MGUS to Multiple Myeloma Diagnostics and Counseling: 5 Pearls Segment

Core IM Podcast

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Time Stamps

• 01:29 What is a monoclonal gammopathy? What is our expected clinical presentation?
• 10:25 What is our initial workup? Understanding SPEP, Immunofixation, and Free Light Chains
• 24:54 Do we need urine testing? When urine testing is necessary and when it is not
• 27:06 How should we differentiate monoclonal gammopathies? The continuum of MGUS, SMM, and MM
• 41:53 Demystifying Monoclonal gammopathy of clinical significance
• 49:10 BONUS Pearl!

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Show Notes

Pearl 1: What is a monoclonal gammopathy? What is our expected clinical presentation?

• A monoclonal gammopathy is a clonal population of one type of plasma cell, which secretes one type of antibody.
  • A monoclonal protein
    • The antibodies made by a single clone of cells, which are all the same type!
• Spectrum of severity:
  • • Monoclonal gammopathy of undetermined significance (MGUS)
      • Waldenstrom’s macroglobulinemia (WM) aka IGM MGUS
    • Smoldering multiple myeloma (SMM)
    • Multiple myeloma (MM)
    • Plasma cell leukemia/myeloma
    • Monoclonal gammopathy of clinical significance
• Epidemiology
  • About 5% of the general population > 50 years-old have a monoclonal protein so 1 in 20!
• Clinical Presentation
  • By definition, MGUS and SMM have no symptoms attributable to their monoclonal protein.
  • Classic presentation of multiple myeloma (CRAB)
    • HyperCalcemia
      • Usually hypercalemia 2/2 lytic bone lesions
    • Renal insufficiency
      • Especially if calcium HIGH, concerning myeloma
      • Since Ca is usually LOW in renal disease
    • Anemia
    • Lytic Bone lesions
  • Additional features:
    • Amyloidosis (“Big tongue” macroglossia, restrictive cardiomyopathy)
    • Hyperviscosity (e.g., WM)
      • Gum bleeding, Epistaxis and Bruising without other explanation
    • Polyneuropathies

Pearl 2: What is our initial workup? Understanding SPEP, Immunofixation, and Free Light Chains

• (1) Serum protein electrophoresis (SPEP)
  • Electrophoresis gel that separates the proteins (e.g., immunoglobulins) in serum according to their electrical charge.
    • A clonal population of proteins all have the same charge, so will end at the same location, leading to a monoclonal (M) spike.
  • SPEP QUANTIFIES this M spike (usually in g/dL).
    • SPEP will NOT tell you what type of immunoglobulin (i.e igG, IgA, IgE, IgD, IgM) the monoclonal protein is.
• Immunofixation (IFE)
  • Test to identify WHAT TYPE of immunoglobulins you have
    • (i.e., IgG, IgM, IgA, kappa, and lambda).
  • More sensitive than SPEP (e.g., an SPEP could be negative, however the immunofixation could show a monoclonal protein)
• Serum Free Light Chains (FLC)
  • Measure serum free light chains (kappa or lambda) that are unbound to immunoglobulins (aka antibodies).
  • Normal ratio of serum kappa to lambda: 0.26 – 1.65
    • Ratio roughly ~1 from pure chance that different plasma cells will either have a kappa or lambda
  • BUT, if there is a clone, the clones will have either kappa OR lambda (NOT BOTH) and will skew ratio
  • Most sensitive test
    • If light chain only disease (~15 of the time)
      • Free light chains can easily be filtered through kidneys
      • It will NOT build up in the blood
      • Will not be detected in SPEP/immunofixation
• CAVETS in interpretation:
  • If GFR declines,
    • Cannot secrete Kappa light chains as fast, which will also skew the ratio to kappa
  • Chronic inflammation (TB, Hep B, etc)
    • Will led to polyclonal elevation of immunoglobulins (ex. IgG and IgA)
• Sensitive of tests:
  • SPEP with ~80% sensitivity
  • IFE increases sensitivity to ~93%
  • All 3 tests (SPEP, IFE and FLC) increases sensitivity to ~98%.

Pearl 3: Do we need urine testing? When urine testing is necessary and when it is not.

• Types of urine testing
  • UPEP (urine protein electrophoresis) and urine immunofixation
    • Similar to SPEP, leading to higher sensitivity to pick up
      • Smaller monoclonal proteins
      • A kappa or lambda process filtered through
  • In the past, urine testing helped detect light chain only monoclonal gammopathies and to add additional sensitivity.
    • Serum free light chains have largely replaced by serum free light chains test
  • 24-Urine protein versus spot protein:creatinine ratio
    • Measures total urine output over 24 hours, ideal form of testing urine as it can more clearly show the quantity of proteinuria versus a spot protein to creatinine ratio.
  • Urine testing is NOT needed for initial workup.
    • When to Use: If a monoclonal protein is detected, urine studies can quantify proteinuria and assess kidney damage.

Pearl 4: How should we differentiate monoclonal gammopathies? The continuum of MGUS, SMM, and MM.

• MGUS (Monoclonal gammopathy of undetermined significance)
  • Definition
    • Asymptomatic
    • SPEP with a total M protein < 3 g/dL.
    • Bone marrow with less than 10% plasma cells.
  • Risk of progression
    • < 1% per year of progressing to myeloma or other plasma cell dyscrasia.
    • What are risk factors MGUS to progress to myeloma? and Referral to hematology?
      • SPEP quantity >1.5 g/dL
        • >3.0 g/dL, no longer MGUS
      • non-IgG (IgM, A, D, or E)
        • Ex. IgM MGUS <3.0 g/dL
      • Kappa/lambda ratio > 5-8:1 (or vice versa)
        • **Normal range for free light chain ratio depend on age and renal function
  • Low-Risk MGUS (ex. igG Kappa MGUS):
    • Omit bone marrow biopsy and hematology referral
      • Repeat serum test in 6 months to ensure process is not evolving
      • If stable, check labs again only as symptoms occurs
    • Myelomarisk.com
  • Light chain only MGUS
    • Serum SPEP and immunofixation are negative with no IgG, A, or M
      • BUT light chain ratio is abnormal.
    • Ratio < 5-8:1 is deemed low risk, you can omit the bone marrow biopsy.
• Smoldering Multiple Myeloma
  • Definition
    • No evidence of end-organ dysfunction.
    • SPEP with total M protein > 3 g/dL.
    • AND/OR Bone marrow with between 10-60% plasma cells.
  • Risk of Progression
    • 10% per year for the first five years (following this the risk is lower if you have not yet progressed).
  • Diagnostic Workup
    • Bone marrow biopsy required if M protein > 3 g/dL.
• Multiple Myeloma
  • Definition (Plasma cell burden > 10% or biopsy-proven plasmacytoma) AND
    • Evidence of end-organ damage from the monoclonal gammopathy.
      • Features of end-organ damage aka CRAB criteria.
        • Hypercalcemia (> 1 mg/dL above ULN OR > 11 mg/dL).
        • Renal insufficiency (CrCl < 40 mL/min OR Cr > 2 mg/dL).
        • Anemia (> 2 g/dL below ULN OR < 10 g/dL).
        • One or more lytic bone lesions on imaging (X-Ray, CT, or PET/CT).
          • Note: MRI not included as so sensitive you need 2 lesions
    • AND/OR Myeloma-defining diagnostic features (SLiM features)
      • Bone marrow with > Sixty percent (60%) plasma cells.
      • Light chain ratio > 100:1.
      • MRI with 2 or more focal lesions deemed from monoclonal gammopathy.
• Note: additional entities (Waldenstrom’s, plasma cell leukemia) were not covered in depth in this episode.

Pearl 5: Demystifying Monoclonal gammopathy of clinical significance (MGCS).

• Definition
  • Clonal gammopathies (not cancer, similar to MGUS aka precancer) in which the clone of plasma cells secrete immunoglobulins that have paraneoplastic properties
    • AKA secreting a functional antibody.
  • This secreted immunoglobulin can target different areas in the body, which typically include: *Non-exhaustive list.
    
    • Kidney (most common)
      • Typically nephrotic syndromes (amyloid, light chain deposition disease).
    • Skin (many different syndromes)
    • Nerves
      • Often axonal or demyelinating; can be very painful.
      • e.g., POEMS, DADSM (Distal acquired demyelinating syndrome with M Protein)

Bonus Pearl: Be Judicious: Overdiagnosis and excessive testing can cause unnecessary anxiety for patients. Focus on clinically significant findings and appropriate monitoring.

Transcript

Dr. Shreya Trivedi: Welcome to the Core IM 5 pearls podcast, this is Dr. Shreya Trivedi.

Dr. Nathaniel Long: Hi! I am Dr. Nate Long, a senior resident at BIDMC

Dr. Shreya Trivedi: Let’s get started on the pearls we’ll be covering in this episode. Be sure to test yourself by pausing after each of the 5 questions. Remember, the more you test yourself, the deeper your learning gains.

Dr. Nathaniel Long: Pearl 1: Clinical presentation of monoclonal gammopathies

Dr. Shreya Trivedi: How common is it? What are typical illness scripts to send off testing for?

Dr. Nathaniel Long: Pearl 2: Initial workup

Dr. Shreya Trivedi: What is our initial workup? Understanding SPEP, Immunofixation, and Free light chains.

Dr. Nathaniel Long: Pearl 3: Urine testing

Dr. Shreya Trivedi: When urine testing is necessary and when it is not?

Dr. Nathaniel Long: Pearl 4: Spectrum of Monoclonal gammopathies

Dr. Shreya Trivedi: How do you counsel patients based on if they have MGUS, Smoldering Myeloma, and Multiple Myeloma.

Dr. Nathaniel Long: Pearl 5: monoclonal gammopathy of clinical significance aka MGCS

Dr. Shreya Trivedi: What is monoclonal gammopathy of clinical significance and what are the different ways it presents?

Pearl 1: What is a monoclonal gammopathy? What is our expected clinical presentation?

1.2 What is a monoclonal gammopathy?

Dr. Shreya Trivedi: So why don’t we start off with what is a monoclonal gammopathy?

Dr. Nathaniel Long: So I sat down with Dr. Aaron Goodman, a hematologist at UC San Diego, and also known as Papa Heme on X, who broke it down in an easy to understand way without giving me too much anxiety everything I have forgotten around immunology.

Dr. Aaron Goodman: A plasma cell is our professional antibody producing cells. Okay. And each plasma cell makes one specific type of antibody, but we got a gazillion plasma cells. So we make a gazillion different types of antibodies and it helps us fight infections. So what is a monoclonal gammopathy? Just like you can get clones of cells in your skin like moles, you can also get clones of cells in your colon called polyps. You can get clones of your plasma cells. And as we age, mutations are happening really in all of our cells. We kind of are selecting for plasma cells that are small clones of each other that are more fit. Now, these small clones, they still do what the normal plasma cell does. They secrete antibody, but now they’re secreting one type of antibody a little bit more than they should. And that’s called a monoclonal gammopathy. So a monoclonal gammopathy really is a small clone of plasma cells, or a large clone depending on what we’re talking about, that secretes one type of antibody that we can detect on testing. And this condition can be anywhere from benign thing that we see with aging (MGUS) to an overt hematologic malignancy called plasma cell myeloma.

Dr. Nathaniel Long: Yes, and there is a whole spectrum of what the clonal population of plasma cells can mean from MGUS to myeloma, and we are going to demystify all of that throughout this episode.

Dr. Shreya Trivedi: Yep and what i didn’t know is just how prevalent plasma cell disorders just are.

Dr. Vincent Rajkumar: Plasma cell disorders are quite common. So about 5% of the general population in the United States above the age of 50 will have a monoclonal protein. And the monoclonal protein is simply the antibodies made by a single clone of cells, and they’re all of the same type, so they really stick out like a church spire on an electrophoresis gel. So since it’s so common, anytime you order an SPEP, you have a 1 in 20 chance of a monoclonal protein.

Dr. Shreya Trivedi: Now that i think about it plasma cell disorders being common does fit with my clinical experience- I have sent off so many SPEPs for heart failure workup as a reflex and have gotten back kappa lambda ratios in the red that I just didn’t know what to do with. And almost all these patients did not have cardiac amyloid.

Dr. Vincent Rajkumar: So what really first needs to be very clear, why are we doing this test? Because otherwise you are going to get a test that’s positive and you have to deal with why this test is positive. So I usually say order the test when you are suspecting multiple myeloma or related plasma cell disorder, like amyloidosis or Waldenstrom’s macroglobulinemia, and not to do the test when you just test part of a routine workup because you will be faced with a positive test that you are not sure how quite to interpret.

Dr. Nathaniel Long: That is really gonna be a theme of the episode – which is to be judicious by choosing wisely about when and who to test.

Dr. Shreya Trivedi: Yes I am so excited to get into the testing later – I learned sooo much from all that. And so before we understand the tests, what type of clinical pictures get our spidey senses up that this could be a possible plasma cell disorder to send these tests

Dr. Nathaniel Long: So I appreciated hearing what these common illness scripts are from Dr. Vincent Rajkumar. Illness scripts that should trigger us to test for these disorders. And it may feel like a whole list of random things but to ground us, let’s build off of the CRAB mnemonic – a mnemonic most of us have heard of. for multiple myeloma

Dr. Shreya Trivedi: which stands for hypercalcemia, renal dysfunction, anemia and bone lesions. And don’t worry if it feels like a lot, we will recap all of this!

Dr. Nathaniel Long: Ok first up, let’s do the first and last letter, the C and B, hypercalcemia and bone lesions since they usually go hand in hand.

Dr. Vincent Rajkumar: Anybody with hypercalcemia is suspect, particularly if they have the lytic bone lesions. Usually you don’t have high calcium without bone lesions. So anybody with lytic bone lesions, I’m thinking Multiple Myeloma unless proven otherwise, and I’m getting that done imaging and if it’s negative then I’ll do bone marrow and if that’s also negative, then I’m biopsying one of the lesions.

Dr. Shreya Trivedi: Then onto the R, renal failure.

Dr. Vincent Rajkumar: Renal failure, unexplained renal failure, particularly if the calcium is high, because calcium is usually low in renal failure, and if the calcium is high, I’m always thinking that constellation makes me worried about myeloma. Worried about myeloma where the renal failure is accompanied by granular casts or a high urine protein. The dipstick won’t measure it, but a lot of granular casts means there’s proteinuria or you had a 24 hour urine protein, then I am worried that it could be myeloma. And again, you will look at the result and then decide if it’s renal failure caused by cast nephropathy, the light chain level should not be borderline. It should not be like 29 milligrams per deciliter per liter or 50 milligrams per liter. It should be 500 milligrams per liter or 1,500 milligrams per liter or something. So you look at the magnitude of the abnormality, whether it correlates.

Dr. Nathaniel Long: So think about plasma cell disorder if there is renal failure and hypercalcemia and that is because usually we see normal to low calcium in standard chronic kidney disease. Or if there’s a significant cast nephropathy – from all the free light chains being filtered through and plugging up the kidney tubules. And again take this a grain of salt, because many presentations are possible.

Dr. Shreya Trivedi: Yeah, appreciate and then what about A in CRAB. When should anemia clue us that it may be from a plasma cell disorder.

Dr. Vincent Rajkumar: For anemia, unexplained normochromic, normocytic anemia without any other reasons to explain it. One of many, many things could be Myeloma, but oftentimes in those situations, Hematologists are called on to do a bone marrow. Because someone is telling them “there’s no Coomb’s test that’s positive, there’s no B12, folate, or iron deficiency, there is no renal failure to explain this”. So it could be like an MDS or a bone marrow process that’s going on.

Dr. Nathaniel Long: And then there is the other bucket of things that do not fit in the CRAB mnemonic, things like cardiomyopathy and neuropathy.

Dr. Vincent Rajkumar: The next thing that we look for are people who look like they have a restrictive cardiomyopathy or they complain of a big tongue or there’s anything to worry for amyloid. Monoclonal gammopathy can cause peripheral neuropathy in multiple ways. One is an unexplained distal ascending polyneuropathy. Another is patients who can have a significant axonal neuropathy from amyloidosis. Another is a patient who has a demyelinating neuropathy from the POEM syndrome with the osteosclerotic lesions. So again, not every neuropathy, but neuropathies which have those kind of features, numbness, fingers, toes without any explanation. So suspected Myeloma, suspected amyloid, suspected Waldenstrom’s. We had a patient coming in with hyperviscosity, usually presents with bruising and gum bleeding and epistaxis without any reason. The patient’s IgM is like 7,000 or 8,000 milligrams per deciliter. So you worry about you should think of it in unexplained hyperviscosity and so on. You think of all the ways in which plasma cell disorders can cause a real problem and in those situations you will get the test.

Dr. Shreya Trivedi: Okay so what I am taking away is that in addition to the classic CRAB (high calcium and bone lesions, significant proteinuria and casts in the urine and unexplained anemia) features, it was nice to be reminded that there are other ways that monoclonal gammopathies can present, such as features of amyloidosis, polyneuropathies, or hyperviscosity in the setting of an IgM gammopathy which can present as the classic unexplained nosebleeds and gum bleeding.

Dr. Nathaniel Long: And then lastly to summarize what is a monoclonal gammopathy its a clone of one (hence called mono-cloncal) type of plasma cell and that plasma cell produces one type of antibody and depending on how many clones of that plasma cells and that particular antibody there is it can present in a spectrum of ways from MGUS to myeloma.

Pearl 2: What is our initial workup? Understanding SPEP, Immunofixation, and Free light chains.

2.1 SPEP and Immunofixation

Dr. Shreya Trivedi: Ok now that we know what monoclonal gammopathies are and have an idea of types of patients that we should be sending testing on, I can’t wait to clarify in my mind what is the difference between different tests. A lot of just write SPEP/UPEP in our notes and i dont think a lot of us have a good understanding of each of the tests tell us and and how to prioritize them

Dr. Nathaniel Long: Yep let’s start the main serum tests and then we will do the urine tests in Pearl 3.

Dr. Aaron Goodman: So let’s go over the testing for monoclonal gammopathy. So there are three main tests and we have to dig back a little bit to our biochemistry. So SPE serum protein electrophoresis, it’s exactly what it sounds like. It’s an electrophoresis. Immunoglobulins are proteins. Okay? So they’ll carry a charge, and when you put blood on the electrophoresis, on the gel, it will be separated. It’ll separate out the proteins based on the charge. And you’ll see clear distinctive peaks. There’s different regions and one region’s called the gamma region, not immunoglobulin G, but the gamma region on an SPEP. And that’s where all the immunoglobulins will fall, or the majority of them. So Ig (G,A,D,E,M), okay? And you should see a smooth distribution because you’re making different proteins, but if you have a small clone or a large clone of plasma cells, you’ll make more of one antibody than the others, and that will be a spike in the electrophoresis pattern. So we call that an M spike, which means you have an M protein, which means you have a clone of plasma cells. So the SPEP will identify that. This is where I think people get confused. So the SPEP quantifies the M spike, it will give you the quantity in grams per deciliter usually. Okay, so like 0.535, it will not qualify. And what do I mean by qualify? It [SPEP] won’t tell you the flavor. And when I say flavors, they are IgG-A-D-E-M, you need another test for that. The SPEP is also not super sensitive. You can have bonafide amyloidosis and (are) dying of it and a normal SPEP. So, I will repeat this numerous times during this talk. If you are worried about a monoclonal gammopathy, you have to unfortunately order all the tests. But if you’re going to do it, you need to order all the testing, which is an SPEP, immunofixation, and serum free light chains. So that is the SPEP, it quantifies the M spike, but it’s not super sensitive and it can miss it.

Dr. Nathaniel Long: Okay, so to recap, the first serum test is the SPEP – which is an electrophoresis gel that separates proteins. And if your patient’s blood has a clonal population of proteins, these are all the same size and charge, so will end at the same place on the SPEP and create a spike, called an M spike, or monoclonal spike.

Dr. Shreya Trivedi: SPEP allows you to QUANTIFY the different proteins aka the antibodies that the plasma cells are making. SPEP importantly does not qualify the protein, in other words tell you what type (e.g. IgG, IgA, IgM).

Dr. Nathaniel Long: Yep and that is where the immunofixation comes in!

Dr. Vincent Rajkumar: The immunofixation is just like the protein electrophoresis supercharged where we run several lanes and in each lane you add an antibody against IgG, IgM, IgA, and Kappa/Lambda. And so, if you see a monoclonal protein looking at the immunofixation, you can tell based on which bands are reacting. Is it IgG Kappa, is it IgG Lambda? And so on. So, the SPEP tells you – is there a monoclonal protein? If so, how much? The immunofixation tells you – is there a monoclonal protein? If so, what type?

Dr. Nathaniel Long: Love that. SPEP = is there a monoclonal protein and if so HOW MUCH. Immunofixation = is there a monoclonal protein and if so WHAT TYPE. To put it in other words with a coffee shop analogy, the SPEP is the receipt that tells you how many coffees you ordered. The immunofixation is the label on the coffee that tells you if it’s a vanilla latte or a caramel macchiato.

Dr. Shreya Trivedi: And we mentioned that there are 3 different tests and so far, we have learned that we can have SPEPs might not be as sensitive and the immunofixation will show the type of monoclonal protein. So how can a third test help us understand what’s going on in the bone marrow better?

Dr. Nathaniel Long: So the third and last serum test is the serum free light chain assay.

Dr. Shreya Trivedi: And Nate I love going to the basics – what even are free light chains?

Dr. Nathaniel Long: So serum free light chains assays measure the amount and ratios of free kappa and lambda light chains.

2.2 Serum Free Light Chains

Dr. Vincent Rajkumar: The serum free light chain assay is a brilliant assay because what it does is it only measures the light chains that are circulating free, unbound to the immunoglobulin, because the immunoglobulin itself has two Kappa and Lambda light chains. So the assay is quite good in the sense it looks for epitopes that are hidden unless the light chain is actually free and circulating in the circulation. Now, I usually tell people our body is just so well regulated that this immunoglobulin molecule. So we are really good about making only the amount of light chains we need. We don’t make extra. But all of us do have normal serum Kappa level and a normal serum free Lambda level. And normally there is a ratio, the ratio is 0.26 to 1.65. That’s a pretty tight range in which all of us have.

Dr. Aaron Goodman: The final test, serum free light chains, is the most sensitive of the three. You should roughly have equal kappa to lambda. The ratio varies from about 0.65 to 1.5 to 2, but they should largely be equal based off just pure probability. If you have a clone, each clone will only be kappa or lambda. It can never be both. But one clone should only have Kappa or Lambda. So you’ll see a skew in the ratio either towards Kappa or towards Lambda, and that is a hint that there’s a monoclonal gammopathy. That is the most sensitive test.

Dr. Shreya Trivedi: Oh I so appreciate learning that the reason why the ratio is close 1 is that what we should be seeing is roughly the same number of kappa as lambda, purely based on chance with the different types of plasma cells our body is producing -we should have a roughly equal number of plasma cells producing kappa light chains and equal number producing lambda light chains

Dr. Nathaniel Long: And an important caveat to that rule of thumb that the ratio of kappa and lambda is relatively equal to 1 is that when the GFR starts to dip, we might see some skewing to that ratio.

Dr. Aaron Goodman: Keep in mind when interpreting this, as your renal function declines, and unfortunately a lot of patients with decreased renal function are worked up for gammopathies because gammopathies can cause renal failure due to numerous mechanisms, due to a very complex thing, your Kappas go up, you just can’t get rid of ’em as fast. So, as your renal function declines, your GFR, there will be more Kappa and you’ll start seeing a skew towards Kappa. If you go to UpToDate, I always have to look it up. It tells you where it should be for a various GFR, because I get these consults all the time. Just know that when interpreting the Kappa and Lambda.

Dr. Shreya Trivedi: Alright before I consult heme for an abnormal serum free light chain with more kappa, I should peek at their GFR and see if this result may be what is expected with decreased clearance of kappa compared to the lambda free light chains in kidney disease. I love that. So that gets me curious to learn are there any other times when serum testing should be taken with a grain of salt?

Dr. Vincent Rajkumar: Any kind of infection, inflammation, it’s just a polyclonal process. Anyone with infection, inflammation, autoimmune disease, you see polyclonal elevations of IgG and A, just like that, the kappa and lambda free light chains can also go up. And depending on the day of the week, the ratio might be slightly out of range and you don’t want to immediately think the patient has a monoclonal disorder.

Dr. Shreya Trivedi: Oh interesting so what types of infection or inflammation create these polyclonal elevations IgG and IgA?

Dr. Nathaniel Long: It is actually going to be more chronic infections, and inflammation can cause a polyclonal rise in immunoglobulins – things like TB or Hepatitis – which should cause a roughly equal elevation in kappa and lambda free light chains.

Dr. Shreya Trivedi: So the run of the mill UTIs or PNAs wont confound our interpretation of serum test?

Dr. Nathaniel Long: Yeah, acute typical hospital infections shouldnt affect it. Go ahead and send testing in those cases.Patients with myeloma often present with infections and we don’t want to delay the diagnosis because we are worried about how to interpret this.

Dr. Shreya Trivedi: But remember, it all comes back to your level of suspicion for a monoclonal process. And you just have to remember to interpret in your current clinical context of acute vs. chronic inflammation.

Dr. Nathaniel Long: And then one thing I got to appreciate was just one of the reasons why the serum free light chain tests are the most sensitive.

Dr. Shreya Trivedi: Yeah why is that? What so great about serum free light chain tests.

Dr. Nathaniel Long: So there are some plasma cell disorders that are only making light chains. And we have to remember that a normal immunoglobulin is two heavy chains and two light chains and it’s so big that normally it can’t get through the kidney. But If the plasma cell is dysfunctional, sometimes it only produces light chains that can be easily filtered in the kidneys and do not build up in the blood.

Dr. Vincent Rajkumar: If a plasma cell was making only light chains and it was aberrant enough it’s not making heavy chains anymore, those light chains can get filtered in the kidney and so you will miss it. Therefore, the free light chain assay helps you pick up those people who have just light chain only problems.

Dr. Nathaniel Long: So that’s why we say that SPEP is not as sensitive. The light chains can easily be peed out so serum electrophoresis won’t be able to pick up. So the SPEP will not pick those patients with light chain only disease, which is actually about 15% of patients.

Dr. Shreya Trivedi: i forgot about the heavy chains vs. the light chain but sounds like we can always count of two buddies kappa and lambda light chains to be there and tell us if something is off and count on the free light test

Dr. Nathaniel Long: To ensure we have a clear understanding of free light chains, let’s practice this once with a clinical scenario. We have a patient in her 80s who was admitted to the hospital with heart failure and CKD, with a creatinine of 1.9.

Dr. Shreya Trivedi: And I am guessing somewhere in this story an SPEP/IFE/FLC was sent off at some point given the topic of the podcast.

Dr. Nathaniel Long: Yep thankfully there NO detected monoclonal protein on SPEP/immunofixation. However, the free kappa and free lambda are both elevated. Kappa is 106 and Lambda is 46. The ratio is also abnormal at 2.18.

Dr. Vincent Rajkumar: Excellent question. So your patient has a high kappa, high lambda, but the ratio is almost close to normal, like 2.18, which is close to 1.65. And so up to four I think is just normal. So in your patient’s case, I’ll just say “patient’s got an elevation of serum free kappa and lambda with a very borderline abnormal ratio that’s consistent with just renal failure”. It’s within the renal reference range. And so, reassure them that there is no clonal plasma cell disorder. I’m even more confident because you have other metrics, your IgG/A/M are normal and there’s no serum monoclonal protein. I’m more confident that’s what’s going on. It’s very easy to reassure them.

Dr. Nathaniel Long: Ooo there was a hidden gem in that. The ratio of kappa and lambda up to four can be considered normal even though the technical range for normal is 0.65 to 1.65.

Dr. Shreya Trivedi: Yep usually I like to do the recap but expert discussant so beautifully did it so will let them help cement things for us

Dr. Aaron Goodman: Now I hope you understand the testing, all three of those testing should be done. And to reiterate myself, the SPEP is the least sensitive, but will quantify it. Quantification is very important because that’s how we delineate between MGUS and smoldering myeloma. That is also how we stratify risk for those various disorders. Immunofixation is more sensitive than the SPEP, and it will qualify it. That’s very important because if I have an IgG versus an IgM, I’m thinking about different things. When I have an IgM, I’m thinking of Waldenstrom’s and all these other things versus an IgG. And then the light chain is the most sensitive of the tests. Many amyloidosis or even myeloma can be light chain only. That will be completely missed on the SPEP and immunofixation that only the light chain assay will pick up. So all three of those should be ordered.

Dr. Shreya Trivedi: And then certain states (renal dysfunction can skew kappa/lambda ratios and then chronic inflammation/infection will just cause polyclonal rise in immunoglobulins, not the monoclonal badness we are looking for

Dr. Nathaniel Long: And I also liked the way Dr. Rajkumar also summarized the 3 tests and also added numbers to the sensitivity.

Dr. Vincent Rajkumar: If you suspect multiple myeloma and you did all these three tests, the SPEP will be positive only 80% of the time because 20% of the time, either the patient has only light chains or the M spike is too small to be seen on the SPEP. The immunofixation will increase your sensitivity to 93%. You will still miss the people who have only light chain type of myeloma that’s coming out in the urine. So, if you do all three tests, you’ll pick up 98% of multiple myelomas. So that’s why when you’re looking for something, you’re looking for something, order the three tests, and based on the result you can say with confidence whether somebody is likely to have myeloma or not. Of course, like every test, there’ll be one or 2% who have multiple myeloma, but they’re not really making any immunoglobulins because the cell is malignant, so it’s not normal. And in those patients you’ll need biopsies of the bone and things like that.

Pearl 3: Do we need urine testing? When urine testing is necessary and when it is not.

Dr. Shreya Trivedi: What about urine testing?! We just went over 3 of the serum tests and I’ve always been taught that UPEP or other urine studies as part of the initial workup. Yeah I am curious then if our experts use urine studies during initial workup?

Dr. Aaron Goodman: I don’t actually usually rely on the urine testing that much anymore. We used to use them for response criteria in amyloid and myeloma. We’ve largely moved on from that and just looking at the kappa lambda ratio.

Dr. Shreya Trivedi: Wow it’s interesting the practice of sending off just SPEP/UPEP is written in notes all the time — it sounds like we should be doing serum tests, SPEP/IF/FLC. Sounds like we don’t need to have RN chase down the patient for a urine sample.

Dr. Nathaniel Long: So in the past without FLC, the UPEP was helpful for the added sensitivity (because few other proteins in the urine). Now because the FLC assay is so sensitive, the added benefits (as in added sensitivity) of UPEP are no longer needed.

Dr. Vincent Rajkumar: We are recommending to do the UPEP only if we know the patient has a clonal plasma cell disorder, and when you do a UPEP, it’s the same as the SPEP. The urine doesn’t have that many other proteins, and so the UPEP actually quite easily, it’ll pick up a gamma, an M spike, in the urine. Even much smaller ones than in the serum can be picked up in the urine because the background is so faint and you have a straight line and then an M spike. What the UPEP will tell you is, because you’re measuring a 24 hour sample, it’ll give you the milligrams per deciliter of protein in the urine, the concentration of the M spike, as well as because you’ve measured the 24 hour, it’ll tell you how many milligrams per day, which is dependent on the volume of urine.

Dr. Aaron Goodman: Now, if I have a patient with kidney disease and I’m worried about a gammopathy, the test is really a 24-hour urine protein or a spot protein to creatinine ratio. You want to prove they have proteinuria. None of these gammopathies cause kidney damage without proteinuria, or most of them don’t, I think probably all of ’em. So you can largely forget about that for the time being.

Dr. Nathaniel Long: Great. So let’s summarize this quick pearl, urine testing for initial workup is less important now, particularly because we have more sensitive tests like the free light chain assay. You really only need urine testing if you already have the diagnosis of monoclonal gammopathy OR if you are working up a monoclonal gammopathy in someone because they have kidney disease – in that circumstance you do want to quantify the amount of protein in your urine. But most of the time, this does not need to be sent!

Pearl 4: How should we differentiate monoclonal gammopathies? The continuum of MGUS, Smoldering Myeloma, and Multiple Myeloma.

Dr. Nathaniel Long: Next let’s say we had a patient in the clinic who had a monoclonal protein found on recent admission. Patient is now asymptomatic.

Dr. Shreya Trivedi: Yeah patient has googled M-spike and is worried they have MM. So let’s clarify how to take that abnormal finding and interpret the levels of immunoglobulins and help the patient understand the diagnosis?

Dr. Nathaniel Long: In other words, how do we differentiate our classic continuum of MGUS, smoldering myeloma, and multiple myeloma?

Dr. Shreya Trivedi: Yeo how do I know if it’s something to worry about or not.

Dr. Nathaniel Long: This is where refreshing the spectrum of plasma cell disorders is helpful – starting from MGUS – and with each reviewing what the next management step would be.

Dr. Aaron Goodman: So you need to now know the tools to figure out where they are on this continuum of MGUS to smoldering to myeloma. So MGUS, so MGUS is asymptomatic monoclonal gammopathy of undetermined significance. All of these from clonal plasma cells to overt malignancy, we kind of arbitrarily draw these lines in the sand. This is a continuum, okay? So you have to use clinical judgment too with this. But MGUS means the SPEP, which we learned quantifies it, the total protein is less than three grams per deciliter. And the bone marrow biopsy has less than 10% plasma cells. If you have less than 10% plasma cells and an M spike less than three grams per deciliter, and you are asymptomatic, you have MGUS.

Dr. Shreya Trivedi: All this btw you can look up but the numbers you’ll find when you look it up is 3 and 10%, <3 g/dl of M-spike and less than 10% plasma cells on a bone marrow bx but come to think of it say the patient has 1.0g/dl M-spike on the SPEP, do I need to consult heme for a biopsy?

Dr. Aaron Goodman: Because most of these patients, we don’t get a bone marrow biopsy. So in general, MGUS has a 1% risk per year of progressing to myeloma or another related plasma cell dyscrasia. However, some MGUS are more prone to that than others. And so beautiful studies, largely from the Mayo Clinic, looked at risk factors for worse MGUS versus not so bad MGUS, and the risk factors include the quantity of the M spike. So if it’s greater than 1.5 grams per deciliter, you get a point. It can’t be greater than 3 because, once you’re greater than 3, you’re no longer MGUS. So if it’s greater than 1.5, if it’s a non IgG (so if it’s IgM, A, D, E) that gets you a point, okay? And then if the kappa to lambda ratio is skewed, and there’s different cutoffs, but just remember if it’s skewed more than five to eight to one. If you have none of those, which is actually most of the MGUS, that is extremely low risk MGUS. Their risk of progressing is not zero, but close to zero. They actually don’t even need any follow-up with a hematologist, and they definitely don’t need a bone marrow biopsy. If they have any of the other points, we typically do recommend a bone marrow biopsy, although in some I do not, and that’s a judgment call, but definitely they should be referred to hematology.

Dr. Nathaniel Long: Okay, so in patients with an abnormal SPEP, we need to ask ourselves 3 Qs to see if they need to see heme and possibly get a bone marrow bx . 1) Is the M-spike on SPEP >1.5 g/dl? 2) Is the monoclonal protein on the immunofixation something other than IgG (is it igM or IgA) and 3) is the free light chain ratio( kappa to lambda) skewed that it is >5-8? Then we would be more suspicious of smoldering myeloma and need to check if there are more than 10% plasma cells in the BM.

Dr. Shreya Trivedi: If they don’t have these 3 red flags then you can give them the assurance, that I’m sure they will be grateful for, this has less than a 1% chance per year of progression and no invasive things need to be done

Dr. Nathaniel Long: Okay, but common things being common – let’s say we have a small (< 1.5g/dl) IgG kappa MGUS aka low risk MGUS – let’s hear Dr. Rajkumar’s take on these low risk patients and what monitoring looks like.

Dr. Vincent Rajkumar: 5% of the general population over the age of 50 has an MGUS. I don’t want to do a bone marrow biopsy on 5% of the general population, or a bone survey, or get referrals every time somebody sees a monoclonal protein. The lifetime risk of progression to myeloma related disorder is only like 2%. So it’s not even 1% per year. So it’s like 0.1% per year. So there’s no point in making them anxious and no point in putting them through stuff. So what we recommend is a small IgG Kappa MGUS. What do I do? What we say is just always recheck in six months to make sure you’re not catching something just as it’s taking off. And then, if that’s stable, then you can just check it only if symptoms occur in the future. You don’t need a baseline bone marrow, you don’t need a baseline bone survey.

Dr. Nathaniel Long: I also appreciated hearing just how much this label can affect patients, and how Dr. Rajkumar counsels patients with this diagnosis.

Dr. Vincent Rajkumar: The second thing is, even after you diagnose the MGUS, you can reduce the psychological effects to patients by really reassuring them correctly. I look at their age and I look at the size of the M-spike and I don’t just use the 1% per year risk of progression. I fine tune it to what I know based on the M-spike size, the type, and the free light chain ratio, and their age, and then give them a real judgment call on what is their real risk of progression. And you can even frame it the opposite way. Just tell them you have a 10% risk in 10 years, which means 90% chance you won’t get anything in 10 years, and then they’re a lot more reassured. My friend, Shaji Kumar, at Mayo and another college student who helped us with the website, we launched a website just on our own called myelomarisk.com, where you can just plug in the M-spike, the free light chain ratio, and the type of M spike, whether it’s G or A or M, and it’ll tell you what is the risk of progression over the next 20 years or 10 years. So you can tell the patient for their size of M-spike, what is the risk of progression likely to be, which will be some quite often lower than even the 1% per year. So you can reduce their worries to some degree.

Dr. Shreya Trivedi: Yeah it’s great there is a website now on myelomarisk.com but just to say it out loud we can assure patients with low risk MGUS that they have more than a 90% chance of not getting anything in the next 10 years.

Dr. Vincent Rajkumar: So we say if something is bothering you, something’s not right, definitely go for the workup regardless of the M spike size, 1 gram?, you’ll still do it because you think, no, I think this patient could have myeloma because the calcium’s high or something.

Dr. Nathaniel Long: Okay, I appreciate that caveat that despite the < 1.5 igG M-spike size, if something is off, such as the degree of calcium or proteinuria, you should still consult heme for their thoughts on BM biopsy.

Dr. Shreya Trivedi: And then what about cases such as non-IgG MGUS or light chain only MGUS? We have learned that non-IgG may be at increased risk.

Dr. Vincent Rajkumar: I have recently expanded this low-risk group to also include small IgM MGUS. This IgM hardly ever becomes myeloma, if at all it progresses, it’ll be like a Waldenstrom’s, which is an even more indolent disease. And then finally, the people who have light chain only MGUS, in the sense, the serum SPEP and immunofixation are negative with no IgG, A or M, but the light chain ratio is abnormal. So if it’s [the free light chain ratio] less than eight, I say omit the bone marrow, omit the bone survey, just recheck in six months and if it’s stable, leave them alone.

Dr. Shreya Trivedi: Nice sweet! More types of patients can be reassured! Ok so if it’s free light chain ratio <8 (though some places say 5?) then you’d still just follow the patients q6 months?

Dr. Nathaniel Long: Yeah, now I feel pretty confident managing these low risk MGUS patients myself.

Dr. Shreya Trivedi: Okay, now let’s kick it up a notch. Let’s move to Smoldering Myeloma. What level of M-spike or plasma cells on the bone marrow bx points us to to smoldering

Dr. Aaron Goodman: Okay, and let’s say now you do a bone marrow biopsy and there’s more than 10% plasma cells, but less than 60%, you now carry a diagnosis of Smoldering Myeloma. The other way to get a diagnosis of Smoldering is an M-spike greater than 3 g/dL, so either or, if your M-spike’s more than three, or your clonal plasma cells’ greater than 10%, you have Smoldering Myeloma. In general, Smoldering Myeloma carries a 10% risk per year for the first five years of progressing to myeloma. For the subsequent five years, once you make it five years and don’t progress, you’re not so bad. It’s more like 3 to 5% per year. And if you make it a decade without progressing, you’re just an MGUS, and it’s more like 1% per year. But if you do the math, about 50% of patients or more will progress within five years.

Dr. Shreya Trivedi: And just to say it outloud, when he means progress, he means progress to multiple myeloma. So we can think of MGUS and Smoldering Myeloma as pre-cancers, though the caveat is those pre-cancer have different risks of progression to overt cancer.

Dr. Nathaniel Long: And to reiterate, if a patient has an M-spike greater than 3 g/dL or your bone marrow plasma cell burden is greater than 10%, you have Smoldering Myeloma. Thankfully if your patient makes it about 10 years without progressing to multiple myeloma, their chance of progressing becomes much lower. But we can leave this counseling and decision making to the Hematologists with their patients.

Dr. Shreya Trivedi: And the other key here is that for both MGUS and Smoldering Myeloma – there is NO evidence of end-organ dysfunction, aka CRAB, or hypercalcemia, renal insufficiency, anemia, or bone lesions.

Dr. Nathaniel Long: Okay now let’s talk about when there IS end-organ dysfunction, when you are worried about Multiple Myeloma.

Dr. Aaron Goodman: Now, what’s the definition of Myeloma? So Myeloma’s cancer, all these other things we were talking about are really just “polyps”. They’re not cancer, although they do have different risks of progressing to overt cancer. So Myeloma, up until 2014, all you needed was an M-spike really of any quantity. But usually when they have myeloma, it’s high, or they have a high kappa to lambda and organ dysfunction related to the plasma cell clone in the organ dysfunction. The mnemonic is CRAB, hypercalcemia, renal insufficiency, anemia, [and] bone lytic lesions, but that CRAB needs to be due to the plasma cell. Classic example, I have seen patients with iron deficiency anemia and an M spike of two treated for myeloma. That is not myeloma, that is MGUS with iron deficiency anemia, you need to prove the anemia is from the plasma cell problem. You need to prove that the renal insufficiency is from the plasma cell and that relies on judgment and doing enough of this. That’s where it gets kind of hard sometimes.

Dr. Shreya Trivedi: Yes I appreciate that this can get and appreciate the reminder that two different things can be true and not necessarily linked. We need to make sure end organ damage is from the myeloma itself. Nate – he talked about how the myeloma definition changed in 2014 whatsup with that?

Dr. Nathaniel Long: I thought it was really important to hear the history behind this change from Dr. Rajkumar.

Dr. Vincent Rajkumar: After 2014, the only major changes are that if the bone marrow involvement is 60% or higher, it’s automatically Myeloma. So Smoldering instead of more than 10% became 10 to 60%, 60% and higher becomes Myeloma. We also added some Myeloma defining events because we wanted patients to be started on therapy before they had end organ damage, not after. And unlike other cancers, Myeloma was unique because the diagnosis of the malignancy was not dependent on the pathologist, whereas with say, breast cancer or colon cancer, the pathologist says adenocarcinoma of the colon, then it doesn’t matter what size the tumor was, it’s a cancer, and that’s how you’re going to treat it. Whereas in Myeloma, they just tell you clonal plasma cell disorder consistent with MGUS, myeloma, blah, blah, blah. So we were in a catch 22. We didn’t want patients to get CRAB features and only then be called Myeloma. At the same time, we didn’t want to treat people too early and then be treating people who have MGUS. So a compromise was made that patients who are kind of inevitably going to get CRAB features in the next year or two should really be called as Myeloma, and we shouldn’t be waiting on ’em. So that’s why we have started the criteria we revised, 60% or higher is enough to call it as Myeloma, regardless of whether the patient has CRAB features or not on the bone marrow. Now, same thing with the light chain ratio. The normal ratio as we talked about is like within 0.26 to 1.65, but if the ratio is more than a hundred. That’s very high, markedly high, and in those levels, the kidney can be damaged. And so, we call that as also myeloma with some caveats that the urine should be positive. You don’t want this to be a false positive. So urine should show significant monoclonal protein in the UPEP and if the ratio is higher than a hundred, that’s also Myeloma. And then if you have focal lesions on the MRI, even before lytic lesions show up on the bone survey, that’s also Myeloma.

Dr. Nathaniel Long: Okay, it’s helpful to understand the reasoning behind the changes.. So, since 2014, we now use the “SLiMCRAB” criteria to define Multiple Myeloma.

Dr. Shreya Trivedi: SLIMcrab?!

Dr. Nathaniel Long: In addition to your CRAB features (aka end-organ damage due to the plasma cell), you can be “up-diagnosed” if you will from Smoldering to Myeloma if your plasma cells are greater than 60% (S = sixty), if your light chain ratio is greater than 100 (Li for light chain), or if you have two or more focal lesions on MRI (M = MRI) which it doesn’t have to just lytic bone lesions. Which we can now call SLiMCRAB.

Dr. Shreya Trivedi: Appreciate that these are the types of criteria that are very look-up-able. And then to summarize this high-yield section, I was so impressed by how Dr. Goodman summarized it so succinctly

Dr. Aaron Goodman: So to summarize the continuum of MGUS to myeloma, MGUS is asymptomatic, an M-spike less than three grams per deciliter, and bone marrow plasma cell less than 10%. And then you can further risk stratify them based off those things I’ve talked about. Smoldering Myeloma is in between with a bone marrow burden greater than 10% and/or M-spike greater than three grams per deciliter. And then Myeloma is symptomatic with CRAB or a very high plasma cell burden of 60% or light chain ratio greater than 100 to 1.

Pearl 5: What is MCGS? Demystifying the clinical entity of monoclonal gammopathy of clinical significance.

Dr. Shreya Trivedi: Okay, we talked about MGUS to smoldering to myeloma but what about this thing called Monoclonal gammopathy of clinical significance aka MGCS? We know MGUS is monoclonal gammopathy of undetermined significance and so is this like symptomatic MGUS and so it becomes significant?

Dr. Aaron Goodman: Monoclonal gammopathies of clinical significance are not cancer, okay, they are MGUS. But unfortunately, for whatever reason, the antibody that’s produced by the clone of plasma cells has properties, paraneoplastic properties, that can cause all sorts of havoc on the patient from kidney disease, heart disease, to hemolytic anemias.

Dr. Nathaniel Long: Okay so with MGUS, the plasma cell clone is the worry. BUT in MGCS, the secreted immunoglobulin itself is causing the problems.

Dr. Aaron Goodman: So the most classic example of a monoclonal gammopathy of clinical significance is AL amyloidosis. So amyloidosis is not a bonafide cancer, although it’s very harmful to patients and actually more lethal than many cases of multiple myeloma. But they don’t have cancer, they don’t have problems from the neoplastic cells invading tissue. They just have a problem from the monoclonal protein depositing into tissue and causing organ dysfunction.

Dr. Shreya Trivedi: Yeah and just to reinforce that Dr. Vincent Rajkumar had a good way of separating MGUS vs. MGCS in his mind.

Dr. Vincent Rajkumar: So we are dealing in plasma cell disorders not only with the pre-malignancy, MGUS, or the malignancy, which will be like Myeloma, Waldenstrom’s macroglobulinemia, but a whole slew of disorders which are caused by the simple fact that either of these benign or malignant processes is secreting an immunoglobulin. And this immunoglobulin can cause problems because it targets various things and if it’s by coincidence targeting the peripheral nerve, you’ll get a neuropathy. If it targets the glomeruli, you’ll get a glomerulonephritis, If it just misfolds, it’ll cause amyloid. If it precipitates in the cold, it’ll cause cryoglobulinemia, if it agglutinates in the cold, it’ll cause cold agglutinin disease. So there’s a whole list of diseases it can cost simply by virtue of the fact that this is a functioning antibody. If it doesn’t have any antigen in the body to react to, it’s just an MGUS. But some people have the bad luck that this innocent antibody, which would’ve been innocent and part of a clone like a polyp actually likes your kidney or your lung or your something, and then you have a second problem, which is just bad luck. So those things are collectively now people are giving them the name of monoclonal gammopathy of clinical significance.

Dr. Shreya Trivedi: Ugh bad luck indeed. And I guess it’s bad luck bc we can’t predict which MGUS are going to have immunoglobulins causing problems and become clinically significant. Even if you don’t have too much of an M-spike, you can have awful symptoms?

Dr. Nathaniel Long: Yep so MGCS should be on differential diagnosis for any patient presenting with what appears to be a monoclonal gammopathy of undetermined significance but is also experiencing other unexplained symptoms.

Dr. Shreya Trivedi: Exactly, there are tons of ways these immunoglobulins can wreak havoc so let’s try to make it a little more manageable with learning about the 3 buckets of clinical significance.

Dr. Aaron Goodman: So when I think of my monoclonal gammopathy of clinical significance, I divide it into three categories. Skin, neurologic and renal. So renal is the most common and they’re all nephrotic problems. And you actually don’t need to know all these because you’re going to get a biopsy and the pathologist will tell you which one it is on the biopsy. But the most common is amyloid. And there’s also something called light chain deposition disease. It’s not amyloid, just the light chain’s directly deposited in the glomerulus. And then there’s a gazillion other ones with weird names that I’m not going to go into, but just know that the kidney biopsy will sort that out.

Dr. Shreya Trivedi: So if we see nephrotic range proteinuria, it may be monoclonal gammopathy can be clinically significant for the kidneys if often amyloid or free light chains are depositing

Dr. Aaron Goodman: Then there’s the dermatologic ones that are some of my favorites. One is Schnitzler Syndrome. Okay? So Schnitzler Syndrome is, you get this urticarial rash. Now there’s lots of causes of urticaria, but it’s really pretty bad. And they also have arthralgias and fevers and it’s like a rheumatologic symptom. And typically what happens is they think it’s rheumatologic and they end up getting a skin biopsy and you’ll see this neutrophilic urticarial rash on dermpath, and that’s unusual for the rest of them. And hopefully a dermatologist or someone heard of this. And then you check an SPEP and immunofixation, and it’s always an IgM. Okay? So if you have an IgM and you have a neutrophilic urticaria rash and some of these other symptoms, that’s Schnitzler Syndrome.

Dr. Nathaniel Long: Yeah so the second bucket are the Derm manifestations, and there’s a ton. And ultimately the biopsy might show actual deposition of antibodies, or the antibody could be causing problems in more paraneoplastic way.

Dr. Aaron Goodman: And finally, the neurologic ones, so the most common is IgM neuropathy, but it now has a formal name, it’s called DADSM (distal acquired demyelinating syndrome with M protein) DADSM, but it’s IgM neuropathy. And these patients have an axonal demyelinating neuropathy that usually starts in the feet and ascends upwards. It could be in the hands, it can be quite debilitating. And they will have an IgM. Okay. The other neurologic syndromes, there’s POEMS syndrome, which is polyneuropathy, endocrinopathy, M protein, and skin changes. I would say for the internist that there’s some pretty weird syndromes out there when you have these patients with weird things and you can’t explain it, know that MGCS exists and read the review that I just told you about. There’s three to four pages. It has all these charts to funnel you in and you can maybe think if these are, this could somehow match.

Dr. Shreya Trivedi: Dr. Goodman recommended an article from an ASH education post that we will link in the show notes that nicely summarizes these. Wow, so many ways for these monoclonal gammopathy of clinical significance to present.

Dr. Nathaniel Long: It is helpful to broadly bucket these into renal, skin, and neurologic presentations. As an internist, I think that the take-home point here is that you should understand these exist, and if things are not adding up, you can consider testing for a monoclonal gammopathy, consulting your colleagues (Hematology, Dermatology, Neurology, Nephrology) for assistance, or considering a biopsy of the affected tissue.

Dr. Shreya Trivedi: Nate what do you want ppl to take away from this pearl?

Dr. Nathaniel Long: Yeah, so I think remember that there are a constellation of diseases bucketed into MGCS that are due to the monoclonal plasma cell secreting immunoglobulins that are wreaking havoc on our body. These often affect our kidneys, skin, or nerves. Don’t feel like you need to memorize these entities, but remember that they exist and should be considered in your differential.

Bonus Pearl: The hidden burden of monoclonal gammopathies. A reminder to be judicious.

Dr. Shreya Trivedi: Wow. So many possible ways that monoclonal gammopathies can present. I do worry, however, that I will start sending my SPEP, immunofixation, and light chains too frequently and end up diagnosing a lot of MGUS.

Dr. Nathaniel Long: I think that’s a very valid concern. And brings us full circle back to the beginning of our Podcast, when Dr. Rajkumar reminded us that about 1 in 5 people in the general population above the age of 50 have a monoclonal gammopathy. While we can be excited about diagnosing these entities, we need to be equally judicious about this testing as well. And understand the burden that one of these diagnoses comes with.

Dr. Aaron Goodman: The goal is not to find MGUS. We do not want to identify MGUS. We want less MGUS. MGUS means they’re asymptomatic and they have this protein. So asymptomatic individuals should never have this testing done, ever. This is the truth of the matter. If you look at the data, it is very hard to make healthy people better, but it is very easy to medicalize healthy people. And once you get them an SPEP, depending on who their hands lie into, they get a PET scan, a bone marrow biopsy, and a huge amount of testing and anxiety done, then they’re stuck seeing me the rest of their life. So use with caution. So that’s why I argue if they’re healthy, don’t order these tests.

Dr. Nathaniel Long: And so let’s end with Dr. Goodman who very openly shared a personal story that so aptly highlights the hidden psychological effects of being diagnosed with MGUS. And really, on the broader idea of being humble about our ability to fix problems in medicine.

Dr. Aaron Goodman: I mean, I could tell a personal story. My dad doesn’t care. He’s my dad, a 68-year-old guy. He had mitral regurg that was repaired. He is doing great, and he likes to talk about me. He told his PCP I’m a Hematologist, and my dad had an elevated total protein. He ordered an SPEP. My dad had an M-spike, and at the time I didn’t know better because I was still in training. I set him up with someone of prominence and a lot of testing was done and he’s got Smoldering myeloma. But in my opinion, now that I know this, he’s more, he’s an MGUS’er. But that caused a lot of anxiety for my dad and a lot of testing. And the funniest part about it was on his repeat CMP, his total protein was normal. So what sparked the test completely resolved. And now he’s medicalized and he’s dealing with this.

Dr. Shreya Trivedi: And that’s a wrap for our episode. If you found this episode helpful, please please share with your team and colleagues and give it a rating on whatever podcast app you use! And if you want to learn more, check out the Core IM website and Behind the scenes YouTube channel for an awesome interview with Dr. Vincent Rajkumar!

Dr. Nathaniel Long: Thanks to our reviewers for this podcast. Thank you to Jerome Reyes for the audio editing. This episode was made as a part of the Digital Education Track at BIDMC.

Dr. Shreya Trivedi: Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

References

• Canadian Cancer Society. The plasma cells. What is multiple myeloma?
• iStopMM. Predicting the need for bone marrow sampling in MGUS. Risk Model.
• Eatoure. Myeloma Risk Calculator.
• Angela Dispenzieri; Monoclonal gammopathies of clinical significance. Hematology Am Soc Hematol Educ Program 2020; 2020 (1): 380–388.

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