Experts in the management of multiple myeloma consider promising developments for the future of relapsed/refractory treatment, with special consideration to bispecific antibodies and CAR (chimeric antigen receptor) T-cell therapy.
C. Ola Landgren, MD, PhD: Let’s move on and talk about all these antibodies. We have only 3 more hours to discuss the bispecific antibodies and CAR [chimeric antigen receptor] T cell. I’ll let each of you talk 1 minute. What do you think: bispecifics and CAR T cell. Let’s start with you, Rafael.
Rafael Fonseca, MD: I think—and people have said this—bispecifics are the belle of the ball. There are enough bispecifics that show 3 different targets.... The ones that come out to be BCMA are showing in the very early set of reports that they are active against myeloma cells.
I’m just going to put a plug in here for the audience. We need to stop talking about BCMA therapy. That is not helpful; that’s just a target. We need to talk about the mechanism of action and the target. If there is anything that pushes in that direction, it’s this range of bispecific antibodies that we have.
Here’s the biggest challenge this field will face: The bispecifics are convenient. I would argue that they might be more readily applicable in the community, and they might give the CAR T cells a run for their money. We saw absolutely outstanding results with CAR T cells—bb2121 with CARTITUDE-1 and all those trials. But the bispecifics are coming in very strong.
One of the most important advances this year in hematology was a New England Journal of Medicine paper where they used blinatumomab plus dasatinib for frontline therapy of ALL [acute lymphoblastic leukemia]. No chemotherapy without standing results. I can only hope that’s a future of myeloma in some other way. We’ll have to see, but this is the first large wave. We’ve seen 701 and some of the other early signs for the bispecifics, but this was really the big coming out for the bispecific antibodies in multiple myeloma.
C. Ola Landgren, MD, PhD: Thank you. Luciano, what do you think?
Luciano Costa, MD, PhD: I totally agree, and I tend to be very excited about novelties. The way I feel about the bispecifics now is how I felt about daratumumab 5 years ago. When you see a therapy out in the multiple relapsed setting having better performance than things that you were doing in the first relapse, it is a sign of transformative therapy coming through. That’s how I see the bispecifics.
I could not agree more with Rafael: Putting out the BCMA binding therapy on the same box is a disservice. It upgrades some BCMA-based therapies that shall remain unnamed that have a 30% response rate and a PFS [progression free survival] of 2 to 3 months, which doesn’t tell you anything about setting or mechanism of action.
As we can see, there’s more similarity across bispecifics in terms of toxicity, efficacy, and place in therapy. That seems to be irrespective of the target. The data with talquetamab that Ajai presented were perhaps the most relevant presented at ASH [American Society of Hematology Annual Meeting]. This came from nowhere. We think of BCMA, and then something comes next. Now you have a different target with a bispecific that’s probably the best developed so far, perhaps on par with teclistamab. I keep saying that they don’t have to come up with BCMA; we have to divorce that notion. Those are agents that are prone to combination. They’re prone to promotion in much earlier lines of therapy. It’s very exciting. The future is going to be very bright.
C. Ola Landgren, MD, PhD: Ajai, congratulations on your ASH presentation. Your colleague Deepu Madduri gave the other…presentation. These are the 2 J&J [Johnson & Johnson] compounds; they’re very powerful. Where do you think this is going? Deepu also presented the J&J LEGEND-2 CAR T cell. What do you think? CAR T cells and the bispecific targeted antibodies, both, or a sequence of this? What’s your thinking?
Ajai Chari, MD: I agree with everything people have said. Some other things I would add are that with BCMAs there are 6 companies now that have presented antibodies. I don’t think there’s going to be a standout. Some of them are very small, so the efficacy and safety are going to be comparable. I would say the excitement is even more than DARA [daratumumab]; the response rates we’re getting are 60% to 80%. Historically, when you think about the drugs that have gotten accelerated approval—DARA [daratumumab], belantamab—usually it’s 20% to 30% in 3 months.
This is a game changer. It has a much higher response rate and a manageable CRS [cytokine release syndrome]. What it’s going to come down to, especially for payers, is not efficacy or safety but time to market, convenience, whether there can be outpatient administration, frequency of dosing. One company had an every-3-week dosing; that’s the BCMA. We clearly need more, and obviously talquetamab and GPRC5Dare super exciting. Same preliminary response rate, same toxicity, but novel targets. The question is combination strategy.
Moving to CAR T, I would just ask the listener to think about a hypothetical clinical trial where everybody is randomized to either bispecific or CAR. What would you put your money on? I think right now we have to remember that CAR-T slots have been extremely patient selected. There’s been limited slots. Each side picks their patients who are getting enrolled very carefully. You get 1 slot every couple of months, then you pick the 1 that’s not as explosive, so you can get through bridging during the maintenance manufacturing period and give the chemotherapy for bridging, which is going to affect your PFS. Then you actually get to infusion.
Between the patient selection, bridging, and all those factors, it’s the bispecifics to lose. The only exception is the off-the-shelf CARs, which are looking very exciting because they’re still very early; these are phase 1. Then you eliminate all those factors, right? You eliminate the patient selection, the manufacturing, the bridging. If you could do bispecifics vs AlloCAR [allogenic CAR], now we’re really talking about fairer competition and fairer comparison. The devil will be in how often that AlloCAR might have to be given. Sham [Mailankody] presented really cool data about AlloCAR with no GVHD [graft-vs-host disease], just some typical infectious issues that we see. Those are my thoughts. What about you, Ola?
C. Ola Landgren, MD, PhD: I was counting the number of antibodies last year for ASH, and I counted 14 bispecific antibodies for myeloma in development. This year it was 20-something; they just keep on coming.
I also noticed, similar to what you guys have said, some of them were already subcutaneous. The dosing is very convenient; every 3 weeks for some of them with a 60% to 80% response rate. When you look and see from your own clinical experience, from our own institutions, and we hear from others, you can premedicate and prevent the CRS; you can do steroids. If you start seeing that the fever comes up, you can be more aggressive maybe with tocilizumab; you can prevent a lot of these problems. These are things we need to figure out how to manage on a day-to-day basis to make it more practical. The bispecifics are definitely major players here. Ajai, I agree with what you say with the AlloCAR T cell. Sham, my colleague [from Memorial Sloan Kettering Cancer Center], presented the allogenic CAR T-cell BCMA. These are CAR T cells,…you can give an anti-CD52 antibody.
There were no bad adverse effects, but also we know the series is not that big; the falloff is not that long. If there are a lot of infections in the future, I will change my opinion. It is very attractive with a quick access. The median time from seeing the patient who is starting the allogenic CAR T cells was 5 days in that presentation; that is very quick. You could argue that it would hurt the results of the study. If you could share a particular patient, and they must survive the bridge, you pick out the best patients. Maybe the order for T cells will always have better results than the AlloCAR T cells. People may say they’re not as good, and maybe it’s because of selection. I don’t know.
The antibodies look very attractive, and maybe the CAR T cells will play a role in some setting at big centers in the future. I don’t know. We will have both probably, but the big 1 is going to be the antibodies, in my opinion.
It’s time for us to wrap up, so I would like to thank you all very much for this rich and fun discussion. Before we finish I want final thoughts on this big discussion and where we are in the field heading into the future from each of you. I would like to start with you, Ajai.
Ajai Chari, MD: We should be striving for a cure and just these chronic therapies, but to get that we need powerful agents. I think these T-cell redirection approaches are superexciting and a game changer. The areas that we still need to do a better job of are not just obviously the multiple relapse but the other unmet needs in myeloma: frail, [older patients], persistent renal failure, high risk disease, extramedullary disease. There’s still a lot of work to be done, but there’s a lot of excitement with these novel agents.
C. Ola Landgren, MD, PhD: Luciano?
Luciano Costa, MD, PhD: Thanks for a great opportunity. This is a great interaction. I always learn from each of you when we interact. I share Ajai and others’ enthusiasm. We are at this immunotherapy revolution in myeloma, and I don’t think any of us can really foresee where it’s going to end. We can be confident it’s going to be a better place for patients in terms of a greater efficacy and with greater safety. And not just efficacy—the safety profile of some of the agents coming along is really terrific. I share the will to cure myeloma. We have some intellectual biases that keep us attached to the idea of continuous therapy. There was a time when that was beneficial because as most people, they’ll have great responses and everybody relapses. But continuous therapies are an easy win.
As we’re getting more patients, we need to change those paradigms. There are very few things that add more value to the patients joining that I’d be able to de-escalate and stop therapy. As Rafael likes to say, “We’re given the tools to finish the job early.” Perhaps people don’t have to spend the rest of their lives getting myeloma therapy.
C. Ola Landgren, MD, PhD: Rafael, last thoughts?
Rafael Fonseca, MD: Just to second that, I think we need to finish the job up front. That was also very present at the ASH. We didn’t talk a lot about it, but that will prevent relapse/refractory multiple myeloma....All those clinical trials are showing that that’s the way to go. Even the most pessimistic have to be optimists with the data we’re seeing at the ASH meeting. Now I’m just going to say a couple of things.
First, it’s a pleasure to live in this era because when we look back 10, 20, and 50 years from now, we will clearly see that historically this was a time where the natural history of myeloma was changed for good. We are curing some patients, and it’s sometimes hard to say that when we don’t have the data and the follow-up to say so. It’s like you’re in the fourth quarter of a basketball game and you’re leading by 40 points: You haven’t won, but you know there’s a pretty good chance that it’s happening. Certainly not for our patients but for a fraction of our patients. I can only wait for the bell to ring so we know that is true.
C. Ola Landgren, MD, PhD: Maybe I answered that. First, thank you all for being part of this super fun discussion. It’s great working with you, and I really like our camaraderie. I 100% agree with everything you said. Beyond the discussion we had today, there were so many more abstract [discussions] than at any other ASH meeting I have seen focusing on the role on MRD [minimal residue disease] testing. I also picked up on some of the preclinical studies, and there are no data emerging on myeloma genomic defining events. But you can see myeloma with whole-gene sequencing, even if you go back and extract the low input methods from monoclonal gammopathy.
I wonder: The drugs we have now, are they good enough to cure more patients if we don’t let myeloma get out of control. If we start a little earlier, when the disease burden is lower, we know that is going to be the right time to hit. If we can prove that, we’d be testing with MRD.
These perspectives are a little futuristic, but the new drugs are very important. I also think the right optimal time to start therapy and assess is something that I spent a lot of time thinking about. I know we talk about it on and off, all of us, and I’m sure you’re thinking about it a lot also.
With that, I would like to thank you again very much, and I would like to thank the viewing audience. I hope you found this AJMC® program to be useful and informative. Thank you very much.