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

@article{popat2026firstinhuman,
  title = {{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}},
  author = {Rakesh POPAT and Cyrille TOUZEAU and Aurore PERROT and Sébastien ANGUILLE and Albert ORIOL and Nicolas KINT and Jo CAERS and Monique C MINNEMA and Martin KAISER and Tiago MACHADO and Hans LEE and Alfred GARFALL and Jeffrey MATOUS and Larysa SANCHEZ and Azra BOROGOVAC and Lionel KARLIN and Laura ROSINOL and Wilfried ROELOFFZEN and Saad USMANI and Cindy VARGA and Darren PAN and Tadao ISHIDA and Pansy MINNICK and Damiette SMIT and Nikki DASKALAKIS and Thomas PRIOR and Maria KREVVATA and Ashley NGUYEN and Brandi HILDER and Daniel JONATHAN and Joseph WEIDMAN and Sangmin LEE and Maria-victoria MATEOS and Paula RODRIGUEZ-OTERO and Gala VEGA and Niels VAN DE DONK},
  journal = {Hematology, Transfusion and Cell Therapy},
  year = {2026},
  month = oct,
  doi = {10.1016/j.htct.2026.107871},
  url = {https://doi.org/10.1016/j.htct.2026.107871},
  note = {CC BY},
}

TY  - JOUR
TI  - 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
AU  - Rakesh POPAT
AU  - Cyrille TOUZEAU
AU  - Aurore PERROT
AU  - Sébastien ANGUILLE
AU  - Albert ORIOL
AU  - Nicolas KINT
AU  - Jo CAERS
AU  - Monique C MINNEMA
AU  - Martin KAISER
AU  - Tiago MACHADO
AU  - Hans LEE
AU  - Alfred GARFALL
AU  - Jeffrey MATOUS
AU  - Larysa SANCHEZ
AU  - Azra BOROGOVAC
AU  - Lionel KARLIN
AU  - Laura ROSINOL
AU  - Wilfried ROELOFFZEN
AU  - Saad USMANI
AU  - Cindy VARGA
AU  - Darren PAN
AU  - Tadao ISHIDA
AU  - Pansy MINNICK
AU  - Damiette SMIT
AU  - Nikki DASKALAKIS
AU  - Thomas PRIOR
AU  - Maria KREVVATA
AU  - Ashley NGUYEN
AU  - Brandi HILDER
AU  - Daniel JONATHAN
AU  - Joseph WEIDMAN
AU  - Sangmin LEE
AU  - Maria-victoria MATEOS
AU  - Paula RODRIGUEZ-OTERO
AU  - Gala VEGA
AU  - Niels VAN DE DONK
PY  - 2026
DA  - 2026/10/23
JO  - Hematology, Transfusion and Cell Therapy
DO  - 10.1016/j.htct.2026.107871
UR  - https://doi.org/10.1016/j.htct.2026.107871
AB  - 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.
SN  - 2531-1379
SN  - 2531-1387
ER  -