Dr. Kenneth Anderson:
Welcome to The ASCO Post Roundtable Series on Navigating the T-cell Therapy Landscape in Multiple Myeloma.
I'm Ken Anderson, Kraft Family Professor of Medicine at Harvard Medical School, and Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.
Joining me today are Ajai Chari and Noopur Raje.
I'd ask Ajai to introduce yourself, please.
Dr. Ajai Chari:
Hi, pleasure to be here. Ajai Chari from the University of California San Francisco where I'm the Director of the Multiple Myeloma Program, and a Professor of Clinical Medicine.
Dr. Kenneth Anderson:
And Dr. Raje?
Dr. Noopur Raje:
My name is Noopur Raje. Great to be here today. I'm a Professor of Medicine at Harvard Medical School, and I direct the multiple myeloma program at Mass General in Boston.
Dr. Kenneth Anderson:
So today we'll be discussing the treatment and management of multiple myeloma with three patient case studies. Our second installment will focus on the role of T-cell–redirected therapies in elderly patients with relapsed/refractory multiple myeloma.
So the case is that of Ms. K.P., who's an 80-year-old fit woman with a hematocrit of 30, compression fractures in the thoracic and lumbar spine, but a normal calcium and renal function. Her bone marrow shows 80% plasma cells with hyperdiploidy. IgA is 1,600 mg/dL with a kappa:lambda ratio of 200. She received RVD-lite therapy and achieved a very good partial response. She now has an increasing IgA and kappa/lambda ratio, 24 months later.
So let's talk about the optimal salvage therapy for this patient. But first, let's say, in terms of her initial management, would RVD-lite be the right treatment for this woman in 2025? Any comment on that, perhaps, Ajai?
Dr. Ajai Chari:
Yeah. I think one of the most impressive data we have in myeloma is the MAIA study, daratumumab/lenalidomide/dexamethasone vs lenalidomide/dexamethasone, which gives a PFS of 5 years, and with the median age of 73, which translated to an overall survival benefit. In contrast, VRd, even though we had a randomized study from SWOG S0777, it was a much younger population. The median age was in the 60s, and in fact we did not see an overall survival benefit in that older subgroup, although that was a post hoc analysis. So I think if you practice evidence-based medicine, at a minimum, these non-transplant-containing regimens should probably be containing CD38. So I would do an anti-CD38 monoclonal antibody plus Rd. I think the unanswered question is whether everybody need a quadruplet on top of that. And I think we can discuss that, and maybe I'll punt it to Noopur, or you, Ken, for that topic.
Dr. Kenneth Anderson:
Yeah, Noopur, I would just say that you're the developer of RVD-lite, so what do you think? Should we be adding daratumumab at this stage?
Dr. Noopur Raje:
So I think in 2025, you brought up the issue of what would we do today, Ken, so absolutely, I think adding an anti-CD38 monoclonal antibody makes a lot of sense. We have a lot of experience now, and we have phase III data with the incorporation of an anti-CD38. With the IMROZ trial, for example, you have the CEPHEUS trial, these are all transplant-deferred patients, and they've used quadruplets. I think the argument could be that these are very fit transplant-eligible patients, but in the real world, and Ajai has been bringing up when we discussed our previous case as well, how do you take care of these patients in the real world? What we tend to do is use an RVD-lite regimen, with the addition of an anti-CD38, and extremely well-tolerated. But I do think by combining drugs, you're going to get high response rates. And even in this elderly patient population, I think it's really important that we get deep responses, and even MRD negativity because they're the ones who are going to do really well.
Dr. Kenneth Anderson:
Very nice.
Let's assume, as the case is written, that she did receive RVD-lite, and her myeloma's returned, as we see at 2 years. So of all the options that are available, there are multiple triplet option available with CD38 antibody, and with carfilzomib, pomalidomide, antibodies including daratumumab, isatuximab and elotuzumab. How would we choose the optimal salvage therapy for this elderly patient? Any thoughts?
Dr. Ajai Chari:
I think you alluded there's kind of like we have the big five: bortezomib, carfilzomib, two proteasome inhibitors; two immunomodulatory drugs, lenalidomide and pomalidomide; and then the anti-CD38 monoclonal antibody. So usually those five dance partners get used in sequence, and since she's already refractory, presumably to lenalidomide, it may be bortezomib, though it's hard to give bortezomib long-term. I think if she's CD38, that would definitely be one of the drugs. And since she's also pomalidomide-naive, that would make a natural combination. I do think you can use carfilzomib in older patients, but we just have to be very attentive to the blood pressure control, cardiac screening, cardiac monitoring because we do know that these older patients probably come to the table with more cardiovascular predisposition, and so that's probably why we see a little bit more cardiac toxicity in this population compared to younger, but pretty much, I think, you can give all of those agents.
Dr. Noopur Raje:
Yeah, no, I agree completely. There's lots of different combinations, and also, even if she's lenalidomide refractory, pomalidomide-containing combinations—so pomalidomide with an anti-CD38 antibody—would be a perfectly reasonable option. This is an anti-CD38–naive patient. This is where I would think about if she's really frail, consider an elotuzumab-based combination. But you already have immunotherapies that are approved in this setting now. You have ciltacabtagene autoleuce (cilta-cel) approved after one line of treatment, and I think thinking about immunotherapies early, even in the elderly patient population, is critical because with every line of treatment in myeloma, you see a significant attrition of who will get their next line of treatments. So using the most effective strategies is something that I would focus on, and mostly in the elderly patients because of the comorbidities that are associated as people start aging.
Dr. Kenneth Anderson:
So, Noopur, maybe I can ask a further refinement there, but she’s standard-risk myeloma, hyperdiploid, I believe. And so, the question for either of you, when do you actually use CAR T-cell therapy? Cilta-cel is now approved, as you mentioned, in patients who are lenalidomide refractory in one prior treatment, when would you use CAR T-cell therapy in practice for the first relapse?
Dr. Noopur Raje:
So that's a great question, Ken. As of right now, it's only cilta-cel which is approved at first relapse. Idecabtagene vicleucel (ide-cel) is approved after two to four lines of treatment. I think most of us would use something between. I think the practice has not transitioned to using CARs at first relapse just as yet. With her age being 80, she'll get something as a second-line treatment, an anti-CD38 with probably pomalidomide. And then, as soon as that is sort of working its way, I think thinking about immunotherapies is important, as we have CAR T-cells approved. We do have clinical trials with the bispecifics as well, and this is a patient I would certainly consider for a bispecific as well. It's not yet approved, but we do have ongoing trials wherein, hopefully, it'll be approved pretty quickly with both the BCMA bispecifics. Teclistamab as well as elranatamab are going through their phase III trials. But as of right now, at least, are not using CAR T-cells at first relapse just as yet, unless they have high-risk disease. If they have high-risk disease, absolutely.
Dr. Kenneth Anderson:
Ajai, anything to add on that?
Dr. Ajai Chari:
Yeah, I think at a high level, I would start with the comment, which is that if you think about a bullseye, that transplant is probably the smallest bullseye. CAR-T is bigger. I think there are patients who can get CAR that you might not have considered for transplant. It's not as difficult in terms of quality of life and impact. I would say bispecific is even bigger bullseye. Pretty much I think every patient can get a bispecific, including older comorbidities. I think drilling down to the question of whether or not to do CAR-T, I think there's a couple of patient factors and disease factors. I think from a patient, it's not the age, it's the fitness. What I want to know is, can this patient tolerate a high grade cytokine-release syndrome? Could they potentially tolerate any neurologic deterioration? And then, also, I think another factor we have to consider is, how far do they live from a cancer center?
Because we can think about all these other salvage regimens, but it's hard to do that. If you're in a rural part of US and you have to drive an hour and a half, or two hours to get a parenteral infusion, again, in the real world patient, that's kind of difficult to treat somebody with these parenteral drugs. And then, from a disease perspective, I think the criteria that I think about for CAR-T, or somebody with explosive disease, you have to make sure you're going to get them to CAR-T. And then, I think the more high risk a patient is—and it's not just genomic high risk, I think genomic, extra medullary and functional high risk, like people who for whatever reason are behaving as well—all of those patients, keeping in mind nutrition, you might want to say, "Oh, I'm going to do cilta-cel in X line of therapy," but these patients may not get there. And I think the higher risk these patients are, the earlier we should use cilta cel. But I agree, not for everybody at first relapse, but these kind of high-risk groups really benefit from that.
Dr. Kenneth Anderson:
Yeah, I think these are great points. And one of the considerations in myeloma is the frailty status. Are the patients fit or frail? And I think that we've all grown up with transplant as a paradigm. Is this patient transplant eligible or not? Do they have adequate liver, lung, heart and kidney function. But it turns that the immune therapies really can be used for a broader audience, even quite elderly patients can be, as you said, Ajai, eligible for immune therapies who might not be eligible for transplant. So it's very exciting that these novel modalities can be extended to a broader population in myeloma.
So I think some of the key takeaways here are that in such a patient with first relapse, there are multiple triplet regimens—pomalidomide, carfilzomib, daratumumab, isatuximab, and elotuzumab—often used in different triplets, but very effective, and probably would be used before a CAR T-cell therapy, for example, except if there were high-risk features, which wasn’t true in this patient.
And then, the CAR T-cell therapies are approved. As we discussed, the cilta-cel is approved in one to three prior therapies, lenalidomide refractory, and again would be utilized first relapse in high-risk disease. In patients who have relapsed, who haven't had a CD38-targeting regimen, I think the triplet therapies in particular would be used first. And then, the choice of therapies informed by the frailty status, but excitingly, the spectrum of patients who can benefit from these immune therapies appears to be quite broad as they are well tolerated.
So 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.
