advances in biology and pathophysiology of multiple myeloma
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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” - PowerPoint PPT PresentationTRANSCRIPT
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
Santiago Ramon Y. Cajal
1852-1934
Paul Gerson Unna
1850-1929
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
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
%
0
5
10
15
20
25
30
35
<40 40-49 50-59 60-69 70-79 >80
Age Distribution in Multiple Myeloma
Monoclonal Gammopathies – Mayo clinic
MGUS 62% (659)
MM 16% (172)
Extramedullary 1% (8)
SMM 4% (39)
LP 3% (37)
AL 8% (90)
Other 3% (33)
Macro 3% (30)
Immunophenotype of Multiple Myeloma
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
Marker Features
Long-lived plasma cellPre-B cell
G, A, D, E
Lymphoblast
Plasmablast
Naïve B Cell
Short-lived plasma cell
Lymph Node
Lymphoplasmacyte (memory B Cell)
Follicle center
Bone Marrow
Stimulation with Antigen
Somatic Hypermutation of Ig Sequences
Isotype Switching
::
::
::...
::...
IgM
Normal B-cell Development
IgM
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
Shaughnessy J et al, Blood, 2000; 96:1505
12
11
13
21
14
32
31
22
34
33
Pathogenesis of Multiple Myeloma
Two pathways involved in the early pathogenesis of MGUS and MM
50% non-hyperdiploid50% Hyperdiploid
IgH TranslocationsInfrequent IgH Translocations
4p16 FGFR3+ MMSET
11q13 (cyclin D1)
6p21 (cyclin D3)
20q11 (mafB)
16q23 (c-maf)
Multiple trisomies of chromosomes 3, 5, 7,
9, 11, 15, 19 and 21
Hideshima et al, Blood, August 2004, 607-618
Pathogenesis of Multiple Myeloma
0102030405060708090
100
MGUS MM PPCL HMCLs
Pre
vela
nce
of
IgH
Tra
nsl
oca
tio
ns
Hideshima et al, Blood, August 2004, 607-618
Prevalence of IgH Translocations
No IgH T
6p21
11q13
16q23
4p16
20q11
Lower incidence with MGUS/SMM
de novo MM
Rapid progression of MGUS to MM
Extremely poor prognosis
4p16 or 16q23
Translocations in MM
Hideshima et al, Blood, August 2004, 607-618
PrimarySecondary
6p21
4p16 16q23
11q13 20q11
90% HMCLs
40% adv MM
15% MM
c-myc
Translocation and Cyclin D (TC) Molecular Classification of MM
GroupPrimary
translocationGene(s) at breakpoint D-Cyclin Ploidy
Freq of TC in newly diag
MM, %
TC111q13 6p21
CCND1 CCND3
D1 D3
NH NH
15 3
TC2 None None D1 H 37
TC3 None None D2 H=NH 22
TC4 4p16FGFR3/MMSET D2 NH>H 16
TC516q23 20q11
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
PPC BMPC 6p D111q13 D1+D2 other maf4p16
TC1 TC2 TC5TC3 TC4
D1=Green, D2=Red, D3=Blue
Tarte k. et al, Blood. 2002;100:1113-1122. Zhan F. et al, Blood. 2002; 99:1745-1757
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
p18
p53
c-mycN, K-RAS
FGFR3
NON-HYPER
DIPLOID
HYPER DIPLOID
DEL 13?p16
11q13
6p21
16q23
20q11
4p16
Other
Primary IgH tx
TRISOMY
3, 5, 7, 9, 11, 15, 19, 21
Germinal center B cell MGUS
Intramedullary Myeloma
Extramedullary Myeloma HMCL
Hideshima et al, Blood, August 2004, 607-618
Normal Plasma Cell
MGUS
IgH translocations
Intra- medulary myeloma
Extra- medullary myeloma
Deletion of 13q
Chromosomal instability RAS mutations
Dysregulation of c-MYC
p53 mutations
Progression to Plasma Cell Neoplasia
The TC Molecular Classification Predicts Prognosis and Response to Therapies
Bad prognosis
Increased PC Labeling Index
Tumor Cells with Abnormal
Karyotype
Monosomy of chro 13/13q
Hypodiploidy
Monosomy of chro 17
Activating Mutations of
K-Ras
t(4;14) TC4
Lack of Cyclin D1 ExpressionDeletion of p53
t(14;16) TC5
The TC Molecular Classification Predicts Prognosis and Response to Therapies
t(4;14) translocation (TC 4)
Shortened Survival
Standard
Therapy (42)High-dose
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
t(14;16) translocation (TC 5)
Shortened Survival (worse Prognosis)
Standard
Therapy (15)
Median OS 16 months
The TC Molecular Classification Predicts Prognosis and Response to Therapies
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
Therapy (53)High-dose
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
OFF ON
Cyclin D1Cyclin D2 Cyclin D3
TC1TC3TC4TC5 TC2
11q13 CCND16p21 CCND3
HyperdiploidCyclin D1
OtherFGFR34p16
MMSET
16q23 c-maf20q11 mafB
CDK 4, 6 CDK 4, 6 CDK 4, 6
G1 Phase
S Phase
RbE2F
Rb
E2F
p15
p16
p18
p19
INK4a
INK4d
INK4b
INK4c
pp
p
p
Silencing of CDK inhibitor mRMA
expression might be reversed
Targeting Cyclin DTargeting the genes
Directly dysregulated By translocation
HDAC Inhibitors
DNA methyl Transferase
inhibitor
Novel Therapeutic Strategies targeting Genetic Abnormalities
Desferroxamine
Selective CDK inhibitors
Targeting FGFR3 by monoclonal
antibodies
Targeting FGFR3 by selective
tyrosine kinase inhibitor
MM
BMSC
TNFα TGFβ VEGF IL-6
IL-6 VEGF IGF-1
SDF-1α
NF-KB
Interaction of MM cells and their BM milieu
MEK/ERK
GSK-3β FKHR Caspase-9 NF-KB mTOR Bad
PKC
Akt
migration
JAK/STAT3
LFA-1
VCAM-1 Fibronectin
ICAM-1NF-KB
MUC-1
VLA-4
Adhesion molecules
Proliferation Anti-apoptosis
Survival Anti-apoptosis Cell cycle
Proliferation
p27Kip1
Survival Anti-apoptosis Cell cycle
PI3-K
NF-KB
ERKSmad2
Bcl-xL IAP Cyclin-D
Bcl-xL MCL-1
MEK/ERK
Survival Anti-apoptosis
Myeloma Cells and BM Microenvironment
Bruno et al, The Lancet Oncology, July 2004, 430-442
Apoptotic Signaling PathwaysVelcade ZME-2DexImiDs, Velcade
HDAC-I, 2ME-2
TNFα FasL TRAIL
JNK
Caspase-9Caspase-8
Caspase-3
PARP
Apoptosis
IL-6 IGF-1
SmacCytochrome-cBid
FADDMitochondria
Hideshima et al, Blood, August 2004, 607-618
Novel biologically based therapies targeting MM cells and the BM microenvironment
A
D
C
B
Angiogenesis
Adhesion Molecule
Drug Resistance
Proliferation
Apoptosis Growth Arrest
Inhibition of Adhesion
Inhibition of Cytokines
bFGF VEGF
IL-6 IGF-1 VEGF SDF-1α
Novel Agents
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
Thalidomide and its analogs (Revlimid)
Proteasome inhibitor (Bortezomib)
Arsenic trioxide
2-Methoxyestradiol (2-ME2)
Lysophosphatidic acid acyltransferase-β inhibitor
Triterpinoid 2-cyano-3, 12-dioxoolean-1, 9-dien-28- oic acid (CDDO)
N-N-Diethl-8, 8-dipropyl-2-azaspiro [4.5] decane-2-propanamine (Atiprimod)
Targeting both MM cells and their interaction with BM microenvironment
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)
Telomerase inhibitor (Telomestatin)
bcl-2 antisense oligonucleotide (Genasense)
Inosine monophophate dehydrogenase (VX-944)
Rapamycin
Targeting cell surface receptorsTargeting the bone marrow
microenvironment
IĸB kinase (IKK) inhibitor (PS-1145)
p38 MAPK inhibitor (VX-745, SCIO-469)
TFG-β inhibitor (SD-208)
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
Bruno et al, The Lancet Oncology, July 2004, 430-442
Homoeostasis of Healthy Bone Tissue and MM Bone Disease
TNFα IL1β
Osteoprotegerin (OPG)
T cell
Interferon ɣ MIP1
Osteoclast
IL6
RANK
RANKL
Bone Marrow stromal Cells
Bone DestructionOsteoclast Precursor
Multiple Myeloma Cells
IL7
Osteoblast
Bruno et al, The Lancet Oncology, July 2004, 430-442
Effects of Thalidomide on the Myeloma Microenvironment
Proposed Action of Thalidomide in Myeloma
Mutiple Myeloma Cells
T Lymphocytes
Bone Marrow Stromal Cells
Modulation of Cytokines
Bone Marrow Vessels
Cytotoxicity of NK Cells
Modulation of Immune System
Direct Action
Inhibition of Angiogenesis
VEGF IL6 TNFα IL1β
IL2 ILNɣ
VEGF bFGF
Bruno et al, The Lancet Oncology, July 2004, 430-442
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