(Guest Lecture): June 2022 - Myeloma Precursor Disease

Thank you for this very nice introduction. Now, it's going to be a very tough feat to talk after Dr. Langren has talked because he is not only a great speaker, but he's one of those persons that are those people that is going to do so much and is doing so much for myeloma. And it's just a pleasure because I consider him a friend and a mentor. And it's such a pleasure to see that he's here now and he's doing great things here in South Florida. Now, that being going to talk about myeloma precursor disease. And for those that don't know me, I'm an associate professor at MD Anderson Cancer Center, which is usually ranked number one in the country for cancer care. And so we do have a myeloma program there that's been established for many years. And my myeloma actually training started with Dr. Langren. He's the one that really put this passion in me to investigate myeloma and not only that, but also to look into the precursor disease of myeloma. And so for that, I am eternally grateful. I am originally from Barcelona, so I'm European, and I came here after medical school and I did residency and then I did my fellowship with Dr. Langren. And then that's when I moved to Houston, to Texas. So my slides are going to be very easy. This is very patient centered where we're just going to talk about what it means to have myeloma precursor disease, why is it important? And then some of the most important, I would say treatment advances in smoldering myeloma over the past few years and what is this shaping for us in the future? As you all know, there's a lot of research going on specifically in smoldering myeloma, how to treat it, when to treat it, why to treat it. And I know that you have a lot of questions about what does it mean when you treat it? Why is it good? Why could it be not good? And so on. And so I'm going to touch on some of those things. So this is a very easy introductory slide talking about multiple myeloma. And you see on the left side of the slide that it says that it's really a cancer of a type of white cell that is called the plasma cell and it originates in the bone marrow. And we have on the right side of the slide, on your right, we have the plasma cell. And this is a very large, actually usually the large cell has a nucleus. And then it has this very large, what is called Golgi apparatus, because what the function of the plasma cell is to produce proteins. So that's where a lot of that happens. And so this is a type of cell, this is a normal plasma cell. And we have myeloma is when this cell goes from being a normal plasma cell that produces antibodies to fight infections to a diseased plasma cell or an abnormal plasma cell. And we're very good at detecting what's a normal plasma cell from an abnormal plasma cell. Right now in the clinic, we can do flow cytometry in the bone marrow. And also you can do it in the blood, but it's usually better in the bone marrow because you can acquire more of the plasma cell. But as Dr. Langren mentioned, one of the things that we're going to be very good in the future is also differentiating normal versus abnormal plasma cells doing sequencing. So you can really tell if a plasma cell is normal or normal based on the expression of the genes that they have. And so there are a lot of new technologies that we're seeing that we can identify genetic abnormalities even earlier on in patients, even with MGUS, that we may not be able to identify in the clinic. And we're seeing that just in research. So what happens here is that the plasma cells and the cells that are surrounding the plasma cells, so all the microenvironment, what we call the tumor microenvironment change, and they allow this cell to become malignant and turn into multiple myeloma. So it's not just the plasma cell that changes. It's the plasma cell and the cells around the plasma cell. It's everything kind of changes together and allows for this to happen. They're both important and they both should be studied and are being studied right now. And of course, you know, we classify everything in medicine. These are arbitrary definitions, what we call this monoclonal gummopathy of unknown significance and smoldering myeloma. There are, I know in some, there was a question also in the program, what are the blood lines in between? So there are some smoldering patients that behave like an MGUS. So they're very early smoldering. There are some, you know, MGUS patients that maybe have a higher rates of progression than usual. But overall, we can, the main distinction between these two precursor stages is that a smoldering myeloma has a higher risk of progression to multivitam myeloma. And all that means is that you get to a point where the multiple myeloma is life-threatening, like it could, it endangers your life. That's what it means. It means that if you have a smoldering myeloma, you're a little bit closer to maybe coming to that point where you need treatment, because this is becoming something that is dangerous to your life. Whereas if you're an MGUS, usually that doesn't happen for a very long time. That is the main, you know, the main important thing to know about this two precursor disease. Of course, you can have a smoldering myeloma and stay in that stage for 20 years and you might not progress. So you have, you know, we have both, you know, sides where you could be MGUS and progress more quickly. But overall, if you look at all the patients together, the patients with moldering myeloma tend to progress at a faster rate. So here we have some very easy definitions. So when you're in the clinic and you look at your results, because now, now, you know, you guys look at your results even before we get your results. So you look at your M-spike, right? And you look at, you know, your bone marrow results and everything. And what we see here is that patients with MGUS usually have low levels of monoclonal protein in the blood, low levels of plasma cells in the bone marrow. And usually we don't have symptoms that we can attribute to this. Even though we know that, for example, some patients with smoldering myeloma may have some muscle aches or may have some bony aches or may feel a little bit of fatigue, sometimes. But usually we cannot precisely say, okay, this is contributing to the symptoms that you're having. We always have to look for something else that could be going on. But what we see here is that the risk of progression is from MGUS to smoldering and to myeloma is only about 1% per year, which is, you know, low based on what we know. And then as for smoldering myeloma, overall, it's about 10% per year. So it's, you know, it's 10 times more likely for you to progress to something that is life threatening if you have smoldering myeloma than if you have MGUS. Now, some patients with smoldering myeloma have very low risk, whereas some have very high risk. And one of the important things that we see here also is the proportion of plasma cells that are normal. So when you have MGUS, you can have, you know, when someone does a bone marrow and they look at your plasma cells, a lot of your plasma cells are going to be normal. So you're going to have a significant portion of your plasma cells that are normal. And by that, I mean something like, you know, 15 to 20%. So it's not unusual for MGUS patients to have, you know, 70, 80% abnormal plasma cells in the bone marrow. But if you, with you only having 20 to 30%, you have enough to make normal antibodies. So you, we don't need to have 100% of our plasma cells to be normal for us to actually have lower risk of infections and so on. But then as you move to smoldering myeloma, smoldering myeloma, a lot of these patients, the abnormal plasma cells are 90% plus. And then when you go to multiple myeloma, these patients, they virtually have no normal plasma cells left. It's all, they're all abnormal plasma cells. And so that just tells you also like there's more immune suppression as you go through these stages, which also means that if we're going to treat patients with immunotherapy, a lot of these immunotherapies should work much better in earlier stages than in later stages, just because of how this disease evolves. So the standard recommendation still for myeloma precursor disease is mostly to not to treat it and to observe it. And so we do this thing that is called watchful waiting, in which we just do some blood work and we do some, maybe some urine studies every few months. And we watch the patient and we see if there's progression. We see the numbers are moving up. That's usually one sign that the risk factor for progression, if you're overall, if you have, I don't know, a kappa light chain and your kappa light chain is going up a lot and your lambda is coming down, that's usually not a good sign. If your M protein, you know, goes 0.5, 1, 1.5, 2, that's not a good sign. So that's called an evolving. We call it an evolving M protein or an evolving light chain. And that means that you have a higher risk of progression. There's just a risk factor. So the workup for this, if you've been told that you have myeloma precursor disease, I think it's very important to have a good workup that includes advanced imaging and a bone marrow biopsy because there are some types of myeloma. And I can say, you know, less than 1% of myeloma does not express myeloma protein at all. So you are just going to find plasma cells in the bone marrow that are abnormal. And these patients don't have abnormal, you know, an M protein, for example, and they may not even have like abnormal light chains. In this case, they're just going to be suppressed because the abnormal plasma cells don't make, are not going to make like even the normal light chains. But you could miss a diagnosis of newly diagnosed myeloma if you don't do a good workup in patients that have precursor disease. And that is the reason. So still, you know, if it feels like probably your risk is low and everything, I would recommend that, you know, in most situations, patients should have a good workup to make sure they don't have myeloma that is life threatening. So with patients with M gas, they usually feed some criteria. There's overall, the risk of progression is low to multiple myeloma. Again, the risk of a life threatening event happening sometime in the near future is low. And it can, patients can be followed usually very safely in the clinic. This can be every few months, can be up to, you know, once a year. These patients, again, have low levels of the myeloma proteins in the blood, in the urine, they have low levels of plasma cells that are abnormal in the bone marrow. And so this is just the hallmark of how this is. So if you, you know, this is what the picture of M gas looks like. So this is what we look for when we see a patient in the clinic. This is what we look for to diagnose M gas, something like this. So why is it important to know that you have this monoclonal gamopathy in your blood and what to do about it? So this is a study. This was published in collaboration with Dr. Langren. And this shows here, you know, many patients analyzed over a long time, but shows that patients that knew that they had a monoclonal gamopathy did better in terms of survival than patients that didn't know that they had M gas. And this could be, could be one of the reasons could be because of the biology. So if there's more, you know, if the patients that didn't know that they had M gas, if it came very, very abruptly or not, but in my opinion, and there've been other studies showing the same thing, by the way, oops, what am I going? All right. Oh, I'm like, I'm going the wrong way. Okay. There's been other studies showing the similar thing, but to me, what this is about is not so much about when the disease starts. Like if you, if you have a very slow growing disease, you could catch it earlier and know that you have, you know, M gas, a monoclonal gamopathy, and then you would just do better because your disease is better, your biology is better. You don't have very aggressive disease. Whereas if you have very aggressive myeloma, then that's because, you know, then there's no time to catch you when you are small learning, you know, you just progress very quickly. But I think that again, you know, and this Dr. Lang has been very good at showing this, that patients have had these genetic changes for a long time. So I think that this is truly just from knowing that you have it from being monitored. I think that this is more of an intervention rather than a biology, but you know, I guess we could get the proof of that, but that's my thought. I think it's more the intervention and the monitoring than the biology. So small learning myeloma again, it's a stage or, you know, an arbitrary stage that we have between M gas and multiple myeloma where the risk of progression is just much larger than in M gas. And we do have to do again, a bunch of imaging, bone marrow, lab studies, and you want to follow patients, you know, every two to three months, sometimes depending if you think they're progressing a little bit more. And the important thing about this particular stage of myeloma is that there's a growing interest to treat it because I mentioned before the immune system is, you know, as you go through all these stages, your immune system just gets, it's getting weaker and weaker. And so we have all these new therapies. There's been a, you know, in cancer, this revolution with immunotherapy where we are trying to apply to myeloma and it's potentially the best stages to do this immunotherapy here in the earlier stages. And so it is very possible to delay progression of myeloma by treating this. And it is also possible that we might be able to cure myeloma in these earlier stages rather than trying to treat it when it's really more extensive. So, smaller in myeloma is very heterogeneous. You can have patients with very low risk of progression and patients with very high risk of progression. And there are many different ways to measure risk. There are many risk factors and you can use risk factors from the blood, from the urine, from genetic markers, from the bone marrow, any, you know, and we can come up with 10 to 15 different markers that you can plot and that can give you a predicted risk for a patient. And you can see here that patients that have high risk of progression, they are probably the ones that are most likely to benefit from treatment. However, when we look at, you know, 50, there's low risk, even 25% risk at five years. That's still quite a lot of patients that are going to progress in five years. So, what has been done in the field of myeloma to look at the risk of progression? I mean, this is a cohort that we have at MD Anderson with up to 16 years of follow-up. This is patients that are just followed on observation. These are untreated patients. And we can see the progression-free survival. This means the time that the patient does not progress to myeloma or does not die from myeloma or other causes was here, the median time was 58 months. And what you can see is that there's this curve downward. So, there's no plateau at all, except for the very end. And what you can see is that depending on your risk factors, you have a higher risk of progression. So, the people that are in the blue and yellow lines progress faster and also die faster than the ones that don't have risk factors. So, these are patients with smoldering myeloma where one should potentially focus more efforts, although one could also argue that treating low risk smoldering myeloma or at least some of those patients, if we could separate them a little bit farther, wouldn't probably be wrong either. All right. So, we're going to go over a few studies. So, these are important studies that have changed the way physicians look at especially smoldering myeloma. This is a study that was done in Spain. And in this study, there were two groups of patients. They all had this high risk of smoldering myeloma. In fact, some of them were even newly diagnosed myeloma by old criteria because the criteria in between this study started and finished, the criteria for newly diagnosed myeloma changed. So, these were patients that were kind of advanced, like advanced smoldering myeloma, even to multiple myeloma. And so, what you can see here is a treatment with what we call lanalidomide, which is a very common drug in myeloma and dexamethasone, really delayed the time to progression to myeloma. And it also improves survival in these patients. We also have a US study looking at this time at instead of lanalidomide and dexamethasone, looking at lanalidomide alone versus observation. And what we see here is that in patients with high risk, intermediate risk, and low risk of smoldering myeloma, treatment with lanalidomide led to a best response of 50% in the lanalidomide arm. And also, it favored progression for survival, which means patients just progressed less to multiple myeloma if they were treated than if they were in observation. Then we have, I guess, the total therapy of a smoldering myeloma, which is the Jem Cesar study. This study is currently ongoing in Spain. So, I have to tell you that this is more than even what we treat newly diagnosed myeloma patients nowadays in the US. So, this is a very heavy, heavy regimen. And what they showed, however, for these 90 patients is that at the end of the high dose chemotherapy, 55% of the patients were MRD negative in the bone marrow. So, that's a good outcome. But when you look at this, you know, there were three patients that died, and one of them had a treatment related death. So, there are many ways that you can treat a smoldering myeloma, but I think that it will be better if we can treat the smoldering myeloma maybe with things that are targeted specifically to smoldering myeloma. We have a large program on MD Anderson where we're trying to figure out what are the things that are important specifically to smoldering myeloma. One of the things that we've observed again is the immunotherapies. They work better in smoldering myeloma than in newly diagnosed myeloma or relapsed myeloma. And in this case, there's a C30 antibodies. And Dr. Langley has led the Dara-2-MUMAB study, and we have led the Isatuximab study at MD Anderson. And we have very similar response rates, about 60%. And there were no patients that discontinued treatment due to related adverse events. Right now, there are very large studies comparing combination treatment of lanolidomide with C38 antibodies. And so, these therapies are probably going to shape how we treat this in the future. Some of these are registration of studies, which means that there's going to be an indication for the FDA, which is usually what leads to insurance companies to pay for a treatment. So, it's possible, very possible that in the next five years, five or six years, we could have a therapy that is approved for smoldering myeloma. I think that will be a very big advance for this field. So, in summary, for MGAS, what we usually do is we just observe for a smoldering, what we should do is risk a stratification. And if you are intermediate or high risk for progression, try to find a clinical trial for treatment, if that's something that interests you. And then try to look at the immunotherapy approaches to avoid chemotherapy, like that trial with the high-dose melphalan, and try to prevent later resistance. So, there's Isatuximab or antibodies, there are vaccines. And then consider also enrolling on studies where you can screen family members or first-degree relatives, which are ongoing right now in the United States. All right. Any questions?