Current place of Allogeneic
transplantation in Myeloma
Is there a role for Allo-SCT in
myeloma?
· As part of first line therapy for all patients or
the results of donor versus no donor studies
· In high risk myeloma (only)
in the era of novel anti-myeloma agents
· In relapsed myeloma
is there an alternative strategy for the high NRM and low
efficacy in this category of patients
1
Allo-SCT as part of 1st line therapy
· Randomized controlled studies are the gold standard
for the evaluation of treatment efficacy, but are
difficult to perform for Allo-SCT
· The presence or absence of an HLA-identical sibling
donor can be used as a surrogate marker for
randomization.
Donor versus no donor comparison
Upfront Allogeneic SCT in Myeloma
Prospective donor vs no donor studies
Italian study group showed improved EFS and OS of
patients after tandem auto/nonmyelo- AlloSCT1
80 donor vs 82 no donor
IFM 99-03: no improvement in high risk MM (del13, high -2M)2
65 donor vs 219 no donor
EBMT: late difference in favour of auto/nonmyelo- AlloSCT
for EFS and OS compared to tandem auto
107 donor vs 251 no donor
BMT CTN: Blood and Marrow Transplant Clinical Trials
Network: ASH 2011: no improvement EFS/OS
189 donor vs 436 no donor
DSMM: no improvement in high risk MM except for the small
subgroup of patients with 17P-
126 donor vs 73 no donor
2
HOVON 50/54 MM
Final Donor versus no-donor analysis
of patients included in the phase III study of
Thalidomide combined with Adriamycin,
Dexamethasone and High Dose Melphalan
Results as of April 4, 2010
HOVON 50/54
Myeloma stage II/III 65 years
VAD vs TAD
CAD
HDM 200
HLA-id Sib
2-6 months after HDM
HOVON 54
HOVON 50
Nonmyelo-SCT
IFN vs Thal
TBI: 200cGy
Immune suppression
Cyclosporin/MMF
3
Donor versus no donor analysis
inclusion criteria
- Having received induction and HDM
- HLA-typing of patient and all sibs
- Treated in center with Allo-RIC policy
Eligible for donor versus no donor analysis: 260
122
vs
138
100(RIC) vs
114 (maintenance)
Median time of follow-up: 78 months for patients alive
Patient characteristics
· Age median
54 years (30-65)
· Male/female
64/36
· Salmon&Durie II/III
22/78
· ISS
I
52%
II/III
48%
· 13 (cytogenetics)
18%
Factors equally divided in both arms
4
Complete remission
no donor (146)
donor (121)
overall
42%
45%
n.s.
after thal
15%
after RIC 27%
PFS from HDM
donorPFS1:PFSfrom0months
donor
from auto-SCT
versus no
[mo]
donor
100
versus no donor
S
75
entage
50
P=0.17
ativeperc
Donor
Cumul
No-donor
25
N
e
No-donor
138
111
Donor
122
86
Logrank Stratified
P =0.17
0
0
12
24
36
48
60
months
72
84
At risk:
No-donor 138
109
77
58
40
32
21
11
Donor 122
95
66
54
46
36
20
9
4 Apr 2011-12:20:28
5
Survival from HDM
OS1: OS from 0 months from auto-SCT [mo]
100
Donor vs no donor
75
No-donor
Donor
percentage
50
P=0.63
Cumulative
25
N
d
No-donor
138
67
Donor
122
58
Logrank Stratified
P =0.63
0
0
12
24
36
48
60
months
72
84
At risk:
No-donor 138
129
118
110
99
79
49
19
Donor 122
104
94
86
77
66
38
15
4 Apr 2011-12:20:39
PFS
PFS3: PFS from RIC-allo
Allo
or HDM2/maintenance
versus m
[mo]
aintenance
100
75
P = 0.03
percentage
50
RIC-allo
Cumulative
25
no allo
N
e
no allo
114
95
RIC-allo
100
66
Logrank Stratified
P =0.03
0
0
12
24
36
48
60
months
72
84
At risk:
no allo 114
86
61
46
32
20
11
7
RIC-allo 100
77
57
46
41
29
17
7
4 Apr 2011-12:20:49
6
Survival
OS3: OS from RIC-allo
Allo
or HDM2/maintenance
versus
[mo]
maintenance
100
75
RIC-allo
no allo
percentage
50
P=0.38
Cumulative
25
N
d
no allo
114
56
RIC-allo
100
41
Logrank Stratified
P =0.38
0
0
12
24
36
48
60
months
72
84
At risk:
no allo 114
105
96
88
73
54
32
11
RIC-allo 100
83
82
78
69
52
31
11
4 Apr 2011-12:20:54
Toxicity and TRM of RIC-Allo
Maximum grade acute GVHD
Grade 1
16 %
2
13 %
3
5 % }
4
5 %
10%
39 %
Maximum grade chronic GVHD
limited
9%
extensive
56%
64%
TRM
10% at 12 months
14% at 36 months
7
No subgroup identified that benefits
from RIC-Allo: survival
P
Donor/no Donor interaction
ISS
II/III
0.013
0.79
-2M 3
0.004
0.38
Del 13
0.84
0.37
FISH 13
0.5
0.38
1p/q abn
0.47
0.23
Thalidomide
0.85
0.4
High Risk Myeloma as defined by ISS or -2M
only had no benefit from Allo-RIC
Conclusions I
· Convincing evidence is lacking that Allo-RIC improves
survival as compared to intensive therapy alone
· Even when a late survival benefit becomes apparent, in
the era of novel agents Allo-RIC should not be routinely
offered to patients in first line, even not in high risk
patients.#
· Allo-RIC should only be performed as part of clinical
trials# : novel strategies warranted!
# International Myeloma Working group (IMWG) consensus
H Lokhorst, H Einsele, B Bruno, J San Miguel, N Kroger, A Perez-Simon
P Moreau, G Gahrton C Gasparotto, S Giralt, D Vesole, W Bensinger
JCO: 2011
8
Novel strategies in clinical trials
·"Standard" Auto-Allo therapy followed by novel agents:
HOVON 76: lenalidomide maintenance
· Exploration of regimens with less acute toxicity (GvHD)
and focus on post Allo consolidation and subsequent
immune therapy
Two studies under the umbrella of the European Myeloma
Network (EMN) in first relapsed patients
- EMN- 04/PETHEMA
- EMN- 05/HOVON108
HOVON 65/76
phase II: maintenance with lenalidomide
VAD (3x)
PAD (3x)
Hovon 65
vs
Iv push
Thal 200-400mg/daily
HDM
200mg/m2
No HLA-id Sib
HLA-id Sib
Inclusion
NonmyeloST
200cGy
Bortezomib vs
Phase II
80
vs
thalidomide
study
patients
Lenalidomide
To start between
10 mg/daily
3-6 months
after RIC
9
Flow diagram of patients through HOVON 76 MM until Oct 7, 2009
Registration
n=36
Not eligible
n= 0
Reg. after 1-6-2009
n=7
Included 38
No data yet
n=1
Off protocol untreated n=2
- GvHD (related)
n=1
patients
- Progression
n=1
Lenalidomide cycle 1
n=26 (100%)
Off protocol
n=7 (27%)
- GvHD (related)
n=5
- progression/relapse
n=1
- refusal
n=1
Lenalidomide cycle 2
n=19 (73%)
Off protocol
n=3 (12%)
} 39%only
1 or 2 cycles
NOT
}54%,only
- AEs or dose<5 mg/day
n=3
4 cycles
Lenalidomide cycles 3-4
n=16 (62%)
3 cycles
n= 3
4 cycles
n=13
FEAS Off protoc
IBLEol!
n=4 (15%)
- AEs or dose<5 mg/day
n=1
- GvHD (related)
n=1
- progression/relapse
n=1
(Nfdy: 1)
- other
n=1
Lenalidomide cycles 5-8
n=11 (42%)
Major side effect:
5-7 cycles
n=4
8 cycles
n=7
Induction of GvHD
Off protocol
n=3 (12%)
- AEs or dose<5 mg/day
n=1
- chronic GvHD
n=1
Only 10 % of patients
- progression/relapse
n=1
(Nfdy: 1)
Lenalidomide cycles 9-12
still on study
n=7 (27%)
9-11 cycles
n=4
12 cycles
n=3
Off protocol
n=3 (12%)
- AEs or dose<5 mg/day
n=1
HOVON stopped study
- acute GvHD
n=1
(Nfdy: 1)
- progression/relapse
n=1
Lenalidomide cycles 13-20
n=3 (12%)
13-19 cycles
n=2
20 cycles
n=1
October 16, 2009
HOVON 76 MM
19
Nfdy indicates no further data yet
Rapid increase of activated T cells
after start of Lenalidomide: day 15 immune monitoring
B 100 p=0.002
p=0.003
p=0.004
80
ellscT 60
+ RD 40A-
HL 20
%
0
c1d1
c1d15
c2d1
c1d1
c1d15
c2d1
c1d1
c1d15
c2d1
All Tcells
CD4+ T cells
CD8+ T cells
10
· Exploration of regimens with less acute toxicity
(GvHD) and focus on post Allo consolidation and
subsequent immune therapy
Two studies under the umbrella of the European
Myeloma Network (EMN) in first relapsed patients
- EMN- 04/PETHEMA
* velcade in conditioning and as GvHD prophylaxis
- EMN- 05/HOVON108
* T cell depletion, early consolidation and pre-emptive DLI
SENSITIVE FIRST RELAPSE
Donor search
REP 3-4 x
sibling/unrelated
Melphalan/Fludarabine
Allo-RIC
Alemtuzumab T depletion
T cell depletion
EMN-05/
CsA in
HOVON 108
MUD only
Lenalidomide +/-
Early consolidation
bortezomib
3-6 months
FEASIBLE !
Adoptive T cell
DLI 1.106 T cell/kg
therapy
optional
DLI 1.106 T cell/kg
DLI 1.107 T cell/kg
+ mHa DC vacc
11
Conclusions/Questions
· The role of Allo-RIC in myeloma is undefined
- although the existance of a GvM effect is undisputable
· If we explore novel strategies in clinical trials:
- should "classic" tandem auto/allo still be used? Or:
- focus on prevention of GvHD to allow post ­allo strategies
- should not be explored in standard risk patients
- should be a joint effort of different study groups
acknowledgments
Acknowledgments
HOVON transplantation centers
Amsterdam: AMC,
M.J.Kersten, C.Huisman
Amsterdam: VUMC
S. Zweegman, J.J.Jansen
Rotterdam: Erasmus MC
M. Zijlmans, P.Sonneveld
Nijmegen. AMCN
R. Raymakers, N. Schaap
Maastricht: AZM
G. Bos, H. Schouten
Utrecht: UMCU
H. Lokhorst, M Minnema
Statistical analysis: Bronno van der Holt
October 16, 2009
HOVON 76 MM
12