How will bispecific antibodies fit into the multiple myeloma treatment paradigm?

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Amrita Y. Krishnan, MD: We are very excited about the results of teclistamab and talquetamab, the bispecific targeting antibodies. Currently, they are being studied in patients with very advanced myeloma who have failed anti-CD38 antibodies, IMiDs [immunomodulatory drugs]and IP [proteasome inhibitors]. Naturally, given these responses, given the tolerance of these drugs, there is interest in moving them earlier.

I could see them within 1-3 relapses. The question is would they be given as a single agent or in combination? Because we also have an ongoing study of daratumumab plus teclistamab and daratumumab plus talquetamab. In this first-relapse setting, we might use daratumumab plus 1 of these bispecific antibodies to see if we can achieve similar response rates, depth of response, and long progression-free survival.

Overall, bispecific antibodies are going to be moved earlier in the course of the disease, including first-line, either in first-line combination with daratumumab, or possibly after standard IMiD-PI induction and using the bispecific, for example, as a consolidation, perhaps instead of an autologous stem cell transplant in the future. Ultimately, the bispecifics are going to be displaced very early in the course of the disease. We still don’t know, for example, if you had a BCMA targeting agent, are you going to respond to BCMA CAR [chimeric antigen receptor] T cells. This is where the question becomes, which bispecific do you use first? If you’re concerned about that, maybe people would shift more to talquetamab, the GPRC5D-targeting agent, earlier and keep BCMA targeting for CAR T versus teclistamab. But as the data emerges, it will also become clearer to us in terms of the sequencing of these agents.

ASH [American Society of Hematology Annual Meeting] 2021 has shown us other new targets for myeloma. Among them were FcRH5 and a bispecific antibody, cevostamab, which was also studied in Phase 1 and presented by Suzanne Trudel on behalf of the study team. Similar to other bispecifics, it used gradual dosing to reduce the risk of cytokine release. As with other bispecifics, patients who were treated had extensive prior therapy and a median of 6 prior lines of therapy. Also interestingly, 13 patients in this study had prior bispecific antibodies and 28 had prior CAR T cells. We are seeing patients treated with other therapies involving T-cells participating in the cevostamab trial for the first time.

Overall, the drug seems well tolerated. The usual expected adverse events, including hematologic toxicity and cytokine release, occurred in approximately 80% of patients. We observed a 56% response rate at the target dose, with one-third of patients achieving a very good partial response or better with responses deepening over time. The data is a bit short in terms of the durability of responses, but the median duration of response is 11.5 months, which is certainly encouraging. The news for myeloma patients is that we now have multi-targeting bispecific antibodies. Additionally, we have shown that you can switch from one bispecific antibody to another bispecific antibody and still get responses.

Transcript edited for clarity.

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