According to the initial findings of an ongoing first-in-human phase I trial, reported at the European Hematology Association (EHA) 2025 Congress, promising results have been shown for a novel off-the-shelf tri-specific antibody in the treatment of patients with multiple myeloma highly refractory to other therapies (Abstract S100).
JNJ-5322 is a tri-specific antibody with novel binding domains that target CD3, B-cell maturation antigen (BCMA), and G protein-coupled receptor class C member D (GPRC5D). In triple-class–exposed relapsed or refractory multiple myeloma, the compound appeared to have a similar, or even better, safety profile compared with the available bispecific antibodies targeting BCMA or GPRC5D. At the recommended phase II dose (RP2D) in patients naive to BCMA- and GPRC5D-targeted bispecifics, 100% of patients responded, and 95% were free of disease progression at 12 months, according to Rakesh Popat, MD, of the National Institute for Health Research, University College London Hospitals NHS Foundation Trust in the United Kingdom.
“JNJ-5322 has an overall response rate comparable to CAR T-cell therapy, but it’s an off-the-shelf treatment that can be given in an outpatient setting,” Dr. Popat said during his presentation at the EHA 2025 Congress Plenary Session.
About JNJ-5322
JNJ-5322 has novel binding domains that target CD3, BCMA, and GPRC5D. BCMA and GPRC5D have tight affinity binding, and the CD3 binding domain is a low-affinity binder. As a consequence, this allows for comprehensive targeting of myeloma cells. In addition, the dual-antigen binding of BCMA and GPRC5D essentially yields a “double lock-down” effect that prevents antigen escape and increases the specificity of the antibody for the tumor cells, reducing the potential for toxicity. The low signaling of the CD3 component also reduces the risk of cytokine-release syndrome, Dr. Popat explained.
About the Phase I Trial
This study was designed with dose-escalation and dose-optimization portions to identify the RP2D and define the best administration schedules. It enrolled 147 patients who were triple-class exposed to a proteasome inhibitor, an immunomodulatory drug, and CD38-based therapy. The RP2D was determined to be 100 mg every 4 weeks subcutaneously with one step-up dose of 5 mg administered 2 to 8 days before the first full dose.
“We focused here on the BCMA/GPRC5D-naive population because this was the first-in-human study, so it was important to understand the safety profile and to ensure we had adequate exposure of the drug,” Dr. Popat said. “But secondly, we wanted to understand the efficacy profile of this drug in comparison to the already-approved bispecific antibodies, particularly in this setting.”
Key Findings
Dr. Popat reported findings for 27 patients naive to BCMA- and GPRC5D-targeted therapies treated with the RP2D of 100 mg every 4 weeks and followed for a median of 12.2 months. In that subset, 96.3% achieved a very good partial response or better, of which 70.4% were at least complete responses. For eight patients treated with 300 mg every 4 weeks and followed for a median of 16.4 months, the response rate was 100%, all of which were complete or better, though he suggested these deeper responses might be attributed to longer follow-up.
Response rates were lower in the other (lower) dosing cohorts. The median time to best response was about 6 months. Almost all responding patients remain in response after 12 months of follow-up. The progression-free survival rate at 1 year in the BCMA/GPRC5D inhibitor–naive RP2D group was 95.0%.
Safety Profile
JNJ-5322 was associated with improved or similar adverse effects compared with other GPRC5D-directed therapies.
In the 36 patients treated at RP2D, grade ≥ 3 infections (primarily respiratory) were observed in 33.3%. Half the patients developed hypogammaglobulinemia. There was one dose-limiting toxicity (pneumonia) and one grade 5 event, death from pneumonia in a patient with suboptimal intravenous immunoglobulin (IVIG) support. Across all other doses, there were four dose-limiting toxicities and four grade 5 treatment-related events, including adenoviral encephalitis (in a patient without IVIG support), embolic stroke, multiple organ dysfunction syndrome, and pulmonary hemorrhage. “If you give optimal IVIG and prophylaxis, I think infections can be safely managed,” he said.
As compared with the bispecific antibodies, Dr. Popat maintained that JNJ-5322 does appear to cause less cytokine-release syndrome and immune effector cell–associated neurotoxicity (ICAN); there were no cases of ICAN at the RP2D. The study also demonstrated the impact of prophylactic tocilizumab on this toxicity, based on outcomes of patients who received the drug and those who did not. Without tocilizumab, 69% developed cytokine-release syndrome (54% grade 1, 15% grade 2), but this rate dropped to 20% (all grade 1) with tocilizumab on board. “This really underpins the ability to give this drug as an outpatient strategy,” he commented.
Taste abnormalities did occur, but weight loss was not a significant problem with this drug. “This is a very different profile from what we see with talquetamab, where 30% of those patients develop weight loss,” he noted. “Our patients were doing extremely well without any intervention from us.” The investigators are currently assessing quality of life, and this will include questionnaires specific to oral toxicities.
Disclosure: Dr. Popat reported relationships with AbbVie, BMS, Celgene, GlaxoSmithKline, Johnson & Johnson/Janssen, Pfizer, Galapagos NV, Janssen, Regeneron, Roche, and Sanofi.
