Dr. Kenneth Anderson:
Welcome to The ASCO Post Roundtable Series on Navigating the T-Cell Therapy Landscape in Multiple Myeloma. I'm Kenneth Anderson. I'm the Kraft Family Professor of Medicine at Harvard Medical School, and I direct the Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute. Joining me today are two of my distinguished colleagues, Dr. Ajai Chari, and Dr. Noopur Raje. Dr. Chari, could you introduce yourself?
Dr. Ajai Chari:
Hello to the listeners. Pleasure to be here. My name is Ajai Chari, and I'm at the University of California, where I am the Director of the Myeloma Program.
Dr. Kenneth Anderson:
And Dr. Raje?
Dr. Noopur Raje:
Thank you for having me here. It's a pleasure indeed. My name is Noopur Raje. I am the Director for the Center for Myeloma at the Mass General Cancer Center in Boston, and I'm also a Professor of Medicine at Harvard Medical School.
Dr. Kenneth Anderson:
So today, we'll be discussing the treatment and management of multiple myeloma with three patient case studies. Our first installment will focus on the role of autologous stem cell transplant in the era of quadruplet induction and T-cell–redirected therapies. So the case is Mr. R.G., a 65-year-old man who presents with back pain. He's found to have an IgG kappa monoclonal protein at 4.5 g/dL, a kappa:lambda ratio of 250, and 70% bone marrow plasma cells with 1q amplification and t(4;14). Calcium and renal function are normal, but he does have diffuse bone disease on PET CT scan. So just to kick off the discussion, what would be, in 2025, the optimal induction therapy for this patient? Dr. Raje?
Dr. Noopur Raje:
Yeah, so thank you Ken. This is a classic patient who we would consider a high risk patient given that he has a 4;14 translocation with the chromosome 1 abnormalities as well. As you know, we just have published the new IMWG-IMS risk stratification, and he would be classified as a high-risk patient. And again, with his age and the fact that he is fit, he would be somebody who would be a transplant-eligible patient. I think the needle has moved a lot in terms of treatment for these kinds of patients now, and we are now focused on quadruplets. We started off by using the GRIFFIN regimen, which was a phase II trial with daratumumab with the combination of lenalidomide, bortezomib and dexamethasone. And that has shown incredibly high response rates with MRD negativity, and great progression-free survival. And very similar to that, we now have a phase III trial of the PERSEUS data, again looking at Dara-RVd vs RVd. So I would suggest using a quadruplet in a patient like him with consideration of a transplantation as consolidation.
Dr. Kenneth Anderson:
Anything to add Dr. Chari?
Dr. Ajai Chari:
No, I think the high-risk update is important. Previously, I think 4;14 without 1q would not be necessarily considered high risk. But here, we're given a case with both, so that fits. I think the only other things to flesh out is in these clinical trials, we're often giving people twice-weekly bortezomib. And when you go to the real world, I'm not sure many of us are doing that. And I think that's a departure. And I think to pin what Noopur alluded to, it's interesting that we went to VRD as the default induction regimen in the U.S. for almost a decade on the basis of a phase II study from Boston. And now, we have multiple phase III studies showing not only response improvement with response MRD, but also PFS. So I think it's hard to not do a quadruplet. And then I think it's worth mentioning there's also data for GMMG study showing Isa-VRD. So I think depending on what CD38 folks have access to, quadruplet is definitely the way to go.
Dr. Kenneth Anderson:
And I might ask about the role of MRD in informing therapy here. And maybe we could think about not only the PERSEUS trial, but the recent data that came from the MIDAS clinical trial, really both highlighting the high rates of MRD negativity that can be achieved with this four-drug combination, and again, addressing the issue in this individual, as a 65-year-old transplant candidate, whether in the era of quadruplet therapy, transplant will maintain its role. So any comments about how we would use MRD in helping to manage this gentleman?
Dr. Ajai Chari:
It's really remarkable because there were three studies that showed that transplant adds to PFS, but those were in particularly the era of triplet vs doublet. And so with the efficacy of quadruplets, the question of whether we still need transplant has not been answered because pretty much all the quadruplet studies have incorporated transplant. And that's what makes this recent MIDAS study that was published in The New England Journal of Medicine so important, because it does take the question of a quadruplet, Isa-KRd, and after six cycles, randomized patients with or without a transplant. And I think that's unique in terms of asking the question of transplant and quadruplet, also with the question of MRD, because we have a lot of data that MRD has been a prognostic test, that people who are MRD negative do better. But based on the ODAC vote, we now have MRD as a regulatory endpoint in randomized phase III studies.
But I think of what to do with it at the bedside is basically trying to move a prognostic test into a predictive one. And to do that, you need really randomized studies like MIDAS. You can't just do these post hoc “people who do better, do better” circular logic. And that's what's really cool about this study, showing that at current follow-up with 16 months, there was no value add to a second transplant nor the role of transplant compared to just continuing the quadruplet alone. But the only caveat I would make is the follow-up is short, 16 months. So I think we need to get longer follow-up. And then the other caveat is if you don't do the transplant, it was 12 months of quadruplet therapy, which I think again, it's easy to say we're going to do that, but when you go from clinical trials with motivated patients and healthcare teams to the real world, will every real world patient get that 12 months of quadruplet therapy without transplant? But really exciting data.
Dr. Kenneth Anderson:
Very nice. And Noopur, any thoughts on this one?
Dr. Noopur Raje:
I think one very important feature, we focus a lot on the RVD plus daratumumab quadruplet, but the MIDAS study, for the first time, has used Isa-KRd. This patient particularly is a high-risk patient, Ken. And this is where I think thinking about using a carfilzomib-containing regimen is perfectly reasonable. We have data now, not just from the MIDAS study, we have data from the ISKIA trial which enriched for high-risk patients. We also have data from the GMG-CONCEPT, high-risk patient population, where they used Isa-KRd in their quadruplets. So using a carfilzomib-containing regimen, we, as you know in Boston, Ken, have used the SKYLARK trial. We've used Isa-KRd in this patient population. A lot of these patients were transplant-deferred by choice, and MRD was an endpoint there. And with the use of carfilzomib-containing quadruplets, we are seeing very high response rates if they're able to tolerate it.
I think I agree completely with Ajai. I think the MIDAS trial is the first step towards using minimal residual disease testing as a way to de-escalate treatment or inform treatment decisions. And I do think we need to wait a little bit longer before we can say that we can do a wave with transplant. I think the one conclusion we can make is two transplants are not required. One transplant, I think we still have ways to go. And I think importantly, this is a high-risk patient. So for standard-risk patients, I think potentially doing away with the transplant based on the MIDAS trial makes a lot of sense, but we just need to be a little more careful and have a longer follow-up there to say that no transplant in everybody.
Dr. Kenneth Anderson:
Yeah, I would just add, I totally agree with both of you. I think the unprecedented excitement in myeloma is, with quadruplet therapies, you can get such high rates of MRD negativity. That was recently published from the MIDAS trial, again in Blood. And then as Ajai said, the value in somebody who's MRD negative compared to just continuing drugs for another six cycles of the transplant appears not to be significant. And I would add that the PERSEUS trial in standard-risk myeloma, quadruplet therapy transplant, and then daratumumab/lenalidomide maintenance, the projected PFS there was close to 17 years. And so I think transplant in this context should still be considered strongly, certainly in the standard-risk patient. We need to wait, in other words, I think to see some PFS data before solely based on the MIDAS trial that we jettison transplant. I think also, one of the key things about MRD in myeloma that we've learned through the MIDAS trial is that people become MRD negative at different rates.
And in the MIDAS trial, they really looked after the six cycles of four drugs and found a certain MRD negative rate. But it turns out, for example, that 11;14 translocation myeloma is more gradual in achieving MRD negativity. It's unprecedented, it's very, very exciting, and it is starting to be true as a paradigm that MRD status is starting to inform therapy.
So in this context, maybe for both of you, as you know better than most in the world, CAR T-cell therapies and bispecific T-cell engagers are now being incorporated even into the initial therapy. So maybe you could comment on both. And what is the data now and prospects for these immunotherapies to be considered as part of the initial treatment in a patient like this?
Dr. Noopur Raje:
I'm happy to get started with this one. I think immunotherapies obviously have been a game changer in the context of myeloma. We've used them in the back end, but now we have data in the newly diagnosed setting, and that's the question you're asking, Ken. So there's ongoing studies. As you know, CARTITUDE-6 is looking at the role of ciltacabtagene autoleucel, which is an anti-BCMA-directed CAR-T cell, and it is pitching it against transplant. And this is after a quadruplet four-drug regimen. They're being randomized to either autologous transplant or CAR T cells. The early phase II data from this looks absolutely incredible, 93% response rates, with the majority of patients remaining progression-free at about 2 years. So the data is robust, and I do think these immunotherapies are going to move earlier and earlier. Bispecifics are also being studied, and those studies are ongoing. Again, high response rates, high MRD negativity, and we'll have to see which one is the one. With transplant-eligible, at least, I would generally favor using CAR T cells as opposed to bispecifics.
Dr. Ajai Chari:
Yeah, I would add, I think for the listeners that the current labels for CAR-T were initially four-plus lines of therapy. And recently on the basis of two randomized phase III studies, BCMA CAR T-cell therapies are approved in one to three lines, whereas bispecifics currently have only been approved under accelerated approval strategy, single-arm, and therefore currently, they're restricted to four-plus lines of therapy. But I think as Noopur has alluded to, a lot of data showing the promise and excitement. With bispecifics in particular, MajesTEC-4 and -5 have shown almost a 100% MRD negativity, whether you're using the BCMA bispecific prior to transplant or as a consolidation posttransplant.
And every drug I think in the history of myeloma has always purported to work better in less heavily treated patients. But I think we're really seeing data for that now. And I think the true example of that would be, again, coming from Boston, the Immuno-PRISM data showing a 100% response rate in smoldering myeloma. I think it does shed some light that perhaps the better T-cell health of patients might give us more bang for our buck as we move these products. But I think we need those phase III studies to really contextualize the safety issues. How much value add are we going to get, and can we displace these 17-year PFS with long beautiful treatment-free interval potentially? So I think those data are needed, but a lot of excitement for this space. What about you, Ken? What do you think your crystal ball says?
Dr. Kenneth Anderson:
Yeah, I totally agree with both of you. I think we eagerly await the results of the CARTITUDE-6 trial, for example, to look at the role of CAR T upfront. I want to emphasize, Ajai, what you've just said, we have quite good results with the transplant and the quadruplet incorporated into that transplant paradigms. We mentioned almost 17 years in standard-risk, median progression-free survival. So we really need to see the data before we assume that the CAR-T or BiTEs might be better. Having said that though, I'm extremely excited, the more recent data from Marc Raab and colleagues from Germany incorporating to teclistamab into the initial quadruplet therapy, it's a 100% MRD negativity rate. So it's really unprecedented. When I started treating myeloma, people had even survivals of months to 1 or 2 years. And to see this opposite extreme, it's unprecedented, and I think the future is really very bright in this context.
Dr. Ajai Chari:
One other quick point to mention on this is that I think, particularly for these transplant-eligible patients, who I completely agree, as Noopur mentioned, pretty much all of them are CAR T eligible down the road, we just need also very clear data on how much bispecific exposure prior to CAR T could compromise that CAR T? So I think that's just another, really a big question in the field is 3 months, 6 months, 1 year, will any of that compromise the really outstanding CAR-T data that we're seeing in one to three plus lines of therapy?
Dr. Kenneth Anderson:
No, a super point. And we'll talk about sequencing at some interval later. But I think the other comment just to make is we're incorporating these new therapies early now, and I think, obviously with curative intent, which is very exciting. But we need to think about also what would be possible for patients should myeloma relapse in that setting as well.
So perhaps what we've really talked about is that quadruplet induction regimens have unprecedented rates of MRD-negative complete responses, that in fact, MRD status can inform induction therapy such as the MIDAS data and the potential role for transplant given the high MRD-negative rates just with drugs alone. And we all just discussed that CAR T cells and BiTEs are under evaluation for initial therapy and newly diagnosed myeloma. While we're very excited about the prospects, we do think we need to await the results from some of the pending phase II and large phase III trials. This brings us to the end of this case. Please see the other segments for further discussion about the latest research in multiple myeloma, or visit ascopost.com.
