Confused about Multiple Myeloma: SPEP, UPEP, Serum IFE, Urine IFE, Serum Free Light Chain Assay?

[Redpancreas]

In short, I am confused about the principles involved in working up Multiple Myeloma. What I understand is that Protein Electophoresis (PEP) provides the amount of monoclonal protein (if present), but not necessarily the type where IFE comes in and tells us the type and whether or not it is there.

It seems like the standard work up is SPEP+UPEP. Adding the Serum IFE though adds to the sensitivity and Urine IFE does so even more...and then there is a serum free light chain assay.

The boards say that 20% of patients only secrete a urine light chain...so it's critical to get an IFE? Why can't that urine light chain be detected on the UPEP?

I think I am confused on what monoclonal proteins and light vs. heavy chains actually are which could be leading to this confusion. I guess i really don't understand the fundamentals of these tests and was wondering if someone can break this down what goes through their head when they're ordering these for?

1.) Initial screening/diagnosis
2.) Monitoring of known MM

Thanks!

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[DrStephenStrange]

I'm just a M4 so here's my 2 cents. The M-protein spike detected by UPEP or SPEP is actually made up of monoclonal light chains, so they definitely can detect light chains. IFE on the other hand detects the subtype of monoclonal light chain being produced Kappa vs Lambda. Monoclonal basically means the abnormal subtype. The one (Mono) that is being produced uncontrollably (clonal). If it's being produced uncontrollably, there won't be enough heavy chains to go around to couple with every single light chain because they (as in the heavy chains) are not being uncontrollably produced, hence why you have free monoclonal (meaning one subtype) light chain hanging around in serum and excreted in the urine (Bence jones protein). SPEP won't tell you what subtype it is (it just tells you that there is a light chain being overly produced), so you have to get IFE to tell you if it's Kappa or Lambda.

I certainly hope I didn't just botch this lol

 

[gutonc]

In short, I am confused about the principles involved in working up Multiple Myeloma. What I understand is that Protein Electophoresis (PEP) provides the amount of monoclonal protein (if present), but not necessarily the type where IFE comes in and tells us the type and whether or not it is there.

It seems like the standard work up is SPEP+UPEP. Adding the Serum IFE though adds to the sensitivity and Urine IFE does so even more...and then there is a serum free light chain assay.

The boards say that 20% of patients only secrete a urine light chain...so it's critical to get an IFE? Why can't that urine light chain be detected on the UPEP?

I think I am confused on what monoclonal proteins and light vs. heavy chains actually are which could be leading to this confusion. I guess i really don't understand the fundamentals of these tests and was wondering if someone can break this down what goes through their head when they're ordering these for?

1.) Initial screening/diagnosis
2.) Monitoring of known MM

Thanks!

2. is easy. Whatever was abnormal before, keep checking that.

 

[Chemist0157]

In short, I am confused about the principles involved in working up Multiple Myeloma. What I understand is that Protein Electophoresis (PEP) provides the amount of monoclonal protein (if present), but not necessarily the type where IFE comes in and tells us the type and whether or not it is there.

It seems like the standard work up is SPEP+UPEP. Adding the Serum IFE though adds to the sensitivity and Urine IFE does so even more...and then there is a serum free light chain assay.

The boards say that 20% of patients only secrete a urine light chain...so it's critical to get an IFE? Why can't that urine light chain be detected on the UPEP?

I think I am confused on what monoclonal proteins and light vs. heavy chains actually are which could be leading to this confusion. I guess i really don't understand the fundamentals of these tests and was wondering if someone can break this down what goes through their head when they're ordering these for?

1.) Initial screening/diagnosis
2.) Monitoring of known MM

Thanks!

I tend to get SPEP, serum free light chains, inmunofixation on patients I see for kidney disease and proteinuria, especially nephrotic and especially older patients.

There are times when only the SPEP would be sent, and the lab would report an abnormality but could not definitively say without the immunofixation.

There are times when SPEP is fine but free light chains have been grossly abnormal, sometimes in amyloidosis.

I don’t tend to the UPEP along with the other tests. I don’t think it offers anything else. I believe UpToDate suggested either FLC or UPEP.

 

[bobsmith]

In short, I am confused about the principles involved in working up Multiple Myeloma. What I understand is that Protein Electophoresis (PEP) provides the amount of monoclonal protein (if present), but not necessarily the type where IFE comes in and tells us the type and whether or not it is there.

The boards say that 20% of patients only secrete a urine light chain...so it's critical to get an IFE? Why can't that urine light chain be detected on the UPEP?

I think I am confused on what monoclonal proteins and light vs. heavy chains actually are which could be leading to this confusion. I guess i really don't understand the fundamentals of these tests and was wondering if someone can break this down what goes through their head when they're ordering these for?

1.) Initial screening/diagnosis
2.) Monitoring of known MM

Yes, SPEP will quantitate an excess of the protein, and the immunofixation will help determine what type of protein it is; combined together, you'll get a read out such as "3.4g/dL of IgG kappa" or something like that. This is fundamentally why you need both SPEP and IFE.

In this example, IgG Kappa refers to the type of immunoglobulin protein (IgG is the heavy chain component, kappa is the light chain component) that is being produced by the neoplastic plasma cells. However, you also can have light chain myeloma in which the neoplastic plasma cells are only producing a light chain immunoglobulin (kappa or lambda alone, without an IgG/IgD/IgA, etc).

So of 100 myeloma patients, ~80 or so will have a +SPEP and +IFE like above, maybe another ~10 or so will have only a +IFE alone (in which the result will say something like "Kappa light chain detected on immunofixation" without a number or associated heavy chain), and then another ~7 or so will have a positive urine study or FLC assay alone (negative SPEP and negative IFE), with 3 of them having "nonsecretory" myeloma.

2. is easy. Whatever was abnormal before, keep checking that.

Well similarly, 1. is also easy, then - if you're an internist/nephrologist/neurologist, order until you find something abnormal, at which point you refer to hematology who orders everything to figure out what the best thing to track is.

Seriously, though, in practice I find that many of the patients we'll see for the first time for a monoclonal gammopathy will have an SPEP/IFE and FLC ordered by the referring provider, and the 24-hour urine studies may be done at initial diagnosis to be thorough, but are kind of a pain to do and track (unless needed for formal treatment response, clinical trials, etc)

 

[NotAProgDirector]

bobsmith has a nice review. Most myelomas produce both heavy and light chains -- that causes an elevated serum protein level, serum M spike. Most are IgG (50%), iwth 25% IgA. Of the rest, most produce only light chains. Light chains are fltered by the kidney, so they don't cause elevated serum levels of protein but you'll see them in the urine. You can measure free light chains in the serum and diagnose it that way, obviating the need to measure the urine -- but once you know it's light chain disease, you then want to measure urine levels to follow disease activity. Light chains do not react with urine dip sticks.

Also worth reviewing:

Waldenstrom vs IgM MM -- IgM MM is very rare, so if you find serum IgM spike WM is much more likely. The two diseases are totally different -- WM is a lymphoma and presents with enlarged LN's, etc.

POEMS - a syndrome more consistent with MGUS but appears to secrete VEGF, which causes all of the problems in POEMS.

AL Amyloid / Light chain deposition - Plasma cell disorder, probably like MGUS, but the light chains polymerize. This causes amyloidosis in tissues. This causes AKI, but for completely different reasons than classic MM.

Hyperviscosity - classic in WM or IgM MM, but can be seen in any MM esp if protein levels are very high.

Lab pearls - Free light chains / Bence Jones protein does not show up on dip sticks. Because IgG is negatively charged, MM can cause a low or even negative anion gap. In light chain disease, protein levels are usually low (the abnormal clone suppresses other Ig levels)

 

[MedicineZ0Z]

bobsmith has a nice review. Most myelomas produce both heavy and light chains -- that causes an elevated serum protein level, serum M spike. Most are IgG (50%), iwth 25% IgA. Of the rest, most produce only light chains. Light chains are fltered by the kidney, so they don't cause elevated serum levels of protein but you'll see them in the urine. You can measure free light chains in the serum and diagnose it that way, obviating the need to measure the urine -- but once you know it's light chain disease, you then want to measure urine levels to follow disease activity. Light chains do not react with urine dip sticks.

Also worth reviewing:

Waldenstrom vs IgM MM -- IgM MM is very rare, so if you find serum IgM spike WM is much more likely. The two diseases are totally different -- WM is a lymphoma and presents with enlarged LN's, etc.

POEMS - a syndrome more consistent with MGUS but appears to secrete VEGF, which causes all of the problems in POEMS.

AL Amyloid / Light chain deposition - Plasma cell disorder, probably like MGUS, but the light chains polymerize. This causes amyloidosis in tissues. This causes AKI, but for completely different reasons than classic MM.

Hyperviscosity - classic in WM or IgM MM, but can be seen in any MM esp if protein levels are very high.

Lab pearls - Free light chains / Bence Jones protein does not show up on dip sticks. Because IgG is negatively charged, MM can cause a low or even negative anion gap. In light chain disease, protein levels are usually low (the abnormal clone suppresses other Ig levels)

What's the diagnostic criteria for light chain deposition disease without a biopsy?