Role of Bone Marrow Transplant
Transplant
in the Treatment of My
M eloma
Ed
d
war A. St dt
a
mauer,
dt
MD
Professor of Medicine
Abramson Cancer Cente
t r
e
University of Pennsylvania
Philadelphia,
Philadelphia Pa
Pa
Challenges of Treating
Treatin
gg
Multiple Myeloma
)
ASYMPTOMATIC
SYMPTOMATIC
(g/L
teins
REFRACTORY
Pro
RELAPSE
M
Durie. International Myeloma Foundation. 2007. www.myeloma.org.
Multiple Myeloma:
Strategy for Cure?
Tumor Burden
Induction or Initial Therapy
(Bulky)
High Dose Melphalan +
Autologous Stem Cell Tr
T ansplant
r
(Minimal)
Immunotherapy + anti-myeloma
vaccines or Consolidation therapy
Targeted Maintenance Therapy
Initial Approach for Myeloma Patients
Requiring Disease-Specific Therapy
Patient with
with active/symptomatic myeloma
Not a transplant candidate
Transplant candidate
Induction with agents that do not cause
Melphalan,
marrow damage (no alkylating agents,
prednisone +/-
such as melphalan, minimize radiation)
thalidomide, bortezomib
or other drug
Stem cell collection: ensure adequate
combinations
stem cell numbers collected for
two or more transplants
Stem cell transplant
(one or two autologous or autologous
role for maintenance
maintenance therapy
followed by
by allogeneic*)
allogeneic*)
*Allogeneic stem cell transplantation for myeloma
is being studied in clinical trials
Indications for Hematopoietic Stem Cell
Transplantation in the U.S.
5,500
5,000
Allogeneic (Total N~8,150)
Autologous (Total N~11,500)
4,500
4,000
ts 3,500
nla 3,000
sp 25
2, 00
500
na 2,000
Tr 1,500
1,000
500
0
Mult
u ip
lt le
ip
NHL
NH
AML
Ho
H dgkin
ALL
MDS
MD /
S MPD
CML
Aplastic Other
Ot
Leuk
Othe
Ot r
Non
No -Mal
Malig
ig
My eloma
Disease
Anemia
Cancer
Disease
Blood Cells
Red Blood Cells
Stem Cell
White Blood Cells
Platelets
Types of Stem Cell Transplant
Type
yp
Source of Stem Cells Role in Myeloma
y
Treatment
Autologous Patient's blood
blood or
Current standard of
of care
care
marrow
Allogeneic
Sibling or Unrelated
Under study in clinical trials
Donor blood or
marrow or
bili
um
l
ca
cord blood
Atl
Auto
t logous St
Stem
St
Celll Transp
T
lant
· An important treatment
for patients with myeloma
· Generally must have
adequate lung, liver and
heart function
· More than one transplant
can be performed at
various stages
· Consider benefits vs.
risks
Autologous
Stem
St
C l
e l
lll T
l
ransp
t
an a
t tion
ti
Mobilization
and
Autologous
High
Autologous
High
Leukapheresis
Stem
Dose
Stem
Cells
Chemotherapy
of Patient
Cells
Stem Cells
Autologous
Stem
Thawing and infusion
Cells
Cryopreservation
of patient stem cells
of Patient Stem
-190oC Freezer
Cells
High-dose melphalan
Some studies with improved overall survival compared with standard
dose therapy
VMCP/VBAP x4-6 MEL140+TBI
CVAMP x3 MEL200
VMCP/VBAP x18
ABCM x4-12
INTERGROUPE FRANCAIS DU MYELOME
MEDICAL RESEARCH COUNCIL
(IFM)
(MRC)
Attal, NEJM 1996
Child, NEJM 2003
Tandem transplant Improves Response in
Patients with <90% Response to
to First
First Transplant
Response to first gra
pg ph
p <90%
Response to first gra
pg ph
p >90%
IFM 99
999 02:
-
Overall Survival
100
Thal +
75
P<0.04
%
Thal
50
rvival,uS
25
0
0
19
38
57
76
Ti
T me,
i
mo
Attal M et al. Blood. 2005;106:335a [abstract 1148]
Ongoing Study of Lenalidomide As Maintenance
Therapy Following Autologous PBSCT for
for MM
CALGB/ECOG 100104: Phase III Randomized, Placebo-
Controlled Trial
Trial
R
A
Lenalidomide
Patients with
N
10 mg/day po to
Pi
i h
RE-
active MM,
D
progression
stable disease
PBSCT
STAGING
O
(n=250)
90100 days
or responsive
M
to
ft
a er PBSCT
I
Placebo
4 months
Z
(n=250)
induction
E
therapy
(n=588)
1° Endpoint: Time to disease progression after autologous PBSCT
2° Endpoints: CR rate, PFS, overall survival, feasibility of long-term lenalidomide
BMT CTN 0702: SCHEMA
Lenalidomide
Maintenance**
Register
d
MEL ASCT
ASCT
Lenalidomide
and
VRD x 4*
Randomize
Maintenance**
MEL
Lenalidomide
ASCT
Maintenance**
* Bortezomib
Bortezomib 1.3mg /m2
/m2 days 1,
1, 4,
4, 8,11
8,11
Lenalidomide 15mg days 1-15
Dexamethasone 40mg days 1, 8, 15
**Lenalidomide 10mg daily x 3years
Allogeneic Bone Marrow Transplantation
· High dose chemotherapy + XRT :
Anti-tumor effects, immunosuppression, myeloablation
· Replace with normal donor hematopoietic cells.
· Get a graft
g
versus tumor immune beneficial effect
· Get a graft vs host (skin, gut, liver) detrimental effect
Allo
Cond
BMT
Rx
T
T
T
Recipient Blood
Donor
And Leukemia
Blood Cells
SCT for MM
· Allogeneic SCT still investigational, but may
benefit selected patients
· Tf
Types of Al
Allo SCT
SCT
Myeloablative or Full
Non-myeloablt
bla itive or Red
d
uce It
Intensitity or Mi
Mi i
n
· Who should consider allografts?
Pi
Patients i
w th poor prognostic factors
LDH
Cytogenetic abnormalities
2M, albumin
Young age
Short progression-fi
free interval aftfter autologous
SCT
BMT CTN
CTN #0102
710 enrolled
MM
MM Me
M etin
eeti g
n Eli
l g
i i
g b
iblity
lit
l t
as 3/07
endpoint 3 y PFS
Mel 200 Autograft
Recovered at least
60 days post autograft
HLA-matched Sibling
No HLA-matched Sibling
200 G
c y TBI
TB Al
Allogr f
a t
ft
M l
e 200 A t
u ogr f
a t
ft
CSA + MMF
Observati
tion
Th l
a i
lid
i
om d
ide +
Decadron for 1 yr
Tandem Autologous or Auto-
>Nonablative Allograft
Allograft for
ffor MM
Actually Transplanted
P =.03
N=58
N=46
Bruno B et al. N Engl J Med. 2007;356:1110
The Problem is Graft-vs-Host Disease (GVHD)
GVHD
()
CD3/28 T Cell Autologous Infusion Therapy for
Myeloma
1. Obtain leukocytes
from patient blood
T
M
B
M
M
B
T
M
T
6. reinfuse T cells
T
T
T
T
B
M
5. Remove beads with magnet,
2. enrich T cells with magnetic bead
wash and concentrate cells
depletion of Monocytes/Macrophages
T
T
T
T
T
T
3. culture for 12-14 days in gas
T
T
permeable bag with bead
4. Cells expand ~16-32 fold
immobilized anti-CD3/anti-CD28
in 12-14 days
Results: 54 patients with MM treated
·
Combination immunotherapy
A single early post-transplant infusion of
in vivo vaccine primed and ex vivo
costimulated autologous T cells
Post-transplant booster immunizations
·
Results
Improved the severe immunodeficiency
associated with high-dose chemotherapy
Led to the induction of clinically relevant
ii
immun tity (
l
pneumococca I G
g )
G) in d
a l
u tlts
within a month after transplantation.
Accelerated restoration of CD4 T-cell
numbers and function, significantly
improved T-cell proliferation.
Conclusions
· Exciting new agents in the treatment of multiple
myeloma have been introduced in the last 5-10 years
· Survival has improved, particularly in patients under
age 70 due at least in
in part to
to Autologous Stem Cell
Transplant
· The potential for longer survival and cure exists
Clinical trials are in progress to assess novel
combination therapies with transplant (lenalidomide,
bortezomib, etc)
,)
Role of donor (allogeneic transplant)
· Side effects of therapies are manageable but must
consider indi id
v
al
u patient characteristics (biological
(biological
factors, age, performance status, organ function).