Abstract
AMG 420, a bispecific T-cell engager targeting B-cell maturation antigen, may be a safe and effective treatment for patients with relapsed/refractory multiple myeloma. In a phase I trial, the drug elicited a response in 31% of patients and was associated with relatively manageable side effects.
AMG 420 (Amgen), a bispecific T-cell engager (BiTE), may be safe and effective for patients with relapsed/refractory multiple myeloma, according to preliminary results presented at the 2018 American Society of Hematology Annual Meeting in San Diego, CA, in December. In a phase I trial, the drug elicited responses in a high percentage of patients and was associated with relatively manageable side effects.
AMG 420 consists of light chains derived from two antibodies: One targets B-cell maturation antigen (BCMA) on multiple myeloma cells and the other binds to CD3 on T cells. “The idea is that the bispecific will engage with the myeloma cells and bring in T cells” that then kill the cancer cells, says Max Topp, MD, of the University Hospital of Würzburg in Germany, who presented the results. Topp notes that blinatumomab (Blincyto; Amgen), a BiTE targeting CD19 on acute lymphoblastic leukemia cells, is already approved.
To investigate AMG 420, Topp and his colleagues tested the drug at doses from 6.5 to 800 μg/day in 42 patients with multiple myeloma who had received a median of four prior therapies. Overall, 13 patients (31%) responded to the drug, with seven complete responses and six partial remissions; seven out of 10 patients (70%) treated at 400 μg/day exhibited a response. Sixteen patients (38%) developed cytokine release syndrome, with most cases classified as grade 1, and 12 patients (29%) developed infections related to treatment, with nine cases classified as grade 3 or higher.
“I do definitely see this as a potential emerging option for fourth- and fifth-line patients,” Topp says. He adds that because AMG 420 is an off-the-shelf therapy, patients can be treated right away, whereas those treated with personalized BCMA-targeting CAR T-cell therapies such as bb2121 (Bluebird Bio) and JCARH125 (Celgene) must have their T cells extracted, modified, and reinfused. Researchers plan to start a phase II trial of AMG 420 at 400 μg/day later this year.
“What we saw from AMG 420 was the first evidence that using a bispecific, or BiTE-based, approach would have efficacy in myeloma—it's proof of principle to me that this kind of approach can work,” says Sagar Lonial, MD, of the Winship Cancer Institute at Emory University School of Medicine in Atlanta, GA, who was not involved in the trial.
Suzanne Lentzsch, MD, PhD, of Columbia University Medical Center in New York, NY, who was also not connected to the trial, was impressed by the results. She points out that AMG 420 had a lower rate of cytokine release syndrome than BCMA-targeting CAR T cells, potentially making it more suitable for older patients. However, she has concerns about the relatively high infection rate, which may result from needing to administer AMG 420 via continuous infusion. Lentzsch is involved in an ongoing phase I trial of AMG 701 (Amgen), a BiTE with a similar mechanism as AMG 420, but a longer half-life that allows it to be given weekly.
“BCMA probably does represent the best target we have in myeloma,” Lonial says, adding that all three BCMA-targeting approaches being developed'BiTEs, CAR T cells, and antibody–drug conjugates—are likely to become valuable therapies. “I don't think only one of them is going to win—I suspect we're going to have, hopefully, more than one way to get at BCMA.” –Catherine Caruso
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