(Guest Lecture): An Increasing Arsenal of Therapeutic Options | MCRT Webcast: Why Physicians Are Optimistic About Newly Diagnosed Myeloma

Thank you for inviting me. And I'm a little intimidated in such a crowd of notables here. This is a big topic that we're talking about. On the itinerary, the topic was standard therapies for myeloma, the role of autologous transplant and maintenance therapy. It's a very familiar topic, though, because this is something that we're dealing with routinely when we see new transplant patients, I'm sorry, new myeloma patients and considering folks for bone marrow transplant. Just a little background on myself. I am at the University of New Mexico, a NCI cancer center. And prior to this, I was in Seattle for 22 years, where one of the other speakers, Dr. Ed Libby and Andrew Cowen are located. So I have a lot of experience with stem cell transplant, both with autologous transplant, which is typical for multiple myeloma and for allogeneic transplants. Here at UNM, though, I see a lot of myeloma patients and transplant. Myeloma is the number one diagnosis for transplant. So we had a very nice introduction to the history of myeloma. I'm going to kind of build on that a little bit. And just as a reminder, you know, multiple myeloma is a disease of plasma cells. And we saw some of the history of that very nicely. Plasma cells are activated B lymphocytes that ordinarily live in the bone marrow and secrete these antibodies. That's what's kind of shown on the right, a bone with the marrow on the inside. And when you acquire a series of gene mutations in a single plasma cell, it starts to grow. So because it came from one cell, that's called a clone. And that clone of cells makes a single antibody that's a monoclonal antibody. And so that's a very convenient test in the blood where we can monitor the progress of the disease. Over on the left is just kind of a schematic of all the other cells that grow in the bone marrow space, too. And that's important because some of our treatments like high dose melphalan therapy and stem cell transplant, it kind of wipes out all of those cells. They're all very sensitive to that drug. And so we have to manage that and have a solution. So when we see a myeloma patient, our first question always is, is this the proper diagnosis? The diagnosis means what is it you're dealing with exactly? And the finding of the plasma cells in the myeloma increased is a key finding. But there are a lot of actually sophisticated genetic tests that are done as well. It's called multiple myeloma when it's advanced to the point where it's symptomatic. If it's at an earlier stage, it might be a slower process like smoldering myeloma or monoclonal gammopathy that can be monitored and doesn't need therapy. The next question we ask is where is it at? And how extensive is it? So finding out where it's at often requires imaging. And since myeloma causes holes in the bone, you can see that on x-rays. But MRI and PET CTs are very useful as well as kind of getting an idea of the extent. Those serum proteins or those proteins that the myeloma makes in the blood and in the urine are very helpful. They don't tell you how much disease there is, but they're very useful at telling the relative change in how much there is in the individual patient over time. So you sort of have to calibrate your imaging and your assessments of how much disease there is to a particular patient's myeloma protein level in the blood and urine. And then you can follow that change over time to know if they're responding or if the disease is coming back. And then finally, the consequences of those extra plasma cells in the bone marrow is, you know, is some significant symptoms. And that can be the holes in the bones themselves make them fragile and cause fractures, even with very minimal trauma or no trauma at all. They can fill up the bone marrow space and so it can start to interfere with normal blood cell production, but the red blood cells which carry oxygen and the white blood cells that fight infection and the platelets which are important for to stop bleeding. And then finally, that protein that the myeloma makes can get to the point in the blood where it starts to gum up the kidneys and can actually cause the kidneys to completely fail. And so one of the major goals of myeloma treatment is to prevent all of these complications as well as improving the quality of life of the patient and their life expectancy. So those are some basics. I thought I'm going to talk about standard therapy. I better talk about some of the basics of what myeloma is and what the treatments are. And these goals, you know, is the next objective to figure out what can we do about it. For a patient who has a lot of immediate problems, our first goal is to really try to relieve those as quickly as possible if their kidney function is not good, if they have impending fractures or something. And then with our systemic therapies, the goal is to get the disease into remission and postpone the recurrence of those problems as long as possible. Finally, of course, we would like to improve the life expectancy and quality of life of the patients. And compared to where things were 20 years ago, even when I started my career in cancer medicine, things are, you know, the life expectancy of patients are three or four times longer than they used to be. What's most elusive, of course, is curing the disease. And I think we are hopeful in myeloma because we've had such huge strides in improving the overall life expectancy. But I think it may take some fundamental new approaches and new types of therapies that may be coming in the future. So this slide, I'm sorry, it doesn't quite fit on my screen, is meant to show the timeline of therapies and it's kind of color coded to the class of therapies. The earlier treatments that Dr. Bergseigel mentioned was these alkylating chemotherapy agents that actually go in, damage the genetic material of DNAs and induce a self-destruct mechanism. But it's pretty nonspecific because any cell that's growing and dividing the body will have that same kind of effect. However, it was found to be effective and when done at high doses, it's even more effective. And that's basically the basis of an autologous stem cell transplant. Early on, transplants were done using the bone marrow of the patient, which is very, a lot of morbidity go and have that harvested, especially if you're sick and have brittle bones. But later we learned that we can harvest stem cells from the peripheral blood. After giving the patient a growth factor shot, it turns out not only do the white blood cells increase but stem cells go into the circulation and we can collect them that way. And then of course, around the year 2000, there was just a whole series of remarkable innovations in myeloma therapy with the development of the thalamids, as we heard, and the proteasome inhibitors. Both of these interfere with protein turnover in the cells and alter the signaling pathways. And then finally, there's a series of immune therapies, which we'll probably hear about later today, that include antibody therapies, antibodies conjugated to toxins, and finally, genes fused to T cell receptors in a modified T lymphocyte. So it's a cell cellular based immune therapy. And then a recent medication that's come out is exciting because it functions by a different mechanism, and that is selenoxor. And it interferes with protein nuclear export. The reason why it's exciting that something has a new mechanism is that sometimes the resistance that we see to one drug carries over and also confers resistance to other drugs. So it's nice to have a medicine that works by a different mechanism. So, for example, the alkylating agents work by a different mechanism than these proteins, these drugs involved with protein turnover. And so transplant is often beneficial, even if these other therapies aren't working and vice versa. So this is the same thing kind of listed in kind of a list format, the different classes of medicines and just naming them. So probably folks have seen many or all of these medications in their therapies. And as you can see, there are several drugs in the imid class of medicines, the proteasome And if one drug stops working, you sometimes can get benefit from the other one, but oftentimes it's not as long lived. So it is nice to have treatments that work by different mechanisms. So one of the topics was what is standard therapy for myeloma? And that's a little bit difficult to say because there's a larger and larger smorgasbord of options for myeloma therapy. But in the US, it's pretty standard in the majority of patients to use a triple therapy for the initial treatment of myeloma patients. And a common regimen, which I'll show you a little bit more information about, is the combination of Velcade Relemin and dexamethasone, or we might call that VRD. But there are other triple combinations. And most of these have the same similar classes of medicines in them. So they're slightly just different flavors of the same thing. The Cyborg is slightly different because there's an alkylating agent in this one. After the initial treatment period, if the disease has achieved a good response, then you may decrease the level of therapy and do what we call maintenance therapy. And I'm going to talk a little bit about the pros and cons of these treatments and what we know and what we don't really know. One of the things that we first think about when we're considering treatment also, though, is how sick is the patient and how able are they to withstand these treatments? Patients can get myeloma at all different ages and they can have all different kinds of health status. One consideration that we think about is, are we thinking that this person might benefit from a transplant later on? Are we thinking that they're not interested or wouldn't really be suitable? And actually, you may have more treatment options if you're not the transplant candidate because some of these medicines reduce your ability to collect stem cells and you may not want to do them as long or upfront if you are thinking of doing a transplant. On the other hand, if you're not very fit, then doing many drugs all at the same time may also be too toxic, as Dr. Bergsegel mentioned. This is actually real data from a study comparing the combination of two drugs, Velcade and dexamethasone, versus three drugs, Velcade, Revlimid, and dexamethasone. This primary endpoint was just how many people's disease responded. The definitions of the response, you have to set some kind of criteria for putting them into categories. The PR or partial response is if the markers in the blood and urine went down by more than 50%, so there was only 10% to 50% of what you started with. This is how many people achieved a partial response. There was also some patients who had over 90% of their markers go down, so there was less than 10% of what they started with, and that's here the very good partial response. Then the holy grail is to get a complete response where all the markers are completely not detectable, and that's what's seen at the bottom. But if you add all of this up, patients who had at least a 50% reduction with the triple drug regimen, you see over 80% of patients have achieved at least a 50% reduction in the Bertanum disease, and about 16% of patients or more have had a complete response where it's actually not detectable at all. All of this is really just numbers on paper. What does that really mean for translating to how somebody's doing? Well, it turns out that those responses really do have a significant impact on the experience the patient has. On the left is how long the disease is in remission according to which category of response you saw in the patients. So the patients whose disease kind of stayed the same, didn't go down by 50%, you can see that it was a much shorter time, less than two years before their disease started progressing again. On the other hand, if you had more than 90% reduction, a very good partial response or complete response where you can't see it at all, these folks went about four years before you saw their disease progress again. The same kind of thing actually was seen with the life expectancy of the patients. That's shown over here. Everything shifted to the right, but you can see that the disease getting in remission was a predictor for how long somebody lived as well. Now, one of the concepts I think it's important to understand that some even physicians sometimes forget is that what this largely represents is the variations in the biology of individual patient's disease. So some folks just have more gene mutations or have gene mutations in the myeloma that makes her harder to treat. And this difference in response isn't so much having to do necessarily on how long you did the therapy or a combination, particular combination you chose. It's just some disease is slower growing or some disease just melts away much easier in some patients versus others. It's still important to know, but it doesn't necessarily guide you too much in your treatment. So a question that comes up a lot then in myeloma therapy is should you be adding drugs together and doing them in combination or should you separate them and do them separately? And I think the benefits of doing them in combination is that if you do more at once, you're likely to have more of a response. If you get it down into a deeper remission, the remission duration will be longer as well. However, you're going to have more side effects because all those drugs all at once, you're going to have more side effects. And that's why it's appropriate if you're not too concerned about the disease or you think someone may not handle too many things all at once, you can do things sequentially and you may get just as much benefit from it doing it that way. In the end, we don't know too much about the differences in overall benefit from combining things or doing them sequentially. Oftentimes what we see studies aren't designed this way. They just look at a combined therapy versus a solo therapy, which is not a really fair comparison because you wouldn't normally do that. You would normally want to know if it's better to do them together or to do them separate. So I think we should take it a little bit with a grain of salt about getting too ambitious and having that 20 drug regimen that Dr. Bergsebel mentioned. The side effect profile and expense would probably not warrant it. So what about stem cell transplant? Stem cell transplant is a way to just give more melphalan chemotherapy. The oldest drug we have in myeloma is most effective if it's given in a high dose. If it's given in a high dose, it knocks out the normal blood cells as well. And a way around that is just to get the bone marrow from a patient and give it back to them after the chemotherapy. We do this from the peripheral blood as shown down here on the left using an aphoresis machine. It's a pretty benign procedure, much more benign than if you harvest it from the bone marrow in the old days. Just for completion's sake, I'm showing that stem cells can be obtained from umbilical cord blood as well. That would be appropriate for a donor transplant or allogeneic, and I won't be talking about that right now. So collection of stem cells. In order to get enough stem cells in the blood, you have to give a growth factor shot for about four days, and then you can go on to an aphoresis machine like I showed. And sometimes that'll get you enough stem cells in the blood where you can get enough for one or two transplants. But oftentimes we add this extra medicine, plurixaphor, which pushes even more stem cells out into the blood. When you give the treatment, it's really just a single day, a single dose of melphalan that takes an hour or two to infuse, and then you have all the consequences to deal with because it's given in a high dose. The drugs out of your system a couple days later, so we infuse the stem cells back in just like a blood transfusion. And over the course of the next week, we see the blood counts go down, and then about two weeks later, we see them rebound and come back up again. But there's a lot of other side effects that go along with that. So for example, the next most sensitive organ is the GI tract. So patients really struggle with anorexia, diarrhea, nausea, and need a lot of supportive care during that time period. And because of that, the treatment isn't necessarily appropriate for everybody. You have to be pretty fit to be able to do it. And so that's a careful conversation we need to have with all patients who might be interested. So is it right for you? I think the things to think about are your age. There's not a hard cutoff at age 70, but we're often reducing the dose of the drugs because the side effects are harder to deal with, and then you might not get as much benefit from it. If you're over age 80, I think it's generally not even worthwhile considering. And in your 70s, I think if you're on the lower end of that and you're super fit, it may be more appropriate. If you're 40 years old and you have myeloma, then the chances are you're going to run out of treatment options. So I would definitely recommend it in younger patients because you really should take advantage of everything that's out there. The other question is how fit are you? I ask my patients, are they able to walk a mile a day? Not necessarily in one straight stretch, but it's just a general, it's a pretty good indicator of whether your medical condition or the myeloma itself has made you too sick to be able to really withstand that. And the other aspect of that is if you're not in good shape, it takes longer to rebound. So you're more likely to get benefit and get back to your normal lifestyle quicker if you're in better shape. Is the disease intermission? It's best to do a transplant when the disease is under good control because you'll get a longer duration of benefit, but also it's hard to do intensive therapies afterwards. So you want to have a time period where you don't have to do very intensive treatment after transplant. There's a big time commitment. You shouldn't have other serious health problems and then you have to think about the side effects that we talked about. The benefit, it doesn't cure the disease. On the median time of remission is about three years. If you go into transplant with the disease under good control, if it's not under good control, then it's going to be less than that. The overall impact on survival is pretty minimal as we saw. But randomized studies, old randomized studies showed zero to one year of improved overall survival in transplant patients. It's relatively cost effective when you think of the outrageous cost of other myeloma therapies. So it makes sense to do cost effective therapies up front. And it's a different mechanism, as I said, the alkylating agents versus the other sort of newer treatments. The complication rate nowadays is pretty low because we know how to support these patients and to select patients who are reasonably healthy. But infections are the biggest risk that can happen when the blood counts are low. And GI side effects add to that infection risk and also add to the morbidity and the discomfort of patients. So what about revlimid maintenance? I'm going a little bit late here, so I'll try to be brief. The maintenance therapy is when you do a single drug or drugs that are reduced dose after getting a disease intermission with the idea of trying to improve the overall benefit to the patient. There have been a variety of randomized studies looking at maintenance therapy, and this is one looking at revlimid maintenance. And on the left, you see the duration of time that people's disease stayed in remission if they took low dose revlimid as maintenance after their primary induction therapy. So you can see they stayed in remission longer. On the right, what you see is that the impact on the survival, the life expectancy of the patient with the revlimid maintenance was pretty minimal. And so you could argue what the benefit of this is. This is mostly a number on paper. Your markers on your lab results look better longer. If you see the progression, you probably have to go back on therapy, but if you were not on revlimid maintenance. Whereas if you're on revlimid maintenance, you may not have to go on to such an intensive therapy as long. So whether that's worth it, I think, is arguable. It's harder to make the argument that you're going to live longer and it should be strongly recommended. However, it is often a standard and it is the same kind of benefit with progression free survival or this time that your remission is seen after transplant as well as after other induction therapies. So this is kind of the dilemma. Do you do a maintenance therapy? Do you do an induction therapy and then a maintenance? And the clinical trials often compare these two things. But why is it that you don't actually live longer if it keeps your disease in remission longer than why wouldn't the life expectancy be longer? And the simple reason is that in reality, this is not what happens. The people who were not on maintenance therapy, they got their induction, they did not get maintenance, but when their disease came back, then they could get the revlimid off study. So it's not that you can't get the drug. It's the question more is the timing of the drug. And it turns out that you may get just as much benefit by doing that maintenance drug at a later time versus if you did it at an earlier time. And so the question that we often don't address in our clinical trials is the timing and sequencing of drugs as opposed to whether or not the drug has some kind of benefit. That's my last slide. I hope I didn't go over time too much. I hope that we address kind of the concepts here as well as some of the details. Thank you very much. Yeah, I know it's fantastic. So thank you so much. That's a lot to cover. Creative time. And I think for newly diagnosed patients, it's okay if you feel overwhelmed with all the content that you're going to be seeing today. It's like a fire hose. And it really takes some time to kind of get used to one of the drug classes. And you did a really nice job going through the different drug classes and transplant. And I like how you focused on just stay fit no matter what stage of myeloma you have. I know some patients have more bone damage than others, but stay as fit as you possibly can because it opens up opportunities for you.