Screening for cancer: are biomarkers of value?

– February/March 2011 20 Tumour markers
of pre-malignant MGUS and SMM cases
that are diagnosed each year, it is important
to have a strategy for managing
“benign monoclonal gammopathies” versus
“malignant monoclonal gammopathies”.
A study of 1,384 MGUS cases from
a South Eastern Minnesota, USA cohort
demonstrated that 1% of MGUS patients
progressed to myeloma per year, the size
of the M-spike and heavy chain isotype
being prognostic for progression [5]. This
was extended to include a third factor –
an abnormal serum free light chain ratio
and a risk stratification model was developed
that identified “very low risk MGUS
patients” using low serum monoclonal
protein levels, IgG isotype and a normal
serum free light chain ratio [6]. These
MGUS patients’ disease progression rate
was 0.1% per year. Whilst not synonymous
with a “normal case” it is consistent
with placement at the benign end of
the monoclonal gammopathy disease
spectrum. Conversely, MGUS patients at
very high risk are starting to be identified;
the risk is not necessarily high enough at
presentation to warrant immediate treatment,
but these patients are most likely to
exhibit the clinical symptoms and signs
required (i.e. by CRAB criteria) for a
diagnosis of myeloma in the future.
11-12% of MGUS patients
undetected by a simplified
screening panel of serum PEL and
FLC: should we be concerned?
If MGUS patients’ lab tests are negative with
serum protein electrophoresis and free light
chain assay, with a small M-spike and a normal
free light chain ratio, thus there is no, or
just one adverse prognostic factor, they are
placed in a low risk group. There is a very
low probability of progressing to disease and
it may be preferable that laboratorians and
clinicians do not identify them. This avoids
placing a psychological burden on patients
and an economic strain on the healthcare
system. More incumbent is to examine why
recommendations for monitoring these individuals
are what they are. Our patients’ lifelong
interests are probably better served if
Assay
Coefficient of
Variability
Figure 2. Serum FLC terminology: involved, uninvolved
and difference in free light chain derivation.
their clinical symptoms and signs of disease
are monitored in the community by their
primary healthcare physician in the first
instance, as opposed to extensive lab-based
monitoring under the hospital out-patient
care of a haematologist.
Monitoring
The free light chain immunoassay is recommended
for monitoring of oligosecretory
PCD (AL, NSMM, LCDD), that is, those
patients who do not have a measurable
serum or plasma M-spike and for documenting
a response to therapy [6,7]. The recommendation
for what a partial response (PR)
is in these oligosecretory PCD patients has
been set at a 50% reduction in the involved
free light chain or dFLC [Figure 2].
Dr Katzmann presented newly generated
data from stable patients addressing the total
coefficient of variation (CV) of some of these
screening panel assays i.e., the biological and
analytical variation combined. This patient
cohort was not receiving therapy, had a stable
diagnosis over time and blood was sampled
every few months [Figure 3]. These data
show that serum M-spike quantitation has a
CV of 6.1% implying that a minimal change
is approximately 12.2% in M-spike (i.e. 2
standard deviations) with confidence in a
partial reduction at 50%. Less change could
be due to chance alone or evolution of disease
over time. Immunoglobulin quantitation has
a similar CV. The urine M-spike, in sharp
contrast, has a CV that is much higher at
29.1%, in accordance with a minimal change
Analytic CV
Biologic CV
Serum M-spike [SPE] 6.1% 5% 3.5%
Serum Ig [nephelometry] 9.9% 5% 8.5%
Urine M-spike [SPE] 29.1% 6% 28.5%
iFLC 26.0% 6% 25.3%
rFLC 38.1%
Figure 3. Coefficients of variability of monoclonal protein measurements in stable patients. Personal
communication, Dr. Katzmann, February 2011. Reproduced with permission. iFLC = involved FLC,
rFLC = free light chain ratio.
in a urine M-spike, which itself necessitates at
least a 50% change to define it correctly and
more than a 90% reduction to consider it a
partial response.
A long held assumption has been that this
very high variability was due to the quirks
associated with 24 hour urine collection.
However, when Katzmann examined the
CV for the free light chain assays these data
[Figure 3] showed a very similar CV to that
of urine M-spike quantitation. So for both
assays, despite low analytical CVs [Figure 3,
column 3], some biological CV common to
both [Figure 3, column 4] leads to a higher
overall coefficient of variation. This biological
variation is related to the light chains
themselves in a way that is currently not fully
understood but is most likely related to the
short half lives of the free light chains. Table 3
shows that biological variability of the serum
free light chains, measured in this study at
25.3% as well as last year [8] is similar to that
for the urine M-spike at 28.5%. With this in
mind a review of the IMWG guidelines is
timely. From these data there is no reason to
think that serum free light chain analysis is
inferior to urinalysis, but criteria should be
used for sFLC assay changes that are comparable
to those currently used for urine assays.
Perhaps it is time for a 90% reduction in FLC
to be considered a partial response. In conclusion
we should both honour the past contribution
made by Henry Bence Jones but also
address the need for assays to become more
stringent and standardised internationally.
References
1. Drayson M et al. Blood 2001; 97: 2900-2902.
2. Lachmann HJ et al. Br J Haematol 2003; 122: 78-84.
3. Dispenzieri A et al. Leukemia 2009; 23: 215-224.
4. Katzmann JA et al. Clin Chem 2009: 55:
1517-1522.
5. Kyle RA et al. N Engl J Med 2002; 346: 564-569.
6. Rajkumar SV et al. Blood 2005; 106: 812-817.
7. Gertz MA et al. Am J Hematol 2005; 79:
319-328.
8. Snyder M et al. Blood 2009; 114: 1803a.
Editors comments: clarifications to the IMWG
criteria for coding CR and VGPR in patients in
whom the only measurable disease is by serum
FLC levels were published during the writing of
this manuscript:
S. Vincent Rajkumar, Blood. Prepublished online
Feb 3 2011;doi:10.1182/blood-2010-10-299487.
The authors
Alison Levoguer, Scientific Affairs Manager
Richard Hughes, Senior Research Scientist
The Binding Site Group Limited,
Birmingham, UK
www.cli-online.com & search 25501