Radiology
Review
Edgardo J. C. Angtuaco, MD
Athanasios B. T. Fassas, MD
Ronald Walker, MD
Rajesh Sethi, MD
Bart Barlogie, MD
Index terms:
Bone marrow, diseases, 48.3452
Bones, CT, 48.12111
Bones, MR, 48.121411, 48.121412,
48.121413, 48.121415
Myeloma, 48.3452
Review
Published online before print
10.1148/radiol.2311020452
Radiology 2004; 231:11–23
Abbreviations:
FDG ⫽ fluorodeoxyglucose
Ig ⫽ immunoglobulin
MM ⫽ multiple myeloma
STIR ⫽ short tau inversion recovery
1
From the Department of Radiology
(E.J.C.A., R.W., R.S.) and the Myeloma
Institute (A.B.T.F., B.B.), University of
Arkansas for Medical Sciences, 4301
W Markham, Slot 596, Little Rock, AR
72205. Received April 22, 2002; revision requested June 19; revision received March 4, 2003; accepted
March 17. Address correspondence
to E.J.C.A. (e-mail: angtuacoedgardoj
@uams.edu).
©
RSNA, 2004
Multiple Myeloma: Clinical
Review and Diagnostic
Imaging1
Multiple myeloma (MM) is a malignant clonal neoplasm of plasma cells of Blymphocyte origin that commonly results in overproduction of large amounts of
monoclonal immunoglobulins. Important advances in the therapeutic management
of this disease in the past decade have resulted in higher rates of durable complete
remission, prolonged event-free survival, and improved overall survival. Clearer
understanding of the effects of abnormal plasma cells on bone has led to therapeutic
approaches that help prevent vertebral body fractures. Current imaging technologies and, in particular, survey marrow studies with magnetic resonance (MR) imaging have improved detection of the extent and location of disease in MM patients.
In newly diagnosed cases, MR surveys of the axial skeleton accurately demonstrate
the extent of disease— diffuse or focal involvement—and the presence of associated
compression fractures and cord compression. After treatment, MR images show the
effects of treatment and the presence of residual disease. Multiple sites of focal bone
lesions detected on MR studies allow a more appropriate choice of biopsy site than
the usual random iliac marrow biopsy. Use of MR to determine biopsy sites and
computed tomographic guidance for biopsy performance have increased the safety
and accuracy of sampling. These biopsies have resulted in increased identification of
cytogenetic abnormalities, particularly the presence of chromosome 13 deletion,
which is a grave prognostic indicator in MM.
©
RSNA, 2004
Multiple myeloma (MM) is a clonal B-lymphocyte neoplasm of terminally differentiated
plasma cells. It accounts for approximately 1% of all malignant diseases and represents about
10% of hematologic malignancies. The annual incidence of newly diagnosed cases in the
United States is three to four per 100,000 population per year, with an estimated 14,000 new
cases each year. The median age at diagnosis is 65 years, and about 3% of patients are younger
than 40 years (1). The disease has a higher incidence in men and African Americans.
The cause of MM is unknown. Radiation exposure increases the risk, as evidenced by a
higher than expected rate of disease in atomic bomb survivors, radiation workers, and
postirradiated patients with ankylosing spondylitis. The origin of the malignant plasma
cell remains a mystery. Data from cloning and gene-sequencing studies strongly imply
that the malignant clone in MM arises from a late cell in B-cell development (2,3).
CLINICAL PRESENTATION
The clinical findings vary from totally asymptomatic in patients whose disease is discovered incidentally to life-threatening symptoms. The common clinical presentations are
fatigue and bone pain (back or ribs) with or without associated fractures or infection. In
15%–30% of patients (4), the finding at presentation is hypercalcemia with concomitant
renal insufficiency caused by precipitation of monoclonal light chains in the collecting
tubules (5). Ten percent of patients present with other symptoms, including hyperviscosity
syndrome, compression of the spinal cord (Fig 1), radicular pain, soft-tissue deposits, or
bleeding problems. In patients who are asymptomatic, the disease is incidentally discovered because of laboratory findings of anemia or hyperproteinemia.
The hallmark of MM is the detection in blood and/or urine of a monoclonal protein, M
protein, produced by the abnormal plasma cells. Serum protein electrophoresis reveals a
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localized band in the globulin part of the
␣ (immunoglobulin [Ig] A) or ␥ (IgG) region in 80% of patients. The remaining
20% of patients will have either hypogammaglobulinemia or a normal-appearing pattern (nonsecretory type). By using
the more sensitive techniques of immunofixation and immunoelectrophoresis, M protein (in serum or/and urine)
will be detected in 99% of patients (6).
The IgG isotype is seen in 60% of MM
patients; the IgA isotype, in 25%; the IgD
isotype, in 1%; the IgM isotype in 1%;
and light chain disease, in 20%.
Once the diagnosis is suspected, a radiographic skeletal survey and bone marrow
aspiration and biopsy are performed. Samples are sent for plasma cell labeling index
and cytogenetic analyses. Minimal criteria
for establishment of a diagnosis of MM
should be the detection of at least 10%
abnormal plasma cells in a random bone
marrow biopsy specimen and M protein in
either the serum (usually ⬎3 g/dL) and/or
urine (usually ⬎1 g/24-hour collection).
Osteolytic lesions on a skeletal survey may
be found (7). In most patients, the diagnosis of MM is established without difficulty.
CLINICAL STAGING AND
PROGNOSIS
In patients known to have MM, clinical
stage is based on the Durie-Salmon system (8) (Table 1). Staging criteria are simple and help estimate suspected tumor
burden. This system is based on a combination of clinical factors: amount of M
protein, serum hemoglobin level, serum
calcium level, number of lytic bone lesions on a skeletal radiographic survey,
and renal function. The staging system is
used as a predictor of patient outcome
and is currently used as a standard for
ongoing clinical trials.
Prognosis for the disease is highly variable, with survival ranging from a few
months to more than 10 years (9). In
recent years, advances in the treatment
of the disease have resulted in substantially improved clinical outcomes, with
improved overall survival and better response to chemotherapeutic regimens,
particularly high-dose therapy. Other
prognostic factors have been developed
that help better identify the subgroups of
patients with different outcomes and tailor treatment intensity to disease risk.
Serum ␤2-M level is one of the most
important prognostic factors in MM. The
level is a measure of tumor burden and
renal function (10). C-reactive protein level
is another important predictive factor. C12
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Figure 1. Multiple plasmacytomas with cord compression.
(a) Sagittal T1-weighted spin-echo (repetition time msec/echo
time msec, 400/15) (left) and short tau inversion-recovery
(STIR; repetition time msec/echo time msec/inversion time
msec, 2,000/150/20) (right) magnetic resonance (MR) images
of thoracic spine show scattered focal lesions involving vertebral bodies and posterior elements of thoracic spine. Both
(b) transverse (600/15) and sagittal (a, left) T1-weighted spinecho MR images show cord compression by a focal expansile
mass (arrow) at the T10 spinous process.
reactive protein is a surrogate marker of
interleukin 6, which is an osteoclast-activating factor. The combination of high levels of C-reactive protein and ␤2-M indicates a poor prognosis in MM patients who
were treated with conventional chemotherapy (11). The plasma cell labeling index reflects the proliferative capacity of
plasma cells. The index typically increases
during disease progression (12). The median survival of patients with a low plasma
cell labeling index and low ␤-2 M level
who are treated with conventional chemotherapy is 71 months, compared with 17
months when both parameters are elevated (13).
Elevated lactate dehydrogenase levels
are predictive of short survival, as they
are frequently associated with plasmablastic morphology, extramedullary sites of
disease, and adverse-risk cytogenetic abnormalities (14). The presence of cytogenetic abnormalities has recently emerged
as the most important prognostic factor in
MM. Abnormal karyotypes are observed in
30%–50% of MM patients (15)—more
frequently in patients with relapse (35%–
63%) than in those with newly diagnosed disease (20%–30%). Karyotypic abnormalities are complex, involving more
than three chromosomes in 80% of the
patients (16). Multiple trisomies and transAngtuaco et al
TABLE 1
Durie-Salmon Staging System for MM
Radiology
Stage and Criteria
burden†
I: Low tumor
Hemoglobin level
Serum calcium level
Radiograph
Low paraprotein level
Serum IgG
Serum IgA
Urine light chain
II: Intermediate tumor burden
All criteria
III: High tumor burden‡
Hemoglobin level
Serum calcium level
Radiograph
High paraprotein level
Serum IgG
Serum IgA
Urine light chain
Associated renal involvement
A: serum creatinine level
B: serum creatinine level
Value*
⬎10 g/dL (100 g/L)
⬍12 mg/dL (3 mmol/L)
No bone destruction, or solitary plasmacytoma
⬍5 g/dL (0.05 g/L)
⬍3 g/dL (0.03 g/L)
⬍4 g/24 h
Between values for stage I and values for stage III
⬍8.5 g/dL (85 g/L)
⬎12 mg/dL (3 mmol/L)
More than two advanced lytic lesions
⬎7 g/dL (0.07 g/L)
⬎5 g/dL (0.05 g/L)
⬎12 g/24 h
⬍2 mg/dL (177 ␮mol/L)
⬎2 mg/dL
* Value in parentheses is in SI unit.
† All criteria must be satisfied.
‡ Any criterion must be satisfied.
locations are the most common abnormalities. In patients treated with high-dose
chemotherapy and autologous stem cell
transplantation, a particularly poor outcome was observed in the presence of any
translocation or abnormality involving
11q and partial or complete deletion of
chromosome 13 (17).
MYELOMA BONE DISEASE
Before a discussion of imaging findings in
MM, it is important to understand myeloma bone disease. The effects of abnormal plasma cells on bone lead to severe
bone pain and skeletal fractures, especially
spinal compression fractures. Histologic
studies of bone have revealed excessive
bone resorption in the vicinity of the myeloma cells, with severe inhibition of bone
formation (18). Once myeloma cells invade the bone marrow, they adhere to the
stromal cells and induce secretion of osteoclast-activating factors, including interleukins 6 and 1␤ and tumor necrosis factor–␤. These factors prompt the stromal
cells and osteoblasts to secrete tumor necrosis factor–related induced cytokine, or
TRANCE, a member of the tumor necrosis
factor family (19), which induces differentiation and maturation of osteoclast progenitors (20). The activity of TRANCE can
be blocked by osteoprotegerin. The delicate balance between TRANCE and osteoprotegerin, which normally regulates the
osteoclastic activity in healthy individuals,
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is totally disrupted in patients with MM.
This disruption is due to overproduction
of TRANCE and inactivation of osteoprotegerin by elevated amounts of syndecan-1, a molecule actively shed from the
plasma cell surface. Furthermore, unchecked osteoclastic activity promotes
the production and release from stromal
cells of various cytokines, which lead, directly or indirectly, to further MM clone
proliferation. A vicious cycle, with bone
destruction “feeding” tumor growth and
MM cells promoting bone destruction, is
therefore set in motion (21). This set of
factors leads to the common findings in
MM: severe osteopenia and multiple spinal compression fractures.
This vicious cycle can be broken by the
use of bisphosphonates. These agents (used
in conjunction with cytotoxic chemotherapy) have been found to be superior to
chemotherapy alone in decreasing skeletalrelated events in MM patients, such as
need for radiation therapy, pathologic fractures, and bone pain (22). Besides their
skeletal effects (achieved through direct osteoclast inhibition), bisphosphonates may
have an antimyeloma effect (23), and their
use may lead to prolonged survival in myeloma patients (24).
IMAGING STUDIES
The role of imaging in the work-up of
patients with MM consists of studies that
allow recognition of the effects of my-
eloma cells on the skeletal system. In the
past, these studies included radiographic
skeletal surveys, computed tomography
(CT), and nuclear medicine bone scanning (7). Recently, MR imaging of bone
marrow has allowed a direct look at the
actual tumor burden within the bone
marrow (25–30). Direct visualization of
marrow disease allows assessment of the
extent of disease in newly diagnosed
cases and of the effects of therapy. More
recently, positron emission tomography
(PET) with fluorodeoxyglucose (FDG) has
been used to study relapsing patients in
whom recurrent disease is not easily detectable with routine imaging. PET, in
this instance, has been found to aid in
detection of unsuspected sites of medullary and extramedullary disease (31).
SKELETAL RADIOGRAPHY
AND CT
Skeletal radiography continues to be the
primary diagnostic study to aid in detection of destructive bone changes in MM.
Estimates suggest that approximately
50% of bone destruction must occur before there is radiographic demonstration
of the abnormality and that 75% of patients with MM will have positive radiographic findings (28). Four distinct forms
of involvement have been described: the
solitary lesion (plasmacytoma), diffuse
skeletal involvement (myelomatosis),
diffuse skeletal osteopenia, and sclerosing myeloma (32).
Plasmacytomas typically are lytic lesions that primarily affect the spine, pelvis, skull, ribs, sternum, and proximal appendages (28). The skeletal radiographic
survey continues to have an important
role in the Durie-Salmon clinical staging
criteria for newly diagnosed MM. The
presence of two clearly defined lytic lesions indicates high tumor burden and
stage III disease (8). In addition, the skeletal survey is used to judge progression of
disease and has a complementary role to
MR imaging in following the course of
disease in patients with MM (33). Diffuse
myelomatosis classically manifests as osteolytic lesions with discrete margins and
uniform size. These lesions are often subcortical and elliptic and may coalesce
into large segments of destruction. Diffuse skeletal osteopenia without well-defined lytic lesions predominantly involves the spine. Multiple compression
fractures may be seen with this condition. Bone sclerotic lesions are seen in
MM and are associated with the polyneuropathy, organomegaly, endocrinopaMultiple Myeloma
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Radiology
thy, monoclonal gammopathy, and skin
changes, or POEMS, syndrome (34,35).
CT is a sensitive tool for detection of
the bone-destructive effects in MM (Fig
2). CT findings consist of punched-out
lytic lesions, expansile lesions with softtissue masses, diffuse osteopenia, fractures, and, rarely, osteosclerosis (28,36)
(Fig 3). Recently, Mahnken et al (36)
compared multi– detector row CT with
conventional radiography and MR imaging in 18 patients with newly diagnosed
MM. Multi– detector row CT was superior
to conventional radiography for defining
lytic lesions and, in combination with
MR imaging, aided in staging the extent
of disease. Multi– detector row CT allowed a better evaluation of areas at risk
for fracture than did MR imaging. Our
experience with the role of CT in MM has
been with its adjunctive role in defining
possible lytic or sclerotic lesions and in
guidance for spinal and pelvic biopsy of
MR imaging– defined focal lesions (37).
NUCLEAR MEDICINE STUDIES
Utilization of the various nuclear medicine radiopharmaceuticals in MM relate
to either a direct association with tumor
biology (ie, imaging of tumor cells) or an
indirect effect (eg, imaging of compression fractures, dystrophic calcifications).
MM is primarily an osteolytic neoplasm.
However, detection of bone involvement
with the usual technetium 99-m (99mTc)based bone scanning agents relies on an
osteoblastic response of the skeletal system
for uptake. Bone scans obtained with
99m
Tc have therefore resulted in underappreciation of the extent of disease (34,35,
38 – 40). In a report (34) comparing the
skeletal radiographic survey with bone
scans, uptake of the radioisotope in radiographically abnormal regions occurred in
44% of cases, normal findings were seen in
48%, and diminished uptake was seen in
8%. Lesions that are well defined on bone
scans are the result of complications in
MM: namely, osteoblastic response to a
compression fracture of a vertebral body or
pelvic insufficiency fracture, soft-tissue calcifications within a plasmacytoma (41), or
tumor-associated amyloidosis (42).
In recent efforts to image MM, investigators have turned to radiopharmaceuticals that allow direct imaging of tumor
physiology. Agents known to accumulate
in tumor tissue, such as gallium 67 (67Ga)
citrate, thallium 201 (201Tl) chloride,
99m
Tc sestamibi, or FDG PET have all met
with greater success in imaging MM than
have typical bone scanning agents.
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Figure 2. Multiple compression fractures on CT and MR images.
Comparative images from sagittal reformatted CT data set (left) and
sagittal STIR MR image (2,000/150/20) (right) of thoracic spine show
multiple compression fractures of thoracic vertebral bodies, with severe thoracic kyphosis and marked osteolysis of the T1 vertebral body
(arrow).
67
Ga citrate localizes in areas of active
tumor either through primary localization within the tumor or through the
secondary “inflammatory response” induced by the tumor. This inflammatory
response is evidenced by the associated
presence of mononuclear cell and lymphocytic infiltrates observed with the
plasma cells. Whether these mechanisms
act singly or in combination remains unknown (43– 46). 67Ga is not likely to be
used in tumor detection in MM owing to
its expense, lack of advantage over sestamibi or PET imaging, and possible need
for multiday scanning. In instances
where infection is suspected in MM patients, 67Ga citrate may be used and uptake by the tumor may be observed.
201
Tl chloride has also been used in the
detection of MM. The mechanism of uptake is either increased metabolic demands
of the tumor or secondary inflammatory
response induced in the marrow (47). A
recent study comparing 201Tl and 99mTc
bone scans in MM found 201Tl to be promising in detection of disease owing to its
complementary detection rates (48). The
role of this agent in MM is, however, currently supplanted by 99mTc sestamibi,
which shows similar localization on images of higher quality and lower cost.
99m
Tc sestamibi is thought to accumulate preferentially in malignant cells, ow-
Figure 3. Lytic expansile mass of C5. Transverse CT image at level of C5 shows expansile
soft-tissue mass along right side of C5 vertebral
body, with associated bone destruction.
ing to a higher transmembrane electric potential that results from a higher metabolic
rate in MM cells (49–52). The primary site
of localization is in the mitochondria
(52,53). Pace et al (50) classified the activity
patterns of 99mTc sestamibi as focal, diffuse, a combination of focal and diffuse, or
normal in 39 patients with MM. Activity
was correlated with active disease, and norAngtuaco et al
Radiology
Figure 4. One-month comparative FDG PET images show good response to therapy. Left: Initial
image shows increased metabolic activity in spine and pelvis. Note separate focal mass (arrow) in
left iliac region. Right: Posttreatment (1-month follow-up) study shows decrease in overall
metabolic activity in spine and pelvis, with resolution of left iliac mass and residual disease
(arrowhead) in left sacrum. Decrease in metabolic activity indicates good response to chemotherapeutic agents.
gested in 75% of patients overall and in
100% of patients with mixed focal and
diffuse disease (Fig 4). An additional use
for FDG PET in patients with solitary
plasmacytoma is to aid in detection of
other unsuspected sites. El Shirbiny et al
(59) reported a case of combined use of
99m
Tc sestamibi and FDG PET, where the
former seemed to correlate better with
overall extent of disease and the latter
with areas of active disease.
One final use of nuclear medicine in
MM is in the evaluation of patients for
the treatment of painful bone metastases.
Isotopes such as strontium 89 (89Sr) have
been used to palliate the pain in MM
(60). Because response is dependent on
osteoblastic activity, a purely osteolytic
process might not be effectively treated.
A routine bone scan can help document
the presence of osteoblastic response in
these patients and is therefore helpful to
predict response to 89Sr treatment.
MR IMAGING
Figure 5. Skull involvement of MM. (a) Craniovertebral junction disease. Unenhanced
sagittal T1-weighted spin-echo MR images
(450/15) of the head in two patients. Left:
Clivus shows diffuse hypointensity with nonexpansile distal mass (arrow). Right: Focal expansile mass of dens (arrowhead) causes
compression of cervicomedullary junction.
(b) Multiple calvarial diploic lesions. Coronal
fat-suppressed contrast-enhanced T1-weighted
spin-echo MR image (550/15) of the head shows
multiple focal areas of enhancement (arrowheads) of the diploë with an expansile mass
(arrow) in left lateral frontal diploë.
mal scans were related to remission. Unfortunately, the value of follow-up studies is
limited because of the known development of multidrug resistance by myeloma
cells, which causes blockade of the accumulation of the sestamibi (54 –57).
Fluorine 18 FDG PET has been reported
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in MM (58,59). In a series of 43 patients
with MM and solitary plasmacytoma,
Shirrmeister et al (31) reported focal
tracer uptake on FDG PET scans of 38 of
41 lesions (sensitivity, 93%) with known
osteolytic pattern. FDG PET depicted 71
additional lesions missed on radiographs
in 14 patients. Some of these additional
lesions were confirmed by other means
in 10 of these patients, which resulted in
a change of disease management in 14%
of the patients. Diffuse disease was sug-
MR imaging findings in MM closely reflect the broad spectrum of pathologic
tumoral spread (25–30). The distribution
of malignant plasma cells in MM includes sites that show normal areas of
active hematopoiesis in adults. These are
in the bone marrow of the axial skeleton.
The combination of the diagnostic accuracy afforded by current MR units and
the extensive coverage by phased-array
spine coils allow the acquisition of survey
studies of long segments of the axial skeleton within a reasonable time period. MR
images can then be used to determine the
exact location, size, and local compressive effects of the focal plasmacytomas
and possible associated fractures. MR images can help precisely define radiation
therapy ports used in the primary treatment of patients with solitary bone plasmacytoma (61). Posttreatment MR images help define response to treatment
(62– 64). An additional use of MR imaging is the delineation of the effects and
complications of the highly involved
therapeutic protocols, to help explain
whether observed clinical findings are
the result of complications of the disease
or of a failure to respond to therapy.
MR Imaging Parameters
The type of MR sequence applied
greatly affects the MR image. Multiple
sequences have been proposed for use in
identifying focal or diffuse disease of the
bone marrow. These sequences include
spin-echo (T1-weighted and T2-weighted),
Multiple Myeloma
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Figure 6. MR imaging patterns in MM. Multiple midline sagittal MR images of thoracic or
lumbar spine. (a– c) Left: T1-weighted spinecho images (400/15). Middle: STIR images
(2,000/150/20). Right: Gadolinium-enhanced
fat-suppressed T1-weighted spin-echo images
(500/15). (a) Normal MR pattern in lumbar
spine. Note primarily fatty marrow (normal
MR pattern) with diffuse hyperintensity on
T1-weighted spin-echo image, diffuse hypointensity on STIR image, and no marrow enhancement on gadolinium-enhanced image.
Note homogeneity of marrow signal intensity
for all imaging sequences. (b) Diffuse marrow
involvement in lumbar spine. Note primarily
cellular marrow demonstrating reversal of normal MR pattern, with diffuse hypointensity on
T1-weighted spin-echo image, diffuse hyperintensity on STIR image, and marked enhancement on gadolinium-enhanced image. There
is associated fracture of the T12 vertebral body.
(c) Diffuse heterogeneous marrow involvement in lumbar spine. Note heterogeneity of
marrow signal intensity through all observed
vertebral bodies, with mixed areas of hypointensity and hyperintensity on T1-weighted
spin-echo, STIR, and gadolinium-enhanced
images. Note reversal of signal intensity on
T1-weighted and STIR images (Fig 6 continues).
gradient-echo (T2*-weighted), STIR, and
contrast material–enhanced spin-echo (with
and without fat suppression) sequences
(26,29,65–67).
T1-weighted spin-echo images generally
depict a focal plasmacytoma as a hypointense area within a generally hyperintense
marrow background. On the other hand,
diffuse involvement is identified as generalized hypointensity of the overall marrow, compared with the intensity of the
disk interspace or adjacent skeletal muscles. On T2-weighted spin-echo, gradientecho, and STIR images, focal lesions are
hyperintense relative to the hypointense
marrow background. Diffuse involvement
is identified as a generalized hyperintensity
of the marrow background relative to the
intensity of skeletal muscles. With these
sequences, we believe that inclusion of a
fat-suppression technique (in our experience, STIR imaging) is important, as it
allows better assessment of marrow involvement (diffuse, focal, speckled) and
characterization of involvement (uniform
or homogeneous, nonuniform or inhomogeneous) (65– 68). Contrast-enhanced
studies with fat suppression can supplement these other studies with demonstration of enhancement in focal or diffuse disease.
At initial evaluation and follow-up in
MM patients, we obtain survey MR images
of the entire axial skeleton. These consist
of T1-weighted spin-echo and STIR spinecho sequences (sagittal projection of
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Angtuaco et al
MR Imaging of Normal Marrow
Radiology
In MR imaging evaluation of the marrow, the patient’s age must be taken into
consideration. In the young patient,
most of the marrow in both the axial and
appendicular skeletons is cellular, primarily inhabited by hematopoietic cells
(red marrow). In adolescence, the red
marrow of the appendicular skeleton
changes to yellow marrow, with change
occurring initially in the diaphysis and
epiphyses and later in the metaphyses.
By the age of 20 years, the appendicular
skeleton is mostly made of fatty elements, while the axial skeleton—the
spine, pelvis, ribs, skull, and proximal
metaphyses of the femur and humerus—
is largely hematopoietic (69). In the 4th
decade of life, the axial skeleton changes in
cellular makeup to fatty marrow; by the
6th decade, the marrow is mainly fatty. On
T1-weighted images, fatty marrow is hyperintense and cellular marrow is hypointense, relative to the intensity of skeletal
muscles. Ricci et al (70) described four normal marrow patterns in various age groups
(Table 2). In the age population where MM
is most often found, one should be cautious in identifying diffuse nonuniform or
bandlike areas of hypointensity on T1weighted images as abnormal, because
these findings can be normal in this age
group.
MR Imaging of MM
Figure 6 (continued). MR imaging patterns in MM. (d, e) Left: T1-weighted spin-echo images
(400/15). Middle: STIR images (2,000/150/20). Right: Gadolinium-enhanced fat-suppressed T1weighted spin-echo images (500/15). (d) Diffuse speckled marrow involvement in thoracic spine.
Note nodular abnormalities in entire spine are better seen on STIR and gadolinium-enhanced
images. Speckled, or salt-and-pepper, appearance is better appreciated on STIR and gadoliniumenhanced images, again with posterior-element lesions better seen on these images. (e) Focal
disease in thoracic spine. Note several focal lesions at T3 and T4 spinous processes and T12
vertebral body. The smaller spinous process lesions at T4 (arrows) can be seen only on STIR and
gadolinium-enhanced images.
spine and coronal projection of pelvis).
These studies are complementary in the
analysis and detection of focal and diffuse
disease in MM (65– 68). Gadolinium-enhanced fat-suppressed T1-weighted images
are added to studies of the thoracic and
lumbar spine. This allows better differentiation of smaller focal lesions and characterization of diffuse disease. Transverse T1Volume 231
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and/or T2-weighted images are obtained to
characterize the effects of focal expansile
lesions. MR imaging of the brain is performed to examine diploic involvement of
the calvarium and skull base (Fig 5). This is
accomplished with sagittal T1-weighted
and coronal and transverse gadolinium-enhanced fat-suppressed T1-weighted sequences.
In MM, localization of tumor spread by
using MR imaging closely mimics the
findings in patients with spinal marrow
metastasis. In general, abnormalities are
identified as hypointensities on T1weighted images, hyperintensities on
STIR images, and enhancement on gadolinium-enhanced images. These imaging
features are not pathognomonic for MM
and may also be seen in other diseases
that affect the marrow. In general, however, MM is suspected whenever MR images depict an expansile focal mass; multiple focal masses in the axial skeleton;
diffuse marrow involvement, particularly
at known sites of normal hematopoiesis;
or multiple compression fractures in a
patient with no known primary malignancy.
In patients with newly diagnosed MM,
several MR patterns have been described
that define tumor burden (25,28,30,
71,72) (Fig 6). Low tumor burden is normally associated with a normal MR pattern. On the other hand, high tumor
burden is suspected when marrow is diffusely hypointense on T1-weighted imMultiple Myeloma
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Radiology
ages, hyperintense on STIR images, and
enhancing on gadolinium-enhanced images. Overall marrow signal intensity
may be homogeneous or heterogeneous.
Findings of diffuse marrow involvement
may also be appreciated in a setting of
increased hematopoiesis in patients with
severe anemia or in states of marrow repopulation, which are usually drug
induced (stimulation with growth factors). Moulopoulos and Dimopoulos (26)
described a variegated marrow appearance on T1-weighted images, suggestive
of scattered focal nodular deposits of
plasma cells. Plasmacytomas are usually
multiple and highly variable in distribution, with the majority located in the
thoracic and lumbar spine and the pelvis.
They range from small to large expansile
focal masses. Focal lesions with diffuse
marrow involvement may coexist (25)
(Fig 7).
In patients with stage I MM, who are
usually asymptomatic, MR images commonly show a normal MR pattern (no
evidence of diffuse or focal disease). A
defined group of patients were, however,
identified who had abnormal MR studies.
This group showed a more progressive
disease pattern with a shorter latency period before the need for systemic chemotherapy (73–76).
In newly diagnosed stage III disease,
various MR patterns have been demonstrated (25,29,34,77). Lecouvet et al (77)
found that 24% of patients had a normal
MR pattern. This group of patients responded better to therapy and achieved
complete remission more often than did
those with diffuse disease. On the other
hand, MR images revealing diffuse involvement were shown to correlate with
increased marrow cellularity, increased
plasmacytosis, anemia, and overall poorer
survival when compared with images in
patients with a normal MR pattern
(25,27,28,30,71,77).
MR images accurately reflect response
to treatment by showing a decrease or
resolution of focal lesions seen on initial
studies. Resolution of diffuse disease can
also be identified (78 – 80). In a group of
90 patients studied at our institution
with survey MR imaging of the axial skeleton before and after high-dose therapy
and tandem bone marrow transplantation, the posttreatment MR images
showed improvement in successfully
treated patients. Complete resolution of
MR findings to a normal MR pattern
without focal lesions, which was achieved
in 40 patients, was associated with an improved patient survival of 65 months or
longer versus 46 months in those without
18
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Radiology
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April 2004
TABLE 2
Patterns of Normal Signal Intensity on T1-weighted MR Images of Spine in
Different Age Groups
Pattern and Site
Age Distribution
1: Hypointense
Cervical
Thoracic
Lumbar
2: Hypointense with bandlike and triangular hyperintensity at endplates
Cervical
Thoracic
Lumbar
3: Hyperintense*
Cervical
Thoracic
Lumbar
92% ⬍40 y
70% ⬍30 y
99% ⬍30 y
87% ⬎40 y
88% ⬎50 y
86% ⬎40 y
75% ⬎50 y
Uniform
76% ⬎40 y
* Pattern 3a is homogeneous; pattern 3b is heterogeneous.
Figure 7. Diffuse disease with multifocal lesions. Noncontiguous coronal STIR MR images (2,000/150/20) demonstrate diffuse overall hyperintensity of marrow as compared with signal
intensity of adjacent muscles. Focal lesions involving right
posterior ilium (curved arrow), right and left ischium (arrowheads), and L4 and L5 vertebral bodies with extraosseous mass
at right side of L5 (straight arrows) are noted against background of hyperintense marrow.
complete resolution of MR findings (81)
(Fig 8).
FRACTURE IN MM
Spinal compression fractures occur in
55%–70% of patients with MM (82) (Figs
2, 9). These fractures may be due to bone
destruction by a focal mass or to increased osteolysis. MR imaging provides
an opportunity to detect the offending
cause (83,84). Lecouvet et al (82) classified spinal fractures into benign or malignant, primarily on the basis of the presence of an associated focal mass. Sixtyseven percent of 224 total fractures in 37
patients were identified as benign. In our
review of MR imaging surveys of the entire spine in 264 patients with newly diagnosed MM (84), fractures were present
in 117 (44.3%). A single fracture was seen
in 50 (42%) of 117 patients, and a focal
lesion causing the fracture was seen in 40
(80%) of those 50 patients. In patients
with multiple fractures, 273 sites of fracture were seen in 67 (58%) patients; of
the 273 fractures, 126 (46%) had an associated mass. These results indicate that
spinal fractures in MM do not require the
presence of a focal mass and can occur in
a setting of marrow that appears benign
on MR images (82– 84). Tricot (21)
proved this point in laboratory studies
that showed that the presence of myAngtuaco et al
Radiology
Figure 9. Plasmacytoma with associated compression fracture of C7. Sagittal T1-weighted (left; 600/15) and STIR (right;
2,000/150/20) MR images of cervical spine show focal lesion
(arrows) involving C7 vertebral body, with associated fracture.
There is protrusion of the plasmacytoma into adjacent spinal
canal.
Figure 8. Complete resolution of diffuse and focal lesions. Left:
Pretreatment sagittal (top) and coronal (bottom) STIR MR images
(2,000/150/20) of lumbar spine and pelvis show diffuse disease with
focal lesions (straight arrows) in pelvis. Right: Follow-up sagittal (top)
and coronal (bottom) STIR MR images (2,000/150/20) of lumbar spine
and pelvis show complete resolution of both diffuse and focal lesions.
Note normal MR appearance of diffuse hypointensity without focal
lesions. Superior end-plate fracture at L4 (curved arrow) has developed.
eloma cells in bone marrow stroma increases the formation of osteoclast-activating factors, leading to increased bone
resorption and subsequent fractures.
Spinal fractures also occur following
treatment. Moulopoulos et al (79) reported 35 new sites of fracture in 29 successfully treated MM patients. In patients
with relapse, fractures were also noted. In
another study, Lecouvet et al (85)
showed 131 new fractures in 37 patients
undergoing therapy. They found that the
group of patients with an initial MR
study showing diffuse disease or more
than 10 focal lesions had a shorter fracture-free interval than did the patients
who did not have diffuse disease shown
on MR images. They suggested that
the initial MR study may help identify
patients at increased risk for subsequent fracture of the spine. Currently,
bisphosphonates are standard drugs administered to MM patients undergoing
therapy, because these drugs are known
to decrease the incidence of compression fractures. Bisphosphonates disrupt
the vicious cycle of increased osteolysis
and myeloma cell production.
Volume 231
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Number 1
New treatment methods for spinal
fractures related to MM include percutaneous vertebroplasty and kyphoplasty. Percutaneous vertebroplasty is
now accepted as a method of alleviating
the bone pain associated with a spinal
fracture (86). The procedure also has
the secondary aim of preservation of
the remaining height of the vertebral
body. Kyphoplasty, on the other hand,
aims at restoration of the original vertebral height and elimination of spinal
deformity (87). MR findings of abnormal signal intensity in spinal fractures
aid the interventionalist in determining the treatment level in cases of multiple spinal fractures. Parallel zones of
hypointensity on T1-weighted images
and hyperintensity on STIR or T2weighted images in the fractured vertebra correlated with localized pain during percussion at the site of fracture.
COMPLICATIONS AND
PROGRESSION OF DISEASE
The multiple drug therapies currently utilized in the treatment of MM result in com-
plications that are identifiable on MR images. High doses of corticosteroids, a frontline drug in treatment of MM, may cause
spinal fracture and avascular necrosis of
the femoral heads. Immunosuppression
caused by cytotoxic drugs results in a
higher incidence of infections in the spine
(eg, discitis) and the brain (eg, cerebritis,
cerebral abscess). Cyclosporine used in
marrow transplantation regimens may result in neurologic changes of posterior reversible cerebral encephalopathy.
A rare progression in MM is leptomeningeal spread within the central nervous
system. In a recent review of 1,856 treated
patients at our institution, Fassas et al (88)
showed this complication in 18 patients.
MR findings of leptomeningeal enhancement in the brain or spine were seen and
helped establish the diagnosis (Fig 10). The
definitive diagnosis was made with results
from cytologic analysis of cerebrospinal
fluid. This complication was associated
with unfavorable cytogenetic results such
as chromosome 13 deletion, histologic
findings of plasmablastic cells, other extramedullary sites of disease, and plasma
cell leukemia. Myelofibrosis and amyloidosis can develop as a consequence of treatment in patients with MM. Myelofibrosis
can be suggested on MR studies as a conversion of the entire bone marrow to diffuse hypointensity on both T1-weighted
and STIR images. Amyloidosis can be seen
as focal areas of hypointensity on both T1weighted and STIR images.
Relapse and poor response to treatment are well evaluated with MR imaging. In patients with clinical relapse, new
focal lesions or an increase in the size of
previously identified focal lesions in
Multiple Myeloma
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19
Radiology
medullary or extramedullary sites are
seen (Fig 11). In severe relapse, conversion of a normal pattern to one of diffuse
involvement may also be seen. Poor response to treatment protocols also can be
demonstrated on follow-up MR studies,
where they appear as no change or deterioration in the previously identified areas of involvement.
MGUS AND SOLITARY BONE
PLASMACYTOMA
Monoclonal gammopathy of uncertain significance (MGUS) is the most common
cause of laboratory-discovered monoclonal
gammopathy. MGUS is usually an incidental finding, and its incidence in patients
over the age of 70 years is 3% (89). The
serum M protein component is typically
low, Bence-Jones proteinuria is rare, and
there is less than 10% plasmacytosis in the
marrow. M protein levels remain relatively
stable over time. Although most patients
die of comorbid conditions, MGUS can
“evolve” to MM, Waldenström macroglobulinemia, chronic lymphocytic leukemia,
plasmacytoma, amyloidosis, or lymphoma.
The longer the follow-up, the higher the
percentage of patients whose condition
eventually progresses to malignant disease. In a recent study of almost 1,400
patients with MGUS and with 11,000
person-years of follow-up, the cumulative probability of progression was 12%
at 10 years, 25% at 20 years, and 30% at
25 years (90). Initial monoclonal protein
(M protein) concentration was a significant predictor of progression at 20 years.
Vande Berg et al (91) performed MR imaging in 35 patients with MGUS and
found MR abnormalities in seven. Of the
patients with no MR abnormalities, none
required treatment after a follow-up of 30
months. On the other hand, four of
seven patients with abnormal MR findings required treatment within 5 years of
diagnosis. MR imaging provides important information concerning prognosis
in patients with MGUS, and an abnormal
MR study warrants closer follow-up for
signs of progressive disease.
Solitary bone plasmacytoma is uncommon (representing 2%–3% of plasma cell
dyscrasias) and usually manifests with
bone pain. The diagnosis is based on histologic evidence of tumor consisting of
monoclonal plasma cells. Associated laboratory findings include normal blood levels
of hemoglobin, creatinine, and calcium,
with negative bone marrow biopsy results
and skeletal radiographic survey findings.
20
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Radiology
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April 2004
Figure 10. Leptomeningeal spread in MM. Contrast-enhanced sagittal (left) and transverse (right) T1-weighted spin-echo (450/15) MR
images of lumbar spine show abnormal enhancement of nerve roots
(arrowhead) and surface of conus medullaris (arrow). Transverse image shows distinct nodular enhancement of the cauda equina, indicative of leptomeningeal spread of tumor.
Figure 11. Extramedullary spread in MM. Left: Transverse T2weighted spin-echo MR image (2,000/80) in a patient with clinical
findings of relapse show a mass (curved arrow) in the left pararenal
space. A separate mass (straight arrow) is in the right pararenal space.
Right: On transverse T2-weighted (2,000/80) section obtained at a
lower level, right pararenal mass is shown extending into adjacent
right neural foramen and epidural space (arrowhead). Associated dural sac compression is noted. Biopsy of both masses revealed malignant plasma cells.
A small, if any, M protein component
should decrease with treatment (definitive local radiation therapy) (92). The
rate of reduction of M protein level may
be slow (93), and in many patients the M
protein persists for years despite adequate radiation therapy, implying the
presence of tumor cells beyond the radiation field. The median overall survival
after radiation therapy in patients with
solitary bone plasmacytoma is 10 years.
The median time to progression to MM is
2–3 years. In some studies, the size of the
lesion, osteopenia, and low levels of uninvolved immunoglobulins were predictive of progression to overt MM (94). Results of several studies indicated that
screening of patients with solitary bone
plasmacytoma by using MR imaging or
in combination with a skeletal radiographic survey revealed a high prevalence of other plasmacytomas. This
group of patients also showed a shorter
latency of progression to MM (95–97).
Angtuaco et al
CONCLUSION
Radiology
In the past decade, important advances
in the understanding of MM and the
therapeutic options available to patients
with the disease have resulted in improved patient survival. This has gone
hand in hand with the advanced capabilities of modern imaging methods, particularly MR. MR imaging bone marrow surveys in patients with MM demonstrate
the broad spectrum of involvement, the
results of treatment, the areas of potential complications, and the sites of focal
disease for safe bone biopsies.
Figure 12. MR-directed CT-assisted biopsy. Left: Sagittal contrastenhanced fat-suppressed T1-weighted spin-echo (600/15) MR image
shows two enhancing lesions at T3 (arrow) and T9 (arrowhead). Right:
Transverse CT image obtained with patient in prone position during
CT-assisted biopsy of the T9 lesion shows biopsy needle (arrow)
entering the lytic lesion of T9 vertebral body by using a transpedicular
approach.
MR-DIRECTED CT-ASSISTED
SKELETAL BIOPSY
PERSPECTIVES IN THE
TREATMENT OF MM
Cytogenetic abnormalities (in particular, chromosome 13 deletion) in the
plasma cells in patients with MM is an
important negative predictor of durable
clinical response and overall survival
(17). Obtaining proper biopsy specimens of the tumor that can lead to this
discovery has become a necessary clinical tool. MR survey studies that depict
unsuspected sites of focal lesions help
direct this process of specimen collection (Fig 12). Bone biopsies with largebore needles (generally 12–14-gauge
bone biopsy needles) are difficult to
perform in the MR setting. CT guidance
of these MR-depicted focal lesions has
aided the safe performance of these procedures, especially in spinal bone biopsies. Our experience with biopsies of
the spine and pelvis of MR-depicted focal lesions has led to a 20% increase in
the yield of positive cytologic and cytogenetic information from biopsies at
these sites, compared with results in
samples obtained from random iliac
crest biopsies (37). This had led to a
more aggressive clinical approach once
cytogenetic abnormalities are detected.
The treatment of patients with MM continues to evolve. In a recent review of current
treatment options in patients with MM,
one of the authors (B.B.) indicated the superiority of high-dose therapy over conventional therapy in terms of event-free
survival and overall survival (98). The rate
of complete remission improved from 5%
to 50%, with event-free survival extending
beyond 3 years and overall survival beyond
6 years. The author stressed the importance of the detection of cytogenetic abnormalities, particularly chromosome 13
deletion, in cytologic specimens as indicative of a poor outcome. His review showed
favorable outcomes in patients without the
cytogenetic abnormality and with low ␤-2
microglobulin and C-reactive protein levels. Improved outcomes were achieved
with the addition of thalidomide, owing to
the antiangiogenic activity of that drug.
Finally, good outcomes were seen in the
group of patients who achieved complete
clinical remission shown on follow-up MR
studies with a normal MR pattern without
focal lesions (81). These patients had a better overall survival rate and prolonged
event-free survival than did those with persistent lesions on MR images.
Volume 231
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Number 1
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