ASCO/EHA 2024 Myeloma Highlights | Ajai Chari, MD | EHA 2024

So I'll divide my ASCO eHa updates into two buckets. One is transplant ineligible populations with newly diagnosed biloma, and the second is more transplant eligible and also CAR T. So for the transplant ineligible population, I think as many people know, the MYA study, which was Dera-Tumumab-Lenalidomide-Index versus Len-Dex, showed an unprecedented median remission duration of five years. This is for a median age population of 73. So we're not talking about 60-year-olds. We're talking about 70-plus-year-olds where the new therapy of Dera-Tumumab-Lenalidomide-Index was leading to remission lasting five years. So the question is, can we do better than that? And here at these last two meetings, we heard about a couple of studies. One is called IMRONS, which is Dera-Tumumab-Lenalidomide-Index, or ESA-VRD, that quadruplet, versus the and that showed superior results, better PFS, and we don't even know the median PFS. The control arm did quite well. The control arm, VRD alone, gave a pretty good remission of about five years. And yet now, with the addition of ESA-Tuximab, which is another CV38 monoclonal antibody, we're getting unreached median projected at somewhere around 80 to 90 months. So that's amazing, right? So for a median age, again, of 73. The one asterisk is that the devil's in the details. We know that Velcade or Bortezomib is not easy to give twice weekly, right? Because it gives you peripheral neuropathy, constipation, or diarrhea. And yet, in IMRONS, these patients are getting twice weekly Velcade. And I always wonder, who are these 73-year-olds that are getting twice weekly Velcade? Because that's hard for even young patients to do. So I would just put a cautionary tale that I don't think this is one of the ways that We always have to look at the study, but then how do you apply it to the patient sitting in front of you in clinic? I think maybe we'll be more comfortable using Velcade in transplant ineligible patients, but maybe not twice weekly, right? So maybe quadruplets, once weekly Velcade with a CD38 rev limit index. But I think the message here is we shouldn't be scared about the number of drugs for older patients. It's the dosing and schedule, right? So three is better than two, four is better than three, but doesn't mean full doses of Because that's where you get into trouble with older patients. You cannot give full doses of all these drugs to older patients who have a lot of other medical problems. The other study for this population that was done was called BENEFIT, where they took ESA rev limit index and added Velcade. So sounds similar, but it's very different because in IMRONS, you're trying to improve on VRD. In this BENEFIT study, you're trying to improve on esatuximab rev limit index. So it's a harder regimen to beat. And we only have preliminary data. We only have MRD negativity. We don't have PFS, but it looks like the addition of Velcade. This was dosing appropriate. It was once weekly Velcade, three weeks on, one week off, and then it diminishes to every other week. And then eventually it's discontinued after 18 months. So it's not Velcade forever. And so I think this is exciting. The one question I have in my mind is the follow up is only two years. It's one of the questions we have to ask is if we know that Maya gives you a five year remission, are we confident that giving you a squirt of Velcade up front for one to one and a half years is actually going to lead to better than 60 months a few years from now? So I think we need a little bit more follow up. But I think both studies are giving this message that we don't need to shy away from four drugs for transplant ineligible patients. Again, this study was also 73. So that would be, I think, the exciting updates for transplant ineligible population. So then I assume you wanted a space, right? Okay. So we're taking gears to the transplant ineligible population. We've heard Griffin for a while now, which is DERA-VRD over VRD. That was a phase two study. But that's been now confirmed by Perseus, which is DERA-VRD for transplant ineligible patients. That's a quadruplet versus the triplet. And so both studies, almost identical results, identical benefits. And here we've seen at ASCO and IHA subgroup analysis showing that pretty much all these patients benefited from the quadruplet. I think what's generating a lot of questions is, okay, so we believe the quadruplet is better and we should probably be using quadruplet induction therapy. But there's been a lot of controversy of what to do after transplant. And that controversy comes from the regimen known as Cassiopeia. So in Europe, they gave VTD plus or minus DERA. And in that study, prior data showed that if you got DERA before transplant, maybe you don't need it after transplant. If you didn't get it before transplant, then you should get it after transplant. So basically, as you can imagine, people who never got DERA did the worst. But DERA either before or after or continuous seemed to all stack up together. Well now we have some interesting updates at this year's IHA. And perhaps one of the most interesting updates is that continuous DERA did do the best. And this is the danger of making decisions based on MRD at a single time point or a decision based on a single time point. So let's say your myeloma is well controlled. You got four-drug therapy. You got transplanted and you're negative. Should you just do one drug or two drugs? Well, you really need long follow-up, right? Because at that moment in time, OK, maybe you don't need two drugs. It seems intuitive if your myeloma is well controlled. But that's not what the studies are telling us. Cassiopeia is telling us that continuous DERA does make a difference. And with the PERSIA study, what's important to highlight with all of these studies is that when you're giving DERA, you don't give it continuously. You give it for two years and then you stop. Why do I bring that up? Because it's like any other thing we do in medicine. Do you want to treat an infection when you get it or do you want to take preventative antibiotics? You could do both. But if you take preventative antibiotics, you're going to breed resistant drugs, bugs, right? So in the same way, if you're going to give a preventative treatment for myeloma, do you really want resistant myeloma at the end of that? And so if you're going to do that kind of approach, you need to make sure that you're not just extending PFS, but that you're actually improving overall survival. And we have that data for Revlimid, but we don't have that for DERA. So I do think that all of these studies are supporting doublet maintenance for DERA and lenalidomide for transplant-eligible patients. But we need a little bit longer follow-up to go beyond two years. I think I would caution people from going beyond that. And lastly, I'll say when we try to make these decisions based on a single time point of I was involved in the Griffin analysis. And let's just say that the overall population had a 60% benefit from the DERA for two years in initial therapy and maintenance. But those who are MRD-negative transplant had a 90% benefit. And this is the danger of using MRD at a particular time point. Sometimes it's the responding patients who might do better with more therapy. And so you really have to look at these longer follow-up. And so that would be, I think, one of the major take-home messages from the ASCO and EHA.