Autografting for Myeloma in 2009
The Way Forward
Sergio Giralt, MD
Professor of Medicine
Department of Stem Cell Transplantation and Cellular
Therapies
University of Texas MD Anderson Cancer Center
MYELOMA 2009
New Collection and Conditioning Techniques
Optimal
Induction
COLLECT
Regimen
A
HD THERAPY+SCT
A
A
Maintenance
A
A
A
m
m
HARV
HAR EST AND
m
HOLD
SCT UPON RELAPSE
Risk Profile
Annual Number Of Transplants For Myeloma In
North America
Type of transplant
Year of Transplant
Total
2000
2001
2002
2003
2004
Allogeneic
77
88
65
50
29
309
Autologous
1311
1529
1657
1822
2021
8340
No planned 2nd tx
668
1205
1338
1535
1506
6252
Planned 2nd auto
134
149
132
154
330
899
Planned 2nd allo
12
26
35
21
73
167
Missing
497
149
152
112
112
1022
* From a subset of patients who submitted detailed disease specific information to the CIBMTR, N= 1855
MOBILIZATION STRATEGIES IN MM ACCORDING
TO CIBMTR 2004-07
· MOBILIZATION
N
%
None
81
3.62
Chemo
50
2 2
. 3
23
Chemo+GF
1254 56.03
GF
853
38 11
.
· MOST COMMON USED CHEMO
CYCLOPHOSPHAMIDE
Plerixafor (AMD3100)
· A bicyclam molecule
· Reversibly binds to CXCR4
receptor and blocks SDF 1
-
interaction
· Vt
Very water
l
so b
u l
ble
· Highly charged (plus 4 at physiological pH)
· Low molecular weight (MW = 502)
· Rapidly increases mobilization of CD34+
hematopoietic stem cells
De Clercq E. Nat Rev Drug Discov. 2003; 2:581-7.
What role for plerixafor in
myeloma?
MOBILIZATION FAILURES
Risk Factors For Mobilization According To Lenalidomide Use
Variable
Lenalidomide Used
Lenalidomide Not Used
N=64
N=238
% Failed
P value
% Failed
P value
Age
<60 vs >60
15% vs 37% .05
4% vs 4%
Prior Chemo
11
<1 vs >1
13% vs 36%
.04
3% vs 6%
Dx to Mobilization
<12m vs >12m
15% vs 42% .02
3% vs 12%
.01
Lenalidomide
Cycles
1-
1 3v
3 s
vs >3
16% vs 78% .001
Popat, et al. American Society of Hematology Meeting 2008.
What role for plerixafor?
IMPROVING COLLECTION
EFFICIENCY
Patients (%) Achieving 6 x 106 CD34+
Cells/kg by Apheresis Day ITT Population
of
HR=2.54, p<0.0001
n ells/kgc 100
86.8
86.8
90
77.9
Plerixafor
80
proportio CD34+6
70
of
54.2
10
56.0
x
60
49.0
6
Placebo
50
stimate
s
35.3
e
40
30
17.3
-Meier reaching
20
3 day improvement in median time to target
n
10
0
Kapla patients
1234
Apheresis Day
DiPersio J, et al. Blood. 2007;110:137a-138a. Abstract 445.
Improving Myeloma Outcomes
Focusing on the Stem Cell Product
A
A
A
Graft engineering
A
A
A
A
Purging?
Collection
SC
T Cell Activation?
Supportive
Care
PBSC Transplantation: Faster Engraftment and
Less Resource Utilization
·
Comparative analysis of PBSC and bone marrow autologous
transplantation in children with various malignancies
PBSC Transplantation
BMT
5 × 106/kg
<5 × 106/kg
(n=37)
(n=65)
(n=29) p Valuea
Neutrophil and Platelet Engraftment
Days to ANC >0.5 × 109/L
9
10
14
0.0001
Days to platelets >20
>20 × 109
10 /L
12
14
21
0 0001
.
Resource Utilization
Transplantation unit LOS, d
17
28
<0.0001
b
b
Antibiotic use, d
7b
10
14
<0.0001
RBC transfusions
2
2
4
<0.0001
Platelet transfusions
3
4
8
<0.001
BMT, bone marrow transplantation; LOS, length of stay; a p value between PBSC and bone marrow transplantation groups; b p<0.005 for difference between cell
dose groups.
Vicent MG, et al. Haematologica. 2001;86(10):1087-1094.
Randomized Phase IIII LD/HD
LD/HD CD34
Symptom Severity by CD34 Positive Cells Infused
6
4 - 6x10^6 CD34 Cel s/Kg
10 - 15x10^6 CD34 Cel s/Kg
5
ms
4
to
ymp
evereS
3
Ssto
5Mfo
2
neaM
1
0
Baseline
Conditioning Regimen Day of Transplant
Nadir of WBC
Hospital Discharge
30 days post BMT
Time
High Dose vs Low Dose CD34
Assessments:
QD
Q ay
Day x2
x 8d
28 ays
day
Q Week
W
Study End
Toxicity
Cytokines
Cytokines
MDASI
Cognitive
Cognitive
Fx
Fx
35 million CD34+ cells/kg
Rando
adomize
Eligibility:
Multiple myeloma > 60
Amyloidosis
CCI > 3
High-
High dose melphalan
melphalan
Autograft
1015 million CD34+ cells/kg
ALC recovery as prognostic factor
Ml
Myeloma P
t
orra a t
e l
a .
Re-exploring
-
Purging
Purging
Cumulative Incidence of
Relapse
100
ce
80
Autologous (n=168)
% 60
Inciden se,p
40
Rela
Syngeneic (n=42)
of
mulative
20
Cu
0
02
1
3
4
5
Years
Effect induced by Velcade in normal stem cells
(CD34
3 +
4 cellll )
s
100
velcade 16hrs
n
80
Velcade 24hrs
tiobi 60
Inhithw 40
o
Gr
20
%
0
25
2.5
5
10
20
40
80
160
Velcade nM
Improving Myeloma Outcomes
Conditioning Regimens
Maintenance
Induction
A
A
A
Regimen
Salvage
A
A
A
A
SC
Supportive
A
A
Care
Prep
A
A
A
A
m
Regimen
A
m
A
m
m
Risk Profile
Risk Profile
Moreau et al. Mel 200 is
Superior to Mel-TBI Blood 2002
Probability of Survival after Hematopoietic Stem
Cell Transplants for Multiple Myeloma, 1998-2004
- by Donor Type -
100
CR rates after HD Mel +/-40%
80
%
60
Auto (N=12,565)
lity,
40
Probabi
HLA-id sib (N=763)
20
Unrelated (N=103)
0
02
1
3
45
6
Years
Slide 51
SUM06_45.ppt
Increasing the Melphalan
Dose
The issue of Tandem SCT.
Is it settled?
Common Wisdom: Patients
achieving a VGPR or greater
gg
do
not benefit from tandem SCT
Overall Survival According to Whether Patients Had at Least a Very Good Partial Response
after One Transplantation (Panel A) or Had No Such Response (Panel B)
Attal, M. et al. N Engl J Med 2003;349:2495-2502
The Tandem
Tandem SCT Question
Question
· NO STUDY HAS PROSPECTIVELY EVALUATED THE
QUESTION OF
OF THE
THE BENEFIT OF
OF A 2nd
2 CONSOLIDATION AFTER
AFTER
AN INITIAL HIGH DOSE THERAPY SO ANY CONCLUSION WITH
CURRENT DATA IS AT BEST CONJECTURAL AND AT WORST
MISLEADING.
· Pt
Post Hoc
l
ana
i
ys s
In the IFM 94 analysis 84 patients were compared to 46
patients in the tandem SCT group.
In the BOLOGNA
BOLOGNA 96: 45 patients in ARM A (single
(single
transplant) vs 76 in ARM B (TANDEM TRANSPLANTATION)
were compared in a NON PREPLANNED FASHION.
· In the context of conventional induction therapies (ie no IMIDS
or bortezomib) tandem SCT
SCT is associated with the highest
highest CR
rates and improved PFS with a POTENTIAL survival benefit.
Thus the role of tandem SCT needs to be re-explored in the
context of proteosome inhibition and IMID's.
Time for a Randomized
Randomized Trial
· For an expected 3 year PFS = 60% in the control one arm, and PFS
= 70% in the other
other a sample
sample size
size of
of 441 evaluable subjects
subjects per
group is required for a level .025 one-sided test of non-inferiority to
have 90% power to reject.
·
· For a test of superiority, with a 3 year PFS = 70% in one arm and 3
year PFS = 85% in the other arm, a sample size of 172 evaluable
subjects per group is required for a level .05 two-sided test of
superiority
py to have 90% power
p
to reject.
·
· For a test of superiority, with a 3 year PFS = 70% in one arm and
superiority PFS = 80% in the other arm, under a binomial sampling
model, a sample
sample size
size of
of 410 evaluable subjects
subjects per group is
required for a level .05 two-sided test of superiority to have 90%
power to reject.
Incorporating Novel Agents
Into the Conditioning Regimen
Optimizing Conditioning
Si
Spanish R i
eg stry
HD Melphalan-Arsenic-Vitamin C
Treatment Plan
Qazilbash t
e l
a BBMT 2008
Arm 1
Arm 2
Arm 3
Melphalan
Melphalan
Melphalan
100 mg/m2 IV x Days
100 mg/m2 IV
100 mg/m2 IV
-4, -3
Days -4, -3
Days -4, -3
Ascorbic acid
Ascorbic acid
Ascorbic acid
1000 mg IV
1000 mg IV
1000 mg IV
Days -9 to -3
Days -9 to -3
Days -9 to -3
Arsenic trioxide
Arsenic trioxide
Arsenic trioxide
None
0.15 mg/kg
0.25 mg/kg
Days 9
- to -3
Days 9
- to -3
The Kaplan-Meier Estimates For Progression-free Survival
Probability-
y Excluding Prior Autograft:
gg
Impact
p
Of ATO
Dose
1.0
Cumulative
0.9
Group 1, N=14
0.8
Proportion
Group 2,
p, N=13
0.7
Group 3, N=9
0.6
Su
rviving
05
0.5
MEL 100 x 2
Auto PBSCT
Progre
0.4
Current trial
0.3
s
--99 --88 --77 --66 --55
s
--44 --33 --22 --11 0
sion
0.2
Free
AA+As03
0.1
B
B
B
p value 0.2
0.0 0
5
10
15
20
25
30
Months Post Transplant
Treatment Plan
Arm 1
Arm 2
Arm 3
Melphalan
Melphalan
Melphalan
100 mg/m2 IV
100 mg/m2 IV
100 mg/m2 IV
Days -4, -3
Days -4, -3
Days -4, -3
Ascorbic acid
Ascorbic acid
Ascorbic acid
1000 mg IV
1000 mg IV
1000 mg IV
Days -9 to -3
Days -9 to -3
Days -9 to -3
Arsenic trioxide
Arsenic trioxide
Arsenic trioxide
0.25 mg/kg
0.25 mg/kg
0.25 mg/kg
Days -9 to -3
Days -9 to -3
Days -9 to -3
Bortezomib
Bortezomib
Bortezomib
None
1mg/m2
1.5 mg/m2
Days -9, -6, -3
Days -9, -6, -3
Table 1: Patient Characteristics and Outcomes
Arm 1 (n=19)
()
Arm 2 (n=20)
()
Arm 3 (n=19)
()
p Value
Age (median)
61
59
64
0.08
Abnormal
2 (10%)
5 (25%)
8 (42%)
0.08
Cytogenetyics
Relapsed
6 (32%)
7 (35%)
3 (16%)
0.4
disease
Prior ASCT
2
0
1
0.3
Interval
12.2
9.6
8.8
0.3
Diagnosis to
ASCT
C (mo
(m nt
on hs
th )
s)
Median CD34
4.2
4.1
3.6
0.6
106/kg
Engraftment
10
10
10
0.1
(days)
CR
5 (26%)
2 (10%)
3 (16%)
0.4
ORR
14 (74%)
12 (60%)
16 (84%)
0.3
Progression
3 (16%)
8 (40%)
5 (26%)
Dead
2
2
0
Maint
n enance
6 (32%)
(32%
4 (20%)
(20%
3 (16%)
(16%
05
0.5
Rx
Grade II-IV
15 (79%)
18 (90%)
18 (95%)
0.4
Toxicity
Grade III-IV
6 (32%)
(32%
6 (30%)
(30%
6 (32%)
(32%
0.9
Toxicity
Grade I-II
16 (84%)
14 (70%)
18 (95%)
0.1
Weight gain
There Was No Significant Difference In PFS
Between The 3 Arms
Melphalan + Bortezomib
Transplant
control
Day -4
Day 3
Day 2
Day 1
Day 0
Melphalan 100mg/m2 (all
XX
groups)
Bortezomib 1.0, 1.3, or 1.6
A*
mg/m2
Bortezomib 1.0, 1.3, or 1.6
B*
mg/m2
Bone Marrow Aspirate
XX
Stem Cell Infusion
X
Lonial et al, ASH 2007
Response/Toxicity data
Overall Response rate 35/37 = 94%
CR+VGPR 19/37 = 56%
Median time to Platelet and Neutrophil engraftment 16
and 13 days and no difference between historical
lb
controls or between
d
ran
i
om zed arms.
No additional toxicities noted.
CR=complete response; VGPR= very good partial response; PR= partial response; PD= Progressive Disease
Other Combinations to be Explored
·Melphalan and hyp
pypomethylating agents
Dacitabine- 5 Azacytadine
Preclinical data
Clinical data in allograft setting
· Melphalan and lenalidomide
Preclinical data
· Melphalan and HDAC
Preclinical data
· HD Melphalan and anti-IL6 antibody
Clinical data
Figure 3. Overall survival
IFM9904
High risk
(B2M/del13)
Mel200+Mel220
CR rate:51%
Moreau, P. et al. Blood 2006;107:397-403
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
Incidence of Moderate to Severe Symptoms
Baseline MDASI Score Major Predictor of
of
Persistant Moderate to Severe Symptoms
%
Symptoms and Toxicities and
C t
y okines Wang et al
Conclusion
· The advent of plerixafor should encourage
us to re-explore the role of the stem cell
product in improvin
pp
g transplant
p
outcomes.
· Many of the new agents being explored for
myeloma have sy
yynergistic
g
activity with
alkylators in vivo and in vitro.
· This synergy
ygy should be explored
p
in well
designed clinical trials of high dose
melphalan to improve SCT outcomes.
Acknowledgements
·
Department of SCT
·
Department of Lymphoma/Myeloma
Muzaffar Qazilbash MD
Robert Orlowski MD, PhD
Muzaffar Qazilbash, MD
Richard Champlin, MD
Raymond Alexanian MD
Rima Saliba PhD
Donna Weber MD
Michael Wang MD
SCT Faculty
Sheeba Thomas MD
Research Nurses
Nurses
Qing Yi MD,PhD
· Jane Brown
·
GIM/ Nephrology
· Kathy Mroczkowski
Amit Lahoti MD
Data Managers
·
Biostatistics
· Floralyn Mendoza
Peter Thall PhD
·Eric Han
Xuemei Wang
· Harold Booc
·
Symptoms Research
· Jiulianne Chen
Charles Cleeland Ph.D.
Fellows/ Residents
Karen Anderson, Ph.D
Xin Shelley
Shelley Wang
Wang, MD