Jeffrey Zonder, MD

Jeffrey Zonder, MD, professor of hematology and oncology at the Karmanos Cancer Institute at Wayne State University, discusses the efficacy results of a first-in-human trial of a bispecific monoclonal antibody in patients with relapsed/refractory multiple myeloma, which were presented at the 2021 American Society of Hematology Annual Meeting and Exposition.

The phase 1/2 trial (NCT03761108) is designed to investigate the safety, tolerability, and dose-limiting toxicity of REGN5458, a BCMAxCD3 bispecific antibody, in patients with at least triple-refractory multiple myeloma. Patients received 16 weekly infusions of REGN5458 followed by infusions every 2 weeks until disease progression.

Objective response rate (ORR) as measured with the International Myeloma Working Group (IMWG) criteria is a secondary end point in the phase 1 portion and a primary end point in the phase 2 portion of the trial. Minimum residual disease (MRD) rate according to IMWG criteria was another secondary end point.

According to Zonder, REGN5458 had an impressive ORR that was comparable to approved agents even in the dose-finding phase, with an ORR in 51% in all patients. Of those who responded to treatment, 92.6% had a very good partial response (VGPR) and 48.1% had a complete response (CR) or stringent CR. At the 96 mg and 200 mg dose levels, the response rate was 73.3%. Zonder says it was 75% in those who received the highest dose levels of 200 mg to 800 mg.

Of the 10 patients who were tested for MRD, 4 had reached a status of undetectable MRD, according to Zonder.

The study is currently recruiting for the phase 2 portion to further assess ORR and other outcomes including overall survival and progression-free survival for up to 5 years.

We saw early, deep, and durable responses with this bispecific antibody. The ORR for the whole study was 51%, which is impressive, because in a dose-finding study where you're starting at very low doses, you don't necessarily expect to see a particularly high response rate. Fifty-one percent compares pretty favorably to the products that are approved in the same space in multiple myeloma.

So it was 51% overall, [but] in the higher dose levels tested, the 200 to 800 mg dose levels, the ORR was 75%. The majority of those responses were pretty deep, with over half of patients achieving a VGPR or better. And that was actually also true—when you looked at responses across all dose levels, the rate of VGPR remained high, regardless of whether the response happened with low dose or at a higher dose. We saw CRs: 43% of the responses that we saw were CRs.

 There were a handful of patients that we did MRD testing on, which is ultra-sensitive testing, looking for extremely low levels of remaining disease. We had that data on 10 patients, and 4 patients actually achieved MRD negativity, which means we don't have a test that could detect the myeloma.

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Jeffrey Zonder, MD, discusses the efficacy results of a first-in-human trial of a bispecific monoclonal antibody in patients with relapsed/refractory multiple myeloma.

Deep Responses in Multiple Myeloma Seen With Bispecific Antibody

Jeffrey Zonder, MD, professor of hematology and oncology at the Karmanos Cancer Institute at Wayne State University, discusses the safety results of a first-in-human trial of a bispecific monoclonal antibody in patients with relapsed/refractory multiple myeloma, which was presented at the 2021 American Society of Hematology (ASH) Annual Meeting and Exposition.

The ongoing phase 1/2 trial (NCT03761108) is investigating the safety, tolerability, and dose-limiting toxicity of REGN5458, a BCMAxCD3 bispecific antibody, in patients with at least triple-refractory multiple myeloma. Patients received 16 weekly infusions of REGN5458 followed by infusions every 2 weeks until disease progression. Primary end points in the phase 1 portion were incidence of dose-limiting toxicities and incidence and severity of adverse events (AEs).

According to Zonder, REGN5458 was well tolerated by the 68 patients assessed in the trial. Common AEs included fatigue in 42.6%, cytokine release syndrome (CRS) in 38.2%, nausea in 32.4%, anemia in 32%, and neutropenia in 23%. While incidence of grade 3 or higher treatment-emergent AEs was 76.5%, there were no grade 3 or higher CRS or neurotoxicity events. Only 4.4% of patients had grade 2 CRS.

Zonder says that CRS rates were low compared with some other bispecific antibodies currently in clinical trials. It usually begins 1 day after administration of REGN5458. Notably, there was no link between the higher dosage of 200 mg and higher incidence of CRS, and the safety profile was consistent across dose levels.

Going forward, the phase 2 trial is currently recruiting using the recommended phase 2 dose regimen determined in phase 1. The primary end point for phase 2 is objective response rate by an independent review committee.

 So there are 2 parts to the results. The first, of course, is the safety data, and the drug was very well tolerated. We saw very manageable hematologic and non-hematologic toxicity; the most common hematologic AEs were anemia and neutropenia; anemia occurred in 32% of patients; neutropenia occurred in 23% of patients. And then for non-hematologic toxicities, they were all generally mild, very manageable, [and] the most common was fatigue.

The next most common was CRS, which is an infusion reaction that generally occurs early on with bispecific antibodies, and it's seen with basically all bispecific antibodies, and also with CAR [chimeric antigen receptor] T cells. And the incidence of that that we saw was actually low compared to what's seen with some other molecules that are being reported on at ASH. The overall incidence of cytokine release was 38%. Almost all of the cases were grade 1, there were 3 cases that were grade 2, and there were no grade 3 or worse.

And, importantly, in addition to the incidence only being 38%, there was no association with the dose level that was being tested. Cytokine release almost always happened within that first 2-week step-up dosing period, usually within 1 day of administration of the antibody. So it was a very predictable pattern of occurrence—and they were—which reduces the chances that there'll be some sort of surprise reaction, if you are administering this drug in patients in practice.

Jeffrey Zonder, MD, discusses the safety results of a first-in-human trial of a bispecific monoclonal antibody in patients with relapsed/refractory multiple myeloma.

Jeffrey Zonder, MD | Authors

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