Speaker A
What's up, Ninja Nerds? In this video today, we're going to be talking about plasma cell disorders. That includes the following: multiple myeloma. It includes monoclonal gammopathy of undetermined significance. That's a heck of a name.
Comprehensive overview of plasma cell disorders including MGUS, multiple myeloma, and Waldenstrom's macroglobulinemia with clinical insights.
Key Takeaways
- MGUS is a premalignant plasma cell disorder without organ damage and an M spike less than 3 g/dL.
- Multiple myeloma is malignant with >10% plasma cells in bone marrow and organ damage per CRAB criteria.
- Monoclonal antibodies produced are mainly IgG or IgA along with light chains kappa and lambda.
- Serum protein electrophoresis and M spike analysis are critical diagnostic tools.
- Waldenstrom's macroglobulinemia is characterized by IgM production and lymphoplasmacytic proliferation.
What the video covers
- Introduction to plasma cell disorders focusing on MGUS, multiple myeloma, and Waldenstrom's macroglobulinemia.
- MGUS is a premalignant condition characterized by increased plasma cells producing monoclonal antibodies without organ damage.
- Multiple myeloma is a malignant plasma cell disorder with high plasma cell proliferation and organ damage defined by CRAB criteria.
- Discussion of immunoglobulin types produced, mainly IgG, IgA, and light chains (kappa and lambda).
- Explanation of serum protein electrophoresis and the significance of the M spike in diagnosis.
- Differences between MGUS and multiple myeloma based on M spike levels and presence of organ damage.
- Waldenstrom's macroglobulinemia involves lymphoplasmacytic proliferation and IgM antibody production.
- Complications of plasma cell disorders including autoimmune hemolytic anemia, hyperviscosity syndrome, and renal impairment.
- Diagnostic criteria including plasma cell percentage in bone marrow and clinical presentation.
- Support resources and exam preparation materials offered by Ninja Nerd for medical students.
Chapters
- 00:00Introduction to Plasma Cell Disorders
- 04:17Monoclonal Gammopathy of Undetermined Significance (MGUS)
- 08:49Diagnostic Features and M Spike Significance
- 13:40Risk of Progression from MGUS to Multiple Myeloma
- 19:14Complications of Plasma Cell Disorders
- 23:40Pathophysiology and Clinical Manifestations
- 33:16Laboratory Findings and Peripheral Blood Smear
- 43:04Autoimmune and Hematologic Complications
- 53:11Summary and Treatment Considerations
Full Transcript — Download SRT & Markdown
Speaker A
And also Waldenstrom's macroglobulinemia. We won't be talking about amyloidosis in this lecture. That'll have a dedicated lecture on its own. But these are going to be the primary things that we're going to focus on in this clinical medicine lecture. If you guys
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It really makes a difference. Also, if you are a student who sometimes just really struggles with the burdens that come with going to medical school and PA school and MP school, etc., I really do understand and I think we have a way
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If you become a member, you'll have access not just to our videos, but you'll have access to a ton of notes, and these notes are really high yield.
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They really will help you to understand the topic. We have tons of quiz questions that will help you with that repetition-based learning and really see if you guys truly understand that topic.
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And then if you want, we also are, uh, developing exam prep courses. So, those of you taking things like the Step 2, go check that out. All right, without further ado, let's dig into plasma cell disorders. Plasma cell disorders are
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sometimes viewed as kind of complicated, but it's truly, I'm telling you, the pathophysiology, the causes behind this, it's actually probably one of the easier topics to understand, and I know, which is crazy because when you think about hem, you think about
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anemias and it's like, oh my gosh, those are challenging. Uh, you think about platelet disorders, that's enough to kind of jump off of a, you know, a bridge. So there's a lot of complicated topics in hem. I think when it comes to plasma
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cell disorders, thankfully these are pretty straightforward, and when you come down to it, it's really a monoclonal gammopathy. So there is an abnormality within the plasma cells or cells that are almost plasma cells. They're like tweeners, like between B cells and
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plasma cells. But there's three different types that I want to discuss, and this is going to be monoclonal gammopathy of undetermined significance. I'm going to say MGUS a lot. Multiple myeloma, I'm going to say MM. And then Waldenstrom's macro
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globulinemia, I'm going to say WM. For each one of these, there is a kind of somewhat similarity with slight differences.
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So for MGUS, there is a—it's a premalignant condition. That's the way I want you to think about it. So it's an increased number of plasma cells.
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So you have an increased number of plasma cells. It's not a malignant condition yet. It's premalignant. So here, let's actually write that down. This is a premalignancy. So I'm going to put it's like a premalignant.
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It's like a tweener where you're not at the point yet of it being malignant. But again, this is a premalignant condition that causes an increase in the number of plasma cells. Now, if you have an increased number of plasma cells, what
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happens is these plasma cells, they make normally antibodies. And if you have a lot of plasma cells, guess what? You end up with a lot of, a lot of antibodies.
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And the primary antibodies that can come out of this scenario is you end up with this plasma cell, right? And this plasma cell, when you actually kind of cause this condition where you keep proliferating them, you sometimes proliferate the same one repeatedly,
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repeatedly, repeatedly, and it produces the same antibodies in an overproduction manner. One of them, and this is probably the most abundant one, I'd say most of the time this is 50% of the cases, sometimes even higher, is you
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overproduce IgG antibodies, and it's important to remember that these are not really truly functional. The other one that you can produce, um, a lot of is going to be the IgA antibodies, right? This is kind of lower, maybe 20%. And then the last
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thing that you also produce a decent amount of, which is going to account for about 15 to 20%, is going to be these light chains. And so you have these things called light chains. Now, there's different types of light chains, but
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oftentimes the two big ones are going to be what's called kappa—that was a long a kappa—and lambda. All right, these are going to be the two big ones here. But what happens is you're making a lot of
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these. All right, so in patients who develop MGUS, all right, they make lots of IgG or they make lots of IgA and they also make light chains kappa and lambda. The concept behind this is when you look at an antibody, this
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sequence here, if I kind of follow with a black line, this part here, this part here, right here, right here, that's your, um, your heavy chain, right? And then these little guys that are coming off the edge here that are connected by
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disulfide bonds, those are going to be your light chains. So whenever a plasma cell makes antibodies, they are supposed to have these as immunoglobulins, which is a combination of these heavy chains and light chains. But what ends up
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happening, you make a lot of these normal immunoglobulins and then you also have an excess amount of light chains.
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So that's the big, big thing I want you to remember. Now here's the big, big concept to understand with MGUS. When you make a lot of these, you make these monoclonal antibodies and increased light chains. The big thing to remember is
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that these are present but they do not precipitate organ damage. So there is no presence of organ damage due to these antibodies. And the most important types of organ damage presentation is usually something that we'll call the CRAB criteria, which is
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classic in multiple myeloma. But the other thing that's really important, and we'll talk about this a little bit later, is with MGUS when you make these lots of immunoglobulins and light chains, it causes whenever you do something called
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a serum protein electrophoresis, where you basically separate the proteins in the serum based upon their electronegativity and their charge, etc. It separates them out into different proteins. You can remember it via like the shaka. And so the shaka kind of goes
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you have albumin, the alpha-1 globulins, alpha-2 globulins, the beta globulins, and then the gamma globulins. And so what happens is in patients who have normal cases, they have like a normal gamma globulin level. But what happens is
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when a patient starts to develop a plasma cell disorder, that puppy goes up and so the pinky side will really, really shoot up and end up with a what's called an M spike. And that's really important to remember. We'll talk about
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that in the diagnostic section, but their M spike is less than 3 g per dL.
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I'll get into that a little bit later, but again, remember it's less than 3 g per dL and they have no organ damage.
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That's one of the big ways that we can differentiate MGUS from multiple myeloma. Now, multiple myeloma is a malignant condition. So, this is a malignant condition. And what happens in this situation here is you end up with a lot
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of these plasma cells, dude. And it's like, it's like a lot, lots and lots and lots of these plasma cells. And these plasma cells, what happens is that they end up making a lot of antibodies. If you have lots of plasma cells, you're
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going to end up with a lot of antibodies. And again, this is a quick recap. What's the most common one? IgG.
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Or what's the other one that you could make less commonly? Because again, it's either going to be one or the other. It can't be both in these scenarios. So, it's either the plasma cell makes a lot of immunoglobulin G and light chains or
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it makes a lot of IgA and light chains. There's other types. They're less common. Sometimes you only make light chains and sometimes you only make heavy chains. We're not going—
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or a lot of IGA plus a lot of kappa lambda light chains. And I'm talking a lot. So, let's do a double arrow here for these. Now, when you make all of these, these actually are high enough and you have enough of an M spike
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greater than 3 g per DL that it's actually able to precipitate organ damage. All right? And this organ damage again, we'll talk about a little bit later when we get to the complication, but it's often referred to as the crab
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criteria. We'll talk about that a little bit later, but again, that's the big difference. So, when you look at these, you're like, "Oh, wow." similarities here, right? Pretty close. Only thing that's different is is that you get more
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of these monoconal proteins. So, I'll write it down now here, but this is going to cause an M spike.
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This is basically all of these less than 3 g per DL. This right here is going to cause an M spike greater than or equal to greater than equal to 3 g per DL. It's important to remember these concepts. So you're going
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to have so many monoconal proteins in these scenarios that it's going to cause an M spike, but the height or the degree of the M spike determines somewhat of a difference between multiple myoma and MGUS. And the presence of organ damage
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or not determines the difference between myoma and MGUS. Walden Strums. This one's a malignant condition as well. And what happens with this one is it's technically a tweener. And what I mean is you have like a B cell and a plasma
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cell. It's like a B cell that's trying to proliferate differentiate into a plasma cell, but it doesn't completely differentiate. So we call these lympho plasma.
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We call them lymphopplasmocytes. Now lymphopplasmices basically you have a overp proliferation of these bad boys.
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When you have an over proliferation of these bad boys these are going to start producing a pentimer a very specific type of amunoglobulin and you're going to make a lot of them. So you'll make a lot of this IGM
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antibbody which is our pentimer and this is a problematic because this can cause a lot of problems and so this will precipitate organ damage. This will precipitate organ damage. The way that it presents is not a crab criteria though. We'll
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talk later. It's usually something called hyper viscosity syndrome or sometimes it can also cause tumor infiltration and um sometimes it can even potentially cause neuropathy. But big thing here is again you're going to get so many of these that that on that
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SPE that gamoglobulin spike the M spike which consists of the monoconal proteins is going to be elevated. So what would the M spike here look like?
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Greater than or equal to 3 g per DL. And so it's important to remember that you're going to get an M spike for all of these. This one not as intense. These two intense. These two organ damage.
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This one no organ damage. Malignant premalignant. All right. Now let's come down and talk about what are the causes of having too many plasma cells or too many lymphopplasma sites.
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It's actually thank goodness so straightforward. MGUS is a disease of old age. I know that sounds crazy, but we see that the prevalence is high when a patient is greater than or equal to 70 years of age. All right. And so what we
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notice here is something kind of interesting that for every year the percent chance that a patient can convert from MGUS into multiple myyoma is about 1% chance per year. Let me let me explain something. There's a really reason I want to talk about MGUS because
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MGUS is usually asymptomatic. If there's no organ damage, there's no symptoms. All right? Not usually. So, you have kind of this array, right? Our spectrum.
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So, we're going to say MGUS. It can convert into what's called smoldering myoma. Sounds like what was that movie?
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Um, Jumanji, right? He's like the smolder. It's a smoldering myoma. And then you have what's called multiple myoma. So, this is kind of a spectrum, if you will. And so when a patient kind of uh goes they can go from MGUS to
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smoldering myoma and smoldering myoma to multiple myoma. How do you differentiate them? All right. So this one's going to have the M spike, right? So it's going to have that M spike and it's going to be less than 3 g per
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DL. All right. But what happens is is when it starts to get to smoldering myoma, so maybe over a year or years the chances of get this kind of going up can happen. But it's a low chance. If it
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does break that point where you get to an M spike greater than equal to 3 g per DL, you'd be like, "Okay, you smoldering myoma." All right. Well, Zach, you just told me if I bump above three, that's
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multiple myoma, though, right? No, because in this scenario, guess what? No organ damage here. No organ damage. All right. So, there's and we're going to actually call this the crab criteria. I just want you to trust me for right now. I promise it's the way
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that they have organ damage, but just trust me. And then here, they're not going to have any crab criteria. So, the only thing that really changed is the number of these amunoglobulins, whether that's the IGG or the IGA, and the
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increase in light chains. It just went up. All right? So, it's kind of progressed. So, we started here, we got to this. How do I then finally get that chance for a patient to eventually convert? You see right away that now you
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have to have an M spike greater than or equal to three grams per DL plus you have to have the presence of crab criteria.
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All right, that's really where it kind of comes down to. But this chance of converting is about a 1% chance. So this has a chance of converting of about 1% chance per year of this eventually converting from MGUS
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into what multiple myoma. So about a 1% chance per year of them transforming. So that's why it's important to know this.
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So now when we talk about multiple myoma what really happens here is we actually don't have good reasons as to why this condition occurs there could be a lot of different factors but what we've seen is it could be due to chromosomeal
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transllocations and there's a lot of them and I don't want you to stress about them I want you to know the most common one that's associated with the standard risk of multiple myoma and you'll see why I'm telling you that and
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it's usually the 11 14 transllocation So on chromosome 11 there may be this gene and then over here on chromosome number 14 there is this kind of gene usually on 11 it's a cycl D gene right and then on 14 is a IG
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amunoglobulin heavy chain enhancer so basically this controls the production of amunoglobulins this controls the it's a protoonco gene so it controls proliferation of cells What happens is you get this little chunk here that kind of moves over here.
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And so then what you end up having is is you have this transllocation on chromosome number 14 where I'm going to have this amunog globulin enhancer and then I'm going to have this cycl D gene and this is going to really enhance this
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activity and what it'll do is is it'll cause a massive proliferation of plasma cells. So basically it'll stimulate the proliferation because the cycl D gene is going to go ham and so it's going to cause massive proliferation and
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it's also going to kind of make them survive. So so they're going to be resistant to apoptosis but on top of that it's also going to have in these every single one of these uh plasma cells will have that IG enhancer. And so
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now it's also gonna trigger this to increase antibbody production. And so now I'm gonna end up with all these dang antibodies. So you see the point here, right, is that you're stimulating these cells to proliferate, but you're also
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stimulating um amunoglobulin G or amunoglobulin A production plus the light chains. That's the concept that I want you guys to understand here. So, it's kind of cool when you think about this. And so, this is the standard risk, meaning that
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they'll develop the common common course. It's actually could have somewhat of a positive prognostic kind of factor to that. And we I'll talk about that in a little bit later when I talk about the RISS kind of like staging
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system. Um, we actually look at chromosomal transllocations and 1114 is more of a favorable one. Other ones, they have less favorable outcomes. And so it's important to remember that with Waldenstrum's macroglobulmia, this is also um potentially due to a mutation.
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One of these may be um called uh the M uh YD88 mutation. I'm just mentioning it. I don't think that this is like super super high yield. I just want you to understand that there's a mutation on a
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chromosome. And what happens is is this actually causes the um kind of the lymphopplasmocytes right to kind of go into this hyperactive proliferative state and improve their survival. Uh the way it does is it actually caused a mutation
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that increases the expression of a transcription factor. Again take this with a grain of salt with how important this is, but it causes an increase in what's called nuclear factor kappa beta.
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And this is a transcription factor that when it actually kind of gets into the nucleus, it really amps up the proliferative process. And so that's really really important because it's going to go act on these plasma um these
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lymphopplasma sites and really cause them to proliferate like crazy, right? So it'll definitely stimulate this proliferation. But not only that, it will lock these kind of cells into a state of antibbody production and it'll trigger these lymphopplasma sites to
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start producing lots of antibodies. And again, what are these antibodies that uh it's making? It is IgM predominant. Now, you're probably wondering, how do I tell if a patient is making like, you know, IGG versus IGM versus IgA? When you do
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the serum protein electropharesis, it separates it out and says, "Okay, here's the gamma globulins. Any of these imunoglobulins are elevated. You just don't know which one. So then you take that sample and you do what's called amunofixation." Um, and that should tell you which one
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is actually elevated. All right. So, we've talked about the patho, right? About how you separate them based upon antibbody and organ damage. And then we talked about causes particularly uh talking about MGUS how it's pretty much a preliminated condition but it does
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carry a risk of converting into multiple myoma. We talked about how chromosomeal transllocations could be a source of really good or poor prognostic indicators from multiple myoma. And then we talked about the mutation in Waldenrums that causes hyper
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proliferation of lymphoplasmittes and IGM antibody production. Now let's talk about the complications of these disorders. All right. So let's talk about the complications with plasma cell disorders. So, one of the big things we already talk about with MGUS is that
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it's pretty much asymptomatic. So, you're like, "Okay, well, how do I know if people have it?" We'll talk about that. There's something called a protein gap and it's actually kind of helpful and potentially having a degree of suspicion, but often times MGUS is an
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incidental finding. So, you do a lab and you're like, "Oh, wow. Look at this.
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They have an elevated protein gap, you get an SPE, and you find out that they have an M spike less than or equal to, you know, 3 g per DL." So, with MGUS, there is that chance that it can convert
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to multiple myyoma, but you have to remember those antibodies aren't causing organ damage. With multiple myoma, there is organ damage. And we remember that organ damage by the pneummonic crab criteria or just the crab. I like to add
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on another one. And I'm just going to do that to be like, you know, extra, but I like to grab add in crab eye criteria.
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So if a patient has crab eye criteria, they really kind of show me that they have high risk of multiple myoma. So let's go through this. So C is hypercalcemia, R is renal failure, A is anemia, B is bone pain and then I is
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infections especially recurrent ones. So hypercalcemian lyic lesions. I want to talk about these together because they have similar kind of presentations and these are often times the way that these patients may present. So in patients of hypercalcemia or litic lesions here you
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have your plasma cell right there's your plasma cell. Now one thing about these plasma cells is that when you have these being super malignant, right? All right, so these are malignant plasma cells. They not only do they release tons of antibodies,
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guess what else they release? They release other cytoines that are kind of detrimental. All right, one of them could be what's called um interlucan one uh and tumor necrotic factor alpha.
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These often times go together. Another one could be osteoclass activating factor and another one could be what's called the rank liand. Right? So because they're malignant, they gain the capacity to produce these and they produce them in kind of like abnormally
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large amounts. Now the why this is important is because these top two they really hit osteoclass in the bone. So these plasma cells will kind of get into near the bone and they'll go to these osteoclass. Look at these little puppies
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here. These are some big cells dude. And what happens is these two primarily really go and act on these receptors.
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And what they do is is they're normally supposed to stimulate these osteoclass. the osteoclass when they're stimulated by rank lian and osteoclass activating factor they release things like hydrochloric acid and they release um technically it's called collagenase.
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It's just it's basically in all seriousness it's a looal enzyme but you know one of the big components of bone is type one collagen. So we're going to release a lot of these things like hydrochloric acid and collagenase from
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these osteoclass and these going to tear that bone up right it's going to get in here and this is going to start you know jacking things up. So it's going to rip through the bone and they're going to
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start chewing up the bone and generating a lot of different types of contents. Hydro hydrochloric acid chews up hydroxyapatites. When you chew up hydroxyites, what does that um liberate into the bloodstream? Calcium and phosphate, dude. So you start getting
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high amounts of calcium that is liberated into the bloodstream, right? So this is called reorption, right? So it's called resorption. So there's going to be this like resorptive process where you chew away at the bone and this leads to high calcium, high
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calcium. Now when a patient develops hypercalcemia, they could be completely asymptomatic, right? You may not have any symptoms, but often times this calcium can get pretty high, at least up to like greater than 11. What happens with that is is that calcium can do a
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lot of different detrimental things. One of those things is if it's bad enough, it could actually cross the kidney tubules. when it crosses the kidney tubules, it does have the ability, if it's in the right circumstances, to combine with oxalate or to combine with
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phosphate. And then guess what could happen? They could form calcium stones. And so that's a really really important thing to remember is with high calcium comes high risk of kidney stones. And again, I'm not going to write it down, but I want you to
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remember the two big ones that are associated with hypercalcemia and that is calcium oxide, calcium phosphate stones. Right? That's one thing that you want to watch out for. Definitely high risk. They could come in with kidney cells. The other thing is that calcium,
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dude, this guy is cool because what can happen is he can get over here, right, and he can jack up the way ADH, you know, ADH ADH is supposed to u bind on to what's called the V2 receptor, right?
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Let's do that here in this blue color here. So, it's supposed to bind on to this receptor. But whenever there's high calcium, that inhibits ADH from working on this receptor. And then what happens is your ADH is supposed to help you with
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water reabsorption. You going to reabsorb water now? No. And so this process of water reabsorption is inhibited because of this, right? So ADH is supposed to drive this process of water reabsorption. But because you have high calcium, it inhibits this process.
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you don't reabsorb water and you lose tons of water in the urine and this is called nephrogenic dirogenic DI. So you're going to end up with lots of water into the urine. So it's important to remember that they can have
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polyurea they can have kidney stones. So remember that pneummonic stones bones grow thrown psychiatric overtones. These are the big ones to watch out for is kidney stones, right? But you also definitely want to watch out for nephrogenic DI that can cause polyura
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and then also guess what the other effect here is the lesions the lit litic lesions you're going to have the bone problems right so let's talk about that now as you rip apart the bone you get these hydroxy appetites you break up the
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collagen you're going to start really breaking these bones down right and this is going to cause litic lesions to form all right you're going to stimulate the formation of these dang litic lesions These litic lesions, they're pretty nasty, man. They can
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occur all over the place. The skull is a big one. The vertebrae is by far the most common one. So, if it occurs in the vertebrae, right? And I would say this is definitely definitely the most common. The next one is it can occur in
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the skull. This is definitely common. What does it look like? If you get these lesions, sometimes they may not present with any clinical symptoms. I will say that since this is the most common one, if you get these
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like litic lesions, you may find them on imaging, but sometimes it may be bad enough that it can cause fractures of the bones, right? So, that's one thing you want to watch out for is is there any development
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of pathological fractures, right? because that can definitely cause a lot of back pain or the lesions itself can cause back pain. So the complications that you want to watch out for is with these litic lesions comes about fractures or just comes generalized
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pain especially back pain and that's often times the way that these patients present. Worst case scenario and I've seen it. It's terribly sad is that sometimes if you get enough of these lesions, right? So let's say here's the
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body of the vertebrae. Let's say you get a lesion right here. Look what it's right next to. So, here's my litic lesion.
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Look what it could be next to the spinal cord. And dude, sometimes these litic lesions can cause compression of the spinal cord. Sometimes plasma cells can infiltrate into the bone and what's called a plasmocytoma. They can cause like a a so a solid tumor right
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there and that can compress the spinal cord. And so the big thing that you got to watch out for here is the litic lesions having enough encroachment on the spinal cord, especially since they occur in the vertebrae. So spinal cord
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compression is an emergency in this scenario. So definitely watch out for spinal cord compression. This could be due to a fracture that causes that displacement.
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It could be due to the litic lesion being enough to compress on the area or sometimes it could be due to a plasma.
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All right, definitely be wary of these. Now one other thing here. So we know that if a patient comes in with hypercalcemia or these litic lesions, we have an idea of what we would be looking for radioraphically in worst case
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scenario. But how do I know that this hypercalcemia isn't from something else? Because hypercalcemia can cause kidney stones, nephrogenic DI, and it can cause a lot of these different lesions of the bone. How do I know it's not something
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else? Well, remember high calcium is going to suppress your parathyroid gland. So what's going to happen to your PTH levels? That should drop, right? So we know that it's not a problem with hyper parathyroidism.
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The other thing that you have to ask yourself is could it be due to any other kind of malignancy? Could this be another source? And so remember, you always want to check other reasons. And so the big thing that you want to look
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for is these patients will have normal PTHrPS. Do you guys remember that? Come on, tell me you do. That was the squamas cell carcinoma. There's none of those.
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What about the granulominous diseases like um patients who have sarcoid or lymphoma? Do you remember what those could do? They could cause abnormal vitamin D. These patients will have normal vitamin D. So if they have normal vitamin D, normal PTHrP, and their PTH
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is low, it's not hyperarathyroidism. It's not a malignancy from the squamas cell. It's not some kind of sarcoidosis or a lymphoma. This is a malignancy of a litic lesion, multimoma. That's really important to remember. Now one other thing I want to talk about here it's a
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small add-on because we're going to talk about this more specifically when we get into amaloidosis but there is a type of amaloidosis when these plasma cells when they make these antibodies right they make these different antibodies right some of these
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can get misfolded and if they get misfolded these can go and deposit into different organs and that's where it gets kind of scary um and So one of these things that can happen is if it starts to cause misfolding of the
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proteins. So let's say misfolded proteins and they start depositing then we get something called amalidosis. It's called light chain amalidosis. This can cause um deposition into the heart and we'll talk about this later. You can get something called restrictive
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cardiammyopathy. That's one thing. It can also deposit into the um the glomemelia basal membrane into the ptoytes and you can get something called nefertic syndrome.
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All right, these are the two big ones. There's other areas but again I don't want to talk about this too much because we're going to talk about this in its own lecture but do know that there is a
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high correlation of multiple myoma with light chain amaloidosis and we'll talk about that later but there is other types of amalidosis. All right.
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Hypercalcemia, litic lesions with multimoma. We've already covered what part of the crab criteria. C for hypercalcemia and the litic lesions, the bone pain. Usually it's the back. Also, watch out for the ribs. The ribs are another one. Sometimes long bones, not
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too common. Skull. All right. Now, we got to take care of the other parts.
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Renal failure and anemia and infections. So, let's come down. Renal failure baby. Not a good thing. Really, really important to know multiple myoma. So what happens here when a patient develops u myoma they can make all those amunoglobins we talked about but these
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little puppies here dude the light chains here's all those light chains these are the problematic guys all right so here's my light chains and again these were the uh kappa lambda light chains when you're making a lot of these
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in a patient who has multiple myoma problem with these is that they get into the circulation and they get filtered across the GBM.
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When they get filtered across the GPM, GBM, they can get taken up by the proximal tubular cells. Once in the proximal tubular cells, they can cause tissue death. They can cause a bunch of different types of chemical reactions,
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but eventually what they're going to do is they're going to cause necrosis, right? So, they're going to cause necrosis of this tissue.
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As these tissues start to undergo necrosis, right, what starts happening? They start shedding off their layers, right? So, they start sloing some of their tissue layers off here. And then here is going to be this cast, this muddy brown cast
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that can form here. You know what else? Sometimes these light chains can actually bind with other proteins and they may even cause like a cast nephropathy where they actually cause a little bit of obstruction there as well. But basically
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what you get here is you get an obstruction, right? You get an obstruction due to casts. When that obstruction forms this basically prevents the normal flow of urine, right? So this ability to go here is now impeded. The problem with
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that is is that now the pressure inside of the capsule goes up and you start inhibiting the filtration.
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If you inhibit the filtration, your GFR starts to go down. Right? So now what happens is the patient's GFR drops.
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Right? So let's say over here their GFR starts to drop as a result here. If the GFR drops, you lose the ability to excrete waste products. One of those waste products is creatinine. That can start to go up. And so what happens is
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you're supposed to be excreting things that can be impaired. Your creatinine can start to go up. All right? So watch out for an increase in the creatinine and and a decrease in their GFR. The other thing is that sometimes if your
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inability to actually secrete waste products occurs, you also run the risk of AKI complications. So the other thing that you want to watch out for is a elevated potassium and ele elevated protons elevated um volume so hypervalmia and then elevated bu which can cause
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uremia right these are all things that you want to be careful that the patient doesn't develop hypercalemia acidosis hypervalmia uremia these are all potential complications now when a patient comes in they have multiple often times they'll have a degree of
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renal failure failure but that's present due to this um this kind of what we call cast nefropathy right as a kind they form casts and these kind of get stuck there in the proximal tubial obstruct the flow and lead to a drop in the
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filtration that'll lead to a steady rise in the creatinine and then over time you can get complications from AKIs or from severe CKD thing to remember here is that it's about the light chains and so sometimes what we'll do is is we'll
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measure these chains when they get into the urine And what we can do is sometimes we'll do something called a UPEP. And so when you do a UPEP, what it detects is it detects the proteins that are in the urine and it'll
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separate them out. You'll get an M spike just like you would in the serum. But that MEP, if there is the spike, what it tells me is that there's lots of these light chains that got stuck in the
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urine. And these are going to be elevated. So you get a positive UPEP. But all that tells you is you have lots of these light chains. It's important to know another name for this. Another name for these proteins that get into the
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urine that cause kidney damage is they're called Ben Jones proteins and these are basically those kappa and lambda light chains that when they get into the kidney and they cause this nephrotoxic damage they're called these benones proteins. All right. So if
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you have a positive upp that M spike it may indicate the presence of these Ben Jones proteins and multiple myoma. All right. Now another thing here anemia. This is a big one to talk about. The reason why is anemia can
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be due to a lot of different kind of things. One of them is it could be due to the plasma cells just kind of infiltrating into the bone marrow. And as they infiltrate into the bone marrow, they make less space. Right? So let's
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say here I infiltrate the bone marrow. So this could be due to infiltration. What I mean by infiltration means that I take these dang plasma cells. Right? Here's all my plasma cells. And I got a lot of them. And I go
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ahead and say, "Hey, go into the bone marrow." and really kind of get up on in there, right? Get in there nice and dig black. And when it gets in there, it starts crowding out that space. And so
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if I crowd out the bone marrow, I I make less room. I take away the nutrients that are needed to make other cells and it may cause cytoenas. Unfortunately, the one that we notice the most pronounced is the red cells. And so if I
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crowd out that bone marrow, what I do is I decrease my red blood cell production, right? And so I can end up with anemia due to that. And this is more of a um a normocitic anemia. But there's another
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concept here. If I crowd out that bone marrow, that's one way. Another thing that also happens is that in anemia, these plasma cells, remember the cytoines that they were making sometimes unfortunately interlucan one, interlucan 6 is another one, tumor necrotic factor
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alpha, all of these are inflammatory cytoines. When you have inflammatory cytoines that are present, what can they do? What do they tell the liver? They tell the liver, hey, lots of inflammation, bro. Do something about it. And the liver makes a molecule
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called hepsiden. And what does hepsidin do? It basically shuts down the macrofase and shuts down the intestines so that you can't release iron or absorb iron.
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And so this process gets inhibited. So you inhibit the macrofasages, you inhibit the feroportin channel and you inhibit the release and absorption of iron. So what happens to the iron levels in the blood? They go down. If you have less iron in your
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circulation to be delivered to the bone marrow, can you make red blood cells? No. And so that's another factor here where you're going to inhibit the production of them.
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That's kind of an anemia of chronic disease. And so it's really kind of interesting when you think about this.
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Another thing that's really really important is when you have all of these um proteins and lots of inflammation, one of the things that happens is the red blood cells because of that inflammation, they like to stack.
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And so you end up kind of getting these stacks of red blood cells. And this is usually due to lots of proteins like amunoglobulins as well as lots of inflammation. And this is really important to know. So when you get these
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like stacked up red blood cells, it's called a ruo formation. This is actually kind of helpful when we look at this on the peripheral blood smear. So when you look at the peripheral blood smear and you actually assess this, you're going to
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see these red blood cells that are all stacked up really, really nicely. All that tells me is that again there's lots of inflammation, lots of proteins that are actually present there. And when you have that, sometimes the red blood cells
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start stacking up on one another. And what actually this could indicate, you know, when you take a red blood cell, you put it in a tube and you see how fast it drops, it determines the ariththraite sedimentation rate, ESRs
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will go up. ESRs are indicative of systemic inflammation. They don't tell you what what's causing it, but it tells you there's some inflammation going on within the body. So low formation tells me that there's in inflammatory processes that are going on or there's
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lots of proteins that are increasing the viscosity to some degree in the blood. This is really important that you can pick this up on the peripheral blood smear. All right, it actually looks a little bit like this.
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So anemia is another factor looking for a low hemoglobin, low hematocrit, a low formation on a peripheral blood smear.
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And usually these red blood cells, they're normals sized. And so that's actually important to remember that the MCV is normal. All right? So it's usually what we call normocitic uh anemia. And whenever you have a normic anemia, you always ask yourself
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the question uh is it a lower tick index or higher tick index? You would check the retick index. it probably be to some degree low. And then you say, okay, is it something with a bone marrow like an
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alastic or an infiltrative process? Multim myoma does that. Or is it due to anemia, chronic disease? Multimoma does that. So it's both of them. All right.
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Infections. This one's kind of interesting. And the reason why is it causes a relative hypo gamma globulmia. What I mean is is that these plasma cells, right, they produce, let's say, decreased functional.
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These are less functional um amunogloabbulin G or amunoglobulin A, right? So it's less functional uh amunoglobulins. They don't really do as good of a job as they should. All right, that's these plasma cells are making these malignant plasma cells are
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making these. But the other thing is malignant plasma cells actually end up decreasing. So let's say here's a normal plasma cell. So here's your malignant ones and this is going to be a normal plasma cell.
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The interesting concept here is that when you have all these like malignant plasma cells, what they do is is they can actually suppress your normal plasma cells from producing true good healthy normal polyclonal antibodies. And so this is actually kind
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of what happens is that these malignant ones can actually come over here and they can take up space or crowd out or suppress your normal plasma cells. And so that causes this kind of drop in other amunoglobulin lines. And so you'll
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end up with a lot of these uh functional so you end up with a a lot of these less functional amunogloabbulins and you'll also end up with less of your functional imunogabulins. The whole point of that is if I don't got good amunogloabbulins,
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so I got less functional ones. All right, so I have let's actually put it like this. Let's say I have more I have lots of less functional amunoglobulins and then less of true functional imunogloabbulins. That's the concept that I want you to think about.
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So less of functional amunogloabbulins, right? That's the thing that's important to remember. because of that you end up with what's called a relative hypogamagulinemia.
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So you don't have true antibodies that can bind onto these bacteria and neutralize them or opsinize them um or help with enhancing the fagocytosis process or causing them to be cleared uh by the spleen, right?
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Or helping other cells to cause cytotoxic damage to these types of um uh uh bacteria. And so what happens is you end up with an ability to allow certain types of bacteria to thrive. And those two bacteria that are really important
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to remember is streptococcus pneumonia. So you have a higher risk of infections due to streptoccus pneumonia and hopus influenza.
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These are going to be the two particular type of bacteria that are encapsulated that you can have a higher risk of infection with. All right, watch out for that. And so if a patient gets these kinds of infections, oftentimes strep
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numo and uh influenza are cinopulmonary kind of areas. So they like to cause like sinusitis like bacterial sinusitis and pneumonia. So patients who are developing recurrent episodes of pneumonia, that's an important thing.
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All right. So with this being said, we've really talked a lot about how multiple myoma can cause a lot of different kinds of devastating effects.
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It's important to remember multiple myoma, lots of amunoglobulin G or lots of imunogloabbulin A plus a lot of light chains. The less functional amunoglobulins can cause problems with being able to fight off immunity. Plus, these malignant plasma cells are
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suppressing normal plasma cells from producing true functional antibodies. A lot of these plasma cells infiltrate the bone marrow and they crowd out the space to be able to make red blood cells. They also suppress red blood cell production by lowering the true
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sufficiency of iron. that's needed to go to the bone marrow. The light chains chalk up the actual kidney tubes and cause renal failure and plasma cells can actually signal the bone to start causing destructive processes and in worst case scenarios multiple myyoma can
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increase the risk of light chain amalidosis. So you see a lot of different things here. What I want you now to talk about or to learn about is Waldenstrms.
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Walden's macroglobial anemia is again it's a malignant condition. What happens in this one is these lymphopplasmic sites can do a bunch of different things. Let's say the first one, son of a gun. The first one is that these
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lymphopplasmic sites can come over and what they could do is they could deposit into different types of organs, right? Let's say that they come over here, right? And you got lots of them and they decide to infiltrate. So
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there's a tumor infiltration process. they decide to infiltrate into the lymph nodes. If they cause lymph node infiltration, this will cause the lymph nodes to get bigger and this can lead to lymph adenopathy which is basically kind of an enlargement and swelling
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of the what lymph nodes. And usually this is like the cervical lymph nodes that get affected or the axillary lymph nodes that are get affected. So it's important to look for any kind of like painless and enlarged swelling of a lymph node.
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And when you palpate it, you'll be able to feel that kind of like rubbery feeling of that lymph node. That could be due to Walden's macro globalmia.
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The other thing is it likes to deposit into the liver and the spleen. And if it deposits into the liver and the spleen it can cause liver and spleen infiltration and that can cause hpateno megaly.
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If this kind of event happens how would this patient often times present? Well with hpatosplenomegaly it'll cause enlargement of the liver. They may have kind of some some potential like feeling there around that costal vertebral angle. The spleen gets enlarged as well.
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But here's the big thing. As they get bigger, they take up space and they start pushing on the stomach and so it makes less room for whenever you want to take in food. And guess what that leads to? It leads to an abdominal fullness
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and early satiety. So this can lead to abdominal fullness and distension sometimes too. Abdominal fullness and it can also lead to distension. So these are things to definitely consider for that one. The other thing that can happen is that these lymphopplasmic
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sites can also infiltrate the bone marrow. If they do infiltrate the bone marrow, again we already kind of have an idea of what that may do. If they do cause bone marrow infiltration, what may that do? That may make less space. If
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there is less space inside of the bone marrow, that may crowd out that ability to make other types of cells. The most common one to be affected is the red blood cells. And so by crowding out that space, crowds out
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the bone marrow and by crowding out that bone marrow, you're going to lead to a decrease in red blood cell production. And again, this is going to be kind of a normidic process. And so when I look at these
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patients MCVs, you're going to notice that they will be normal. All right. The other thing here is that these lymphopplasma sites, they also can do some other things. This is only 10% of cases. So this is most common in 10%
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of cases. Let's say this there. In 10% of cases, they can make these auto antibodies.
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And these auto antibodies may go and bind onto different types of antigens that are present here. So let's say here we have a antigen. These auto antibodies may go and bind onto these antigens here. And what it may do
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is it may cause these red blood cells to be tagged and to be killed or to be ripped up per se in the spleen. And so this may cause these cells to get hemalyzed.
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All right? And that is called autoimmune hemolytic anemia. So this is this will go to the spleen and it'll get hemalyed.
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This is called autoimmune hemolytic anemia. So sometimes you may have these patients who can develop an autoimmune hemolytic anemia. It's funny enough uh one of the things here is that this can actually uh you can see this increase in
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lymphopplasmosytes. It's kind of like lymphoma essentially honestly it's a bell neoplasm and so because of that bell neoplasms especially CLL is associated with autoimmune hemolytic anemia right so that's why we could see this as well as the source of the
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patient's anemia only 10% of cases though all right so if the patient has lympadinopathy it's because the lymphoplasmic site infiltrated apatosphonomegaly because the lymphoplasmic site infiltrated and anemia because of infiltration into the bone marrow but also they could have
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anemia because in 10% of cases is you can develop auto antibodies. Which ones are these?
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Ig M. And these IgM antibodies may go and bind to the antigens here and trigger autoimmune hemolytic anemia. All right.
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Now the next concept it may cause hyper viscosity syndrome. This is the high yield. If you forget this that's okay. This one you cannot forget. Now in patients who have hyper viscosity syndrome, these lymphoplasmosytes are pumping out the IGM antibodies. So here's all my IGM
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antibodies. And again, you got to remember, I know I'm representing them like little Y's, like they're monomers, but these are pentimer. They're huge, dude. And so because of that, you're going to get tons and tons of these IGMs. They're going to take up a lot of
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space and they're going to really thicken up the blood. So imagine here I have good, you know, normal blood, you know, no viscous flow. So let's say here decreased viscosity and here you're going to have increased viscosity. Let's compare the flow. So
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here's normal viscosity and here's super super high viscous blood. What's going to happen to the flow? Well, normally it's going to be laminer, right? You're going to have that laminer flow here.
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It's going to be maybe laminer, but it's also going to be super sludgy. So you're going to have a very, very, very, very slow flow. It's going to be super slooper slow.
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So you're going to have good blood flow here and then decreased blood flow here. So increased blood flow and here you're going to have decreased blood flow.
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You can imagine how that'd be problematic. Right? So if you have super high viscous blood that blood flow is going to be really really low. And imagine having poor cerebral profusion.
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If I have decreased cerebral profusion, how could that potentially present? It may present with headaches. It may present with dizziness. It may present with an altered mental status. Right?
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And this is because of decreased cerebral blood flow. So decreased cerebral profusion. What if I congest the So what if I have sluggish blood flow coming out of the retinal vein? So the blood leaving the retinal vein is impaired. Well then the
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retinal veins can start getting super super enguled engorged and big. And so sometimes what can happen is you can have uh what's called retinal vein stasis or engorgment. And so what happens is you end up having decreased retinal
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drainage because it's super super viscous blood there bro. Right? So decreased retinal drainage leads to these retinal veins being gargantuous. So ends up happening is you get these enlarged retinal veins.
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All right? So this causes enlarged retinal veins which if you do fundoscopy on these patients, you may see this. It actually can look a little bit like this.
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The other things that you may have seen on that potential image is that sometimes that backflow can actually cause like small hemorrhaging into the retina. It can cause like retinal hemorrhaging. The other thing that's also important to remember is that
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sometimes you can even get swelling of the optic disc and cause papa edema as well. So watch out for poor cerebral profusion which can cause these features. Watch out for poor retinal drainage which can cause enlarged retinal veins which may cause
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fundoscopic findings. But how would they present clinically? What would they may say? Well, what's the retina designed to do? Help with your vision. Guess what could happen? You can get blurred vision, right? So the other thing to watch out for is blurred vision. These
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are often times the main ways that patients will present is a headache, blurred vision. Sometimes it's very rare, but imagine you have this super high viscous blood and you have to pump that blood out of the heart. It's going to be really hard and
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so it's going to be difficult to get the amount of volume you want out. And so the stroke volume may go down, the cardiac output may go down as a result of having this super super viscous blood. If that happens
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and you end up aren't able to get your heart isn't strong enough to push this super high viscous blood out, you end up with a low cardiac output that may cause blood to back up, right? So blood may
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back up into the left atrium and then into the lungs. How could that present?
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With pulmonary edema, india. So these patients sometimes can develop congestive heart failure. I wouldn't say worry too much about this one, but consider it. All right, congestive heart failure may be a potential symptom here, but definitely blurred vision, the
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fundoscopic findings, and then features of headache, dizziness, and altered mental status. The other thing is that these little jacked up fingers here that you see, I look I can I can't draw a hand. I know, don't laugh at me, but you
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can get these real jacked up fingers. And the reason why is whenever you get in cold temperatures, this can actually cause again sluggish flow. And so you get poor profusion to the digits and they can actually end up with cyanosis
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of the digits. And so watch out for rain outs phenomenon. This is going to be that bluish discoloration of the digits due to poor flow. If you get them out of the cold temperatures, it should actually help.
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The other thing that's really important, I'd say this often times is the way that I would be potentially worried to see this is that whenever you have all these IgM antibodies, not only do they increase viscosity leading to these
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types of presentations, but the other thing is these um antibodies, the IGMs can actually bind to platelets and kind of coat the surface of the platelets.
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And when you do that, you basically inhibit the platelets. So you inhibit the platelet aggregation. When you inhibit platelet aggregation, are you going to be able to form a clot if needed? No. Guess what that leads to?
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Impairment in primary hemostasis. What's going to happen? The patients can bleed. And so bleeding is another way that these patients often times present. What are the ways that you bleed when you have um uh superficial or we say
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platelet disorder related bleeding. Do you guys remember superficial bleeding? So how' that look? peticier papiraa but the most common presentation is epistaxis that's the one that you have to watch out for watch a patient who has gingerville bleeding or epistaxis
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oronasal bleeding is the most common way that patients with hyper viscosity syndrome will present now that we've done that let's move on to the next step here when a patient develops hyper viscosity syndrome you have to watch out
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for these big complications and it's super important because if you miss this you're going to miss the proper treatment for the next one is neuropathy neuropathy so was tumor infiltration that caused all these. It was circulating IgM that caused all these.
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What the heck about this one? All right, these lymphoplasmosytes are pumping out these antibodies, right? These IgM antibodies, these IgM antibodies may attack certain types of areas and sometimes this can cause an autoimmune like activity. So here, let's actually bring it over here.
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Let's say here I'm going from this guy to this guy. And what I'm going to show you is something happens to these mileins. Here, this milein was normal.
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Here, where's my pink marker here? This myelin is jacked up beyond belief. Look, I got pieces flying everywhere of myin.
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Milin's all jacked up. Demiselination going ham. So, what you're going to notice here is that there is some demyelination that is occurring. And I think you have an idea as to why the demyination is occurring. I'm taking this neuron,
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ripping apart that milein. The reason why is these IgM antibodies come in here and trigger that process.
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They bind on to they have like specific areas. It's called myelin associated glyoprotein. I don't want you to go crazy. I'm going to put it here. I'm going to put like a little molecule here. And I'm going to call this MAG.
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All right. Myelin associated glyoprotein. This is an area where these IGM antibodies may bind and then activate the immune system and cause demalination. If this causes demalination, what happens to the neurons? and they fire properly. No. And so you end up with this drop in the
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ability to send proper action potentials and conduct these things. Right? So now these usually occur to peripheral nerves. Peripheral nerves, dude, they're supposed to be supplying the peripheral, especially the lower extremities. Guess what ends up happening? Well, the first
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thing that happens is it's going to be a progressive. So I'm going to represent this in red. You're going to start off with some progressive but symmetrical paristhesas. So some numbness, some tingling. And this will get worse and
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worse and worse over time. So you're going to see symmetrical progressive paristhesas and sometimes worst case scenarios. These nerves, they don't just carry sensory information. Guess what else? They carry motor information. So what else could happen? Weakness. So the
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one thing that you want to watch out for here is if this continues to happen, these patients can get what's called progressive symmetrical paristhesas. In worst case scenario, I'm not going to add it here. That's the most common way. But in worst case
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scenarios, they may develop weakness. So if a patient comes in, you're trying to determine which kind of plasma cell disorder they have. You have to say, okay, are they asymptomatic? All right, cool. Could be MGUS. Do they come in
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with crab criteria, hypercalcemia? Do they come with litic lesions? Do they come in with anemia? Do they come in with renal failure? Do they have any potential evidence of infections? Could be multiple myyoma. Does the patient come in with hyper viscosity syndrome?
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What's the most common way? Headache, dizziness, altered mental status and blurred vision. And then the form of bleeding, oral nasal bleeding. If you got the memory capacity, remember CHF, remember phenomenon. What is another way? They can also have neuropathy and
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tumor infiltration with anemia, lymphenopathy and apatosangle. These are really important things to remember. The also big difference here is that MGUS and multiple myoma are IGG or IGA with light chains. Waldenstrums is IGM predominant. So this is a lot of stuff
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that we talked about. How are we going to put this together? I got you. All right, my friends. Now let's move on to the diagnostic approach. Let's put all of this stuff together to see if we can come up with a way of being able to
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truly differentiate. Is this imgus? Is this Waldenstrums? Is this multiple myoma? I think I had a good good way for you guys to think about this. So we can do a lot of different tests whenever we suspect plasma cells. Oftentimes doing a
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really good history in physical can give you a ton of information. Right? Thinking about this patient and saying, "Hey, do you have any kind of bone pain, any kind of pain anywhere? Do you have any kind of symptoms where you're
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changing of in your urination, your drinking p process, any kidney stones?" Like going through those kinds of things are really really helpful to see if the symptoms are kind of manifesting from the resulting like issues. So things like hypercalcemia, the litic lesions,
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anemia, etc. A CBC is also going to be really good because it's going to be able to pick up anemia, right? A CMP will be great because it can actually tell me my protein gap, which I'll explain what that is, and it can also
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tell me what my calcium is and if that's elevated. And a skeletal survey to go along with a good physical exam to say, hey, they have pain in their back and I find that this is a lesion here or they
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have pain around their ribs or on their skull and I find these lesions here.
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That can be associated with a good kind of like combining of physical exam and also appropriate imaging. And this can start kind of really helping us to think about which one of these plasma cell disorders is presenting. So let's say
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for example we think about just general clinical presentation. MGUS really shouldn't present with anything. It's pretty much asymptomatic and so we don't have that classic crab criteria.
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Multiply myoma should have at least in some way shape or form a crab criteria.
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That means that they should have hypercalcemia um or renal failure or anemia or bone pain and lesions or recurrent infections is another additional thing to think about. Walden Strums the primary one I want you to remember is hyper viscosity syndrome
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plus or minus neuropathy is another one to consider but that's the really big one and again remember hyper viscosity was the you we're talking about the headaches the dizziness the altered mental status the blurred vision from impaired cerebral profusion and impaired
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retinal drainage and then superficial bleeding from inhibiting platelet aggregation that's the real thing I want you to think about here so again when we think about that in combination with one other thing is what's the protein gap the protein gap I'll tell you a little
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bit later is the total protein minus the albumin and if that is elevated it tells me that there's a bunch of different proteins in the bloodstream are elevated we just don't know which ones and we got to dig in a little bit deeper so
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elevated protein gap can be seen in all of these but this is just a simple way to kind of start kind of like developing a dichotomy to think about how can I truly organize these in my brain now
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let's say that we kind of get pieces of information on the clinical vignette and we see that okay their CBC shows me that they have some normic anemia they even give me a peripheral blood smear and it shows me this this is indicative of a ru
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right and a ru is telling me there's lots of ariththraite sedimentation that proteins are kind of present in large amounts and the red blood cells are sticking to one another and they would e easily be able to fall down the test
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tube super quick. Another thing is if I got a CMP and I told you that protein gap is elevated. Now protein gap is really important to discuss. Um it's not something that we routinely do but it is something I think it's always a good
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part of your process when you're evaluating blood work. So when you evaluate blood work you should look at the protein gap just as a quick little monitoring. You take the total protein and you subtract the album and all you
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want to know is where does that number fall and usually if it's pretty high like greater than four we start getting a little bit more concerned and thinking about potential possibilities. Now the protein gap isn't a perfect test. And
Speaker A
the reason why is it tells you that the total protein is elevated. And that doesn't help you to determine if it's the alpha, the beta or the gamobbulins that are elevated. I can't really tell you. All I know is that one of those or
Speaker A
maybe a bunch of them were elevated because when you actually look at an electropharesis which looks at concentration on the Y and then protein migration on the X you have albumin which is the most abundant. Then you have your alpha and then you also have
Speaker A
your beta and then you have your gamma globulins and all of these can be various different types of proteins.
Speaker A
Alpha 1 can be alpha 1 antitripin a alpha 2 you have ceruppo plasma heaptoglobin these are made by the liver betal globulins things like transferin c3 compliments fibbrronogen but gamag globulins is where we're spending our time and this is where the antibodies
Speaker A
are amunoglobulin gam d I just want to know if these are elevated especially in plasm cell disorders I don't really care about these other ones so how do I really determine that I'd have to get an SPE if my protein gap's elevated and I
Speaker A
got some of these other problems I would actually take the time to go ahead and order an SPE so that's what I want you guys to remember is it just tells me that protein's elevated. It just doesn't tell me which one. All right? And that's
Speaker A
what I got to figure out because this could be the thing that's rising up my total protein. I just don't know that off of a protein gap on its own. All right? So, let's say that I keep evaluating the patient. I see that they
Speaker A
have an elevated protein gap. They have some anemia. Their CMP shows that they have hypercalcemia and their skeletal survey going along with their physical exam shows that they have litic lesions.
Speaker A
Maybe they have some scolytic lesions. Maybe they have some vertebral lesions. Maybe they even have some rib lesions.
Speaker A
But these things are present. That's what I really want you guys to think about. Now, if a patient came and they had a protein gap that's elevated greater than four and then on top of that, they presented with crab criteria.
Speaker A
They have hypercalcemia. They have renal failure. They have anemia. They have bone pain or lesions. Or maybe they even have hyper viscosity syndrome, which you can get from their exam. Maybe they present with a altermental status, blurred vision, maybe they're headache,
Speaker A
maybe they're presenting with um, you know, vision changes. And on top of that, they have superficial bleeding.
Speaker A
And if they have a protein gap that's elevated, you should think about Waldenstrms. So, at this point, I'm definitely thinking they could have a plasma cell disorder. So, how do I really determine which plasma cell disorder it is? That's really the
Speaker A
question. So, I have to determine if it's even antibodies or light chains that are even elevated. So, I'm going to get an SPE and that's going to test for the the proteins. And I'm really looking at gamaglabulins in the blood, the bench
Speaker A
proteins, your light chains in the urine, and just your free light chains, how many of them are in the bloodstream.
Speaker A
And this is really going to be super helpful and something they could easily test you with on the exam. This is kind of trying to put everything together.
Speaker A
So, ESP is again testing the proteins in the blood and it's quantifying which one of these out of all of these is elevated. That's what I want to know.
Speaker A
And if I see this as an M spike, so that's a monoconal protein spike indicating that this is priam globulins of some sort that are elevated. That's all I want to know. It doesn't really detect light chains. It looks at the
Speaker A
amunoglobulin G, the imoglobulin A, the imunogabulin M, E, and D. Now, when we have an M spike, all it tells me is that the gamma globulins are elevated.
Speaker A
doesn't tell me which one of those is elevated like the IGG am I have to do amopixation and that's going to tell me which one of those is elevated if I see IGG and IGA it could be multiply myoma
Speaker A
could be MGUS how do I determine that it's looking at the degree of the M spike if it's less than three that that's MGUS bro right but if it's greater than three that's multiple myoma especially if it's associated with crab
Speaker A
criteria we're putting this stuff together now if I'm immunoixate and it shows IGM it's pretty much done bro we got Waldenstrums we good and that's the way I want you to think about that. Now this doesn't mean that it's definitely
Speaker A
that disorder but it definitely adds a lot of emphasis and support to it. So that's when I would move to the next concept here which is again SPAP less than three no crab criteria that's MGUS SPAP greater than three and there is
Speaker A
crab criteria multimoma msp spike greater than three and it's IGM on amunofixiation that is wald and shrubs really important make sure you guys add that note if it's IGM wenums IGG IGA are elevated it could be these two just
Speaker A
depends upon the degree of the spike that differentiates them all right now let's move into the upupep the urine protein electropheresis this is really helping me to look for bench Jones proteins. So I would be looking for those light chains to be enough in the
Speaker A
urine that it's going to cause a spike. And so I would see this M spike just like you would see in the SPEP. And then when I look at that, I would actually be able to determine if it is the Bench
Speaker A
Jones proteins, those light chains that are building up in the urine. And that's the problem. That's the one that's causing all the acute tubular necrosis and the renal failure. That's what we see in multiple myoma. We don't see that
Speaker A
in MGUS. We don't see that in Waldenstrms. And so that's what you're really looking for is the UPEP to be negative on these two and positive for this one. So again, we're adding more layers of how to differentiate these.
Speaker A
You differentiate all of these based upon the mspike, the degree between these two and then the type based upon these two. And then upp is negative for these and it's positive for this one.
Speaker A
Let's add one more layer. Then we talk about the free light chain ratio. Right?
Speaker A
So the free light chain ratio is just telling me the amount of free light chains that are present in the bloodstream. And the primary one that's going to be significantly elevated is going to be multiple myoma. You can have
Speaker A
some free light chains that are elevated in MGUS. It produces IGG, IGA and free light chains. It's just going to be nowhere near the degree of multiple and you shouldn't have any light chains for Waldenrums. So when I look at these, I'm
Speaker A
going to look at the plasma cells and the ones that have a high free light chain ratio. It could be MGUS or it could be multiple myoma. It's the number that we look at. And usually we say if
Speaker A
that ratio is greater than 100 that's highly suggestive of multiple myoma. So a mildly elevated free light chain ratio could be seen in MGUS. So when we put all of this together if I say a mildly elevated one cool but if I say this
Speaker A
thing is huge greater than 100 we highly associate that with multimoma. Normal is walden. We've added layers to this. Okay so we talked about SPEP. If the M spike is greater than three it could be multimoma could be walenrums. How do you
Speaker A
differentiate? Which one's IGGA? Multimone. Which one's IGM? Waldenstroms. If I say Mspikes less than three, no crab criteria. That is MGUS.
Speaker A
If I said which one has the Bench Jones proteins that are detected on UPEP, you would say multiple myoma. If I say which two have an increased free light chain ratio, that means that they make a lot of light chains. That's MGUS and that's
Speaker A
multimoma. Which one's way higher? It's multimoma. We really, I think, dove into this pretty good. But now we're not done because now we got to take it one step further and confirm the diagnosis. And you can't do that until you've done a
Speaker A
bone marrow biopsy. Once you've done that and you need to determine the number of plasma cells or lymphopplasma cells that are in the bone marrow, you can then conf confirm and definitively make that diagnosis. So for example, if
Speaker A
I took the bone marrow, took it out, drew up, aspirated all of that actual cells out of there, sent it to the lab and had them quantify the number of plasma cells or lymphoplasmittes, I could go from there. If I said the
Speaker A
plasma cells are less than 10% that's mgus. If it's greater than or equal to 10% that is going to be multiple myoma.
Speaker A
And if I see lymphopplasmic sites are greater than 10% that is walden's macrolab anemia. Right? So we're really putting to this together in layers where you start off with a protein gap is maybe a presentation or maybe the crab
Speaker A
criteria is a presentation or maybe hyper viscosity is a presentation or maybe you have one of these two plus an elevated protein gap. You go to the links of getting an SPE, a UPEP, a free light chain. that's really going to
Speaker A
differentiate them and at that point you confirm with a bone marrow biopsy. Now, out of all of these, there's one that I really do have to dig a little bit deeper, and that's the multioma. And the reason why is I need to know if they
Speaker A
have the 1114 transllocation or not, because that's going to determine how I'm going to be with these patients, right? The other thing is that when we do this, we actually check the 1114 with the cytogenetics. We'll check an LDH
Speaker A
level. We'll check a beta 2 microlab. And we'll check an albumin level. And all of these things really help me to determine the patients risk and their prognosis and how well they're going to do and respond to therapy. If they have
Speaker A
the 1114 transllocation and normal beta 2 microlabulin LDH album, this is actually a good thing. This means I can have a standard risk kind of patient. I they may have a good prognosis.
Speaker A
If I have the other one where they don't have the 1114, they have an elevated beta 2, an elevated LDH, and a low albumin. This is a very high-risisk patient. This is going to be the one that's going to be a little bit more
Speaker A
challenging. All right. So, this is something that just takes you the extra step to really kind of like prognosticate for these patients.
Speaker A
All right. We've gone through, we've talked about the different types of plasma cell disorders. We talked about the potential complications. We talked about the ways that we should diagnostically approach these disorders.
Speaker A
How do we treat them? Well, lesions are pretty straightforward. You treat them kind of similarly to how you would treat a patient who has osteoporosis. A lot of the times with these plasma cells again they're pumping out rank lian. They're pumping out
Speaker A
osteoclass activating factor and other cytoines and that's activating those osteoclass, right? They're really hitting those osteoclass and triggering them to release hydrochloric acid collagenase that's ripping apart the bone and that's causing these litic lesions and even hypercalcemia, right?
Speaker A
And what I want to do is I want to come up with a drug that can target this. And so that's where things like bisphosphinates or denosimab comes in.
Speaker A
Right? Bisphosphinates are great. And the reason why these are great is because they would probably be your first line. And this is going to be things like alenronate, zoland droneate.
Speaker A
And what they're going to do is they're going to directly inhibit osteoclass proliferation. If you inhibit these cells from proliferating, you lose the ability of these cells to release hydrochloric acid and collagenase. That leads to less litic lesions. That leads
Speaker A
to less calcium released from the bone. Also, it kills these cells. It puts them into an apoptoic pathway. So you have less of them in addition to that. Not only killing them, but you're also triggering some of them to undergo that
Speaker A
apoptosis process. So you're inhibiting them from proliferating, you're killing them, you're really going to drop down this kind of litic lesion pathway.
Speaker A
Denosimmab is another really good alternative. Um it's kind of like a monoconal antibbody. It's kind of a second line. And what we would do with this one is it really is just going to be an antibbody that binds to the actual
Speaker A
rank liant and so then it can't bind to the rank receptor. That means it can't trigger this pathway. It can't release hydrochloric acid. It can't release collagenates. It can't cause litic lesions and calcium release from the bone. So that's another alternative I
Speaker A
want you guys to think about. All right, pretty cool to think about how that kind of works there. Let's move on to the next thing, infections. Now, what do we want to do? Well, these patients are super high risk for strep pneumonia,
Speaker A
homophus influenza type B, vaccinating them, making sure that they're up to date with their homophus influenza.
Speaker A
Making sure that they're up to date with their streptoccus pneumonia is really, really key to reduce the risk of having these infections. But if they keep developing these infections, that's when we would go the links of saying, "All
Speaker A
right, now we need something a little bit stronger." Then I would go to IVIG because you're going to be giving them functional immunoglobins. With vaccinations, you're helping them to develop their own antibodies, right, against that type of infectious
Speaker A
pathogen. With IVIG, you're giving them imunoglobulins. You're giving them the amount to help them to opsinize, to help them to be able to neutralize the pathogen, to help them to trigger the cytotoxic killing, to trigger the process by which we actually get rid of
Speaker A
these pathogens. And so that can help to reduce the risk of pneumonia and sinusitis, right? And again we neutralize these pathogens. We opsinize them to help them to get either destroyed by macrofasages or getting taken up by the um the spleen. We help
Speaker A
to allow for cytotoxic killing by natural killer cells or tea cells that will kill these pathogens. And we even help complement activation to lead to membrane attack complexes and putting holes in these pathogens. So that's what the IVIG would help us with. And that's
Speaker A
all going to help to reduce the risk of those infections of the lungs as well as the sinuses. Now acute acute renal failure when you get this a lot of the times you can do a couple different things plasma feresis or like a special
Speaker A
type of like dialysis could be an option um usually dialysis and you can even combine that with plasma feresis but you got to think about the problem with acute renal failure it's all of these light chains if you can clean the blood
Speaker A
of these light chains you can get rid of those you'll reduce that nephrotoxic injury that's the key thing to think about right hyper viscosity syndrome is a similar concept there's tons of IGM antibodies that circulating through the bloodstream and they're causing an
Speaker A
increase in viscosity. They're reducing cerebral profusion, they're reducing retinal drainage, they're helping to inhibit the aggregation of platelets. If I can remove some of those IGMs, I can potentially reduce the hyper viscosity types of presentations, right? And so
Speaker A
that's something that plasma freezes would be really, really, really good for is acute renal failure, multiple, and then hyper viscosity syndrome in Walden Strums. You can kind of think about this very simply and the multimoma again, it's making a lot of these antibodies,
Speaker A
IGG, IGA, it's making a lot of light chains. The light chains are really where the cappa lambda ones are causing the nephrotoxic injury. They're getting in there. They're destroying the actual proximal tubular cells. Right? With walden shrums, it's pumping out IgM
Speaker A
antibodies. And the IGM antibodies are causing decreased platelet aggregation and that's causing bleeding. It's also causing hyper viscosity syndrome which is causing reduced retinal profusion. Uh reduced cerebrusion, reduced retinal drainage. These are all issues. What if I had a machine that could help to get
Speaker A
rid of the light chains and get rid of the IgM antibodies and normalize that level? If I did that, I could potentially reduce the free light chain ratio, right? And on top of that, reduce the IGM antibodies and that would be a
Speaker A
great way to deal with this disease. So that's what I want you guys to know there. Okay? And all plasma freeases is you're taking the patient's blood, you're removing these kind of like antibodies and light chains and you're
Speaker A
kind of just sifting them off, right? waste those off and then you're going to send back a substitution fluid and back all their plasma that's free of these circulating antibodies and light chains back into their circulation. That's all
Speaker A
you're doing. Now with Waldenstrom specifically there is some things that we should talk about. We can consider things like a BTK inhibitor called a brute. This is I'd say becoming the more prominent kind of method that we use to
Speaker A
treat patients who have Waldenstrums. We do this if they have lympadenopathy or anemia or any kind of organomegaly. So they have padosplinomegaly. These are things that we would treat these patients with a BTK inhibitor and it's actually going to kill a lot of these
Speaker A
malignant cells and that's going to reduce the IGM production. Retoximab plus or minus chemotherapy is going to be for the patients who are very very uh symptomatic but also they can't tolerate the BTK inhibitor because this is a
Speaker A
pretty powerful drug. Um or they have neuropathy. Retoximab may be a little bit better in those scenarios but they do the same kind of thing. When you think about Retoximab, it's actually kind of interesting. Retoxmab needs a CD20 molecule to bind onto on your
Speaker A
lymphopplasma sites. And so it's going to go and bind onto the CD20, right? And what that does is natural killer cells will use that as a way of being able to release things like granzymes. And granzymes will then get released onto
Speaker A
the lymphoplasmittes, trigger them to undergo an apoptoic process. So when we give retoximab we need these patients to be CD20 positive but then we can really give them this to help to really help to cause the destruction of
Speaker A
lymphoplasmittes because if we destroy these guess what happens I stop producing all of those IGM antibodies that are causing hyper viscosity syndrome and neuropathy right and tumor infiltration such as organomegaly all right now what happens though transiently and we shouldn't stop it we
Speaker A
just have to monitor for it is you can get an IGM flare ups because because you're killing these things and they're containing what antibodies IGM so that can spill out a little bit and they can get a transient little IGM flare but
Speaker A
that doesn't mean that you have to stop it you can you can just keep riding that out usually all right so next thing is plasma cell disorders talking about you know bone marrow transplants and I'd say this more particularly with multiple
Speaker A
myoma and you're not going to need to know this and walnums even to that degree you probably won't even have to really apply this it's mainly multiple myoma so we want to know are these patients eligible for a transplant and
Speaker A
if they are we have a very specific process we're going going to start off with induction therapy and that's called your VRD. That's that's your bortezib, linenolyomide and dexamethasone. That's going to be induction. Then after that we're going to condition them. We're
Speaker A
going to get them prepared for the bone transplant with highdosese mephalam. Then after that we'll do the bone marrow transplant. They're going to replace that with normal plasma cells and then we're going to try to make sure that we
Speaker A
keep them in remission and that's when we'll do just just the bortesib and lenolyomide. All right.
Speaker A
Now if they are not eligible unfortunately we just do the VRD therapy and then we'll just continue after that after we try to do induction with the remission therapy which is linenomide plus or minusib. All right, so let's put
Speaker A
all this together that it's a simple concept here. Let's say that a patient comes in, they're eligible for a matopetic stem cell transplant. What's going to be your first one? Induction therapy. Then after that, you condition them with malf. After you condition
Speaker A
them, you give them the bone transplant. And after they they obtain remission, what do you do? You maintain little plus or minus bortees. If they're not eligible, you just do VRD. And that's going to hopefully like nuke a lot of
Speaker A
these like malignant cells. But after that, what do you do? Your just design is to maintain remission. And if you have, then what are you going to do?
Speaker A
You're going to do linolyomide plus or minus partisan. All right, my friends. That's plasma cell disorders. That was a lot. I hope that you liked it. I hope it made sense. I hope that you guys enjoyed it. And uh, man, I just love you guys. I
Speaker A
thank you guys so much for being so awesome. And I hope you learned a lot.
Speaker A
And as always, love you. Thank you. Until next time. [Music]
Topics:plasma cell disordersmultiple myelomaMGUSmonoclonal gammopathyWaldenstrom's macroglobulinemiaimmunoglobulinsM spikeserum protein electrophoresisCRAB criteriahematology
