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Future Perspectives in Myeloma
Kt
Kenne h
th C. A d
n erson, M.D.
Jerome Lipper Multiple
Multiple Myeloma
Myeloma Center
Center
Dana-Farber Cancer Institute
Harva
aard Med
e i
d ca
cal Sc
Schoo
o l
o

Integration of Novel Therapy
gpy Into
Myeloma Management
· Thalidomide, Lenalidomide, Bortezomib
· Treatment of Relapsed/Refractory MM
(single agent/combinations)
· Induction/First-line Therapy
· Transplant/Maintenance

Oncogenomics and Technologic Advances:
· Identification of novel targets in MM and
BM milieu
· Prognostic and risk stratification
· Validation of novel targeted therapies
· Inform design of combination strategies
strategies
to enhance cytotoxicity, abrogate drug
resistance, achieve prolonged PFS
PFS and
? Cure.

Oncogenomics to Identify Targets and
Validate Targeted Therapies
Integrated platform aCGH, SKY and expression profiling
55 MM Cell Lines; 73 Patient Samples
Samples
60
ence 40
e 20
0
20
recurr 40
46 amplicons - 658 NCBI genes
% 60
%
Chr.
Chr 11223344556677889910
10 11
11 12
12 13 15
17
19
21 X
Expressed Genes : 258
Functional validation of MM candidate genes.
Small molecule
Monoclonal Abs
Carrasco et al. Cancer Cell,
Vaccines
2006 9:313-325

Vaccines Against Novel Targets:
Prediction of Peptides
Bi di
n ng to HLA
HLA-A2
IGF-1
BCMA
RANKPEP
Syndecan-1
Caveolin 1
·
- HLA-A0201 binding
Cyclin D1
·
- 9mer or 10mer
Intergrin a8
a8
·
- proteasome cleavage
Amphiregulin
HLA-DOB
Prediction of 37 peptides
IL-5 receptor a
from 9 genes
genes
RANK
POS.
N
SEQUENCE
C
MW (Da) SCORE
% OPT.
1
3
MG
KISSLPTQL
FKC
968.16
75
65.79%
2
38
LAL
CLLTFTSSA
TAG
924.08
67
58.77%
3
106
DLR
RLEMYCAPL
KPA
1077.34
64
56.14%
4
19
FCD
FLKVKMHTM
SSS
1116.43
61
53.51%
5
39
ALC
LLTFTSSAT
AGP
922.04
58
50.88%

Diverse Inhibitors of NF-B
Ci
Canonical
Non-Canonical
TNF-
IL-1, LPS
BAFF, CD40L
CD40 Ab
Autocrine/Paracrine
NF-Bt
B ac i
ti t
va i
TACI
T
-Fc
tion
TNF-R
TLR
BAFF-R
Plasma membrane
RIP
MyD8
IRAK
TRAF-3
TRAF-6
TRAF-2/5
Hsp90 inhibitor
NIK
(Complex)
Ub
(Complex)
Protea
Prote s
a o
s m
o e
m
PS-1145,
P
IKK
IKK
IKK
IKK
MLN120B, Thal
IKK
(IKK- activity)
NPI-1387-IKK
IKK
Bortezomib
P
inhibitor
Ub
p100
(Blocks IB- degradation)
Ub
Proteasome
P
p50
IB
RelB
Ub
P p65
IB
IB
p52
RelB
Proteasome
Translocation
SN50
Nuclear membrane
Translocation
IB
p52
degradat
ad ion
io
B
binding
bindin site
site
p65
RelB
p50
B binding site
Dex;
Target genes
Lenalidomide
Chauhan et al., BJC (In press)

Multiple Myeloma array CGH Prognostic Classification
groups
Sub
1.0
k1
0.8
(ratio) 0.6
k2-4
0.4
Survival 020.2
p=0.03
0.0
Time (days)
Carrasco et al. Cancer Cell,
0
200
400
600
800
1000
1200
2006 9:313-325

Gene Modulations Triggered
by Binding of MM Cells to BMSCs
Growth
Survival
BM
Drug resistance
MM
Adhesion molecules
stromal cells
Cytokines

MM cells
BMSCs
IL
IL--6,
6, IL
IL--1
1 ,
HGF,
HGF IL
IL--8,
8,
IGF
IGF--1,Gas6,
1,Gas6, MIP2
MIP2 , --2
2 ,

CXCL
CXCL--1,
1, --5,
5, --6,
6, --10,
10, --13
13
Cytokines
Cytokines
DKK
DKK--1,
1, Wnt
Wnt--5a,
5a, SHH
Chemokines
Microenvironmental
Apoptosis
FLIP,
FLIP survivin,
,, cIAP
cIAP--2,
2 Mcl
Mcl--11
interactions
regulation
IL
IL--6,
6, VEGF
IGF
IGF--1,
1, LIF
Proteasome
Hsp90, hsp70
Heat shock
pathway
proteins
integ
in
rin
teg
5

fibrillin 1
Proteasome
26S proteasome subunits
collagen V1
pathway
ubiquitin B, UCEs
USPs
26S subunits
6, 4, AT
A Pase
T
3,
non
non--ATPases
A
3,
3 --4,
4 --77
pim
pim--1,
1, pim
pim--22
Tr
T anscription
r
Oncogenes
control
HDAC2
XBP
XBP--1,
1, cc--maf,
maf, TCF8, rel
rel--B
B
eIF
eIF--2,
2, --3,
3, --4,
4, HDAC1
Tr
T anscription/
r
translation
control
MM cell

BM Microenvironment Triggers Proteasome
Activity in MM Cells
MM cells
BMSCs
Chauhan et. al., 2006

XBP-1s Transgenic Mice
)1
CONTROL
XBP-1s
10
Bone Lytic Lessions
X
XBP-1s
Ig(mg/mlm
Seru
sitometryn
De
istologyH
Bone
Carrasco et al, 2006

Plasmacytoid Dendritic Cells Promote the Growth
of MM Cells Ex-Vivo
* 4-5 fold increase in
CD138+
growth of MM cells
MM cells
* Increase in IL-1-, IL-6,
TNF- & VEGF
* NF-B induction
Myeloma Patient
Separation of MM cells
with CD138-magnetic beads
for further utilization
Co-culture
Proliferation/Propagation
of patient MM cells
Plasmacytoid
dendritic cells
Healthy donor or
Myeloma
My
patient
patient
Potential use for
In Vitro studies of
Genomics & Proteomic
deriving new MM cell lines
durg-efficacy/drug-resistance
studies
Chauhan et al., 2006

Growth of the MM Cell in the
MM
BM Microenvironment
migration
GSK-3
SC
FKHR
CD40
PKC
Survival
Caspase-9
Anti-apoptosis
Akt
NF-B
Cell surface
Cell cycle
cy
mTOR
targets
PI3-K
Bad
Bcl-xL
Survival
JAK/STAT3
Mcl-1
Anti-apoptosis
BAFF-R
Raf
MEK/ERK
proliferation
p
VEGFR
Bcl-xL
Survival
Cytokines
NF-B
IAP
Anti-apoptosis
Cyclin-D
Cell cycle
IL-6, VEGF
IGF-1, SDF-1
TNF
TNF
BAFF, APRIL
Proliferation
TGF
MEK/ERK
BSF-3
Anti-apoptosis
VEGF
p27Kip1
Smad, ERK
Adhesion
cytokines
NF-B
adhesion
LFA-1
molecules
ICAM-1
NF-
NF B
MUC-1
BMSC
NF-B
VCAM-1
Fibronectin
VLA-4
Hideshima T and Anderson KC. Nat Rev Cancer 2002, 2:927. Hideshima T et al. 2004, Blood 104:607

CS1 in
in Multiple
Multiple Myeloma
Myeloma
· Universal gene expression in multiple myeloma
· Confirmed CS1 protein expression by flow cytometry
and IHC with anti-CS1 antibodies
· Normal tissue
tissue staining
staining shows
shows exclusive
exclusive expression
expression
only in tissue plasma cells
Plasma ce
cells in normal
Multiple my
pyeloma cells
gut
in a plasmacytoma
Staining was performed with HuLuc63 humanized anti-CS1 monoclonal antibody

HuLuc63 Anti-
Anti CS
-
-1
- Antibody
Antibody Induces
Specific MM Cell Lysis
A
C
80
70
killing 60
CS1
fic 50
40
speci 30
% 20
10
0
0
1
B
10
0.0001
0.001
0.01
0.1
MM1S
HuLuc63, g/ml
Effector cells
Effector cells
MM1R
MM1S
U266
CD19+B cells
Phase I trial ongoing in MM
CD19+B cells
Tai et al ASH # 3470, 2006

Direct Effects of VEGF on MM Cells
VEGF
fibronectin
VEGFR
pazopanib
integrin
Src
Cav-1
cPKC
PI3K
MEK-1
p130Cas
survivin
cMyc
ERK
Mcl-1
actin
reorganization
VEGF secretion
proliferation
Podar et al., Blood 2001
Podar et
et al
al., JBC
JBC 2002
Podar et al., Cancer Research 2004
survival
Podar and Anderson, Blood 2005
Podar et al., PNAS 2006
migration

VEGF-Receptor Inhibitor Pazopanib
Targets
T
Both
Both Myeloma
Myeloma and
and Endothelial Cells
Cells
IL-6
Cytokines
Phase I Trial
Ongoing in MM
VEGF-A
cMyc
Growth, survival,
Autocrine
VEGF
drug resistance
VEGF
ICAM1/ LFA-1
secretion
VCAM1/ VLA4
Angiogenesis
Adhesion
Podar et al., PNAS
2006: 103: 19478-83.

MEK Inhibitor AZD6244 Specifically
Inhibits pERK and Induces Apoptosis
A
in MM Cells
AZD6244
-
- - -
+ + + +
AZD6244
AZD6244
0.01-10 µM
00 0.01-10 µM
IGF-1 0 5 10 30
0 5 10 30 min
pAKT
pERK
pERK
pAKT

-tubulin
-actin
IL6 stimulation CD40 activation
B
C
LD M
50
Patient MM cells
INA-6
0.485 + 0.013
120
MCCAR
0.7 + 0.024
100
MM1S
24.86 + 0.98
80
MM1R
25.312 + 1.23
60
RPMI8226
13.9 + 1.03
survival
40
%
DOX40
16.74 + 20
2. 5
05
20
0
LR5
7.5 + 0.945
0
0.02 0.2
2
20
28PE
28.7 + 1.368
28BM
0.92 + 0.034
AZD6244, µM
Tai ASH # 3460 and 3463, 2006

AZD6244 Blocks Osteoclast
Differentiation
A
C
AZD6244
--
+
-
+
control
AZD6244
M-CSF+RANKL
-
+
+ +
+
hour
2
2
224 24
OCL
OCL
pERK
ERK
OCL
B
AZD6244 M
-
0.2
0.5
OCL
M-CSF+RANKL
+
+
+
cathepsin K
GADPH
cathepsin K/GADPH
2.0
1.2
0.6
ratio
AZD6244
AZD6244
Mature OCL
Bone
OCL precursor
resorption
Tai #3460 ASH2006

Cyclin D1 Inhibitor P276-00 Induces Multiple Myeloma
Cytotoxicity in Vitro and in Vivo
48 Hour Cytotoxicity of MM Pt Cells
120
100
ono
80
fCoeg 60
tanerc 40
Pe
20
0
0 nM
200 nM
400 nM
1000 nM
P276.00 Dose (nM)
Control-D1
Control-D15
P276.00-D1
P276.00-D15
1
P276.00
.8
.6
onAlive .4
Control
P<0.05
.2
Proporti
0
0
5
10
15
20
25
30
35
Days
Raje et al, ASH 2006

Proteasome Inhibitor NPI-0052 Inhibits Growth
andT
d Triggers Apoptosis in MMP
MM Pati
tientC
t Celllls
Chauhan et al Cancer Cell 8:407, 2005

Novel Proteasome Inhibitor NPI-0052 Inhibits Human MM
Cell Growth and Prolongs Survival in a Murine Model
Phase I clinical trial in myeloma ongoing
Chauhan et al, Cancer Cell, 2005.

Proteasomal Active Site Specificity
20S proteasome
2
particle
-subunit
1
T
3
T
ring

caspase- trypsin-
Three distinct
like
like
N-ti
termi l

na
chymotrypsin-
4
7
threonine

like
protease active
T
sites
6
5
IC50s (nM)
Chymotrypsin-like
Caspase-like
Trypsin-like
PR-
PR 171
6
2400
3600
Bortezomib
7
74
4200

Preclinical Rationale for Carfilzomib
(PR-171)
-
Differential qualitative/quantitative
proteasome inhibition differences versus
bortezomib
Active against bortezomib resistant cell lines
and patient
patient cells
Active in xenograft models
models.
Stewart et al, ASCO 2007

Clinical Activity of Carfilzomib (PR-171)
1. Effective in Bortezomib resistance
2. Neuropathy not reported, dose related
thrombocytopenia
3. Daily x 5 activity in
in MM: 1MR, 1PR
1PR
(45,78d): discontinued due to "treatment
fatigue"
4. Daily x 2 activity in
in MM: 1MR, 4PR
4PR (100-
288+d) Thrombocytopenia, hypoxia
5. Two phase II trials planned
pp
in relapsed
p
refractory MM
Stewart et al, ASCO 2007

Proteasome: Present and Future Therapies
Potential
UB enzymes E1, E2 and
E3-UB-Ligases
Therapeutic Targets
Ub
ATPases/
Ub Ub
Cdc48
immunoproteasome
ATP
ADP
Poly-ubiquitinated proteins
(proteasome substrates)
19S
Six Proteolytic
activities
5, 5i
20S

20S
1, 1i
2, 2i
19S
Free Ub
for
li
re-cyc ng
Degraded protein
26S PROTEASOME

Rationally Based Combination Therapies
Bortezomib
d
an D
il
ox
Bortezomib and Hsp90 inhibitor
Bortezomib and Lenalidomide
Bortezomib and NPI-0052
Bortezomib and Akt inhibitor
Bortezomib and HDAC6 inhibitor
Bortezomib and Smac peptides
Bortezomib and Bcl 2 inhibitors
Bortezomib
d
an
3
p 8
38 MAPK
MAPK i hibit
n
or
Lenalidomide and Dex
Lenalidomide and mTOR inhibitor
Lenalidomide and Anti-CD40 antibody
Lenalidomide, Dex, and Perifosine

Superior Overall Survival with Combination
of Bortezomib and PLD
100
e
PLD + Bortezomib
Aliv
80
Bortezomib
jects
0
Sub
tofn 064
PLD +
Bortezomib
Bortezomib
Perce
Censored
82%
75%
20
Died
18%
25%
HR (95% CI) 1.41 (1.002;1.97)
0
p < 0.05
0
50 100 150 200 250 300 350 400 450 500 550 600 650 700
Time, days
Harousseau et al Abstract 8002

Bortezomib and Hsp 90 Inhibitor Therapy
Hsp 90
90 gene
gene and
and protein overexpressed
overexpressed in MM;
Bortezomib further upregulates hsp 90 (2002)
Hsp90 inhibitor and Bortezomib induces synergistic
cytotoxicity and overcome Bortezomib resistance in
vitro and in
in vivo (2003
(2003 4)
-
Phase I/II clinical trials show safety and that hsp90
yp
inhibitor can sensitize or overcome resistance to
Bortezomib (2005-6) (Richardson et al, ASH 2006)
Phase III trial of Bortezomib/hsp90 inhibitor versus
Bortezomib in relapsed MM for FDA
FDA approval

Bortezomib and Lenalidomide Therapy
Lenalidomide induces
induces caspase 8 mediated
mediated apoptosis
apoptosis of
of MM
MM
cells in BM in vitro and in vivo; Dex (caspase 9)
enhances response (2000)
Phase I-III clinical trials show favorable toxicity,
remarkable activity,
activity and that
that lenalidomide/Dex
lenalidomide/Dex prolong
prolong
OR,CR,TTP,OS versus Dex in relapsed MM leading to
FDA approval (2006)
Synergistic MM cell toxicity of lenalidomide with
Bortezomib in vitro and in vivo (dual apoptotic signaling)
Phase I-II trials show that majority of patients refractory to
either agent alone
alone respond to the combination.
combination. Upfront
trials ongoing.
Richardson et al, ASH 2006

NPI-0052 + Revlimid (LenalidomideTM):
Low Doses Trigger
gg
Synergistic
g
Anti-MM Activity
Synergistic
Additive
MM.1S cells
MM.1R cells
CI = 1.00
CI < 1.00
CI = 1.00
CI < 1.00
O hr
24 hr
48 hr
Rev
NPI-0052
Chauhan et al., 2007

Apoptotic Signaling of NPI-0052 vis-à-vis
Bortezomib
Bortezomib
NPI-0052
Bax/Bak-/-
Caspase-8, and -3
Mitochondria
Smac
Cyto-c
Caspase -9, and -3
Caspase-9, and -3
Apoptosis

Combining Two Proteasome Inhibitors
Tr
T igger
r
Synergistic
Synergistic Anti
Anti MM
-
Activity
MTT assay
Annexin V/PI Staining
Isobologram
CI = 0.43
analysis
3.1%
3.2%
Control
NPI-0052 (1 nM)
19.4%
41.4%
Bortezomib (3 nM) NPI-0052 (1 nM)
+
Bortezomib (3 nM)
Tr
T eatment time: 24h
Chauhan et al., 2007

Increased Aggresomes (HDAC6) in Myeloma

Blockade of Ubiquinated Protein Catabolism
Protein
Ub
Ub
protein aggregates
(toxic)
Ub
Ub
Ub
Ub
26S proteasome
HDAC6
Ti
Tri l
a
f
o LBH
LBH l
a one
Bortezomib
Ub
Ub
and with Bortezomib
Tubacin
LBH
HDAC6
LBH
dynein
Ub
Ub
Lysosome
y
Aggresome
HDAC6
Ub Ub
dynein
Ub Ub
Ub
Ub
Microtubule
At
Aut
h
op agy
Hideshima et al, Clin Cancer Res;2005; 11: 8530
Catley et al, Blood 2006; 108: 3441-9.

Targeting Proteasome and Aggresome
Tr
T iggers
r
Synergistic MM
MM Cytotoxicity
Cytotoxicity
MM.1S
RPMI
5
ox40
CT
B
T+B
CT
B
T+B
26
R
D
RPMI-
MM.1S
MM.1R
U266
INA-6
RPMI82
RPMI-L
HDAC6
-tbl
tubu i
lin
MM.1S
C: control T: tubacin (5M)
CT
B T+B
Bb
B: bortezomib
ib (5
(5 nM)
M)
p-JNK
120
JNK
100
Caspase-9
Bortezomib
CF
80
trol
Caspase-8
0 nM
60
con
5 nM
CF
% 40
10 nM
Caspase-3
20
CF
0
PARP
05
10
CF
Tubacin (µM)
Hideshima et al. PNAS 2005; 102: 8567.

Lenalidomide Induces Increased anti
anti--
CD40 induced
iinduced ADCC Against
Autologous MM Cells
Clinical Trial in MM in 2007
Patient 1
Patient 2
Patient 3
60
**
50
**
25
** **
50
40
**
20
lysis
40
15
fic
30
f
30
*
*
10
20
20
*
5
Speci
10
*
*
10
%
con
0
0
0
on
gG
40
de
+L
med
gG
40
de
+L
on
gG
SGN-40
g
alidomide
+L
c
I
S+
I
S+
c
I
S
len
med
con
SGN-
con
SGN-
med
con
lenalidomi
lenalidomi
Tai et al. Cancer Res 2005, 65: 7896-7901.

Akt Inhibitor Perifosine Enhances
Bortezomib-Induced Cytotoxicity in MM Cells
Bt
Bortezomib
ib
Bortezomib
048h
p-Akt
caspase
Akt
Perifosine
Akt
apoptosis anti-apoptosis
8h
24h
CP
BP+B
120
Perifosine (M)
p-JNK1/2
100
0
5
caspase-8
80
7.5
CF
60
PARP
control
CF
40
%
C: control
20
B: Bortezomib (10 nM)
0
05
7.5
P: Perifosine (5 M)
Bortezomib (nM)
Clinical trial of Bortezomib and Perifosine Ongoing
Hideshima et al. Blood 2006; 107: 4053-52

Perifosine Enhances MM Cell
Cytotoxicity Induced
by Lenalidomide + Dexamethasone
(Clinical Trial Ongoing)
120
(OPM1, 48h MTT)
100
80
control
60
%
40
20
0
Hideshima et al., 2006

High-Throughput Screening for Combination Therapies
Bradner et al, 2007

Compartment Specific Bioluminescence Imaging (CS
(CS--BLI)
BLI)
High
High--Throughput
Throughput Screening of MM with BMSCs
100
75
ival
Dex
rvi 50
uS
No BMSCs
25
+HS--55 stroma
stroma
% 0
0.0
0.5
1.0
1.5
2.0
Dex (uM)
100
No BMSCs
75
+HS--55 stroma
stroma
Doxo
Luc+
Luc-
Myeloma
y
+
vival 50
rv
Myeloma cells
Stromal cells
Stromal cells
uS 25
%
0 0
10
20
30
40
50
60
Doxo
Dox (ng/mL)
Biolum signal
No signal
Biolum signal
100
75
Bortezomib
No BMSCs
rvival
No
50
r
+HS-
+HS 5s
5 trom
o a
m
u
stroma
S 25
%
0
McMillin et al. IMW 2007 abs # S11
0
10
20
30
40
PS
PS--34
3 1
41 (nM)
(nM)

Conclusions and Future Directions
1. A new treatment paradigm targeting both the
tumor cell and its microenvironment has
already markedly improved OR, CR, EFS and
OS.
2. Ongoing oncogenomic and proteomic
proteomic studies
are informing clinical protocol design and
identifying
yg novel therapeutic
p
targets.
g
3. Future moleculary-based, rationally designed
bi
com nation th
i
erap es ill
w achieve durabl
ble CR
CR
in the majority of patients (immunomodulatory
drug, proteasome inhibitor, hsp
hsp 90 inhibitor,
HDAC inhibitor, and MoAb).

United Nations Against Myeloma
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Mariateresa Fulcinitti

Collaborative Models for Rapid Translation of
Novel Drugs from Bench to
to Bedside
Bedside
Pharmaceuticals
Academia
Advocacy
NIH
FDA
NCI

Improvement in EFS in Childhood ALL
as a Model for MM
1980s
1970s
1960s
1950s
N.B. In ALL, progress not due to new drugs but to new
combinations. In MM, We have both!!
Pui, NEJM 1995; 332: 1618

"Cure is growing old and dying from something else"