Evaluating Bispecific T-Cell Engagers for the Treatment of Patients With Multiple Myeloma

At the 2023 Lymphoma, Leukemia & Myeloma Congress in New York, New York, Dan Vogl, MD, MSCE, University of Pennsylvania, Philadelphia, Pennsylvania, provides expert insight on the use of bispecific T-cell engagers for the treatment of patients with multiple myeloma. 

Transcript:

Hi, I'm Dan Vogl from the Multiple Myeloma Program at the University of Pennsylvania. I was invited to speak at this year's Leukemia, Lymphoma & Myeloma Congress on the topic of bispecific T-cell engagers for multiple myeloma. We're very lucky this year to have seen the approval of 3 new agents in this class: 2 targeted against B-cell maturation antigen teclistamab and elranatamab, and 1 targeted against GPRC5D, talquetamab. These agents have high response rates, generally favorable toxicity profiles, and are an important addition to our myeloma armamentarium.

Teclistamab and elranatamab, which target BCMA, are given with inpatient step-up dosing, and then weekly or every 2 weeks. They have toxicities that include cytokine release syndrome (CRS) in a fair number of patients, sometimes requiring the administration of tocilizumab and immune effector cell associated neurotoxicity syndrome in a relatively smaller number of patients, and importantly, for both the rate of severe toxicity is relatively low.

Long-term toxicities with BCMA directed bispecific [antibodies] include cytopenias and infections, and attention to these toxicities is important, especially the risk of infection, which requires regular administration of intravenous immune globulin and prophylactic antibiotics, including anti-shingles prophylaxis and pneumocystis prophylaxis.

Talquetamab, which targets GPRC5D, has [a] similarly high response rate in the 70 to 80% range and [a] toxicity profile that does include cytokine release syndrome and [immune effector cell associated neurotoxicity syndrome] (ICANS), but at relatively low rates, especially of severe toxicity, and the long-term toxicities are less infection, but more dysgeusia and skin and nail toxicities as well as cytopenias.

All these agents are now available for use and are important additions to our armamentarium. In the future, we're probably going to see combination studies including either teclistamab or talquetamab with daratumumab. There's recent new data combining teclistamab with talquetamab, and interesting trials that are beginning combining both agents as well as other bispecific T-cell engagers that are in development, including cevostamab targeted against FcRH5, and these agents are being used by themselves and in combination with CAR-T cells in further studies.

I also gave a brief mention to a molecule that's not a bispecific T-cell engager, but which I find very exciting, called modakafusp [alfa], which is an anti-CD38 interferon fusion protein that directs interferon signaling to CD38-positive cells, including both multiple myeloma cells and immune cells that leads to direct myeloma cell cytotoxicity as well as immune stimulation.

We presented the results of our phase 1 trial of modakafusp at last year's ASH meeting, showing an impressive single agent response rate of 43%, as well as a response rate in BCMA-naive patients of 60% at the recommended Phase 2 dose of 1.5 milligrams per kilogram given every 4 weeks. The side effect profile of modakafusp includes cytopenias, including some severe neutropenia and thrombocytopenia that's generally manageable over time, as well as some low-grade infusion related reactions in this agent, which has a mechanism of action completely unrelated to all of our other anti-myeloma agents, is a particularly exciting development to them, and this agent which has a mechanism of action that's completely different from any other myeloma agent, I think will also be an exciting addition to myeloma therapy.

Source:

Vogl D. T Cell Engagers (Bispecifics) BCMA and Other Targets. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-21, 2023. New York, NY