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Tabuk University
Faculty of Applied Medical Sciences
Department Of Medical Lab. Technology
3rd Year – Level 5 – AY 1434-1435
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Dr. Walid ZAMMITI
Msc, PhD. MLT
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Objectives
 To recognize the presenting symptoms and signs of multiple
myeloma.
 To identify criteria for diagnosis of multiple myeloma and related
disorders.
 To relate the clonal expansion of immunoglobulin-producing
plasma cells and accompanying destructive skeletal changes that
occur with multiple myeloma in terms of manifestations and
clinical course for this disorder.
 To explain how expansion of a single clone of plasma cells that
produce immunoglobulins results in the pathologic changes seen
in multiple myeloma .
 To discuss risk factors, prevalence, diagnosis, clinical
manifestations, and treatment for multiple myeloma.
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Definition
•Multiple Myeloma is a plasma-cell neoplasm characterized by the
proliferation of a single clone of plasma cells engaged in the
production of a monoclonal immunoglobulin. ( M protein ):
•Multiple myeloma (myeloma or plasma cell myeloma) is a cancer of
the plasma cells in the bone marrow. There are different clones of
plasma cells in the bone marrow, which make the numerous types of
immunoglobulins (antibodies) needed for the immune system.
• In myeloma, the cancerous plasma cells are monoclonal and
overcrowd the bone marrow, causing some of the complications
associated with the disease.
Definition
• These abnormal cancerous plasma cells make a similar
immunoglobulin (monoclonal immunoglobulin, also called an Mprotein). This can be of any type: IgG, IgA, IgD or IgE; IgG is,
however, most common.
•Overall, approximately 70% of patients with myeloma will have
elevated IgG, 20% IgA, and 5%-10% light chains only (Bence
Jones protein). About 1% will have IgD, IgE, IgM or
nonsecretory disease (cancerous plasma cells that do not secrete
immunoglobulin).
•About 30% of the time there is an imbalance in the production of
light and heavy chains resulting in excess light chains along with
the monoclonal antibody.
In healthy bone marrow (A), B-cells develop into antibody-producing plasma cells when foreign
substances (antigens) enter the body. Normally, plasma cells make up less than 1 percent of the cells
in the bone marrow.
In multiple myeloma (B), genetic damage to a developing B cell transforms the normal plasma cell
into a malignant multiple myeloma cell. The malignant cell multiplies, leaving less space for normal
blood cells in the bone marrow, and produces large quantities of M protein.
Myeloma cells in the bone marrow cause osteolytic lesions, which appear as
“holes” on an x-ray. Weakened bones increase the risk of fractures, as shown in
this x-ray of a forearm. DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer:
Principles and Practice of Oncology. 5th ed. 1997:2350. Adapted with permission
from Lippincott Williams & Wilkins.
Causes
 There is no known cause, although, patients
with MGUS are at increased risk for developing
multiple myeloma.
 Radiation.
 Recently viruses like HHV-8 and SV-40, have
been linked to myeloma development.
 MGUS: Monoclonal Gammopathy of
Undetermined Significance= is a condition in
which a paraprotein is found in the blood or
urine.
 The paraprotein is an immunoglobulin or light
chain; produced by a single clone of plasma cells.
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Immunoglobulin Molecular
Structure
Paraprotein = M protein
• The plasma cells in myeloma are identical ('clonal'), because they
originate from a single abnormal cell that starts to multiply out of
control. The protein produced is, therefore, also identical
('monoclonal' meaning the product of a single clone).
• So Paraprotein is:a monoclonal immunoglobulin observed as a
result of an isolated increase in a single immunoglobulin type as a
result of a clone of plasma cells arising from the abnormal rapid
multiplication. Examples of such proteins : Myeloma proteins,
Bence-Jones protein, amyloid proteins,
Waldenstrom's
macroglobulinemia, or cryoglobulins.
Clinical Presentation
•The clinical presentation of multiple myeloma is variable;
approximately 30% of patients are asymptomatic at diagnosis.
• Diagnosis is usually made because a healthcare practitioner
notices an elevated protein on routine blood tests and follows up.
• Clinical findings suggest a possibility of multiple myeloma
include:
• Bone disease
• Hypercalcemia
• Anemia
• Renal Insufficiency
• Infections
• Venous Thromboembolism
• Hyperviscosity
Clinical Presentation (cont,)
BONE DISEASE
Generalized bone loss throughout the body and lytic bone
lesions are seen.
Bone pain is a common finding in multiple myeloma, often
from vertebral compression fractures.
The bone marrow microenvironment and the myeloma cells
produce many factors that promote the proliferation of myeloma
cells and bone loss.
These include growth factors such as vascular endothelial
growth factor (VEGF), tumor necrosis factor (TNF), and
interleukin 6 (IL-6), among others.
Clinical Presentation (cont,)
HYPERCALCEMIA
 About 20% of patients will have hypercalcemia upon presentation.
Hypercalcemia can cause nausea, confusion, constipation, polyuria, and
fatigue.
ANEMIA
 About 60% of patients will have anemia at the time of diagnosis;
most will develop it eventually.
 It can cause fatigue and weakness.
 The anemia is caused to some degree by crowding out of the normal
cells, but there is also inhibition of red blood cell production by various
cytokines.
 Sometimes neutropenia can also occur, and paradoxically platelets
may be elevated or lowered.
Clinical Presentation (cont,)
RENAL INSUFFICIENCY
 Kidney disease is commonly associated with multiple myeloma.
Renal impairment is present at diagnosis in approximately 20% to
25% of patients with multiple myeloma.
 The abnormal proteins from the myeloma cells can cause a
kidney damage through a variety of mechanisms.
 Hypercalcemia can contribute to kidney disease, as well.
mechanisms for immune dysfunction are not fully elucidated.
Clinical Presentation (cont,)
Venous Thromboembolism
Patients with multiple myeloma are at a high risk of
developing venous thromboembolism (VTE).
 This risk is increased by several of the agents used
to treat it such as thalidomide and lenalidomide.
Clinical Presentation (cont,)
INFECTIONS
Recurrent infections are common in patients with multiple
myeloma.
 Patients with multiple myeloma:
 have approximately a 15-fold increase in the risk of
infections, particularly pneumonia.
 are more susceptible to bacterial infections, especially
from encapsulated microorganisms, such as pneumococcus,
as well as viral infections.
Clinical Presentation (cont,)
HYPERVISCOSITY
Hyperviscosity is less common than the above disease
characteristics.
 If blood levels of immunoglobulin are very high, blood
viscosity may increase.
Retinal hemorrhages, mucosal bleeding, and cardiopulmonary
symptoms, may occur.
Laboratory tests
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ESR > 100 ( Marked Rouleux formation in blood films)
anaemia, thrombocytopenia
marrow plasmacytosis (usually > 20%)
Hyperproteinemia : elevated total protein levels
Hypercalcemia : elevated blood Ca++ levels ; in 45% of patients.
Proteinuria: protein in urine
Serum Alkaline Phosphatase is normal
Serum β2-microglobulin is often raised
Immunophenotyping : malignant plasma cells phenotypically
expressing CD38, CD56, and CD138. In addition, approximately
20% of malignant plasma cells express CD20
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Diagnosis
Initial work-up
 If multiple myeloma is suspected, the initial work-up should
include:
• CBC
• Chemistry, including calcium, BUN, and creatinine
• Serum protein electrophoresis and immunofixation
• Quantitative immunoglobulin levels
• 24-hour urine protein electrophoresis and immunofixation
 If a monoclonal protein is detected, a bone marrow aspirate and
biopsy should be performed and sent for pathological examination to
assess the amount of plasma cells, as well as for chromosomal
studies and flow cytometry.
Diagnosis of Multiple Myeloma
1-Increased plasma cells in the bone marrow.(more
than10%)*
2- Monoclonal protein in the serum or urine (usually >
3g/dl)
This is done using Serum Protein Electrophoresis (SPE).
3- Evidence of end-organ damage
hypercalCemia, Renal insufficiency, Anemia, or Bone
lesions (a group of findings referred to as CRAB)
* If the bone marrow plasma cell Count is >10% but there is no
evidence of tissue damage the disease is termed asymptomatic or
smouldering myeloma.
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pathologic fractures in MM
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A skull x-ray taken from
the side shows typical
findings
of
multiple
myeloma and multiple
"punched-out" holes. The
arrow is pointing at one
of the larger holes.
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Plasma cells : basophilic cytoplasm and an eccentric
nucleus. The cytoplasm also contains a pale zone.
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Plasma cells
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ROULEAUX FORMATION IN BLOOD FILMS
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Background staining and
rouleaux formation in myeloma.
The excessive immunoglobins
produced by the neoplastic plasma
cells in myeloma are acidic and
take up the basophilic stains used
in blood smears. (slide on right)
compared with normal (slide on
left). The abnormal immunoglobins
also cause the RBCs to adhere.
This resulting rouleaux (“stacking
of coins”) formation may be visible
on those portions of the smear
where erythrocytes are normally
apart .
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Diagnosis
 The quantitative immunoglobulin test will show if there is an
increase in any particular type of immunoglobulin, but it does not
determine if immunoglobulin is monoclonal.
 Electrophoresis is an essential test in the work up of myeloma.
Electrophoresis will identify if the elevated antibody level is
monoclonal or polyclonal.
 Other tests are used to help determine prognosis including: B2
microglobulin, lactate dehydrogenase (LDH), albumin, and Creactive protein. An elevated level of B2 microglobulin, LDH, and
C-reactive protein, and a low level of serum albumin are all markers
of a poor prognosis.
 Electrophoresed serum is separated to: albumin,
alpha 1, alpha 2, beta, and gamma regions.
 The gamma region contains the 5 types of
Immunoglobulin's (Ig’s): G, A, M, E, and D
 Any increase in this region is considered as an
increase in 2 or more of the immunoglobulin's
(polyclonal) which shows as an expansion of the
whole gamma region (in the electrophoresis).
 On the other hand, if the increase shows as a sharp
peak in the gamma region, this is conclusive of an
increase in one of the Ig's only, i.e., “monoclonal”.
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Genetics and Prognosis
 Certain chromosomal abnormalities are associated with prognosis
in multiple myeloma.
 A translocation between chromosome 4 and 14 (t(4;14)),
translocation between chromosome 14 and 16 (t(14;16)), or
deletions in chromosome 13 are poor prognostic factors in
myeloma. Patients with these abnormalities are considered
high risk.
 Translocations between chromosomes 11 and
(t(11;14)) may be associated with an improved survival.
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Bence Jones proteins
Bence Jones proteins are immunoglobulin light chains
(paraproteins) and are produced by neoplastic plasma cells.
They can be kappa (most of the time) or lambda . They are
found in the blood or urine.
The light chains have traditionally been detected by heating or
electrophoresis of concentrated urine. More recently serum
free light chain assays have been indicated over the urine
tests.
Causes of Bence Jones proteins:
Amyloidosis, benign monoclonal gammopathy,
cryoglobulinemia, Fanconi syndrome, hyperparathyroidism,
multiple myeloma , osteomalacia, Waldenström's
macroglobulinemia .
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