CAR T, Clinical Trials & the Future of Myeloma Treatment | Multiple Myeloma Q&A

Speaker 1 (01:30):
All right. Hello everybody. I'm Dr. Sagar Lonial, a member of the International Myeloma Foundation Scientific Advisory Board, an international myeloma working group member. I'm thrilled to welcome you to this special Facebook Live as part of Myeloma Action Month. Myeloma Action Month is a global campaign each March focused on raising awareness and empowering patients and care partners with valuable information. Whether you're a patient, care partner, or simply interested in learning more, this Q&A is for you. Please drop your questions in the comments and I'll do my best to answer as many as I can. If you'd like to learn more or get involved, please visit the www.myelomaactionmonth.org. So as we get started, I'm going to ask you all to please, when you join, tell me where you're joining from so I can get a sense for the global reach of this call. And again, please submit questions into the comments. 
Speaker 1 (02:36):
And certainly I'm happy to get to as many of these as I possibly can in the 30 minutes that we have scheduled. And again, you can see the URL for the myelomaactionmonth.org if you want to learn more and get more information. So I certainly see some folks coming from Florida. I see somebody here from Idaho. Looks like we've got somebody from Burbank, Atlanta, Evansville, lots of different places all around the country. So very excited to see you here right now. While we're letting people log on, there are a couple of important things that I do want to talk a little bit about just while we're waiting for some of the questions to come in. And the two topics that I really want to cover very briefly are the significant advances that we've made in the context of newly diagnosed myeloma. We know now that for FIT patients, and FIT is truly in the eye of the beholder, but that for FIT patients, the median expected first remission for a myeloma patient diagnosed today is somewhere between 10 and 15 years, depending upon genetics and other comorbidities that may be present at the time they initially present. 
Speaker 1 (03:51):
And that data is really because of quadruplet-based induction using the anti-CD38 antibody daratumumab, and it's also in combination with high dose therapy and transplant, as well as with maintenance therapy. The other pieces of information that I think are really hopeful for the future are the movement of BCMA directed therapies from late line therapy to earlier lines of therapy. And I'm speaking specifically about CAR T-cells as well as about BCMA-directed bispecifics where the data presented in the last six months on early relapse is really quite impressive and demonstrates that in many ways, early relapse, meaning first relapse, may be the new newly diagnosed myeloma that some patients may do just as well, if not longer, after that first relapse using BCMA directed therapies. And I think in conjunction, these treatments, along with many others that we may discuss in the coming moments, really should give patients, caregivers, and families hope that we are not only going to make this potentially a chronic illness where patients live their lives with good quality of life and are healthy, but also perhaps increasing the fraction of patients that are cured. 
Speaker 1 (05:15):
And the cure word is really being spoken in the context of myeloma for the first time. We had the first International Myeloma Society Cure Summit almost a month ago now, and the Tuesday after that clinic, I walked into a patient's room and had the privilege of telling them that based on that definition from a consensus group of myeloma physicians from around the world, that this patient met the definition of cured myeloma. So really, really exciting, especially when you consider when I began my career in this field almost 25 years ago, the median expected survival was only two years, and now I'm giving you median first remissions of 10 to 15 years and even talking about the cure word. So really, really exciting data that I hope will give patients a lot of important hope and make sure that you get your care in combination or conjunction with a major myeloma center so that you or your family member or your friend can get the benefits of some of these great new advances. 
Speaker 1 (06:26):
So there certainly are some interesting data sets here and some questions. It looks like we've got a large number of people from all over the country. Really, really excited to see some of the locations and thank you so much for the hellos and the welcomes to this Facebook Live here. 
Speaker 1 (06:48):
I do see one question here that we can tackle, which is, is the anito-cel CAR T-cell as effective as the other CAR T-cells? So we currently have two BCMA directed CAR T-cells that are FDA labeled. The first one that was approved is ide-cel. The second one that was approved is cilta-cel. And you've probably seen a wealth of data from trials, including CARTITUDE-4, which was looking at CAR T-cells in first relapse. And what I think was so exciting about that trial was really long remissions, both for standard risk and high risk patients, and they didn't need any ongoing therapy. There was no maintenance therapy after the CAR T-cells, and so patients did well really, really for a long period of time. The question from the audience here is about anito-cel, which is a new type of BCMA directed CAR T-cell. Just from a molecular perspective, it's a little simpler than what we've seen with either cilta-cel or ide-cel. 
Speaker 1 (07:54):
And early phase one and phase two data suggest that the rates of cytokine release or CRS, as well as ICANS or neurologic toxicity, or any other adverse events within the first six months, appears to be lower than historically what we've seen with either cilta-cel or ide-cel. And I think that that's really encouraging in an early trial setting. Phase three trials for anito-cel are currently ongoing, and so we'll see whether this improvement in adverse events translates into a larger group of patients and whether the benefit is better than best available therapy. So I think it's certainly an exciting trial, and I think we'll see more or hear more about that in the coming year as we begin to follow it. But certainly one of the potential advantages of Anito-cell is that it may have a different adverse event profile than the other BCMA CAR T cells that are currently approved. 
Speaker 1 (08:58):
I'm going to keep looking here through some of the questions. One is, is getting a second opinion always necessary? How do you find a good second opinion? Well, I would tell you that unless you're at one of the 12 or 15 major myeloma centers in the country, there always is a good reason to get a second opinion. I think that seeing a doc that specializes in myeloma, that's all they see every day, all day when they're in clinic is really important because there is a specialized expertise that comes from that experience. However, it doesn't mean that you have to get all your treatment at that center. And I know that many of you, I saw somebody from Idaho, I see somebody here from Chile. It may be hard to get your care at a specialized center, but I think you go to that specialized center with the intent of creating a plan, identifying what the best treatment approach is going to be, and then you've always got access to that center down the road if you have questions, you have side effects, you have complications that perhaps your local doctor is just not experienced with because they don't have the same number and experience of treating myeloma patients. 
Speaker 1 (10:14):
You also potentially have the ability to go on trials and have access to new therapies sooner, as many of those are only available at specialized myeloma programs. And so I think there is value. One of my colleagues in my cancer center says, "The only simple cancer is the one that you don't have. " I think that that's a pretty straightforward answer to the idea of, "Well, my myeloma is pretty straightforward. My doctor tells me I don't need a second opinion." I don't know that that's necessarily the case and seeing somebody who sees this stuff all the time can only add to your comfort, your state of mind, as well as provide resources for your local doctor who may gain benefit and knowledge from that second opinion as well. So there's a question here that says, "If treatments stop working, what happens next?" And I think that there are a couple of different ways to frame that. 
Speaker 1 (11:13):
I think even with FDA approved agents, we now have four or five different lines of therapy. So if a treatment doesn't work, you certainly have the option of many other potential new treatments, not even necessarily on a clinical trial. Now, what a clinical trial does offer you potentially is access to new drugs that may have different or fewer side effects, and that certainly is a big attraction of many of the new treatments that are in phase one, phase two, and phase three clinical trials, is that perhaps they have a different adverse event profile, and that may benefit you in your journey with multiple myeloma. I'll also say that there are sometimes subtleties to the drug is not working anymore, and there may be tricks that many of us who use these agents use these combinations and look at the numbers and the imaging on a regular basis, may be able to bring to bear on your specific case. 
Speaker 1 (12:16):
For instance, adding in other partner drugs. So as an example, if a bispecific isn't necessarily working or offering you the benefit, perhaps it was six months ago, do you need to stop it or can you add in a medicine like pomalidomide, and that might recapture the response. These are some of the subtleties that go into many of the treatment decisions that I think you benefit from when you're at a major myeloma center, that the physicians really do only see plasma cell disorders to be able to offer you some of that benefit. So I think just to shortly answer that question, there are a number of treatment approaches, both on and off clinical trials, and I think being aware of when to add them, when to subtract them, when it's okay to just sit tight and watch those numbers, I think those are really, really important questions. 
Speaker 1 (13:14):
There's another question here asking at first relapse, how long must KPD be administered six to 12 months and then maintenance. I think that is a little bit of a situational answer in terms of how long it's working, what the magnitude of response is, what kind of situations patients are in. I often think of a treatment like KPD as a bridge to get to something else, whether it's a bispecific or a CAR T. Are these treatments definitive therapy or bridging therapies? I think those are a number of questions that can come into play to answering that specific question. And I need more details and perhaps a conversation outside of this forum to be able to really address that and answer that. There's another question here about myeloma being located in the sacrum, a lot of pain in the hips. Would a hip replacement be potentially an option? 
Speaker 1 (14:17):
I think the real question is the sacrum obviously physically is separate from the hip joint for the most part. And so the question is, are there areas there that could benefit from additional therapy, either injection, like a kyphoplasty or a vertebroplasty? I have had patients where we've done that in the sacrum to suppress some of the nerves that may be causing pain, but I think this is a situation where seeing a pain specialist or an interventional radiologist may offer you some benefit. A hip replacement would really only be indicated if you were worried that there was significant damage to the joint that was causing the pain as opposed to potentially myeloma related pain, even if it's in the joint, which might be remedied with therapy if your disease is beginning to grow again. So I think there are a number of ways to answer that question, but I think partnering with getting imaging, particularly an MRI dedicated to the sacrum and hips, followed by potentially a consultation with an interventional radiologist might offer you some benefit. 
Speaker 1 (15:30):
I see another question here about Majestic three. There were 15 patients who had prior therapy with DARA and had a 92% response rate. Are there any other studies for patients pretreated with DARA and TEC since most of patients will have had DARA as part of their initial induction therapy? So I think there are two ways to answer that question. First, MAJESTIC three was a randomized trial of teclistamab plus DARA or TECDARA versus best available therapy. And really the question in that trial was, is the doublet of TECDARA better than other available therapies? And in that trial, most patients had not been exposed to prior DARA. Now what I'd say to you is that most trials currently or most exposures for DARA are really in the induction therapy setting. So it's four cycles of DARA. You then go on to transplant and then likely are on lenalidomide based maintenance afterwards. 
Speaker 1 (16:31):
And you've not seen a lot of DARA after that. So in that context, I wouldn't have any concerns or worries that the DARA would not be offering significant benefit if a patient were to get TECDARA. What I think we're also all very excited potentially to see in the near future is the data from MAJSTIC-9, which looks at single agent teclistamab in the context of DARA exposed or DARA resistant patients. And once we have that, we'll understand the relative additive benefit of DARA, whether or not you're DARA naive or your DARA exposed or even DARA resistance. So stay tuned for the answer to that question. We're likely going to see a little bit more on that hopefully in the coming months. Okay. So other questions that are coming in here, thrilling to see that newly diagnosed may be able to go straight to CAR. I just did a CAR in November, doing well, so much easier than a transplant. 
Speaker 1 (17:32):
I think that we need really the bigger trial and CARTITUDE-6 is that bigger trial to understand whether in a population of patients that the CAR T-cell is really easier than the transplant. I think that this is something that we will know more about probably in the next few years, but certainly a majority of patients do very well with a CAR T-cell in terms of side effects in the first six months, but some patients do have side effects and complications and weighing that on balance with a transplant I think is really an important question, particularly since we have such a long track record with transplant and understanding again, that 10 to 15 year remission is what we see with a quad induction transplant and then risk adapted maintenance after that. So another question comes here, are clinical trials only for people who have run out of treatment options? 
Speaker 1 (18:31):
And the answer to that question is easy. No, they are not. We at our center have clinical trials for patients at every phase of their disease. We have patients with smoldering, we have newly diagnosed trials, we have early relapse, we have late relapse, we have five prior lines of therapy, we have exposed and resistant to every available therapy out there. And so until we have one simple treatment that is good for everybody and cures everybody, there will always be a role for clinical trials. And even when we have those, like they had in Hodgkin lymphoma in another blood cancer, they continued to work on refining those treatments with trials to see if we could reduce short-term and long-term side effects or toxicities. So from my perspective, every patient in every phase of the disease is potentially a clinical trial candidate, and that's the benefit of being at a major myeloma center so that you can get those kinds of benefits as a potential option if you need it. 
Speaker 1 (19:37):
So somebody picked up here on my comments earlier about the cure definition. The cure definition is five years of continuous MRD negativity at 10 to the minus six with a negative PET CT and not on therapy. So one of the real shifts in the way that we're thinking about myeloma therapy now in 2026 and moving forward is while myeloma historically has been dependent on continuous therapy, we're getting away from that model of continuous therapy. And so part of what we're trying to do now is get to curative regimens, get sustained MRD negativity, and potentially discontinue treatment. That's not something we could do with our previous classes of drugs, as good as they were. These are things that we can begin to think about now with agents like the bispecific antibodies, the CAR T-cells, the cell mods like ibertamide and mesignamide, and many of these new classes of drugs potentially can get us to the point of discontinuation of therapy and get us to an ultimate cure. 
Speaker 1 (20:49):
There's another question on thoughts on venetoclax. I think that venetoclax is a highly effective disease. We know that the 11 / 14 myeloma patients are sometimes slower to respond to induction, but they actually gain significant benefit from high dose therapy and autotransplant, almost more so than many other subsets of myeloma. And at the same time, we know that they do on average gain significant benefit from the medicine venetoclax, which targets BCL2 overexpression, which is one of the major issues in patients with 11 / 14 translocation. The questions that I think are ongoing now is what are the better partners for venetoclax? Clearly daratumumab plus then was very active in a phase two study. There are other BCL2 inhibitors that are currently in clinical trials that are being combined with carfilzomib as well as daratumumab. And we hope to see some of those data, see some of that data in the coming months now. 
Speaker 1 (21:54):
Another question here is how successful has been doing a second CAR for people who came out of remission? I'm guessing following a first CAR. I think it depends on the target and it depends on the CAR T-cell itself. If the target is different, there clearly is a track record for significant and deep responses for many patients. So for instance, if you got BCMA and then you relapsed and then got a GPRC5DCAR, that could offer significant benefit. If you've had a BCMA CAR going back to another BCMA CAR, you may want to understand the mechanism of resistance. And this is something that we don't really fully appreciate. And there are differences in patients who relapse at six months after a CAR versus somebody who relapses three years after a CAR. And one of the questions that many of us in the field are asking is, "Is that BCMA receptor still normal or is it mutated?" And several of us, particularly at major myeloma centers, now have sequencing tests we can use to evaluate BCMA to understand whether or not that BCMA is normal or mutated. 
Speaker 1 (23:07):
And if it's normal and there was a long first remission, one could consider a second BCMA directed CAR. I've done that for a few patients and have seen significant benefit as well. So it's a complicated question, lots of data in terms of how to interpret this, but certainly at the right places, there may be a role for retreating with the same target with a different CAR T-cell. The next question that comes in is, do myeloma patients need to stay on maintenance therapy even if they have MRD negativity? So this is a really hot topic in our field right now, particularly as you heard me talk about limited duration maintenance therapy. What we're starting to appreciate is that patients who are MRD negative at year two and year three after a transplant may be able to discontinue. That to me means that your MRD negative at 10 to the minus six, so less than one in a million, and that has been sustained for at least a year at two separate time points, two and three years out. 
Speaker 1 (24:16):
That's a group of patients where we're beginning to have those conversations with patients. If you don't have MRD testing available, many of my patients I've been taking care of for 15 to 20 years, and so we don't have MRD status on many of them, and so they're choosing to continue on lenalidomide maintenance because we just don't know. And I think that that's a reasonable approach as well, but I think these are some of the questions that we're beginning to answer. There's some data from the UK, there's some data actually from our center and other emerging centers that suggest that two years of sustained MRD negativity may be sufficient to be able to talk about discontinuation of maintenance therapy. There are a number of factors that play into that, so it's not a simple yes or no question. There's another question here, 17p deleted, but MRD negative, 10 years post-transplant, okay for me to go off rev maintenance. 
Speaker 1 (25:13):
Again, it's a hard question for me to answer because I don't know all the specifics of your case, but certainly I've had patients exactly like what you described who told me they were coming off their Revlimid maintenance and are now five years out in ongoing MRD negative remission. So I think it's certainly a discussion worth having with your physician or myeloma specialist regarding whether or not you can discontinue maintenance at this juncture, given how long you've been in remission. Here's another question. Should I wait to start treatment to request a second opinion? I think that that really in part depends on how urgent the need for treatment is. I never want to tell you to wait and delay treatment and potentially cause your body harm by waiting, but at the same time, if you're able to wait, I think it's a good idea because I think that a second opinion may give you reassurance that you're going in the right direction or it might look at the picture slightly different and perhaps tell you to go in a slightly different direction. 
Speaker 1 (26:19):
So I think it really depends on a number of factors as to whether or not you should wait. I think certainly even if you start getting that second opinion, probably not a bad idea. 
Speaker 1 (26:31):
Here's another question. What are your thoughts on the REVIVE trial to prevent smoldering from progressing to active myeloma? There are a number of trials evaluating patients with high risk smoldering myeloma. We even have an FDA approval now to prevent the progression of high risk smoldering in the context of daratumumab. There are a number of randomized phase three trials being done in the US and around the country. I would encourage certainly participation in those trials if you meet the definition of high risk smoldering. If you're outside of the high risk smoldering group, I think a discussion with a myeloma specialist in terms of whether that trial is optimal for you certainly does potentially make sense. There's another question here about in doing stem cell harvest and freeze, what are the side effects from stem cell retrieval? The side effects really from mobilization are pretty minimal. You may get a little bit of GI disturbance from the plurixafor, one of the medicines used to improve or enhance stem cell collection. 
Speaker 1 (27:38):
You may get some bone pain from the GCSF, but otherwise stem cell mobilization is relatively straightforward. There's another question here. Is there any test to predict the efficacy of treatments, how to choose between different treatment options? We don't have that ability right now to be able to use sort of ex vivo testing to do that, except perhaps for venetoclax. What we do know, however, again, this is where somebody with a lot of experience in taking care of myeloma patients can guide you through this process. And so while we don't have a hundred percent predictor of a response in the context of relapsed myeloma, we certainly do have experience and access to clinical trial data and an experts may be able to help you make those decisions. Here's another question. How long do you have to stay on maintenance if you are MRD negative? I think we've touched on that one a little bit already. 
Speaker 1 (28:38):
It depends on the clinical situation that arises in that context. And I think we've got time for one more question here. 
Speaker 1 (28:52):
There's one question here about, I have high risk smoldering, I have an IgA antibody and light chains, no CRAB criteria, but my doctor recommends starting with daratumumab. Daratumumab is FDA labeled for the management of patients with high risk smoldering. There also is a randomized phase three trial evaluating daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone. It's a really important trial. I can tell you we've got 50 patients left before we complete enrollment and it's going to ask the question, is more than daratumumab better or worse for high risk smoldering? So I'd encourage you all, if you're able to go on that trial, please take a moment to potentially go on that trial as well. So I think we're going to have to wrap up. I think it's been a great discussion. Thank you all very much. You can see some messages in the chat here about how to gain additional questions or how to gain additional information on multiple myeloma. 
Speaker 1 (29:59):
I do want to really thank our Myeloma Action Month sponsors without whose support we couldn't do a lot of this critical education for patients, for caregivers, and their families. And that includes companies like Adaptive Biotech, Amgen, The Binding Site, or Thermo Fisher, Bristol-Meyer Squibb, GSK, Johnson & Johnson, Karyopharm Therapeutics, Kite Pharma, and Arcellx, Legend Biotech, Pfizer, Regeneron, and Sanofi. And again, thank you to everyone who joined today. Before you log off, we have one small ask. During the final days of March, please help raise awareness of myeloma. Increased awareness leads to more research, earlier diagnosis, better access to treatment, and greater equity in care. Before you go, please visit the IMF Facebook page and share a fact, statistic, or educational video. You can also share this live stream on your own feed. Use the hashtag MoreThan Myeloma to please help spread awareness. Thank you very much for your attention this evening. 
Speaker 1 (31:12):
Have a good night and please go to the website to let everybody know and be more aware about this. Thank you so much.