Dr. Jorge Castillo (Harvard, Dana Farber) walks us through immunology basics, teaches us the limitations of the SPEP, plus some additional tests that complement it (think Immunofixation), shares his clinical gestalt about when to suspect MGUS, Myeloma, Waldenstrom’s, and Amyloidosis–and finally, how to talk to patients about them. If you, like Stuart, have ever wondered what on earth to do with that pesky free light chain ratio or the SPEP that so often gets inboxed to you without explanation, then fear not, Dr Castillo has your back!
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Let’s start from the very beginning….well not the very beginning: The Plasma Cell. Plasma cells are mature B-Cells, a type of Immune Cells that produces antibodies (or Immunoglobulins) to fight infection (see Figure 1 of this article for a nice graphic on B-Cell development from Blood). Normally, in fighting infections, our Plasma Cells are activated and produce many different antibodies. This results in a polyclonal gammopathy, or an increased level of many different Immunoglobulins, (and a relatively wide Gamma peak on the SPEP). Other things, like Autoimmune diseases and cirrhosis, can also cause increases in many different Immunoglobulins (see AAFP’s Table 2 for a complete list of what causes the increase in Gamma levels).
There are specific hematologic disorders, called monoclonal gammopathies or paraproteinemias (and which include the plasma cell dyscrasias), in which a single malignant immune cell replicates abnormally and produces too much of one type of Immunoglobulin. These abnormal proteins can accumulate, and be detected, in the blood and in the urine.
Antibodies normally have a combination of two types of polypeptide chains, heavy and light chains, in their structure. See Janeway’s Immunobiology Text, and Figure 3.2, for more details on Immunoglobulin structure.
In most monoclonal gammopathies–whether Waldenstrom’s Macroglobulinemia or Multiple Myeloma or MGUS (Monoclonal Gammopathy of Undetermined Significance)–the proteins overproduced consist of both a single heavy chain (the part that dictates whether an antibody is IgA, IgG, or IgM) paired with a single free light chain (Kappa or Lambda). The malignant cells overproduce a combination of IgG and Kappa, for example. Rarely, the malignant plasma cells produce only free light chains, without an accompanying heavy chain–as in Kappa- or Lambda-only Myeloma. In rare scenarios, malignant cells overproduce only heavy chains.
An SPEP is a way of measuring and mapping proteins. The electrophoresis curve is a curve of five smaller peaks, which represents the breakdown of proteins in the serum. The big, first peak going (left to right) is Albumin. Next you have the Alpha 1 peak, the Alpha 2 peak, the Beta peak, and then the Gamma peak. We know the typical distribution of these proteins in normal patients. Most of the proteins that account for the Alpha and Beta parts of the curve are acute-phase reactants like CRP, ferritin, and transferrin (see O’Connell Table 2 – AAFP for more). We use the shape of changes to the curve to determine whether a higher protein level is polyclonal (softer rounder peak because lots of proteins are being overproduced) or monoclonal (sharp spike, like a “church spire” because only one protein is being overproduced).
Dr. Castillo’s “Handy” SPEP Guide: Make the Shaka Sign with your right hand, facing you (yes, there is a name for the hand sign to “hang loose,” a fact which I just learned) to illustrate what a normal SPEP should look like, with the Pinky peak as the Albumin, the three middle fingers bent down to represent Alpha 1, Alpha 2, and Beta, and then the thumb to represent the normal, rounded gamma peak (see figure above).
An M-spike is an abnormal, sharp peak on the SPEP that represents abnormal, monoclonal protein (or M-Protein) production, otherwise known as a monoclonal gammopathy. We can get semi-quantitative data about the amount of abnormal protein from this, using the Area-Under-The-Curve (see EClinPath’s detailed summary for more).
In most monoclonal gammopathies like Myeloma, we typically see a peak in the Gamma region. This is because the most common protein affected in Myeloma is IgG, which travels into the Gamma region. That said, there are rarer monoclonal gammopathies like Waldenstrom Macroglobulinemia, or variants of Myeloma, which have an overproduction of IgM or IgA. These proteins can go to the Beta region of the curve (and very rarely, in the Alpha region). Per Dr. Castillo’s expert advice, This is where it can get tricky, and this is why it’s important for an expert pathologist to look at the curves and their shape to determine if there is indeed an M-spike not in the Gamma region but hidden elsewhere.
What an SPEP misses: It also doesn’t tell you the specifics of what kind of protein is being produced. The better test for this is Immunofixation.
After the SPEP reveals an M-spike, Immunofixation tells you which subtype of globulin the M-spike contains. It can differentiate whether you are seeing a monoclonal gammopathy of the heavy chain part of the Immunoglobulin (which determines IgA vs IgG vs IgM) alone, the light chain (Kappa or Lambda) only, or a heavy chain PLUS a light chain (IgG and Kappa, for example).
Kashlak Pearl: Production of both a heavy and light chain by the clonal cell is most common in these diseases.
This is a quantitative assay to tell you how much extra Immunoglobulin is being produced. The downside: This test doesn’t differentiate polyclonal (normal excess protein, e.g. in infection) from monoclonal Immunoglobulin protein production–it just tells you the extra amount, beyond the normal level. So it’s best used together with the SPEP protein level to assess the monoclonal protein contribution.
The two main protein types in the total protein measurement are Albumin and Globulin. The albumin is the nutrition protein, and the globulin is the antibody protein. There are normal ranges for each in the human body, and there is a normal ratio (usually with the globulin slightly lower than albumin, and an A/G Ratio of slightly over 1). In a monoclonal paraproteinemia (like Myeloma or Waldenstrom), the globulin level goes up.
Kashlak Pearl: As paraproteinemia disease progresses, the Albumin (which is a negative acute-phase-reactant) will go down and the A/G ratio will reverse and become <1 (Dr. Castillo’s expert note)
The Bence Jones protein is another name for excess light chain in the urine from a monoclonal gammopathy. This correlates to an M-Spike in the Urine on the Urine Protein Electrophoresis (UPEP) with Immunofixation, and typically occurs in Multiple Myeloma. On Immunofixation, the protein will be light chain only, since the light chain proteins are smaller and can be filtered by the kidney earlier in disease. That said, later in disease as kidney injury worsens, one can see both heavy and light chains in the urine. N.b. Bence Jones protein will not be identified as “protein” on a urine dipstick, since the dipstick looks only for albumin. See StatPearls for more detail on Bence Jones.
We love the way Dr. Castillo explained it, so consider using his explanation:
The body has many ways to fight infection. One of these ways is by creating antibodies. If you’re infected, you increase all of the antibodies to fight this infection. The SPEP tells us if there are many antibody increases or just one–a so-called “spike.” In an SPEP that is abnormal, there’s one specific antibody that is elevated–but not all of them. Having just one antibody elevated suggests that there’s something happening besides normal healthy reaction to infection. Different cells produce each antibody, and if there’s just one antibody, it suggests that there is a population of cells that is getting out of control to produce these antibodies. So the next natural question, of course, is whether the increase in these antibodies and these cells is a benign increase or a malignant increase.
Even with the benign condition, MGUS, one needs to be monitored. In terms of risk of progression, Dr. Castillo says: “For Myeloma, you’d have to be alive for 100 years to have a 100% chance of progression from MGUS into Myeloma–and around 70 years for progression into Waldenstrom’s (depending on the heavy chain type).”
If there is an M-Spike, this is not normal. But it could be a benign process, like Monoclonal Gammopathy of Undetermined Significance (MGUS) or a malignant process, like Myeloma or Waldenstrom Macroglobulinemia. The rate of MGUS, if one were to screen asymptomatic individuals in the United States, is between 3-5%, depending on the study (Wadhera 2010; Kyle 2006). The incidence of MGUS increases with age, and each year, there is a 1 % chance of progression from IgG/IgA MGUS into Myeloma (Kyle 2002), and a 1.5% per year chance of progressing from IgM-producing MGUS into Waldenstrom’s or another lymphoma (Kyle 2003).
We differentiate benign disease from malignant disease with both the abnormal protein level and additional testing to look for abnormalities on Complete Blood Count, Basic Metabolic Panel, Albumin level, or bone marrow biopsy (% percent of Bone Marrow occupied by plasma cells, which can be used to differentiate MGUS from Myeloma). The Immunoglobulin protein level is also useful, with > 3 g/dL suggestive of Myeloma (Mateos 2016).
There are three big diseases to think about: Myeloma (most common), and then two rarer conditions–Waldenstrom Macroglobulinemia (actually a lymphoma), and Amyloidosis, another plasma cell dyscrasia.
All of these diseases have a pre-malignant, benign condition called MGUS. Each year, there is a 1-1.5% chance of progression from MGUS into the malignant disease condition. Which heavy chain is overexpressed in the MGUS suggests which disease the MGUS may progress into: IgA and IgG more likely to progress into Myeloma, IgM most likely into Waldenstrom’s, and free light chain gammopathy into Amyloidosis or Myeloma (see Kyle et al.’s 2018 NEJM paper for more data on long-term follow-up of MGUS).
Watch out for the classic clinical CRAB signs: HyperCalcemia, Renal Disease (usually because of a light-chain cast nephropathy), Worsening Anemia (usually normochromic and normocytic), and Bony Lesions (lytic, can be seen on skeletal survey or MRI). Some level of kidney dysfunction may occur in up to 50% of cases of Myeloma by presentation (Yadav 2016).
You ought to treat when you have diagnosed myeloma (or if you satisfy myeloma-defining events even without CRAB criteria), because the mortality in a patient with Myeloma is from the Myeloma, with 80% of Myeloma patients dying ultimately from the disease itself (Mai 2018). Moreover, median overall survival has improved dramatically in the last two decades from 3 years at 2000 to > 6 years in 2010 (Kumar 2014), with the advent of many new FDA-approved non-chemotherapy treatments such as immunomodulators, proteasome inhibitors, and monoclonal antibodies alongside steroids (see MMRF’s nice summary of treatment options for more details).
In WM, the main malignant cell is not the plasma cell itself, but the lymphoplasmacytic lymphoma does lead to oversecretion of IgM by plasma cells. IgM is a larger pentamer that can get stuck on various surfaces, whether within blood vessels or on nerves.
There aren’t as well-defined clinical criteria for WM, but watch out for anemia, new neuropathy (bilateral, sensory, slowly progresses distal to proximal), and the symptoms of hyperviscosity, specifically blurred vision, headaches, and nose bleeds. They may have an anti-Mag Antibody (buzzword!) that leads to demyelination of nerves. N.b. The symptoms of hyperviscosity usually occur when the IgM level is above 4000 (Gustine 2016).
The mortality from Waldenstrom’s is around 20% (Castillo 2015). This means that 4 out of 5 patients will die from something besides Waldenstrom’s. Median overall survival, meanwhile, is thought to be 10-12 years or greater (Castillo 2015), perhaps closer to 20 years based on the center (Treon 2018).
Treatment does not always begin immediately on diagnosis of Waldenstrom’s; there may be a period of observation prior to treatment-initiation. Treatment is slightly different than in Myeloma, in that it is more chemotherapy-sensitive than Myeloma (and also in that oral BTK-inhibitors are used), though many of the Myeloma drugs have also been adopted in Waldenstrom’s treatment.
This is the toughest of the three to diagnose, and the mortality is the worst, especially with cardiac amyloidosis. The classic patient in whom to suspect amyloidosis is in someone with new nephrotic syndrome, neuropathy, and cardiomyopathy.
You diagnose it with biopsy and tissue analysis (classically, with fat pad, transrectal, or myocardial biopsy), but you cannot rule it out just because you cannot find it. The other challenge of amyloidosis is that there are multiple types. There is a light chain amyloidosis (AL), but there are many other types (AA, TTR), and you need to differentiate with extensive tissue testing because the treatment options are different. The prognosis for AL Amyloidosis is poor, with median survival from months to years (Kyle 1999; Muchtar 2019), though it does depend on the stage at diagnosis.
The kidney damage in Amyloidosis is glomerular disruption, which causes albuminuria. This is different than in Myeloma, where light chain cast nephropathy affecting Creatinine predominates. Furthermore, the neuropathy is also different from the sibling disease, Waldenstrom’s. It is an axonal disease, with muscle wasting, both sensory and motor involvement, more rapid progression, and not quite as length-dependent (hands and feet at the same time). Lastly, the cardiomyopathy is classically restrictive, with cardiomegaly and macroglossia (and Factor X deficiency/coagulopathy) as other possible features.
Basically, refer for any patient found to have MGUS or an M-Spike, or when you suspect any of the above. Not to say that the MGUS patient in whom all labs are normal and there are no symptoms cannot be followed by primary care. But even these patients are often followed by a hematologist because even though MGUS itself is benign, these patients can progress. Moreover, there are rarer types of paraproteinemias (e.g. Smoldering Myeloma) that cannot be ruled out just because of a low protein level on SPEP.
SPEP with Immunofixation, CBC and CMP, Total Immunoglobulin Level, and Serum Free Light Chain Levels. Consider a Skeletal Survey (Baseline X-Rays of Skull, Spine, Ribs, Hips, and Long Bones) as well if suspicious for myeloma.
No need to get a UPEP (urine protein electrophoresis) on every patient in whom you suspect myeloma, because the above tests are sensitive enough in diagnosis.
If a patient has any kidney abnormalities AND you suspect Myeloma or Amyloidosis, get a 24-hour urine collection with a UPEP, protein quantification (to look for albuminuria), and a spot urine protein:creatinine ratio. The protein electrophoresis can indicate the presence or absence of Bence Jones Protein and Myeloma, or Amyloidosis, as a driver of kidney disease. This can be helpful if patients (as they often do) have other potential causes of kidney disease, such as Diabetes.
Kashlak Pearl: Yeah, this is confusing. But unfortunately there is such a thing as a “Free Light Chain Only” Myeloma. The SPEP may actually be normal in this disease, because you need to have the Heavy Chain Immunoglobulin component to see an M-Spike in protein on the SPEP.
So the free light chain levels and ratio (the ratio of Kappa to Lambda) can tell you if there’s abnormal production of one over the other, which can happen in Light Chain Myeloma or regular Myeloma. Both the absolute level of kappa and lambda protein, and the ratio of one to the other, are important. In kidney dysfunction, absolute kappa and lambda protein levels will be elevated, so important to use in conjunction with the ratio of one to the other.
Moreover, the levels of free light chains can help you assess response to treatment better than the SPEP, since the M-Spike, representing the heavy chain, can disappear somewhat earlier than the free light chain levels return to normal. It’s therefore important to have a baseline level of free light chains before treatment.
Because it’s an emergency, and because you probably haven’t seen it. Up to 10% of patients with Waldenstrom’s can present initially with hyperviscosity. Anyone with an IgM level > 3000 mg/dL can have hyperviscosity, though it is most typically seen at IgM levels greater than 6000 (Gustine 2016).
The classic presentation is hard-to-control, recurrent nose bleeds. Also watch out for headaches that wake up the patient in the morning and get worse over time. Lastly, blurred vision that doesn’t correct with glasses, with retinal vessel engorgement and tortuosity, sausaging, and retinal hemorrhage on fundoscopic exam.
What to do when you’re concerned about hyperviscosity?
Plasmapheresis. Keep in mind that because the blood is so thick, more fluid comes into the intravascular space, making the patients appear more anemic than they actually are.
Kashlak Pearl: Do not transfuse before plasmapheresis. The Hemoglobin may go up with plasmapheresis, and transfusing before pheresis may worsen the viscosity and the symptoms.
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Listeners will learn how to interpret serum protein electrophoresis, when to suspect a paraproteinemia clinically, and what to order when suspicious.
After listening to this episode listeners will…
Dr. Castillo reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
Taranto NT, Castillo J, Brigham SK, Watto MF. “#247 SPEP Up Your Step: MGUS, Paraproteinemia, and Immunology Galore ”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. Original Air Date: December 21, 2020.
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Great episode. I've hear that if a patient has iron deficiency anemia, the SPEP won't be accurate and can be misleading. Is this true and if so can you elaborate on the reasoning? Also, in a patient (lets say in their 70s) with persistent normocytic/normochromic anemia, and symptoms or persistent fatigue, loss of appetite, and fatigue, how often would you consider repeating an SPEP?