Affecting up to 5% of the U.S. population (and increasingly common with age), monoclonal gammopathy of undetermined significance (MGUS) raises the risk of multiple myeloma, but – as its full name suggests – it can be hard to say by how much. Through this talk from hematologist-oncologist Sirisha Tummala, MD, providers will better understand which patients they should screen for MGUS, the potential damage to multiple body systems caused by plasma cell disorders, and the determinants of MGUS diagnosis and classification. What's more, Tummala offers a “go-to workup” for patients with certain symptoms, lab results or family histories, as well as guidance on helping patients with MGUS understand their myeloma risk and how it changes over time.
Um, hi, everyone. Thank you for tuning in. Um, so, like, uh, Christie said, my name's um Doctor Thelmala, but I go by Siri. I am a new hire at one of our affiliate sites, so I'm at the UCSF Cancer Center in San Mateo. I'm a hematologist and an oncologist, and um today I'll be talking about MGUS, um, trying to be geared towards the primary care audience, um, specifically about the diagnosis and interpretation of the lab tests you would get. So with that, I'll go ahead, um, so our outline is we'll be talking about what exactly is MGUS, what are the diagnostic criteria, what does MGUS mean, uh, when you should consider testing for plasma cell disorders in general. What's involved in the laboratory diagnosis? Uh, how do you interpret those tests? What's the risk stratification of patients with MGUS? I do have a couple of cases if time allows, um, and then we'll leave time for questions as well. So what is MGUS? It stands for monoclonal gammopathy of undetermined significance, MGUS MGUS. It's a disorder of abnormal plasma cells. And what has happened is these plasma cells have undergone mutation and are secreting um either or or together heavy and or light chains in excess. It can, based on the studies, uh, performed a curve between 3 to 5% of the US population. We find that the rate is higher in older individuals, so age 15 and older. There was a study in Minnesota which found the incidence in men was about 120 per 100,000 at the age of 50, and that increased significantly to about 530 per 100,000 by the age of 90. They found that the corresponding rates in women were about 60 at age 50 and then 370 per 100,000 at age 90. We like to tell patients, um, and this can be dependent on the risk stratification, but generally, MGUS carries about a 1% per year likelihood of progression to myeloma. So the way I explain it to my patients and counsel them is at 20 years after your diagnosis, about 1 in 5 patients end up developing multiple myeloma. The majority of patients do not, uh, ultimately develop cancer, so I think it's important when you've made that diagnosis that you counsel them accordingly so it doesn't lead to, um, obviously a lot of stress um when they hear the word pre-cancer or um precursor lesion to cancer. And just to touch on some cell biology, so a plasma cell is a type of lymphocyte. The function of a plasma cell is to produce immunoglobulins. It plays a role in our humeral immunity. So the plasma cells comprised of heavy chains and light chains. So, the heavy chains are the blue part of this diagram, the light chains are the red part. All immunoglobulins have a variable region which makes them all different and a uh more constant region. But the heavy chains are what identify immunoglobulins is what we know as IgG, IgA, IgM, IgD, IGE, and then the light chains that red parts, those are smaller pieces of the immunoglobulin, and those are comprised of either kappa light chains or lambda light chains. So a normal individual will have many different types of immunoglobulins, and those are identified as IgG lambda, IgG kappa, and so on. What we want is many different types of many different antibodies. That's normal. Now, I wanted to touch briefly on how many different plasma cell disorders there are. Um, generally we think of MGUS as a precursor lesion to multiple myeloma, but in between those two, there's smoldering myeloma, there's also solitary plasma cytoma, which is where someone has one singular tumor that's based of plasma cells. There is AL amyloidosis, where you have those um Monoclonal fragments um create amyloid fibrils, which then deposit into organs and can cause organ dysfunction. You can have monoclonal gammopathies of clinical significance, so there's MGRS, which is renal significance or MGNS neurological significance. These may require treatment of the plasma cell clone because there's some clinical um Symptoms ongoing. And then others we have Waldenstroms, which is uh associated with an IGM monoclonal gammopathy. This is more of a lymphoplasmocytic disorder, and then we have POMS, uh, which is a syndrome full of a constellation of symptoms that is thought to be secondary to an underlying plasma cell clone. So many different plasma cell disorders. The pathogenesis of plasma cell disorders can include the disruption of bone modeling, um, excessive activation of osteoclasts, which can lead to these classic lytic lesions, uh, which we all know well from med school. You can have infiltration of your bone marrow, which can lead to anemia, obstruction of the kidney tubules, which leads to cast nephropathy. And there's various mechanisms that can lead to damage of the nerves or neuropathy, but you can get direct demyelination, light chain amyloidosis, and uh infiltration of the nerves, autoimmune phenomenon, and even cryoglobulin anemia. I think when you would consider testing an individual for plasma cell disorders are, you know, we all know very well from medical school, the crab criteria. So if you have a patient with hypercalcemia, renal insufficiency, anemia, bone lesions, and you can't quite um explain ideology, plasma cell disorder should certainly be considered. In patients who have age inappropriate osteoporosis or bone pain that you can't quite explain, an elevated total protein, patients with proteinuria or neuropathy of unclear ideology, and then this is more for the Waldensstrom's patients, but B symptoms and symptoms of hyper viscosity. I will say in my practice, um, The referrals I get for MGUS are a lot of times incidental findings, as opposed to the clinician was specifically looking for MGUS and diagnosed MGUS. Um, you could also consider screening based off of family history. There was a study that showed about 5 to 7% of myeloma diagnoses occur in individuals who had a close relative, uh, previously diagnosed with myeloma or MGUS. So in patients who are older than 50, with two or more affected first degree relatives that had a myeloma or myeloma related disorder, um, you can consider screening them in the absence of symptoms. So the initial workup for a plasma cell disorder includes um the following lab tests, a CBC. You can get it with differential, um, which I like because if there are other cytopenias specifically with the white blood cell count, it kind of gives you a better idea of what's going on. Um, I'd like to get a CMP and the reason I get a CMP is because it shows you creatinine, it shows you the calcium, and then you can evaluate for a protein gap as well with the total protein and albumen. A serum protein electrophoresis or SPEP, and this should be done with an immunofixation. I'll explain what that means, um, serum free light chains and quantitative immunoglobulins. Additional testing, which I personally feel can be directed by hematologists, so I would not expect a primary care physician to order these or necessarily interpret these, but LDH beta2 microglobulin, 24 hour UPEP, bone marrow biopsy with aspiration, and then bone imaging. We are starting to move away from skeletal survey and Um, move towards whole body, low dose CT, PET or MRI, but I will say it depends um on what the patient's insurance may approve and costs, that sort of thing. So in practice, I do sometimes still get skeletal surveys. So Diagnostic tests, in terms of SPEP, the way that it works is it separates protein based on the size of the protein and the charge of the protein. Now, in a normal individual, it'll be like the image, um, the top part of the image where you'll have, um, on the more positive side, an albumin spike followed by alpha and beta, which for the purposes of diagnosing a plasma cell disorder, these spikes are not so useful. It's the gamma spike where you will find all the immunoglobulins. So in a monoclonal gammopathy, you'll see a gamma spike, um, and that tells you essentially how much of that protein there is. The problem is it doesn't tell me what the protein type is. It only tells me, um, it only quantifies it. So that's where an immunofixation is helpful, because the immunofixation will detect the type of monoclonal protein in the serum or urine. Now, depending on the lab, you may need to place orders for SAP and immunofixation separately. I've found that uh when I've seen patients in clinic in Redwood City and San Mateo, I do place the orders separately, uh, because they may not always be done together. I recently had a patient where only the immunofixation was done and not the SEPs, so I knew that they had a monoclonal protein, but I didn't know how much they had, so we had to go back to the lab and have them run the SPAP. So that's just another consideration when you're doing your workup, but the immunofixation is important because it tells us what type of protein there is. In terms of free light chains, so the normal reference range is specific to each laboratory. Generally, the normal ratio is between 0.6 to 1.65, but it's important to note that the concentration of free light chains is affected by the kidney function. Um, so a ratio of up to 3 can actually be normal if someone has kidney dysfunction, and there are new proposed reference ranges based off of the GFR of a patient that all comes from a massive study done in Iceland, where they essentially got blood from about 75,000 patients, I believe. And so there is a um lab company called the binding site that has adopted these proposed reference ranges based off of GFR and this is what I use in my clinical practice. The biology behind why the reference range might change and be normal for someone in CKD is um In a normal individual without organ dysfunction, We have found that kappa light chains are formed at about twice the rate of lambda light chains. These light chains are removed by the kidney. Um, but lambda light chains tend to form dimers, so therefore they're bigger in size and have decreased clearance by the kidney. So what we find is in normal situations without any organ dysfunction, the kappa lambda ratio is generally less than one. Despite being produced at an increased rate, they are then um cleared. At an increased rate by the kidney compared to lambda light chains. So then you have that ratio that's actually closer to one or lower than one. So in renal failure, you have less clearance of the light chains by the kidneys. So you'll see increase in both the chains. That's normal. The clearance tends to be done more by the reticular endothelial system, so this is not affected by weight. So what you'll find is as the kidney loses function, the kappa light chains will start to rise and you can get an increased ratio as well. But that can be expected and normal and not reflective of a monoclonal gamopathy. So, now that we know a little bit more about the testing, I want to talk about the diagnostic criteria. So, to diagnose an MGUS, you need to have a serum and protein, so that's that monoclonal and protein on the SPAP, of less than 3 g per deciliter. If a marrow has been done, you should see less than 10% clonal plasma cells. And then you should make sure the patient does not have any so-called myeloma defining events, which, uh, in medical school, I learned crab, but we've since added three more criteria to create a new acronym called Slim Crab. Um, a couple considerations are for light chain MGUS. You won't have an M protein because heavy chains are not involved. It's just the light chains. So what you should see is an abnormal ratio of the light chains with an increase in the involved light chain. And then you want to ensure you're referencing the ranges based off the patient's GFR. For IGM MGUS, there is a concern obviously of underlying possible lymphoma. So you want to ensure they're not having these symptoms or symptoms of hyperviscosity. When I do my exam, I look for any lymphadenopathy or hepatosplenomegaly. So I just wanted to quickly go through what are myeloma defining events that slim crab criteria. So that's 60% or greater clonal plasma cells in the marrow, a light chain ratio greater than 100. An MRI bone lesion, so you should have more than one on MRI and then the classic crab criteria, hypercalcemia, renal insufficiency, bone lesions, um, anemia. Essentially, there's a spectrum based on your protein and your lab findings. So the spectrum of Mgus to myeloma is, you know, as Defined by this chart here, so for MGUS, you should have a serum protein less than 3. We don't use the urine uh protein to necessarily diagnose MGUS. If you do Omera, there should be less than 10% plasma cells, and absolutely the patient should not have any myeloma defining events. So the risk of progression, we tell patients about 1% per year. If the M protein is greater than 3, if they have an uh urine M protein, or if they have more than 10% plasma cells without any myeloma defining events, then the patient can be considered to have smoldering myeloma, and that has a higher progression risk than MGUS, but the progression risk is higher in those 1st 5 years. And then obviously at the other end of that spectrum we have multiple myeloma, which is now no longer defined based off the M protein, but um is rather the slim crab criteria plus 10% or more um clonal marrow. Plasma cells or a biopsy proven proven plasma cytoma. The way MGUS is classified is we have non IGM MGUS, um, which is what I've seen most commonly in my practice, IGM MGUS or light chain MGUS. And then in terms of risk factors for progression, so there have been several studies that have identified the following risk factors and correlating risk at 20 years of progression to myeloma, but uh we use a serum and protein greater than 1.5. Patients who have a non IgG MGUS, and then people who have an abnormal free light chain ratio, we have found that those people, if they have between 1 and 3 of those factors, have a slightly higher risk than that 1% per year. So if you have none of these risk factors, the risk of developing myeloma is next to nothing. If you have one of these factors, then it's about the same as any average patient, that 1% per year. But if you have 2 or 3, the risk of developing myeloma is significantly higher, and in someone with 3 factors or 2 factors, you may want to consider keeping a closer eye on them. And um maybe getting additional studies. So again, from that same study they they found with these risk factors and if they have symptoms or not, they would recommend bone marrow or skeletal survey. So going through this algorithm here, if someone is low risk, meaning that M protein is less than 1.5, they're an IgG type and have a normal ratio. Or if they have an IGM less than 1.5, or if they have a light chain MGUS with a low ratio and otherwise don't have any signs or symptoms concerning for plasma cell disorder, you can reasonably defer getting a bone marrow and a skeletal survey. If they don't meet that low risk criteria, then you should be getting an upfront marrow, you should be getting upfront imaging, um, or if they meet that low risk criteria and you can't quite explain why they're having certain symptoms, then maybe you want to look for plasma cell disorder to make sure that they are still meeting criteria for MGUS. There is also another um useful resources that I've been using in my practice, and this is again from that huge Icelandic database as part of the ISop MM study. So this is a great online calculator where you can plug in what the values that you found, and it'll tell you the probability of a patient having more than 10% plasma cells in their bone marrow. So this is another thing that I'll use in counseling my patients about. Monitoring and whether I recommend a bone marrow or not. It's just more information that helps me feel better about deferring studies if that probability is low. And so in conclusion, you want to consider evaluation for plasma cell disorders based off of symptoms, so people with bone pain, uh, if you're considering Waldenstrom's be symptoms, hyperviscosity, unexplained neuropathy, um, if they have abnormal findings such as bone loss, elevated protein, those crab criteria proteinuria, or if you're considering screening in one of those individuals with a family history. For diagnostic workup, you want to get a CBC. I prefer with diff, um, but not necessary for diagnosis. CMP SPEP with immunofixation, free light chains and quantitative immunoglobulins. So that should be your go to workup if you're ever considering a plasma cell disorder. And just remember to meet criteria for MGUS, you must have an M protein that's less than 3. Um, or if you have a light chain MGUS, you're not gonna see the M protein, you'll see an abnormal light chain ratio with an increased involved um light chain. And also, uh, and more importantly, you should have no myeloma defining events, which is that slim crab criteria. So and it's my recommendation to consider a referral to hematology to determine the need for any further evaluation, like if they would get a UPAP, bone marrow biopsy and imaging, and then also to help with recommendations on monitoring. So in my practice, if I feel like someone's quite low risk, I will ask the primary care, do you feel comfortable getting these labs in 1 year, in 2 years, etc. and sending them back to me if anything comes back abnormal. And um that's worked well for your patients in the past.
