(Guest Lecture) Syed Abbas Ali Presents Case Studies: Discussion with Morning Faculty | RT Austin, TX Mar 25, 2023 -

Thank you all very much for giving me the opportunity to be here today. And I'm going to start with a Bill Matsuiism. So when I started at Hopkins, the good Dr. Matsui was my boss. And he sat me down, he was like, you're coming in from the NIH. What do you want to do? I'm not quite sure. I'm still young. I don't know what I want to do with my life. That's a mistake. What do you want to do? Bill Matsui said, I want to cure myeloma. I thought that was a really impressive and ambitious statement. And I think Bill is one of those guys who has really changed how people think about conceptually. And now that we find that we're in this position where we have not quite an embarrassment of riches but options for patients to access different kinds of drugs, but at the same time we make things go longer and longer. I tell my patients who I see and if any of them are watching today, they'll recognize this. I tell them my goal for my patients is for them to die at the age of 99 in a skydiving accident. And I think it's OK if we're taking something to help keep things under control at the time. But it would be ideal if we managed to get there without more drugs than we needed, beyond what we used at the beginning. And I think, again, Bill is, as you'll hear later today, Bill has come up with concepts that helped move that paradigm. So what Greg asked me to do was to talk a little bit, these are my disclosures, to talk a little bit about smoldering myeloma and newly diagnosed myeloma. And just to correct one other thing he said, he said two cases, but it's really two-ish cases, maybe a little more than two cases. So smoldering myeloma, MGUS and smoldering myeloma, these are just a little bit of background. These are precursor conditions to active myeloma. And people who get MGUS, in general we say that 1% of people with MGUS will turn into myeloma over a period of a year. That number increases quite a bit when people have smoldering myeloma. So it's not just about having more proteins and then more proteins and then turning into myeloma. These entities are biologically different. And although they sit here in these neatly defined boxes, there actually is a little bit of overlap. And so when you look at smoldering myeloma, you'll see this blue line underneath, which is MGUS, which is people who have MGUS, the entity called MGUS, turning into myeloma. That's a very flat line. When you look at smoldering myeloma, you find that half the people with smoldering myeloma will turn into active myeloma within the first five years. That's a lot. That's a much bigger progression than MGUS. And over the next 15 years, it will be another quarter of that whole population that will develop active myeloma. So this is a group of people that it makes a lot of sense to sort of do an intervention in. And there are a lot of people that have looked at defining why smoldering myeloma or who may have smoldering myeloma and what that means for how things might progress. Our friends at the Mayo have shown that depending on the kind of proteins that you have, big M spikes, lots of bone marrow plasma cells, and high light chain ratios, these are all labs that you guys may see your doctors performing, that gives you a sense for what the chances of progression are. And so when you look at this and you go, well, if I don't have any of these, I have a 23% chance of progressing in five years. But if I have two of these, then there's 80% plus chances of turning into active myeloma, meaning that somebody might have a high calcium, low blood counts, or bone lesions. So why not intervene, right, rather than wait for something to happen in these patients? So for my colleagues here, there is this gentleman who I saw, 58-year-old African-American gentleman who came to me with, was referred with IBS and peripheral neuropathy. And what happens whenever anyone walks into the doctor's office with peripheral neuropathy, somebody does a workup to look for MGUS. They always find MGUS because as we get older, a lot of people do get MGUS. That doesn't necessarily mean you have to do a lot about it, but these are things that are actively being studied. But in the course of his workup, he was found to have very high capital light chains. And he was a little bit anemic, slightly low blood counts. He was a little bit neutropenic, and slightly low white cell count. But the rest of his blood work looked normal. But his bone marrow biopsy showed between 10 and 20% plasma cells. And when I did some imaging to make sure that his bones looked OK, he didn't really have lytic bone lesions, which are typical of myeloma. But he did have slightly thin bones, right here in myelostopenia, which is the precursor to osteoporosis. And he had some chronic compression changes in the vertebral, in the spine. And as we know, myeloma patients, as you guys know, you get bone lesions. Some of those can include compression fractures of the spine. And the MRI confirmed the same, but again, no lytic bone lesions. So my question for my colleagues is, what would you guys do next? I think I'll start with Bill. So I think there's a lot in this case that I think is very illustrative. So one is that there's not going to be a right answer here, right? I think that if it's clear cut that there was nothing at all, there was no, all the bones looked normal. There was no issues with the blood counts. They were all perfectly normal. Then I think we would all feel comfortable saying, well, we think that they're defined as having some sort of precursor condition that we're not going to have to worry about thinking about treatment. So here I think the dilemma is, is that, is there some sort of, are we just catching things early? And then the question is, I think the million dollar question is, is that if we catch things early and decide to treat early, are we going to actually make things better over time, right? So this is the dilemma that we face a lot. And the way I typically explain it to people is that, so if we had two of you, one person we would treat and the other person we would not treat, and then we could figure out which one is the better way to go. And so that is obviously not a satisfactory thing. So for me, I think we have general philosophies about how we want to do things. So a good example of that is that if I am getting ready to retire, I'm going to put all of my city things, all of my retirement in bonds, right? Or is it my son, who's 22, lives in New York, is a software engineer and is making a lot of money, he's going to put his money into stocks because that fits, right? And so I think that there's just general philosophy. So my general philosophy taking care of patients is that if you don't know what to do, I almost always err on the side of not doing anything, right? Because my own philosophy is that I can do, I have a lot of things in my bag of tricks that can really hurt people and I would rather not be the person doing damage than not. I think it's still, you take that approach and you have to be incredibly vigilant with the patient, right? Be available if they come up with something, you want to evaluate it very quickly. But in the end, my general philosophy is if you don't know what it is, I would not go ahead and treat it, but I would probably check on all of this stuff in a month and just not a bone marrow, but blood counts for sure. Any pain that comes up, I'm going to do a scan right away, I'm going to be vigilant about it, but I would personally not pull the trigger. So I too am a big fan of not upsetting that apple card. Dr. Butler? Yeah, no, I think I've had this conversation with patients and I think I've ended up in a very similar place with Dr. Muthui. It really comes from this instinct that's ingrained into doctors from the day we take the Hippocratic oath, primum non nocari, first do no harm. So when there's uncertainty, we kind of hold back a little bit. There is some data, there have been research studies showing that certain patients with bouldering myeloma may benefit from treatment even before it progresses to active myeloma. The guidelines say that this is an okay thing to do, but they also don't strongly endorse it. It's kind of a, it's in a gray zone. And so I've sat down with people and I feel like because this option is there, I should at least offer it or talk about it with the patient. And so we get into, well, what are the risks of not doing it? You know, what could, what benefit could treatment have? We think that if we start treatment at this stage, we can slow the progression to another stage. But of course, the biggest thing that happens if the patient, if someone does progress to active myeloma is they need to go in treatment. And that's, if that's already happened, it's harder to say that we've really improved any more important or longer term outcome. And of course we have to think about the ways that we could hurt someone with treatment. And so we talk about the drug that would be used for this, which is lenalidomide or Revlimid. It's a wonderful drug, but it has some risks. And I talk about the risk of developing blood clots and the risk of lowered blood counts, sometimes fatigue, diarrhea. And then I talk about that there's a small risk of developing other cancers that seems to be increased for people who have been on Revlimid for a long time. And usually that's the point of the conversation where both the patient and I say, maybe it's just not worth it at this point. That, you know, the risks are small, but they are real. The benefits are still very unclear. And with myeloma, it's really a long term journey. And we try not to act in haste because we can watch it. If things change, they usually change slowly and we'll have time later on down the road to alter course. So that is excellent. So I think one of the key things that we've heard so far is that surveillance and vigilance are really very important. And the reason these are important is because of what happened a little bit later. You see, so we look at some numbers, we look at light chains, we look at proteins, we try and make sense of whether it's time to do something, right? Is something dynamically changing? And when you see things changing dynamically over time, light chains rising, proteins rising, then that's an opportunity to sit down and say that, is it time for me to do something? Is something changing enough where my risk versus benefit profile favors doing something? Or do I need to keep waiting or be vigilant? So there are a lot of ways to sort of look at what the risk of progression is. There's a Spanish model, a male model, an international myeloma working group model, and people end up being in these categories where they're high risk or intermediate risk or low risk. And you say that, okay, perhaps if you have high risk myeloma, and that means that something is going to happen in the next 18 months or two years, then maybe it is time for me to do something. But if you have a more intermediate risk myeloma or a low risk myeloma, these patients behave more like they might actually have MGUS and people who have high risk myeloma might behave like people who are early detected multiple myeloma. And so the trials that the good Dr. Butler was mentioning, these were studies about lenalidomide that our friends in Spain did, and then the one on the right that you see that our friends down at Emory did. And what they showed was that in patients who had high risk myeloma, with a lot of caveats, what these curves are showing is that the line that's, the blue lines are generally better. Doing something was, in these people were generally better than observing in both these groups. But this is not a slam dunk. And this is an individual conversation everyone should have. So what I like to do then is what I did with this lady over here. So this is a 57 year old lady who was found to have fatigue and maybe a little bit of anemia. And so she was found to have a large M-spike, more than three, a large light chain ratio of more than 40. And she was anemic with hemoglobin of 10. And the bone marrow showed 30% plasma cells, but we couldn't, or she couldn't get a fish. And so the skeleton survey, there were no bone illusions. But what would you guys do here? Because she is a little bit anemic. What are our options? Libidoctor Lee. So technically, this patient would still be considered a smoldering myeloma, but much, much high disease burden. And if we use the different models, we consider the patient to have high risk smoldering multiple myeloma. And so I think you probably heard the general opinions from the group are fairly homogenous in the sense that we tend to wait and not pull the trigger on giving therapy right away. And we tend to watch and observe smoldering myeloma closely. So I would say that, perhaps they're saying that smoldering myeloma in itself, there's a lot of different opinions. So if you have a group of 20 different myeloma doctors, you probably have 10 different opinions about what to potentially do in this context. My general approach is that if the patient is symptomatic, so for instance, the hemoglobin is a little 10.7. So we'll have to see what the baseline was initially. So if the patient's had a three to four gram drop, technically more than two gram would be considered myeloma. But if they had a significant drop in hemoglobin that potentially could explain the fatigue, then that's one thing. The iron deficiency could also explain the fatigue as well and anemia. In generally, what I would do is, so this patient hasn't had a PET scan yet. So we do advanced imaging, is that correct? Yeah, her insurance denied this three-quarter. Okay, sorry. I could not convince her. Sorry. Despite the phone calls, I could not convince them otherwise. So first of all, I'll get advanced imaging first to make sure that the patient doesn't have actual myeloma. But even in such patients like this, I'm probably on the very conservative end of the spectrum where I actually am very hard pressed to pull the trigger in treating smoldering myeloma. And actually, at least don't make a decision on the first visit, actually. I like to kind of see how things go over the next three to six months with close observation. And that would potentially then give a better sort of picture, essentially the movie of what's going on instead of the snapshot. And so that's generally my approach initially, even though the patient does have significant high disease burden. So these are excellent points. And I think that sort of covers everything that we've spoken about this morning. So the traditional paradigm for smoldering myeloma is to follow someone's numbers every three months. I see patients coming to me who have a smoldering myeloma with a large disease burden whose doctors see them six months or a year apart, and that isn't appropriate. And why that's appropriate is because when you look at these two labs, the one in red up and the one lower down, these were done about two and a half months apart. And there's already a trend in our numbers. These are just two snapshots. So you want to get additional numbers as well. But in addition to that, what Bill was talking about earlier about shared decision making, this patient really wanted to do something. And she does meet criteria for what we call high risk smoldering myeloma, which is there is an indication to treat lenalidomide. Or what I personally like to do is in this situation is to refer people for clinical trials, which is what happened here. And now she is on a clinical trial with our colleagues at the NIH where she is getting DiRTU-MAP, Kyprolis and dexamethasone. And she got a PET scan for free or at least on Uncle Sam's dime. And we didn't run into issues with insurance approval, which I think worked out with her wishes, worked out with the fact that there were perhaps early dynamic changes. And that's something to consider. The clinical trials, right, as was being discussed earlier, these are, you know, should be considered and should be in the right context. People come to me and say that, look, I've heard about, I don't know, some ground herb somewhere that I might be able to get some other country that I would say, this is probably a waste of your time in terms of a clinical trial. But if there's a rationally designed drug, there are good preclinical data, and it looks promising that maybe that's something to consider. There are a couple of trials, or actually numerous trials for smoldering myeloma. And there have been a couple that have been what would have been termed the cure trials for myeloma, the CSER study and the ASCEND trials, which have looked at aggressive combinations for patients with smoldering multiple myeloma to see that if you get in early in high risk smoldering myeloma, can you move the, can you shift that paradigm? Can you get people, keep people from having myeloma and perhaps even functionally cure them? And I think that remains to be seen. I think we see that these patients have a lot of minimal residual disease negativity with this treatment, which is not unexpected, but I think it still remains to be seen how this is going to pan out. I want to see what my colleagues think about these trials though. Well, Cure has been talked about in the context of myeloma for a long time, and it's something that we think about constantly. When we approach treating any cancer, the very, for the top level, the kind of guiding decision that we have to make is what is our goal of treating it? What are we trying to accomplish? And in cancers that are considered curable, we have a totally different mindset. We are willing to accept a lot more, or at least we're willing to suggest or encourage patients to go through a lot more hardship and toxicity and struggle if the end result of that may be permanently beating the disease. And myeloma, we have never yet reached that consensus that we have a curative treatment and that it's a realistically achievable goal. So we think of it as a chronic disease. We try to manage it. We try to help people live as long and as well as they can with it. That being said, all of us have seen patients who seem to be cured anecdotally. There are people that beat the odds. And if you look at one of these curves, the curve comes down, people relapse, but there's often a tail. There's a few lucky people at the very end who seem to kind of not have to deal with the disease anymore. And if we could get that to where it would be a predictable and a likely outcome of treatment, then I absolutely would encourage people to go on treatments earlier and earlier, more and more intensive treatments like these trials. And smoldering myeloma may be exactly the time to do that, where you can nip the disease in the bud before it has a chance to start mutating and becoming more heterogeneous and more complicated to try to deal with. Unfortunately, I think that's a hope and that's a work in progress, but it's not something that we can offer people today, except in the context of this research. So I think that one of the things to remember is that in the, let's say, the sort of most contemporary kind of way of guessing whether someone is going to be high-risk lowers, whatever, right? So there are different systems that are in play. I think that in almost all of them, the high-risk people, it's not 100% of people get to myeloma, right? And so to me, doing something in one of these trials, I think that if it's a clinical trial well-designed, I agree with Abbas that it's informed consent. You're deciding what you're doing when you're signing up for the trial. It should be explained fairly well. And I think presenting that as an option, I think, is a great thing to do because it's really talking to patients about that. I think as a general standard to do something like this, really the data do matter. And so to me, I think one of the things about both of these trials is that since you don't get 100% of people there, this approach is probably not going to help 100% of people, right? It might help some proportion of people. So what I always ask in trials like this is, well, what other things are you looking at? Because these are opportunities to figure out what parameters may predict who's going to go ahead and what sort of, for any of these treatments, are there specific patients where they benefit the most, right? And so that would be something where everyone always says, well, I get the plasma cells and I sequence them to find mutations. Or I look at their end protein or I do these other things. And you know, well, what about the patient's immune system? Are you evaluating their immune system? Maybe their immune system is important in deciding whether they progress or not. Or what are other parameters that you're looking at? So I think these are good trials. I wish that they were much more extensive at collecting a lot of data about the patients because I think if you could guess with 99% accuracy, if Selman's going to get to myeloma, I would be happy to treat them early, right? I think if it was a 50-50 thing, I'm like, no way. I'm going to watch and let you get there, right? But I think getting better, and I think over time we're doing that, getting better predictive who's going to actually get to that place. That is the critical thing. And then matching up a treatment for specific patients that benefits them, I think that's the critical thing. So these are opportunities to collect that data. And I think that a lot of times they fall short on doing that. Yeah, I mean, I agree completely. I think these are ultra-aggressive trials. And I think the bar should be very high to admit patients to ultra-aggressive trials. I also like trials that are potentially randomized. I also wonder if the patients that do really well are patients that are probably going to do really well anyway. And so these are all questions that we're trying to answer. But these were interesting trials that got a lot of press at the various ASH meetings. And I wonder if we have a minute or two. Are people hungry? No, we're guarding you and I after this. So basically you're just eating it. Good stuff then. So I had this young lady that came to me this past Tuesday, actually. And she's 49 years old. She went to see her PCP, who happened to notice that she was anemic on routine labs. And her creatinine was a bit elevated. And she had high protein, lambda-light chains. And she got a bone marrow biopsy that showed a lot of plasma cells. And she has a gain of 1q. And she's got a PET scan because she has good insurance. And it was unfortunately found to have bone lesions. And then in the 14 days between when her first set of labs was done and her next set of labs was done, her creatinine has gone from 1.5 to 2.65. The question for my colleagues is, what next? So this is a little bit, I think, of an easier situation because clearly the person has myeloma and has symptomatic disease. It gets into that thing that I talked about early on of, well, you have different choices now. What is the best choice for you? And I think part of that is for this individual, she's young. And I think that thinking about not what the first thing you're going to do is, but what is part of that entire paradigm? So are you going to give chemotherapy and see how it goes? Are you going to get chemotherapy and then automatically go to a transplant? Are you going to find a clinical trial because the person is relatively young? I think that there's a tendency for patients who are younger to have more aggressive disease at times. Even though it's cut and dry, the person has myeloma, something needs to be done. She should be treated. How you go about that, I think there's still subtleties there. So it's not one size fits all. I think it just depends on, like if we were with Hans at MD Anderson, I'm sure there are like 10 trials that she could go on and it's really deciding on those. But I think that if it's here where we don't have newly diagnosed trials and it's kind of thinking about what's the best paradigm for this individual. And I think it's making sure that the patient understands what's going to happen and is agreeable to that. So I mean, I would agree very much. So the first thing that I did was at the end of the clinic visit, I called her doctor and I said, why don't you get her started on chemotherapy this week? Because before the kidney function deteriorates further and that's time we notice in these interventions is important. And the other question then in my mind was, and for my colleagues as well, is that she has a gain of one cue, which we consider to be a high risk feature, right? And to varying degree, there's some debate as to what discussion as to whether gain of one cue and application one cue, these have different implications. So in general, what I tell my fellows who occasionally find all the choices in myeloma to be challenging is that most patients should get initial treatment. Most patients who are in the shape where it should probably get a transplant. And most people should get a maintenance paradigm to keep a lid on things. This is generally the way that we approach things absent at trial. So a good question to ask over here is that now people are using quadruplets up front, right? They're using Dara2MAP plus Zadalcade plus Revlimid and Nexmedazone. So would we use a standard of care quad like DaraVRD or would you prefer a different drug? Like I promise. So one of the lessons if you listen to this group talk about cases is being an easy case for us is not something that you as a patient ever want. The easiest cases for us are the ones that are the most, where the disease is the most obvious and the course of action is very narrow and very necessary. This patient needs treatment as effective and as quickly as she can get it. There are a few constraints which with the kidney function the way it is, it makes it difficult to use some of our drugs, particularly Revlimid. So we sometimes give a slightly different treatment initially for someone like this and then transition to a more long-term preferred regimen. And I think the preferred regimen nowadays is a four-drug regimen. The Mayo Clinic has some guidelines and they recommend giving those to higher risk patients like this based on that genetic change that she has. The frustrating thing that we have looking at the data is nothing that we know to do right now really cancels out that high risk status. In other words patients with more favorable risk features do better with three drug regimens and they also do even better than that with four drug regimens, whereas the higher risk patients get less benefit but they still get benefit and I think she deserves everything done. I don't think there's good data support using something like Carfilizumib right out of the gates with this patient, although that may certainly come into play. And I think most people would recommend that she go through a stem cell transplant when she's able to do that, assuming she's able to do that. If the kidney function doesn't improve that creates some complexity there as well. But we're actually hopeful. It's to me encouraging that her kidney function got worse quickly because those patients sometimes it also gets better quickly when we start treatment, whereas if it's been bad for a while then it can be more stubborn and harder to reverse. So I've seen patients like this have their kidneys returned completely to normal and able to go through the full treatment plan including a transplant and that's what I would try to achieve for her. And as you heard Dr. Lee talk about, more advanced therapies like CAR-T may someday be even better but at the moment that's very much in the research stage. you