Novel Bispecific Antibodies for Relapsed/Refractory Multiple Myeloma


Expert perspectives on two bispecific antibodies, teclistamab and talquetamab, that have been investigated in multiply relapsed multiple myeloma.

Rafael Fonseca, MD:
We’re very fortunate to have a large number of bispecifics that are being tested against multiple myeloma. The majority of the bispecific antibodies have been directed against BCMA. Several were presented at ASH [American Society of Hematology Annual Meeting] and ASCO [American Society of Clinical Oncology Annual Meeting] in 2021 and ASH 2020. But other bispecifics target different molecules like GPRC5D and FCRH5. The selection of these agents needs to include the integration of biomarkers.

Most patients who receive this type of therapy, if they ultimately progress, do so because there’s an exhaustion of the T cells or some other immunoregulatory component, which is lost. A small fraction of patients seem to be losing expression of BCMA. There are at least 3 publications that I’m aware of that show this. Nevertheless, if a patient retains the BCMA—for instance, they failed prior therapies—and even had a prior BCMA-directed therapy, they could still respond nicely to 1 of the device-specific antibodies. I don’t like to use the term BCMA therapies because BCMA is just a target on the cell surface. It’s different if we talk about a CAR [chimeric antigen receptor] T cell vs talking about an ADC [antibody-drug conjugate] vs talking about a bispecific antibody. Each is different, and understanding how that relates to the mechanism of action, or not, will be quite important.

At ASH, we heard about some of these trials. Regarding BCMA, we have the MajesTEC-1 clinical trial, which was a phase 1 study targeting both BCMA and CD3. Dr Philippe Moreau presented this on behalf of the investigators. It was a decent-size trial. It looked at 159 patients who were treated with this bispecific. The patients like the ones in the BCMA and CAR T cells have prior extensive treatment, with a median of 5 prior lines of therapy. In the case of the study, 77% of them were considered triple-class refractory, and 29 were penta-refractory, which is advanced multiple myeloma.

The follow-up is short because patients were still enrolling in the study at the data cutoff, but the overall response rate that was quite decent, at 65%, with a VGPR [very good partial response] rate or better of 60%. There were even patients who achieved a complete response, which was reported in 40% of patients. With the administration of the drug, as time went by, 1 of the most interesting things they have in their presentation is that the quality of the responses improves—the depth of the responses improves over time. I’m eager to see the long-term effects of a bispecific. We’re hoping to have FDA approval this year for what could be the first bispecific for the treatment of multiple myeloma.

Dr [Amrita] Krishnan presented on another bispecific. The is the MonumenTAL-1 study, which tests talquetamab. Talquetamab targets not BCMA but another protein that’s quite restricted to plasma cells, though not 100%. It’s also expressed in certain aspects of our skin and hair follicles, but it’s called GPRC5D, which stands for G-protein coupled receptor family C group 5 member D. It has the same activities. It also targets CD3. Dr Krishnan also presented that this is a sizable fraction of patients: 95% were treated with this compound that was administered in a subcutaneous fashion. It was administered weekly subcutaneous and had 405 µg/kg for the dosing.

At the time that this was submitted, 30 patients were available for response. They showed an overall response rate of 70% and a VGPR or better of 57%. This is a highly active compound and something that we’re very excited about because it targets something different from BCMA. In the future, [we could ask] how we sequence this. Do we even use concurrent? One thing seen in this trial that’s worth knowing is that 65% of patients had skin-related adverse events. Some were nail disorders, and they had other changes in the skin. But overall, it seems to be a well-tolerated regimen. We’ll keep this under observation. But I’m hoping that this will be a path toward a future bispecific approval.

Transcript edited for clarity.

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