Updated efficacy and safety results of JNJ-5322, a novel, next-generation BCMA×GPRC5D×CD3 trispecific antibody, in patients with Relapsed/Refractory multiple myeloma

Abstract Introduction: JNJ-5322 is a novel, next-generation trispecific antibody with capabilities to target dual myeloma antigens with a single molecule, and contains novel B-cell maturation antigen (BCMA), G protein–coupled receptor class C group 5 member D (GPRC5D), and CD3 binding domains. JNJ-5322's binding to both BCMA and GPRC5D results in improved binding avidity that may enhance efficacy by overcoming clonal heterogeneity and preventing antigen escape. The first-in-human study (NCT05652335) in patients with relapsed/refractory multiple myeloma (RRMM) showed an improved or similar safety profile of JNJ-5322 compared with BCMA/GPRC5D bispecific antibodies (BsAbs) as monotherapy or in combination, and an overall response rate (ORR) of 100.0% at the recommended phase 2 dose (RP2D) in BCMA/GPRC5D naive patients. These data were supported by pharmacokinetic and exposure–response analyses that led to selection and dose optimization of the RP2D (100 mg every 4 weeks [Q4W]) and step-up dose (SUD; 5 mg). Here, we present updated safety and efficacy results of JNJ-5322 at the RP2D from part 1 of the ongoing phase 1 study. Methods: Dose escalation/expansion cohorts enrolled patients with RRMM who were triple-class exposed to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. The primary objectives were to identify the RP2D and to assess safety at the RP2D. Treatment-emergent adverse events (TEAEs) were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. ORR was assessed by IMWG criteria. Minimal residual disease (MRD) negativity was assessed at a threshold of 10–5 using next-generation sequencing. Results: As of July 9, 2025, 36 patients received JNJ-5322 at the RP2D with a median follow-up of 14.4 months. At baseline, 26.5% (9/34) had high-risk cytogenetics, 13.9% had ISS stage III disease, and 8.3% had extramedullary disease. Patients received a median of 4 (range 2–11) prior lines of therapy; 75.0% were BCMA/GPRC5D naive and 52.8% were triple-class refractory. The most common nonhematologic TEAEs were infections (80.6% [gr 3, 33.3%]) and skin-related (66.7%, all gr 1/2) and nail-related (61.1%, majority [58.3%] gr 1) TEAEs. The most common hematologic TEAEs were lymphopenia (47.2% [gr 3/4, 44.4%]) and neutropenia (44.4% [gr 3/4, 33.3%]). The cumulative incidence of gr ≥3 infections plateaued within the first year of therapy. Intravenous immunoglobulin (IVIg) use was recommended to maintain Ig levels ≥400 mg/dL; 91.7% of patients received IVIg. Hypogammaglobulinemia was reported in 52.8% of patients; among these, 94.7% received IVIg. CRS occurred in 52.8% (gr 1, 41.7%; gr 2, 11.1%). In cohorts without (received 100 mg Q4W) and with (received 100 mg Q4W/Q8W) prophylactic tocilizumab, CRS occurred in 69.2% (gr 2, 15.4%) and 20.0% (gr 2, 0%), respectively. No ICANS events were reported. Taste changes occurred in 58.3% (gr 1, 41.7%; gr 2, 16.7%); median duration was 57 days. Of 36 patients who received the RP2D, 27 were BCMA/GPRC5D naive with a median follow-up of 15.0 months; these patients showed a high ORR of 100.0% with deepening of response (complete response or better [≥CR], 77.8%) and a 12-month progression-free survival rate of 96.3%. Apart from 1 patient who died while in very good partial response (due to pneumonia in the setting of hypogammaglobulinemia <200 mg/dL), all 26 patients remain in response at 15.0 months of median follow-up, demonstrating durable responses. MRD negativity at 10–5 was achieved in 100.0% (10/10) of evaluable patients. Updated analyses with 6 additional months of follow-up will be presented at the conference. Conclusions: With longer follow-up in part 1 of the phase 1 trial, JNJ-5322 continues to demonstrate responses comparable to CAR-T therapy (ORR 100.0%) that are durable and continue to deepen (≥CR 77.8%), with a safety profile similar or improved compared with BsAbs targeting BCMA or GPRC5D. JNJ-5322 offers off-the-shelf, Q4W dosing and 1 SUD with low rates of gr 2 CRS that may enable an efficient approach to dual antigen targeting via convenient administration and outpatient treatment. These findings support further evaluation of JNJ-5322 in patients with RRMM.