Anti-angiogenic therapies for
Multiple Myeloma
Shaji Kumar, MD
Associate Professor
Division of Hematology
Scottsdale,
Scottsdale Ari
A
Ari ona
z
Rht
Roches
h ter
t ,
er Mi
M
Mi
t
nneso a
t
Jk
Jack
i
sonv lille,
ill Fl
F
Fl i
or d
ida
id
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Disclosures
· Research Funding for Clinical
Clinical Trials
Celgene, Millennium, Novartis, Bayer
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Ai
Angiogenesis and cancer
· Increased angiogenesis and its contribution to
cancer has been recognized for
for decades
Mayo Clinic College of Medicine
Mayo Clinic
Folkman 333Comprehensive
(26): NEJM,
Cancer
1757,
Center
December 28, 1995
Pro- & anti-Angiogenic
Factors
· VEGF
· Ai
Angiost t
a itin
·bFGF
+
-
· Endostatin
·PDGF
· Arresten
·EGF
· Canstatin
· Ang1, Ang2, TIE2-mab
· Tumtatin
· Ephrins
·Restin
·HGF
· Prolactin
· MMP
· Vasostatin
· Thrombin, Tissue factor
· Kininostatin
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Bevacizumab (Avastin)
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Is angiog
ggenesis relevant in
myeloma?
Angiogenesis is increased in myeloma
Normal
compared to MGUS, and increase with
disease progression
MM
Mayo Clinic College of Medicine
May
Va o Clinic
cca et al, Comprehensive
BJH, 87 (3), 503 Cancer
(1994); Center
Rajkumar et al, Clinical Cancer Research 6, 3111, (2000)
Angiogenesis is a prognostic factor
1
.8
ng
.6
survivi
P = 0.02; n = 400
.4
ortion
Low MVD
Prop .2
0
High MVD
MVD
0
25
50
75
100
125
150
175
200
Time (months)
Mayo Clinic College of Medicine
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Kumar et Comprehensive
al, ASH Abstracts Cancer
2005
Center
BM
Bone Marrow Angiogenesis
Angiogenesis is
is increased
increased in
correlates with other biological
plasmacytoma and is a prognostic
features in myeloma
factor for progression
Bone marrow microvessel density
l
corre t
a es
ith
w
· plasma cell labeling index
· Presence of circulating plasma
cells
· Cytogenetic abnormalities like
13q-
·ISS stage
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Kumar et al, Blood, 2003, 101 (5), 1715
Angiogenesis in myeloma:
Why and how?
· Likely multiple mechanisms are involved in
the increased angiogenesis seen in the
marrow and plasmacytomas in myeloma
· Endothelial cells: functionally abnormal or
structurally?
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Marrow angiogenic activity and disease
stage
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Kumar, Comprehensive
S. et al. Blood
Cancer
2004;104:11
Center
59-1165
Id
Inducers of angiogenesis
Interleukin-6 (IL-6)
Tumor necrosis factor alpha
Vascular endothelial growth factor
Fibroblast growth factor-2
Hepatocyte growth factor
Insulin-like growth factor-1
Macrophage inflammatory protein-1
Monocyte chemotactic factor-1
Stromal cell-derived factor-1
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Ribatti et
Comprehensive
al, Oncogene
Cancer
(2006) 25,
Center
42574266
Angiog
ggenic cytokines in
myeloma
VEGF
· The cytokine contribution by the individual cell does
not appear
pp
to change
g with disease progression
Mayo Clinic College of Medicine
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Kumar, S. etComprehensive
al. Blood
Cancer
2004;104:1159-1
Center
165; Leukemia (2003) 17, 20252031
Clonal abnormality of ECs?
·
Increased circulating endothelial cells
with disease burden
·
Clonal abnormalities present in
circulating endothelial cells
·
Di ti
s
t
nc gene expression
fil
pro es have
been described for the myeloma
endothelial cells compared to normal
endothelial cell
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Rigolin, G.
Center
M. et al. Blood 2006;107:2531-2535 ; Vacca et al
How does angiogenesis help?
· Endothelial cells in myeloma have multiple
multiple
effects on myeloma cells
· Studies in 5T2MM model suggest that
di
decrease in
l
norma hypoxic st t
a e f
o
marrow may lead to selective survival
d
a
t
van age for CD45- tl
tumor ce llls
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MM1.S
350000
HUVEC
HUVEC+MM1.S
300000
250000
200000
m
cp 150000
Endothelial cells stimulate
100000
myeloma cell growth in vitro
50000
0
0
2
4
8
12
16
20
24
Huvec number (X1000)
OPM2
U266
140000
120000
HUVEC
HUVEC+U266
HUVEC
HUVEC+OPM2
120000
100000
100000
80000
80000
m
m
60000
cp
60000
cp
40000
40000
20000
20000
0
0
0
2
4
8
12
16
20
24
02
4
8
12
16
Huvec number (X1000)
Huvec number (X1000)
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Dexamethasone
MM1.S
Huvec+MM1.S
lro 120
nto 100
C
80
eof
60
Endothelial cells protect
tag
40
n
20
rcen
0
Pe
0
0.01
0.05
0.1
0.5
1
myeloma cells from drugs
Drug Conc(µmol/L)
Revlimid
MM
MM+HUVEC
HUVEC
60000
50000
40000
00
m 30000
cp 20000
10000
0
01
5
10
50
100
Drug Conc (µmol/L)
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HUVECs stimulate multiple sig
pgnaling cascades in
myeloma cells
When MM1 S
. cells were cultured in contact with a confluent layer of HUVECs,
multiple signaling cascades were induced in the MM cells.
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Human bone marrow derived
endothelial cells
·
Similar results were obtained when MM1.S cells were grown in
co-culture with bone marrow derived endothelial cells from
patients with MM.
·
MM1.S cells were added to the confluent layers of BMEC and
then harvested at different time points.
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Neutralizing antibody
gy to IL-6 partially
py abrogates
g
the
stimulatory effect
Effect of IL-6 Neutralizing Antibody
+ Huvecs
200
l 180
ro 160
ont 140
C 120
eof 100
10
tag
80
60
rcen
40
Pe
20
0
0
0
15
1.5
6
25
Antibody Conc (g/mL)
IL6 Antibody
Hours
6
4
2
0246
0
2
4
6
pSTAT3
pAkt
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pErk
Mayo Clinic Comprehensive Cancer Center
Neutralizing antibody to
to VEGF
VEGF partially
partially abrogates
abrogates
the stimulatory effect of HUVECS
Effect of VEGF Neutralizing Antibody
+ HUVEC
80000
70000
60000
50000
m 40000
cp
30000
20000
10000
0
0
0
200
400
1
Anti-VEGF Ab (ng.mL)
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Endothelial cells
cells increase
invasiveness of MM cells
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I Vande Broek, Leukemia (2004) 18, 976982
Myeloma ECs
ECs secretes
chemokines
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Pellegrino et al, BJH, Volume 129, Issue 2, Pages 248-256
Is angiogenesis a reasonable
reasonable
target?
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"Anti-angiogenic" therapies for
myeloma
· Two paradigms:
· Drugs with
ith known actitivitity in
l
mye oma, with
ith
anti-angiogenic activity
·Drugs which are "targeted"
gg
to be anti-
angiogenic
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Thalidomide and angiogenesis
Pre-MVD Post-MVD
45.0
40.0
35.0
30.0
25.0
VDM 20.0
15.0
10.0
5.0
0.0
Responders
Non-responders
Kumar et al, Leukemia (2004) 18, 624
Vacca et al, JCO, 23, 2005: 5334
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Lenalidomide and anti-
angiogenesis
Lentzsch et al, Leuk
i
em a (2003) 17
17, 41
4144
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Dredge et al, Microvasc Res, 69, 56-63
Bortezomib
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Roccaro, A. M. et al. Cancer Res 2006;66:184-191
Targeted "anti-angiog
ggenic"
therapies
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Kumar et al, Blood. Podar et al
Phase II:Bevacizumab +
Thalidomide
· Relapsed myeloma
· Bevacizumab 10 mg/kg iv q 2 weeks alone
(in thalidomide
thalidomide exposed
-
patients)
· Versus a randomized comparison of
bi
bevaci
b
zuma
/
+ th lid
a
id
om e 50 400
mg/day (in thalidomide naïve patients)
· 12 patients were enrolled
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Somlo et al, Blood (ASH Annual Meeting Abstracts) 2005 106: Abstract 2571
Phase II:Bevacizumab +
Thalidomide
· Fatigue, neutropenia, hypertension
· Median time to progression for 6 pts on
bevacizumab alone was 2 (1 4)
months.
· Progression-free survival for 5 evaluable
ti
pa
t
en s t
t
rea d
e with bevaci
b
zuma
d
an
thalidomide is 6 +, 7, 8 +, 10, and 30 +
th
mon s
· Closed due to poor accrual
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Somlo et al, Blood (ASH Annual Meeting Abstracts) 2005 106: Abstract 2571
Phase II:Bevacizumab +
Len/Dex
· Relapsed or refractory MM, failing >1
therapy, with no previous exposure to
lenalidomide
· No current history of unstable
cardiovascular disease or
or uncontrolled
thrombosis
· 4k
4 week cycle:
lenalidomide 25 mg PO d121
bevacizumab 10 mg/kg IV every two weeks
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Raschko et
Cancer Center
al; dexamethasone
Blood (ASH Annual Meeting
40
Abstracts) mg
2007 1 PO
10:
q
Abstract week
1173
Phase II:Bevacizumab +
Len/Dex
· 17 pts enrolled, ages 53
53 89, with median
number of previous regimens 3 (range 1
6)
· 10 pts completed 4 cycles and evaluable
for response
response.
· 7/ 10 pts had a PR after median of 2
cycles
· Fatigue, DVT (2) and dyspnea (due to
bevacizumab)
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·N
Raschko et
o
al;
h
Blood ypertension
(ASH Annual Meeting Abstracts) 2007 110: Abstract 1173
Pazopanib (GW786034B)
Mayo Clinic College of Medicine
Mayo
Podar Clinic
K.
Comprehensive
et.al. PNAS
Cancer Center
2006;103:19478-19483
Pazopanib (GW786034B)
· Open-
Open label, single arm phase IIII trial
trial in
patients with relapsed/refractory MM
· 800 mg pazopanib p o
. . daily
· 21 pts were treated: median age 59 yrs
(2
(range 9
29 74)
-
;
· All pts were heavily pre-treated, including
86% with > 4 prior chemotherapy
regimens and 71% with prior stem cell
transplantation
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Prince et al, XIth International Myeloma Workshop and the IVth International Workshop
Pazopanib (GW786034B)
· Duration of treatment 14 to 279 days
· No clinical responses; 18 (86%) were
discontinued due to disease progression;
progression;
· 2 (10%) discontinued due to toxicity
· Nausea, fatigue, hypertension, epistaxis,
and headache most common toxicities
· No venous thromboembolism
· PK data paralleled that in RCC, OvCa,
sarcoma studies
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Sorafenib
· Sorafenib is a bisaryl urea designed to
specifically target
VEGFR2 and
Raf kinase by binding to its ATP binding site
· Hd
Has demonst t
ra d
e ii
in v t
itro
di
and in vivo
efficacy in a broad range of cancers
renall
l ce lll, hepatocelll l
u ar,
l
co on, breast,
pancreas, and ovarian cancer
· Ct
Curren ltly
d
approve for t
t
rea
t
men f
o renal
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cell carcinoma.
Mayo Clinic Comprehensive Cancer Center
Sorafenib in vitro activity
120
RPMI
ANBL6
Kas6/
Ka
1
s6/
100
MM1.S
OPM2
LR5
l)
80
tro
Dox40
noC
MM1.R
fo 60
%(yitil
IC50
biaV 40
20
0
MM1.S
OPM-2
0
0.01
0.1
0.5
1
2
5
10
Drug Concentration (Mol)
0
1
2
4
6
0
1
2
4
6
Hours
Mcl-1
pERK
pAkt
pSTAT3
Mayo Clinic College of Medicine
Actin
Mayo Clinic Comprehensive Cancer Center
Sorafenib in vitro activity
Cytotoxicity in primary patient cells
100
cc 90
tito 80
po 70
p
60
0 µM
fao 50
5µ
5 M
µM
e
40
10 µM
tag
30
20
ercen
10
P
0
Pt 1
Pt2
Pt3
Pt4
Pt5
Pt6
Pt7
Pt8
Patient Number
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Sorafenib-antiangiogenic
activity
200
Sorafenib + Myeloma marrow plasma
180
160
Sorafenib Alone
140
lle 120
lW
tron 100
o
fCo
80
%
60
40
20
0
Positive
Negative
m
M
M
Control
Control
1n
nM
10nm
50nM
0n
1uM
Drug
1nm
10
10nm
50
No
100nM
1u
Mayo Clinic College of Medicine
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Sorafenib clinical trials
· Sorafenib single agent phase 2 ongoing in
SWOG
· Two Phase 1/2 trials of sorafenib +
bt
bortezomib
ib ongoing
· Phase 1/2 trial of sorafenib + lenalidomide
currently accruing
yg
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Sorafenib + RAD001
90
80
70
Sorafenib
60
Rapamycin
leb
Combinatio
t n
ia 50
v
llse 40
C% 30
20
10
0
U266
RPMI
MM1R
MR20
Cell line
· Phase 1/2 clinical trial ongoing
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Sunitinib
· Inhibits VEGF and PDGF receptor
· Active in renal cell cancer
· Oi
Ongoing h
p ase 2 st d
u y
d
sponsore by
CTEP
· Currently accrued 14 patients
· Results awaited
· Fatigue, hypertension, heme toxicity
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VEGF Trap
· Tightly binds VEGF
· CTEP sponsored Phase II trial ongoing
· IV over 1 hour on day 1
· Repeated every 2 weeks for up to 6
courses
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Other agents in clinical trial
· Bevacizumab + Bortezomib
· ENMD-2076: activity against Aurora A and
multiple tyrosine kinases
· Vatalanib (PTK787):VEGF Receptor
I hibit
n
or
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Conclusions
· Bone marrow endothelial cells a valid
valid
target based on studies so far
· Likely that targeted disruption of
endothelial cells or its interaction with MM
cells may not work alone
· A combined approach with a myeloma cell
tt
target d
e th
therapy may make th
the tumor cellls
more susceptible
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