Post
Post--Transpla
Tr
n
anspla t
n Maintenance
Thierry FACON
Lille University Hospital , Lille,
France
The optimal consolidation/maintenance
o
regimen
·
Effective
- Maximize number of responses
- Maximize depth of responses (induce molecular remissions)
- Delay relapse w/o compromising treatment of relapse
- Maximize the possibility
py of cure in a proportion
pp
of patients
p
·
Minimize short-term side effects (consolidation)
·
Minimize long-term side effects
- Eliminate significant
significant neurological
neurological o
or hematological toxicity
- Eliminate unexpected toxicities
·
Provide oral administration (for long term maintenance)
·
Provide affordable treatment
In recent years, thalidomide, bo
ortezomib, lenalidomide, and their
their
combinationshave provided the opportunity to achieve these
goals
Post
Post--Transpla
T
n
ranspla t
n Maintenance
with thalidomide, bortezomib, or lenalidomide
monoth
monot erapy
Maintenance therapy with thalidomide after
ASCT for MM: phase 2 studies
Study
No. of pts
Thal dose
Conclusion
Brinker et al.
112
200
Thal. seems to improve the OS of pts
compared with historical controls
Sahebi et al.
29
200
Thal. feasible and may improve
outcome after single ASCT
Stewart et al.
67
Randomized
Only the 200 mg arm met the definition
200 or 400
of a tolerable maintenance therapy (no
(+ 50 mg pred. on
dose reductions or discontinuation in
alternate days)
65% of pts for a minimum of 6 mo.)
Feyler et al.
100
5 dose-escalating
Doses > 200 mg/d largely unachievable
cohorts 50-300 mg/d
Per. neuropathy = main toxicity
15 pts PR CR
Brinker al. Cancer 2005;106:2171-80
Stewart et al. Clin Cancer Res 2004;10:8170-817
Sahebi et al. BMT 2006;37:825-29
Feyler et al. BJH 2007;139:429-433
Maintenance therapy with thalidomide
h
after ASCT for MM
Phase III randomized studies
Patients characteristics and Thalidomide regimens
IFM 99
99-021
02
Tunisian
T
MSG2
MSG
ALLG MM63
MM6
Year
2000 2003
2003 2006
2002 2005
No. pts (Thal.)
597 (201)
195 (98)
269 (114)
ASCT
Double
Single/Double
Single
Pamidronate + Thal vs
Tandem ASCT
Zoledronic Acid + Thal + Pred
Randomization
Pamidronate vs
vs
vs
no maintenance
Single + Thal
Zoledronic Acid
Acid + Pred
Thal. dosing
400 mg daily/until PD
100 mg daily/6 months
200 mg daily/1 year
1 Attal et al. Blood 2006;108:3289-94
2 Abdelkefi et al. Blood 2008;111:1805-1810
3 Spencer et al. JCO 2009; in press
Maintenance therapy with thalidomide
h
after ASCT for MM
Phase III randomiz
randomi ed studies: results
IFM 99-021
Tunisian MSG2
ALLG MM63
CR/VGPR*
Thal -
56
50
40
Thal +
67
66
63
P
.001
.04
<.001
3-year PFS (%)
Thal
37
57
23
Thal +
52
85
42
P
.002
.02
.001
3-year OS (
y(%)
Thal
87
65
75
Thal +
93
85
86
P
.04
.04
.004
Best response after randomization1, 6 mo. after second ASCT vs 3 mo. after maintenance2, 12 mo. post-randomization3
In 3 of 3 studies, Thal. maintenance was superior to no maintenance in terms of response, PFS, and OS
MRC Mye
My loma
e
IX
Randomise
Randomise
Clodronate
VS Zoledronic acid
Bisphosphonate
Clodronate
VS Zoledronic acid
CVAD
CV
VS
CTD
Chem
MP
VS
CTDa
motherapy
HDM 200mg/m2 + PBSCT
Randomise
Randomise
Thalidomide VS No Thalidomide
Main
Thalidomide
No Thalidomide
ntenance
VS
Thalidomide maintenance
t
treatment
·
Non-significant improvement in PFS across maintenance randomization
·
Intensive pathway
py
Significant improvement in PFS in patients with less than a VGPR post induction
(p=0.007)
PFS difference did not translate into survival benefit because survival after
progression in PR patients receiving maintenance thalidomide was poor (p=0.002)
Trend towards longer survival in patients with longer recovery time (time between
stopping thalidomide and progression) (p=0.056)
·
Impact of maintenance in different cytogenetic subgroups
PFS and OS in patients with del17p significantly worse in thalidomide maintenance
group
Although thalidomide maintenance may improve PFS, there is no
demonstrable benefit on OS
Morgan et al. Blood 2008;112:245 (abs. 656)
Updated results of phase 1/2 trial
t
of ASCT with bortezomib
maintenance for intermedia
intermedi te
a
and advanced stage MM
Liao et al.Blood 2008;112:1272(abstract 3710)
· Treatment
Bortezomib 1.0, 1.3, and 1.6 mg/m2 once weekly for 3
weeks, one week rest period, for 8 cycles
· Results (n=24)
MTD 1.3 mg/m2
DLT: grade 3 diarrhea
Median follow up
-
from tran
nsplantation 22 7
. months:
months:
· Median relapse-free survival: 20.2 months
PAD induction + reduced
reduced--in
intensity
t
ASCT + lenalidomide
consolidation/maintenance in elderly
eelderly patients with newly
diagnosed MM (102
(10 pts aged 65
65--75
75 y)
Palumbo et al. Blood 2008;112:65 (abstract 159)
Induction
VGPR
CR
PAD x 4
59%
13%
Intensification
Tandem Melphalan 100 mg/m2 + ASCT
88%
51%
Consolidation
Lenalidomide 25 mg days 1-21 + Prednisone
50 mg every other day
(four 28-day LP cycles)
88%
43%
Maintenance
Lenalidomide 10 mg days 1-21 every 28 day
Post-
Post Transplant
T
Conso
olidation/Maintenance
with thalidomide, bortezomib, or lenalidomide
± chemotherapyy combinations
Lessons from Total Therapy 1 & 2 programs
Zangari et al. BJH 2008;141:433-444
Induction
Transplant
Consolidation
Maintenance
VAD X 3
TT 1
MEL 200 x 2
NONE
Interferon
HD CTX
231 pts
EDAP
VAD
MEL 200 x 2
DPACE
Interferon + DEX
TT 2
DCEP
668 pts
Randomize +/- Thalidomide
CAD
The introduction of post-transplant consolidation therapy in TT2
DCEP
delayed the onset and
d decreased
decreased the magnitude
magnitude of relapse
especially benefiting pts CA-
Role of both Thal. and chemotherapy in pts CA+
Thalidomide arm of total therapy 2 improves complete
remission duration and
and survival in myeloma patients
patients
with metaphase cytogenetic abnormalities
Barlogie et al. Blood 2008;112:3115-3121
Total Thera
Ther py
a
3 (TT3)
Completion of therapy
·
INDUCTION
TT3A = 303
TT3B = 177
- VTD-PACE x 2 cycles
96%
94%
·
TRANSPLANT
- MELPHALAN 200 mg/m2 x 2 cycles
83%
75%
·
CONSOLIDAT
CONSOLIDA ION
T
- VTD-PACE x 2 cycles
70%
47%
·
MAINTENANCE
- TT3A : VTD x 1 yr, TD x 2 yr
70% (year 1)
35%
- TT3B : VRD
VRD for 3 r
y
35% (year 2)
0%
Barlogie et al. Blood 2008;112:66 (abs. 162)
VTD consolidation : GIMEMA Study
Ladetto et al. Blood 2008;112:1261 (abs. 3683)
·
Aim
Assess impact of VTD consolidation on residual MM cells in patients
achieving VGPR after ASCT by qualitative and quantitative PCR
·
Treatment
VTD started within 6 months after ASCT (for 4 cycles)
· Bortezomib 1.6 mg/m2 once weekly (days 1, 8, 15, 22)
· Thalidomide up to 200 mg/day
· Dexamethasone 20 mg/day, days 1-4, 8-11, 15-18
·
Results (n=40)
(n=40)
Six patients converted to MR
No clinical relapse observed in MR patients at median follow-up of 26
months
Among patients not achieving MR: 8 relapses occurred at median 12
months
New agents can substantially improve the quality of remission even
with optimal response to ASCT
Future Directions
Ongoing trials asssessing the role
role of
o
of
consolidation
consolidatio /maintenance
n
fl
fo
f l
flllow
ll
ing
i
tl
transp
t
l
ransp
t
an
IFM 2005
2005--02:
02: Lenalidomide as maintenance therapy
After ASC
ASC
CT for MM
M
MM
Ongoing phase III randomized, placebo-controlled trial
Patients < 65 years, with non-progressive disease, 6 months after
ASCT in first line
Randomize
Consolidation
Lenalidomide 25
25 m
mg/day p.o., days
days 1-
1 21 of
every 28 days for 2 months
Lenalidomide
10 -15 mg/day p o
. .,
Pl
b
ace ou til
n
l
re apse
continuous dosing
until relapse
Primary end-point: time to relapse.
Secondary end-points: CR rate, PFS, OS, feasibility of long-term lenalidomide.
CALGB 100104: Lenalidomide as maintenance
therapy after
aafter ASCT for MM
M
MM
Ongoing phase III, randomized, placebo-controlled trial
Patients with active MM, SD, or disease responsive to
4 months of induction therapy (N = 588)
ASCT
Re-staging
90100 days after ASCT
Random
Rando ization
Lenalidomide
Placebo
10 mg/day p.o.
10 mg/day p.o.
increasing to 15 mg if
tolerated (n = 250)
(n = 250)
Primary end-point: time to disease progression after autologous ASCT
Secondary end-points: CR rate, PFS, OS, and feasibility of long-term lenalidomide
Trial NCT00114101. Available from: www.ClinicalTrials.gov.
Phase 3: HOVON 65 MM / GMMG
GMMG--HD4
HD4
Accrual goal: 8000 patients
MM Stage II or III, Age 1865
Randomization
3xV
3 x AD
VA
3xP
3 x AD
PA
CAD + GCSF
CAD + GCSF
MEL 200 + PBSCT
MEL 200 + PBSCT
Depending on local
Depending on local
policy for patients PR MEL
Allogen
A
e
llogen ic
e Tx
policy for patients
200 + PBSCT
PR MEL 200 + PBSCT
Thalidomide
Bortezomib
50 mg/day for
1.3 mg/m2/2 weeks for
2 years maintenance
2 years maintenance
PETHEMA / GEM 2005 TRIAL
Symptomatic M
MM pts < 65 yrs
1st randomization
VBMCP/VBAD
THALIDOMIDE/
THALIDOMIDE/
X 4
DEXA
DEXA/
VELCADE
X 6
VELCADE
X 2
X 6
ASCT (Melphalan 200)
2nd randomization
INTERFERON--2b
THALIDOMIDE
THALIDOMIDE/
X 3 yrs
X 3 yrs
VELCADE X 3 yrs
Protocol for newly diagnosed MM < 61 yrs. - DSMM XI
optional Dex
Dex
VelCyDex
VelCyDex
VelC
CyDex
y
IEV
1H
1. HD-Ml
Mel
200 mg/m²
High risk
Standard risk
HLA identical sibling/MUD
2. HD-Mel
yes
no
200 mg/m²
Allo-SCT
2. HD-Mel 200 mg/m²
R
R
R
Observe
Vel weekly
Observe
Vel weekly
Observe
Vel weekly
Nordic Myeloma Study Group 15/05
Bortezomib conssolidation study
study
Primary end-point: event-free survival
Bortezomib 1.3 mg/m2
mg/m -
Bortezomib 1.3 mg/m2
mg/m -
R
twice weekly for
fo two
weekly for three weeks
A
3 months
R
weeks
A
N
Followed by
b
by one week
following
N
DD
Followed by one we
w ek
e
rest
rest
ASCT
O
O
M
M
Tt
I
Target
I
es
Z
2 cycle
4 cycles
N = 400
A
Z
(close
T
A
I
T
April 2009) ONIO
Observation
N
Response, toxicity and feasibility data will be presented at the end of
2009 and survival data in 2010
Conclusions
s
(1)
· Post-transplant consolidation/maintenance is feasible with
single agent thalidomide, bortezomib, or lenalidomide, and with
combinations
· Data suggest that consolidation is effective but randomized
studies will have to be design
ned
· Three studies have shown that thalidomide maintenance is
superior in terms of responseeP
e, FS
PFS, and
and OS
OS
· In the MRC Myeloma IX, no improvement in OS was found for
th lid
a
omide maintenance
a significant improvement in PFS was found for a subgroup of patients
with a sub-
sub optimal response
response po
po
ost-transplant
Conclusions
s
(2)
· Thalidomide maintenance has limitations: toxicity, pts with
del 13q and del 17p
· Thalidomide consolidation treatment may be useful. The
duration of this treatment has not been defined (6 months?)
· Need to define pts who will benefit from consolidation and/or
maintenance (cytogenetics-defined or GEP-defined risk)
· Need to monitor response in order to adjust treatment
· Results from
from several recentlyy completed
completed or ongoing phase 3
studies are eagerly awaited
Jean-Paul Fermand
Philippe Moreau
Thierry Facon
Proteasome
DSMM X:
Bortezomib Consolidation after
ASCT in patients age 61-75 years
PBSCs
PBSCs
Konsolidierung
Bortezomib
ex
MEL
MEL
e
IEV
R
D
140
140
G-CSF
G-CSF
G-CSF
2 Mo
Observation
3 Mo
GEP
GEP--defined
define risk
risk--directed
directed
therapies TT4 and TT5
· TT4 FOR LOW-RISK MM PHASE
· TT5 FOR HIGH-RISK MM PHASE
III: reduce toxicity while
II: avoid host exhaustion
sustaining efficacy
DOSE-DENSE BUT LESS
TT3 STANDARD versus
DOSE-INTENSE
TT3 LIGHT
· M-VTD-PACE induction x 1
· M-VTD-PACE induction x
· MEL80-VRD-PACE tandem
1
transplants
· MEL50x4 + VTD tandem
· MEL20-
MEL20 VTD-
VTD PACE X 2
transplants
peri-transplant
· M-VTD-PACE
· R-VD alternating with M-
consolidation x 1
VD maintenance
· VRD maintenance
Post-BOR/MEL GEP of both
Post-BOR/MEL GEP of both
PC and marrow biopsies
PC and marrow biopsies
· Drug action & prognosis
· Drug action & prognosis
Maintenance therapy in MM before
b
the era of novel agents
· Maintenance therapy with alkylating agents had failed to
demonstrate any benefit 1,2
· Most randomized studies and meta-analyses evaluating
maintenance interferon showed a modest increase in PFS
without any, or
or with minimal
minimal, survival benefit after
after
conventional or high-dose therapy 3,4,5
· Corticosteroid maintenance w
was found
found to prolong the
duration of response but the effect on survival was
controversial 6,7
1. Alexaninan et al, Arch Intern Med 1975;135:147-52
5. Schaar et al, Ann Oncol 2005;16:634-39
2. Belch et al, Br J Cancer 1988;57:94-99
6. Berenson et al. Blood 2002;99:3163-68
3. Th
The M
l
ye oma Tri l
a i
li t
s 'C
s
ll
o G
. roup BJH
BJH 2001;113
11 :1020-34 7. Sh
Sh
t
us ik
tik t
e
l
a , JCO 2004 22
;
558
:
s
4. Fritz et al, Ann Oncol 2000;11:1427-36