Hermann Einsele:

Hello, everybody. My name is Hermann Einsele. I am based in Würzburg in Germany, and it’s my great pleasure to report from the Myeloma 2022 in Scottsdale. And it’s a great pleasure for me for the discussion to have two real experts with me on T-cell engaging therapies in myeloma, Professor Nina Shah and Professor Tom Martin from California. And the topic of our discussion today should be challenges and opportunities of T-cell engaging therapies in myeloma. And now we have already one CAR-T cell product approved. The second approval is soon coming. Probably we will also have a T-cell engager targeting BCMA being available commercially also, maybe at the end of this year or beginning of next year. What do you think? Where are we going to see the T-cell engaging therapies in myeloma? Will it be the very last, late stage of the disease, the relapsed/refractory patient? Or do you perceive that we are going to move treatment with T-cell engaging therapies to earlier lines of therapy? Nina, what’s your opinion?

Nina Shah:

Yeah. So in the United States now we have two CAR-T cell therapies that are approved, which is great. And we are really excited to anticipate the approval of a bispecific T-cell engager, hopefully at the end of the year. And I think what’s going to happen is we’re going to realize that even in the late stages of myeloma, we’re getting such great responses that it seems only natural that we’d want to move these more proximal in the patient’s treatment course. And I really look forward to some of the clinical trials that are being conducted now, both with CAR-T cells and T-cell engagers in the earlier stages of disease, really to get this benefit sooner than later for our patients.

Tom Martin:

Yeah, I completely agree. In our natural progression of myeloma therapeutics, everything that’s currently approved for use in myeloma had a single agent response rate of 20 to 30%. We’re now having T-cell engagers, as Nina presented, that have single agent response rates between 50 and 80%. That’s amazing, and then with CAR-Ts 80 to over 90% single agent response. So our natural progression is try them in the relapsed/refractory, and then move them in earlier lines of therapy. But my guess is that five years from now these are going to be front line therapies for most of the patients.

Hermann Einsele:

And, now, you mentioned already that these treatments are extremely effective. Extremely high response rates, and also quite good tolerability. So do you expect that all other myeloma treatment will disappear, and we will only give T-cell engagers or CAR-T cells to our patients from the beginning?

Tom Martin:

I would say that combinations have always been our strategy going forward, so I do think that we’re going to try to put these together to try to get 100% response rate. I think that should really be our goal. But not only that, is to give them for a certain period of time and then potentially to stop therapy. So maybe we can use some drugs together for a certain period of time, maybe a year or two years, get MRD negative for that period of time, and then just stop. What do you think, Nina?

Nina Shah:

Yeah. I think that if we could take anything that’s a benefit from this… I mean, how are you going to get better than 98% response rate in the relapsed/refractory setting? So one of the things that I love about CAR-T cells is that it’s a one-and-done treatment. So that’s something I would love to do for patients upfront, to get that to be something that they can have a treatment-free interval. But then specifically with the bispecifics, even though they’re weekly or whatever the schedule is, maybe we could use the benefit of what they do in the relapsed/refractory, bring them up front, and as Tom was saying, maybe limit the time that patients have to keep going to the oncologist’s office. So that would, I think, really be a new frontier for myeloma patients, not to be on indefinite therapy.

Hermann Einsele:

Mm-hmm (affirmative). And I think we also need these more conventional treatments, because it’s well known that the higher the tumor load the patient is going into these T-cell engaging therapies, the more likely he is having severe side effects like cytokine release syndrome or neurotoxicity, and it might also increase the risk of resistance. So I think we need some kind of debulking before we actually interfere with T-cell engaging therapies. Now you have already pointed out that it’s a treatment that is maybe once, it’s a one-shot therapy. So are we going to see disappearance of maintenance, disappearing of consolidation if we use these T-cell engaging therapies?

Nina Shah:

That’s a really good question, because right now, as the studies were done for the relapsed/refractory setting, patients only got one dose of CAR-T cell therapy, for example. But now there are studies going on to see if we can extend the efficacy of the CAR-T cell therapy by having immunomodulatory agents, and I think that might help. But one of the things that we’re really excited about is learning from our past experience, kind of going to your previous conversation about combinations, that maybe the immunomodulatory agents will pair best with the T-cell engagers. And so there might be some maintenance in there, but it would be an oral pill, for example, or something less frequent. I don’t know. What do you think?

Tom Martin:

Yeah. In the CAR-T scenario at the current time we have what I call as flattening of the line envy. We don’t have flattening of the line. We don’t have patients that are cured. And in fact, people are relapsing at three years, at four years, at five years. And the question is, why? And will some type of maintenance prevent that dormant cell from reactivating two and three years later? So, I think that’s a really good question. And what to use as maintenance, if we were going to do it, is do we use CELMoDs or immunomodulatory drugs to try to tell the microenvironment, “Go back to normal, go back to your usual, keep everything under control”? Or do we use more aggressive therapy like T-cell engagers after CARs to try to wipe out every last little cell? I don’t know. What do you think?

Hermann Einsele:

Yeah, well, I think that’s the strategy. I think we are moving into that. We really try to get the patient in the best possible response, and then try to keep the patient in the response. And I think it will also depend on how long the CAR-T cells are persisting. I think we have seen this nice paper from Carl June that in CLL patients the CAR-T cells can persist for 10 years, and thereby really probably curing these patients. But in myeloma at the moment we don’t see this long term persistence, and that’s why I’m with you. I think we need something in addition, or maybe just to prolong the persistence of the CAR-T cells and to prevent the escape of these dormant cells from really inducing a relapse of the multiple myeloma.

Tom Martin:

I would say in the last 10 to 15 years we really have not innovated with autologous transplant, right?

Hermann Einsele:

Mm-hmm (affirmative). Mm-hmm (affirmative).

Tom Martin:

It just hasn’t been a strategy that we could add on, or change the prep, or et cetera. And so there’s been no innovation. This is the beginning of CARs, right? This is the beginning of innovation, in my mind. Just like you said, can we make them more persistent? Can we target two antigens? What can we do to change the T-cells that make them healthier, more proliferative, more persistent? This is really going to be fun for the next five to 10 years.

Nina Shah:

Yeah. I think the interesting thing, just like as you pointed out, it’s we don’t have that persistent CAR-T cell for years on end. First of all, we don’t have the data yet. And secondly, it seems like we can’t find them for most patients, particularly since there is no plateau on the curve, as Tom mentioned. But what is interesting is that it seems like you can re-treat people, for example, targeting BCMA. There’s also, as we are discussing at this conference, GPRC5D targeting T-cells. It could be where if we find enough different antigens, enough different types of T-cell products, a patient could progress after three years, get another lymphodepletion, get another CAR-T cell, have another three years. And we could stretch people out because it would be a new CAR-T cell therapy, it wouldn’t be something they would reject. So that might be one way to get a lot of… Or minimal treatment doses, with a lot of time.

Hermann Einsele:

Mm-hmm (affirmative). Now, I think you already mentioned some of the challenges that we face also with T-cell engagers and with CAR-T cells. So obviously the persistence of the CAR-T cells could be a problem. The T-cell engagers, the question is how long do we have to give them until the optimal response? Are we going to give them, like the lenalidomide, forever? I don’t think that’s the way to use bispecific antibodies. And the other problem, as you also mentioned, is target antigen loss. So we have seen target antigen loss. We know that in CD19 directed CAR-T cell therapies, 50 to 75% of heavily pre-treated patients are losing the target antigen. And I guess in myeloma we have now probably something like 4%, but I think the more we are using it, and the earlier we are using it, we probably see more target antigen loss. So we need additional targets to be addressed with the T-cell engaging therapy. So you mentioned GPRC5D, so are there other targets that we might actually use in the future for T-cell engagers or CAR-T cells?

Nina Shah:

Yeah. I’m excited about the data with GPRC5D not only for the bispecifics T-cell engagement therapy with talquetamab, but also with the upcoming CAR-T cell therapy. And then now we have cevostamab, which targets FcRH5, and which we’re also discussing at this meeting. And I think that the more we do investigation in targets and target antigen discovery, the better it’s going to be. And what we might find out is that there are some subclones of myeloma cells, like Tom was saying, the dormant cells that tend to express certain antigens more. Or maybe it’s not a CD138 positive cell. Maybe it’s a precursor cell, and we could target that. But I think that the more we put into antigen discovery, we are going to have a greater variety of therapies for the patient.

Tom Martin:

I do have this feeling that five or 10 years from now, we’re going to have the menu card, and we’re going to flow these cells and see what’s on the cell service and say, “Yes, check. I’ll take basically the GPRC5D CAR, and then for maintenance I’ll take the FcRH5 bispecific.” And we’ll have different type of menus. Every time they relapse, we just pull out a new menu of what’s on the cell surface and there we go at it. So I do think immunotherapy is not going to just be for first line therapy. It’s going to be for second, third and subsequent line as we go forward.

Nina Shah:

It’s like a myeloma sushi menu.

Tom Martin:

Yeah. Right, right, right.

Hermann Einsele:

But then the question comes up, what’s the optimal target sequencing of the therapies? So should we give CAR-T cells first, or bispecifics first? So what would you recommend?

Nina Shah:

That’s a really difficult question, in the sense that we don’t know what’s going to be better first, and we haven’t of course studied that. We would love to know that answer now. I mean, my preference would be if I could give somebody a CAR-T cell therapy first, for a variety of reasons. One, it’s a one-and-done treatment. Two, it uses the healthiest T-cells upfront, versus if you gave bispecific therapy you may have exhausted T-cells after years of therapy. We don’t know yet. And so that would be my preference, but then on the flip side the logistics may not permit this, so it might not be that you can give everybody a CAR-T cell therapy upfront. And I think we’re really going to see sort of a change in how the workflow is for that, and maybe something like we’ve done with transplant where now we try to make sure everybody has access, and who’s eligible for a transplant would have an apheresis slot. I don’t know. What do you think about sequence?

Tom Martin:

Yeah, I agree. And the current data suggests an 80 to 98% response rate with CARs. I want to have that patient get a CAR first, if I can. If I have a CAR-T cell slot and I have the ability to give them a CAR-T cell right now, I’m going to give them that right now in relapse, right? And then potentially think about basically a T-cell engager down the road. But what you said earlier I really liked, and that is when we debulk people and then give them a CAR-T, or give them a T-cell engager, are we going to have even less toxicity then? Can we do that all as an outpatient, which would be really great? And then I think choosing between one or the other is going to be really interesting, because I think the response rate is probably going to be pretty similar. We’ll just have to see how that evolves.

Hermann Einsele:

Mm-hmm (affirmative). And do you think that all the patients will nicely respond to CAR-T cells and T-cell engagers? Or are there different subgroups where we’ll still have problems to really get these high remissions and long term remissions?

Nina Shah:

Yeah, I think the extramedullary patients are really difficult, and I’m not sure. Sometimes I think CAR is better for them, sometimes I’m not sure. And maybe it’s that we don’t want them to get to this point. And that goes back to the earlier point, getting these patients treated with effective immunotherapies before their disease is too out of control. Sometimes there’s something about the disease biology we don’t know. The subgroup analysis suggests that there is something about being high-risk that makes it less likely for you to respond, for example, in the cilta-cel data. So, there, that’s still a challenge. As usual with myeloma, great patients do great, standard risk does great, and high-risk patients are challenged. Would you agree?

Tom Martin:

Completely. And when you look at the cilta-cel data, in fact, 113 patients signed consent but 97 were treated. And so that difference right there, of people that didn’t make it to CAR-T cell, that’s the patients that I think we really have to focus a lot of our energy on. The really proliferative and the tough patients, they could have gotten an off-the-shelf, potentially a T-cell engager at that point in time. But the big question is, would they have responded to that off-the-shelf TCE at that time? That is something going forward that I think is really important. That’s the unmet need, it’s those really rapidly progressive people. And hopefully we’re not going to have to address it too much, because we’re going to be treating people in remission rather than when they’re six line prior therapies. It’s a tough population.

Hermann Einsele:

You mentioned off-the-shelf. So there are now also these alloCAR-T cells. So how do you think they are going to develop? Are we going to see alloCAR-T cells in the future replacing autologous CAR-T cells? Or will the immunological issue, the immunogenicity and maybe also the genetic modification we have to perform to really make them kind of safe without infusing graft-versus-host disease, put such a lot of problems around the alloCAR-T cells that they are not making it into the clinic? So what do you think?

Nina Shah:

Yeah, I think allogeneic CAR-T cells could be a game changer in the sense that it really eliminates that step of apheresis. Which is important because it does then increase accessibility, not just for the patients at our large medical centers, but you could imagine that people in smaller medical centers would now have access to off-the-shelf. Okay, so that’s great. But the problem, as you mentioned, is the immunologic rejection. And I really think that allogeneic CAR-T cells at the first infusion and in that first month have to do the job that they came to do, so they have to put people in deep remissions within that first month before patients’ own autologous T-cells have recovery. So if we can find a very powerful allogeneic CAR-T cell that can do that, I would even be willing to take a 10% hit in the efficacy to increase the availability of that therapy.

Hermann Einsele:

Mm-hmm (affirmative), mm-hmm (affirmative). What do you think, Tom?

Tom Martin:

Yeah, I completely agree. If they can actually cause a significant response in those rapidly progressive patients, that is really key. The other thing that I think, what we need to test and be able to do, is to give multiple infusions for these. So maybe we give an infusion now, we give another infusion three months later, and another infusion six months later. Maybe it’s not just one and done, but three and done. But you have to be able to do it without more lymphodepleting chemotherapy, and maybe in that regard we’ll have a more persistent CAR-T cell. I don’t think they’ll live forever, obviously, even probably not more than a year. But at least they’ll be present maybe for six months or longer and provide that deep myeloma effect. Anti-myeloma effect.

Hermann Einsele:

Now, Nina, you’re not only an expert on CAR-T cells, but also NK cells. So what about CAR NK cells?

Nina Shah:

Yeah, I think that CAR NK cells have the potential to be very useful, similarly to an allogeneic T-cell, because it is an off-the-shelf product. And it also is known to not cause graft-versus-host disease, so that allows you to have a better variety in donors. And I do think that having the ability to get these from various donors without worrying about it, without as much engineering as you would need for an allo T-cell, may make this more available. What I think will still be a problem is the rejection, because ultimately you can’t avoid the host immune system. I mean, that has to regenerate at some point, and that’s going to be a difficult thing to overcome. So if the NK cells can not only be engineered for an antigen, for example the CAR NK, but also be infused in conjunction with an antibody to take advantage of that, and that’s being done in various NK products, we might have another off-the-shelf option that’s going to be very well tolerated.

Tom Martin:

And there’s other cell products too, right? Gamma delta T-cells, the NK T-cells.

Hermann Einsele:

Mm-hmm (affirmative).

Tom Martin:

All these products need to be tested to see which one really is going to rise to the top as being the best. So, again, this is part of innovation with cellular therapy that we haven’t been able to do in autologous transplant, et cetera. My feeling is autologous transplant is going to be gone soon.

Hermann Einsele:

Yeah, that was my last question. What do you think about autologous stem cell transplant [crosstalk 00:17:11]-

Nina Shah:

We never agree on this.

Hermann Einsele:

Are we still doing it in two or three years?

Tom Martin:

Well, actually, unfortunately that high-dose melphalan does elicit a significant mutation burden in those plasma cells. I think it makes them more difficult down the road to treat, and so I would really like to get rid of high-dose melphalan. And I don’t think the literally two log fold reduction in myeloma burden with an autologous transplant comes close to the four to five log reduction we see with CARs. All right, Nina?

Nina Shah:

Well, I still think that randomized control data will answer these questions. And these questions, unfortunately, that high-quality data is always five years behind what we’re doing now. And so now the question is, are people going to get a CAR versus a transplant? It might be that it would be a consolidative CAR after the transplant. So, that remains to be seen. I still call melphalan the Brillo pad of chemotherapy. Really digs out those bad myeloma cells. But I agree with Tom, it would be nice to find something a little bit less barbaric. But I think, data-wise, that we’re probably still going to be using it for a few more years.

Hermann Einsele:

Yeah. Yeah, and then of course there is the cost issue. And I think not all the health systems in worldwide will be able to afford CAR-T cells, so I guess there will be countries that will continue to do autologous stem cell transplantation.

Nina Shah:

Right. There’s definitely that.

Tom Martin:

I do believe that, but I also believe that if we can get to a point where we can shorten the therapy to two years, or maybe even three years, 36 months, versus a myeloma patient’s average survival being a decade or longer right now and they’re on therapy 80 to 90% of that time. That is so costly, all that.

Hermann Einsele:

Yeah, that’s true. Right.

Tom Martin:

If we can get them two years of therapy or three years that gets them the seven, eight, nine years, that’s going to be a huge cost savings actually, I think.

Nina Shah:

Yeah, that’s true. And there are a lot more analyses being done, now more than ever, about the qualities and how much effort we’re getting, or how much bang for our buck we’re getting from these. And as that moves in the more proximal lines, we’re going to have more data to inform us. And better, I think, than we’ve ever done before, as far as acquiring this data. So it’s really important for all of us to sort of think outside the box about how these immunotherapies may best be used, not only for which right patient, but which type of patient as far as the course of myeloma, and then how to position those amongst other therapies.

Hermann Einsele:

Well, that was a great discussion. Thanks so much, Nina and Tom.

Nina Shah:

Thank you.

Tom Martin:

Thank you.

Hermann Einsele:

It was good fun. Thanks.