Overview

Multiple myeloma is the most common primary malignant neoplasm of the skeletal system.
The disease is a malignancy of plasma cells. Radiologically, multiple destructive lytic lesions
of the skeleton, as well as severe demineralization, characterize multiple myeloma. The
etiology of the disease is the monoclonal proliferation of plasma B cells, with resultant
marrow infiltration and increase of a single immunoglobulin and its fragments in the serum
and urine. Electrophoretic analysis shows increased levels of immunoglobulins in the blood
as well as light chains (Bence-Jones protein) in the urine.
See the images below displaying different areas of the body affected by multiple myeloma.

Lateral radiograph of the skull. This image demonstrates

numerous lytic lesions, which are typical for the appearance of widespread myeloma.

Lateral radiograph of the lumbar spine. This image shows

deformity of the L4 vertebral body that resulted from a plasmacytoma.

Radiograph of the right femur. This image demonstrates the typical

appearance of a single myeloma lesion as a well-circumscribed lucency in the

intertrochanteric region. Smaller lesions are seen at the greater trochanter.

Radiograph of the right humerus. This image demonstrates a destructive lesion of the

diaphysis. Pathologic fracture is seen.

A T1-weighted
magnetic resonance image of the humerus. This image demonstrates a predominantly
hypointense to isointense myelomatous lesion in the medullary space of the diaphysis. The

lesion extends through the anterior aspect of the cortex.

A T1weighted magnetic resonance image of the shoulder. This image shows the full extent of
myelomatous involvement within the glenoid and coracoid process.
The marrow infiltration process may involve any bone, but the predominant sites include the
vertebral column, ribs, skull, pelvis, and femora. Although the osseous structures may appear
radiographically normal or simply osteopenic, the classic appearance is of multiple, discrete,
small, lytic lesions. Occasionally, a single lytic lesion is discovered and is termed a
plasmacytoma (solitary myeloma). Patients with a single focus of disease often progress to
multiple sites of myelomatous involvement.[1, 2, 3, 4, 5, 6]

Preferred examination
The preferred initial imaging examination for the diagnosis and staging of myeloma
(according to the 2009 International Myeloma Working Group consensus statement) remains

the skeletal survey. Patients suspected of having multiple myeloma based on bone marrow
aspirate results or hypergammaglobulinemia should undergo a radiographic skeletal survey.
Conventionally, this skeletal survey consists of a lateral radiograph of the skull,
anteroposterior (AP) and lateral views of the spine, and AP views of the humeri, ribs, pelvis,
and femora. Inclusion of at least these bones is important for both diagnosis and staging.
Whole body imaging, especially with new MR techniques, is advocated when possible. Other
whole body techniques, including low-dose CT scanning, positron emission tomography
(PET) scanning with fluorodeoxyglucose (FDG), and scintigraphy with 2-methoxy-isobutylisonitrile (MIBI) are still being evaluated.
Shortt et al compared FDG PET, whole body MRI, and bone marrow aspiration and biopsy in
24 patients (13 women, 11 men; mean age, 67.1 years; range, 44-83 years) with multiple
myeloma proven by bone marrow biopsy. Whole body MRI had a higher sensitivity and
specificity than PET, and the positive predictive value of whole body MRI was 88%. When
used in combination and with concordant findings, PET and whole body MRI had specificity
and positive predictive values of 100%.[7]
Dimopoulos et al (writing in 2009 for the International Myeloma Working Group) reviewed
the literature of all imaging modalities used in multiple myeloma and provided
recommendations for each modality. Conventional radiography, according to the authors,
remains the criterion standard for staging newly diagnosed cases and in cases of relapse. MRI
can provide information that is complementary to a skeletal survey and was recommended for
use in patients with normal radiographic images and in all patients with an apparently solitary
plasmacytoma of bone.
According to Dimopoulos et al, urgent MRI or CT (if MRI is not available) is the diagnostic
procedure of choice to assess suspected cord compression. Standard99m Tc bone scintigraphy
should play no role in the routine staging of myeloma, and sequential dual-energy
radiographic absorptiometry (DXA) scans are not recommended, according to the authors.
PET or MIBI imaging are also not recommended for routine use, according to the study
findings, although both techniques may be useful in selected cases that warrant clarification
of previous imaging findings.[8]
Agool et al studied somatostatin receptor scintigraphy (SRS) in 29 myeloma patients and
compared the results with radiographic findings. A positive SRS was demonstrated in 44% of
9 newly diagnosed patients; 83% of the 18 relapsed patients; and both of the patients with
plasmacytoma. In 40% of the patients, the SRS findings corresponded with radiographic
abnormalities, but in 60% of relapsed patients, SRS uptake was demonstrated in areas
without new radiographic abnormalities.[9]
Focused examinations of newly painful bones are of value for assessment of impending
pathologic fracture. Correlation with all other available imaging studies should be done to
help determine the risk of pathologic fracture.
The unequivocal diagnosis of myeloma is made when the following 3 criteria are satisfied:

A minimum 10-15% of a bone marrow aspirate demonstrates abnormal plasma cells

Radiographic survey demonstrates typical lytic lesions

Monoclonal immunoglobulins are present in the urine or blood

Limitations of techniques
The skeletal survey has limitations. Most importantly, a large number of patients diagnosed
with asymptomatic myeloma may have radiographically occult myeloma deposits. At least
30% cancellous bone loss is required to visualize an intramedullary destructive process, such
as myeloma, with radiographs. In addition, myeloma is a disease of older patients; the disease
can present with diffuse demineralization, which may be indistinguishable from the pattern
found in patients with simple senile osteoporosis.
Magnetic resonance imaging (MRI) has been suggested as an additional imaging examination
in patients with myeloma. MRI has the advantage of rapidity and sensitivity for the presence
of disease; however, specificity is limited. Whole body imaging is preferred but if this is not
possible, at least an MRI examination of the spine should be done, because radiographically
occult lesions or extramedullary lesions may be found that can change the stage and influence
the need for therapeutic intervention.

Staging
Morbidity and mortality, in myeloma patients, are directly related to the stage of disease at
initial diagnosis. In 1975, Durie and Salmon proposed the initial clinical staging system for
multiple myeloma. The system was revised in 2003 and is now referred to as the
Durie/Salmon PLUS system, since additional information from advanced imaging modalities
has been added. Radiologists should use the revised system (outlined below) to accurately
stage these patients.[10, 11]

Stage IA Normal skeletal survey or single lesion

Stage IB - Five focal lesions or mild diffuse spine disease

Stage IIA/B - Five to 20 focal lesions or moderately diffuse spine disease

Stage IIIA/B - More than 20 focal lesions or severe diffuse spine disease

Subclasses A and B (A = normal renal function, B = abnormal renal function)

Mild, moderate, and diffuse spine disease is established by MR imaging. Moderate diffuse
disease is defined as vertebral body signal intensity brighter than adjacent disc on a T1weighted sequence. Severe diffuse disease is defined as vertebral body signal intensity less
than or equal to the adjacent disc on a T1-weighted sequence. Mild disease has not been
precisely defined.

Radiography
The classic radiographic appearance of multiple myeloma is that of multiple, small, wellcircumscribed, lytic, punched-out, round lesions within the skull, spine, and pelvis. Lesions
are lytic without reactive bone formation because of tumor factors that combine to activate

osteoclasts and inhibit osteoblasts. The lesions tend to vary slightly in size. In addition, the
bones of myeloma patients are, with few exceptions, diffusely demineralized. Because
myeloma is a disease of the medullary compartment of the bone, more subtle lesions can be
detected by the appearance of endosteal scalloping that is seen as slight undulation to the
inner cortical margin of bone. This finding is indicative of myelomatous involvement in the
appropriate clinical setting.
See the radiographic images of multiple myeloma below.

Lateral radiograph of the skull. This image demonstrates

numerous lytic lesions, which are typical for the appearance of widespread myeloma.

Lateral radiograph of the lumbar spine. This image shows

deformity of the L4 vertebral body that resulted from a plasmacytoma.

Radiograph of the right femur. This image demonstrates the typical

appearance of a single myeloma lesion as a well-circumscribed lucency in the

intertrochanteric region. Smaller lesions are seen at the greater trochanter.

Radiograph of the right humerus. This image demonstrates a destructive lesion of the

diaphysis. Pathologic fracture is seen.

Anteroposterior radiograph of
the left shoulder. This image shows an expansile process in the glenoid.
Although patients with advanced and extensive myeloma tend to have a number of
circumscribed lytic lesions, some may simply have diffuse osteopenia on radiography. Fewer
than 10% of patients present with a single myelomatous lesion, a plasmacytoma, found on
radiographs. These lesions are most common in the vertebral bodies. In other skeletal sites,
they may manifest as bubbly expansile lesions, often in a rib or posterior element of the
spine, but they can have a variety of shapes and sizes. They are occasionally associated with a
soft tissue mass.
There are 2 sclerotic forms of myeloma. One is a rare form, known as POEMS syndrome
(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin
changes), that may demonstrate sclerotic lesions on radiographs, but this condition is
responsible for less than 1% of myeloma cases. Major and minor criteria to diagnose this
condition have been proposed. The second form is a standard multiple myeloma case with
mixed lytic and sclerotic lesions. Radiographs of treated myeloma lesions also may rarely
show areas of abnormal bone architecture with sclerosis. Usually, little reactive bone sclerosis
or periosteal reaction is seen.[12]

Degree of confidence
As many as 90% of patients with myeloma demonstrate skeletal involvement. The finding of
multiple lytic lesions on a skeletal survey involves 2 primary differential considerations,
including myeloma and metastases. However, when these lesions are found together with
bone marrow plasmacytosis and elevated blood gamma-globulins, the diagnosis of myeloma
is certain.

If tests for these 2 parameters have not been performed (ie, bone marrow plasmacytosis,
blood gamma-globulins), the finding of multiple lytic lesions statistically represents
widespread metastatic disease in 60-70% of patients, with most of the remainder representing
myeloma. Rarely, other conditions that may have multifocal involvement, including infection,
sarcoidosis, and primary lymphoma of bone can mimic myeloma and metastatic disease. In
diffuse osteopenia found on radiography, consider the diagnosis of myeloma and perform
additional tests; however, most of these patients only have age-related decreased bone
mineral density.

False positives/negatives
False-positive examinations are encountered when multiple lytic lesions are found. In these
patients, perform additional studies because the most likely source of this pattern is metastatic
disease, not myeloma.
Diffuse osteopenia that is found on radiographs is often a source of false-negative
examinations because a substantial amount of cancellous bone must be destroyed before an
intramedullary lesion becomes visible radiographically.

Computed Tomography
Computed tomography (CT) scanning readily depicts osseous involvement in myeloma.
However the usefulness of this modality is still being studied, and CT scanning is not
required in most patients. Low-dose whole body CT, with newer multislice scanners, may be
able to replace the standard skeletal survey at institutions where it is available. In one recent
study of 42 patients, whole body CT scanning showed an average of nearly 4 times more
lesions than conventional radiographic skeletal survey.[13]
One clinical situation in which CT scan study may be of value is in cases in which the patient
has bone pain and a negative radiograph.[14] In this scenario, demonstration of a myeloma
lesion may alter therapy significantly. CT scanning can also guide percutaneous biopsies,
especially of osseous or extraosseous lesions that are suspected of being plasmacytomas.
See the CT images of multiple myeloma.

Axial computed tomography (CT) scan of the glenoid. This

image shows a well-defined lesion, with the typical CT scan appearance of myeloma. The

cortex is intact.
Axial computed tomography scan of the
glenoid (same patient as in the previous image). One year later, the myeloma lesion had
grown significantly, extending to the coracoid process and through the cortex of the glenoid.

Axial computed tomography (CT) scan through the left

shoulder during a CT-guided biopsy (same patient as in the previous image). This image
shows a core biopsy needle has been advanced through the coracoid process to obtain a tissue
sample.
The literature also shows that the use of fluorine-18 fluorodeoxyglucose (18 F FDG) positron
emission tomography (PET) scanning can be helpful in the staging and posttherapeutic
monitoring of multiple myeloma by providing functional detection of high metabolic lesions.
[15, 16]
However, a preliminary report by Nanni et al in a small population of patients indicates
that carbon-11 (11 C)-choline PET scanning may be more sensitive than18 F FDG PET
scanning for detecting myeloma lesions. The authors cautioned that more large-scale studies
are needed to verify their results.[16]
FDG PET scans that show a lesion with a standardized uptake value (SUV) greater than 11
has been reported as an indicator of a poorer prognosis. Additionally, patients with 3 or more
FDG avid lesions that do not respond to treatment have poorer outcomes.[17]
Recognition of a serially increasing SUV at a given location, such as within a vertebral body,
may help predict an impending pathologic fracture, especially if there is a correlating MRI
that shows diffuse vertebral body involvement.[18]

False positives/negatives
Because of the small size of many myeloma lesions, PET scans must be carefully evaluated
to decrease the number of false negatives. The usual SUV cutoff value of 2.5 does not apply
to myeloma lesions that are less than 1 cm in size. For a lesion less than 5 mm, any degree of

FDG uptake should be reported as active disease. Lesions between 5 and 10 mm are
considered indeterminate.

Magnetic Resonance Imaging

MRI is useful for imaging multiple myeloma because of its superior soft-tissue contrast
resolution. The typical appearance of a myeloma deposit is a round, low signal intensity
(relative to muscle) focus on T1-weighted images, which becomes high in signal intensity on
T2-weighted sequences. The images below demonstrate the appearance of a typical myeloma
lesion in the proximal humerus. Myeloma lesions tend to enhance with gadolinium
administration. In addition, diffuse areas of marrow replacement may be seen, resulting in
large regions of low T1-weighted signal.[19]

Coronal T1-weighted magnetic resonance image through a

myeloma lesion of the humerus. This image shows that the lesion has a low signal intensity.
The outer cortical margin is eroded but intact; however, the lesion has transgressed the inner

cortex.
A T1-weighted magnetic resonance image of the
humerus. This image demonstrates a predominantly hypointense to isointense myelomatous
lesion in the medullary space of the diaphysis. The lesion extends through the anterior aspect

of the cortex.
A T2-weighted, fat-suppressed magnetic resonance
image of a myeloma lesion of the humerus. This image demonstrates the lesion is
hyperintense on this sequence, a typical finding.
Fast whole body techniques are available on some magnet systems.[20] MRI also can provide
important information for prognosis. One study of 611 myeloma patients showed that the
presence of more than 7 focal lesions was an independent predictor of poorer prognosis and
that resolution of all focal lesions was an indicator of superior survival.[21]
See the images below of myeloma of the shoulder

A T1-weighted magnetic resonance image of the shoulder.

This image shows the full extent of myelomatous involvement within the glenoid and

coracoid process.
A T2-weighted, fat-suppressed magnetic
resonance image of the shoulder (same patient as in the previous image). This image
demonstrates the myeloma lesion is hyperintense.
Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate
dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK],
gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic

fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). The disease has occurred in
patients with moderate to end-stage renal disease after being given a gadolinium-based
contrast agent to enhance MRI or MRA scans.
NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark
patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow
spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms,
hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

Degree of confidence
Unfortunately, almost any musculoskeletal tumor has the same signal-intensity profile and
enhancement pattern as myeloma. MRI, although sensitive to the presence of disease, is not
disease specific. Additional tests must be used to diagnose myeloma, such as measurement of
gamma-globulin levels and direct aspiration of bone marrow to assess for plasmacytosis.
Because of this, MRI may understage or overstage patients with myeloma.
In patients with extraosseous lesions, MRI is the study of choice to define the degree of
involvement and to evaluate for cord compression.

Nuclear Imaging
Myeloma is a disease that results in overactivity of osteoclasts, with resultant liberation of
bone and suppression of osteoblasts. Nuclear medicine bone scans rely on osteoblastic
activity (bone formation) for diagnosis. As such, standard technetium-99m (99m Tc) bone scans
have underestimated the extent and severity of disease and should not be used routinely.[22]
However, a study by Erten et al appeared to demonstrated that whole body scintigraphy with
technetium-99m 2-methoxy-isobutyl-isonitrile (99m Tc-MIBI) may be a useful adjunct for the
diagnostic imaging of multiple myeloma.[23] The authors reported that in 24 patients,99m TcMIBI demonstrated the extent and intensity of bone marrow infiltration equally as well as
MRI, and they suggested that99m Tc-MIBI may serve as an alternative to MRI in cases in
which MRI is not readily available or when its use is limited. Another, larger study by Mele
et al of 397 scintigrams showed a sensitivity of 77% and a specificity of 86% for MIBI.[24]
Khalafallah et al in 2013 reported that MIBI predicted overall disease outcome and mortality
better than whole body MRI in their study of 62 patients.[25]

Degree of confidence
The false-negative rate of standard99m Tc bone scintigraphy in diagnosing multiple myeloma
is high. Scans may be positive with normal radiographs, requiring another test for
confirmation.

Angiography
Angiographic findings are nonspecific. Lesions may have a peripheral zone of increased
vascularity. Generally, this technique is not used for the diagnosis of myeloma.

http://emedicine.medscape.com/article/391742-overview#showall