advances in biology and pathophysiology of multiple myeloma

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


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


In 1890s, Paul Unna and Ramon Cajal identified the plasma cell as a cell type and the cause 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


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


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


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


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


Shortened Survival (worse Prognosis)

Standard

Therapy (15)

Median OS 16 months


Fonseca R et al, Blood. 2003; 101:4569-4575



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 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.


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


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


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


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


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


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

advances in biology and pathophysiology of multiple myeloma

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