JNJ-5322 Demonstrates Preliminary Efficacy and Is Safe in R/R Multiple Myeloma

Niels van de Donk, MD, PhD

JNJ-79635322 (JNJ-5322)—a trispecific antibody targeting BCMA, GPRC5D, and CD3—demonstrated deep and durable responses with a manageable safety profile in patients with relapsed or refractory multiple myeloma, according to Niels van de Donk, MD, PhD.

Findings from a first-in-human phase 1 trial (NCT05652335), which were presented at the 2025 ASCO Annual Meeting, showed that subcutaneous JNJ-5322, administered every 4 weeks at the recommended phase 2 dose (RP2D) of 100 mg following 1 5-mg step-up dose, was associated with an overall response rate (ORR) of 100.0% in BCMA- and GPRC5D-inhibitor–naive patients (n = 27). Complete responses (CRs) or better were observed in 70.4% of patients, and 96.3% of patients achieved at least a very good partial response (VGPR). The estimated 12-month progression-free survival (PFS) rate was 95.0%.

Regarding the agent’s tolerability, cytokine release syndrome (CRS) occurred in 69.2% of patients not receiving prophylactic tocilizumab (Actemra; n = 26), though all events were grade 1 or 2. Use of prophylactic tocilizumab (n = 20) reduced the CRS rate to 20.0%, with no grade 2 or higher events reported. Grade 3 or higher infections were observed in 28.6% of patients treated at all doses (n = 147), prompting the recommendation for early intravenous immunoglobulin (IVIG) initiation when immunoglobulin G (IgG) levels fell below 4 g/L.

“These results look promising, although follow-up is still short, [and] we need to have larger cohorts of patients,” van de Donk said in an interview with OncLive® during ASCO 2025.

In the interview, van de Donk discussed the biologic rationale behind trispecific antibody development to reduce antigen escape; outlined the clinical implications of these early findings; and previewed planned next steps for JNJ-5322, including combination trials and phase 2/3 studies in earlier lines of therapy.

van de Donk is a full professor of hematology at the Amsterdam University Medical Center in Netherlands.

OncLive: What was the rationale behind developing this dual-antigen–targeting, T-cell–redirecting trispecific antibody?

Van de Donk: JNJ-5322 binds simultaneously to 2 antigens on the myeloma cell surface and to CD3 on the T cell. The advantage of dual targeting is that it can potentially prevent antigen escape. In mouse models and in patients, we have seen that with single-targeting bispecific antibodies, relapse often occurs because of loss of the target antigen. With dual targeting, that can [hopefully be prevented]. That’s why we started this study with JNJ-5322, which targets BCMA and GPRC5D at the same time.

What were the design and objectives of the study, including the patient population, dosing strategy, and key end points?

In the phase 1 study, we enrolled a total of 147 patients. All the patients were triple-class exposed—that was the key inclusion criterion—[meaning they had been] exposed to proteasome inhibitors, CD38-directed antibodies, and immunomodulatory drugs. In the phase 1 study, we evaluated several doses of JNJ-5322, [including] different administration schedules—every 2 weeks, every 4 weeks, or every 8 weeks. We also assessed prophylactic dose [regimens] to enable future easy outpatient dosing.

What preliminary safety outcomes were observed?

Across all the dose levels and different administration schedules, based on the overall [pharmacokinetics], safety, and response/efficacy data, we selected the RP2D as 100 mg of JNJ-5322 administered subcutaneously every 4 weeks with a single step-up dose of 5 mg. We showed that at this RP2D, the toxicity profile is manageable.

We saw—as expected with T-cell immunotherapy—lymphopenia and neutropenia, and we also saw nonhematologic adverse effects [AEs], including CRS, infections, and GPRC5D inhibitor–related AEs. Importantly, with 1 step-up dose [and across all dose levels], the CRS rate was 56.5%, and most of the events were grade 1. There were no grade 3 or higher [CRS] events. With prophylactic tocilizumab, the CRS rate went down to 20.0%, and all those events were grade 1. This paved the way for easy outpatient dosing.

Infections were observed, with grade 3 or higher infections [occurring in] approximately 28.6% of [all treated] patients. One of the contributing factors [of these infections was] hypogammaglobulinemia, so it’s important to give the patients [IVIG] as soon as IgG levels drop below 4 g/L. We also saw GPRC5D inhibitor–related AEs, such as dysgeusia—loss of taste, decrease in appetite, and dysphagia. However, overall, these GPRC5D inhibitor–related AEs were less frequent, less severe, and especially of shorter duration than what we typically see with talquetamab-tgvs [Talvey]. This also translated into a low rate of weight loss, which is much higher in talquetamab-treated patients.

What were the key efficacy findings?

Regarding the efficacy, we saw a 100.0% ORR at the RP2D in BCMA- and GPRC5D inhibitor–naive patients. The responses were also deep, with CRs in 70.4% of patients and at least a VGPR in 96.3% of the patients. This translated into a promising PFS rate of 95.0% at 1 year. [These outcomes] look better than what we would expect from a single-targeting bispecific antibody alone and are comparable [with outcomes associated with] the best CAR T-cell therapies that we currently have available.

What are the next planned steps for the clinical development of JNJ-5322?

[Based on the favorable safety and efficacy profile], we are now investigating combinations containing JNJ-5322—for example, with daratumumab [Darzalex] or pomalidomide [Pomalyst]. [We are exploring these combinations] in earlier stages of the disease, such as early relapsed/refractory myeloma and newly diagnosed myeloma. In the end, larger phase 2 and phase 3 trials are planned to further evaluate the efficacy in a broader population of patients, [including comparisons with standard-of-care regimens].

If these data continue to show positive signals, what role do you envision this agent playing in the treatment armamentarium for multiple myeloma?

If the [data are] confirmed in larger cohorts of patients—which I’m convinced [will be the case], because I have a lot of experience with this drug, and we [have] treated more than 30 patients—it may gradually move to earlier stages of the disease. Trispecific antibodies will probably replace [bispecific] antibodies based on their ability to induce deeper, more durable responses, [and] potentially [doing so] by preventing antigen escape.

Reference

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