Multiple Myeloma Workshop Jakarta, 9th Nov 2017

PATHOGENESIS OF

MULTIPLE MYELOMA

Kartika Widayati Taroeno-Hariadi

Hematology and Medical Oncology Department of Internal Medicine
Faculty of Medicine Universitas Gadjah Mada-Dr Sardjito Hospital
Yogyakarta
Introduction
• Multiple Myeloma is a monoclonal tumor of plasma cells
• Its development is preceded by a premalignant tumor with which it
shares genetic abnormalities, including dysregulation of CyclinD/RB
pathway
• A complex interaction with the bone marrow microenvironment leads to
lytic bone disease
• Intratumour heterogeneity and inter tumor heterogeneity contributes to
the rapid emergence of drug resistance

Kuehl WM & Bergsagel PL. The Journal of Clinical Investigation 2012; 12:3456--3463
NORMAL B CELL DEVELOPMENT AND PLASMA
CELL
B-cell development process in BM, spleen, and Lymphnode

Piepier et al. Journal of Allergy and Clinical Immunology 2013;131:959

Secondary lymphoid follicle
Pathpedia/education/eatlas
Immunoglobulin structure
IgH GENE REARRAGEMENT, SOMATIC HYPERMUTATION, CLASS SWITCH RECOMBINATION
IN B CELL DEVELOPMENT

Blood 2007: 110; 3112-3121

IgƘ, Igƛ GENE REARRANGEMENT, SOMATIC HYPERMUTATION,
IN B CELL DEVELOPMENT

Blood 2007: 110; 3112-3121

KEY OF MYELOMA PATHOGENESIS

IMMORTALIZATION

ESTABLISHMENT

ESCAPE FROM APOPTOSIS

Hallek et al .Blood 1998;91

PATHOGENESIS OF MULTIPLE MYELOMA

Alteration of Normal Plasma Cell

to MGUS

Progression of MGUS to MM

Pathogenesis of Bone lesion and

related end organ involvement

Abeloff Clinical Oncology 4 Ed 2010

• Myeloma arises from an asymptomatic premalignant proliferation of
monoclonal plasma cells that are derived from post–germinal-center B
cells.

• Multistep genetic and macro and micro environmental changes lead to the
transformation of these cells into a malignant neoplasm.

• Myeloma is thought to evolve most commonly from a monoclonal

gammopathy of undetermined clinical significance (MGUS) that progresses
to smoldering myeloma and, finally, to symptomatic myeloma

Palumbo A et al. N Engl J Med 2011:364

WHO Tumor of Hematopoetic and Lymphoid Tissues
 Alteration of normal plasma cell to MGUS and
development to Multiple myeloma

• Antigenic stimulation and immune suppresion

(aberant expression of TLR and IL-6)
• Cytogenetic changes (IgH translocation, non IgH
translocation, del 13, NRAS, KRAS, cMYC , p53
• Activation of Cyclin D
• Stromal interaction, cytokine secretion
(microenvironmental factors)

Abeloff Clinical Oncology 4 Ed 2010

Immune Dysregulation in MM
 Adhesion molecule Activation
T h1/Th2/Th17
Cell influx Bone resorption
Th2 differentiation
Apoptosis resistance

T reg differentiation
blockade

IL-6
Differentiation
Plasma Cells
Proliferation
Tumor growth

Macrophage Acute phase protein

differentiation CRP
 Toll like Receptor

• Important sensor for microbes,

inflammed or damaged self cell.
• TLRs initiate downstream signal
to produce chemokine, cytokine,
and inflammatory mediator
• TLRs is also regulate sell
proliferation and survival
Multiple genetic abnormalities
Blood 2007: 110; 3112-3121
Cytogenetic Changes for progression to
multiple myeloma

Hideshima T et al. Blood 2004;104:607-618 © 2004 by American Society of Hematology

UNIFYING EVENTS IN THE PATHOGENESIS OF MULTIPLE MYELOMA

Hideshima T et al. Blood 2004;104:607-618

 Translocation and Cyclin D (TC) molecular classification
group Primary Genes at D Cyclin ploidy Prognosis
translocation breakpoints
TC1 11q13 CCND1 D1 NH better
6p21 CCND3 D3 NH
TC2 none none D2 H
TC3 none none D2 H=NH
TC4 4p16 FGFR3/MMSET D2 NH>H Shortened
survival
TC5 16q23 c-maf D2 NH
20q11 maf-B D2 NH

Hideshima et al. Blood 2004:104:607-618

 PI3K
JAK/STAT 3
MERK/ERK
NFkB
o
Wnt

Palumbo A et al. N Engl J Med 2011:364 Hu J and Hu W. Cancer letters 2018;414:214-221

Walker R et al British Medical Bulletin, 2014, 111:117–138
Novel Players in MM pathogenesis : The role of CK2 and GSK-3

Piazza F. Leukemia Research 2013;13:221-227

 SUMMARY
• Pathogenesis MM involves all
process that predispose and alter
normal plasma cells into MGUS
and then transforms them into
malignant myeloma cells
• Antigenic stimulation,
cytogenetic changes
accompanied by bone marrow
microenvironment , and
angiogenesis play important role
in Multiple myeloma patogenesis