Trispecific Antibody JNJ-5322 Shows Potential to Redefine Treatment in R/R Multiple Myeloma

Provided that the early antitumor activity and safety observed with JNJ-79635322 (JNJ-5322) in relapsed/refractory multiple myeloma can be replicated in larger cohorts, the agent could eventually serve as a replacement for individual bispecific antibodies and provide patients with the option of fixed-duration therapy, according to Rakesh Popat, MBBS, MRCP, PhD, FRCPath.1

Data from a phase 1 trial (NCT05652335) evaluating JNJ-5322 showed overall response rates (ORR) of 55.0%, 66.7%, 100.0%, and 100.0% at doses of 50 to 300 mg (n = 20), 50 mg (n = 21), 100 mg (n = 27), and 300 mg (n =8), respectively. Of note, the 100-mg dose of JNJ-5322 was identified as the recommended phase 2 dose (RP2D).

The current treatment arsenal in multiple myeloma includes teclistamab-cqyv (Tecvayli) and talquetamab-tgvs (Talvey), which target BCMA and GPRC5D, respectively. In October 2022, the FDA approved teclistamab for the treatment of patients with relapsed/refractory multiple myeloma who previously received at least 4 lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody.2 In August 2023, the FDA approved talquetamab for the same patient population.3

“The idea here was to develop a trispecific antibody that has dual plasma cell targeting. This [not only] allows for the targeting of BCMA- [and] GPRC5D-positive cells, but, more importantly, it allows cells that express both [BCMA and GPRC5D] to be targeted,” Popat said in an interview with OncLive®. “This improves the specificity of the molecule. Accordingly, we hope it will reduce off-tumor toxicities.”

During the interview, Popat detailed the rationale for evaluating JNJ-5322, the mechanism of action and optimal dosing of this trispecific antibody, its toxicity profile and efficacy according to phase 1 data, and the potential future role of this agent.

Popat is a consultant hematologist at the University College Hospital at the University College London Hospitals (UCLH) in England, lead of the myeloma clinical trials program, and the cancer program lead for the National Institute for Health Research UCLH Clinical Research Facility.

OncLive: What are the background and rationale for evaluating JNJ-5322 in relapsed/refractory multiple myeloma?

Popat: In multiple myeloma, we already have several different [FDA-approved] bispecific antibodies, such as teclistamab and elranatamab [Elrexfio], that target BCMA. We also have talquetamab, which targets GPRC5D. In the relapsed/refractory setting, approximately 40% of these patients do not respond [to treatment with these agents]. Additionally, although talquetamab is a very effective bispecific antibody, it's associated with on-target, off-tumor toxicities. [These are] namely skin, nail, and oral toxicities, such as dry mouth and taste problems.

What is the mechanism of action of JNJ-5322?

This is a novel antibody. It's been augmented such that the BCMA/GPRC5D binding is very tight. Of note, it binds to different epitopes than teclistamab and talquetemab. The second element is that the CD3 portion is a low-affinity binder that lends itself better for outpatient dosing with a lower [cytokine release syndrome (CRS)] profile. In addition, the modulation of that component allows for improved [pharmacokinetics (PK)], such that we can be dosing [every 2 and 4 weeks].

What was the design of the study?

We decided to run a first-in-human study for patients with relapsed multiple myeloma who had been exposed to the 3 main classes of agents: CD38 monoclonal antibodies, PIs, and IMiDs. Essentially, we started at a low dose and worked our way up in a typical phase 1 dose escalation manner. We also investigated [several] different types of step-up dosing, and we went from 50 mg as a flat dose, right up to 300 mg at the maximum dose. We investigated a few cohorts and tried to optimize the dosing for outpatient dosing that involved looking at different step-up dosing. [We also tried to optimize the] use of prophylactic tocilizumab [Actemra] to reduce the incidence of CRS. We concluded that the recommended dose was 100 mg given [4 times a week], based on the PK analysis that we had, and with a single step-up dose of 5 mg, which could be given between 2 and 8 days prior to [receipt of] the main dose.

What were the key safety findings?

In terms of the [agent’s] toxicity profile, we found that the CRS rate was 56.5% [at all doses]; however, [the incidence was] 69.2% for patients not treated with prophylactic tocilizumab and 20.0% for patients who had prophylactic tocilizumab. Interestingly, in the prophylactic tocilizumab group, not only was there a substantial reduction in overall CRS rates, but there were no grade 2 CRS events. This lends itself nicely to the outpatient dosing strategy. We also saw infections as one would expect with BCMA-targeted antibodies, and the rates were likely equivalent to those [seen with] teclistamab. However, we found that with the use of [intravenous immunoglobulin], this was quite well mitigated. The most interesting feature was that the rate of GPRC5D off-tumor toxicities—namely oral toxicities—was much improved. We saw a lower rate of dysgeusia, which was predominantly grade 1. There was no mucositis, no dysphagia, and, interestingly, there was no significant weight loss, [the latter of] which is very different from what we see with talquetamab. Overall, the oral toxicity profile was much better [with JNJ-5322 vs talquetamab]. Personally, in my patients that I treated, the difference was very clear.

What were the key efficacy data?

We looked at efficacy in both the BCMA/GPRC5D–naive and –exposed populations. Now, [the BCMA/GPRC5D-naïve cohort comprised] 85% of patients, because we wanted to focus on that group. At the RP2D, all patients responded; [of these responders,] 96.3% achieved a very good partial response. These are very strong efficacy data. In the BCMA/GPRC5D–exposed cohort, the ORR was 55.0%, which is in keeping with what we've seen previously. Of note, in the clinical trial, we didn't mandate any washouts with prior BCMA or GPRC5D targeted therapies.

At the RP2D, all patients responded, and no patients have progressed. Sadly, 1 patient did die from an infection. The 12-month progression-free survival rate was 95% but that's purely because of the treatment-related death.

What are the potential next steps for research?

We were very encouraged by these preliminary phase 1 results, and we've also spent quite some time optimizing the dose; hence, this study is now moving forward into later phase clinical trials. For example, there is a phase 2 clinical trial running in combination with daratumumab [Darzalex], and phase 3 trials in the relapsed/refractory setting are already being planned.

Although JNJ-5322 is still in the early stages of development, what potential role could it have in the treatment paradigm based on these initial findings?

I find the results super interesting, particularly in the BCMA/GPRC5D–naive population, where we have such a high and strong efficacy signal. In the future, this could take the place of the individual bispecific [antibodies], because you'll get a very rapid response and there's a good toxicity profile.

In this phase 1 study, we also had the option of stopping therapy after 18 cycles, which allows us to give a fixed duration of therapy that patients will [likely] welcome. That's something to bear in mind as to where this drug could go in the future. It could replace the current bispecific [antibodies] that we have in place, and importantly, give us that fixed duration of therapy.

References

1. van de Donk NW, 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
2. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed August 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma
3. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. FDA. August 9, 2023. Accessed August 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma