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How to Treat – Multiple myeloma
Pathophysiology
MULTIPLE myeloma involves the
clonal proliferation of plasma cells
within the bone marrow, most
commonly secreting a monoclonal
immunoglobulin (called a parapro-
tein) which can be detected in the
blood or urine (see figure 1). 2,6
A paraprotein is a clonal immu-
noglobulin that reaches detectable
levels in the bloodstream due to
abnormal excessive production
by the malignant clone. Immuno-
globulin consists of two main com-
ponents — heavy chains and light
chains (see figure 2).
Most multiple myeloma involves
secretion of whole immunoglobu-
lin in which the heavy chain is
clonally IgG or IgA, is seen in
around 80% of cases. 7 Secretion
of only the light chain component
of the immunoglobulin, referred to
as light-chain myeloma, occurs in
around 18% of cases. Excess light
chains, known as Bence Jones pro-
teins, are excreted in the urine (see
figure 3).
There are also rare cases (around
2%) of non-secretory myeloma
where disease manifestations relate
solely to plasma cell expansion
within the bone marrow.
Clonal expansion of plasma cells
results from genetic mutations,
most often involving gene translo-
cations between chromosomes or
alterations in the number of chro-
mosomes (hyperdiploidy or hypo-
diploidy).
With time, myeloma cells accrue
further genetic abnormalities lead-
ing to increasing proliferation and/
or treatment resistance. Plasma cell
development also relies on a con-
ducive bone marrow environment,
and thus treatments aimed at dis-
rupting the bone marrow microen-
vironment are under investigation. 2
Renal impairment
While whole immunoglobulin is
too large for glomerular filtra-
tion, light chains are secreted in
the glomeruli, then reabsorbed
in the proximal tubule. Once this
resorptive capacity is saturated,
they precipitate as casts in the dis-
tal tubules. This causes obstruction
and local inflammation, resulting
in acute kidney injury. Most renal
impairment in myeloma is due to
A
IgG
Heavy chain
| Australian Doctor | 15 September 2017
Light chain
Figure 2. Heavy and light chains.
B
Figure 1. Serum protein electrophoresis normal (A) and paraprotein (B). Figure 3. Bence Jones protein
Source: Simon Caulton bit.ly/1SXJ0DE Source: National Institutes of Health, US http://bit.ly/2uxDrtG
SEVERE
HYPERCALCAEMIA,
INFECTION,
HYPERURICAEMIA AND
MEDICATIONS ARE
OTHER POTENTIAL
CAUSE FOR RENAL
IMPAIRMENT IN
MULTIPLE MYELOMA.
Figure 4. Skull x-ray with classic myeloma lytic lesions.
22
IgA dimer
such cast nephropathy. 2,6
Less common causes of renal
impairment in myeloma are light
chain amyloidosis and monoclo-
nal immunoglobulin deposition
disease (MIDD). 8 Severe hypercal-
caemia, infection, hyperuricaemia
and medications are other potential
cause for renal impairment in mul-
tiple myeloma.
Bone disease
Dysregulation of the balance
between osteoclast and osteoblast
activity is responsible for the ostey-
olytic bone lesions seen in multiple
myeloma. This dysregulation is due
to production of various stimula-
tory/inhibitory factors by the mye-
loma cells. This relatively increased
osteoclast activity leads to a state
of osteolysis, leading to the lytic
lesions and hypercalcaemia com-
monly seen in multiple myeloma. 2
Figures 4 and 5 depict the clas-
sic appearance of ‘punched out’
lesions seen on X-ray in multiple
myeloma. Lesions are most com-
monly seen in the axial skeleton.
The standard X-ray skeletal survey
for the detection of lytic lesions has
now largely been replaced by the
low-dose CT skeletal survey, MRI
or PET-CT.
Anaemia
Multiple myeloma causes anae-
mia via two mechanisms — most
significantly, expansion of plasma
cells within the marrow occupies
space needed for normal erythro-
poiesis. Secondly, like all malig-
Figure 5. Pelvis and femur X-rays with diffuse myeloma lytic lesions.
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nancies, multiple myeloma causes
an inflammatory state, contribut-
ing to anaemia of chronic disease. 9
Recurrent infection
The cause of infection varies
depending on disease stage. Defi-
ciency of normal/functional immu-
noglobulins is common in myeloma
due to the clonal expansion of one
plasma cell line. In bone marrow
crowded with myeloma cells, nor-
mal haematopoiesis is prevented,
which may lead to neutropenia. 7
Immunosuppressive and immu-
nomodulatory
treatments
in
patients with known multiple
myeloma can also contribute to
recurrent infection in those on
treatment.
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