CLINICAL GUIDELINE

Practical radiology
of plasmacytoma

and multiple
myeloma

Andrew du Toit
MB ChB, FFRad

Lucille Wood
BA (Nurs Sci), MSc (Medicine)

(Haematol), RN, RM, Dip. Intensive
Nursing Care, Ward Admin and Clinical

Teaching

Peter Jacobs
MBBCh, MD, PhD (Medicine), FCP

(SA), FACp, FRCp, MCAp, FRC Path,
FRS

Department of Haematology and Bone Marrow
Transplant Unit incorporating the Searl/ Research

Laboratory for Cel/ular and Molecular Biology,
Constantiaberg Medi·C/inic, Cape Town

Abstract
The traditional approach to diagnosis
and staging in myeloma, based on
haematologie and biochemical crite-
ria, can be improved by inclusion of
new forms of imaging. Standard radi-
ographs have limited value but are still
required because the majority of
patients present with disease readily
detected by this means. Also rapid
extensive skeletal coverage is possible.
Scintigraphy is limited by its poor sen-
sitivity. CT is restricted to a region of
interest but is however more accurate
than DXA for demonstrating trabecu-
lar bone loss and density so that it
emerges as valuable in the evaluation
of therapy. MR! is currently the best
choice for revealing marrow infiltra-

tion and, in ideal circumstances, the
most sensible combination includes
spine, pelvis and proximal femur MR!
with skull, chest and rib X-rays.
Furthermore MR! is finding a place in
documenting prognosis when these
individuals are treated.

Introduction
Localised or disseminated mono-

clonal proliferation of plasma cells
produces a wide range of symptoms
and signs primarily in the skeleton.
Prominent among the latter is dis-
comfort due to generalised osteo-
porosis, solitary or multiple lytic
lesions I in addition to pathological
fracture.' Associated is synthesis of a
paraprotein which can typically be
detected in serum and as Bence-lones
proteins in urine although the more
primitive variants may not secrete and
occasionally not even produce the
aberrant immunoglobulin molecule.'
Metabolic consequences are increases
in blood calcium and urate that are
risk factors for kidney failure.'
Invasion of the bone marrow impairs
haematopoiesis' with both humoral
and cell-mediated immunity being
compromised," The cause is unknown
although the natural history is well
described with median survival of
only 7 months.' In contrast modern

22 SA JOURNAL OF RADIOLOGY • February 2003

management improves quality of life
by optimum support and combina-
tions of alkylating agents with corti-
costeroids while investigational
approaches centre on haematopoietic
stem cell transplantation and thalido-
ruide."

Clinical features
Presentation may be protean and

with the increasing use of routine bio-
chemical screening, as part of health
care management, diagnosis can be
made when only biochemical changes
are reported incidentally from the lab-
oratory.

Prominently pain is axial reflecting
demineralisation that may be severe, is
often aggravated at night and is char-
acteristically responsive to biphospho-
nates." Areas of destruction vary in
number and size. Strong correlations
exist with cytokines that alter both
osteoclastic and osteoblastic activity.II
Myelomatous masses may erode the
cortex and give rise to large subcuta-
neous swellings, underlie breaks, pre-
dispose to vertebral compression and
occasionally present as tumours in
breast, stomach or adjoining the
spinal column.

Haematologically there are vary-
ing degrees of normochromic and
normocytic anaemia pathophysiolog-
ically attributed to the chronic inflam-
matory state and associated with a
marked increase in erythrocyte sedi-
mentation rate. Until late in the course
leucocyte and platelet counts are pre-
served." Bone marrow aspiration
reveals increased numbers of plasma-
cytes many of which may be pleomor-
phic and, together with their extent
and distribution seen in the trephine,
are included in some staging proce-
dures." Biochemical consequences are



CLINICAL GUIDELINE

increases in calcium and urate with a
distinctive spike in the gamma region
on serum protein electrophoresis.
Free light chains, filtered at the
glomerulus, are then deposited in the
tubules so contributing to renal dys-
function with polyuria and dehydra-
tion culminating in a self-perpetuat-
ing cyde that is, however, initially
reversible.

Sometimes profound degrees of
immune compromise reduce poly-
donal antibodies and predispose to
sinopulmonary infection. Approxi-
mately 10% of patients develop amy-
loidosis that has widespread effects
typically producing nephrotic syn-
drome but perhaps more ominously
restrictive cardiomyopathy. A wide
range of other features exist to trap the
unwary diagnostician and a high
degree of awareness will often lead to
an early diagnosis."

Laboratory
evaluation

There is no substitute for a careful-
ly taken history followed by meticu-
lous examination, maintaining a high
degree of awareness and simple bed-
side tests of which urinalysis remains
invaluable."

The next stage is confirmation and
since a number of the findings are
mimicked by other disorders it is wise
to combine as many abnormal find-
ings as possible to secure the diagnosis
but primarily rely on the presence of
the serum paraprotein designated an
M-peak and intramedullary plasma-
cytosis.

Staging defines anticipated out-
come and provides a practical means
for monitoring management. The
most widely used of these is that
described by Durie and Salmon

(Table I)." Recent studies support the
use of B2 microglobulin and C-reac-
tive protein."

An approach to
imaging

Plain film radiography
Approximately 80% of individuals

have abnormalities at presentation
and this remains a logical first step in
studying the skeleton." However no
systematic approach appears to have
been described for the integration of
these changes into established staging
systems":" although there is, not sur-
prisingly, a loose correlation implicit
between advancing tumour and skele-
tal damage. To provide a more struc-
tured approach to this risk factor a
new grading is proposed (Table II).

Bone mineral density
As part of an ongoing evaluation,

(Jacobs, Wood, Hitchcock and du Toit
- unpublished data) this is quanti-
tated initially and followed serially
seeking to define the influence of dif-
ferent interventions, particularly the
use of biphosphonates." We have
found that the much favoured DXA
often underestimates trabecular thin-
ning which is readily evident on com-
puterised axial tomography."

Scintigraphy
Radionuclide scanning using tech-

netium-99m labelled diphosphonate
is typically normal or shows areas of
decreased uptake. The explanation for
this relative insensitivity is that the
osteoblastic activity in these tumours
is outweighed by the aggressive

Stage Criteria

TableI.Classificationof myeloma (modified from Durie and Salmon'S). The best
predictors are degree of anaemia, quantitation of paraprotein and serum calcium

level

I: All must be present

II

III: One or more only needed

Subclassification
A:= Serum creatinine < 120 lJmol/l
il= Serurn creatinine> 120 IJ.mol/l.

23 SA JOURNAL OF RADIOLOGY • February2003

• Haemoglobin value> 100 gil
• Serum calcium < 2.2 mmol/l
• Radiographically

Normal bone structure
Solitary bone plasmacytoma

•M-component
IgG < 50 gil
19A< 3 gil
Urine light chain < 4 gl24 hours

Fitting neither Stage I nor Stage III

• Haemoglobin value < 85 gil
• Serum calcium value >2.2 mrnol/l
• Advanced osseous destruction
• M-component

IgG > 70 gil
19A> 50 gil
Urine light chain> 12 gl24 hours



CLINICAL GUIDELINE

Table II. Constantiaberg grading of skeletal changes (Jacobs, Wood and du Toit-
unpublished data). Uncertainty exists as to whether the total amount of cortical

damage reflected in multiple small defects has different value to a smaller number
of much larger areas of destruction

Grade Criteria
o
I
II
a.
b.
c.
III
N

Normal
Diffuse demineraIisation
Less than 10 lytic lesions
Maximum 1 cm
2-4cm
Greater than 5 cm
More than 10 bony defects
Associated pathological fracture

destruction of the hypertrophic osteo-
clasts."

Computerised tomography
(CT)

Although not routinely used it
may nevertheless demonstrate early
trabecular bone destruction within a
vertebral body where other imaging
modalities are negative.

Magnetic resonance imag-
ing(MRI)

Support derives from a greater
sensitivity in revealing otherwise
occult invasion which is seen in about
50% of asymptomatic patients with
normal Xvrays." Representative areas
are full spine, pelvis and proximal
femora because these contain the nor-
mal haematopoietic tissue that har-
bours the neoplasm. Three patterns
are discern able (Table III).21 Focal
accumulations exhibit low- Tl and

low or high T2 signal in approximate-
ly equal numbers of untreated cases.
The variegated or salt and pepper
appearance has small nodules on Tl
and is sometimes best appreciated in
the pelvis. A diffuse involvement has
similar intensity to the isolated
deposits with homogenous replace-
ment resembling other intra-
medullary proliferative disorders.
Mixed pictures occur depending on
the status of the immunoproliferative
neoplasm. This variable appearance
results from relatively even neoplastic
distribution throughout the
haematopoietic tissue in widespread
disease contrasting with the small or
large nodules composed entirely of
tumour in localised patterns. Com-
pounding factors are increasing age
with conversion of red to yellow mar-
row that influences both detection
and character of the image produced
by the myeloma. Thus, although nor-

Table m. Magnetic resonance imaging in myeloma (modified from Kaplan et al.21)
Signal

Pattern Tl T2
Focal Low High or low
Variegated or salt & pepper Low Mild high
Diffuse Low High or low

24 SAJOURNAL OF RADIOLOGY. February2003

mal haematopoiesis is impaired with
replacement of the former, the relative
increase in the adipocytes gives an
enhanced signal, which offsets reduc-
tion from areas of infiltration, and so
the scan may look normal. Contrast
enhancement with gadolinium is
often marked but neither specific nor
essential if any abnormality has
already been demonstrated. Similarly
medullary invasion may be patchy
although widespread overall so that
an adequate trephine biopsy will
invariably demonstrate the aetiology.
Hence MRI is not usually required to
direct the aspiration site.

Vertebral fractures are seen with
significant osteoporosis, which is fre-
quent, and approximately 60% of
compression fractures look benign.
Thus in 37 patients with 224 fractures,
67% had this appearance, 33%
appeared malignant and, interestingly,
14 of these or 38% had no sinister fea-
tures." The distribution of such radi-
ological changes was similar to that
observed in non-myelomatous dem-
ineralisation predominantly in the
lower dorsal and upper lumbar
regions. In contrast ominous features
are low Tl signal extending from the
vertebral body into the pedicles and
posterior elements, diffuse body
involvement, multiple level involve-
ment and extension outside of bone
to form a soft tissue mass." The
anatomical site may be helpful in
detecting malignancy since those
above T4 are usually pathological.

A prognosis on therapeutic out-
come can be correlated with Durie
and Salmon stage III where four
groups are defined; normal, fewer or
more than 10 focal sites and wide-
spread infiltration." It is notable that
with apparently solitary lesions MRI
will typically reveal other deposits.



CLINICAL GUIDELINE

Following therapy those with lower
grades based on both biopsy and radi-
ological criteria experienced signifi-
cantly longer fracture-free survival
than where more extensive changes
were present.

It is also useful to forecast
response. In Durie and Salmon stage I
invasion is associated with subsequent
progression." Stage III patients with
normal images (24%) achieve better
results with therapy and survive
longer than those where this is abnor-
mal." When coupled with CRP this
pair were the best independent prog-
nostic indicators for survival. This
method can be refined using contrast
when complete response is defined as
resolution of the baseline abnormality
and is superior to persistence of any
change even if this is only peripheral
rim enhancement."

References
1. Ravaud p, Thepot C, Auleley GR, Amor B.

Imaging of multiple myeloma. Ann Med Interne
1996; 147: 370-375.

2. Scutellari PN, Orzincolo C. Bone disease in mul-
tiple myeloma: analysis of 253 controlled cases,
with reappraisal of diagnostic criteria and cur-
rent imaging techniques. Radiol Med 1993; 85:
235-246.

3. Bartoloni C, Flamini G, Logroscino C, et al. IgD

(kappa) 'nonsecretory' multiple myeloma:
report of a case. Blood 1980; 56: 898-901.

4. Clark AD, Shetty A, Soutar R. Renal failure and
multiple myeloma: pathogenesis and treatment
of renal failure and management of underlying
myeloma. Blood Rev 1999; 13: 79-90.

5. Rajkumar SV; Fonseca R, Dewald Gw, et al.
Cytogenetic abnormalities correlate with the
plasma cell labeling index and extent of bone
marrow involvement in myeloma. Cancer Genet
Cytogenet 1999; 113: 73-77.

6. Paglieroni T, MacKenzie MR. Studies on the
pathogenesis of an immune defect in multiple
myeloma. J Clin Invest 1977; 59: 1120-1133.

7. Bataille R. Multiple myeloma. N Engl J Med
1997; 336: 1657-1664.

8. Huff CA, Jones RJ. Bone marrow transplanta-
tion for multiple myeloma: where we are today.
Curr Opin Oneo12002; 14: 147-151.

9. Tosi P, Cavo M. Thalidomide in multiple myelo-
ma: state of art. Haematologica 2002; 87: 233-
234.

10. Berenson JR. Bone disease in myeloma. Current
Treatment Options in Oncology 200 I; 2: 271-283.

11. Ely SA,Knowles OM. Expression of CD56/neur-
al cell adhesion molecule correlates with the
presence of lytic bone lesions in multiple myelo-
ma and distinguishes myeloma from monoclon-
al gammopathy of undetermined significance
and lymphomas with plasmacytoid differentia-
tion. Am J Patho12002; 160: 1293-1299.

12. Jacobs P, Wood L. Myeloma and other immuno-
proliferative disorders. CME 1999; 17: 253-257.

13. Bartl R, Frisch B. Bone marrow histology in
multiple myeloma: prognostic relevance of his-
tologic characteristics. Hematol Rev 1989; 3: 87-
108.

14. Jacobs P. Myeloma. Disease-a-Month 1990; 36:
317-371.

15. Durie BG, Salmon SE. A clinical staging system
for multiple myeloma: correlation of measured
myeloma cell mass with presenting clinical fea-
tures, response to treatment, and survival.
Cancer 1975; 36: 842-854.

16. The Myeloma Trialists' Collaborative Group.
Combination chemotherapy versus melphalan
plus prednisone as treatment for multiple
myeloma: an overview of 6,633 patients from 27
randomised trials. J Clin Oneo11998; 16: 3832-
3842.

17. Collins C. Multiple myeloma. Tn:Husband JES,
Reznek RH, eds. Imaging in Oncology. New
York: ISIS Medical Media, 1998: 625-634.

18. Berenson JR, Lichtenstein A, Porter L, et al.
Long-term pamidronate treatment of advanced
multiple myeloma patients reduces skeletal
events. The Myeloma Aredia Study Group. J Clin
Oneal 1998; 16: 593-602.

19. Solomon 0, Jacobs P.Bone densitometry- role
of quantitative computed tomography. S Afr
Med J2oo2; 92: 486.

20. Abildgaard N, Glerup H, Rungby J, et al.
Biochemical markers of bone metabolism reflect
osteoclastic and osteoblastic activity in multiple
myeloma. Eur J Haematol2oo0; 64: 121-129.

21. Kaplan PA, Helms CA, Dussault R, Anderson
MW, Major NM. Musculoskeletal MRT.
Philadelphia: Saunders, 2001: 23-53.

22. Lecouvet FE, Van de Berg BC, Maldague BE, et al.
Vertebral compression fractures in multiple
myeloma. Part 1. Distribution and appearance at
MR imaging. Radiology 1997; 204: 195-199.

23. Lecouvet FE, Malghem J, Michaux L, et al.
Vertebral compression fractures in multiple
myeloma. Part U. Assessment of fracture risk
with MR imaging of spinal bone marrow.
Radiology 1997; 204: 201-205.

24. Lecouvet FE, Van de Berg BC, Michaux L, et al.
Stage TIJ multiple myeloma. clinical and prog-
nostic value of spinal bone marrow MR imag-
ing. Radiology 1998; 209: 653-660.

25. Van de Berg BC, Lecouvet FE, Michaux L, et al.
Stage I multiple myeloma: value of MR imaging
of the bone marrow in the determination of
prognosis. Radiology 1996; 201: 243-246.

26. Moulopoulos LA, Dimopoulos MA, Alexanian
R, Leeds NE, Libshitz HI. Multiple myeloma:
MR patterns of response to treatment. Radiology
1994; 193: 441-446.

25 SA JOURNAL OF RADIOLOGY • February 2003