Patient Selection and Combination Therapies


Ajai Chari, MD: With this 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 that, as we said, we have so many first-line and first- and second-relapse agents that most patients end up becoming triple-class refractory earlier in evolution of their illness than what we were used to. We kinda need some of these agents in the first lines of therapy, but right now where things are starting is obviously with the CAR [chimeric antigen receptor] With T approvals being in the prior 4 line population, this is a bit too far for many of these patients. And unfortunately, due to lack of availability, many patients wait or cannot get to their CAR T infusion.

Then you have something like this, which I think splits the difference nicely. You see 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 see the PFS [progression-free survival] approaching almost a year, which is similar to what we saw with the original ide-cel [idecabtagene vicleucel] studies, at RP2T [randomized phase 2 trial] dosage. I think it’s a tough argument to go for something like this versus it’s much easier.

Ajai Chari, MD: Queen idecabtagene vicleucel is sitting right here.

Krina Patel MD: I give him these darts for the eyes.

Omar Nadeem, MD: I think this is going to be the big question in the future. How will you choose between the two available simultaneously? Is there a patient for whom you are going to go one way rather than the other? I think it’s important to recognize that the data we see with cilta-cel [ciltacabtagene autoleucel] looks, essentially 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 we may not see that as clearly, but I think there will be differentiating factors that will make us choose. There is still so much to learn about toxicities and durability of real-world responses, etc. But I think that applies to a large majority of myeloma patients, especially when they receive the other agents.

Ajai Chari, MD: A perfect transition for Cristina, a lot to learn. We have heard of monotherapy. What can you tell us about combination strategies with bispecifics?

Cristina Gasparetto, MD: Everyone is waiting for the combination because we tested this agent in monotherapy 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 will be hard to improve. There were a few presentations on the combination. It makes sense, the mechanism of action between daratumumab, the anti-CD38 antibody, the immunomodulator, and the anti-BCMA, the bispecific. Some preliminary data from Phase 1 shows you can potentially improve response. One of the summaries of, I believe, [Paula] Rodríguez Otero, [MD, PhD,] showed that in each pre-treated population, because we are still talking about 7 prior lines of treatment, their responses were a bit higher.

The Spanish group…they’re starting the MajesTEC-3 trial, where they’re combining teclistamab with daratumumab vs doctor’s choice, and it’s going to be very interesting. Now it’s going a little earlier because they may be refractory to daratumumab, and they must have been on daratumumab more than 90 days ago. It will be a different patient population. It’s not the classic triple refractory, penta-exposed yes, but not necessarily refractory.

Ajai Chari, MD: I think encouraging data, but it’s always difficult with these single-arm studies to know what the combination adds.

Cristina Gasparetto, MD: Exactly.

Ajai Chari, MD: We will need more data.

Cristina Gasparetto, MD: Phase 3 will be very important.

Ajai Chari, MD: But this is very interesting data. Rafael, you alluded to it, targets other than BCMA. What else do you have to give us?

Rafael Fonseca, MD: A small warning, it is difficult to discuss the study of which I will speak because you were obviously the main person in charge of it, but the GPRC5D is another large target. I’m going to take a step back. I don’t think we should talk about agents targeting BCMAs, which is meaningless. BCMA is just the anchor. We have ADCs [antibody-drug conjugates], we have bispecific cells and we have CAR T cells. I think there’s a real danger of people saying, “Oh, somebody had a BCMA.” In particular, I’m afraid that with the prior authorization it’s a big rabbit hole, but the fact is that BCMA is just a target. We need to think about the mechanism of action.

Going back to the monumental clinical trial, it was talquetamab, which again targets this specific anchor. Interestingly, it is also expressed in epidermal tissues. One of the things that is understood is dermal nails and other forms of toxicity, which need to be taken into account; dysgeusia has also been reported. But they report a very good level of response. With weekly administration, which is moreover subcutaneous, there is a response rate of 70%. Every two weeks, or about double the dose, you get about a 60% response rate. It’s really active. About three-quarters of patients get CRS, but most of the time it’s grade 1 and 2. I can imagine a future where you get something like teclistamab, and if you progress, well, luckily, we have talquetamab. I won’t mention the other agent because I think Dr. Patel will talk about it, but we will have several avenues to approach patients in the future. For me, it’s very exciting.

Ajai Chari, MD: It’s good to have choices, and it’s a perfect transition for you, there’s even more than BCMA and GPRC [G protein-coupled receptor].

Krina Patel MD: Yes, cevostamab, I think with FCrH5, is another big target. I tell people that we’ve had the craving for CD19 for so long, and now they envy us, because we have so many goals we can aim for, and now is the perfect time to learn all of that. We know this is another big target that is found in almost all patients; myeloma cells have a high antigen density. It is a bispecific with FCrH5 and CD3. They had patients who had previously received anti-BCMA treatments, including bispecifics and ADCs, etc. Initial dosage was IV [intravenous], and it was every 3 weeks, which is a bit different, and it’s a fixed dosage. So far, all other bispecifics have been administered continuously. I think a lot of people are excited to see what happens when you do a fixed dosage.

What was really impressive were the response rates, even in patients exposed to BCMAs, different mechanisms of action, but when they put them together, about 40-50% of patients still responded, which was nice to look at. The next try they do they change a bit where they give subq [subcutaneous] cevostamab, because we know our patients like subq better than IV. I think it will be every 4 weeks at 13 cycles. It will be really interesting to see.

Transcript edited for clarity.

Martin E. Berry