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Background: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma., Methods: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better)., Results: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2)., Conclusions: Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: There is a need for novel therapies for relapsed or refractory multiple myeloma, and B-cell maturation antigen (BCMA) is a validated target. Teclistamab is a bispecific antibody that binds BCMA and CD3 to redirect T cells to multiple myeloma cells. The aim of the MajesTEC-1 study was to evaluate the safety, tolerability, and preliminary efficacy of teclistamab in patients with relapsed or refractory multiple myeloma., Methods: This open-label, single-arm, phase 1 study enrolled patients with multiple myeloma who were relapsed, refractory, or intolerant to established therapies. Teclistamab was administered intravenously (range 0·3-19·2 μg/kg [once every 2 weeks] or 19·2-720 μg/kg [once per week]) or subcutaneously (range 80-3000 μg/kg [once per week]) in different cohorts, with step-up dosing for 38·4 μg/kg or higher doses. The primary objectives were to identify the recommended phase 2 dose (part one) and characterise teclistamab safety and tolerability at the recommended phase 2 dose (part two). Safety was assessed in all patients treated with at least one dose of teclistamab. Efficacy was analysed in response-evaluable patients (ie, patients who received at least one dose of teclistamab and had at least one post-baseline response evaluation). This ongoing trial is registered with ClinicalTrials.gov, NCT03145181., Findings: Between June 8, 2017, and March 29, 2021, 219 patients were screened for study inclusion, and 157 patients (median six previous therapy lines) were enrolled and received at least one dose of teclistamab (intravenous n=84; subcutaneous n=73). 40 patients were administered the recommended phase 2 dose, identified as once per week subcutaneous administration of teclistamab at 1500 μg/kg, after 60 μg/kg and 300 μg/kg step-up doses (median follow-up 6·1 months, IQR 3·6-8·2). There were no dose-limiting toxicities at the recommended phase 2 dose in part one. In the 40 patients treated at the recommended phase 2 dose, the most common treatment-emergent adverse events were cytokine release syndrome in 28 (70%; all grade 1 or 2 events) and neutropenia in 26 (65%) patients (grade 3 or 4 in 16 [40%]). The overall response rate in response-evaluable patients treated at the recommended phase 2 dose (n=40) was 65% (95% CI 48-79); 58% achieved a very good partial response or better. At the recommended phase 2 dose, the median duration of response was not reached. 22 (85%) of 26 responders were alive and continuing treatment after 7·1 months' median follow-up (IQR 5·1-9·1). At the recommended phase 2 dose, teclistamab exposure was maintained above target exposure levels, and consistent T-cell activation was reported., Interpretation: Teclistamab is a novel treatment approach for relapsed or refractory multiple myeloma. At the recommended phase 2 dose, teclistamab showed promising efficacy, with durable responses that deepened over time, and was well tolerated, supporting further clinical development., Funding: Janssen Research & Development., Competing Interests: Declaration of interests SZU received grant support from Bristol Myers Squibb and Pharmacyclics; grant support and consulting fees from Amgen, Celgene, Sanofi, Seattle Genetics, Janssen, Takeda, SkylineDx, Merck, and GlaxoSmithKline; and consulting fees from AbbVie, Karyopharm, and Mundipharma. ALG received grant support from Novartis and CRISPR Therapeutics; grant support and consulting fees from Janssen and Tmunity Therapeutics; consulting fees from GlaxoSmithKline and Surface Oncology; and holds a pending patent (15/757,123) with royalties paid, and pending patents (16/768,260 and 16/746,459) licensed to Novartis. NWCJvdD received grant support and advisory board fees from Bristol Myers Squibb/Celgene, Janssen, Novartis, and Amgen; advisory board fees from Takeda, Servier, Bayer, Adaptive Biotechnologies, Roche, GlaxoSmithKline, and Sanofi; and grant support from Cellectis. JFS-M received consulting and advisory board fees from Amgen, Celgene, Takeda, Bristol Myers Squibb, Merck, Sharp & Dohme, Novartis, Sanofi, Janssen, Roche, AbbVie, GlaxoSmithKline, Karyopharm Therapeutics, and Secura Bio. AO received consulting fees from Amgen, Celgene, Sanofi, Janssen, and GlaxoSmithKline. LR received consulting fees from Amgen, Celgene, Sanofi, Janssen, and Takeda. AC received grant support and consulting fees from Amgen, Janssen, Celgene, Novartis Pharmaceuticals, Seattle Genetics, Millennium/Takeda; consulting fees from Bristol Myers Squibb, Karyopharm, Sanofi, Oncopeptides, Antengene, GlaxoSmithKline, Secura Bio, Shattuck Labs; and grant support from Pharmacyclics. MB received payment for speaker bureaus from Amgen, Bristol Myers Squibb, and Takeda; served as a consultant for Sanofi Genzyme; and received grant support from Janssen, MedImmune, Takeda, Prothena, Bristol Myers Squibb/Celgene, Cerecor, and Celularity. LK received consulting fees from Janssen-Cilag, Celgene, Amgen, Takeda, and GlaxoSmithKline. LP, RV, SG, TS, YE, JI, JDG, and AB are employed by Janssen. M-VM received consulting fees from Janssen-Cilag, GlaxoSmithKline, Celgene, Amgen, Regeneron, Pfizer, AbbVie, Takeda, Roche/Genentech, and Adaptive Biotechnologies. AK received consulting fees from Janssen Oncology, GlaxoSmithKline, Celgene, Adaptive Biotechnologies, Regeneron, Pfizer, Bristol-Myers Squib, Takeda, and Sutro Biopharma. HN and LB declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)