A New Wave of Progress in The Treatment of Multiple Myeloma: Translating Evidence to Clinical Practice - Episode 11
After reviewing other novel bispecific antibodies including talquetamab, cevostamab, and elranatamab in RRMM, panelists consider how these agents compare and might be selected for specific patients.
Ajai Chari, MD: Rafael, you alluded to this, other targets besides BCMA [B-cell maturation antigen]. What else do you have to give us?
Rafael Fonseca, MD: A little disclaimer. It’s hard to discuss the study I’m going to talk about because you obviously have been the senior leader of that, but GPRC5D is another great target. I’m going to take a quick step back. I don’t think we should talk about BCMA-targeting agents, which means nothing. BCMA is just the anchor. We have ADCs [antibody drug conjugates], we have bispecifics, and we have CAR T cells, and I think there’s a real danger in people saying, “Oh, someone has had a BCMA”—particularly I fear that [with] prior authorization. It’s a big rabbit hole to go into, but the point is, BCMA is just a target. I think we need to think about the mechanism of action, taking it back to the MonumenTAL clinical trials. This was for talquetamab, which again targets this specific anchor. Interestingly, it’s also expressed in epidermal tissues. One of the things that are being understood iscutaneous nails and other forms of toxicity, which need to be considered and defined; dysgeusia as well has been reported. But they report a very good level of response. At the weekly administration, which by the way is subcutaneous, [it’s] 70% response rate every other week, which is about twice the dose, and you have a 60-something percent response rate. It’s really active. About three-quarters of the patients get cytokine release syndrome [CRS], but mostly it’s grade 1 and 2. I can imagine [in the] future, you get something like teclistamab, you progress¼fortunately, we have talquetamab, and I won’t mention the other agent because I think Dr Patel’s going to talk about that, but we will have multiple lanes to approach patients in the future. To me, this is very exciting.
Ajai Chari, MD: It’s good to have choices, and that’s a perfect segue to you. So there’s even more than BCMA and GPCR [G protein-coupled receptor]?
Krina Patel, MD: Yes, cevostamab, I think with FcRH5, is another great target. I tell people we had CD19 envy for so long, and now they’re envious of us, because we have so many targets that we can go after, and it’s a great time to learn all of this. We know that that’s another great target that’s on almost every patient, myeloma cells have a high antigen density of it, and this is a bispecific with FcRH5, and CD3. They actually had patients that had prior anti-BCMA therapies, including bispecifics and ADCs, etc. I think the initial dosing was IV [intravenously] and it was every 3 weeks, which is a little different, and it’s fixed dosing. All the other bispecifics so far have been continuous dosing. I think a lot of people are excited to see what happens when you do fixed dosing. I think what was really impressive was that the response rates, even in the BCMA-exposed patients, [it’s with a] different mechanism of action, but when they put them together, it’s still about 40% to 50% of patients responded, which was nice to see.I think the next trial that they’re doing, they’re changing it up a little bit where they’re giving sub-q [subcutaneous] cevostamab because we know our patients love sub-q better than IV. I think it’s going to be every 4 weeks at 13 cycles. That’ll be really interesting to see.
Ajai Chari, MD: There are other BCMA constructs as well that we’re presenting this year.
Krina Patel, MD: Exactly, because we have so many, so going back to the BCMA, I think elranatamab was also presented. This is a weekly subcutaneous BCMA-specific bispecific, and for their patients, again, lots of lines of therapies, I think 6 lines of prior therapies. They had a lot of triple-class refractory, about 96%. I think most of their patients did pretty well; it’s a 60% response rate. And we don’t necessarily have a median PFS [progression-free survival] yet, but I know they had their swimmers’ plots look pretty impressive so far. Their CRS is still a grade 1 to 2. I think they had a little bit of peripheral neuropathy that they talked about. One patient had grade 3, and 2 patients had to come off [of it], but otherwise, the toxicity has been pretty well tolerated.
Ajai Chari, MD: I think you guys have done a great job laying out the BCMA, GPRC, and FcRH5 bispecifics. How are you going to pick among these? And where should they be compared to our other choices for drugs, which we heard—we already had 15 New England Journal-level relapsed/refractory studies [RRMM]? Now you’re giving them a bunch more. What are you going to do with all this?
Krina Patel, MD: It’s going to be when I can get it. So the faster I can get it, the better. I think initially it is going to be like what Omar [Nadeem, MD] said; we have so many patients that are just waiting. And so whatever I can get them, great. But I don’t think you have to use a BCMA before GPRC5D or before FcRH5. I think right now it’s just that’s what we have. We don’t know any biology regarding antigen expression, etc, if you target one vs the other. We’ll have to learn a lot from this. I do think, again, we don’t have lots of data. We have some data, or people have gotten prior, let’s say BC5 bispecifics, and then got a different bispecific and they still did OK. But I think we need a lot more real-world data on that to see how we should sequence these. And then how people are going to start combining them in future trials.
Cristina Gasparetto, MD: I completely agree. It was very interesting in the elranatamab trial that about 20-something percent of patients had prior BCMA-targeted therapies, and the responses were equal, amazing. So very interesting, because we’re talking about the BCMA as a target, and we need to differentiate these drugs. They are different.
Ajai Chari, MD: Just to expand on that, because Rafael alluded to this. We need a little bit more granularity in that. Because ADC, the one we have currently, has a lot of, as we know, keratopathy and dose interruptions. And it’s not always being given consistently until progression. And CAR T, by definition, is more of a one and done. So to really go from one BCMA modality directly to the next one, I think we need a little bit more granularity on that. But I’m curious then, maybe we can talk a little bit about the side effects. We’ve talked about this, but just to summarize: All of these bispecifics, again, are phase 1 studies. And yet we’re talking about efficacy of 60% to 80% at a variety of doses. I think we see that. I always joke I have patients on homeopathic doses, because they started 3 years ago on these micro amounts of bispecific, and they’re still in remission. So I don’t think we even know the right dose and schedule and duration.
Transcript edited for clarity.