(Guest Lecture): Balancing Today with Tomorrow’s Opportunity | MCRT Webcast: Why Physicians Are Optimistic About Newly Diagnosed Myeloma

Well, first of all, I want to thank the Milo MacRow for inviting me. Hopefully you can still see me, and I'm not sure. I want to thank you for inviting me. It's truly an honor to be here. Dr. Berksigal gave just an outstanding and exciting and humbling presentation. And I honestly do get really excited with these things. The science, it's like great music. I could feel my heart racing as he was speaking. Just thank you so much. Dr. Farrow, also excellent presentation. He's laid a great groundwork. And so it's going to be easy for me to talk today. But I can start right off with the first slide saying, am I optimistic? Well, I'm not just optimistic. I'm excited. As I pointed out, when I talk to patients about this subject, and I can even feel it welling up in me right now, I really get emotional because it's just mind blowing what's happened and how much better and better and better things are getting for my patients. We're going to focus a little bit on what another colleague of mine calls newbies. So newly diagnosed myeloma patients. And I hope this is valuable to you. Next slide. So we're going to talk about balancing the standards that are currently being used today with what's coming in the very near future. And we've had a nice coverage about RVD. I think we're really building on this. There's a couple of studies that have been presented and I'm going to talk about them again, we're just building on this particular study. The IFM 2009 has been very central to how we think around the world and especially in the United States about treating multiple myeloma. So for the newbies, of course, Revlimid is a pill. RVD is Revlimid, a pill. Velcade, which is a shot under your skin and your abdomen and dexamethasone pills. So to me, one question about, well, why would you, are things really promising right now, are they as good as you're saying they are, Dr. Libby, how good is RVD? And I'm really just going to talk about the IFM 2009 trial. This is the F in IFM is for French. So it was done in France, but there's also a sister study that we don't have the results to yet that was done here in the United States at Dana Farber, led by Dana Farber in Boston. Next slide. Thank you so much. So this is the, just a cartoon of how this important trial that sort of is, is right now when we think and talk about myeloma, whether you're in private practice or you're in academic practice, like I am, this particular trial is right now a key benchmark for, for how we treat. And this shows that there were two groups of patients. This was 700 patients and another 700 have been treated in the United States. So ultimately we're going to combine these two trials and we're going to have about 1500 patients to look at how they did. We've learned so much from this study. The first part of it was done though, in France and Belgium for 700 patients. So everybody got RVD for three cycles. Then they got their stem cells collected. That's the mobilization. They got their stem cells collected. This is pretty much what's done in the community and in academic practice. Sometimes we wait longer to collect the cells, but it's roughly the same thing. And then half the group got an autologous stem cell transplant with that amazing drug. How did Leaf's father stumble over this drug 60 years ago? It's just incredible. So shocking and it still works. It's still one of our best drugs. So then half the patients got a transplant, got a little more RVD and went on to Revlimid maintenance. And one of the biggest things about this study to me, that's interesting is in France, they only gave the lentilidamide maintenance for one year. So that's kind of a flaw or it makes when we talk about how people did with this study, it's different from how they're going to do here, I believe, because here we give maintenance indefinitely. The other half of patients got standard RVD. They collected their stem cells and put them in the freezer. They got five more cycles of RVD. And then they took lentilidamide or Revlimid maintenance for a year. And then they watched the patient. Next slide. So as we've just, you've seen these pictures before, if you could hit the button. Next slide. One more time. And what we saw in this study, this is really important, is that the transplanted patients in terms of progression pre-survival, which you see in the left upper hand there in terms of how long was it before the disease? Left upper hand there in terms of how long was it before the disease came back? The transplanted patients did better. It took 14 months longer for their myeloma to come back. That they're the guys up on the top blue. They did better. The ones in the red didn't do quite as well. Please hit the button one more time. And so you can see that red arrow showing that the patients who did not got a transplant, their disease returned at three years. The other patients got a little bit more than four years before their disease returned. Advanced slide. Now, what we would have liked to see and what has been shared with us, I believe by Dr. Berksical is that apparently overall survival, this was early in the study, the first four years overall survival was no different. And now they, we have follow-up data from the French that survival is no different seven years out. So, so this approach of giving an early transplant, transplant in the first year that you're diagnosed is no better than getting, at least in this study, than just getting RVD and maintenance. Very interesting and really important. Because the thing we'd like to do the most for patients is help you to live longer. Next slide. One more. That's, that was important. So 81% of patients in that study, we skipped by that real quickly, but 81% of patients were still alive four years out. So that's a, that's a superb result. Is it perfect? No, but it's, it's very good. And, and I think it's in general patients, it's a good starting place. It's a good starting place. Next, next slide. So my conclusion on this part of my talk is standard therapy works pretty darn well. I think early on Dr. Berksical mentioned that right now for the average myeloma patient, most myeloma physicians are quoting that an overall survival of at least seven to 10 years, probably even perhaps even better in now that we're almost in 2021. So standard therapy works pretty darn well. Please advance. Please advance. So the tolerability of RVD, this, this foundation therapy, this backbone therapy, the tolerability of RVD is acceptable. I probably tend to say that it's quite good, but patients do have side effects. But I tell all of my patients that, that almost everybody I treat, the great majority of them can be on RVD and continue their lives, whether they're in their forties and they're raising kids and working, which I do know is a working, which I do have patients with myeloma who are in their forties and fifties or still got full-time jobs and families, or if you're in your seventies or even eighties and you're, you're strong enough to get this triple therapy, you can keep enjoying your retirement. There are some people have major side effects, no question about it, but it's a very, it's a good therapy backbone therapy. I'll use that term just for a second. Uh, that is quite acceptable. Usually after, as Dr. Ferro said, after four to eight cycles or months of induction therapy, induction, meaning starting with or without a transplant, we can go on just maintenance. Next slide. And it's low doses usually of Revlimid. The standard maintenance is Revlimid. Sometimes it's Velcade and no, importantly, no dex, none of that devil dex. Uh, next slide. Maintenance is without dexamethasone. So what you'll hear oncologists talk a lot about, especially myeloma physicians is backbone therapy, foundational therapy. So we've built like this, like this good brick wall, solid brick wall with RVD with or without a transplant, we can debate whether or not what the role of transplant is in 2021, um, which is right around the corner, but we have we have good foundation backbone therapies, RVD in the United States, RVD with or without a transplant. Next slide. So RVD is a great backbone. This, uh, I want this person I'm showing is really kind of to show us where we were before we were with RVD. Or we didn't really have a spectacular back, but you know, maybe this is, uh, somebody who's ready to start working out. Uh, but with RVD with or without a transplant, we've got a good foundation that we can build on really good foundation. You've heard good news there for your newbies out there. Next slide. But that's where this is where we want to be. And so how do we get there where our backbone, our foundation is much more powerful and we have even better results and we can't sit on our laurels and accept the fact that except that seven, uh, the, I'm sorry, the average patient can live for seven to 10 years. That's not good enough. We want it. We want the average patient. We want to turn this into a chronic disease so you can live your normal lifespan with this disease or even better cure it. So how do we make our foundation RVD with or without transplant even better? Next slide. Next slide. Great. So you can stop there. So a standard approach when we're doing research studies is to take a well established effects, effective therapy, like RVD with or without transplant and add a new drug and the drug right now that's, that's generating the most excitement is deratumumab. And the reason for that is deratumumab is quite effective in myeloma. It really isn't all that good by itself. It's, it's okay. But if, but it's, it's pretty darn effective and it has very low side effects. So what that means is next advanced line. If you added a drug with minimal side effects, that's pretty effective to an, a good backbone like RVD, you're probably not going to be creating a really toxic combination. Next, please advance. So that's something that's being intensively studied around the world is combining RVD with deratumumab or RVD and transplant with deratumumab. Deratumumab is still, we're all still very excited about that drug, even though it's four to five years old now. Pardon me. Other drugs that are being looked at in combinations using that same kind of principle are belentimab, methadone and selenexor. Next slide. Well, so where do we go from here? What if something came along that just changed all the rules like CAR T cells? It's, it's when I talked to patient, to physicians who've been transplanting patients for 30 years, especially I remember when we started doing CAR T cells and myeloma and talking to people who'd been doing myeloma transplants for 30 years, they, they almost didn't have words to it. They couldn't believe what we're seeing with CAR T cells. The disease just melts away and disappears in a matter of days. It's not perfect though. I don't want to oversell CAR T cells. The effect generally disappears after 12 to 18 months right now. We're probably going to make that better, but what if we got a therapy like CAR T cells that just seems to change all the rules? First of all, it's not FDA approved. CAR T cells are not approved. It's only in studies and it's, and currently we're not unless when it is being done, it's usually not in combination, but combination therapies are coming in CAR T cells and up until very recently CAR T cell therapies for your newbies out there were only being given to patients who'd had a lot of therapy that relapsed many times. Often they had every drug in the book and then they got CAR T cells. But studies are now just now being opened using CAR T cell therapy in newly diagnosed patients, in particular in newly diagnosed patients who have high risk, aggressive multiple myeloma combination. Therapies are coming though for CAR T's. Next slide. So we're going to move on to side effects. And as you can see, I'm coughing and I apologize for that. So my quarantine and my COVID test is pending. Side effect, what about side effects with our treatments? RBD, so here's our backbone. What about side effects with this pretty darn good therapy? When I talk to patients, I think some of the top things I talk about would be rash. You can get a rash with Revlin, but it's reversible. Get diarrhea with Revlin. That's treatable and reversible. Velcade neuropathy. This is a huge problem. We haven't come up with a way around it, except an initial thing was to go from intravenous Velcade to subcutaneous Velcade. So that significantly decreased the amount of neuropathy, but neuropathy is still a problem. And I think it's a terrible issue. And so for you newbies out there, if you start getting numbness or tingling, make sure your doctor notices it, but usually it's in your feet. And once it gets to any, particularly if getting any pain, any pain, you've got to stop that drug and wait for the pain to get better. We might restart at a lower dose or switch to a different drug. But anyone who's prescribing Velcade should do everything in their power to avoid neuropathy. It is a horrible and sometimes permanent side effect. Fortunately, only a small minority of patients get it, but it's still a problem. Blepharitis is an issue. I've been seeing a lot of this lately. It's a stye in the eye and sometimes it can be really impressive. I actually don't usually mention it to patients, but it's an interesting side effect from Velcade and dexamethasone, of course, the devil dex, insomnia, anxiety and irritability. These are common side effects. So that's the end of the side effects story, right? Well, actually, no. Next slide. That's the list of side effects. If you pull a package insert out or look up the list of side effects for these drugs, it's a very long list. So, but most, the vast majority of the side effects are at a very low frequency. So your chances of getting all of these possible side effects is very low. The only way you can really know about all the side effects or most of the major side effects with the drugs that you're being given by your oncologist is for you to take the time to get informed. It's really not possible or realistic, in my opinion, for the pharmacist or your physician to go through everything. I mean, I mean everything. You can't do it. It would take days. So, but I think it's important for you as a patient or your friend or your significant other or family member to get informed and to be aware. So you might read about it, look it up, get information from the myeloma, from the myeloma crowd or from other myeloma support groups about side effects. There are a lot of different things that can happen with these drugs. In general, though, they're pretty well tolerated. Next slide. Go ahead. Okay, great. Stop there. So will transplants be obsolete? I can say with 100% confidence that this form of therapy will one day no longer be standard therapy. And by the way, combustion engines are also going the way of the dinosaur. We will not be driving cars that run on gasoline or most of us in the foreseeable future. So things are changing and transplants have been a huge advance. But I think what may happen is they'll be used more as salvage therapy and in patients who have not had a transplant and are no longer responding to other drugs. I could be wrong about that, but there's some issues that I'm going to talk about that I think are leading to a transplant no longer being standard therapy. At this point in time, though, I can't emphasize this enough. In general, they're still a standard of care, the gold standard as part of your treatment. By the way, transplant is not the only therapy for myeloma. So sometimes I think we may give that message that if you don't get a transplant, all is lost. That, in my opinion, is not true by any stretch of the imagination. We've got many, many other therapies. Transplant is part and a very important part of therapy, but it's not the only part. Advance, please. So as I was mentioning, foundation therapy are good brick wall therapy at the moment. At this point in time, autologous stem cell transplant is a backbone therapy. It's still significantly effective, especially in certain scenarios, patients who haven't had a good response. In particular, people who need a dramatic addition to how they're responding because they're not getting a good response to RVD. There are patients like that. Next, please advance. No question. We've had tremendous experience and success with transplant. Advance. There have been a beautiful paper written by my colleague, Fred Albebaum, here at the Hutch a few years ago. In his paper, well over, this was several years ago, well over one million stem cell transplants had been performed at that time around the world. And most of these were for multiple myeloma. So this is a huge success story, but time moves on. Life moves on. You know, the golden days of transplant may be dwindling with all these great new therapies. Next slide. So what will lead to the death of transplant? New drugs, Dr. Bixigel, beautiful presentation and the curves so convincing. The new drugs are changing everything. What was the first new drug that really changed the playing field? Revlimid. So, and then since then, many, many other great drugs, new combinations, new combinations of anti-myeloma drugs. So not just Revlimid index, that was the initial breakthrough, but Revlimid and Velcade index. Wow. That was a great combination published not very long ago, the first study, a little more than 10 years ago. And now it's a backbone therapy. The use of minimal residual disease testing. What is that? It's been touched on already. So our, how good is our ability to see how, how good the kill is of the myeloma cells? Have we gotten, how good have we been at getting rid of your myeloma cells down to maybe there's only one myeloma cell in a million normal cells. So we, we now can, can measure this really well. And that's becoming a new standard. We want everyone to be minimal residual disease negative, MRD negative is where you want to be, meaning we can't measure your disease. So in, in view of the success of these, these fantastic new therapies, the toxicity of transplant and how well people respond to it, it may no longer be acceptable or it may no longer be our best choice. Next slide. What are the side effects of transplant? Whether they're very real, prolonged, the transplant can injure your bone marrow and it can last for a long time. You can have low blood counts for weeks and weeks. You can get serious life threatening infections. You can get serious bloodborne infections. That's one of the most serious forms of any infection. The liver can be damaged and even destroyed. The kidneys and other critical organs can be damaged and destroyed by transplant. This is in a minority of patients, but given the fact that you can die from this therapy at a low percentage, is it still the right choice? That's the question. So, and there is a real risk of dying within 90 days of a transplant. And this is in, Dr. Farrow said 2%, I believe. You know, I usually, I often will say 0.5 to 2% is going to depend on which transplant center you're seen in. Are you seen at one of the most, the more experienced centers with armies of people who do nothing but see transplant patients or are you doing it in a smaller center? It depends on a lot of things. It depends on your health. But I don't want you to hang on a 3 to 5%. My point is you can die from a transplant. It's relatively low risk, but it's not zero. And is it still acceptable in 2021? That's a question. Next slide. There's, so we talked a minute ago about short-term toxicity. I'm running a little over time, my apologies, but there's also long-term toxicity. I will speed up. The long-term toxicities can include cataracts, infertility in younger people. That can be an issue. You can get secondary cancers. This is something that's really on myeloma doctors' minds, in particular, acute leukemia, terrible disease, and myelodysplastic syndromes can also be terrible. And now that myeloma patients are living so long, they've tripled or quadrupled their life expectancy. This risk for a second cancer, we've got to think about it a little bit differently. If our goal is to perhaps turn this into a chronic disease where you live for 20 years with it or 30 years, this risk of a second cancer, this becomes a real issue. We've always been concerned about it, but maybe we need to think about, maybe it's even more important now that people are living longer. Next slide. Another important thing about transplant is that there may be a reduction in the quality of life for patients with transplant. So some studies have shown significant impacts with treatment related toxicity that lasted for six months after our transplant. Patients also may have more problems with pain, interfering with what you do on a day-to-day basis, persisting for up to two years. So there can be, this is a very important point. Next slide. So is this the current status? Is this in 2021, where are we with transplant? Is the benefit significantly and clearly outweigh the risk and therefore we should continue using it? Next slide. So we've got to think about this. We've got to think about this. We've got to think about this. We've got to think about this. We've got to think about this. We've got to think about this. Next slide. Or is this the case where risk is now outweighing the benefit given the dramatic changes that have happened in the past 10 years? Next slide. So I love, this is one of my favorite cartoons. I can't hear you laughing at darn it. That's a lot of foam when you present this slide, but. So someone talking to their cat never ever think outside of the box, but doctors like to think outside of the box and I love to think outside of the box. And so my perspective on transplant, I'm going to show you in just a second, which is a little bit perhaps outside of the standard box. And I think pretty much every myeloma physician is a thinker and they're considering different ways of approaching newly diagnosed patients with myeloma. Next slide. So this is from a recent review. And so this is a possible, and I think it relates very pretty strongly to my current approach with myeloma. And this is that you get your in upper left hand, you see the box where it says four to six cycles of modern combination therapy, either the RVD or VRD or KRD, which is Kyprolis, Reclamation of Dex. You get yourselves collected and if you're MRD negative, which significant number of people now after just getting four to six months of induction therapy. If we can't detect your disease at all, it's disappeared. It's not cured, but we can't find it anymore. Maybe give to a couple of more cycles of therapy and then go on to maintenance. Your stem cells are in the freezer. You know, you've got an insurance plan for a rainy day there, but you did so well with current therapy that it's not clear that you're still going to benefit from a transplant. But if after you get four to six cycles of modern induction therapy, you're MRD positive, you don't want to be MRD positive, meaning we can still detect the disease. Then we discuss the benefits and risks of a transplant as we sort of did just now. I usually take an hour and a half to talk to people about risks and benefits of a transplant and then perhaps move ahead and get a transplant to deepen your response to get you to MRD negative status. If you and then go on to make general, generally, lentilidomide maintenance, relevant maintenance or Velcade maintenance for high risk disease. So this is a way that many people, and there are some, I think very interesting studies looking at the strategy as well. Many myeloma docs are now approaching the treatment of newly diagnosed myeloma. One size does not fit all. We can now use a rational, thoughtful approach to how we treat patients. And we can argue, which we love to do as physicians about what's the right is this really the right thing to do? But ultimately, we'll want studies to prove it. Next slide. So am I optimistic? You bet. I am incredibly optimistic, especially after hearing people like Dr. Bergstegel speak and advance, please. Thank you so much. I really appreciate it. And sorry about the coughing. Dr. Libby, we're so grateful. You're a stalwart. Thank you so much. For joining us. It was a great deeper dive. And I want to point out also that the Hutch was really the first facility that started stem cell transplant. Were they not? They were key in advancing stem cell transplant to a routine therapy for many different types of cancer. Yes. And they did. Yes, there was extensive experimentation here many decades ago, looking at stem cell transplant. So they were critical, I think, in the advancement of this to being routine therapy and to treating myeloma patients and treating many other patients with horrible diseases like acute leukemia. Oh, and cellular therapy. I mean, you're doing a lot of leading work too in the CAR T space. So yes. Yes, the Hutch has been when I say the Hutch, it's the University of Washington and Seattle Cancer Care Alliance. But we have done somewhere between three and four hundred CAR T cell transplant patients. Most of those, the great majority of those are for people with leukemia and lymphoma. And we're now well into doing myeloma. We're going to have we have soon to have four CAR T studies for multiple myeloma. So, yes, the Hutch has played a central role. And over at the Fred Hutch Center, I love to tell patients the story if they walk across the street and the Fred Hutch Center, where I think Dr. Farrow used to work, there is a Nobel Prize hanging on the wall. And that also gets my heart racing. So what an exciting feel to be in and just how thrilling and honorable it is to be part of seeing patients do better. And I love science. Yeah, well, you can tell this is so fun to have you. So thank you so much for your presentation.