Novel trispecific antibody may be a game-changer for relapsed/refractory MMF

The investigational trispecific antibody JNJ-5322 was associated with high response rates in patients with relapsed or refractory multiple myeloma (MM). Moreover, the agent appeared to have an improved or similar safety profile to the available bispecific antibodies, presenting a potential paradigm shift in the field.

The experimental trispecific antibody JNJ-5322 targets CD3, BCMA, and GPRC5D and this product was tested in a phase 1 trial among 147 patients with triple-class-exposed relapsed or refractory MM. “In total, 36 patients were treated with the recommended phase 2 dose (RP2D),” added Dr Rakesh Popat (University College London, UK) [1]. Also, about 80% of the patients were BCMA/GPRC5D-naïve, whereas 20% had been exposed to at least one of these drug mechanisms.

Grade 3 or 4 neutropenia (41.5%), lymphopenia (35.4%), and anaemia (15.0%) were the most common haematologic adverse events, with comparable rates in the RP2D subgroup of patients. Next to that, 28.6% of the patients had an infection of grade 3 or 4. “Importantly, infections can be managed with monthly IgG monitoring and Ig replacement to maintain IgG ≥400 mg/dL,” commented Dr Popat. The rate of cytokine release syndrome (CRS) was 69.2%, with all events being of grade 1 or 2. However, prophylactic use of tocilizumab strongly reduced the incidence and severity of CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) was not observed in this study population.

The overall response rate was 100% in patients who were BCMA/GPRC5D-naive, with 70.4% achieving at least a complete response. The corresponding rates for patients who had been exposed to prior BCMA/GPRC5D therapies were 66.7% and 38.1%, respectively. Finally, the 1-year progression-free survival rate was 74.1% for the overall study population and 95.0% for patients who had received the RP2D.

“The BCMA/GPRC5D T-cell engaging trispecific antibody JNJ-5322 demonstrated a manageable safety profile and a response rate that is comparable to CAR T-cell therapy,” concluded Dr Popat. “However, this is a convenient off-the-shelf product with monthly dosing, which facilitates outpatient management.”

1. Popat R, et al. First-in-human study of JNJ-79635322, a novel next-generation trispecific antibody, in patients with relapsed/refractory multiple myeloma: initial phase 1 results. S100, EHA2025 Congress, 12–15 June, Milan, Italy.

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Posted on 2 September 20252 September 2025