Friday, October 1, 2010

Screening tests for multiple myeloma

I recently saw a biopsy for a patient who was suspected of having myeloma-related kidney disease, whose biopsy slides were sent to the pathology department at BWH. Along with them came results from a slew of screening tests, including serum free light chains (SFLCs). Since at BWH we usually screen for monoclonal immune deposition diseases (MIDD) with SPEP and UPEP only, I decided to review the indications and utility of available myeloma screening methods, including SFLCs.

In SPEP, serum is aliquotted onto an agarose gel through which an electrical current is run. Proteins, which are negatively charged, separate out on the gel, with the larger and more negatively charged ones moving faster than the smaller ones. Monoclonal gammopathies are identified when an M spike, or a large quantity of a single globulin (represented by a dense, narrow band on the gel) is found. A positive SPEP is followed by a serum immunofixation (SIFE) assay, in which soluble antibodies against the immunoglobulin are added to the serum, precipitating out the monoclonal protein and allowing better characterization. SPEP sensitivity is good for identifying production of monoclonal immunoglobulins (light chain + heavy chain), which comprise about 80% of multiple myelomas. They are much less sensitive when only a light chain is being produced, which happens in about 15% of myelomas.

In contrast, UPEP is much more sensitive for picking up light chain-producing myelomas. Free urine light chains, also called Bence-Jones proteins, are more readily picked up due to the lower protein concentration in urine, which allows for greater sample concentration. Urine proteins can also be fixed by soluble antibodies for further analysis (UIFE).

How are myelomas that do not secrete light or heavy chains (nonsecretory myelomas, about 3% of total cases) detected? Recently, it has been shown that almost 70% produce detectable levels of serum free light chains (SFLCs). Serum free light chains are detect using an antibody raised against a unique epitope on kappa and lambda light chains that are exposed only on light chains not bound to Igs. SFLCs have also been shown to be more sensitive than UPEP in detecting light chain secretory myelomas: in one series, 25% of patients with light chain MM had positive M spikes on UPEP, versus 54% with positive SFLC tests. The increased sensitivity of SFLCs may be attributable to renal proximal tubular absorption of light chains, lowering their concentration in the urine (and on UPEP).

Are there any disadvantages to the SFLC assay? Two identified by the International Myeloma Working Group include variability of 10-20% between lots of the antibody, and falsely low SFLC levels in states of antigen excess. To my surprise, SFLC tests are not prohibitively expensive: Katzmann et al estimated that SFLCs are about half the cost of UPEP/UIFE assays.

It seems there is a strong case for ordering SFLCs in our patients with renal disease suspected of having a monoclonal gammopathy. I would be curious to know whether other institutions are using it for screening, and their experiences. Renal function needs to taken into account when interpreting SFLCs (kappa light chains are cleared more than lambda). Resulting in a ratio of 0.6 at baseline. This was reviewed by Finnian here.


Kenar D Jhaveri( kidney 007) said...

nice post
I use serum free light chains as a routine. Most studies have indicated that SFLC is very sensitive and will be probably giving u the diagnosis very early on!

lisajcohen said...

I think we should probably start using them at Brigham, too!

Kenar D Jhaveri( kidney 007) said...

just keep in mind that in someone with renal failure, they will be elevated but if the ratio is too high or too low, then there is a real problem. I am sure if you screen all your dialysis patients, SFLC will be elevated equally

Tarun said...
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Tarun said...

At the University of Minnesota, we are using SFLC more now. And you are right, generally we order a 'slew of tests'. Interestingly, recently a question came up that if on the board exams, we are asked to pick between Urine and Serum IF, which is the one? It seems it may be urine, for reasons, of higher light chain concentration. Any comments?

JBdoc said...

I just spoke to our medical oncologist about this very issue today. We are moving away from SPEP/UPEP and SPEP/SFLC is becoming the standard work-up for MM.