(Guest Lecture): Myeloma Diagnosis and Staging | MCRT Webcast: Experts Discuss Newly Diagnosed Multiple Myeloma Issues

Dr. Kalender, you were going to talk about diagnosis and staging of myeloma. You can frame that in the reference of COVID, but why don't you just talk about that in general? Early precursor conditions, diagnosis of myeloma, and understanding of that. Okay, so I have 20 minutes and I'm going to try to talk a little bit about some general epidemiology and a little bit about how does myeloma or how do we think myeloma starts and then talk a little bit about the precursor stages, m. and smoldering and then diagnosis and treatment. So a lot of people say, you know, is myeloma something that's been around forever? This is a CT scan going through a sarcophagus. Looks like there might be some lytic lesions here. This is actually a slide from Dr. Hari. Yeah, you could use your imagination. This is much more convincing, I think, data. This is a 3000 BC fossil from Spain. It really does look like this particular individual has some lytic lesions that look like myeloma. But in the Western medicine, I think many, many people have seen this drawing of this unfortunate woman, Sarah Newbery, who came in in the 1840s. And she'd actually been ill for a few years. But this depicts the end stage of her life where she came in with multiple bone deformities. And I'm sure as a lot of you know, she was treated in a very unconventional way compared to today with Porter and a mutton shop and some orange peel and survived a few days after she came into the hospital. And when they did an autopsy, they could see that her bones had these very weird changes. They were hollowed out and there was sort of this gelatinous material. And then this gentleman came on a couple of years later. This is Henry Benz Jones, Lord Henry Benz Jones, who actually described some funny stuff in people's urine in one particular patient for this entity that they initially called molythes asium. But so we think myeloma has probably been around for a long time. Now, one of the questions that comes up a lot and people ask all the time is, are we actually seeing more myeloma than we used to? And I think there's now starting to be some pretty convincing data that, yes, it's not just we're better at diagnosing it. If you look at sort of the beginning of the or the end of the century last, you know, the number of cases around 15 to 20,000 a year, and now we're up to about 32,000 a year. So we think that there are more people being diagnosed, not exactly sure why. And certainly there are many more people living now with myeloma. We've known for a long time that there are some differences in terms of sex and ethnicity. So men are more likely to a certain extent than women to be diagnosed with myeloma. And then there's some very striking differences here. So African-American citizens compared to Caucasian have about twice the risk of developing myeloma for reasons that are not clear. And then people of Asian descent have a lower risk. Native Americans and Hispanic are sort of someplace a little bit in the middle. And these have been observed consistently, but we don't really know why. There is a small hereditary risk, also not clear what that might be exactly or what changes are there. Myeloma tends to be an illness of people who are older. So really, there are a couple of cases of kids, but by and large, it's very unusual to see somebody under the age of 30 develop myeloma. And most of our patients are in their 60s and 70s when they're diagnosed. Now, where does myeloma come from? So this is a map that some of you may have seen before. And we think all blood cells come from what's called a blood stem cell, which is actually the source of what we use for a transplant. And the cell that's going rogue or going bad is down here called a plasma cell. And plasma cells have as their job, they're little factories. They are designed to produce in large quantities antibodies or immunoglobulins. Those terms are often used interchangeably. And sometimes I think that is confusing for patients. And these antibodies are produced in large numbers and have this specific structure that's shown here on the right. And so they're made out of two main components. One thing that's called a heavy chain that has different names to it, like IgG or IgA or IgM. And then there's this pink part, which is called a light chain, which is either kappa or lambda. And these plasma cells produce antibodies in all sorts of different flavors, if you will. And normally what these antibodies do is help us fight infection. Now, one of the reasons there's this concern about COVID is it doesn't look like most people have antibodies against this particular coronavirus. But antibodies are a very important response of helping protect us from viruses, as well as bacteria and antibodies interact with other blood cells in various ways to help us clear out infections. So they're very, very important. Now, one thing that we're still trying to flesh out, we don't know for sure, is what makes this a normal plasma cell here on the left going through these steps of sort of growing up and getting older? And what goes wrong to make somebody have myeloma? One theory is that there are, as these plasma cells are going through steps of development, they start acquiring mutations. So one makes them develop a little clone, but then there's other mutations that occur down here that finally turn them into myeloma and those cells that seek out bone marrow, normally a place that there really aren't a lot of plasma cells. So this leads, when you do have myeloma or you have one of the precursor states, instead of the normal where you have all these different types of plasma cells making all these different types of antibodies, you end up with a clone that is essentially making one type of light chain and one type of heavy chain, and you get this excess of monoclonal protein. So how we measure that, how do you know that this is around, is the first technique that was developed in the late 1930s was something called a serum protein electrophoresis. And what you do is you take the liquid part of blood and let it clot, so that's called serum, and you run it across an electric gradient and you can show then there's different proteins in there. There should be. That's the normal here in the green. But when you have myeloma or one of the precursor states, you start to have an excess of one type of protein. And this is the M spike or the monoclonal protein that some of you may know about that you've heard your doctor speak about. And that can be measured specifically to give you a certain amount. We also do what's called immunofixation, and that means that you're figuring out what exact class of antibody is your clone composed of. And this is an example showing you somebody who has an IgG, that's the heavy chain, and a capital light chain. So this test is used to first identify the type of monoclonal protein. And it's also used a lot of times to confirm whether you're in remission or not. So you can also do an electrophoresis on urine. And some of you may have seen this yourselves, but we ask that patients or sometimes they volunteer this information that they have this very foamy or sudsy urine. So they can also have an M protein that shows up in the urine as well. Now, the probably the newest kid on the block and something that we find that's very, very helpful and probably one of those days as urine tests are going to go by the wayside is what's called the free light chain assay. And in this case, this is a blood test on serum that is measuring these light chains that are in circulation. So it's this sometimes I think causes a lot of confusion for patients when they see these results. We all have a little bit of light chains floating around both Kappa and Lambda. So the normal levels aren't zero. It's also important to note, you're comparing from patient to patient, different labs report different units. In other words, sometimes they report it as like, you know, one to three or sometimes 30, you know, three to 19. So you have to be careful about what your lab is reporting. The other thing that's important to know is that these light chains get clear to the kidneys. So if you have kidney changes for any reason, it affects the levels. So we use what's called the ratio to help us to say whether the production or whether the amount of light chains in that serum is actually appropriate. You can also look at heavy chain classes. This is being done, you know, not too much, but probably the most widely used application is to see if a person's in remission when they're on deritumum. So what's mGus? So this is a entity where people have a monoclonal protein. It's very common. Three percent of the U.S. population age 50 and 10 percent by the time you're 80. And we expect there's going to be a lot more people getting mGus as we all get older. So by definition, it means you have a small monoclonal protein and you don't have many plasma cells in a bone marrow biopsy if that's done. And you don't have what's called slim crab that I'll talk about in just a second. So it's interesting. This is a very, very cool study that was done a couple of years ago looking at the incidence of mGus around the world. And so you can see the hot spots are red. So northern European populations, U.S. and Canada, Australia, some of these differences. Blue are the lowest levels. We think some of this blue part is probably lack of testing. But there really are these ethnic differences around the world for reasons that are really unclear and has led to a lot of investigation. And I think it'd be safe to say we still don't understand why. But what we do know, and this is a study done essentially 30 years ago that's held up when looked at again, is the majority of people who have monoclonal gammopathy aren't going to get myeloma. That's this gray bar here. Those are the people who will. So we want to make sure if somebody is picked up with a monoclonal protein, they don't have myeloma or they don't have amyloidosis. That's a very important thing that Dr. Zander, I'm sure, will talk about this afternoon. Waldenstrom is another type of blood malignancy with an IgM monoclonal protein. And then there's a disorder of mGus with renal significance and other hematologic malignancies. So if you have mGus, one of the more interesting studies that has been done recently is a study where weight makes a difference about progression of mGus to myeloma. And this was a study done through the VA where they looked at people who are either overweight or obese. And if you were, you had twice over twice the rate of progression of your mGus to myeloma. So that's a modifiable risk. That's something very important. And there are a couple of studies underway to try to look at that. And this study verified again in the veterans that if you were African-American and had mGus, you had twice the risk of progression of mGus to myeloma. So if you are African-American, the other thing that we know through some studies done recently is that you also develop your mGus at a much younger age compared to patients who are either Caucasian or Hispanic, for reasons that are unclear. And this has led to a call of perhaps for some African-American populations, particularly with a family member with mGus or myeloma, maybe we should start doing a little bit of screening. And there are some studies underway with that. We know that people who have been exposed to Agent Orange have a higher risk of myeloma, but they also have a higher risk of mGus too. And so this is sort of indicating that maybe environmental exposures are important for mGus. And finally, this is some interesting data at first responders, firemen who were participating in 9-11 rescue compared to firefighters in Minnesota, and they have a higher risk of mGus too. Again, so some environmental risk playing a role here. If you have mGus, there's a very couple of simple things that people look at to try to get an idea of what your risk is of getting myeloma. And it's three things. So one is, is your M protein less than 1.5 grams? Do you have an IgG type of protein? And that would be picked up by that immunofixation. And is your free light chain ratio normal? And if the answer to all of those is yes, you're down here. So you have a very low risk of progression to myeloma. Whereas if the answer to these those questions is no, you have a higher protein, you have a much higher risk of developing myeloma. And we try very hard and we pick up people who have this to just see them more often than, say, the typical mGus patient who we might see maybe once a year. Smoldering myeloma is a very specific entity where, again, people have no symptoms, no symptoms of myeloma, but they have more protein and they have, by definition, more plasma cells when a bone marrow is done. But they don't have myeloma. And it's very, very important if you have been told you have smoldering myeloma to make sure that you clearly do not have any evidence of myeloma because we think that's incredibly important. And sometimes it's a little tough to tell. There are many grading systems for risk for development of myeloma from smoldering. This is probably going to become the gold standard because it's easy and it's reproducible. So if you have smoldering, you look at three specific things. One is, do you have more than two grams per deciliter of monoclonal protein? Do you have a free light chain ratio above 20? And do you have more than 20% plasma cells in your bone marrow? If you have two out of three of these, then your risk of developing myeloma is about 50% over two years. So I think a lot of people are now going to use this to decide, you know, are there patients who should potentially be treated outside of a trial? And there's now a couple of trials that have been published that show that there might be some advantage for treatment. This is a Spanish study from a few years ago where they gave steroids in lenalidomide for about nine months and then some maintenance. And they were able to show a reduction in progression pre-survival, that is getting myeloma as well as an improvement in survival for those who got the treatment. This is a more recent study that came out last year, just using lenalidomide indefinitely in patients with smoldering myeloma versus observation. And they were able to show again that they cut down progression to myeloma by a lot. So about 7% of people getting lenalidomide progress to myeloma versus almost 32 by three years. There is a trade-off here. There are some side effects from lenalidomide and not everybody could tolerate this well, although the quality of life appeared to be about the same. You know, our own position or my own position is I think if you have high-risk smoldering, we would still like you to try to participate in research because this is unclear still if we're going to change survival for patients. And this is the latest study from ECoG treating only high-risk smoldering patients with either lenalidomide and dexamethasone with the addition of daratumumab in half. And so we're hoping that we're going to get some answers from the study in a few years. If people suspect you have myeloma, this is typically the workup. Some blood tests. We're looking at are you anemic, the S-PEP, and we talked about these things. There's something called beta-2 microglobulin that gives us kind of a rough idea of how much myeloma you have and something called lactate dehydrogenase. If it's above normal, we consider that important to say you might have more aggressive myeloma. And then we're going to talk a little bit about imaging. Bone survey is the traditional one, but it has some flaws. Everybody who has myeloma has had a bone marrow biopsy. That's important just because you have to have more than 10 percent plasma cells in here to say you have myeloma. But it also helps us look for other things like amyloid. Maybe there's some other problems going on in there. And it also gives us a chance to do these cytogenetic and fish studies. So here's a normal bone marrow, and our pathologists like to say you want to see a mixture. It has to look like sort of a party going on. This is somebody with myeloma. These are all the same guys. This is a clone of plasma cells. They kind of look a little bit like fried eggs. This is a little bit of a higher magnification. And on that piece of bone they took out, this is what's called a sheet of plasma cells. Now the liquid part is used to do these cytogenetic studies. So for cytogenetics, you actually grow the myeloma cells and then realign the chromosomes and photograph them, looking for missing pieces. Only a fraction of patients with myeloma have abnormal cytogenetics. But this is called fish or fluorescence in situ hybridization. This is a much more powerful tool. And this can be done on cells that are not dividing. If you use this technique, we can show in this pie chart here, the majority of people have some abnormalities by fish studies, and we're starting to appreciate that those can confer survival information. In the future are going to be more genetic studies like this, where we're going to look at even more mutations and help decide what the risk is of your myeloma being easier or harder to treat. So to make a diagnosis of myeloma these days, we do slim crab. So crab is what we had used for a while. High calcium, kidney problems, anemia or bone disease. But we added in a few years ago the slim part, which is if your marrow has more than 60% plasma cells, if you have a light chain ratio above 100 or your MRI shows focal marrow lesions, even if you have no symptoms at all, we are calling you myeloma because we think we are going to help save you from having problems if we start treat you if you have these clinical features. So we turn all this information into a staging system that is based on is your albumin normal, is your beta-2 microglobulin normal or high. And then if you have a high lactate dehydrogenase and the presence of some chromosome changes by fish primarily, but cytogenetics too, if you have some of those features, we can split you up into three different stages. And there is a survival data based on the stages with those with stage three having lower survival. Okay, bone surveys. These examples are very easy to see that these are abnormal. These are holes in the bone caused by the myeloma cells telling the bone cells to chew this up. But there are a lot of people who have myeloma in whom the x-rays are completely normal. So we're trying to get people to do better tests. So this is a whole body low-dose CT, very clear that there are lytic lesions going on. And often these studies when this test is abnormal will have had completely normal bone surveys. MRI can help you. Obviously, this is a person who's got a big loss of a bone here, but they've also got these focal marrow lesions. That can be very helpful. And then PET scans are also great. They're positive and close to about 93 to 94% of people at diagnosis. So it's showing you these white spots. And I think almost everybody on the panel would agree that one of these advanced techniques is really important to say somebody does or does not have myeloma. So when we start treating people, we have some goals. We want to make you better fast. If you've got pain and bone pain and problems, we want to improve that. If you've got kidney dysfunction, we absolutely want to fix that and improve your quality of life. And we also, if you're going to have a transplant, we don't want to affect stem cell collection. And we want to, of course, limit side effects. So there are some controversies that I'm sure that Dr. Costa is going to talk about in terms of how many drugs are we supposed to use? How long are we supposed to treat you? And what are we doing for transplant? And then how hard should we go for a deep response? There's a special consideration here if you're older. Because more than 40% of people are above 75, we're very interested these days in a concept called frailty. And basically that means is, are you able to do activities of daily living? So can you walk a block? Can you get to the supermarket by yourself, whether in a car or public transportation? And if the answer for some of those is no, we know based on research, you are going to do worse. And so if you are frail, we know that your survival looks to be worse and the likelihood that you can't stay on therapy is much higher. So this is not meant to be depressing. What it's meant to be is for patients who are frail, we also want to be able to potentially intervene and make them better candidates. I'm just going to show you a list. There's all sorts of regimens that you can use if you're going to get a transplant or if you're not going to get a transplant. I'm sure Dr. Costa is going to talk about that. And this ends up with sort of a little bit of a triage system. If you are frail, we're going to probably give you fewer drugs than if we think that you are doing great. And there are many, many choices. And of course, you're also going to hear about maintenance in just a second. The take home message here is if you do have myeloma, if you have been diagnosed, the survival keeps getting better. I think anybody who's worked in this field appreciates this. And it also, I think very importantly, if you look at a graph like this, the rate of progress keeps going up. So not only are we getting better, but we're getting better faster. So just to review, myeloma is a pretty common blood disorder, second most common. I think it's very important that you understand testing. Diagnosis is very important. This imaging is a key part. And everybody's living longer with myeloma, which is great. And I'll stop there.