Bispecifics | Urvi Shah, MD | ASH 2022

Hi, I'm Urvi Shah from Memorial Sloan Kettering Cancer Center. I'm on the myeloma service. I wanted to discuss the bispecific antibody oral abstract session at the American Society of Hematology Annual Meeting 2022. This meeting was very well attended and there were patients and physicians that filled up but there were many in the overflow room as well, just going to show how important bispecific antibodies are as the next new therapy for myeloma. Within bispecific antibodies, we have the Teclistumab that has been recently approved, but we also have many different antibodies in the pipeline. In this session, six major abstracts were discussed and I'll go over each of them in brief. The first abstract that was discussed was by Dr. Ajay Chari from Mount Sinai and he discussed the updates on Talcuitumab data, which is an anti-GPRC5D antibody. That's going to be our next newest target for myeloma and the first therapy probably that will be approved for this target. What he did show was that he showed data from 150 patients in two different cohorts, 150 in each cohort approximately, and showed that the dosing schedule was different. In one of the cohorts, it was 0.4 milligrams per kilogram weekly and in the second schedule, it was 0.8 milligrams per kilogram every other week. He showed very similar results with an overall response rate in the 70s and some side effects of infection, but the infection risk was all manageable, mostly low grade infections. The skin and nail side effects, which is a very unique side effect to this target because this GPRC5D, while it's expressed on myeloma cells, is also expressed on skin and nails. However, all of those toxicities were mostly mild and very few patients had severe toxicities with it. I think this is a very exciting new target and option for patients who have relapsed on BCMA therapies. He also showed some data in patients who have been on prior BCMA-directed therapies and showed that this is very effective for them as well. The next abstract was discussed by Dr. Nupur Rajay from Mass General. She discussed the abstract on the Magnetism 1 trial. The Magnetism 1 trial was the phase 1 study looking at the bispecific antibody, l-ranitamab. L-ranitamab is very similar to teclistamab, but another option for patients. She showed data for 55 patients and how overall response rates were also great in the 70s and patients overall did well. The median duration of response and PFS was around a year, so patients had a year in remission with these drugs on average. Other than that, there were, again, the infection risk that is something we need to watch out for with all bispecifics. The next abstract was by Dr. Nizar Baylis from Canada, and he discussed the Magnetism 3 trial, where this is a trial looking at the same drug, l-ranitamab, but in a larger study and more patients. He showed very similar results, showing that this is a very effective therapy for patients with manageable toxicities. The main thing to think about is the infection prophylaxis, and a lot of thought is going into it at this time, but it is not clear which therapies, which antipy, I think it's still a matter of debate as to which prophylaxis should be used for all patients. So acyclovir and probably Bactrim as well are things that are being considered for most patients. The next abstract was discussed by Dr. Emma Searle from, Emma Searle, and she discussed the abstract on Majestic 2. So we know teclistamab was based on Majestic 1 data, the approval. Majestic 2 is a study looking at teclistamab in earlier lines of therapy, so before, much before they relapsed. With teclistamab, the current approval is for four or more lines of therapy. With Majestic 2, this is looking at a median of two prior lines of therapy, so patients had fewer therapies when they went on the study. In this study, patients got daratumumab, lenalidomide, and teclistamab, and in this combination, they saw that patients overall were able to tolerate this combination. However, there was a signal of an increased infection risk, and two patients died of infection as well. So this is, again, this toxicity from bispecific antibodies around infection is something we need to understand better, and there were a lot of low blood counts with this combination and needing those reductions in the lenalidomide. The next abstract was discussed by Dr. Carmelo from, discussing RG6234, which is a bispecific antibody for GPRC5D. So the same target like talcuetamab, but this is another antibody from Genentech. I think it's good to have multiple options for the same target, and we will see more data. He presented very early data with the subcutaneous and IV dosing cohort, showing that this is feasible and effective, at least in the early settings. And the last abstract was by Dr. Sandy Wong, and she discussed alnuctumab, another bispecific antibody. So you can see we have a lot of options here, and she discussed the initial results from the IV data, showing that patients actually had pretty long median duration of response of 33 months. However, given the ease of dosing with subcutaneous as well as less cytokine release syndrome like side effects, they are now looking at the subcutaneous option. And she discussed the data around the subcutaneous cohort, but it's very early, the data, so there's more to come with that. So with that, these were the six abstracts discussed. And just to conclude, I think, you know, Telquetamab is already available and lots of patients are starting to get it, but we have many options down the pipeline, like Elranitamab, alnuctamab, and then also whether we do it in different settings, and then newer targets like Telquetamab for GPRC5D and the other antibody from Genentech as well.