, MUC, etc)
3. Velcade, Revimid
Molecular residual disease after allogeneic
stem cell transplantation
Multiple Myeloma (EBMT-Study)
PCR neg
PCR mixed PCR pos
No of pts
16
19
13
5 year cumulative
risk of relapse
0%
33%
100%
Corradini et al., Blood 2003