Teclistamab, a Novel Bispecific Antibody, for the Treatment of Advanced Relapsed/Refractory Multiple Myeloma: Early Promising Results

Teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, is being studied in an ongoing, 2-part, phase 1 trial of 66 patients with relapsed/refractory multiple myeloma (RRMM). It is the first-in-human study of teclistamab and is designed to evaluate safety and antimyeloma activity. Part 1 of the study is focused on dose escalation to identify a recommended phase 2 dose, whereas part 2 is focused on dose expansion.

The study included 65 evaluable patients. They ranged in age from 24 to 82 years, with a median age of 64 years. Approximately 20% were aged ≥70 years. Approximately 30% of patients had International Staging System stage III disease and 30% had high-risk cytogenetics. Patients had been exposed to 2 to 14 prior therapies with a median of 6; however, patients could not have had previous exposure to a BMCA-targeted therapy. Nearly all patients were triple-class exposed, and 83% were triple-class refractory. Approximately 86% of patients were refractory to their last line of therapy, and 80% had prior transplant.

Teclistamab was administered at doses ranging from 38.4 mg/kg to 720 mg/kg. Initially patients received doses twice per week and were switched to weekly dosing with or without step-up dosing. Patients received 1 to 3 step-up doses prior to the first full dose on week 1. Approximately 52 patients have discontinued treatment; 41 patients had progressive disease, of which 27 died. Five patients discontinued due to an adverse event (AE), and 2 deaths were recorded as AEs unrelated to the study drug, one grade 5 respiratory failure and one as a result of COVID-19. Currently, 26 patients are receiving ongoing treatment. The most common AEs were cytokine release syndrome (CRS), neutropenia, thrombocytopenia, and anemia, affecting 56%, 45%, 40%, and 58% of patients, respectively. CRS generally occurred during the first step-up or full dose, and no patients discontinued therapy as a result of CRS. Grade ≥3 anemia and neutropenia affected 36% and 38% of patients, respectively. Infections affected 65% of patients, including 19% where they were considered treatment-related; 21% were grade ≥3. Six patients experienced neurotoxicity, with 2 neurotoxic events considered as grade ≥3. Two dose-limiting toxicities occurred, including one grade 4 delirium at a step-up dose of 20 mg/kg and one grade 4 thrombocytopenia at a full dose of 180 mg/kg.

The overall response rate (ORR) within the 38.4- to 180-mg/kg dose range was 30%, and the very good partial response (VGPR) rate was 25%. The ORR at the 270-mg/kg dose level was 67%, and the VGPR rate was 50%. The efficacy data for the 720-mg/kg dose are not mature. Four of 5 patients were minimal residual disease (MRD)-negative at a 10-6 level of sensitivity and 2 patients had a complete response (CR). Two of 2 evaluable patients maintained MRD-negativity for 5 months (VGPR) and 14 months (CR). The duration of response data suggest that responses deepen over time, and 16 of 21 patients have an ongoing response.

The pharmacokinetic data indicate that weekly dosing is sufficient, and intermittent dosing may be a viable option. Step-up dosing allowed for modulation of cytokine production and transient decreases in peripheral T-cell counts, while maintaining T-cell activation at full doses.

Overall, treatment with teclistamab was shown to be safe across all doses with response rates increasing with higher doses. The dose-escalation and expansion phases of the study are ongoing.

Reference

  • Abstract and Presentation S206. EHA 2020. June 12, 2020. A phase 1 study of teclistamab, a humanized B cell maturation antigen (BCMA) x CD3 bispecific antibody, for the treatment of relapsed and/or refractory multiple myeloma (RRMM).

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