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.
Authors: Niels W.C.J. van de Donk, Gala Vega, Aurore Perrot, Sébastien Anguille, Albert Oriol, Monique Minnema, Martin F. Kaiser, Hans C. Lee, Alfred Garfall, Jeffrey V. Matous, Larysa Jessica Sanchez, Azra Borogovac, Lionel Karlin, Saad Z. Usmani, Joseph Weidman, Sangmin Lee, Maria-Victoria Mateos, Paula Rodríguez-Otero, Cyrille Touzeau, Rakesh Popat
Journal: Journal of Clinical Oncology (2025)

7505 Background: Bispecific antibodies (BsAbs) have begun to transform outcomes in MM. 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 TsAb 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. We report first results from an ongoing phase 1 study of JNJ-5322 (NCT05652335). Methods: Dose escalation/expansion cohorts enrolled measurable RRMM pts 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). Pts received 1 step-up dose (SUD) (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 pts received JNJ-5322 (36 at 100 mg Q4W); median follow-up (mFU) 8.2 mo. Median age 64 yrs; 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 pts had ≥1 AE, most commonly CRS (59%; all grade [gr] 1 [45%]/2 [14%]; no gr ≥3), nail AEs (gr 1/2 56%), taste AEs (gr 1/2 56%), neutropenia (48%; gr 3/4 41%), and non-rash skin AEs (47%; gr 3/4 1%). Overall, 16% had weight decreases (no gr ≥3), 16% had rashes (no gr ≥3), 2% had ICANS (all gr 1), and 75% had infections (gr 3/4 28%). 5 pts had dose-limiting toxicities. 4 pts died due to AEs. In response-evaluable pts, 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 pts naïve to anti-BCMA/-GPRC5D therapies (n=27), and all patients remain in response (mFU 8.5 mo). Median time to first response was 1.2 mo. Conclusions: In the largest data set for a next-generation dual antigen T-cell redirecting TsAb, 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 gr 3/4 infection rates. CRS was mostly gr 1 (no gr ≥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. Clinical trial information: NCT05652335 .