Module 1: Screening, Diagnosis, and Staging of Multiple Myeloma
Initial Detection and Diagnosis
What makes it so difficult to diagnose multiple myeloma?
Dr. Brian Durie: One difficulty in diagnosing patients with multiple
myeloma is that symptoms or abnormal laboratory tests may not be adequately
followed up or investigated. Examples of symptoms that can be misinterpreted
include painespecially in the bones or jointsor fatigue that is
not adequately explained by other findings. Bone pain, particularly in a
young person, [hotlink young person to Slide 5] may be overlooked
as not carrying serious import, but if preliminary testing does not reveal an
immediate cause for persistent or unusual bone pain, further testing is definitely
necessary. This particular point cannot be emphasized too strongly: if there
is persistent bone or joint pain that does not have an explanation based on
simple testing, it is very important to pursue this with further testing of
bone, in addition to the complete spectrum of tests that might lead to diagnosis
of myeloma Slide 6. Inordinate fatigue must also be rigorously evaluated. It
can be an early indication of possible multiple myeloma and should be followed
up with further testing.
The most common test results that are not adequately pursued include an elevated
serum creatinine. There are many reasons for abnormal renal function, but multiple
myeloma should not be dismissed as a possibility, especially the light-chain
or Bence Jones type. Anemia that is otherwise unexplained also needs to be fully
evaluated. This may require a bone marrow test or serum and/or urine electrophoresis
to evaluate for the presence or absence of multiple myeloma.
To evaluate these possibilities, physicians must check for an elevation in
the total protein in the serum or the presence of protein in the urine through
tests that should include measurement of sulfosalicylic acid. The elevation
of total protein in the serum should be evaluated by serum protein electrophoresis
to determine the presence or absence of monoclonal protein in the serum. If
testing of the urine reveals a positive result with sulfosalicylic acid, this
must be further pursued to evaluate for the presence or absence of Bence Jones
VIDEO CLIP, Dr. Robert Kyle: The minimal tests that are necessary
Dr. Robert Kyle: The minimal tests that are necessary for the diagnosis
of multiple myeloma include a CBC and a chemistry group, which must include
calcium [hotlink calcium to Slide 7] and creatinine
[hotlink creatinine to Slide 8] determinations. Serum
protein electrophoresis, [hotlink Serum Electrophoresis to Slide
9] immunofixation, and nephelometric measurement of the individual immunoglobulins
A 24-hour urine specimen should be collected, and the specimen must be concentrated
and electrophoresis performed. Immunofixation must also be performed on the
concentrated urine specimen to look for a monoclonal light chain:
either kappa or lambda. [hotlink monoclonal light chain
to slide 11] The size of the M-protein in the serum and the size of the
M-protein in the urine are a direct reflection of the tumor mass.
In addition to these tests, the patient must have a metastatic
bone survey [hotlink metastatic bone survey to Slide 12] and
a bone marrow examination [hotlink bone marrow examination
to slide 13]. Cytogenetic evaluation should be performed, as well as a plasma
cell labeling index. Beta2-microglobulin, [hotlink beta2 microglobulin
to Slide 14] C-reactive protein (CRP), and (LDH) are helpful prognostic
factors. The plasma cell labeling index and cytogenetics can both be obtained
by mailing the samples to a central laboratory. These diagnostic tests for multiple
myeloma must be obtained before the patient is started on therapy.
A description of imaging tests
Dr. Brian Durie: Obviously, skeletal x-ray films are still the gold
standard in evaluating for the presence or absence of lytic bone lesions or
osteopenia. However, it can be helpful to assess the amount and the extent of
bone damage using other imaging techniques.
These techniques include magnetic resonance imaging (MRI), computerized tomography
(CT) scanning, and nuclear medicine scanning, including technetium 99m sestamibi
(MIBI) and positron-emission tomography with fluorodeoxyglucose (FDG PET) scanning.
MRI scanning has been the most useful supplement to traditional x-ray
imaging. MRI testing reveals diffuse abnormality in bone sites where there is
significant marrow infiltration, and this is a very helpful technique to document
the distribution and pattern of disease. This documentation is particularly
useful for patients who have nonsecretory or hyposecretory disease, as it may
be difficult to otherwise evaluate the status of the disease and the change
in the disease with therapy.
CT scanning can be particularly helpful to evaluate focal sites of disease
when it is important to assess the size or the exact location of a lesion and
to define a site of disease, possibly with a view to local irradiation therapy.
Nuclear imaging has been especially helpful in the overall evaluation
of the disease at the time of diagnosis with a view to future monitoring.
Whole-body PET scanning has been especially helpful in identifying patients
who have disease not just in bone but also outside of bone. Approximately 15%
to 20% of patients have extramedullary disease, as determined by FDG PET scanning
at the time of initial diagnosis. It is important to identify this subgroup,
not just to know the locations of the disease, but also because patients with
extramedullary disease are at higher risk for subsequent relapse.
A discussion of imaging tests, their utility, and their expense
Dr. William Bensinger: I probably use MRI more than some physicians.
I find it very helpful for getting an overall view of the extent of marrow disease,
and I find it useful in following patients conditions. My only caution
is not to use it too frequently because the results do not change that quickly
from month to month. However, for an initial evaluation, and perhaps a 6-month
evaluationespecially in someone who has undergone high-dose therapyMRI
can be useful.
I tell my patients that trying to evaluate the bone marrow is rather like looking
at a wall mural through a long cardboard tube. You get a narrow view, with only
one eye, and that limits your perspective of what is out there. With an MRI,
you can have a more general picture of the extent of disease throughout the
skeleton: you are looking at the whole mural with both of your eyes. That is
what makes it so useful.
Dr. Robert Kyle: That is true, but MRI is a very expensive procedure,
and I think that it should be limited to those patients who have unexplained
back pain or a neurologic deficit from an extradural plasmacytoma.
Dr. David Roodman: I would agree with Dr. Kyle. We use it mostly for
patients who do not have lesions on x-ray evaluation but have an unexplained
symptom. We then perform more sophisticated and more expensive testing.
VIDEO CLIP, Dr. David Roodman: We also routinely do bilateral
We also routinely do bilateral bone marrow examinations. Myeloma is a spotty
disease; it is not like acute leukemia, in which there is diffuse involvement.
Looking for increases in numbers and percentages of plasma cells and sheets
of plasma cells, a single marrow biopsy can miss that diagnosis.
Dr. Brian Durie: That does raise the issue of assessing the amount of
disease versus the cost of doing the tests. In terms of the relative cost, an
MRI or perhaps even a PET scan could provide broader information about the whole
body or significant parts of the body.
VIDEO CLIP, Dr. Seema Singhal: I tend to use MRI the way
Dr. Seema Singhal: I tend to use MRI the way Dr. Bensinger does, but
one note of caution here is that people tend to not realize that these evaluations
require special set-up sequences. I often have had patients undergo MRIs that
have been set up to look for intracranial abnormalities and disk problems. The
myeloma cannot be assessed unless the MRI has been set up for a specialized
Dr. Brian Durie: Right. It is extremely important to set up a sequence
series and to perform it with enhancement.
Dr. Robert Kyle: We do single bone marrow aspirates and biopsies, but
we count the number of plasma cells in the aspirate, the number of plasma cells
in the biopsy, and the number of plasma cells in the specimen for the labeling
index. We then take the highest number of these three and use that as the number
of plasma cells in the patients marrow.
Dr. Brian Durie: I think the scanning techniques are particularly helpful,
as Dr. Bensinger was mentioning, at that 6-month follow-up. You could perform
a bone marrow test, and the results might be normal. However, it allows you
to assess if all of the disease, which may be scattered, has also equally responded.
Dr. William Bensinger: That is one of the reasons I do it.
Dr. Seema Singhal: And in patients who have been thought to have a solitary
bone plasmacytoma, it is probably a good screening technique.
Dr. Brian Durie: I also use these scanning techniques to assess the
presence or absence of bone disease. I think it is important to exclude the
possible presence of other lesions in patients who appear to have only a solitary
lesion, whether in bone or outside of bone.
Dr. Robert Kyle: From a practical standpoint, that is most helpful in
talking to the patient. However, one is not going to treat the patient on the
basis of finding abnormalities on an MRI, unless an extradural plasmacytoma
Dr. Brian Durie: Well, I would disagree slightly on that point. There
are some patients who will go into a complete remission with the exception of
one area of residual disease. On more than one occasion I have radiated a single
site and then not needed to administer any other additional therapy at that
Other tests: Chromosomal analysis of myeloma cells
Link to Dr. Singhals Deletion 13 Topic summary goes here.
Dr. Seema Singhal: Chromosomal analysis of myeloma cells is an important
baseline test that gives valuable information about the biology of the disease
and has been shown to have prognostic significance. For example, the presence
of deletion of part or whole of chromosome 13 has been shown to be a poor prognostic
feature. At present, therapeutic decisions about the primary treatment of myeloma
are not really based upon a patients chromosomal abnormalities. However,
it is still important to get this test recorded as a baseline because it can
be helpful in making decisions about therapy in relapsed and refractory disease.
It can also help physicians give patients an idea of what to expect in the long-term
outcome of their disease, because it is well known that those who have single
or double deletion of chromosome 13 tend to have very short overall survival
even with the most aggressive therapies available today.
Chromosomal analysis done in the traditional method is a technically difficult
test in patients who have multiple myeloma because chromosomes can be analyzed
only in the dividing cells, and these cancer cells are slow to divide. Hence,
it is important to send every bone marrow sample done serially in a patient
over the course of time for this particular analysis. There is a high incidence
of false negative results, and adverse prognostic features may be missed if
only one test is done in the course of a persons illness. There is a newer
technique called fluorescent in situ hybridization (FISH) analysis that can
study the chromosomal makeup of a cancer even when it is not dividing, in the
resting phase, and can study a greater number of cells. Therefore, it is worth
sending off a bone marrow sample for FISH analysis for specific known chromosomal
abnormalities along with the regular cytogenetics.
VIDEO CLIP, Dr. Seema Singhal: There is considerable controversy
There is considerable controversy about the prognostic significance of chromosome
13 deletions picked up by FISH as opposed to those deletions picked up by regular
cytogenetic studies. There are radically opposing views reported by different
groups around the country, but it is a science that is currently evolving and
it is worth getting the test done to have the information for a particular patient.
In the next few years, we will have a clearer idea about the prognostic significance
of chromosome 13 deletions detected via FISH studies.
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