Link to Anderson slides

78 Pages·2015·6.57 MB·English

by  Kenneth Anderson

Development of Novel Therapies for Multiple
Myeloma and Waldenstrom’s Macroglobulinemia

Kenneth C. Anderson, M.D.

Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
Harvard Medical School
Historical Perspective of Multiple
Myeloma Therapies
Proteasome
High-dose therapy inhibitors
ABMT with autologous Other immuno-
stem cell support modulatory
agents. HDACs
VAD
Bisphosphonates
High-dose melphalan
High-dose Thalidomide
dexamethasone
Oral melphalan
and prednisone
1962 1983 1984 1986 1996 1999 2000+

Targeting Growth, Survival, and Drug Resistance of MM
in BM Microenvironment MM
migration
SC
GSK-3
CD40 FKHR
PKC Survival
Caspase-9
Anti-apoptosis
Cell surface Akt NF-B
Cell cycle
mTOR
targets PI3-K
Bad
Survival
Bcl-xL
JAK/STAT3 Anti-apoptosis
Mcl-1
BAFF-R
Raf MEK/ERK proliferation
VEGFR Bcl-xL Survival
NF-B IAP Anti-apoptosis
Cytokines
Cyclin-D Cell cycle
IL-6, VEGF
IGF-1, SDF-1
TNF
BAFF, APRIL MEK/ERK Proliferation
TGF
BSF-3 p27Kip1 Anti-apoptosis
VEGF
Smad, ERK
Adhesion
cytokines NF-B
adhesion
LFA-1
molecules ICAM-1
NF-B
MUC-1
BMSC
NF-B VCAM-1
Fibronectin VLA-4
Hideshima T and Anderson KC. Nat Rev Cancer 2007,
Mechanisms Mediating Anti-MM Activity
of Bortezomib
Anti-Angiogenic &
ER-Stress Induction Apoptosis
Anti-Osteoclastic Actvity

Caspase-12 cleavage;  JNK; Caspases & PARP cleavage;
 Migration, VEGF,
 phospo-PERK;  ROS;  ∆m
Proangiogenic MMP-9, &
 GADD-153, ATF4, GRP 78, &  Cyto-c & Smac release;  IAPs;
Caveolin-1;
XBP-1 splicing  mitochondrial Ca+2 influx;
Osteoclastogenesis via
 Bid cleavage, Fas & FasL, BH-3
MIP1, BAFF
only proteins: Bim, Bik, & NOXA
 Osteoblast formation
Heat Shock Proteins
Growth & Survival
& DNA Repair
NF-B, MAPK,JAK/STAT
Bortezomib  Heat Shock Proteins-27, -70,
IGF-1/IL-6.  PI3K-Akt
90;  DNA-PK
Microenvironment
Cell-Cycle
 MM-BMSC’s interaction; Cdk inhibitors:
Proteasome
 ICAM, VCAM, V3  P21 & p27, p53
IGF-1, IL-6, BAFF,RANKL Cyclins: D1, E1, A, B.
 Chymotrypsin- and Caspase-
like proteasome activities;
 Mono-ubiquitination;
 26S Proteasome subunits
Lenalidomide in Myeloma
C
MM cells
IL-6
TNF
B
IL-1
A
Bone Marrow
ICAM-1 Stromal Cells
Bone Marrow
Vessels NFAT
IL-2
PKC IL-2
IFN 
NK Cells
VEGF
PI3K CD28 NK-T
bFGF
Cells
CD8+ T

Dendritic
Cells
D E
Cells
Mitsiades et al. Blood 99: 4525, 2002
Hideshima et al. Blood 96: 2943, 2000
Lentzsch et al Cancer Res 62: 2300, 2002
Davies et al. Blood 98: 210, 2001
LeBlanc R et al. Blood 103: 1787, 2004
Gupta et al. Leukemia 15: 1950, 2001
Hayashi T et al. Brit J Hematol 128: 192, 2005
Integration of Novel Therapy

Into Myeloma Management
Bortezomib, Lenalidomide, Thalidomide, Doxil,
Carfilzomib, Pomalidamide, Panobinostat

Target MM in the BM microenvironment to
overcome conventional drug resistance in vitro
and in vivo

Effective in relapsed/refractory, relapsed,
induction, consolidation, and
maintenance therapy

Eleven FDA approvals and median survival
prolonged from 3-4 to 6-7 years, with additional
prolongation from maintenance

New approaches needed to treat and ultimately
prevent relapse
Chromosomes and Prognosis
in Multiple Myeloma
For conventional low and high dose theapy:

Nonhyperdiploid worse prognosis than hyperdiploid
t(11;14), hyperdiplody -standard risk
t(4;14), t(14;16),t(14;20), del(17p), del(13q14)-high risk

For novel treatments
Bortezomib, but not lenalidomide, can at least partially
overcome t(4;14), del(13q14)

del(17p) p53 remains high risk
Combinations in the Upfront Treatment of MM

Stewart AK, Richardson PG, San Miguel JF Blood 2009