Myeloma 101: What Patients and Families Need to Know

Dr. Joseph Mikhael:
As some of you know being at Patient & Family Seminars before, we quite routinely include a chat about myeloma 10. Now, you might be sitting here and saying, as we saw from the numbers earlier, many of you have had myeloma for two years, five years, 10 years, 15 years, over 20 years, and you might say, "Do I really need a myeloma 101?" Well, I suggest that, one, it's a good refresher. Two, if I can help you communicate to your friends, to your family, to your community what myeloma is about, then I think it's going to be particularly valuable to you.

As you will be hearing from the IMF very soon, and I'm channeling my inner MarCom team and Jason London who supports a lot of the work that we do, in just a few weeks, September 1st will be upon us and we will be in Blood Cancer Awareness Month, and you're going to see a campaign called Know Myeloma, K-N-O-W Myeloma, which of course in the middle of it has N-O Myeloma, but Know Myeloma. And we do as much as we can to raise awareness about myeloma in general, and one of the ways we do that is to try and empower those of you who have myeloma to be able to explain it to others, to say, "Look, this isn't a skin cancer. No, this is not leukemia," and we explain it in different ways.
So the goal of this talk is to try and give you the big picture, as it were, of multiple myeloma, so we start with how common is myeloma? We did a broadcast this week, a podcast this week I did for the IMF where they were asking me to talk about, well, myeloma is such a rare disease. How common really is it? Well, it accounts for about 2% of all cancers, a little under 2%. We expect in 2025 to probably have about 37, maybe 38,000 new cases in the United States. I'm going to talk tomorrow a little bit more about health disparities, but just so we know, it is a little bit more common in men than women. For those of us of African descent, we have twice the risk of developing myeloma, so we have an increased incidence is the word we use, or increased risk of getting multiple myeloma. So when we look at it on the list of cancers, from breast cancer, prostate cancer, lung and so on, myeloma is number 14 on the list.

And then lastly, yes, myeloma generally speaking is a disease of older individuals, but that's always just an average. So the average age of diagnosis is about 69. There are some differences by race and ethnicity. African-Americans are diagnosed typically four to five years younger and Latino Americans even a year younger than that, so their average age of diagnosis is more like 63, 64, 65, somewhere in that range.

We really don't see myeloma in the pediatric population. Of course, there's never say never. I traveled once to meet with who we think is the youngest person ever diagnosed with myeloma on the planet. It was actually an eight-year-old boy in Uruguay in Latin America, but we almost never see myeloma under the age of 20 and we expect that somewhere around 2% of myeloma patients are under the age of 40, but that's not zero, so there are situations where we can make the diagnosis in the very young.
One of the questions I get all the time is what causes myeloma? And the short answer is we don't know in the vast majority of patients. I had a patient this week in clinic actually asked me say, "Oh, well I was involved in this work or that work. Do you think that put me at risk?" And of course, we can never say no, absolutely no, because we don't fully understand. There are some exposures that we now have seen a strong enough link that we can say there's a connection, for example, Agent Orange.

It doesn't mean that everybody exposed to Agent Orange develops myeloma, but we have seen a sad and unfortunate trend of our veterans who have been exposed to Agent Orange who have had a greater risk of multiple myeloma along with other diseases as well. There have been some connections to firefighters who have been exposed on a repeated basis to fires. This included even some of our first responders after 9/11 in New York City. In fact, the IMF was involved with that and trying to understand the incidence of myeloma diagnoses in that population of individuals who were involved in that obviously most terrible day.

So outside of exposures, I already mentioned your race or ethnicity. If you're like myself of African descent, we're at twice the risk. There are really very few modifiable risk factors that we know are connected to myeloma. There's a bit of a dotted line connection between most cancers unfortunately and obesity. We don't fully understand what that means. Some of you know, there are some of our myeloma doctors who've dedicated a lot of their work and research to understanding the link between diets and cancer, and part of this will, I'm sure, come through our discussions this weekend, but again, the summary is for most patients, we really don't know what caused it. And I think to some degree, that's important because sometimes people think and say, "oh, is it because I lived next to electrical lines when I was a kid or I was exposed to this farm or whatever else?" For the vast majority of us, we really do not know the cause of multiple myeloma.

And so when we describe myeloma, we often describe it as a blood cancer. Some have said bone cancer. I prefer not to call it bone cancer because there actually is a cancer of the bone, something called sarcoma and osteosarcomas, but we think of it as a cancer of the blood and that the blood is made in the factory of our blood, which is the bone marrow. So your bones have stuff inside them that create your blood, and on a regular basis, produce your blood. And we actually did a video this week with our friends here in the back, Roman and Colin, where I talked about the three kinds of cells that your bone marrow makes.

So when you look at what's in your blood, there's liquid and then there's solid stuff. The solid stuff are your cells, the liquid is what we call your plasma, which is what carries the cells and carries some proteins in your blood. And you have three kinds of cells, and being in California, I will describe them as red, white and rosé. So you have red cells, you have white cells, and you have rosé cells. As I always tease my friend, Morie Gertz from Mayo, who some of you might know, when he explains the bone marrow, he talks about a garden. When I talk about the bone marrow, I talk about a vineyard. Where would you rather be?

Anyway, point being that we have red, white, and rosé. So red, red cells. What are red cells? That's the little cells that carry your oxygen. I sometimes describe them as little red trucks. I breathe in, oxygen comes into my lungs. The little red cells, they come, they pick up that oxygen, they go deliver them to the tissues, drop them off and come back for more. That's all they do. I've offended every hematologist in the world, but that's pretty much all that red cells do. They're trucks, they pick up, they drop off.

White cells are a little bit different. White cells are like soldiers in an army that help protect us. We actually have five, I guess, major branches of the military, we have five major types of white cells. I won't even list them off for you. Many of you, especially if you've been through a transplant, you know the one branch we always talk about, the neutrophils. You know I heart neutrophils. Get an old that says that, but neutrophils are ones that particularly help fight off bacteria, but we have five kinds of white cells and they help fight off infections.
And then lastly, your rosé cells. They're not really rosé cells, of course. They're called platelets. Platelets are just little cells that help you clot, so they're the first ones on the scene. If I cut myself, the first thing to get there is a platelet. It plugs up the hole, it makes a phone call to something called a factor, and those factors form strong blood clots. So when people, for example, have hemophilia, they're absent in some of those factors, but that's the essence of what happens in the blood.

But if I go into the factory, I learn a lot more than what comes out of the factory. If there's a car factory here, I can see the cars that have come off the assembly line. I understand it a lot more if I go inside the factory and I see the metal and the rubber and the working conditions. If I go into someone's bone marrow, and many of you have experienced that lovely procedure, we learn a lot more than just the red, white and the rosé, and critically, we find a group of cells called plasma cells. Plasma cells of course are the sentinel cell in multiple myeloma.

What are plasma cells? Plasma cells are great. We love plasma cells because these are the cells that make antibodies. What are antibodies? Antibodies will protect you against all the things that your body thinks is foreign, measles, mumps, rubella, all the things over the years that you've been vaccinated for, COVID, the flu, etc., but also just things you get exposed to on a regular basis. Your immune system, which is ridonkulously complicated, has been built to protect you against anything that could genuinely hurt you, and plasma cells are a critical part of that immune system.

So they make these good antibodies. You know medicine, we love to use words that patients don't understand so we call them immunoglobulins, which is just a Greek wave of saying immune proteins, and they help us fight off these infections. When that plasma cell unfortunately becomes cancerous, that's what multiple myeloma is. So now instead of making the good antibodies or proteins that fight infection, these very antibodies now start to attack the kidney, attack the bone, they mess with the immune system, they start to crowd out the bone marrow. Normally, if I assess someone's normal bone marrow, plasma cells are only about two to 3% of the total. By definition, in myeloma, it's greater than 10%, and as some of you know, we diagnose patients with myeloma that have 50, 60, 70, 90, 95, or even 99% plasma cells.

So imagine I have a car factory where the normal... I sometimes like in the plasma cell to the part of the car factory that's making the steering wheel because it's relatively small in the car, although pretty important to your car. Imagine if 95% of the factory is making steering wheels. It's not going to make a lot of cars, is it? And that's what happens, it crowds out the rest of the bone marrow.

And when we now look at the proteins that are made or those antibodies or those immunoglobulins that are made, there are different types. Of course, I told you the immune system was complicated. Don't believe me, I didn't make it, but it is complicated because we have these different kinds of immunoglobulins or proteins, we've given them letters, G, A, M, D, and E, spelling out the word gamed, G-A-M-E-D, and you have different types there and there are different shapes and sizes, I won't worry too much about that, but each one of them has a part that's called the heavy chain and a part that's called the light chain, and typically, the heavy and the light chain should be connected together forming a single unit. And when we follow someone's multiple myeloma, and now instead of making the good protein, as I said, it's making the abnormal one which means it's identical, or sometimes we use the word monoclonal, right?

Because really, what's cancer? If you had to define cancer in a sentence, how would you define it? I define it as uncontrolled identical growth. It's that one piece of skin tissue or breast tissue or lung tissue that is growing out of control. It's just a bit hard to conceptually capture that when you're dealing with plasma that are circulating or moving around in the bone marrow. It's a liquid tumor so it's harder to appreciate that, but it's the same principle.

And so these are identical cells growing, so the protein that they make is identical, whereas the proteins, the immunoglobulins, the antibodies you make on a regular basis should be varied. They should be all sorts of different types and shapes and sizes for all the different things you need to protect it against. So here, it's making a clone of itself, if you will, and that is what differentiates myeloma immunoglobulins or antibodies compared to normal immunoglobulins or antibodies. That's why we look for the abnormal one. We look for the one that is identical. That's why even in the test, we sometimes call it an M spike, because it all coalesces together because they're all exactly the same when we try to spread them out in the lab, and that's what we call the monoclonal protein.

And so typically, that monoclonal protein is the whole of the intact immunoglobulin here, heavy and light chain together, but in about 20% of patients, that whole thing is not there at all. Only the light chains are present. We don't fully understand exactly why that happens, and for about 60% of patients, they actually have both. You can measure both the whole intact immunoglobulin, the M spike, as well as the light chain. This becomes critical, because if you don't know what kind of myeloma you have, how are you going to know what to follow to see if your treatment's working? And so this is what we capture at the start when we diagnose patients.

Myeloma is part of a spectrum of diseases. I mentioned that to have myeloma, you have to have at least 10% of these plasma cells in your bone marrow, and that's only, remember, 2% of all cancers. But here's the weird thing about myeloma that I'm sure most of you know now is that even though myeloma is rare, the so-called precursor condition or the pre-myeloma condition is incredibly common. In fact, sometimes I make these controversial lectures like, "Myeloma is the most common cancer in the world." People are like, "What are you talking about?" Well, the precursor to myeloma is very common.

So imagine as you go through your life, your plasma cells are constantly being called on to make antibodies. In about 5% of all of us over the age of 40, not everybody in this room is over 40, I'm not going to comment on anyone's age but I would say the majority of us are, if I go out into a healthy population, about 5% of people over the age of 40, if we look for it, they actually have a little bit of this abnormal protein. They actually have a few plasma cells that have decided to make some clones of themselves.

We could even argue they've actually made some... These plasma cells are actually cancerous, but it's such a tiny schmutz of cancer that it's not hurting anybody and we're not going to get too excited about it, which makes me go back to my definition of cancer, that cancer is not just identical growth. It's uncontrolled, identical growth, and sometimes the smallest, tiniest amount of cancer, it's not that it's unimportant, but we're not going to do anything about it because it may not grow, or if it's going to grow, it's going to grow so slowly.
Sometimes I give the analogy of men as we get older, our prostates, typically over time, there's a part of the prostate that can actually become a little bit cancerous. If I go in and test the prostate of every man in California over the age of 80, chances are I could find elements of cancer in probably up to a third of those men. Does that mean that all of those men need to be treated right away? Of course not. That tiny little bit of cancer is actually probably not going to be significantly growing until they reach the age of 150, and chances are they're not going to live to 150. I mean, let's be realistic, most of us are not making it to 150.

So at some point, we have to draw the line between saying, okay, what is a tiny amount of something abnormal? Again, another analogy I use is the things we have on our skin. You might have a tiny, tiny little mole, and if you get to the age of 200, it might become cancerous, but until then, it's not going to be an issue, whereas another one might be very rapidly growing and is an issue. So where do we draw the line between what's tiny and not going to hurt you and real? And in myeloma, because it's so common to have a little bit of it, we've been much more meticulous and we've put it into three categories.

Category number one is MGUS or monoclonal gammopathy of undetermined significance. This was coined at Mayo Clinic over 50 years ago to describe a group of patients that have this tiny amount of protein, and thankfully, the vast majority of them will never develop myeloma, which is why we typically don't treat those patients. We just watch and wait, that if we do a bone marrow, they have less than 10% plasma cells, they don't have any of the damage associated with myeloma. On the other extreme, we have active multiple myeloma, more than 10% plasma cells and it's causing damage or just about to cause damage, and I'll explain what those criteria are in just a few minutes.

And then we have this thing in the middle which is a bit of an active phenomenon because we keep trying to redefine it as our testing gets better, something called smoldering multiple myeloma. And this is really... Actually, I almost included it in the hot topics today because there's really been a lot of great work recently in smoldering multiple myeloma and the potential of treating patients who don't quite yet have active myeloma but are getting close to myeloma, that maybe we could treat them with something a little less aggressive, maybe just a single drug like daratumumab in one of the clinical trials and be able to kick the can down the road as it were, and for some people, even prevent them from ever developing multiple myeloma. So understanding that spectrum becomes important, of MGUS, smoldering and active multiple myeloma.

But what defines myeloma? Well, historically, we called it the CRAB criteria. When I went to medical school, it was all about do you know what the CRAB criteria are? Those four things, C, standing for a high calcium, R, standing for renal or kidney damage, A, anemia or the low red blood cell count. You don't have enough red wine. I mean you don't have enough red cells. Sylvia, are we going to have wine at that reception later? Say, okay. And then lastly, bone disease, because myeloma can affect the bone.

11 years ago, in 2014, we added three more criteria to that because it was unusual. Even though I just made this case to you that you don't want to give chemotherapy to someone with a tiny little bit amount of protein that's probably never going to hurt them, but at the same time, do I really want to wait until someone's in kidney failure? Do I really want to wait until someone's bones are broken before I do something?

And so we are trying to find that sweet spot of saying, again, sorry for all the analogies, but I love to run as many of you know. It was so nice and cool here this morning to run compared to the fire pit that I run in in Scottsdale every morning, although I have to say, running up that hill at the end of my run this morning, I was huffing and puffing a little bit. I needed a little bit more of those red cells into my lungs, but that myeloma is like running towards a cliff. And I don't mean to be too fatalistic about it, but I don't want to wait until someone's falling off the cliff.

Beth, who's a runner too and is probably running faster than me anyway, hopefully she'll catch me before I fall off the cliff, but where do you catch someone? Where do you stop? If the cliff is miles away and they're just enjoying a leisurely walk, well then I don't want to stop them. We want to find that right spot. So we added three more criteria that said you're not quite over the cliff yet. You haven't quite broken a bone or caused damage to your kidneys, but you're getting pretty close, and those three things were if the bone marrow has 60% plasma cells. Remember, normal's 2 to 3, myeloma is defined as over 10, but we found if people got to 60%, that means that there's a lot of myeloma growing in the bone marrow, and maybe they're not sick from it right now but they're getting so close to that cliff, we should treat them as real myeloma.

Number two is what's called the light chain ratio. So those light chains that we talked about, remember the immunoglobulin or the antibody is this Y-shaped thing that's got the heavy chain and the little light chains next to it? When those light chains build up in your system, they particularly like to go and hang out in the kidney, and if you can't filter them through your kidney, they're going to start to plug up. Just like if you're cutting vegetables at the sink and too many of the bits of vegetable get into the bottom of the sink, it's going to clog up that sink. And so we know that if someone's light chains get too high, and this way we measure what's called the involved over uninvolved light chain ratio, if that ratio gets too high, then we know they're at risk of damaging their kidneys.

And then lastly, if we do an MRI of their bone marrow, not their regular bones, the actual bone marrow, and we see that there are little pockets of activity, that tells us that those plasma cells are growing and they're starting to go out of control. And so we added these three criteria called the SLIM criteria, that was my contribution to the myeloma world. I created the acronym SLIM and dropped the mic left, you know?It's not worthy of applause, but thank you Beth. You're sweet. And so now these seven things define multiple myeloma. SLIM-CRAB defines multiple myeloma.

Now, when we then test for it, we typically have to, as I've mentioned, look in the blood, and we have all sorts of different blood tests and there's a lot here so I won't go through every single one of them, but just to give you a sense, there's the tests that we do to make the diagnosis, and one of the things I'll briefly talk about tomorrow that the IMF is working very hard to do is to help our friends in primary care in making the diagnosis earlier. I bet if I could take time to ask every myeloma patient in this room what your story was, the vast majority of you will tell me it took a long time to figure out you had myeloma.

Do you know that the average patient sees a primary care doctor three times with signs and symptoms consistent with myeloma before the diagnosis is invoked? That typically takes about six months. It's even longer in African-American and Latino-American individuals for lots of reasons, which include access to care and even overlapping conditions like diabetes. By the way, diabetes is the great mimic often of myeloma. A lot of our patients get diagnosed with myeloma and they look back and they were told that, oh, all those things that you were having, they thought it was because of my diabetes when in fact it was myeloma. That protein in my urine, that anemia, that neuropathy, a kidney dysfunction was attributed to diabetes when in fact it was truly multiple myeloma.

So though the tests that we use to make the diagnosis, is why we have the little picture of SLIM-CRAB next to them, but just to make sure we're on the same page, how do we find that M spike or the bad protein, the immunoglobulin, I call it different things to try and make sure we're all on the same page with it? We do that test, what's called a serum protein electrophoresis, which basically is just a fancy way in the lab of looking at all the proteins in your blood, and you should have good proteins and we should see zero M spike. That's what the normal level is, but if the lab reports an M protein or an M spike, then that's the abnormal test.

We also look at those light chains. Remember, I told you that 60% of our patients will have some abnormality in their light chains and 20% of them only in their light chains, so we also have to look at what's called the serum free light chain assay. Now, unfortunately, there are still some forms of myeloma, more often than not, we can catch the vast majority of patients by testing their blood, but there are still some forms of myeloma where it is really only detected in the urine, and there are some times that we still do that. So typically at diagnosis, we want to get a urine test, and if it's present and that's the best way to measure the disease, we may have to continue testing the urine, but for most of our patients, thankfully, we don't have to continue doing that, because of course, for those of you who've collected a 24-hour urine, you know it's not the most fun thing in the world.

But myeloma doesn't stop there. Some of you have heard me say yet another analogy. I have often said myeloma is like a crime scene, and that's not just because my mother was a pathologist. I grew up watching Quincy. Anybody remember Quincy? Yeah. Okay, okay, so I got some homies here. Okay, good, yeah. So my mother, who's now a retired pathologist, lives in Toronto and I visit her and she comes down to visit me, and one of our mother-son bonding is over watching old episodes of Quincy. You can still find them here and there. I'm like, "Wow, did they really do that back then?" But nonetheless, the reason why I say myeloma is like a crime scene is that there isn't one piece of evidence that tells you the whole story.

I'm not making light of any other disease or cancers, but when someone has lung cancer or breast cancer or colon cancer, it's typically the one thing that they're measuring. It's a tumor and you get a ruler and you measure it. Myeloma is so much more complicated. We have the blood tests for the blood counts, as I said, the red, white, and the rosé. We have to look at the kidney function, we have to look at the heavy chain, we have to look at the light chain. Sometimes we have to look at the brain. We also have to look at imaging, and this is where my friends at the speaker table gets so excited because one of the doctors here with us has dedicated much of his life to understanding bone disease in multiple myeloma, and so if I didn't have this slide, he might've tackled me later, but we have to remember that myeloma is a disease that affects the bone. And for the longest time, we did the testing with what was called the skeletal survey, or again, shout out to my Canadian homies here, the skeletal survey.

We don't do it anymore, and if your doctor is still testing you with a skeletal survey, let's about it later because it's a little bit old school. It's like still using a Blackberry. I'm teasing you, Diane, because I love you. But there are things that we know can be helpful out of skeletal surveys. If the test is abnormal, it tells you there's a lot of damage to the bone, but the reality is skeletal survey, which is basically just plain X-rays of several of your bones in the body, it'll only be abnormal if there's a lot of damage. It's not as sensitive to pick up subtle changes. So we've moved away from plain x-rays now to typically doing either a PET scan or a form of CT scan or potentially an MRI, and we'll talk a bit more about it over the course of the weekend, but the idea here is that we want to detect even subtle changes.

Not only that. Myeloma doesn't just affect the bone. Sometimes myeloma can live outside of the bone, and this is a particularly important phenomenon. So think of myeloma as these are the cells that they're living in the bone marrow. That's where they're comfortable, that's their environment that they like being in, but sometimes the cells can actually get quite aggressive and they don't need the environment anymore. They can live on their own outside of the bone marrow. We call that extra or outside of the medulla, which is an old word describing the bone marrow. We call that extra medullary disease or EMD.

This is important now because we've come to appreciate, especially with our newer treatments and as people are living longer with myeloma, more and more patients are being diagnosed with extra medullary myeloma because this myeloma, if you will, becomes sadly, unfortunately, with treatment, becomes more aggressive and it can live outside the marrow, and that is also very important for our imaging or for x-rays because we want to look for myeloma that is outside the bone marrow.

And then there's the bone marrow itself. I know this is not everyone's favorite test but this is where we look at the headquarters of myeloma. We're working very hard and we're going to talk this weekend a bit about the IMF's research agenda and the Black Swan Research Initiative, which is a whole initiative designed to bring the best of the world together to find a cure for myeloma. That's the quickest way I could summarize it, and one of the things that we've been working on is trying to find ways to do less bone marrows. Could we just do it with blood tests? But that initial bone marrow is still important because that's the headquarters of myeloma.

So we do a bone marrow test. We don't want to just know, what is the percent plasma cells? We also look at the genes of those plasma cells, what we call the cytogenetics, and there's lots of different ways of doing it. It's crazy complicated. I'm not going to get into a lot of detail, but the point I want to make out of this that becomes important is the following, that we classify about 20% of myeloma patients as having high-risk myeloma, and there's actually just a new set of guidelines around this that the International Myeloma Working Group in the International Myeloma Society came together to make this new definition, and a lot of this is based on the genetics that we find in a bone marrow.

And as Robin showed to you even from the very start, we actually have a dedicated high-risk myeloma support group where we talk about the details of these kinds of things. And what high-risk myeloma means literally is just the myeloma has more horsepower. It typically comes back more quickly than more what we call standard-risk multiple myeloma. And so I won't go through all the numbers and the letters here, but these are the kinds of things, different genetic abnormalities. These aren't the genes you pass on to your kids, to be clear. These are the genes of your plasma cells that we interrogate and we determine and look to see what mutations they have in them that have of course made them cancerous as strong as they are.

In my last part of this myeloma 101, we're going to talk a little bit about treatment, and you're going to hear tomorrow from a couple of my wonderful colleagues from City of Hope about front-line therapy and relapse therapy, but today's meant to just give you the overall view that typically, we start treatment on a patient, we often call it front-line or first-line therapy, and it may or may not include a stem cell transplant, and that's going to be part of the controversy discussion as I already noted. And then we typically give someone what's called maintenance therapy. The idea there is to maintain their emissions. So the concept here is that the disease starts way up here. We want to get it down and we want to keep it down.

As it stands right now, we don't cure the vast majority of myeloma patients, but for many patients, we keep them in remission for a very long time. With our newer strategies, with some of the things that are going to be discussed tomorrow by Dr. Lee in front-line therapy, it is remarkable how much has changed where now we expect many of these patients to go over a decade before they need to be treated again. It's remarkable, but unfortunately, the disease typically will wake up and so we have to go through what we call relapse therapy, line of treatment as it's called here, LOT, number one, number two, number three, number four, and the disease unfortunately keeps relapsing. And typically, every time it relapses, it comes back a little bit more aggressively because it has learned from what it's been seeing before. It's become more resistant.

Remember I talked earlier about minimal residual disease? This is one of the reasons why MRD is so important, because as I get rid of a cancer, so let's say the cancer starts this big, as I get rid of it, get rid of it, get rid of it, that last little bit is sometimes the toughest bit to get rid of. I often say Rambo is the last soldier to be killed. You don't want to leave Rambo to grow into a whole troop of Rambos.

Now, the complexity of myeloma is such that sometimes... Some of you heard this because it went out on social media, there's a big MRD meeting that's held every year in Miami, and I was at this MRD meeting and I was being asked these questions about, well, how is it that in some people, they get this tiny little amount of myeloma left and it's not a big deal? It's kind of like they had with MGUS, remember? Where we said, "I don't want to touch someone with MGUS. Just leave them alone. It's a tiny little bit." But other people, there's that little bit and it's really aggressive, and I said, "That's the challenge of myeloma, is we have to determine, is that minimal residual disease Rambo or Bambi?"

Big difference between the two of them, and for some patients, I just had a conversation with a patient on Tuesday, a patient of mine who we've treated him, he's got very good treatment but he still has a little bit of disease left. And he said, "Well, Dr. Joe, isn't it MRD or bust? Shouldn't we be going, getting, get everything to MRD?" But he has an unusual form of myeloma where I actually think that little bit of myeloma is likely just going to sit there for a very long period of time, so that's why we have to realize how complicated it is. It's not as simple as just getting rid of it all, but nonetheless, the disease comes back and when the disease comes back, thankfully, now we have a huge armamentarium of drugs, and one of the reasons why we give you the QR code to download these slides is that I am not going to talk through all these different classes of drugs because there are so many of them.

Historically, the drugs that you are likely all familiar with, the imides, the ones that end in mide, like lenalidomide and pomalidomide, the proteasome inhibitors like bortezomib and carfilzomib, and the monoclonal antibodies like daratumumab and isatuximab. But you can see here, we have multiple class of drugs. I'm not going to go through them because I just want to give you an overview, and we've just, as I mentioned earlier, added yet a fourth now to the bispecific antibodies in the form of linvoseltamab, and we have many, many more to come.

As we treat people, we want to make sure, as I gave you the example here of bringing the disease down, we want to make sure that we treat them to get that disease low. Typically, we say that there has been response when someone's disease has been at least cut in half, because historically, we've learned that if we can at least cut the tumor in half, patient's outcomes will be better, but we want to do more than that.

So half is called a PR or a partial response, and part of this explaining to your friends and your family is the unfortunate way that in society in general, people hear the word remission and they think it means cure, but remission does not equal cure. Remission means that we get the disease down at a certain level for a period of time, and then it is unfortunately likely to come back up again. So a partial remission or a partial response is cutting it in half. A very good partial remission is cutting it by 90%. A complete remission is cutting it by a hundred percent. That doesn't mean that it's gone forever, but it's gone for as much as we can measure it, and I've already told you a little bit about MRD.

So as I come towards the end here, one of the exciting things you're going to hear about this weekend is that not only do we have different classes of drugs. We just keep learning different ways to attack multiple myeloma, and one of the critical ways we do this is that every cell that we have pretty much have these things that stick out of them, and this is particularly true of immune cells, and to be honest, sometimes we don't even know what some of these things do, but they provide us an opportunity to grab onto them, to be a target as it were. The medical term we often use is an antigen. Remember we talked earlier about antibody or antibody? That's the Y-shaped thing that can hook onto something. If I get my flu shot, then I'm producing antibodies to the flu, and I get exposed to the flu, my little Y-shaped antibodies go and attack the flu to destroy it. What do those antibodies hook onto on the flu or measles or COVID or mumps or rubella or whatever else? They hook onto an antigen.

An antigen is just the medical term for the target that the antibody hooks onto, and we have all these antigens on the myeloma surface, things that are, I am sorry that they're all license plates, but like SLAMF7, GPRC5D, FcRH5, BCMA. There's all sorts of different terminology, but these have become important because cancer is smart. I treat someone that targets FcRH5 and I treat them and treat them. Eventually, the tumor is smart enough and either it doesn't express FcRH5 anymore, or at least not enough of it that I can't grab onto it anymore, so now I have to come at myeloma a different way and a different way, and this is often what we do as we cycle through the treatments we have.

I shared with you already, we have different ways of targeting the cell. One is the antibody-drug conjugate like the drug Blenrep or belantamab that we're still hoping to hear good news on. It's like an antibody that hooks onto the cell at BCMA, but then it drops the toxin inside of it as an antibody-drug conjugate.

The bi-specific antibodies were a huge step forward. Fascinating, almost Star Trek-ian, when you think about it. This is a drug that I explained earlier, hooks onto the myeloma cell as well as one of your local immune cells and engages that cell to help destroy it, so it kind of bridges together by employing your own immune system. Employing your immune system is a brilliant concept. Why? Because it's right there and it's yours. You're not going to reject it, it's your own immune system. You have soldiers right there on the ground that can take out your own multiple myeloma, and we can just give it off the shelf.

And then lastly, for treatments, you're going to hear about CAR T-cell therapy a bit more this weekend. Again, it sounds like a science fiction movie, but this time, instead of just engaging the T-cell inside your body, we actually take it out of your body and we train it. The reason why it's called CAR, that stands for chimeric antigen, and you're all experts in antigens now, antigen receptor. So basically, we put a receptor on the outside of these T cells that is just anxiously looking for the antigen on the myeloma cell, and in CAR T-cell therapy right now, the antigen of note is BCMA.

So I take T-cells out of you, and over somewhere between four to six weeks typically, in the lab, we are engineering these T-cells to have a receptor on the outside that is very interested in finding BCMA, and then we reinfuse them into the patient and these soldiers are just gunning for BCMA, like they are hungry for it. Not only do they start going after BCMA, they can actually trigger more of themselves. They can expand, as we call it, in someone's body to make more of themselves, more soldiers so that they can go attack someone's myeloma. We have never seen any treatment in the history of myeloma that gives us over a 90% response rate like we do with CAR T-cell therapy. It's remarkable. I shared with you earlier the results of the CARTITUDE-1 study where one-third of patients five years later have no evidence of disease, remarkable what we see with CAR T-cell therapy.

Okay. And then lastly, as I said before, we're working towards a cure. How do we even define a cure? As I said, we are working on that definition so that we can have common currency to define it, but as I often say, it's one thing to talk about the disease. I say this all the time, most of you have probably heard me say it before but I don't treat myeloma, I treat people, and so we have to look at the person. It is not very exciting to say, "Oh, great, your myeloma tests are excellent and there's no evidence of disease," and the patient is exhausted and infected and weak and doesn't want to get out of bed. That's not what our goal is. Our goal is not to just get rid of the disease. Our goal is to restore your life back to you.

And look at this incredible list. This is my favorite slide that I try to update. It's reached a point where it's almost not even updatable because there's just too many letters, too many words on the page, but not only do we have all these great new drugs and just added linvoseltamab to it, as I mentioned, we have a whole series of others. I've had the privilege of being involved in myeloma research for 25 years. I have never seen a time like now in the sheer number of clinical trials, the number of new drugs, the number of new ways that we're going to be attacking multiple myeloma as we go forward.

So with that, I'm going to remind you that you can always learn more through the resources that we have at the IMF. There's of course a table here and you can get some of these resources or get them online or ask us to send them to you. We will gladly do that, and we work very hard. I have the privilege of being involved with this group and we literally every month are updating these booklets so that they are giving you the latest and the greatest in multiple myeloma. So with that, I am going to stop, and thank you very much for your attention.