Editor's Note: At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Professor Niels van de Donk from VU University Medical Center, Amsterdam, presented the preliminary results of a first-in-human phase I study of a novel trispecific antibody (TsAb) for relapsed/refractory multiple myeloma (R/R MM) in an oral presentation (Abstract #S100). Oncology Frontier – Hematology Frontier invited Prof. van de Donk for an in-depth discussion on the study's findings and clinical implications. Highlights of the conversation are summarized below.

Oncology Frontier – Hematology Frontier: As a first-in-human study, how would you evaluate the efficacy breakthrough of JNJ-5322, especially achieving a 100% overall response rate in patients naïve to anti-BCMA/-GPRC5D therapies?

Niels van de Donk: So I showed indeed, in a population of patients that was triple-class exposed, so exposed to proteasome inhibitors, immunomodulatory drugs, CD38 antibodies, but naive to BCMA and GPRC5D targeted therapies, that we achieve at the recommended phase 2 dose of 100 milligrams of the trispecific antibody JNJ-5322. We achieved a 100% response rate. But these responses were not only very high, but also very deep. So, 70% of the patients so far achieved complete remission, and 96% of the patients had a very good partial response. So, very deep remissions, and they translate into very promising progression-free survival of 95% at one year. So, these results are very promising. We need longer follow-up, we need more patients, but they are comparable to what you can achieve with CAR T-cell therapy, with the best CAR T-cell therapies. They are better than what you can achieve with a single targeting bispecific antibody. So, we are very happy with these results, also with the manageable safety profile. And because of these promising results, we are also bringing this compound to earlier lines of therapy, including newly diagnosed disease.

Oncology Frontier – Hematology Frontier: The study adopted a single step-up dosing strategy to mitigate cytokine release syndrome (CRS). Could you elaborate on the significance of this approach in managing patient safety?

Niels van de Donk: So at the recommended dose, we give only one step-up dose of 5 milligrams. And with that, we have a very manageable safety profile, including CRS rate. CRS without the use of prophylactic tocilizumab was approximately 60%. And all the cases were either grade 1, and some cases were grade 2, but no grade 3 or higher CRS events. And we also had a cohort of patients which we gave prophylactic tocilizumab prior to the first step-up dose. And with that, the CRS rate is only 20%. So with this CRS profile, it will become easier to treat the patients outpatient without admitting them to the hospital. And this is of course much more, well, it’s easier for the patients, it’s also easier for the doctors. We do not need to occupy beds. So I think this paves the way to outpatient dosing for patients that receive this trispecific.

Oncology Frontier – Hematology Frontier: Compared to currently available bispecific antibodies or CAR-T therapies, what unique advantages do you see in the trispecific design of JNJ-5322?

Niels van de Donk: So the good point about JNJ-5322 is that you can give it every four weeks. So typically, bispecific antibodies need to be given in the beginning at least every week. This is four weeks. So dosing every four weeks, which is very convenient for the patients. Also, the response rate is higher than what we see with bispecifics. 100% response rate versus 60 to 70%. And also the durability of the responses is longer compared to bispecifics. And I think the response rate that we achieve with the trispecific is comparable to what we achieve with CAR-T at the moment, with the best CAR-Ts at the moment. But the trispecific is off-the-shelf available. So you can start treatment as soon as, well, you need the drug. There is no need for a long manufacturing time.

Oncology Frontier – Hematology Frontier: Looking ahead, how do you envision the clinical positioning of JNJ-5322? Do you see potential for it to become a frontline treatment option for patients with relapsed/refractory multiple myeloma?

Niels van de Donk: So based on the promising efficacy and manageable safety results, we are now evaluating, in fact, already combination strategies. So JNJ-5322 in combination with daratumumab is being evaluated, in combination with pomalidomide is evaluated, in earlier lines of therapy, in early relapse refractory space. But we are also treating the first patients in the newly diagnosed space. So we hope to move this effective molecule to earlier lines of therapy, including newly diagnosed disease. But still, these trials are still ongoing. So maybe next year we will have more results from these cohorts.