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EDUCATION EXHIBIT
127
Current Concepts in the
Evaluation of Multiple
Myeloma with MR Imaging and FDG PET/CT1
CME FEATURE
See accompanying
test at http://
www.rsna.org
/education
/rg_cme.html
LEARNING
OBJECTIVES
FOR TEST 2
After reading this
article and taking
the test, the reader
will be able to:
■■Describe
the
spectrum of plasma
cell disorders and
the significance of
focal myelomatous
lesions.
■■Recognize
common bone marrow
infiltration patterns
of multiple myeloma
at MR imaging and
FDG PET/CT and
correlate them with
the disease stage.
■■Identify
MR imaging and FDG PET/
CT features that
may mimic multiple
myeloma and those
that indicate response to treatment
or are related to
treatment.
Christopher J. Hanrahan, MD, PhD • Carl R. Christensen, MD
Julia R. Crim, MD
Multiple myeloma is a heterogeneous group of plasma cell neoplasms
that primarily involve bone marrow but also may occur in the soft tissue. Although the disease varies in its manifestations and its course, it is
eventually fatal in all cases. Over the past 2 decades, significant advances
have been made in our understanding of the genetics and pathogenesis of multiple myeloma and in its treatment. The use of magnetic resonance (MR) imaging and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT) has
improved sensitivity for the detection of this disease. PET aids in the
identification of active multiple myeloma on the basis of FDG uptake,
and MR imaging helps identify multiple myeloma from its infiltration
of normal fat within the bone marrow, which occurs in characteristic
patterns that correlate with the disease stage. The increased sensitivity
of these advanced cross-sectional imaging techniques has led to further
refinement of the classic Durie and Salmon staging system. In addition,
these imaging techniques allow a more reliable assessment of the disease
response to treatment with current regimens, which may include autologous stem cell transplantation as well as various medications. In lesions
that respond to chemotherapeutic agents, the replacement of previously
infiltrated marrow by fat is seen at MR imaging and decreased FDG
uptake is seen at FDG PET; however, a lengthy and intensive regimen
may be necessary before the MR imaging appearance of marrow normalizes. Lytic lesions seen at CT almost always persist even after successful treatment. To provide an accurate assessment, radiologists must
be familiar not only with the appearances of multiple myeloma and its
mimics but also with common treatment-related findings.
©
RSNA, 2010 • radiographics.rsna.org
Abbreviations: FDG = fluorine 18 fluorodeoxyglucose, MGBS = monoclonal gammopathy of borderline significance, MGUS = monoclonal gammopathy of undetermined significance
RadioGraphics 2010; 30:127–142 • Published online 10.1148/rg.301095066 • Content Codes:
From the Department of Radiology, University of Utah School of Medicine, 30 North 1900 East, Rm 1A71, Salt Lake City, UT 84132. Presented
as an education exhibit at the 2008 RSNA Annual Meeting. Received March 24, 2009; revision requested May 6 and received November 2; accepted
November 4. C.J.H. and J.R.C. are consultants with Amirsys; C.R.C. has no financial relationships to disclose. Address correspondence to C.J.H.
(e-mail: [email protected]).
1
The Editor has no relevant financial relationships to disclose.
©
RSNA, 2010
128 January-February 2010
Introduction
Multiple myeloma is a hematologic malignancy
of bone marrow plasma cells. The disease varies widely in its manifestations, aggressivity, and
histopathologic pattern. The neoplastic plasma
cells tend to form clusters, which may be small
(micronodular disease) or large (macronodular
disease). Over the past 2 decades, advances have
been made with regard to the diagnosis, staging,
treatment, and imaging of plasma cell disorders.
Several new chemotherapeutic agents, including lenalidomide and bortezomib, and the use of
peripheral bone marrow stem cell transplantation
have been implemented in the past 20 years (1).
With the administration of high-dose chemotherapy and peripheral stem cell transplantation,
the median survival for a patient with multiple myeloma has increased from approximately 2½ years
to 8½ years, provided there are no genetic factors
present that would confer a high risk (1,2).
With the improvement in chemotherapeutic
options and the increased use of autologous
transplantation, advanced imaging is becoming
more important in the evaluation of multiple
myeloma. Although the radiographic skeletal
bone survey is still the recommended method
for initial diagnostic imaging evaluations, wholebody magnetic resonance (MR) imaging has
higher sensitivity, and it is recommended in a
patient with a solitary plasmacytoma or monoclonal gammopathy and a normal radiographic
bone survey or few (< 5) lytic lesions (3). Posttreatment imaging of multiple myeloma is useful
to monitor the disease response, but the data at
this point are insufficient to support the widespread use of advanced imaging techniques for
such monitoring (4).
The article reviews the epidemiologic profile,
diagnostic criteria, clinical manifestations, genetic
prognostic factors, staging, treatment, and imaging of multiple myeloma, with emphasis on the
increasingly important and complementary roles
of MR imaging and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)
combined with computed tomography (CT).
Imaging features of the disease before and after
treatment are described and illustrated in detail,
with emphasis on potential pitfalls in diagnosis.
Epidemiologic Profile
Multiple myeloma is the most common primary
malignancy of bone (5). It accounts for approxi-
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mately 10% of all hematologic malignancies and
primarily occurs between the ages of 40 and 80
years (6). Male patients are more often affected
than female patients, and the disease is more
prevalent among African Americans than among
those of European ancestry (6). The exact pathogenesis of multiple myeloma is unknown, but environmental factors such as exposure to herbicides,
insecticides, benzene, and ionizing radiation may
contribute to its occurrence (6).
Diagnosis, Prognosis, and Treatment
Clinical and Laboratory Criteria for Diagnosis
The diagnosis of multiple myeloma has been
based mainly on bone involvement (multiple
bone marrow lesions, often with pain), hypercalcemia, anemia, chronic renal insufficiency, and
the presence of M protein (monoclonal immunoglobulin) in samples of blood, urine, or both
(1). Depending on the amount of M protein in
urine and the percentage of plasma cells in aspirate from a nonselective iliac crest bone marrow
biopsy, the disease classification may vary widely
within a spectrum of plasma cell disorders ranging from monoclonal gammopathy of undetermined significance (MGUS) and monoclonal
gammopathy of borderline significance (MGBS)
to smoldering multiple myeloma and symptomatic multiple myeloma (6–8).
In some patients, multiple myeloma may be
preceded by a phase of MGUS. Patients with a
diagnosis of MGUS have a cumulative risk for
progression to multiple myeloma of approximately
1% per year after diagnosis. In a large series of
patients with MGUS, Kyle et al (7) determined
that the percentage of patients in whom MGUS
progressed to malignant plasma cell disorders was
10% at 10 years, 21% at 20 years, and 26% at 25
years after the initial diagnosis of MGUS. In most
cases, MGUS progresses to multiple myeloma or
Waldenström macroglobulinemia. Less commonly,
it progresses to lymphoma, primary amyloidosis,
or chronic lymphocytic leukemia (7).
Patients are stratified according to the risk
level associated with their specific monoclonal
gammopathy to identify those who are in need
of close monitoring. The basic clinical criteria
used to stratify patients according to their risk of
progression to multiple myeloma are the serum
level of monoclonal protein and the percentage of
plasma cells within the bone marrow. Patients with
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smoldering multiple myeloma were found to have
higher serum levels of monoclonal protein (≥3 g/
dL) than patients with MGBS or MGUS (8). Further, patients with MGBS and MGUS were found
to have similar serum levels of monoclonal protein
but differing proportions of bone marrow plasma
cells (10%–30% for those with MGBS, compared
with less than 10% for those with MGUS) (8). It
is therefore not surprising that MGBS is associated with a higher rate of progression to multiple
myeloma than MGUS is, and the diagnostic
category of MGBS has been subsumed under the
category of smoldering multiple myeloma (9).
Clinical Manifestations of Multiple Myeloma
Once the diagnosis of multiple myeloma is established, several terms may be used to describe the
particular form of disease. Symptomatic multiple
myeloma is characterized by one or more of the
following clinical manifestations, which are denoted by the acronym CRAB: calcium elevation,
renal insufficiency related to multiple myeloma,
anemia, and bone abnormalities including lytic
lesions and osteopenia (10). Plasma cell leukemia
is a more aggressive form of multiple myeloma
that is characterized by a proportion of circulating plasma cells of more than 20% at the time of
initial diagnosis or at disease progression (10).
Nonsecretory multiple myeloma accounts for
1%–5% of cases of multiple myeloma; in this form
of disease, the patient meets criteria for a diagnosis
of multiple myeloma on the basis of bone marrow
biopsy results but does not have an elevated level of
M protein in serum or urine (10,11). The results
of various studies reported in the literature suggest
that the prognosis for nonsecretory disease is the
same as that for secretory disease, or better (11).
POEMS syndrome is a rare plasma cell disorder
characterized by polyneuropathy, organomegaly,
endocrinopathy, high M protein levels, and skin
changes (12). The prognosis for patients with this
syndrome initially was thought to be poor, with a
median survival of less than 33 months; however,
in a more recent study, the median survival was
165 months, much better than that for symptomatic myeloma (13). For radiologists, it is important
to remember that POEMS syndrome is characterized by osteosclerotic lesions that may mimic
metastatic prostate carcinoma (12,13).
Plasma cell deposits may occur within bone
marrow (most frequently in the axial skeleton
and the proximal appendicular skeleton) or soft
tissues. A solitary plasmacytoma occurs in less
Hanrahan et al 129
than 5% of patients with plasma cell neoplasms,
is associated with a better prognosis, and can
sometimes be cured with radiation therapy only
(6,14,15). These patients are followed up clinically because the disease in most cases progresses
to multiple myeloma (3,15).
Genetic Prognostic Factors
Multiple genetic factors have been identified
that correlate with prognosis. Factors associated
with a favorable or neutral prognosis include upregulation of several cell cycle proteins, namely
cyclin D1 and D3, through t(11;14) and t(6;14)
chromosomal translocations, respectively. Another factor associated with a favorable prognosis
is hyperdiploidy. Factors associated with a poor
prognosis are related to translocations such as
t(4;14), t(14;16), and t(14;20); loss of the p53
tumor suppressor gene; hypodiploidy; or increased
plasma cell proliferation, as evidenced by abnormal metaphase cytogenetics or increased plasma
cell labeling index (16). The t(4;14) variant in
most cases results in up-regulation of fibroblast
growth factor receptor 3 and multiple myeloma
SET domain protein, whereas t(14;16) and
t(14;20) result in up-regulation of the transcription factor Maf (16). Inactivation of p53, a
transcription factor associated with the development of many other cancers, is associated with
drug resistance (16). Deletion of chromosome
13 by metaphase cytogenetics, which is proposed
to result in a deletion of the retinoblastoma gene
RB-1, is associated with a poor prognosis and,
often, with a translocation involving 14q32 (17).
High serum levels of β2-microglobulin, which
are associated with a high tumor load and renal
insufficiency, are seen in aggressive multiple
myelomas (18).
Staging
Multiple myeloma staging has traditionally relied
on serum and urine markers of disease as well as
conventional radiography. The first widely accepted staging system was the Durie and Salmon
system, which is based on levels of hemoglobin,
serum calcium, and M protein and on the extent
of bone involvement depicted on radiographs
(19). Cross-sectional imaging, in comparison with
radiography and nonselective iliac bone marrow
130 January-February 2010
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Durie and Salmon Plus System for Staging of Multiple Myeloma
Stage*
IA§
IB
IIA, IIB
IIIA, IIIB
Laboratory Findings†
Imaging Findings‡
≥10% plasma cells
≥10% plasma cells, end organ damage
≥10% plasma cells, end organ damage
≥10% plasma cells, end organ damage
Limited disease or plasmacytoma
Mild diffuse disease, <5 focal lesions,
Moderate diffuse disease, 5–20 focal lesions
Severe diffuse disease, >20 focal lesions
Source.—Reference 9.
*In addition to the laboratory and imaging findings listed in the table, stage A disease is indicated
by a serum creatinine level of less than 2.0 mg/dL and no imaging findings of extramedullary involvement, and stage B disease is characterized by a serum creatinine level of more than 2.0 mg/dL,
imaging findings of extramedullary involvement, or both.
†Indicators of end organ damage are an elevated blood calcium level, renal insufficiency, anemia,
and bone abnormalities.
‡In MGUS, unlike multiple myeloma, no evidence of bone marrow disease is seen at imaging. In
multiple myeloma, the degree of diffuse marrow infiltration is assessed on T1-weighted images and
categorized as mild (micronodular or “salt-and-pepper”), moderate (marrow signal intensity lower
than normal but still contrasting with that of the intervertebral disks), or severe (marrow signal
intensity equal to or lower than signal intensity of the disks).
§Smoldering multiple myeloma is classified as stage IA disease.
Teaching
Point
biopsy, has markedly improved sensitivity for the
detection of marrow infiltration. The Durie and
Salmon staging system was adapted to incorporate
cross-sectional imaging information (the number
of focal lesions 5 mm or more in size and the
extent of diffuse bone marrow disease seen at MR
imaging or FDG PET/CT) (20,21). This modified Durie and Salmon staging system (referred to
hereafter as the “Durie and Salmon Plus” system;
Table) is used by many clinicians because it allows
better detection of early disease and helps to more
precisely differentiate patients with stage II disease
from those with stage III disease (9,20).
Another alternative is the International Staging System, which does not incorporate the use
of any imaging criteria and therefore can be used
in locations where imaging is not available. This
system is based on the results of a multivariate statistical analysis of findings in more than
10,000 patients with multiple myeloma, among
whom the most reliable and widely available indi
cators of disease prognosis were β2-microglobulin
and albumin levels (22).
Treatment
Significant progress in the treatment of multiple myeloma over the past several decades
(1,10,23,24) has resulted in dramatic improvement of patient survival. Multiple myeloma has
been widely treated with melphalan in conjunction with a corticosteroid since a randomized
study published in 1969 showed slightly improved survival over that with melphalan alone
(1). Median survival of patients at that time was
2.5 years. Since then, the median survival has
increased to almost 4 years even when high-risk
patients with chromosomal deletions and stage
III disease are included and to 8.5 years when
tandem transplantation (ie, a second transplantation procedure after the patient recovers from the
first) is added to the treatment protocol (1,2,25).
Improvement has been achieved with therapeutic
agents such as lenalidomide, thalidomide, and
bortezomib in the context of autologous stem cell
transplantation (1). Stem cell transplantation is
usually performed in patients younger than 65
years but may be performed in older patients if
they can tolerate the treatment (1). Treatment
protocols for nontransplantation candidates usually involve melphalan, prednisone, and thalidomide (1). Autologous transplantation protocols
typically include induction chemotherapy, which
is followed by peripheral stem cell harvesting and
then high-dose chemotherapy, usually involving
dexamethasone and thalidomide with or without
bortezomib (1). Peripheral stem cell transplantation is then performed. A second transplantation procedure may be performed, if the patient
recovers well from the initial procedure (1).
Imaging of Multiple Myeloma
Radiographic Skeletal Survey
The presence and number of lytic lesions identified in the radiographic skeletal survey may alter
disease staging, and these data are an integral
part of the original Durie and Salmon staging
system (9,19,26). Unfortunately, skeletal surveys
allow identification of only those lesions with
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Hanrahan et al 131
Figure 1. MR imaging appearance of multiple myeloma. Sagittal unenhanced
T1-weighted (a), STIR (b), and contrast material–enhanced T1-weighted (c)
MR images demonstrate areas of bone marrow with low signal intensity in a,
intermediate signal intensity in b, and contrast enhancement in c (arrows). This
signal intensity pattern is characteristic of active multiple myeloma lesions. The
areas with high signal intensity in a, low signal intensity in b, and only mild or
no enhancement in c (arrowheads) represent fat that has replaced the marrow as
a result of radiation therapy.
advanced destruction affecting, in optimal conditions, a minimum of 30% of the trabecular bone,
but possibly as much as 50%–75% (4,27,28).
Conventional radiography can provide only limited depiction of the ribs, scapulae, and sternum.
Moreover, the duration of the examination, with
20 exposures needed for a complete skeletal
survey, may not be tolerable to patients who are
in severe pain (3,4).
Multidetector CT
Multidetector CT provides useful information
in the evaluation of lytic bone marrow lesions.
Several studies have demonstrated improved
sensitivity of multidetector CT over that of the
radiographic skeletal survey for evaluation of
the extent of lytic bone involvement (29–31).
Mahnken et al (29) found that multidetector CT
provided information complementary to that
obtained with MR imaging, and the combination proved more effective for staging than either
modality alone. Although the radiation dose with
CT is a consideration, low-dose multidetector
CT protocols in a recent study were found to
have improved sensitivity over the radiographic
skeletal survey (31). In posttreatment evaluations
of disease response or progression, the combined
results of multidetector CT and clinical followup with laboratory testing proved more accurate
than either multidetector CT or clinical followup alone (32). A CT finding of more than two fo-
cal osteolytic lesions larger than 0.5 cm has been
associated with decreased survival (33).
MR Imaging
Marrow disease in the presence of multiple
myeloma is identifiable at MR imaging as areas
of decreased fat and increased signal intensity
within the marrow on T1-weighted images.
STIR and T2-weighted imaging are the most
sensitive sequences for depicting these changes
(34–38). When contrast-enhanced imaging is
performed, untreated lesions demonstrate diffuse contrast enhancement (Fig 1) (39). However, these changes in the appearance of marrow are nonspecific; therefore, other infiltrative
processes, such as leukemia, lymphoma, and
metastases, should be included in the differential diagnosis at MR imaging (40).
MR imaging protocols described in the
literature vary from standard (unenhanced)
T1-weighted, T2-weighted, and STIR imaging
to contrast-enhanced T1-weighted fat-saturated
imaging, to screening MR imaging with only
T1-weighted and STIR imaging of the marrow
(21,36,37,41). Contrast-enhanced MR imaging
is not routinely performed for the evaluation of
multiple myeloma, because unlike routine T1weighted and fluid-sensitive sequences, it does
not usually allow the identification of additional
132 January-February 2010
Figure 2. Micronodular (“salt-and-pepper”) multiple
myeloma combined with a focal lesion. Sagittal T1weighted (a) and STIR (b) MR images of the lumbar
spine demonstrate multiple small foci of low (a) and
high (b) signal intensity throughout the marrow, with a
single larger lesion (arrow).
Teaching
Point
lesions (36). The use of gadolinium must be
weighed against the risk for nephrogenic systemic
fibrosis in patients with multiple myeloma, who
may have coagulopathy due to thalidomide treatment or may have renal failure (42,43).
Several MR imaging patterns of multiple myeloma infiltration have been described (34–37).
These include normal marrow, a micronodular
pattern (also termed variegated or salt-and-pepper) (Fig 2), a focal pattern (Fig 3), and a diffuse
pattern (Fig 4) (35,38). Focal lesions also may be
seen in the setting of a micronodular or diffuse
pattern of disease (Fig 2) (35,38). Bone lesions
often include cortical breakthrough and extension into the soft tissues. A finding of epidural
extension arouses particular concern because of
the potential for cord compression, an oncologic
emergency (4).
The pattern of marrow infiltration and the
number of focal lesions identified at MR imaging
have been correlated with the original Durie and
Salmon staging system and survival, respectively
(21,38). In their patient series, Stabler et al (38)
found that both normal and salt-and-pepper
appearances of marrow were associated with
stage I disease, whereas focal and diffuse patterns
of infiltration correlated with more advanced
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Figure 3. Focal spinal lesion of multiple myeloma.
Sagittal T1-weighted (a) and STIR (b) MR images of
the cervical spine depict a focus of plasma cell infiltration and a pathologic fracture in the C7 vertebra (arrow). The marrow in other vertebrae appears normal.
Figure 4. Severe diffuse spinal infiltration of multiple
myeloma. Sagittal T1-weighted (a) and STIR (b) MR
images of the lumbar spine show lower signal intensity
in the marrow than in the disks in a and diffuse intermediate to high signal intensity in b.
disease (stage II or III). When normal marrow is
seen at MR imaging in patients with stage III disease, this finding may imply a significant increase
in survival (44). In a recent study, the presence of
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Hanrahan et al 133
Figure 5. MR imaging appearance of multiple myeloma
after treatment. Paired sagittal T1-weighted (a, c, e)
and STIR (b, d, f) images
obtained at the level of the
lumbar spine 1–2 months after
initiation of dexamethasone
and thalidomide therapy (a,
b); 5 months later (c, d), after
induction chemotherapy and
bone marrow transplantation;
and 19 months later (e, f),
after a second bone marrow
transplantation and 12 cycles
of maintenance chemotherapy.
The diffuse infiltration of
marrow seen in a and b is
gradually replaced by increasing quantities of fat in c–f.
Note the progressive decreases
in signal intensity within the
focal lesion at the L4 level
(arrow) after each successive
treatment interval.
more than seven focal lesions with a diameter of
more than 5 mm was correlated with a significant
decrease in survival (21).
The usefulness of MR imaging for the evaluation of multiple myeloma has been compared
with that of the skeletal radiographic survey
and FDG PET/CT. Before the introduction of
whole-body MR imaging, MR evaluations of
multiple myeloma focused on the marrow of
the axial skeleton (the entire spine and pelvis).
Lecouvet et al (45) compared MR imaging of
these sites with the radiographic skeletal survey
and found that axial skeletal MR imaging had
higher sensitivity but that the radiographic bone
survey was superior overall because it demonstrated appendicular lesions. When a whole-body
examination is performed that includes at least
the proximal appendicular skeleton, MR imaging
has higher sensitivity and specificity than the radio-
graphic skeletal survey (46). In another study, it
was shown that spinal MR imaging performed
alone, without whole-body MR imaging, would
not have allowed the detection of bone marrow
infiltration in approximately 10% of cases (47).
Further evidence in favor of whole-body MR
imaging was found in two studies in which T1weighted and STIR MR imaging was compared
with PET (41) and multidetector CT (48). In
both studies, MR imaging had higher sensitivity
for the detection of multiple myeloma.
The posttreatment appearance of marrow
lesions varies at MR imaging. On T1-weighted
images, there is gradual replacement of infiltrated
marrow, first by red marrow and later by fat (Fig
5) (49,50). On MR images obtained with fluidsensitive sequences, lesions may demonstrate
134 January-February 2010
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Point
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uniform high signal intensity or only rimlike high
signal intensity as healing occurs (51). Contrastenhanced images have a variable appearance:
They may demonstrate continued diffuse enhancement, a finding indicative of active multiple
myeloma, or they may demonstrate peripheral
enhancement (49). However, the presence of peripheral enhancement is not necessarily indicative
of a response to treatment. Lecouvet et al (52)
found that some lesions with peripheral enhancement still contained viable tumor cells. Marrow
lesions that have returned to the baseline signal
intensity on images obtained with fluid-sensitive
sequences and have the signal intensity of fat on
T1-weighted images contain no active disease.
Although laboratory measures of disease may
be absent, the signal intensity of focal multiple
myeloma lesions may not return to that of background marrow for as long as 58 months (21).
Conversely, even in the absence of imaging findings, clinical laboratory parameters may indicate
residual disease (21).
FDG PET/CT
FDG PET/CT scans are evaluated for the
following: metabolic activity of bone lesions;
extraosseous manifestations of disease; and
quantification of representative marrow metabolic activity (standardized uptake value). Active
lesions at FDG PET/CT show FDG uptake that
is greater than the background level (53,54).
However, false-negative findings may occur, particularly in lesions smaller than 10 mm and when
a threshold of 2.5 is used for calculating the standardized uptake value (55). It is important that
corticosteroid treatment be suspended for at least
5 days before PET/CT, since the administration
of corticosteroids may result in false-negative
findings (Guido Tricot, MD, personal communication, February 14, 2009).
The CT portion of the PET/CT evaluation
is valuable because multidetector CT provides
high-resolution bone images that allow a higher
rate of detection of lytic bone lesions than that
achieved with conventional radiography (29,31).
Discrete lesions with a diameter of 5 mm or
more are counted, characterized, and monitored
at follow-up imaging over time. Compared with
non–whole-body MR imaging, CT allows easier
detection of lesions in extramedullary sites and in
the ribs, sternum, and scapulae (26,41,54).
Figures 6, 7. Appearance of multiple myeloma at
FDG PET. (6) Sagittal image shows diffuse infiltration
of marrow in the spine and sternum. (7) Coronal image shows multiple foci of intra- and extramedullary
metabolic activity.
FDG PET/CT is an important tool for staging
Teaching
and prognosis in multiple myeloma because of its
Point
ability to depict metabolic activity, extramedullary disease, and secondary lesions that are not
attributable to multiple myeloma (53). FDG
PET/CT is most valuable for evaluating the
disease burden in nonsecretory multiple myeloma
(54). Patients with MGUS have no elevated FDG
uptake (54). The pattern of marrow infiltration in
multiple myeloma at FDG PET/CT, as at MR
imaging, may be focal or diffuse (Figs 6, 7). The
observation of more than three focal lesions at
FDG PET/CT has been associated with a poor
survival rate, compared with that of three or
fewer lesions (33).
FDG PET/CT may be useful for monitoring
multiple myeloma after treatment. Decreased
Teaching
Point
FDG uptake representing decreased bone marrow activity is seen in focal multiple myeloma
lesions after successful treatment (Figs 8, 9)
(53,54). The presence of residual FDG activity
subsequent to induction chemotherapy portends
a poor prognosis, and changes in the treatment
regimen should be considered (33,54).
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Hanrahan et al 135
Figures 8, 9. Posttreatment
appearance of multiple myeloma at FDG PET. (8a) Sagittal image obtained at presentation shows a recurrence of
multiple myeloma lesions.
(8b) Sagittal image obtained
3 months later, after bone
marrow transplantation,
demonstrates decreased
uptake of FDG, a finding indicative of response to treatment. (9) Sagittal images obtained in another patient (same
patient as in Fig 5) depict
mildly increased uptake 1–2
months after initiation of corticosteroid treatment (a) and
greatly decreased uptake 16
months later, after the second
bone marrow transplantation
and nine cycles of maintenance
chemotherapy (b).
Figure 10. Pathologic fracture due to multiple myeloma. Sagittal T1-weighted (a) and STIR (b) MR images at the level of the lumbar spine depict a markedly
wedge-shaped vertebral body that contains a focal area
of abnormal signal intensity (arrowhead), a finding
indicative of a biopsy-proved multiple myeloma. Differentiation of the cause of fracture (disease or insufficiency) in this case was easier because of the presence
of the focal lesion.
Treatment-related Findings
Radiation therapy–related changes in the spine include increased marrow fat, which is depicted with
increased signal intensity on T1-weighted MR
images, decreased signal intensity on STIR MR
images, and decreased FDG uptake on PET/CT
images (56,57). Another frequent imaging finding
of multiple myeloma (seen in 9% of patients) is
avascular necrosis, which usually affects the hips
but also may be seen in the humeral head (58).
Risk factors for avascular necrosis include cumulative doses of corticosteroids, male sex, and young
age (58). Avascular necrosis has a characteristic
MR imaging appearance with a serpiginous and
often concave contour and a “double-line” sign
surrounding the area of abnormality on images
obtained with fluid-sensitive sequences. Avascular
necrosis is less easily identified on FDG PET/CT
images; however, mottled sclerosis may be seen in
the affected region (58,59).
Vertebral body compression fractures occur
frequently in patients with multiple myeloma,
and most such fractures have a benign appearance at MR imaging (27). However, MR imaging
may allow distinction between an insufficiency
fracture and a pathologic fracture (Figs 10, 11).
In an insufficiency fracture, the bone marrow
typically retains the signal intensity of fat on
T1-weighted images or is disrupted by a band
of abnormal signal intensity (low signal intensity
on T1-weighted images, high signal intensity
on fluid-sensitive images, and enhancement on
136 January-February 2010
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Figure 11. Insufficiency fracture. Sagittal
T1-weighted MR images obtained before (a)
and after (b) treatment of multiple myeloma
depict interval wedging of vertebral bodies (arrows) and increased signal intensity of marrow,
findings suggestive of fat replacement. There is
no evidence of residual active myeloma.
Figure 12. Differentiation of atypical hemangioma from focal multiple myeloma. (a, b) Sagittal T1weighted (a) and STIR (b) MR images of the lumbar spine, obtained before bone marrow transplantation, show a subcentimeter lesion within the L2 vertebral body (arrow). The lesion has low signal intensity
in a and high signal intensity in b, characteristics that could represent either an atypical hemangioma or
a multiple myeloma lesion. Multiple myeloma was proved at biopsy. (c, d) Sagittal T1-weighted (c) and
STIR (d) MR images, obtained after tandem marrow transplantations and maintenance chemotherapy,
show decreased size of the lesion (arrow), a finding indicative of response to treatment. The overall increase in marrow signal intensity in c compared with that in a is due to the replacement of marrow by fat.
images obtained after the administration of
gadolinium-based contrast material) (3). The
diagnosis of a pathologic fracture is indicated
when an epidural mass is visible or the normal
fatty marrow signal intensity within the vertebral
body or pedicle is replaced by low signal intensity
on T1-weighted images and high signal intensity
on images obtained with fluid-sensitive sequences
(3). Specialized techniques such as diffusionweighted imaging and opposed-phase (in-phase–
out-of-phase) imaging have been advocated to
help differentiate insufficiency fractures from
pathologic compression fractures; however, only
limited data are available regarding diagnostic accuracy with such techniques (60–62).
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Hanrahan et al 137
Figure 13. Differentiation of bone infarction from multiple myeloma. Coronal STIR images (a obtained
after 5 weeks of dexamethasone and thalidomide treatment, b obtained after peripheral stem cell transplantation) show focal high-signal-intensity lesions in the posterior aspects of both iliac bones. Two lesions
with serpiginous margins and one of two smaller round foci of high signal intensity (arrows) are likely to
represent bone infarcts. The other focal round lesion superior to the infarcts in the parasacral ilium (arrowhead) has resolved in b, a finding suggestive of treatment response of a focal multiple myeloma.
Figure 14. Differentiation of acromioclavicular arthropathy from multiple myeloma.
Coronal STIR MR images of the shoulder, obtained 11 months apart, before (a) and
after (b) salvage transplantation performed in tandem with maintenance treatment
for multiple myeloma, show posttreatment improvement in the distal clavicular
(arrow) and humeral signal intensity abnormalities. These findings are suggestive
of multiple myeloma lesions. Acromioclavicular arthropathy, by contrast, would appear
as a focal subchondral cyst confined in the marrow adjacent to the joint.
Patients with multiple myeloma often are
treated with kyphoplasty or vertebroplasty for
vertebral body fractures. The cement used in
these procedures has low signal intensity on MR
images obtained with any sequence and demonstrates increased FDG uptake at attenuation-corrected PET, findings that might lead to its being
mistaken for metastatic disease if its CT appearance were not taken into consideration (63).
Non–attenuation-corrected PET images tend
to show decreased FDG uptake or no uptake in
the cement (63). Many patients with multiple
myeloma have osteoporosis, which frequently is
treated with bisphosphonate therapy. Long-term
bisphosphonate therapy can lead to osteonecrosis
of the mandible, which most commonly appears
as sclerosis (64,65), and to subtrochanteric insufficiency fractures (66).
Potential Pitfalls in Diagnosis
It may be difficult at MR imaging and FDG
PET/CT to differentiate bone marrow infiltration
due to multiple myeloma from other pathologic
processes. At MR imaging, focal myelomatous
infiltration may be confused with atypical hemangioma (Fig 12), bone infarction (Fig 13),
acromioclavicular arthropathy (Fig 14), and bone
138 January-February 2010
radiographics.rsna.org
Figure 15. Differentiation of a bone marrow biopsy site from multiple myeloma.
(a) Coronal STIR MR image obtained 2 weeks after a right iliac crest bone marrow biopsy shows a single small lesion (arrowhead) in the right posterior iliac
bone, a finding that could represent either the biopsy site or a focal multiple myeloma lesion. (b) Coronal STIR MR image obtained in another patient shows
multiple larger lesions in the posterior iliac bone (arrowhead), findings unlikely to
represent biopsy sites and highly suggestive of multiple myeloma.
marrow biopsy sites (Fig 15). Atypical hemangiomas and foci of multiple myeloma both may
demonstrate low signal intensity on T1-weighted
images and high signal intensity on STIR images
(34,67), and both may appear enhanced at MR
imaging after the administration of a gadoliniumbased contrast material (68). The absence of
changes between pretreatment and posttreatment
MR images is unhelpful for differentiating the
two because some multiple myeloma lesions do
not revert to normal marrow signal intensity until
nearly 5 years after treatment (21). Fortunately,
typical hemangiomas usually can be distinguished
from multiple myeloma by the increased signal
intensity of the latter on T1- and T2-weighted
MR images, a finding that represents internal fat,
or by the “polka-dot” CT appearance produced
by retained trabeculae in typical hemangiomas
(68). Focal regions of low signal intensity on both
T1-weighted and STIR images may represent
amyloidomas (69). Diffuse marrow infiltration in
multiple myeloma may be overlooked or confused
with myelofibrosis (Fig 16) (70), bone marrow
stimulation (Fig 17), or bone marrow reconversion (40,71). Bone marrow reconversion and
stimulation have an imaging appearance similar
to that of diffuse marrow infiltration in multiple
myeloma, with low signal intensity on T1weighted MR images, intermediate signal intensity on STIR MR images, and increased FDG
uptake on PET images (40,71). Moreover, the
appearance of red marrow reconversion may vary
at MR imaging with fluid-sensitive sequences.
Thus, it may be difficult to differentiate bone
marrow reconversion or stimulation from multiple myeloma on the basis of imaging findings
alone, and biopsy may be necessary (40).
Current Recommendations for Imaging
Recommendations for the initial diagnostic imaging evaluation have been modified as a result of
research over the past 2 decades. Radiographic
surveys of skeletal bone have been the mainstay
of multiple myeloma imaging and continue to
be recommended for baseline evaluation (9,26).
Bone scintigraphy is not useful because the
disease process in multiple myeloma inhibits
osteoblastic activity (72,73). The disease findings
with more sensitive techniques such as MR imaging, multidetector CT, and FDG PET may alter
staging in patients with MGUS or smoldering
multiple myeloma; therefore, recently published
guidelines recommend whole-body MR imaging for patients who have MGUS or a solitary
plasmacytoma and a normal skeletal survey
(3,26,29,31,45,46,74). In addition, MR imaging
is recommended for the evaluation of any patient
with multiple myeloma and neurologic dysfunction, which may be indicative of epidural disease
compressing the spinal cord (26). Advanced
imaging techniques also are recommended for
better visualization of extramedullary disease,
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Hanrahan et al 139
Figure 16. Differentiation of myelofibrosis
from active multiple myeloma. Sagittal T1weighted (a) and T2-weighted (b) MR images of the thoracolumbar spine demonstrate
diffuse low signal intensity throughout the
vertebral marrow, a characteristic finding of
myelofibrosis, whereas active myeloma would
appear with intermediate to high signal
intensity on STIR and T2-weighted images.
No enhancement was seen in the marrow on
contrast-enhanced images. Differentiating the
advanced-stage myelofibrosis in this case from
diffuse myeloma is relatively easy; the differentiation of intermediate-stage myelofibrosis
might be more difficult. Multidetector CT,
which usually demonstrates osteosclerosis in
the setting of myelofibrosis, might be helpful
for that purpose.
Figure 17. Differentiation of
diffuse multiple myeloma from
bone marrow stimulation. (a,
b) Sagittal T1-weighted (a)
and STIR (b) MR images of
the lumbar spine demonstrate
homogeneous low signal
intensity in a and homogeneous high signal intensity
in b. (c) Sagittal FDG PET
image shows elevated FDG
uptake in the vertebral bone
marrow. These findings were
believed to be indicative of
marrow stimulation. However,
an iliac crest biopsy specimen
revealed hypercellular marrow
with near total replacement
by plasma cells, a definitive
finding of diffuse multiple myeloma infiltration.
sites of pain, or focal lesions for the purposes of
biopsy or radiation treatment (26,54). Although
the most recent treatment guidelines do not require advanced imaging of all patients with multiple myeloma, findings at multidetector CT, MR
imaging, and FDG PET have led to alterations of
staging in 15%–25% of patients (9), and a recent
publication advocates the use of MR imaging
for routine staging, prognosis, and assessment of
response to treatment (21).
140 January-February 2010
radiographics.rsna.org
There is no currently recommended protocol
or consensus regarding posttreatment imaging of
patients with multiple myeloma (3). Since lytic
lesions do not heal, the radiographic skeletal
survey has no role in monitoring the response to
treatment; however, the skeletal survey may depict disease progression (26). Conversely, clinical
disease may be present even when imaging abnormalities are absent (21). Although posttreatment monitoring with multidetector CT, MR
imaging, and FDG PET alone or in combination
is not currently recommended, it may be useful
in patients with focal symptoms, those undergoing aggressive chemotherapy, and those enrolled
in clinical trials (4,41).
plasmacytoma. Imaging plays an important role
in the detection of bone marrow disease, characterization of the disease pattern, quantitation of
focal lesions, depiction of extramedullary disease,
and differentiation of multiple myeloma from
other normal and pathologic processes, and the
imaging findings may lead to alterations in staging and prognosis. Posttreatment MR imaging or
FDG PET/CT of myeloma also may be useful for
evaluating the response to therapy and assessing
residual disease. Although no recommendations
currently exist regarding the use of imaging for
posttreatment assessments, recent results and
continued research may lead to the development
of such recommendations in future.
Combined Use of MR
Imaging and FDG PET/CT
Acknowledgments.—The authors thank Guido
MR imaging and FDG PET/CT may provide
complementary information for staging and posttreatment monitoring. A recent study by Shortt
et al (41) demonstrated higher sensitivity and
specificity with the use of whole-body MR imaging with T1-weighted and STIR sequences than
with FDG PET/CT. Moreover, the combination
of PET/CT and whole-body MR imaging was
found to have 100% specificity compared with
specificities of 75% for PET/CT and 83% for
whole-body MR imaging alone (41). FDG PET/
CT may be more accurate than MR imaging for
detecting extramedullary disease, especially in
imaging facilities where whole-body MR imaging is not performed, since false-negatives occur
more frequently with non–whole-body MR imaging (21,41,54). In addition, FDG PET/CT may
be helpful for assessing the response to treatment
and evaluating residual disease, because bone
marrow lesions seen at MR imaging may persist
as long as 58 months after treatment (21). However, FDG PET/CT may lead to false-negative
results in the presence of subcentimeter lesions,
skull lesions, diffuse disease, and, occasionally,
larger lesions, which may show only mildly increased FDG uptake (53,75).
Summary
Great progress has been made in the treatment
and imaging of multiple myeloma over the past
several decades. The current literature recommends a routine radiographic skeletal survey for
all patients in whom the presence of multiple
myeloma is suspected and advanced imaging for
those with either a normal radiographic skeletal
survey and monoclonal gammopathy or a solitary
Tricot, MD, PhD, and B. J. Manaster, MD, PhD, of
the University of Utah School of Medicine, Salt Lake
City, Utah, for helpful reviews and discussions of the
manuscript.
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This article meets the criteria for 1.0 credit hour in category 1 of the AMA Physician’s Recognition Award. To obtain
credit, see accompanying test at http://www.rsna.org/education/rg_cme.html.
RG
Volume 30
Number 1
January-February 2010
Hanrahan et al
Current Concepts in the Evaluation of Multiple Myeloma with
MR Imaging and FDG PET/CT
Christopher J. Hanrahan,MD, PhD, et al
RadioGraphics 2010; 30:127–142 • Published online 10.1148/rg.301095066 • Content Codes:
Page 130
Cross-sectional imaging, in comparison with radiography and nonselective iliac bone marrow biopsy,
has markedly improved sensitivity for the detection of marrow infiltration. The Durie and Salmon
staging system was adapted to incorporate cross-sectional imaging information (the number of focal
lesions 5 mm or more in size and the extent of diffuse bone marrow disease seen at MR imaging or
FDG PET/CT).
Page 132
Several MR imaging patterns of multiple myeloma infiltration have been described. These include
normal marrow, a micronodular pattern (also termed variegated or salt-and-pepper), a focal pattern,
and a diffuse pattern.
Page 134
Marrow lesions that have returned to the baseline signal intensity on images obtained with fluidsensitive sequences and have the signal intensity of fat on T1-weighted images contain no active
disease. Although laboratory measures of disease may be absent, the signal intensity of focal multiple
myeloma lesions may not return to that of background marrow for as long as 58 months.
Page 134
FDG PET/CT is an important tool for staging and prognosis in multiple myeloma because of its
ability to depict metabolic activity, extramedullary disease, and secondary lesions that are not
attributable to multiple myeloma (53). FDG PET/CT is most valuable for evaluating the disease
burden in nonsecretory multiple myeloma.
Page 134
FDG PET/CT may be useful for monitoring multiple myeloma after treatment. Decreased FDG
uptake representing decreased bone marrow activity is seen in focal multiple myeloma lesions after
successful treatment.