Factors to Consider When Selecting T Cell-Directed Therapies for Myeloma

In an interview with Pharmacy Times, Rahul Banerjee, MD, FACP, discussed his presentation at the International Myeloma Society 2024 Annual Meeting on available T cell-directed therapies for myeloma treatment, including CAR T-cell therapies and bispecific antibodies.

Q: What factors should be considered when selecting a T cell-directed therapy for a patient with myeloma? Are there specific patient characteristics or comorbidities that might influence the choice of therapy?

Rahul Banerjee, MD, FACP: Yeah, so we kind of looked at this earlier. I would say, truly in the US, we're fortunate to have bispecifics and CAR T [therapies]. My thought should be, can I get this to patient the CAR T? And if not, why not? So, I think the default really should be CAR T for an unexposed patient, again, because of the benefits and efficacy that we've seen so far, and again, because of the time toxicity. So, I think that is the default, and I try to convince myself otherwise. You know, I do put plenty of patients on bispecifics instead of CAR T, and I would say they've kind of fallen into 3 categories. One: they've already gotten CAR T, so we'll come back to that. I would say that if someone's had progressive disease on a CAR T or after CAR T, it’s very reasonable to try a bispecific—either BCMA-targeting or possibly GPRC5D targeting, depending on the timing after the relapse. To those who cannot get CAR T clinically or logistically—so again, those patients a little bit older or frailer, as I alluded to, with cardiac dysfunctions, or logistically. Most centers around the country really strongly prefer a caregiver for CAR T therapy just because of this more intensive modality, you need to relocate to the big city to get it. And there are all these logistical factors that go into play. For some patients, it’s not practical to ask them to move and a caregiver to move with them to the big city. And 3, again, the patients whose disease kind of precludes autologous CAR T. There are studies ongoing of allogeneic CAR T cells that are “off the shelf,” that theoretically would bypass the risk of a very long brain-to-vein time.

However, in the absence of that, I have had patients where their disease is just functionally high risk, right? Like, within a year of transplant, the disease is blowing up again at a very high velocity. Chemotherapy is not really working. That patient does not have the luxury of time. You would move to a bispecific. Interestingly, people have used a bispecific antibody as kind of a holding therapy to get the T-cell collection and then bridging afterwards to CAR T. That is not the usual dogma of how we approach things, where I just said CAR T before bispecifics, but I have done that. So, for example, if someone has rapidly proliferating disease, talquetamab theoretically would preserve BCMA expression for future BCMA CAT T, so I’d start with talquetamab. Get disease under control. Okay, stay with it, but if not, go on to CAR T.

Q: How does the stage and status of the disease impact the decision-making process?

Banerjee: So, I guess the only thing I would say is the status of the disease, I think, is helpful. We've alluded to this, right? So, for rapidly proliferating disease, an autologous CAR T is not practical for them. So, I think a bispecific antibody does make more sense. Stage is not really relevant in myeloma. I will say that this question is important because of lines of therapy. So, at the time that we're recording this interview in September 2024, CAR T is now approved as early as basically a second line therapy with cilta-cel, and third line therapy with ide-cel, versus the bispecifics are all approved for 4 prior lines, so, fifth line therapy-plus. And it's a little bit of an odd state of flux we find ourselves in, because a year ago, all the bispecifics were all 4 prior lines, and I remember kind of choosing a fourth prior line [therapy] that I knew wasn't going to work, just to check off that box and get them to 4. And that was silly. And so hopefully by this time next year, there are studies ongoing of bispecifics in earlier lines of therapy. I hope that they succeed. Because, again, lines of therapy is largely irrelevant to clinicians and decision makers, but the FDA really think about this. Clinicians typically do not. It doesn't really matter, because disease refractoriness and triple class refractory matters much more than have they gotten 2 versus 3 versus 4 prior lines of therapy. So, hopefully, when all the therapies are approved for 2 prior lines or even 1 prior line, that'll help us to actually be able to choose the best one for our patient. But right now, I would say that, for example, if someone's had 2 prior lines of therapy and aggressive relapse, they cannot get a bispecific antibody except on trial, so they have to go to CAR T.

Q: How might T cell-directed therapies be combined with other treatments to enhance efficacy and reduce resistance?

Banerjee: Yeah, so it's an ongoing question at IMS. There will be studies at this International Myeloma Society meeting, there will be studies about, you know, bispecifics being combined with other agents. So, a good example would be the MajesTEC-1 or MonumenTAL-2 trials, teclistamab or talquetamab combined with pomalidomide, which I think is a good example. There's this theory that lenalidomide and pomalidomide can predict T cell fitness, for example, and obviously have some anti-myeloma direct effects. But separately from that, they seem to kind of help T cells, reduce exhaustion, promote activation, and so forth. The newer CELMoDs are being studied in this situation as well. So, CELMoDs are iberdomide and mezigdomide, not yet FDA-approved, but they're next generation and actually work in a different manner entirely. And so those might be really interesting. And there are studies, for example, there's an alliance cooperative group study enrolling that’s actually a randomized study of after ida-cel CAR T, randomized into either iberdomide or no iberdomide to really test its theory of, does a CELMoD after CART help to enhance efficacy and reduce resistance? It’s tricky, right? Because obviously, if you add a new drug, you have more side effects, for sure, and with CAR T, this idea of post-CAR T maintenance is pretty controversial, because the whole point of why patients love CAR T is because it is a one-time treatment, right? And so, in these studies, I really would want to see a high margin of benefit and not that many toxicities to justify their usage.

It's worth noting that the bispecifics can be combined with each other, so there will be data presented at IMS for the RedirecTT-1 study. So, that's teclistamab and talquetamab. I'm looking forward to seeing the data. This was presented by Dr. Yael Cohen and her colleagues a couple years ago at ASCO. They're both commercially approved. I have not tried to combine them commercially, but theoretically one could, if insurance were to pay for it. And that would be interesting, because then even the cells that are trying to down-regulate BCMA, theoretically will still affect GPRC5D and get them then, you know, that model works extremely well, right? The idea of triplet therapy, or highly effective antiretroviral therapy, like combining multiple drugs together to reduce resistance with myeloma, we may see that become a feasible solution, as well, even in patients with aggressive disease, visceral extra-medullary disease, high risk genetics. Tec plus tal might actually work better than either tec or tal alone.