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What is Monoclonal gammopathy of undetermined significance (MGUS)?


- [Voiceover] Let's talk about monoclonal gammopathy of undetermined significance. Now, that's a little bit of a mouthful, so we're going to just refer to it by it's acronym, MGUS. You'll also notice here that I've separated monoclonal gammopathy from undetermined significance. I've done this because I think it will help us to better understand what MGUS actually is. Now, I'm going to start with monoclonal gammopathy over here on the left. To do this, I'm going to go over a simplified explanation of the pathophysiology of MGUS, as well as multiple myeloma. Both of these disorders originate in the bone marrow. Let's draw a bone here. The bone marrow is the central part of the bone. It's where blood cells are produced. I'm going to highlight three types of cells that are located in the bone marrow. The first type are the erythrocyte precursor cells. I'll draw those in red here. These erythrocyte precursor cells produce erythrocytes, which are also known as red blood cells. Next, I'm going to draw in a few thrombocyte precursor cells, and the thrombocyte precursor cells produce thrombocytes, which are also known as platelets. Then, lastly, in green, I'm going to draw in the plasma cell precursor cells. They produce plasma cells. Now, it's important to note that there actually many other types of cells within the bone marrow that are not present in this drawing, but I'm only just highlighting these three types of cells in order to make the pathophysiology of MGUS just a little bit more clear. Both MGUS and multiple myeloma are considered plasma cell dyscrasias. Dyscrasia is just another word for dysfunction, so these conditions are the result of the dysfunction of the plasma cell precursors. These plasma cell precursors produce the plasma cells, and the plasma cells then produce antibodies, which I'm just going to draw in here. Antibodies are a type of protein that are part of the body's immune system and help us fight infection. What happens in MGUS, as well as multiple myeloma, is that for some unknown reason, certain individuals have a monoclonal expansion of plasma cells. Now, what do I mean by this? Well, let's pretend we have a plasma cell here. There's just a problem with one of these plasma cell precursors here in that bone marrow. We'll identify that here with just this one cell. There's a problem with this one cell. The other plasma cell precursor cells are normal. But what happens when this cell replicates is it makes more dysfunctional cells, which then replicate and make more dysfunctional cells. You can see here that this one dysfunctional cell can produce, over time, many dysfunctional cells, but they're all based off of this one cell type. This process is known as monoclonal expansion, mono, meaning one, so it all comes from one cell, and clonal meaning replication. So you just have lots of replication of one cell. We'll just draw that in here. All of these cells are genetically identical because they result from one parent cell. This is where you get the monoclonal part of monoclonal gammopathy of undetermined significance. Now, when you have this monoclonal expansion, the replication rate of this cell for some reason becomes unregulated, so it replicates much more frequently than it normally would. With that, you get plasma cells that are producing a lot more antibodies than normal. I mentioned before that these antibodies are proteins, and these proteins can be measured in the blood with a test known as protein electrophoresis. A normal protein electrophoresis looks something like this. It depicts the different types of proteins that it measures, so this big spike here correlates with albumin, which is the most common type of protein in the blood. But then you also have these other categories of proteins, which are known as alpha one, alpha two, beta, and gamma. What I'm going to focus here is these gamma proteins. These gamma proteins relate to the antibodies, so in someone who has monoclonal gammopathy of undetermined significance or multiple myeloma, you get all of these antibodies that are identical, so on a protein electrophoresis you'll get a spike in this region that looks something like this. This is known as an M spike. The M stands for monoclonal. You get a spike in the gamma region, and this is why it's called a gammopathy. That's why you have a monoclonal gammopathy. I mentioned that this same process occurs in MGUS, as well as in multiple myeloma, but what exactly is, then, the difference between the two of them? To go into that, let me draw another bone here. Once again I'll put in our bone marrow precursor cells. Up top here, in this top bone, we'll have MGUS. Down here we'll describe multiple myeloma, which I'm just going to abbreviate MM. Now, in multiple myeloma, you also have this clonal expansion, this monoclonal expansion, of one dysfunctional plasma cell precursor, but the replication is even more so. It's even more unregulated, and so it kind of ends up looking like this. What happens is the bone marrow becomes jam-packed with all of these dysfunctional plasma cell precursor cells, and then it can't produce the other normal cells. So the big difference between MGUS and multiple myeloma is that MGUS is more minor. These dysfunctional plasma cell precursors are occurring and they exist there, but you're still having normal production of red blood cells and platelets and everything, and so you have no symptoms. MGUS is asymptomatic. In multiple myeloma, this dysfunction becomes so severe that you start crowding out the bone marrow, and you have dysfunction of the other types of blood cell precursors, and eventually someone with multiple myeloma will develop symptoms. In this sense, MGUS is a precursor to multiple myeloma. In fact, some people refer to MGUS as pre-myeloma. From this pathophysiology, you can actually get a better understanding of what the symptoms of multiple myeloma might actually be. What happens is all of these extra antibodies and proteins can result in renal failure, and then, like I mentioned, these plasma cell precursors crowd out the bone marrow here, and you get a decreased production of red blood cells, which results in anemia, and decreased production of platelets, which results in thrombocytopenia. Then also what happens is these dysfunctional plasma cell precursors produce some factors that cause the bone to be broken down, and so you get these almost punched-out lesions in the bone, which are knows as lytic bone lesions that I'm going to just draw in here like this. The result of this, people with multiple myeloma have lots of bone pain. As a result of this breakdown of the bone, the bone releases lots of calcium, and this results in hypercalcemia. These symptoms can be remembered with the acronym CRAB, C for hypercalcemia, R for renal failure, A for anemia, and B for bone pains. Let's just write that in here, CRAB. Because multiple myeloma is this uncontrolled replication of these plasma cell precursors, once it comes to this stage and you have symptoms, it actually becomes a malignancy or a cancer. If monoclonal gammopathy of undetermined significance, or MGUS, is a pre-myeloma and it can produce myeloma which is a cancer, why is that of undetermined significance? For many people you would think if it's a precursor to cancer, that would be of extreme significance. But, the reason it's considered of undetermined significance has to do with the rate at which MGUS becomes multiple myeloma. I want you to imagine a group of 100 individuals who are 60 years old. Let's bring that in here. Once again, when we're starting here, they're all age equals 60. The reason I use 60 years old is because MGUS and multiple myeloma are most common in older individuals, especially above the age of 60. Now, the prevalence or the percentage of individuals at age 60 who have MGUS is actually relatively high. It's somewhere between three and six percent. That would be about five of these individuals. Let's just pull five out here. Any random five. These five individuals have MGUS. Now, the important question to ask is not whether or not these five have multiple myeloma, but the risk of which they will develop multiple myeloma over time. Let's imagine that these five individuals have lived to the average life expectancy in the U.S., which currently is 78, but we'll just make it easier, and we'll make them live until they're 80 years old. Our question is, by age 80, how many of these five with MGUS are actually going to develop multiple myeloma? The answer is just one. So although the prevalence of MGUS in individuals over the age of 60 is actually fairly high, somewhere around the percentage of three to five percent, the rate at which they develop multiple myeloma is actually pretty low. This rate is approximately one percent per year. So MGUS is of undetermined significance for two reasons. The first is that even though the prevalence of MGUS is fairly high in individuals over the age of 60, the chance that any single individual with MGUS will develop multiple myeloma is fairly low, meaning that they will likely die of some other cause before they actually develop multiple myeloma. Then the other reason it's of undetermined significance is because it's very difficult to predict specifically which one of these five individuals with MGUS is going to develop multiple myeloma. So if you can remember that MGUS stands for monoclonal gammopathy of undetermined significance, if you break down the term you can remember that it is a monoclonal expansion of a single plasma cell precursor that produces large amounts of antibodies or proteins that result in an M spike over here in this gamma region of the electrophoresis, and that's why it's called a gammopathy. The significance is undetermined because it's asymptomatic and it is difficult to predict what percentage of those affected by MGUS will ultimately develop multiple myeloma.