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First-in-human Study of Jnj-79635322 (jnj-5322), a Novel, Next-generation Trispecific Antibody, in Patients With Relapsed/refractory Multiple Myeloma: Initial Phase 1 Results

Year: 2026

Type: article

Abstract: Background Bispecific antibodies (BsAbs) have begun to transform outcomes in relapsed/refractory multiple myeloma (RRMM). Emerging data suggest that targeting two MM antigens with T-cell redirection may overcome tumor heterogeneity and acquired resistance to further improve clinical outcomes. JNJ-5322 is a next-generation trispecific antibody dually targeting BCMA and GPRC5D via T-cell redirection, comprising novel binding domains, including low affinity CD3, selected in vitro to enhance on-tumor effects and reduce off-tumor impact. Aims We report the first results from an ongoing phase 1 study of JNJ-5322 (NCT05652335). Methods Dose escalation/expansion cohorts enrolled measurable RRMM patients previously exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody. Escalating fixed Q2W or Q4W SC doses (0.4–300 mg) were explored, including 100 mg Q4W, the putative recommended phase 2 dose (RP2D). Patients received 1 step-up dose (SUD) of 5 mg prior to receiving the 100 mg Q4W dose, allowing faster full dose initiation and attenuation of cytokine release syndrome (CRS) risk. Adverse events (AEs) were graded by CTCAE v5.0; CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Overall response rate (ORR) was assessed by IMWG criteria. Results As of Jan 15, 2025, 126 patients received JNJ-5322 (36 at 100 mg Q4W); median follow-up (mFU) was 8.2 months. Median age 64 years; median 4 prior lines of therapy; 100% triple-class exposed (56% refractory); 31% high-risk cytogenetics; 23% had prior anti-BCMA/-GPRC5D therapy (77% naïve). The putative RP2D was identified as 100 mg Q4W. Overall, 99% of patients had ≥1 AE, most commonly CRS (59%; all grade 1 [45%]/2 [14%]; no grade ≥3), nail AEs (grade 1/2 56%), taste AEs (grade 1/2 56%), neutropenia (48%; grade 3/4 41%), and non-rash skin AEs (47%; grade 3/4 1%). Overall, 16% of patients had weight decreases (no grade ≥3), 16% had rashes (no grade ≥3), 2% had ICANS (all grade 1), and 75% had infections (grade 3/4 28%). Five patients had dose-limiting toxicities. Four patients died due to AEs. In response-evaluable patients, ORR was 86% (75% ≥VGPR) at the RP2D (n=36), and 73% (66% ≥VGPR) overall (n=124). ORR was 100% (89% ≥VGPR) at the RP2D among patients naïve to anti-BCMA/-GPRC5D therapies (n=27), and all patients remain in response (mFU 8.5 months). Median time to first response was 1.2 months. Conclusions In the largest data set for a next-generation dual antigen T-cell redirecting trispecific antibody, the first clinical data for JNJ-5322 showed a 100% ORR at the putative RP2D in anti-BCMA/-GPRC5D naïve patients, with convenient Q4W dosing. Tolerability appeared improved, including lower incidence and severity of GPRC5D-associated AEs vs anti-GPRC5D BsAbs and manageable grade 3/4 infection rates. CRS was mostly grade 1 (no grade ≥ 3 CRS) using 1 SUD. First data with JNJ-5322 suggest a paradigm shift, offering ORRs similar to CAR-Ts but as an off-the-shelf therapy intended for outpatient dosing.

Source: Hematology Transfusion and Cell Therapy

DOI: 10.1016/j.htct.2026.107871

Institutions: University College London Hospitals NHS Foundation Trust, National Institute for Health and Care Research, Centre Hospitalier Universitaire de Nantes, University of Antwerp, Centre Hospitalier Universitaire de Toulouse, Institut universitaire du cancer de Toulouse Oncopole, Antwerp University Hospital, Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, Ghent University Hospital, Royal Marsden NHS Foundation Trust, Royal Marsden Hospital, Centre Hospitalier Universitaire de Liège, University Medical Center Utrecht, Johnson & Johnson (Brazil), The University of Texas MD Anderson Cancer Center, Abramson Cancer Center, University of Pennsylvania, Colorado Blood Cancer Institute, Icahn School of Medicine at Mount Sinai, City Of Hope National Medical Center, Hôpital Lyon Sud, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, University Medical Center Groningen, Memorial Sloan Kettering Cancer Center, Levine Cancer Institute, Tisch Cancer Institute, Johnson & Johnson (United States), Japanese Red Cross Medical Center, Université Toulouse III - Paul Sabatier, Instituto de Investigación Biomédica de Salamanca, Centro de Investigación del Cáncer, Centro de Investigación Biomédica en Red de Cáncer, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam

Language: English

Topic: Multiple Myeloma Research and Treatments

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: diamond

Funder: Johnson and Johnson

OpenAlex ID: W7223128839

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