Dr. Kenneth Anderson:
Welcome to The ASCO Post Roundtable Series on Navigating the T-Cell Therapy Landscape in Multiple Myeloma. I'm Ken Anderson, the Kraft Family Professor of Medicine at Harvard Medical School, and I direct the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. I'm honored to be joined today by Dr. Ajai Chari and Dr. Noopur Raje. Could you please introduce yourself Dr. Raje?
Dr. Noopur Raje:
Hi, it's a pleasure to be here today. My name is Noopur Raje. I am a Professor of Medicine at Harvard Medical School and I direct the multiple myeloma program at Mass General in Boston.
Dr. Kenneth Anderson:
Great. And Dr. Chari?
Dr. Ajai Chari:
Hi, Ajai Chari here. I'm University of California San Francisco where I'm the Director of the Myeloma Program and a Professor of Clinical Medicine.
Dr. Kenneth Anderson:
So today we'll be discussing the treatment and management of multiple myeloma with three patient case studies. Our third and final installment will focus on the optimal sequencing of T-cell–redirected therapies. So the case is that of Mr. G.S., who's a 65-year-old man presenting with back pain, anemia, and lytic bone disease. There are 70% bone marrow plasma cells, which on FISH show 17p deletion and 1q amplification. The IgA kappa monoclonal protein is 6.5 g/dL and the kappa:lambda ratio is 800. He's treated with isatuximab/carfilzomib/lenalidomide/dexamethasone, achieves minimal residual disease, negative complete response after eight cycles, undergoes stem cell collection, but defers autologous stem cell transplant and receives carfilzomib/lenalidomide maintenance for 2 years. He has increasing minimal residual disease while in complete response 4 years later.
So first, should he be treated based on increasing MRD status? And maybe we can expand that and just talk about MRD informing therapy in this setting. Dr. Raje, any thoughts?
Dr. Noopur Raje:
Yeah, no. This is a great question Ken. We are using MRD now because we are seeing such high response rates with quadruplets like this patient has received with carfilzomib, lenalidomide, dexamethasone, and anti-CD38. Close to 100% of people are responding. So using MRD for response is great. There are ongoing trials which are looking at MRD negativity, which are then helping with treatment de-escalation, so to speak. As far as treatment escalation is concerned, and that is the question that you're asking right now. We do not have a lot of data in this space. Having said that, this patient, despite having high-risk disease with a p53 deletion and chromosome 1 abnormalities, this is clearly a high-risk patient. He has done extremely well with the quadruplet without having had a transplant and had carfilzomib with lenalidomide maintenance. For somebody who's progressing on dual maintenance and with the high-risk genetic features that they have, they're at a high risk of developing extramedullary disease, et cetera.
We don't have data in this space, but I would have a low threshold to consider treatment in this patient as soon as we start seeing a monoclonal protein up here.
Dr. Kenneth Anderson:
And Ajai?
Dr. Ajai Chari:
Well, I think ... I completely agree with Noopur. I think if in this kind of a case where you're told they're MRD negative, it's really important to add the scan. Because sometimes we think somebody's a MRD or biochemical relapse, but if you see clinical disease on an imaging, there's not even a question of whether or not to do any treatment. And I think the other thing for the listeners to know about is that recent IMWG criteria, this patient would still be high risk, but we now have a cut-off for deletion 17p of 20%. And also I think important for readers and listeners, to do NGS. It's not just the deletion 17p, but you have a mutation in the other allele, is important to know about for this patient. But clearly he's high risk.
I do think, while we don't have data yet, I worry more about these high-risk patients who are relapsing because the writing on the wall is just a matter of time, and it may not start today or tomorrow, but you really need to prepare this patient to start some kind of a salvage therapy in the very near future.
Dr. Kenneth Anderson:
Yeah, I would just echo those comments, Ajai. I think that a high risk is characterized after all by high response rates, as was true in this gentleman, but early relapse and once one sees and has established definitively that the tumor has relapsed, I think early intervention is particularly key in the patients with high risk disease.
So having said this, this gentleman deferred his transplant initially. So transplant has been used over the years as a salvage therapy, but we also have now CAR T-cell therapy and bispecific T-cell engagers. So thinking about these options or even protocol, should this gentleman be eligible for a protocol for new immune therapy? Maybe we can just talk about of these different options. How would we decide in this gentleman what would be the best treatment for him in 2025? Ajai, do you want to start?
Dr. Ajai Chari:
Sure. From my experience, patients, especially those who are high risk, who deferred transplant, really have a strong bias against transplant. And so even at relapse, many of these patients don't necessarily want to do the transplant and would rather do a CAR-T. And I do think CAR-T data, the cilta-cel data are quite impressive. This year we had an update showing that even with heavily treated patient with five to six lines of therapy, there was a third of patients who didn't relapse at 5 years, who were MRD negative, and imaging negative. And some of those patients were also high-risk patients, which historically we thought, "Oh, high-risk patients don't do as well." But I think the fact that we have a potential cure fraction even for such high-risk patients makes cilta-cel really very compelling for somebody like this patient. And so I would definitely consider this patient for that approach.
Dr. Kenneth Anderson:
Fair enough. And Noopur, do you agree?
Dr. Noopur Raje:
No, I completely agree. High-risk patient, he's had a 4-year remission, and he's progressing on a proteasome inhibitor and an immunomodulatory drug. I would consider cilta-cel very strongly. And I think what the data now show is if you treat patients with CAR T-cells when their disease burden is low, which in this case it is going to be low, this is the kind of patient that you're going to cure despite the high-risk features. So I would absolutely consider something like cilta-cel.
Having said that, I do think we also have to take into consideration what this patient really wants. He's now closer to 70. Is he going to be able to stay close to a hospital setting for the CAR T cells? Does he have a caregiver who can spend 3 to 4 weeks with them during the CAR T-cell process? And if he can't do that, then using a bispecific T-cell engager in this patient population would be very reasonable. That, as of right now, would have to be done in the context of a clinical trial because the approval for the bi-specifics is more in the setting of after four lines of treatment, so he doesn't quite make those criteria. So considering a clinical trial would be reasonable with a bispecific as well.
Dr. Kenneth Anderson:
So just to extend the discussion a bit here, and maybe beyond this patient, but if you have patients that's eligible for CAR-T or bispecific T-cell engager, how do you think about the pluses or minuses for either one? How in particular might you sequence them? And then while we're thinking about that, most first came BCMA and now GPRC5D, but are there issues there in terms of which target would be preferred before alternative treatments? How do you think about sequencing and how do you think about the right target in this setting?
Dr. Noopur Raje:
With the way these drugs have been developed is it came with BCMA first. So we traditionally have used BCMA-targeted immunotherapies early. Having said that, both GPCR5D and BCMA are independent targets and I don't think the sequence should matter. However, when you look at the toxicities of each of these, BCMA-directed immunotherapies seem to be better tolerated and we tend to use them in earlier lines of disease.
When it comes to deciding between CAR T cells and bispecifics. If all is equal and if I have access to both, I think my choice would be to go to a CAR T-cell before I would go to bispecific T-cell engager. I do think you have to take into account the way a patient presents as well. If it's a slowly relapsing patient, you can actually wait for the CAR T-cells for the manufacturing, et cetera. But if somebody is progressing very aggressively, that's the time when you have to consider bi-specific as well. So it is to do with patient factors, but typically we tend to use BCMA when it comes to the CAR T cell with GPCR5D, whether it's a BCMA CAR or a GPCR5D CAR, I would use either or to be honest.
Dr. Kenneth Anderson:
And Ajai, what are your thoughts regarding the utility of one versus the other and the sequence? Any thoughts?
Dr. Ajai Chari:
Yeah, I think when we think about moving CAR-T earlier, the concerns ... Because we talked about this potential cure fraction in long-term remission, but the concerns would be what are the irreversible potential toxicities and how might that fare if you moved it up early? And I would say secondary malignancy was a concern in the heavily treated population: 10% risk of myeloid diseases potentially leading to fatal complications of MDS, et cetera. But in the CARTITUDE-4 that was down to 1%. So I think that seems less. And then there's also, we know, overall survival benefit. So I think that makes us feel better about moving it up early.
The other one is the neurotoxicity. In particular, Parkinsonism, which was as high as 9% in heavily treated patients. But again in CARTITUDE-4 it's 1%. So I think those two make us feel much better about moving the CAR earlier. And those are probably the main concerns with the ... Although there were still a fair amount of cranial neuropathy which reverses very rare peripheral neuropathy, but those are the CAR T.
But the BCMA does give it an infection risk, which is finite with CAR T, and that's the bigger risk with bispecifics, which is this persistent infection risk because you're basically causing B-cell aplasia and you must give IVIG support and PJP prophylaxis. And I think with GPRC5D we actually see immune recovery, humoral immunity improves, but now you get the on target off-tumor dysgeusia, nail and skin changes. So I think those are the three kind of clinical to consider, but I completely agree with Noopur.
Unfortunately with our current data, it seems like everything you do to BCMA with one MOA affects the next BCMA. So if you're going to have to pick a sequence, why not do the best PFS first, which is three years with CARTITUDE 1 for one, so cilta-cel first and then do the bispecific afterwards. I think if you're going to spend that money, give the patient the longest time treatment-free interval with the CAR-T rather than doing a bispecific person potentially compromising the T-cell health. Although I think we need a lot more data again about how much bispecific you can give, and even ADC for that matter, it's the lentiment kind of proof. What about you Ken? When do you use these products?
Dr. Kenneth Anderson:
Yeah, I have very little to add except to say that when thinking about bridging therapy, if it's needed, often nowadays bispecific T-cell engager would be given for a finite period prior to or while the CAR T cells are being manufactured. Given after the collection of the T cells and over those 6 to 8 weeks it takes to get the CAR T. And that data look very exciting, that it doesn't really ... It's a very effective bridging therapy.
In terms of the targets, BCMA, GPRC5D, I think the only thing I'll mention is that as you both well know, there's alternating targeting BCMA and targeting GPRC5D with a view of trying to decrease resistance in so doing, and we now have trispecific T-cell engagers used in patients who have not had prior BCMA- or GPRC5D-targeted treatments which are at the recommended phase two dose achieving 100% response. So I think that we're very blessed to have both CARs and BiTEs, and in fact, in individual patients we can usually offer one or both of them. We also have real-world data now published for all of these new immune therapies that really can help us inform how it's going to work in our individual patients.
And then the final quick point, any immune therapies that are in clinical trials that excite either of you that we might want to mention? Ajai?
Dr. Ajai Chari:
Yeah, I think the dual targeting is really cool. BCMA is being used as a partner, if you will, in CAR T with CD19 and GPRC. So both of those dual CARs are in development and I think looking interesting.
With the T-cell engagers, the BCMA is being partnered with GPRC5D and also CD38, so different trispecifics looking at that. So I think all of these combinations we'll have to see the clinical data, but some of them really demonstrating outstanding efficacy with potentially less toxicity. As you mentioned, the trispecific with the GPRC in particular, one step-up dose, potentially outpatient compatible monthly dosing. Some of those true barriers for bispecifics getting into a community I think could really be affected by these types of approaches. So super exciting.
Dr. Kenneth Anderson:
And Noopur?
Dr. Noopur Raje:
I couldn't agree with Ajai and you more, Ken. Exciting times. I think the dual-targeting bispecifics as well as CARs, we have dual-targeting CARs as well, so the data looks really impressive. I think the future would be to try and get in vivo CARs, so CARs without having to create them ex vivo and wait for the 4 to 6 weeks, and that's coming down the pike soon. So really exciting times in myeloma.
Dr. Kenneth Anderson:
I couldn't agree more. The first four patients treated with an in vivo CAR for myeloma were recently published and they were able to detect the CAR and patients treated, and there were responses. So that may deal with a lot of the logistical issues, if it can be done safely, we might deal with the logistical issues that we currently face.
So what are the key takeaways that CAR T-cell therapy? Cilta-cel is now approved to treat patients who have relapsed refractory myeloma, refractory to lenalidomide, and receive one to three prior therapies. At present, CAR T cells are often used before BiTEs when both are clinically available. And BCMA is at present targeted before GPRC5D using T-cell redirected therapies. But clinical protocols are now evaluating CAR T and BiTEs directed at more than one antigen. For example, BCMA and GPRC5D, or BCMA and CD19.
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. Thanks very much.
