C h a p t e r 1 1
Disorders of White Blood Cells and Lymphoid Tissues
257
with MGUS will go on to develop a plasma cell dyscrasia
(multiple myeloma or lymphoplasmacytic lymphoma).
The strong link between MGUS and multiple myeloma
suggests that a first oncogenic event produces MGUS
and a second event results in multiple myeloma.
4
Multiple Myeloma
Multiple myeloma is a B-cell malignancy of terminally
differentiated plasma cells.
48–52
It accounts for 1% of all
cancers in Western countries. Its incidence is higher in
men and people of African-American descent.
4
It occurs
most frequently in the elderly, with incidence peaking at
the age of 63 to 70 years.
Pathogenesis.
Multiple myeloma is characterized by
proliferation of malignant plasma cells in the bone mar-
row and osteolytic bone lesions throughout the skeletal
system. As with other hematopoietic malignancies, it
is now recognized that multiple myeloma is associated
with chromosomal abnormalities, including deletions of
13q and translocations involving the IgG locus on chro-
mosome 14.
7
Changes also occur in the bone marrow
microenvironment, including the induction of angio-
genesis, the suppression of cell-mediated immunity, and
the development of paracrine signaling loops involving
cytokines such as IL-6 and vascular endothelial growth
factor (VEGF). Other growth factors that are impli-
cated in multiple myeloma include granulocyte-CSF,
interferon-
α
, and IL-10.
One of the characteristic features resulting from
the proliferating neoplastic plasma cells in multiple
myeloma is the unregulated production of an abnormal
monoclonal paraprotein referred to as the
M protein
because it is detected as an M spike on protein electro-
phoresis. In most cases the M protein is either IgG or
IgA. In some cases, the plasma cells produce only the
light chains of the immunoglobulin molecule. Because of
their low molecular weight, the light chains are readily
excreted in the urine, where they are termed
Bence Jones
proteins.
More commonly, however, malignant plasma
cells produce both complete immunoglobulins and free
light chains; therefore, both M proteins and Bence Jones
proteins are present. The excess light chains are directly
toxic to renal tubular structures and are an important
aspect of the pathophysiology of multiple myeloma.
Manifestations.
The main sites involved in multiple
myeloma are the bones and bone marrow (Fig. 11-10).
In addition to the abnormal proliferation of mar-
row plasma cells, there is proliferation and activation
of osteoclasts, which leads to bone resorption and
destruction. This increased bone resorption predisposes
the individual to pathologic fractures and hypercalce-
mia. Very high concentrations of paraproteins may
cause a hyperviscosity of body fluids. The light-chain
component may break down into amyloid, a protein-
aceous substance deposited between cells, causing heart
failure and nephropathy. Renal involvement, gener-
ally called
myeloma nephrosis
, is a distinctive feature
of multiple myeloma. Although multiple myeloma is
characterized by excessive production of monoclonal
immunoglobulin, levels of normal immunoglobulins are
usually depressed. This contributes to a general suscep-
tibility to recurrent bacterial infections.
The malignant plasma cells also can form plasmacy-
tomas (plasma cell tumors) in bone and soft tissue sites.
The most common site of soft tissue plasmacytomas is
the gastrointestinal tract. The development of plasmacy-
tomas in bone tissue is associated with bone destruction
and localized pain. Osteolytic lesions and compression
fractures may be seen in the axial skeleton and proximal
long bones. Occasionally, the lesions may affect the spi-
nal column, causing vertebral collapse and spinal cord
compression.
Bone pain is one of the first symptoms to occur in
approximately three fourths of all individuals diagnosed
with multiple myeloma. Bone destruction also impairs
the production of erythrocytes, leukocytes, and throm-
bocytes. This predisposes the patient to anemia, recur-
rent infections, and thrombocytopenic purpura. Many
patients experience weight loss and weakness. Renal
insufficiency occurs in 50% of patients. Neurologic
manifestations caused by neuropathy or spinal cord
compression also may be present.
Osteolytic bone
lesions
• Bone pain
• Hypercalcemia
• Pathologic
fractures
Renal failure
Proteinuria
• Bence Jones protein
Bone marrow
infiltration
• Anemia (fatigue, pallor)
• Neutropenia (decreased
resistance to infection)
Bone marrow
infiltration
• Thrombocytopenia
(purpura)
Failure of antibody
production
• Recurrent infections
Plasma cell
secretion of
paraproteins
• Hyperviscosity of
body fluids
• Amyloid deposits in
heart and kidney
Ab a
1
a
2
b g
M protein spike
(serum)
FIGURE 11-10.
Clinical features of multiple myeloma.
