Sequencing Considerations Are Important for T-Cell Redirection Therapies in Relapsed/Refractory Myeloma

Darren Pan, MD

As more effective T-cell redirection therapies, including CAR T-cell therapies and bispecific antibodies, join the multiple myeloma treatment arsenal, understanding adequate treatment sequencing is becoming increasingly vital, according to Darren Pan, MD.

“If a patient received a BCMA CAR T-cell therapy, they could still [go on to receive] a BCMA bispecific antibody, and it can work,” Pan explained in an interview with OncLive®. “We also found that it didn't matter which target you hit first. There were patients who received agents directed at GPRC5D first, and then went on to BCMA-directed therapy, and vice versa. Whichever way we go, these treatments can be effective.”

During the interview, Pan highlighted the impetus for his coauthored study on sequencing T-cell redirection therapies, advances in the field of myeloma since the study was published in 2023, and the ongoing development of trispecific antibodies for the treatment of patients with relapsed/refractory multiple myeloma.

In another article, Pan discussed long-term follow-up data from the phase 1b/2 CARTITUDE-1 trial (NCT02548207) and findings from the phase 2 iMMagine-1 trial (NCT05396885), both of which have provided broader insight into the use of CAR T-cell therapy in myeloma.

Pan is an assistant professor of Medicine at the University of California, San Francisco (UCSF) School of Medicine.

OncLive: In 2023, you coauthored the a study evaluating the sequencing of T-cell redirection therapies in relapsed/refractory myeloma. What was the impetus for conducting this study?

Pan: This study was [conducted] before many of the current T-cell redirection therapies were FDA-approved. At the time, [many experts] in the myeloma field were seeing unprecedented efficacy from T-cell redirection therapies. By T-cell redirection therapies, I mean CAR T-cell therapy or bispecific antibodies. [We evaluated these] particularly unprecedented response rates in the heavily relapsed/refractory setting, [which included] patients who were, for example, triple-class refractory. At the time, the typical response rates with a lot of the investigational drugs was 30% or lower; once we started to use trials implementing BCMA-targeted bispecific antibodies, GPRC5D-targeted bispecific antibodies, or [GPRC5D-targeted] CAR T-cell, we were seeing response rates between 60% and 100%, which changes how we think about [patients with] triple-class refractory multiple myeloma. A natural question for us is: As so many different T-cell redirecting therapies are going through the approval process and likely to be approved, how are we going to use them when we have so many options? Should we consider them all as one category, and if you use one, the others aren't going to be as effective? Or can we [achieve] good outcomes by using them in sequence? For example, if one patient received [idecabtagene vicleucel (Abecma)], then teclistamab [Tecvayli], and then talquetamab [Talvey], would that work?

What we found was that even when patients relapse after receiving a bispecific antibody, getting another bispecific antibody or a CAR T-cell therapy can still be very effective.1 Response rates were high, and patients had durable responses. In particular, the efficacy [with T-cell redirectors] was better than non–T-cell redirecting options.

Essentially, the crux of this paper was that rotating between different T-cell redirecting therapies is a very effective and winning approach in patients with relapsed/refractory multiple myeloma—you can hit the same target multiple times.

What advances have occurred with T-cell redirection therapies since the study was published?

Since we published this study back in 2023, we’ve learned more about sequencing T-cell redirection [therapies]. One of the biggest [things we’ve learned] is that if a patient is eligible for both CAR T-cell therapy and bispecific antibodies, we should be administering CAR T-cell therapy before bispecific antibodies, if they are interested in receiving CAR T-cell therapy. When patients are exposed to a bispecific antibody, particularly for a very long period and receive a CAR T-cell therapy after that, the bispecific antibody can be effective, but it's not nearly as effective as if we do it in the reverse order. It’s always better to administer CAR T-cell therapy first, followed by a bispecific antibody if we have the luxury to do so.

What myeloma research are you currently involved with?

Here at UCSF, we recognize that one of the biggest areas of unmet need now is patients who progress on essentially all our standard-of-care [SOC] T-cell redirecting therapies. A lot of our patients have now received CAR T-cell therapy. Here at UCSF, we use teclistamab; elranatamab [Elrexfio] is the other BCMA bispecific antibody, and we've also gotten talquetamab. Each of these therapies is highly effective, but there is a subset of patients who have received each of these therapies. They've progressed after each one. The question is, what do we do now? One of our main focuses at UCSF is making sure that patients have good treatment option. That includes not only looking at all of our SOC drugs, but also prioritizing clinical trials that focus on this very high-risk patient group, where these patients can be eligible to enroll on these trials, and where the drugs that are being offered are likely to be effective.

Secondly, as a general research endeavor, we're trying to assess the outcomes of patients in this group who have very limited treatment options after receiving T-cell redirection therapies. What treatment options are they receiving after they've exhausted all T-cell redirection therapies, and which therapies, after this late stage, are effective for them?

Beyond CAR T-cell therapy, your interests also lie in bispecific antibodies. What are some recent shifts to the treatment paradigm regarding bispecific and trispecific antibodies?

I'm one of our bispecific antibody leads at UCSF. When it comes to bispecific antibodies, there have also been some very exciting findings, and in my mind, the CARTITUDE-1 long-term follow-up abstract was neck-and-neck with the trispecific antibody abstract, which is a [phase 1] trial [NCT05652335] that UCSF was involved in as well. The [JNJ-5322] trispecific antibody is one that targets both GPRC5D and BCMA, rather than just one or the other.2 This is an interesting approach for several reasons. One of the initial questions I had was, how is this different than just putting teclistamab and talquetamab together? Why is it important to have an antibody that targets both? There are some compelling reasons that this approach is better. A trispecific antibody has these three arms: CD3, GPRC5D, and BCMA. By hitting 2 antigens at the same time, this antibody is likely to have a higher affinity for myeloma cells that have both of these antigens than healthy endogenous cells, such as plasma cells in the case of BCMA, or keratinized cells on the skin, nails, and tongue for GPRC5D. There's also a theoretical benefit in terms of a toxicity profile. With a lower dose of a trispecific antibody, patients can have a high affinity for these myeloma cells without hitting their other targets as much.

What we've seen for one is that the toxicity profile is manageable, so infections do not seem to be as prevalent and are lower grade than with teclistamab. The oral skin and nail toxicities generally seem to be much more manageable and less severe than with talquetamab. That seems to be playing out the way that we might expect. More impressive than those numbers is that, so far, the response rate has been 100% at the recommended phase 2 dose, in patients who have not been previously exposed to drugs hitting these targets. It's remarkable and unheard of that every patient treated has responded and has had very durable remissions. [Responses are so] durable that right now, it's hard to know what the duration of response, or the [median] progression-free survival will be, because patients have not been progressing. Essentially, all the patients who have been treated, with a few exceptions, have remained in remission. If this drug continues in this fashion, it may change the way we apply T-cell redirection therapy. There may be a time that comes when, instead of reaching for all these previously treated, previously approved agents individually, we use this trispecific antibody instead.

References

1. Mouhieddine TH, Van Oekelen O, Melnekoff DT, et al. Sequencing T-cell redirection therapies leads to deep and durable responses in patients with relapsed/refractory myeloma. Blood Adv. 2023;7(6):1056-1064. doi:10.1182/bloodadvances.2022007923
2. van de Donk NWCJ, Vega G, Perrot A, et al. First-in-human study of JNJ-79635322 (JNJ-5322), a novel, next-generation trispecific antibody (TsAb), in patients (pts) with relapsed/refractory multiple myeloma (RRMM): initial phase 1 results. J Clin Oncol. 2025;43(suppl 16):7505. doi:10.1200/JCO.2025.43.16_suppl.7505