Paraprotein managementBMJ 2006; 333 doi: https://doi.org/10.1136/bmj.333.7560.185 (Published 20 July 2006) Cite this as: BMJ 2006;333:185
All rapid responses
Dr Mehta raises a number of points in his rapid response submission
which I will answer individually. However it should firstly be understood
that these illustrative cases and brief discussion do not in any way
constitute a detailed review of myeloma, but illustrations of a few
specific points to stimulate interest and debate.
They serve as a peg to hand guidance for generalist doctors and refer to
the J Clin Pathol review cited, the series of which covers a wide range of
testing situations which arise particularly in primary care. Some are
common, others rarer.
The two cases here are synoptic and stylised although relate to true
situations which do actually occur.
The first case was indeed referred to the National Amyloidosis centre and
the second will be familiar to many laboratories which perform
electrophoreses: whilst regular follow up is recommended, the prevalence
of smaller paraprotein bands in the community is high and follow up
testing can be missed, either inadvertently or because of a lack of
readily available guidance. That is precisely why we presented this case.
It is sometimes too easy for secondary care to refer to patient
mismanagement, when ultimately part of the role of the laboratory is to
advise on testing in chronic disease management and to develop mechanisms
to support this being done correctly. Any failure to use or correctly
interpret a laboratory test can result in suboptimal medical management.
Dr Mehta alludes to a similar issue he is currently examining in his
general practitioner and physician colleagues. The issue facing
laboratories is how it can use its extensive result record archive to
facilitate improving management, at least to the level of supporting
Baseline full blood counts are indeed referred to in this case and in
the guidance box as immediate tests following identification of a
paraprotein, along with renal function and serum calcium, also of crucial
importance. Some of these, although quite possibly not calcium, are likely
to have been done already or at the same time as the electrophoresis.
The specialist investigation described in case 1 was, as should be
apparent from the case, initiated following secondary referral (in fact at
the tertiary centre).
The summary of the use of electrophoresis is a short listing of patient
categories, notably suspected blood cell dyscrasias, and includes, but is
not restricted to, the groups listed by Dr Mehta (in addition to elevated
ESR, bone pan, undetermined anaemia and renal failure it will also for
example include investigation of hypercalcaemia, recurrent infections and
other possible haematological findings). These could be brought out in a
larger review covering the investigation of blood dyscrasias. Similarly,
the explicit criteria for MGUS, myeloma and ‘smouldering’ myeloma would
form part of a full subject review.
Box 2 does not pretend to be evidence based, but a summary of other
published guidance discussed in the original review . It differs
slightly from the UK Myeloma Forum, Nordic Myeloma Study Group and British
Standards for Haematology guideline, published after the original review,
(15 versus 20g/L) for which the correct reference in the British Journal
of Haematology is 2006 not 2005. Like these guidelines the recommended
guide to further investigations (which would normally require referral)
differs from the quoted threshold representing probable MGUS. This is to
be expected, as there is no reason why a referral guide should necessarily
be the same as the disease diagnostic threshold in a disease in which
paraprotein band quantitation band represents only one of a range of
criteria used to identify possible disease and early diagnosis is being
sought. These suggestions, as made clear in both publications, serve as a
guide and the evidence level for monitoring lower risk MGUS in the UK
Myeloma Forum, Nordic Myeloma Study Group and British Standards for
Haematology guideline is also cited as level IV, consistent with much of
the ‘evidence’ in laboratory testing. Interestingly the principles of MGUS
monitoring have changed little over recent years, suggesting that some of
the ‘out of date’ references we cite have stood the test of time. There
have always been slight differences in thresholds for investigation and or
referral, which probably reflect the inexact nature of paraprotein band
quantitation as a prognostic index.
Interestingly also this guideline does not specifically advocate routine
continued blood count monitoring in MGUS, and I would leave my haematology
colleagues to advise on when this should be performed. It presumably would
be indicated along with renal function and calcium as a minimum if a
paraprotein band increased considerably in quantity or over a certain
The point referring to the NICE Velcade draft decision does not relate to
this article and is not discussed.
Also, to avoid any confusion, the website www.myeloma.org.uk is that of
Myeloma UK, (International Myeloma Foundation (UK)), and www.myeloma.org
is that of the International Myeloma Foundation.
Finally I am grateful to Dr Mahtu for correctly highlighting a
proofing error in the final summary point, which should read: ‘Absence of
paraprotein bands does not exclude plasma cell dyscrasia'.
 Smellie WSA, Wilson D, McNulty CAM et al. Best Practice in
Primary Care Pathology: review 1. J Clin Pathol 2005;58:1016-24
Competing interests: No competing interests
Re: Paraprotein Management
W Stuart A Smellie, Gavin P Spickett
BMJ Vol 333, 22nd July 2006
As a haematologist with a special interest in myeloma, I read the
article by Smellie and Spickett (1) with interest. We are currently
conducting a study to ascertain the time it takes for our myeloma patients
to be appropriately referred by our GP and physician colleagues; we
frequently find there has been avoidable delay and that patients have
suffered complications as a result.
It is disappointing therefore, that the article contains a number of
errors. The paper should commence with a clear description of the
appropriate initial assessment of a patient presenting with a paraprotein.
When should patients be referred ? To whom ? What is an appropriate
patient pathway? What baseline investigations should be undertaken ? Both
case histories illustrate patients who were mismanaged – Case 1 should
have been referred to the National Amyloidsis centre for further
assessment (2) and Case 2 should have been followed up and treated much
earlier than she was. The authors’ failure to emphasise the crucial
importance of a baseline full blood count is a serious omission in an
educational article on Laboratory medicine. The investigations mentioned
are either not routinely available – eg serum amyloid component P
scintigraphy – or should, in my view, only be requested by specialists
once a diagnosis has been established – eg serum immunoglobulin free light
chains. Box 1 contains serious printing/proof reading errors. Box 2 is
not evidence – based and gives values of paraproteins typical of MGUS
which differ from those quoted in the text. There are explicit criteria
for MGUS, myeloma and ‘smouldering’ myeloma which should be quoted (3).
Box 3 fails to emphasise that serum immunoglobulins should be measured and
an electrophoresis performed in all patients presenting with renal failure
or anaemia which is not due to haematinic deficiency or which occurs in
association with bone pain, renal impairment or an elevated ESR. Most of
the references are out of date; the UK myeloma forum guidelines have been
updated (4); and myeloma.org.uk takes you to the International Myeloma
Foundation (not ‘organization’) which, along with all of us who work for
myeloma patients, is outraged by the NICE draft decision on Velcade
announced this week.
1. Smellie W Stuart A, Spickett P Gavin. Cases in primary care laboratory medicine. Paraprotein Management.
British Medical Journal, 2006, 333, 185-187.
2. Bird J, Cavenagh J, Hawkins P, Lachmann H, Mehta A, Samson D. Guidelines on the diagnosis and management of AL amyloidosis. British Journal of Haematology, 2004, 125, 681-700.
3. IMF Website – www.myeloma.org.uk
4. Smith, A, Wisloff F, Samson D on behalf of the UK Myeloma Forum,
Nordic Myeloma Study Group and British Committee for Standards in Haematology. Guidelines on the diagnosis and management of multiple myeloma 2005. British Journal of Haematology, 2005, 132, 410-451.
Competing interests: No competing interests
Editor: Professor Bradwell advocates measurement of free light chains
in the patients we described in out pitfalls article on paraproteins.
Whilst we do not disagree that evidence exists suggesting that this test
may be of additional value in some patients, the guidance we have
presented in the original review around which the cases are constructed
 is a summary of existing good practice documents as they apply to the
primary care use of laboratory tests. This is an attempt to assist primary
care colleagues with common clinical scenarios which arise in laboratory
We have found reports supporting the additional diagnostic or monitoring
value of individual tests in a range of diagnostic or monitoring
situations, although the challenge in this work was to attempt to separate
those which might form part of a primary care battery of investigations
and those which might be expected to be ordered in conjunction with
secondary care advice.
We did not find consensus guidance recommending the routine use of serum
free light chains in this situation from our search. The patient with AL
amyloidosis will be followed in a specialist centre with a different range
of tests to those which would be used to point towards the initial
diagnosis in primary care, and we could not at present recommend primary
care monitoring of serum light chains in all patients with monoclonal
gammopathy of unknown significance (MGUS) based on our literature search.
We do intend, however, to update these reviews to take account of new
guidance as it emerges, and will revisit serum light chains at that time.
1. Smellie WSA, Wilson D, Bareford D et al Best Practice in primary
care pathology. Review 1 Best Practice Working Group J Clin Pathol
Competing interests: No competing interests
Editor: A recent article concerned with paraprotein management
describes best practice for patient investigation and monitoring. We
do not agree with several aspects of the article because there is no
mention of serum free light chain measurements. The first patient had
AL amylodosis which is a light chain deposition disorder. In such
patients, serum free light chain measurements have greater diagnostic
sensitivity than either serum or protein electrophoretic tests. This
is specifically discussed in recent guidelines, such as those issued by
the British Committee for Standards in Haematology, and is key to the
diagnosis and monitoring of the disease. The second patient they
discussed progressed from a monoclonal gammopathy of undetermined
significance to multiple myeloma. They correctly reported current
limitations in urine protein electrophoretic tests but failed to comment
that a serum free light chain test would have been better. In addition,
patients can be risk stratified based upon testing serum IgG and serum
free light chain concentrations. It has been shown that patients with
high concentrations of serum free light chains are more likely to
progress. Regular monitoring could identify myeloma early and might
prevent serious complications of the disease. The authors made rather
confusing statements on this issue.
In conclusion, we would like to reiterate that serum free light chain
assays have greater sensitivity than their electrophoretic counterparts,
avoid difficult urine collection requirements and are used in many
laboratories in the UK and elsewhere. Whilst acknowledging the
appropriate use of current serum and urine protein electrophoretic tests,
the authors should have considered that best practice now includes serum
free light chain measurements.
1) Smellie WSA and Spickett GA. Paraprotein management. BMJ.2006;
2) Bradwell AR, Carr-Smith HD, Mead GP, Tang LX, Showell PJ, Drayson
MT Drew R. Highly sensitive, automated immunoassay for immunoglobulin free
light chains in serum and urine. Clinical Chemistry 2001: 47:4 673-680
3) Lachmann HJ, Gallimore R, Gillmore JD, Carr-Smith HD, Bradwell AR,
Pepys MB, Hawkins PN. British Journal of Haematology 2003 122:1 78-8
4) Bradwell AR. Serum Free Light Chain Analysis 4th Edition.
Birmingham, UK. The Binding Site Ltd 2006: 128-146
5) Rajkumar SV, Kyle RA, Therneau TM, Melton LJ III, Bradwell AR,
Clark RJ, Larson DR, Plevak MF, Dispenzieri A, Katzmann JA. Serum free
light chain ratio is an independent risk factor for progression in
monoclonal gammopathy of undetermined significance (MGUS). Blood 2005: 106
The Binding Site Ltd produce a kit designed to measure serum free light chain protein (Freelite [TM]
Competing interests: No competing interests