First-in-Human Study of AMG 420, an Anti-BCMA Bispecific T-Cell Engager (BiTE®), for Relapsed or Refractory Multiple Myeloma

In this first-in-human study, up to 5 cycles of AMG 420 were given every 6 weeks until disease progression, toxicity, or consent withdrawal. Five more cycles could be given for benefit. Single-patient cohorts—1 patient receiving 0.2 to 1.6 µg/day—were followed by cohorts of 3 to 6 patients receiving 3.2 to 800 µg/day of AMG 420.

Eligible patients had relapsed or refractory multiple myeloma (RRMM) that progressed after ≥2 lines of therapy, including a proteasome inhibitor and immunomodulators. Excluded were plasma cell leukemia, extramedullary relapse, central nervous system involvement, and prior to autologous stem-cell transplant.

Minimal residual disease (MRD) was defined for this study as <1 tumor cell/10–4 bone marrow cells per flow cytometry using antibodies to cytIgλ, cytIgκ, CD19, CD56 or CD138, CD38, and CD45. 

As of April 2019, 42 patients received AMG 420 (0.2-800 µg/day). Their median age was 65 years and median multiple myeloma duration was 5.2 years. They had received a median of 4 prior therapies.

Patients discontinued for disease progression (n = 25), adverse events (AEs; n = 7, including 3 dose-limiting toxicities), death (4), completed 10 cycles (3), and consent (1). Patients were treated for a mean of 2.8 (± 2.9) cycles of AMG 420. Serious AEs (n = 20; 48%) occurring in >1 patient were infections (14) and polyneuropathy (2). Treatment-related serious AEs included the 2 cases of grade 3 peripheral polyneuropathy and 1 case of grade 3 edema. There were 2 deaths from AEs, acute respiratory distress and fulminant hepatitis; neither was related to treatment. Grade 2 to 3 cytokine release syndrome was seen in 3 patients. No anti–AMG 420 antibodies were detected.

In this study, 800 µg/day of AMG 420 was determined to not be tolerable since 2 of 3 patients had dose-limiting toxicities, grade 3 cytokine release syndrome, and grade 3 polyneuropathy. Both events required hospitalization and subsequently resolved. There also was 1 grade 3 dose-limiting toxicity of polyneuropathy among the 10 patients receiving 400 µg/day, which also resolved.

At 400 µg/day, there were 5 MRD-negative complete responses (CRs), 1 very good partial response (VGPR), and 1 partial response (PR), for a response rate of 7 of 10 (70%). As of the April 2019 data cutoff, responses had lasted for 5.8 to 13.6 months. Two patients continued receiving treatment. Overall, there were 13 of 42 (31%) responders to AMG 420, including 6 MRD-negative CRs, 3 CRs, 2 VGPRs, 2 PRs. Median time to response was 1 month, with 11 of 13 patients responding during the first cycle.

In this first-in-human study, AMG 420, a short half-life BiTE molecule that targets BCMA and CD3, showed encouraging evidence of activity in patients with RRMM. Other than 1 dose-limiting toxicity of polyneuropathy at 400 µg/day, no major toxicities were observed with 400 µg/day. This dose is being investigated further. 

Abstract OAB-025: Einsele H, Duell J, Zugmaier G, et al. The Anti-BCMA Bispecific T-Cell Engager (BiTE®) Molecule AMG 420 Induced MRD Negative Complete Responses in R/R Multiple Myeloma in an FIH Study

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