Novel Bone Targeting Agents in
Myeloma
Noopur Raje, MD
Center for Multiple Myeloma
Myeloma
MGH Cancer Center
Clonal plasma cell proliferation:
microenvironment-dependent
T cells
IL2
Endothelial cells
IFN-
..........
NK cells .....
Myeloma cells
IL6
VEGF
BAFF
IGF1
RANKL
LFA-1
VEGF
VLA-4
IL6
VCAM-1
DKK1
MIP-
MIP 1
ICAM-1
Bone marrow
stromal cells
Osteoblasts
Osteoclasts
Bisphosphonates in MM
· Inhibit bone resorption
· Pamidronate better than placebo
· Pamidronate and Zoledronic Acid
equivalent
ONJ :Clinical features:
Patient #2: p/w roughness and irritation
h/o dex 4 mths, CTX, EDAP 3/3 mths, PBSCT and
Pamidronate 61 mths and Zometa 20 mths
h/o dental extraction
Raje et al. Clin Can Res 2008
ASCO Clinical Practice Guidelines:
Update
·
Bisphosphonates
Indicated for MM pts w/ lytic bone disease
osteopenia
·
Useful as an adjunct for pts w/ bone pain
·
The bisphosphonates recommended are either
Zoledronic acid: 4 mg over 15 mins, IV q 3-4 wks
Palmidronate: 90 mg over > 2 hrs, IV q 3-4 wks
·
Monitoring w/ serum creatinine (both BPs) and/or urine albumin
(for palmidronate only)
·
PA
PAM preferred
preferred in
in setting of renal dysfunction
dysfunction
·
Re-evaluate after 2 years and consider stopping if stable disease
Kyle R, et al. JCO. 200725: 2464-2472
Biochemical and GEP studies suggest inhibition of bone formation
PROTEIN KINASE C FAMILY
ONJ
MM
Normals
Raje et al. Clin Can Res 2008
Ntx levels stay suppressed for upto 8
weeks following a single dose of
of
zoledronic acid.
Berenson et al, 2001; Chen et al, 2002
Pharmacodynamic Study of
Zometa in
in MM
MM
30 MM
ti
pa ents
in CR and or
6 m end of study
PR with h/o 8-
with BM aspirate
12 months of IV
and biopsy and
Skeletal S
bisphosphonate
urvey
therapy
Baseline NTX followed by monthly x 6
Serum Markers followed by monthly x 6
BM aspirate and core
Skeletal Survey
Zoledronic acid single dose
Phase IV ZMARK Tr
T ial
r
Tri
Tr a
i l
a
NTX < 50nM-q12w
NTX < 50nM-Obs
NTX >50nM-q4wk
NTX >50nM-Rx
Multiple Myeloma
BP treated:
Upto 6 -24mo
n = 120
NTX directed q4 or 12 wk
Obs or NTX directed
N = 120
0
24 months
36 months
* Primary efficacy endpoint: Time to first SRE
Denosumab in MM
· Phase I study completed
· Phase II: Treatment of
Relapsed/Plateau phase MM
96 patients 53
53 R and 43 P no
-
effect on
paraprotein
Decrease in sCTX
CTX l
lb5
evels by 0
50 70%
-
for
upto 7 months
Vij R et al, Blood 2007;110:1054A
Denosumab in
in MM
MM
· Ongoing phase III trial in
in patients
patients with
with
advanced cancer with bone metastasis
Denosumab
·Time to first SRE
120mg SC
·Multiple Event Analy
pysis
nt
·OS
nrollme
·AEs
E
Zoledronic Acid
4 mg IV
MLN 3897, A NOVEL CCR1
INHIBITOR
Smalll molecule, CCR1 antagonist
Highly specific for human CCR1, IC50= 0.8 nM; CCR5, IC50 =
4M.
No inhibition of RAF, AKT or receptor tyrosine kinase up to 10µM
Long half-life= 2-3 days
Oral available
MLN3897 inhibits Osteoclastogenesis
Vallet et al, Blood 2007
Anti-BAFF Neutralizing Ab Prolongs Survival and
Inhibits Osteoclasts in SCID-Hu Model of MM
Control Animal
Anti-BAFF Ab-Treated
Survival in Days
70
CNT Isot.
BAFF
60
50
40
p=0.048
30
Ab(+)
20
10
Ab(-)
P<0.05
0
0
5
10
15
20
25
30
Days from treatment
Neri et al. Clin Can Res 2007
Myeloma Bone
Rd
Remodeliling
MCSF
MIP-1
OPG
DKK1
RANKL
osteoclast
osteoblast
Bortezomib and Bone Disease
Bortezomib induces OBL
Differentiation
Mukherjee et al. J Clin Inv 2008
Bortezomib induces OBL Differentiation
Mukherjee et al. J Clin Inv 2008
Phase I Study of
LY2127399(Anti-BAFF Ab)
antibody in combination with
Velcade in the treatment of
relapsed/ refractory Multiple
Myeloma
Anti-DKK-1 BHQ880 Reverses the
Inhibitory Effect of MM Cells on
Osteoblastogenesis
A
Isotype control BHQ880, 1 g/ml
-BHQ880
+BHQ880
no
150
P=0.08
MM cells
P= 0.0001
eposition
ntrol) 100
ed coof
with
50
(%
P= 0.0001
MM cells
Calcium
0
no MM cells
with MM cells
B
P=0.002
ml
8
ng/
6
P=0.0002
-BHQ880
4
+BHQ880
huIL-6
P=0.0003
2
0
no MM cells
with MM cells
Fulciniti et al Blood 2009
Activin A levels are increased in osteolytic
disease
Induction of alkaline phosphatase
Induction of osteocalcin mRNA
mRNA expression, day 7
expression, day 14
4
6
3.5
5
3
4
2.5
change
2
3
2
Fold
1.5
2
1
1
0.5
0
0
BM
OB
OB RAP
BM
OB
OB RAP
BMSC
OB
OB+RAP011
BMSC
OB
OB+RAP011
50µg/ml
50µg/ml
Enhanced calcium
Dual staining for ALP and calcium at day21
deposition, day 14
4.5
4
3.5
3
2.5
OD
2
1.5
OB+RAP011
OB+RAP01
1
BMSC
OB
50 µg/ml
0.5
0
BM
OB
OB RAP011 4ww
BMSC
OB
OB+RAP011
50µg/ml
RAP-011 STIMULATES OB FUNCTION
RAP-011
STIMULATES BONE
FORMATION AND
HAS INDIRECT
ANTI-TUMOR
ACTIVITY IN AN
INVIVO MM MODEL.
ACE-011 Effect on Bone
iH
in Health
lthy Volunteers
ACE-011
01 Increases
Increases
ACE-011
01 Decreases
Decreases
Markers of Bone
Markers of Bone
Formation (BSAP)
Resorption (sCTX)
)
(%
ACE-011
01 SC
SC 4 doses every 4 weeks
Data Presented at 2008 San Antonio Breast Cancer Symposium
# 1160 Courtesy;Acceleron and Celgene
ACE-011 generates Rapid and
Significant Increases
Increases in BMD
ACE-011 Generates Significant Increases Total Hip BMD
4.0
3.5
(%)
P=0.0066
(%)
3.0
MDB 2.5
Hip
2.0
Total
1.5
nein
10
1.0
Baseli
0.5
0.0
from
nge -0.5
Cha -1.0
-1.5
Percent -2.0 Placebo 0.1 mg/kg 0.3
0.3 mg/kg
1 mg/kg
Data Presented at 2008 San Antonio Breast Cancer Symposium # 1160
Courtesy;Acceleron and Celgene
A Phase 2 Study in Multiple
Myeloma is Currently Underway
Study Title
A Phase 2, Multi-Center, Randomized, Multiple-Dose Study to Evaluate the
Safety, To
T lerability and Efficacy
Ef
of ACE-
ACE 011
01 (hActRIIA
(hActRIIA-IgG1) in
in Patients
Patients With
With
Osteolytic Lesions of Multiple Myeloma
Study Objectives
To evaluate the safety and tolerability of multiple doses of ACE-011
in patients with multiple myeloma and determine the effect of ACE-
011 on biochemical markers of bone formation and resorption
To determine the pharmacokinetics (PK)
(PK) of multiple doses of ACE-
011 in patients with multiple myeloma, assess skeletal-related
events and evaluate bone pain
Study Design
Randomized, Double-Blind, Placebo Controlled
Dose-
Dose Ranging, Multiple
Multiple Dose
Dose, Parallel
Parallel-Assignment
N=30
www.clinicaltrials.gov (ID: NCT00747123)
Future Directions
· Optimize duration of BP therapy
· Incorporate
I
Novel Imaging
· Use of novel agents---
RANK Ligand inhibitors
Bortezomib
MIP1alpha inhibitors
DKK1 inhibitors
RAP011
RAP01
Acknowledgements
Sonia Vallet
Vallet
David Scadden
Samantha Pozzi
Sidhartha Mukherjee
Kishan Patel
MB
Mary Bouxsein
Yan Hua
Ernistina Schipani
Diana Cirstea
Loredana Santo
Ken Anderson
Our Patients
Nikhil Munshi
Clinical Team
Paul Richardson
Teru Hideshima
Dharminder Chauhan