Is there a role for allogeneic stem cell
transplantation (SCT)
(SCT) in Multiple Myeloma (MM)
(MM)
in the era of novel agents?
JP Fermand
Immuno-Ht
Hematology U i
n tit,
Saint-Louis Hospital, Paris, France
May be ...
With high dose therapy and autologous SCT± the novel agents:
-higher complete
gp
remission (CR
(
) rate
- longer remission
but no plateau in
in overall
overall survival (OS) curves
median follow-up 15.8 yrs
Medi
ed an
a
EFS
3.7 yrs
OS
6.6 yrs
still alive: 12 (19%)
in 1st remission: 4
(MAG phase II trial, 1986-1990, n = 63)
0
4
8
12
16
1012
What do we need?
Further tumor mass
mass reduction
reduction
Improved disease control mechanisms
1012
in most "CR"
"CR"
i
pat ents
still one to one hundred billion (109 to
1011) residual tumor cells !!
(Kinetics of tumor growth and regression in IgG
myeloma, P.Sullivan & S.Salmon, JCI, 1972)
Can the immunologic effect of allogeneic SCT
meet these needs?
DLI
Matched unrelated donor SCT
(Blood, 1996)
Graft-versus-Myeloma (GvM) effect: limitations
Disease related:
· residual tumor mass
mass
· kinetic of tumor growth
· weak and variable expression of target
minor histocompatibility antigens
on plasma cells
Genetic mapping of the minor histocompatibility
antigen recognized by a HLA class II-restricted T
cell clone derived from an allografted myeloma
patient
a CD19-encoded epitope,
not usually expressed on plasma cells !!!
(Spaapen et al, JEM, 2008)
Allo-immune effect in MM: disease-related limitations
Insensitive
Intermediate
Sensitive
Acute lymphoblastic
Acute myelogenous
leukemia
leukemia
rapid
High-grade lymphoma
llgrowth
ce
Graft-versus-myeloma
intermediate
Multiple myeloma
effect = modest
Intermediate
Mantle cell lymphoma
ftumor
grade lymphoma
o
Hodgkin's disease
Low-grade lymphoma
Chronic lymphocytic
Kinetic
Renal cell carcinoma
leukemia
slow
Renal cell carcinoma
leukemia
Breast cancer
Chronic myelogenous
leukemia
Sensitivity to graft vs. malignancy effects
(Adapted from Storb et al. Blood, 2001)
Allo-immune effect in MM: limitations
Disease related:
· residual tumor mass
mass
an ll
a ogeneic "
d
para ox"
· kinetic of tumor growth
no GvM without GvHD
· weak and variable expression of target
antigens (minor histocompatibility complex) on
plasma cells
efficacy implies toxicity !!
Treatment related:
Graft vs. Host Disease (GvHD) + infection
= high toxicity
particularly in myeloma patient
(age, immune deficiency,
renal impairment, ....)
Allogeneic stem cell transplantation (SCT) in MM
Applicable to ...
2nd allogeneic "paradox"
· young
High-risk treatment
·n tl
ot or only l
s ili h
g tl
htly
tt
pre-treated
(mortality, quality of
of life)
d
for low-risk/"good-
· in good remission
prognosis"patients !!
· without comorbidities (# normal renal function)
± HLA-identical sibling
only highly
highly selected
selected myeloma
myeloma patients
Allogeneic stem cell transplantation (SCT)
In theory,
theory MM is not a very
very good indication
What about clinical data?
Allogeneic SCT using myeloablative conditioning (MAC) regimen
US Intergroup Trial (autologous SCT vs. conventional chemo) if
55 yrs + matched sibling =
allogeneic SCT with
myeloablative conditioning
n=36
Transplant-
related mortality
mortality (TRM):
(TRM): 53%
too high toxicity!
(Barlogie et al. JCO 2006)
Reduced intensity conditioning (RIC) allogeneic
SCT in
in MM: pilot studies
studies
Alone or
after autologous SCT
SCT (Tandem
(T
auto/RIC allo
allo SCT)
Feasible, including
· it
in pa iti t
en s up to 60
60 yrs f
o age (l
(even o d
lder)
· with matched-unrelated donor
Insufficient
fll
Transplant-related mortality # 20% (15- 41%)
follow-up
(Bensinger, 2007)
Tandem auto/RIC allo SCT from HLA-identical sibling:
the Seattle series
n=102, med. age 52 yrs (35-71)
(auto within 10 mths from treatment initiation = 72%)
GvHD
median follow-up: 6.3 years
- acute, grade
grade 2-
2 4:
42%
- chronic extensive: 74%
5-yr non relapse mortality: 18%
CR rate post
p
allo: 65%
5-yr OS: 64%
Quality of life!!
5-yr PFS: 36%
(Rotta et al, Blood 2009)
"Donor vs no donor" comparative trials
of tandem auto/RIC allo SCT vs. tandem auto-SCT
Myeloma stage II/III 65 years, at diagnosis
HDM 200
HLA-id Sib?
yes
no
RIC-SCT
2nd auto-SCT
IFM
GITMO
Pethema
13
& 2>3
/
mg L
/L
tl
at least one sib
ib.
PR post
t
-au o
65 vs. 219
80 vs. 82
25 vs. 85
(Moreau et al. Blood 2008)
(Bruno et al. NEJM 2007)
(Rossinol et al. Blood 2008)
Tandem auto/RIC allo SCT vs. tandem auto SCT
GITMO
No striking
survival benefit of
RIC SCT vs.
med..OS:
80 vs 54 mths
a second auto
IFM
(PR post auto) Pethema
IFM
(13 and 2>3 mg/L)
med..OS:
med..OS (from 2nd SCT):
34 vs 48 mths (p.07)
NR vs 58 mths (p.9)
Comparative trial of auto/RIC allo SCT vs. auto SCT +
maintenance : the Hovon "donor vs no donor" study
Myeloma stage II/III 65 years, at diagnosis
HDM 200
HLA-id Sib?
yes
no
RIC-SCT
maintenance
HOVON
TBI 2 Gy / Thalidomide
Thalidomide or
or IFN
IFN
121 vs. 146
(Lokhorst et al, ASH 2008)
Tandem auto/RIC SCT vs. auto SCT+ maintenance
OS1: OS from auto-SCT [mo]
Hovon
100
No-donor
75
Donor
percentage
50
tivea
Cumul
25
N
d
No-donor
141
39
Donor
126
46
Logrank strat P =.03
RIC SCT not better
0
RIC SCT not
0
12
24
36
48 months 60
med..OS:
than maintenance
At risk:
No-donor 141
129
118
83
36
4
Donor 126
107
94
58
24
1
# 60 vs 70 mths (NS)
with Thal or IFN !!
21 Oct 2008-13:32:32
(Lokhorst et al, ASH 2008)
Allogeneic stem cell transplantation (SCT)
Overall, not better than
than auto-SCT
Cure in some patients, even in only a few?
Molecular monitoring in clinical CR after allo-SCT
Molecular complete remission (CR)?
Short follow-up in many
PCR-negative patients
Cure ??
not sure,
Late relapse
relapse in
in 3 patients with
even
with
for patients
repeatedly PCR-negative samples
in "molecular CR"
(Corradini et al, Blood 2003)
Plateau in survival curves?
OS from allo-SCT
Disease relapse from allo-SCT
MAC: lower relapse rates
compared to RIC
MAC (n= 196)
RIC (n= 320)
RIC (n= 320)
Reduced-intensity = no plateau
MAC = higher
MAC (n= 196)
Myeloablative = plateau ?
mortality rate than
RIC b t
u b tt
e er
GvM effect?
EBMT registry (Crowley et al. Blood 2007)
Allogeneic stem cell transplantation (SCT)
Cure ?
with MAC, not with RIC-SCT?
fewer residual tumor cells?
enhancing role of cytotoxic drugs in GvM?
Conclusions
No role for allo SCT in MM in current clinical practice
· whatever patient's age
· using either MAC or RIC regimen
But line of
of clinical
clinical research
To improve GvM while reducing GvHD and toxicities
· bd
better understand h
t e l
a lll ii
o-immune anti
l
-mye oma response
· combine novel agents with (RIC) allo-SCT
- for further
further tumor mass
mass reduction
reduction
- to synergize with GvM
·explore other innovative op
pptions
To be evaluated through well designed prospective studies
reject and GvHD,
more immunosuppressive
drugs
GvM and relapse,
less immunosuppression!
Toxicities and mortality,
y
less immunosuppressive
tumor mass reduction,
and cytotoxic drugs!
GvM and relapse,
more cytotoxic drug
ygs!
You have been
warned!
Infections,
li
less immunosuppression!
Allogeneic SCT
can drive you
crazy!
Thank you for your attention!
Thanks to Henz Lokhorst, Philippe Moreau and to many other friends