Shifting toward the practical use of bispecific antibody teclistamab in RRMM, experts consider appropriate patient selection and investigational combination strategies.
Ajai Chari, MD: With that information, Omar, who do you think is the right patient for a BCMA [B-cell maturation antigen] bispecific like teclistamab?
Omar Nadeem, MD: Everybody. No, I think the reality is as we’ve discussed, we have so many agents in the front line and first and second relapse that most patients end up becoming triple-class refractory earlier now in their disease course than what we were used to. We need some of these agents a bit in earlier lines of therapy, but right now where things are starting is, obviously with the CAR [chimeric antigen receptor] T approvals being in the 4 prior lines population, that’s a bit too far out for a lot of those patients. And unfortunately, because of lack of availability, many patients are either waiting or unable to make it to their CAR T infusion.
Then you have something like this, which I think splits the difference nicely. You’re seeing off-the-shelf capabilities, overall as a single agent, amazing responses in this heavily pretreated patient population. It seems to have manageable toxicity. Cytokine release syndrome [CRS] rates are lower. I think it could be primed for more widespread use compared to CAR T-cell therapies. I think that’s why we’re all so excited about it, and now seeing the PFS [progression-free survival] approaching close to a year, which is similar to what we saw with the original ide-cel [idecabtagene vicleucel] studies, at the RP2T [randomized phase 2 trial] dosing. I think that makes it a tough argument to go for something like that versus this is a lot easier.
Ajai Chari, MD: The idecabtagene vicleucel queen is sitting right here.
Krina Patel MD: I’m giving him those eye darts.
Omar Nadeem, MD: I think this is going to be the big question going forward. How are you going to choose between both that are simultaneously available? Is there one patient for whom you’re going to go in one-direction vs the other? I think it is important to acknowledge that the data we’re seeing with cilta-cel [ciltacabtagene autoleucel] looks, basically in terms of PFS, more than twice as good. There seem to be differences between the different CAR products. I think so far with bispecifics, perhaps we’re not seeing that as clearly yet, but I do think there’ll be some differentiating factors that’ll make us choose. There’s so much to still be learned about toxicities, and durability of responses in the real world, etc. But I do think this applies to a large majority of patients with myeloma, particularly as they get the other agents.
Ajai Chari, MD: A perfect segue for Cristina, a lot to learn. We’ve heard about monotherapy. What can you tell us about combination strategies with bispecifics?
Cristina Gasparetto, MD: Everybody is waiting for the combination because we tested this agent as a single agent and in a heavily pretreated population, and then we want to improve, we want to do better. The problem I have with these agents is that the responses are already amazing; it’s going to be tough to improve. There were a couple of presentations on combining. It makes sense, the mechanism of action between daratumumab, the anti-CD38 antibody, the immunomodulation, and the anti-BCMA, the bispecific. Some preliminary phase 1 data are showing that potentially you can improve the response. One of the abstracts by, I believe, [Paula] Rodriguez-Otero, [MD, PhD,] showed that in every pretreated population, because we’re still talking about 7 prior lines of therapy, their responses were a bit higher.
The Spanish group…they’re launching the MajesTEC-3 trial, where they are combining teclistamab with daratumumab vs the physician’s choice, and that is going to be very interesting. Now, it is going a little earlier because they can be refractory to daratumumab, and they have had to receive daratumumab more than 90 days prior. It will be a different population of patients. It is not the classic triple refractory, penta-exposed yes, but not necessarily refractory.
Ajai Chari, MD: I think encouraging data, but it’s always hard with these single-arm studies to know what the combination is adding.
Cristina Gasparetto, MD: Exactly.
Ajai Chari, MD: We’ll need to see more data.
Cristina Gasparetto, MD: The phase 3 will be very important.
Ajai Chari, MD: But they are very interesting data. Rafael, you alluded to this, other targets besides BCMA. 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. I think there’s a real danger in people saying, “Oh, someone has had a BCMA.” Particularly I fear that at prior authorization, it’s a big rabbit hole to go into, but the point is BCMA is just a target. We need to think about the mechanism of action.
Taking it back to the monumental clinical trial, this was for talquetamab, which again targets this specific anchor. Interestingly, it’s also expressed in epidermal tissues. One of the things that is being understood is cutaneous nails and other forms of toxicity, which need to be considered; 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, there is a 70% response rate. At every other week, which is about twice the dosing, you have about a 60% response rate. It’s really active. About three-fourths of the patients get CRS, but mostly it’s grade 1 and 2. I can imagine a future where you get something like teclistamab, and if you progress, well, fortunately, we have talquetamab. I won’t mention the other agent because I think Dr Patel is 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, there’s even more than BCMA and GPRC [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’s another great target that’s in almost every patient; myeloma cells have a high antigen density of it. This is a bispecific with FCrH5 and CD3. They had patients who had prior anti-BCMA therapies, including bispecifics and ADCs, etc. The initial dosing was IV [intravenous], 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.
What was really impressive was the response rates, even in the BCMA-exposed patients, different mechanism of action, but when they put them together, about 40% to 50% of patients still responded, which was nice to see. The next trial that they’re doing, they’re changing it up a bit where they’re giving subq [subcutaneous] cevostamab, because we know our patients love subq better than IV.I think it’s going to be every 4 weeks at 13 cycles. That’ll be really interesting to see.
Transcript edited for clarity.