Journal Reading:

Multiple Myeloma: a review

BAGUS GEDE KRISNA ASTAYOGI

INTRODUCTION

Myeloma is a malignant proliferation of neoplastic plasma cells

of B-cell lineage within the bone marrow, leading to increased
production of plasma paraprotein and immunoglobulin

Multiple myeloma is an incurable condition, although with

treatment, symptoms can be managed and survival
extended

It most commonly arises in the marrow-containing bones of

the vertebrae, pelvis and femur, though lesions can occur in
any bone
AETIOLOGY & PATHOGENENESIS

• The aetiology of multiple myeloma is poorly understood.

• Some studies have confirmed an association with
occupational/environmental risk factors such asbestos,
farming, petroleum and ionising radiation
• Further research needed
 GENETICS

Rises as a result of multiple genetic mutations of

plasma cells and the immunoglobulins they produce

The events which cause the propagation from MGUS

to myeloma are unclear but they share
translocations of genes encoding both heavy chain
(IgH) and light chains (IgL)

Chromosome 13 abnormalities are also commonly

detected, in approximately 50% of patients -> worse
prognosis

Up-regulation/overexpression of oncogenes
and interferon regulatory factors -> increased
cell survival and proliferation
GENETICS
Increasing mutations in oncogenes and inactivation of
tumour suppressor genes causes the induction of genes
that code for angiogenic cytokines such as vascular
endothelial growth factor and fibroblast growth factor-2
(FGF-2)

This, combined with a loss of anti-

angiogenic activity, may herald the
conversion of MGUS to Multiple
Myeloma
Bone Environment

• MM -> focal osteolytic

lesions, generalised bone
loss (osteopenia), and
elevated bone turnover.

• MM -> induced bone marrow

stromal cell (BMSC) release
of osteoclast activating
factors Interleukin (IL)-6, IL-1,
tumour necrosis factor-b
(TNF-b) and parathyroid
hormone-related peptide
(PTHrP) which increase the
cell surface expression of
receptor activator of nuclear
factor-kB (RANKL) on
osteoblast and stromal cells
 Bone Environment

• RANKL binds to RANK receptors on

osteoclast precursors, triggering
their differentiation into mature
osteoclasts

• Osteoprotegrin (OPG) normally

regu- lates RANKL induced
osteoclastic activity, but in the
presence of syndecan-1 secreted by
the malignant plasma cells, OPG is
inactivated

• This vicious cycle promotes bone

resorption, which in turn stimulates
the myeloma cells, inducing bone
loss.
 Bone Environment

• Osteoblastic activity and differentiation

from precursors are interrupted by
dickkopf-1 (DKK- 1)

• DKK-1 is a major osteolysis factor in

myeloma and is abundantly expressed
in bone marrow aspirates from
myeloma
INVESTIGATIONS – SCREENING TEST

To assess the degree of end-organ damage and disease severity

haemoglobin levels, erythrocyte sedimentation rate, renal
function and calcium measurements are mandatory

Serum free light chain levels are also useful for the
diagnosis of light chain-only myeloma, when electro-
phoresis is negative

Quantification of the monoclonal serum M-proteins is useful to

estimate tumour burden and prognosis.
BONE MARROW BIOPSY

Diagnosis requires analysis of a bone marrow biopsy

The sample phenotype is assessed by flow cytometry

or immunohistochemistry to detect antigen and is
recommended in all cases

The International Myeloma Working Group (IMWG)

diagnostic criteria for myeloma include: Serum M-protein
>30 g/l and/or; Bone marrow clonal cells >10%
 IMAGING

• Radiographs of the spine, skull,

pelvis, ribs/sternum, and the
humerus/femurs

• Classical ‘punched-out’, osteolytic

lesions with cortical thinning can be
seen -> skull may cause a ‘pepper-
pot’ appearance

• More often found in the axial

skeleton (particularly spine, skull
and pelvis), should lesions develop
in the long-bones they are located
in the proximal metaphysis
 IMAGING

• CT is superior for demonstrating fractures, osteolytic lesions, and

soft tissue masses and may aid in distal staging of disease.

• MRI scanning is useful to stage the extent of marrow infiltration

and for visualisation of focal masses and areas most at risk of
fracturing. MR may reveal hypointensities on T1-weighted
sequences and hyperintensities on STIR, though these
characteristics are not specific for myeloma
STAGING
PROGNOSTIC MARKERS
Adverse prognostic factors include anaemia,
hypercalcaemia, renal failure, hyperuricaemia, low serum
albumin, and elevated beta-2 macroglobulin level.

The combination of high levels of C- reactive protein,

IL-6 and b-2 microglobulin indicate a poor prognosis
in multiple myeloma

Lactate dehydrogenase levels are associated with a very

short survival, high tumour load and mass, and poor
responsiveness to chemotherapy
CLINICAL PRESENTATION
PATHOLOGICAL FRACTURES

ANEMIA

RENAL DYSFUNCTION

IMMUNOSUPRESSION

HYPRERCALCEMIA
PATHOLOGICAL FRACTURES

• Bone disease in myeloma may cause severe bone pain, spinal cord
compression, diffuse osteoporosis, hypercalcaemia and
pathological fracture

• Pathological fractures occur in approximately 40% of patients with

multiple myeloma, compromising mortality, mobility,
independence and quality of life

• There is a nine-fold increase in fracture risk with myeloma

compared to the normal age adjusted population.

• Most commonly found in the thoracic and lumbar spine but are
also found in the ribs, skull, pelvis and femur

• The risk of fractures is increased with high dose corticosteroids

often used in the treatment of myeloma.
PATHOLOGICAL FRACTURES
 ANEMIA

• Anaemia commonly impacts the quality of life and functional capabilities

of myeloma patients, occurring in more than two – thirds

• Firstly MM can cause anaemia of chronic disease due to the production

of excessive inflammatory cytokines such as IL-1, IL-6 and TNF

• The chronic inflammatory cytokines (IL-1, IL-6 and TNF) produced in

chronic disease suppress erythropoiesis and renal impairment reduces
erythropoietin production.

• Chemotherapy causes myelosuppression

• Treatment for anaemia may involve blood transfusion or erythropoietin

which improves survival and minimises transfusion
RENAL DYSFUNCTION
• Commonly found in symptomatic myeloma patients at
presentation and may progress to end stage renal failure
necessitating dialysis during the course of the disease.

• Renal damage occurs secondary to amyloidosis, light chain cast

nephropathy and the nephrotoxic effects of chemotherapy.

• Amyloidosis causes organ dysfunction due to amyloid

(monoclonal light chain) deposition typically in the glomerulus,
causing significant proteinuria and slow renal failure progression.

• Cast nephropathy results from the formation of plugs in the renal

tubules with free immunoglobulin light chains, obstructing the
tubules or rupturing the tubular epithelium leading to tubular
atrophy and fibrosis
 HYPERVISCOCITY
• Rare complication in myeloma patients

• Serum viscosity is increased by excessive immunoglobulin load,

abnormally large immunoglobulin molecules and abnormal
polymerisation.

• Hyperviscosity is therefore more likely with large pentamer IgM

monoclonal antibodies (though much rarer than IgA and IgG
myelomas) and is reflected by greater serum erythrocyte
sedimentation rates (ESR).

• Causes characteristic micro-vascular occlusive problems such as

malaise, haemor- rhagic diathesis, ocular disturbances, Meniere’s
syndrome, central nervous system, renal and cardiac dysfunction,
depending upon the organs primarily affected.
 IMMUNOSUPPRESION

• Rare complication in myeloma patients

• Serum viscosity is increased by excessive immunoglobulin load,

abnormally large immunoglobulin molecules and abnormal
polymerisation.

• Hyperviscosity is therefore more likely with large pentamer IgM

monoclonal antibodies (though much rarer than IgA and IgG
myelomas) and is reflected by greater serum erythrocyte
sedimentation rates (ESR).

• Causes characteristic micro-vascular occlusive problems such as

malaise, haemor- rhagic diathesis, ocular disturbances, Meniere’s
syndrome, central nervous system, renal and cardiac dysfunction,
depending upon the organs primarily affected.
MANAGEMENT

Chemotherapy/Radiotherapy

Stem Cell Transplantation

Surgery

Biphosponate
THANK
YOU