Transcript Multiple Meyloma - Tallahassee Cancer Institute

Advances in Biology and
Pathophysiology of Multiple Myeloma
Amer G. Rassam, MD
History of Multiple Myeloma
 First case, a London grocer “Thomas
Alexander McBean”
 Jumped from a cave in 1844
 According to Drs. Thomas Watson and
William MacIntyre, Mr. McBean had
“Mollities et Fragilitas Ossium”
 Mr. McBean died on New Year’s day in
1846
History of Multiple Myeloma
 Urine sample presented
to “Henry Bence Jones”
 Large amount of protein
was found in the sample
 The protein has became
known as Bence Jones
Protein
History of Multiple Myeloma
In 1890s, Paul
Unna and Ramon
Cajal identified the
plasma cell as a
cell type and the
cause of Multiple
Myeloma
Paul Gerson Unna
Santiago Ramon Y. Cajal
1850-1929
1852-1934
History of Multiple Myeloma
 In 1873, Rustizky introduced the name
Multiple Myeloma
 In 1922, Bayne-Jones and Wilson
identified 2 distinct groups of Bence
Jones protein
 In 1956, Korngold and Lipari identified
the relationship between Bence Jones
protein and serum proteins
Epidemiology of Multiple Myeloma
 Prevalence (at any one time) : 40000
 Incidence: 14000 diagnosed each year
 Median age: 65
 Median survival: 33 months
 M:F 53:47
 1.1% of all cancer diagnosis
 2% of all cancer deaths
Age Distribution in Multiple Myeloma
35
30
25
20
%
15
10
5
0
<40
40-49
50-59
Age
60-69
70-79
>80
Monoclonal Gammopathies – Mayo clinic
Extramedullary
1% (8)
SMM 4% (39)
Macro 3% (30)
Other 3% (33)
LP 3% (37)
AL 8% (90)
MGUS
62% (659)
MM 16% (172)
Immunophenotype of Multiple Myeloma
Marker
Features
CD10
Subset
CD19 & CD20
Rarely expressed
CD28 & CD86
Occurs with progressive disease
CD34
Not expressed by malignant clone
CD38
High expression of most but not all
malignant cells
CD56 (N-CAM)
Absent in MGUS and PCL
CD138
Syndecan-1 is over expressed
Normal B-cell Development
Lymph Node
IgM
::..
.
Lymphoplasmacyte
(memory B Cell)
IgM
Follicle
center
Short-lived
plasma cell
Lymphoblast
Somatic Hypermutation
of Ig Sequences
Stimulation
with Antigen
Plasmablast
Naïve B Cell
Isotype
Switching
Bone Marrow
::..
.
G, A,
D, E
Long-lived plasma cell
Pre-B cell
Mechanisms of Disease Progression in
Monoclonal Gammopathies
Kyle RA et al. N Engl J Med. 2004 Oct 28;351(18):1860-73
Chromosomal Abnormalities in MM
Translocations (listed in order of frequency)
14q32 with
11q13 (cyclin D, other new fibroblastic growth factors)
4p16 (FGFR3)
6p25 (Interferon regulatory factor 4)
16q23 (C-MAF transcription factor)
8q24 (C-MYC)
18q21 (BCL-2)
1q with
5, 8, 12, 14, 15, 16, 17, 19q, 21, 22
Losses
6q, 13q
Gains
3, 5, 7, 9q, 11q, 12q, 15q, 17q, 18, 19, 21, 22q
Chromosome 13 Deletions in MM
11
12
13
14
21
22
31
32
33
34
Shaughnessy J et al, Blood, 2000; 96:1505
Pathogenesis of Multiple Myeloma
Two pathways involved in the early pathogenesis of MGUS and MM
50% Hyperdiploid
50% non-hyperdiploid
Infrequent IgH
Translocations
IgH Translocations
Multiple trisomies of
chromosomes 3, 5, 7,
9, 11, 15, 19 and 21
Hideshima et al, Blood, August 2004, 607-618
11q13
(cyclin D1)
4p16
FGFR3+
MMSET
16q23
(c-maf)
6p21
(cyclin D3)
20q11
(mafB)
Prevelance of IgH Translocations
Pathogenesis of Multiple Myeloma
100
90
80
70
60
50
40
30
20
10
0
MGUS
Hideshima et al, Blood, August 2004, 607-618
MM
PPCL
HMCLs
Prevalence of IgH Translocations
20q11
4p16 or 16q23
 Lower incidence with
MGUS/SMM
4p16
16q23
 de novo MM
11q13
No IgH T
 Rapid progression of
MGUS to MM
6p21
 Extremely poor prognosis
Translocations in MM
Secondary
Primary
c-myc
6p21
15%
MM
40%
adv MM
90%
HMCLs
Hideshima et al, Blood, August 2004, 607-618
11q13
4p16
20q11
16q23
Translocation and Cyclin D (TC)
Molecular Classification of MM
Group
Primary
translocation
Gene(s) at
breakpoint
D-Cyclin
Ploidy
Freq of TC in
newly diag
MM, %
TC1
11q13
6p21
CCND1
CCND3
D1
D3
NH
NH
15
3
TC2
None
None
D1
H
37
TC3
None
D2
H=NH
22
TC4
4p16
D2
NH>H
16
TC5
16q23
20q11
None
FGFR3/
MMSET
c-maf
mafB
D2
D2
NH
NH
5
2
Bergsagel and Kuehl, Immunol Rev, 2003, 194:96-104
Cyclin D Expression in Normal and Malignant Plasma Cells
D1=Green, D2=Red, D3=Blue
PPC
BMPC
6p
11q13
TC1
Tarte k. et al, Blood. 2002;100:1113-1122.
Zhan F. et al, Blood. 2002; 99:1745-1757
D1
TC2
D1+D2
other
TC3
4p16
maf
TC4
TC5
Dysregulation of cyclin D1, D2, D3
“a unifying oncogenic event in MM”
 MGUS and MM appear closer to normal
PCs than to normal PBs
 >30% of cells can be in S phase
 Expression level of cyclin D1, D2, D3
mRNA in MM and MGUS is distinctly
higher than normal PCs
 Expression level of cyclin D2 mRNA is
comparable with that expressed in
normal proliferating PBs
Dysregulation of cyclin D1, D2, D3
“a unifying oncogenic event in MM”
 Cyclin D1 is not expressed in normal
hemopoitic cells
 Cyclin D1 expressed in 40% of MM lacking a
t(11;14) translocation
 Ig translocations that dysregulate cyclin D1 or
D3 occur in about 20% of MM tumors
 Therefore, almost all MM tumors dysregulate
at least one of the cyclin D genes
Progression to Plasma Cell Neoplasia
Germinal
center B cell
Primary
IgH tx
11q13
6p21
16q23
20q11
4p16
Other
MGUS
Intramedullary
Myeloma
HMCL
NONHYPER
DIPLOID
DEL 13
?p16
N, K-RAS
FGFR3
TRISOMY
3, 5, 7, 9, 11,
15, 19, 21
Extramedullary
Myeloma
p18
c-myc
p53
HYPER
DIPLOID
Hideshima et al, Blood, August 2004, 607-618
Progression to Plasma Cell Neoplasia
Normal
Plasma Cell
Intramedulary
myeloma
MGUS
Extramedullary
myeloma
IgH translocations
Deletion of 13q
Chromosomal
instability
RAS mutations
Dysregulation of c-MYC
p53 mutations
The TC Molecular Classification Predicts
Prognosis and Response to Therapies
Deletion of p53
Increased PC
Labeling Index
Monosomy of
chro 13/13q
Hypodiploidy
Activating
Mutations of
K-Ras
t(14;16) TC5
Lack of Cyclin
D1 Expression
Bad
prognosis
Monosomy of
chro 17
Tumor Cells
with Abnormal
Karyotype
t(4;14) TC4
The TC Molecular Classification Predicts
Prognosis and Response to Therapies
t(4;14) translocation (TC 4)
Shortened Survival
Standard
High-dose
Therapy (42)
Therapy (22)
Median OS
26 months
Median OS
33 months
Fonseca R et al, Blood. 2003; 101:4569-4575
Moreau et al, Blood. 2002; 100:1579-1583
The TC Molecular Classification Predicts
Prognosis and Response to Therapies
t(14;16) translocation (TC 5)
Shortened Survival (worse Prognosis)
Standard
Therapy (15)
Median OS
16 months
Fonseca R et al, Blood. 2003; 101:4569-4575
The TC Molecular Classification Predicts
Prognosis and Response to Therapies
t(11;14) translocation (TC 1)
Better Survival
Standard
High-dose
Therapy (53)
Therapy (26)
Median OS
50 months
Median OS
80 months
Fonseca R et al, Blood. 2003; 101:4569-4575
Moreau et al, Blood. 2002; 100:1579-1583
The TC Molecular Classification Predicts
Prognosis and Response to Therapies
 The TC classification may be clinically
useful way to classify patients into
groups that have distinct subtypes of
MM (and MGUS) tumors.
 The TC classification identifies clinically
important molecular subtypes of MM
with different prognosis and with unique
responses to different treatments.
The TC Molecular Classification Predicts
Prognosis and Response to Therapies
 High dose therapy and TC1
 Microenvironment-directed
therapy and TC2
 FGFR3 inhibitor and TC4
 maf dominant-negative and TC5
Critical role for Cyclin D/Rb pathway in MM
TC5
TC4
TC3
16q23 c-maf
20q11 mafB
4p16
FGFR3
MMSET
Other
Cyclin D2
CDK 4, 6
Cyclin D1
CDK 4, 6
CDK 4, 6
p
p
OFF
Rb
11q13 CCND1
6p21 CCND3
p16
INK4a
p15
INK4b
p18
INK4c
p19
INK4d
Cyclin D3
G1
Phase
E2F
TC1
TC2
Hyperdiploid
Cyclin D1
p
S
Phase
p
Rb
E2F
ON
Novel Therapeutic Strategies targeting
Genetic Abnormalities
Targeting the genes
Directly dysregulated
By translocation
Targeting FGFR3
by monoclonal
antibodies
Targeting FGFR3
by selective
tyrosine kinase
inhibitor
Targeting Cyclin D
Silencing of CDK
inhibitor mRMA
expression
might be reversed
HDAC
Inhibitors
Desferroxamine
Selective CDK
inhibitors
DNA methyl
Transferase
inhibitor
Interaction of MM cells and their BM milieu
migration
PKC
Akt
GSK-3β
FKHR
Caspase-9
NF-KB
mTOR
Bad
Survival
Anti-apoptosis
Cell cycle
PI3-K
TNFα
TGFβ
VEGF
IL-6
JAK/STAT3
Bcl-xL
MCL-1
MEK/ERK
Proliferation
NF-KB
IL-6
VEGF
IGF-1
SDF-1α
Survival
Anti-apoptosis
Bcl-xL
IAP
Cyclin-D
Survival
Anti-apoptosis
Cell cycle
MEK/ERK
p27Kip1
Proliferation
Anti-apoptosis
MM
ERK
Smad2
NF-KB
Adhesion
molecules
NF-KB
LFA-1
ICAM-1
MUC-1
BMSC
VCAM-1
Fibronectin
VLA-4
Myeloma Cells and BM Microenvironment
Bruno et al, The Lancet Oncology, July 2004, 430-442
Apoptotic Signaling Pathways
TNFα
FasL
TRAIL
ImiDs, Velcade
HDAC-I, 2ME-2
Velcade
ZME-2
Dex
JNK
Mitochondria
FADD
Bid
Cytochrome-c
Caspase-8
Caspase-9
Caspase-3
PARP
Apoptosis
Hideshima et al, Blood, August 2004, 607-618
Smac
IL-6
IGF-1
Novel biologically based therapies targeting
MM cells and the BM microenvironment
Apoptosis
Growth Arrest
Novel Agents
B
Inhibition of Adhesion
Adhesion
Molecule
Proliferation
bFGF
VEGF
C
Inhibition of
Cytokines
IL-6
IGF-1
VEGF
SDF-1α
D
Angiogenesis
Drug Resistance
A
Novel Agents for Myeloma
 Targeting both MM cells and interaction of
MM cells with the BM microenvironment
 Targeting circuits mediating MM cell
growth and survival
 Targeting the BM microenvironment
 Targeting cell surface receptors
Novel Agents for Myeloma
Targeting both MM cells and their
interaction with BM microenvironment

Thalidomide and its analogs (Revlimid)

Proteasome inhibitor (Bortezomib)

Arsenic trioxide

2-Methoxyestradiol (2-ME2)

Lysophosphatidic acid acyltransferase-β
inhibitor


Targeting circuits mediating MM cell
growth and survival

VEGF receptor tyrosine kinase inhibitor
(PTK787/ZK222584, GW654652)

Farnesyltransferase inhibitor

Histone deacetylase inhibitor (SAHA, LAQ824)

Heat shock protein-90 inhibitor
(Geldanamycin,17-AAG)
Triterpinoid 2-cyano-3, 12-dioxoolean-1, 9-dien28- oic acid (CDDO)

Telomerase inhibitor (Telomestatin)

bcl-2 antisense oligonucleotide (Genasense)
N-N-Diethl-8, 8-dipropyl-2-azaspiro [4.5]
decane-2-propanamine (Atiprimod)

Inosine monophophate dehydrogenase (VX-944)

Rapamycin
Targeting the bone marrow
microenvironment

IĸB kinase (IKK) inhibitor (PS-1145)

p38 MAPK inhibitor (VX-745, SCIO-469)

TFG-β inhibitor (SD-208)
Targeting cell surface receptors

TNF related apoptosis-inducing ligand (TRAIL) /
Apo2 ligand

IGF-1 receptor inhibitor ( ADW)

HMG-CoA reductase inhibitor (statins)

Anti-CD20 antibody (Rituximab)
Proposed Mechanism of Action of Drugs in Targeting
Myeloma Cells and BM Microenvironment
Kyle RA et al. N Engl J Med. 2004 Oct 28;351(18):1860-73
Homoeostasis of Healthy Bone Tissue and MM Bone
Disease
Bruno et al, The Lancet Oncology, July 2004, 430-442
Osteoclast Precursor
Bone Destruction
Osteoclast
Osteoprotegerin (OPG)
Bone Marrow
stromal Cells
Interferon ɣ
MIP1
Osteoblast
T cell
IL7
IL6
TNFα
IL1β
RANKL
Multiple Myeloma
Cells
RANK
Effects of Thalidomide on the Myeloma Microenvironment
Bruno et al, The Lancet Oncology, July 2004, 430-442
Proposed Action of Thalidomide in Myeloma
Mutiple
Myeloma
Cells
Modulation of Cytokines
VEGF
IL6
TNFα
IL1β
Direct Action
Bone Marrow
Stromal Cells
T Lymphocytes
VEGF
bFGF
Bone Marrow Vessels
Inhibition of Angiogenesis
IL2
ILNɣ
Modulation of
Immune System
Cytotoxicity of NK Cells
Mechanism of Action of
Bortezomib
 Phosphorylation of NFKB
inhibitory partner protein IKB
leads to degradation of IKB by
the proteosome and release
of NFKB
 NFKB migrates into the
nucleus to induce arrest of
apoptosis and expression of
adhesion molecule
 Affinity of Bortezomib for the
proteosome inhibits protein
degradation, and prevents
nuclear translocation of NFKB
Bruno et al, The Lancet Oncology, July 2004, 430-442
Mechanism of Action of
Arsenic Trioxide
 Mutated P53:
Arsenic trioxide triggers the
caspase cascade by
activation of caspases 8
and 10
 Functional P53:
The cascade is activated
through the mitochondrial
apoptotic pathway and the
activation of caspase 9
Bruno et al, The Lancet Oncology, July 2004, 430-442