Multiple Myeloma: Relapsed Disease
Sagar Lonial, MD
MD
Associate Professor, Winship Cancer Institute
Director of Translational Research,
B-cell Malignancy Program
What are the Major Questions?
Questions?
Second generation agents
Combinations in development
New drug development
Monoclonal Antibodies
Smallll molecule i hibit
n
ors
Who do we clinically define Sy
yynergy
gy?
Effect
Ef
of Agent A + Effect
Ef
of Agent B=
more than A+B
Or
1+1=5
Chou et al, Pharmacol Rev. 2006 Sep;58(3):621-81
Overview of phase III trials with novel
agents in
in relapsed/refractory
relapsed/refractory MM
MM
TTP or
Median
ORR,
CR or
VGPR,
DOR,
Regimen
Trial
PFS,
OS,
%
nCR, %
%
months months months
Len + Dex
MM-0091
009
61
24
NE
16
11
355
Len + Dex
MM-0102
60
25
NE
17
11
Bortezomib
APEX3
43
15
NE
8
6
30
Vdox
MMY-30014
44
13
27
10
9
NE
1. Weber DM, et al. N Engl J Med. 2007;357:2133-42.
2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-32.
DOR = duration of response;
3. Richardson PG, et al. Blood. 2007;110:3557-60.
NE = not evaluable;
4. Orlowski RZ, et al. J Clin Oncol. 2007;25:3892-901.
Vdox = bortezomib + pegylated liposomal doxorubicin.
5. Weber DM, et al. Blood. 2007;110:[abstract 412].
Molecular Structure of Thalidomide,
Lenalidomide and Pomalidomide
O
O
O
O
O
O
H
H
N
N
N
N
O
N
O
N
O
O
NH
O
NH
2
2
Thalidomide
Lenalidomide
Pomalidomide
(CC-4047)
Structurally similar, but functionally different both qualitatively
and quantitatively
Phase II trial of Pomalidomide in
Relapsed/Refractory
py Myeloma
y
(N
( = 60)
· Dose: Pomalidomide - 2mg po daily days 1-28
Dexamethasone - 40mg po
po days 1, 8, 15
15 & 22
Aspirin - 325mg po days 1-28
Confirmed Response
Response
N=
N 60
=60
sCR
1 (2%)
CR +VGPR 25%
VGPR
14 (23%)
ORR 58%
58%
PR
20 (33%)
SD
11 (18%)
Among the first
first 37 patients, there were
were 13
13 lenalidomide
lenalidomide refractory
refractory
patients, with responses seen in 29%
One death due to pneumonia while neutropenic
Primarily fatigue Grade ¾
28%
Neutropenia
32%
No DVT
Lacy et al, ASH 2008; Abstr. 866
Comparison of Proteasome Inhibitors
Bortezomib (reversible)
Carfilzomib (irreversible)
()
NPI-0052 (irreversible)
()
Bortezomib
NPI
NPI
Post-
Post-
Tryptic
glutamyl
glutamyl
Tryptic
NPI
Chymo-
Chymo-
tryptic
tryptic
PX-171-004 Carfilzomib Phase 2 Study Design
Design
Relapsed MM
2
20 mg/m IV push; 12 cycles
Premedication: dexamethasone 4 mg PO (Cycle 1 only)
D1 D2
D8 D9
D15 D16
Schedule
0
28day
QDx2 weekly
Rest period
cycle
easomeot
(12 days)
for 3 weeks
pr
inhibition 80
%
Week: 12
3
4
Primary endpoint
Overall response rate (ORR = CR + VGPR + PR)*
Secondary endpoints
DOR, PFS, TTP, OS
Safety
*IMWG response criteria
PX-171-004: Response Summary (N = 31)
100
6.5%
CR
14%
18%
VGPR
VG
10%
PR
MR
s
29%
SD
ct
PD
e
45%
NE (TLS)
ubj 50
59%
s
36%
of
3%
%
ORR:
26%
ORR:
6%
57%
35.5%
14%
ORR:
6.5%
18%
3%
18%
7%
0
All
Bortezomib
Bortezomib
Subjects
Exposed
Naive
(N = 31)
(N = 17)
(N = 14)
90% of responses occurred by the end of Cycle 2
HDAC6 Inhibitor Tubacin Inhibits
Aggresome
gg
Formation and Augments
g
Bortezomib-
Induced Cytotoxicity in MM Cell Growth
misfolded protein
Ub
Ub
protein aggregates
(toxic)
(MM.1S, 24h MTT assay)
Ub
120
Ub
proteasome
100
HDAC6
Bortezomib
80
Velcade
control
0n
0 M
nM
% 60
5 nM
Tubacin
Ub
Ub
10 nM
40
HDAC6
20
0
05
10
Ub
Tubacin (µM
(µ )
Ub
Ub
Aggresome
Hideshima et al. PNAS 2005; 102: 8567.
Phase I vorinostat + Bortezomib in Relapsed/ Refractory MM:
Overall Response Rate
Rate
Sub-Population of 9 Patients Refractory
to Prior Bortezomib
60
50
44%
40
33%
tients
30
Pa
20
%
10
11%
11%
0
n=3
n=4
n=1
n=1
0
CR
PR
SD
PD
NE
Badros et al ASH 2007
11
Vorinostat-Bortezomib: Response
Bortezomib Refractory Patients
Patients
100
ents 80
e
Trial 1
42%
60
Pati
29%
29%
(n=3)
(n=7)
% 40
(n=2)
(n=2)
20
0
0
0
CR
PR
MR
SD
PD
100
80
Tr
T ial
r
2
tsn
50%
2
60
38%
(n=4)
(n=8)
Patie
(n=3)
% 40
12%
20
(n=1)
0
0
0
CR VGPR
PR
SD
PD
Monoclonals in Development
CD74
CS1
CD138
CD40
CD56
IMiDs Augment anti-MM Immunity
T Cell
NK Cell
NFA
NF T
A
IL-2
IL-2
PKC
D
d
en ritic Cell
PI3K
CD28
Apoptotic
MM Cell
MM Cell
IMiDs
VEGF
IL-6
Bone Marrow Stromal Cell
LeBlanc R et al. in press Hayashi T et al. in press
Lenalidomide Induces
Induces Increased anti
anti--CD40
CD40
induced ADCC Against Autologous MM Cells
Patient 1
Patient 2
Patient 3
60
**
50
**
25
** **
50
40
**
20
lysis
40
30
15
fic
30
*
20
10
*
10
20
*
*
10
5
Speci
10
%
0
0
0
n
e
L
e
L
n
0
L
o
G
0
0
o
4
d
+
on
G
4
d
+
o
G
o
4
de
4
+
c
Ig
S
c
Ig
S
c
Ig
S
med
con
SGN-
med
con
SGN-
med
con
SGN-
lenalidomi
lenalidomi
lenalidomi
Clinical Trial in MM in 2008
Lenalidomide + SGN40
Tai et al. Cancer Res 2005, 65: 7896-7901.
Lenalidomide + anti-CS-1
Targeting Cell Surface CS1
in Multiple Myeloma
· Universal gene expression in MM
· Confirmed CS1 protein expression by flow cytometry and
immunohistochemistry with anti-CS1 antibodies
· Normal tissue staining showing exclusive expression only
in tissue plasma
plasma cells
Plasma cells
Multiple myeloma cells
in normal gut
in a plasmacytoma
Staining was performed with HuLuc63
humanized anti-CS1 monoclonal antibody
Lenalidomide Enhances Elotuzumab-
Ind
d
uce ADCC A
i
ga
t
ns P ti
a ent MM
MM C ll
e s
Phase 1 Trial Ongoing
gg in MMRC
Elotuzumab, Lenalidomide
Iso IgG1, Lenalidomide
50
HuLuc63
40
Iso IgG1
s(%)
Ta
Target
rget cells:
30
patient MM cells
ysiL 20
ific 10
Spec
0
01
10
10
-
mAb (g/mL)
Response Data
Pre-clinical Rationale: Combination of
Hsp90 and Proteasome Inhibitors
Inhibitors
120
100
ntrol)oc 80
of
60
(%
val
40
20
Survi
0
Bortezomib
0 2 4 8 16 24 (hrs)
24
Hsp90
Transcription / Translation Regulation
Signal Intensity
Hsp70
Mitsiades N et al. PNAS 2002;99(22):14374
2002;99(22):14374--9
9
Hsp27
Mitsiades CS et al. Blood (in press)
Overall Response: CR/PR/MR
·
In those pts
p
who received a dose of BZ 1.0 or 1.3
mg/m2 in this trial (MR/PR/CR):
BZ
BZ--naïve
naïve
5/8
5/8 with response
63%
BZ
BZ--pretreated
pretreated
6/12
50%
BZ-
BZ refractory
2/3
67%
OVERALL
13 / 23
57%
SUMMIT (BZ
(BZ--naïve)
naïve)
67 / 188
35%
· 19 CR, 34 PR, 14 MR
· Source: Summary Basis of
o
of Approval
A
Approval, Velcade 2002
More than an
an Experiment
Experiment...
Bortezomib and FTI Preclinical Rationale
Ml
Myeloma C l
e lll
Tipifarnib
IL-6
proteasome
RAF
RAS
Bortezomib
MEK
JAK/STAT
IB
SHP2
MAPK
(Blocks Dex
IB
induced apoptosis)
NFB
1.
Activation of
NFB
Caspase 3 9
, 8
,
2. Down regulation
of p-AKT
3. Synergistic
Apoptosis
Eh
Enh
d
ance Gene Expression
Adhesion molecule expression
-VLA-4
-MUC-1
-LFA-1
X Angiogenesismediators
-VEGF
-bFGF
More than an in vitro study
Circulating Plasma Cells
"Intercept Concept for Myeloma"
SHH
VEGF
Notch
EGF
IL-6
Wnt
IGF-1
IL-8
51
FGF
MIB1
RANKL
Growth factors
Hormones/chemokines
matrix proteins/other
PTHrP
TNF
OPG
PI 3k
-3 inase
kinase
PIP
SF1126
3
PTEN
"INTERCEPT"
LY294002
AKT/PKB
Angiogenesis
Apoptosis
Proliferation
Tumor-stromal interactions
Slide courtesy of Don Durden MD, PhD
Not all
all combinations are good...
Bortezomib effect can be blocked
bD
by
i
Di l
o Group
R2
O
O
OH
HO
OH
O
R1
H
H
-
N
N
B
N
N
B
N
OH
+
N
O
R
OH
H
1
R2
H
O
O
N
N
PS-341 (Velcade or Bortezomib)
Diol
Complex
H2O
H+
HO
OH
R1
O
OH
-
R B
R B
+
R1
R2
HO O
OH
R2
boronic acid
Diol
Complex
Vitamin C: Not For Breakfast Anymore...If you have Myeloma
Editorial in
in Press
Press, Leukemia
R. Donald Harvey, PharmD, Jim Nettles, PhD, Binghe Wang, PhD, Shi-Yong Sun PhD, Sagar
Lonial MD
MM Trials at Emory
· Carfilzomib
· Bz + tipifarnib
· HuLuc + Rev
· Bz + SGN 40
· LBH + Rev
· NPI-0052
· CD74 Ab
· CC-4047
· CD138 Ab
· KSP inhibitor
· N d
e d
dd 8 i h
n ibit
hibitor
· RVD + SAHA
· SF1126
· XL 228
· Oral PI