EHA 2025 | Initial results of JNJ-79635322, a novel next-generation trispecific antibody, in R/R myeloma

Currently we are familiar with the use of bispecific antibodies for multiple myeloma and we have available those that target both BCMA and GPRC5D. Whilst these are highly effective treatments we know that approximately 30 to 40 percent of these patients do not respond to these bispecific antibodies. In addition with talquetamab there is the association of on-target off-tumor toxicities, namely oral toxicities, skin and nail adverse events. And so this paved the way for the development of a trispecific antibody which is a novel antibody that targets both BCMA and GPRC5D. The advantage of this approach is that it can target myeloma cells that express BCMA, it targets myeloma cells expressing GPRC5D, but importantly it has a double down effect which means that it can target both antigen expressing cells BCMA and GPRC5D. The relevance of this is that it improves the specificity of the targeting which can reduce the amount of off-tumor toxicities. 

So this was the first in human clinical trial which was run globally. We recruited over 120 patients and was determining the recommended Phase II dose. So we looked at the various different step-up doses, various different recommended doses. We started at 50 milligrams and we dosed patients all the way up to 300 milligrams. We also looked at outpatient strategies which involved optimizing the step-up dosing and the use of prophylactic tocilizumab to mitigate cytokine release syndrome. 

In terms of the toxicity profile we found that the overall CRS rate was 50 percent. It was up to 70 percent without prophylactic toci but with prophylactic tocilizumab the CRS rate drops to 20% and importantly there were no grade 2 CRS events. Infections were of course observed but they were typically mitigated with the use of prophylactic antibiotics and IVIG which really limited the number of grade 3 events down to about 30%. And then in terms of oral toxicities we were very pleased and encouraged to see a much lower rate of oral associated toxicities. Specifically, very few patients actually lost any weight, which is markedly different to what we see with talquetamab. And personally, given that I treated a large number of patients, many of my patients were reporting a lower rate of dysgeusia and taste disturbances. 

In terms of efficacy, at the recommended Phase II dose for patients who are naive to BCMA and GPRC5D, all 100% of patients responded to treatment. And over 90% of these patients achieved a VGPR and greater. In terms of those patients who are exposed to the BCMA or GPRC5D, the response rate does drop to around 55%. These responses, however, were very durable and all patients treated at the RP2D responded to treatment. Sadly, one of those patients did die from an overwhelming infection, but in terms of the progression-free survival, therefore, at the 12-month mark, 95% of these patients are progression-free. 

So overall, I would summarize in saying that this is the earliest results of a trispecific antibody. In terms of the toxicity profile, it appears to be quite well tolerated. Specifically, it has a much lower oral toxicity rate compared to talquetamab. And very strikingly, the overall response rate for BCMA GPRC5D naive patients was 100%.

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