STEM CELL TRANSPLANTATION
IN MULTIPLE MYELOMA
Sundar Jagannath MD
Professor of Medicine
St. Vi
t'
ncen s C
h
ompre
i
ens ve Cancer C
t
en er
New York, NY
Where is transplant today in the management of Myeloma?
Autologous Stem Cell Transplantation
Mobilization and
Leukapheresis
Autologous
High
Autologous
Stem
Dose
of Patient
Stem
Patient
Cells
Chemotherapy
Cl
Ce l
lls
Stem Cells
Autologous
Cryopreservation
Thawing and
Stem
Cells
of Patient Stem
infusion of patient
Cells
-190oC Freezer
stem cells
Stem Cell Mobilization
From Bone Marrow to Blood
· Gt
Grow h
th factor alone: G-CSF (N
®
(Neupogen )
®
­ Recent experience indicates that prior Revlimid use
decreases stem cell yield
· Cytoxan® plus G-CSF
· Plerixafor + G-CSF is
is superior
superior to G-CSF alone
alone
for stem cell mobilization
­ Patients receiving the combination were more likely to
achieve target collection earlier and achieve a successful
transplant
Redefining Role of Transplant in Novel
Therapy Era
· What does autotransplant represent?
­ Melphalan given at myeloablative high dose
· What does transplant offer?
­ Higher CR and VGPR
­ Durable remission
· What are the Challenges?
­ Early vs. late transplant has equivalent survival
­ Survival Improvement is 1 year
­ For over 65 years MP + Novel agent is better
­ What abo t
u second
second transplant in tandem?
5YR Relative Survival Ratio
Population Based Study from Sweden
High dose melphalan vs. Low dose
0.73
0.65
0.59
0.36
0.25
0.20
Variable
1973-79 1980-86 1987-93 1994-2003
Sweden HDT
0
0
77
1124
Kristinsson et al. J Clin Oncol. 25:1993, 2007
SEERS: 5 Yr Relative Survival
1990-1992
2002-2004
PE
PE
increase
p
5-y relative survival
All ages
28.8
34.7
5.9
<.001
< 50 y
44.8
56.7
11.9
.001
50 to 59 y
38.8
48.2
9.4
.001
60 to 69
30.6
36.3
5.7
.09
70 to 79
27 1
.
28 7
.
16
1.6
21
.
80+
13.8
15.2
1.4
.96
· Ml
Mel hl
phalan i
g ven as i
s
l
ng e hi
high dose is superior to chronic
low dose therapy
Brenner et al. Blood. 111:2521, 2008
PE = Point Estimate
Conventional Chemo vs. AutoTX
Pat
CR
EFS
OS
(n)
(%)
(mo)
(mo)
p Value
Chemo
100
5%
18
44
Attal et al
IFM90
0.03
NEJM 1996
Auto Tx
100
22%
27
57
Child et al
Chemo
200
9%
20
42.3
MRC7
00
0. 3
03
NEJM 2003
Auto Tx
201
44%
32
54.1
Palumbo et al
Chemo
98
6%
16
43
IMMSG
<0.001
Blood 2004
Auto Tx
97
25%
28
58+
Barlogie et al
Chemo
255
11%
27
65
USIG
JCO 2006
Auto Tx
261
11%
30
69
IFM 90 ­ 10 year update
HDT
CC
High Dose Therapy for patients up to age 65 years!!!
ECOG E4A03:
Lenalidomide + Dexamethasone
431 Patients Alive
at 4 cycles
Off therapy
Primary therapy
@ 4 cycles
beyond 4 cycles
N=176
N=255
No transplant
Transplant
Rd
RD
N9
N= 1
91
N8
N= 5
85
N 142
=
N 113
=
(Median Age 68)
(Median Age 57)
(Median Age 66)
(Median Age 65)
Rajkumar ASCO 2008, Abs#74
Overall Survival:
Survival: No
No transplant
transplant following 4
cycles of RD vs. Rd
72% Rd
69% RD
p=0.632 (Wilcoxon); p=0.790 (log-rank)
Rajkumar ASCO 2008, Abs#74
Overall Survival:
Survival: Transplant
Transplant following 4
cycles of RD vs. Rd
94%
RD
92%
Rd
p=0.801 (Wilcoxon); p=0.776 (log-rank)
Rajkumar ASCO 2008, Abs#74
Upfront vs. Rescue Transplant
70
60
PSCT (early)
PSCT (late)
50
40
30
20
10
0
Median OS
Median EFS
TWiSTT*
*Time without symptoms and treatment toxicity
Fermand J et al. Blood. 1998; 92:3131
Tandem ASCT
· Tl
Two planned
t
au
l
o ogous SCT
SCTs withi
ithin 6
months
­ Stem cells collected before the
the initial transplant
transplant
­ Half of the stem cells used for each procedure
· Second transplant may
py benefit:
­ Patients who do not respond or have marginal response to
1st transplant
Single vs. Tandem AutoTX
Age
Pat
CR
EFS
OS
(yr)
(n)
(%)
(mo)
(mo)
Si
l
199
42
25
48
Attal et al
ngle
IFM94
< 61
NEJM 2003
Tandem
200
50
30
58
Fermand et al
Single
113
39
31
49
MAG95
<5
< 6
56
Hematol J 2003 abs
Tandem
114
37
33
73
Cavo et al
163
33
23
65
Bologna
Single
< 61
J Clin Oncol 2007
96
Tandem
158
47
35
71
Tandem
Goldschmidt et al
Single
130
23
GMMG
< 66
Hematol J 2003 abs
Tandem
131
NR
Sonneveld et al
148
13
21
55
HOVON
Single
< 66
Haematologica 2007
24
Tandem
156
32
22
50
Overall survival after double SCT
A. Ve
V ry
e
Good Partial Response
B. Absence of Ve
V ry
e
Good Partial
after First
F
First Tr
T ansplantation
r
Response after
a
after First
F
First Tr
T ansplantation
r
100
100
)
)
%
%
75
(
Double
Double--
75
(
transplant
Double
Double--
(n=46)
transplant
50
50
(n=128)
Survival
Survival
Single
Single--
25
Single
Single--
25
transplant
Overall
transplant
Overall
(n=84)
(n=81)
0
0
0
022
22
44
66
88
0
022
22
44
66
88
Months after First Tr
T ansplantation
ansplantatio
Months after First Tr
T ansplantation
ansplantatio
Attal et al. NEJM; 349:2495, 2003
Brtz-Dex is Better Than VAD
Brtz/Dex vs. VAD (Phase III)
()
·Response* to Induction
Intention-to-
VAD
Ve
V l/Dex
e
P value
Treat Analysis
n=219
n=223
CR
3%
10%
0.004
CR+nCR
8%
19%
0.0004
> VGPR
19%
47%
0.0001
> PR
66%
83%
<0.0001
Pt
Post ASCT
-
Response
Intention-to-Treat
VAD
Vel-Dex
A1 + A2
B1 + B2
P value
Analysis
y
n=219
n=223
CR+nCR
23%
35%
0.0063
> VGPR
44%
63%
< 0.0001
> PR
79%
83%
NS
*modified EBMT criteria
Harousseau JL, et al. ASCO 2008, abstract #8505
Pamidronate With or Without Thalidomide as
Post-transplantation Maintenance Therapy
ppy
· Thalidomide is effective as maintenance therapy
­ Longer progression-free survival (PFS)
­ Significant benefits
benefits only in
in patients
patients with
· < 90% response at randomization (P = .05)
· No deletion of chromosome 13 (P < .002)
· Overall survival similar in all 3 groups
Attal M, et al. ASH 2004. Abstract 535.
No
Pamidronate
Response
No
Maintenance Pamidronate
+
P Value
Thalidomide
Median PFS, mos
27
28
> 38
0.002
3-year EFS, %
36
37
52
0.009
OS at 4-year, %
77
74
87
<0.04
Bone events, %24
21
18
0.4
3-yr risk of bone
65
26
24
0.04
events, %
Auto-Tx Followed by Thal Maintenance
Superior to Tandem Auto-Txs
Abdelkefi Tunisian
T
MM Study Group ASH 2006; abs#59
Auto-Tx + Thal maintenance
Tandem Auto-Txs
2 Txs
Tx + Thal
Parameter
P-value
(n=97)
(n=98)
CR + VGPR ­ after 1st Tx
39%
41%
NS
CR + VGPR ­ 6 mo. after Tx2 or Thal
51%
67%
.024
PFS at 3 years
57%
85%
.038
OS at 3 years
63%
88%
0.52
Improving Results with Auto-transplants
Age (yr)
Pat (n)
CR (%)
EFS (mo)
OS (mo)
Attal et al
IFM90
Single
< 61
100
22
27
57
NEJM 2003
Attal et al
Single
199
42
25
48
IFM94
< 61
NEJM 2003
Tandem
200
50
30
58
Harousseau
IFM 99
NR at
Tandem
< 61
1064
36
02-04
66 mo
Barlogie et al
TT 1
Tandem
< 71
231
36
31
68
Blood 1999 BrJH 2006
Barlogie et al
- Thal
345
43
44%
65%
TT2
< 75
at 5 yr
yr
Blood / NEJM 2006
+ Thal
323
62
56%
65%
Reasons for Improvement:
1. Double Auto
Auto-transplantation
2. Further Dose Intensification
3. Novel Agents
Newly Diagnosed
Bortezomib in Total Therapy 3
Patients: 303 pts with newly diagnosed MM; 28% 65 yrs
Dose: 2 cycles of VTD-PACE, tandem SCT with MEL200, consolidation with
2 cycles of VTD-PACE
PACE, followed by
by maintenance
maintenance VRD
VRD for 3 yrs
Efficacy: Median follow up 3 yrs; TT3 showed improved EFS (p=0.004) and
CR duration (p=0.0008) compared to TT2
CR Duration
EFS
100%
100%
TT3 (13/162)
TT3 (56/303)
80%
80%
P=0.0008
P=0.004
TT2+Thal
60%
(78/201)
60%
TT2+Thal (160/323)
P=0.19
40%
P=0.0006
40%
TT2-Thal
TT2-Thal (67/148)
(218/345)
20%
P=0.0003
P=0.0002
TT1
20%
TT1 (204/231)
TT1 (78/94)
0%
0%
0
5
10
15
20
0
5
10
15
20
Years from start of treatment
Years from complete response
Barlogie et al. ASCO 2008, abs # 8516
SLIDE 23
The Indomitable Gauls
Obelix
Data
supporting
tl
transpl
t
an
Rene Goscinny and Albert Uderzo 1959
EBMTR DATA ON MM
· 4 YEAR
-
SURVIVAL (
th
case-match
l
ana
i
ys s)
Syngeneic
25 pts
77%
Autologous
125 pts
46%
Allogeneic
125 pts
31%
· ALLOGENEIC TRANSPLANT (BMT vs. PBSCT)
Rapid engraftment with PBSCT
No difference in CR rate, OS or PFS
1-year mortality for BMT 20% vs. PBSCT 34%
Double Auto vs. Auto-Allo Transplants
Italian Study
Bruno et al. NEJM 356:110, 2007
Double Auto vs. Auto-Allo Transplants
Italian Study
Bruno et al. NEJM 356:110, 2007
Two Autotransplants vs.
Auto ­ Miniallo Transplants
p
Survival
1.0
0.9
0.8
0.7
0.6
52.1%
0.5
45 9%
.
0.4
P = .60
0.3
0.2
0.1
0010
20
30
40
50
Non-Ablative Allografts for Multiple Myeloma: A
Work in Progress
g
· Non-ablative transplants are feasible with early
transplant related
-
mortality
mortality as
as low
low as 10%
· Response rates low unless disease is minimal pre-
transplantation
p
· Best regimen has not been defined
· Tandem auto/allo
auto/allo transplants are
are feasible
­ Low transplant related mortality (20%)
­ High response rate CR 57%, PR 29%
· Non-ablative transplants should only be performed
within clinical trials
Stem Cell Transplantation for
Myeloma: Conclusions
· High dose therapy in combination with stem cell
transplantation improves
improves survival over standard dose
therapy for myeloma
· High dose melphalan is standard
· Performed in first remission or early relapse
· Double transplant may
py be superior
p
to single
g
transplant
p
in select patients
· Allogeneic transplant has more complications than
autologous transplant
­ But tandem autologous SCT followed by
non-
non myeloablative allogeneic
allogeneic SCT is
is promising
promising
· Post-transplant maintenance therapy promising
TT1: Impact of Novel Therapy on Survival
Barlogie et al. Br J Haematol. 135:158
ASCT for Relapsed MM
· Uf
Usef l
u rescue t
t
rea
t
men : no diff
difference in OS
OS between
upfront and rescue ASCT ­ Fermand Blood 1998
· In the US
US Intergroup
Intergroup study medain OS after rescue
rescue
ASCT is only slightly better than salvage chemo (30
mo. vs. 23 mo. P=0.13) ­ Barlogie J Clin Oncol 2006
· Results are better for chemosensitive relapses and
relapses off therapy
· Stem cell harvest
harvest is better done upfront than in relapse
­ Gertz BMT 2000