Pooled Efficacy and Safety of Teclistamab in 217 Patients with Triple-Class Exposed Relapsed/Refractory Multiple Myeloma from 3 Registrational Clinical Studies

Introduction: Teclistamab (tec) is the first approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody (BsAb) for the treatment of patients (pts) with triple-class exposed relapsed/refractory multiple myeloma (RRMM), with weight-based dosing and the longest study follow-up of any BsAb in MM. Tec has demonstrated rapid, deep, and durable responses with a manageable safety profile in 3 clinical studies with registrational intent: the pivotal MajesTEC-1 cohort (NCT03145181/NCT04557098), the China cohort of MajesTEC-1, and the Japan phase 1/2 study (NCT04696809). Here, we present pooled data of 217 pts treated with tec at the recommended phase 2 dose (RP2D) in this globally representative population. Methods: Pts had RRMM and received ≥3 prior lines of therapy (LOT), including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Pts received tec at the RP2D (1.5 mg/kg subcutaneous [SC] once weekly preceded by step-up dosing with the option to switch to less frequent dosing if responses were maintained); study population included 165 pts from the pivotal MajesTEC-1 cohort (enrolled Mar 2020-Aug 2021, 30.4-month [mo] median follow-up), 26 pts from the China cohort of MajesTEC-1 (enrolled Dec 2021-Sep 2022, 15.3-mo median follow-up), and 26 pts from phase 2 of the Japan study (enrolled Jul 2022-Mar 2023, 14.3-mo median follow-up). The primary endpoint was overall response rate (ORR). Key secondary endpoints were complete response or better (≥CR), very good partial response or better (≥VGPR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety graded per Common Terminology Criteria for Adverse Events v4.03. Results: Of 217 pts, 53.9% were male, median age was 65 years (range, 33−84), median weight was 69.4 kg (range, 37.5-138.9), median prior LOT was 5 (range, 2-14), 29.0% had high-risk cytogenetics, and 18.9% had extramedullary disease. At 29.2 mo median follow-up, ORR (95% CI) was 66.4% (59.7-72.6), with 49.8% and 63.6% achieving ≥CR and ≥VGPR, respectively. Median DOR, PFS, and OS were 26.7, 15.1, and 26.3 mo, respectively. For pts with ≥CR (n=108), estimated 18-mo DOR, PFS, and OS were 76.3%, 77.7%, and 91.2%, respectively; medians were not reached. Eighty-eight pts (65, 10, and 13 in the pivotal, China, and Japan cohorts, respectively) switched to less frequent dosing. The most frequent treatment-emergent adverse events (TEAEs) were cytokine release syndrome, cytopenias, and infections, which are consistent with the known profile of anti-BCMA BsAbs. Infections occurred in 80.6% of pts (53.0% grade 3/4), including COVID-19 in 31.3% (22.6% grade 3/4). COVID-19 was the most common primary cause for grade 5 AEs (8.3%), all from the pivotal cohort that enrolled during the first peak of the COVID-19 pandemic. Discontinuations occurred in 9/217 (4.1%) pts due to TEAEs, with 5/9 due to infections. In the 52 pts who were enrolled after the pivotal MajesTEC-1 cohort (China cohort and Japan study), baseline features were generally similar except for weight (median, 58.0 kg [range, 37.5-86.4]). At 14.9 mo median follow-up, ORR (95% CI) was 76.9% (63.2-87.5), with 61.5% and 76.9% achieving ≥CR and ≥VGPR, respectively. Estimated 18-mo DOR, PFS, and OS were 73.0%, 61.1%, and 74.9%, respectively; medians were not reached. For pts with ≥CR (n=32), estimated 18-mo DOR, PFS, and OS were 81.3%, 81.8%, and 93.1%, respectively; medians were not reached. Of pts with evidence of hypogammaglobulinemia, 91.3% (42/46) received ≥1 dose of intravenous or SC immunoglobulin (IVIg/SCIg) in this Asian cohort. There were no discontinuations due to infections; 1 pt had grade 5 pneumonia that occurred in the setting of COVID-19 in the China cohort. Conclusions: In the largest clinical cohort to date treated with tec at the RP2D (N=217), with a median follow-up of 29.2 mo, tec consistently demonstrated deep and durable responses, including an ORR of 66.4%, ≥CR of 49.8%, and median DOR of 26.7 mo, with a manageable safety profile. Evolving evidence, awareness, and International Myeloma Working Group guidance on infection management strategies, such as IVIg/SCIg use with tec, were reflected in the more recent China and Japan cohorts, which translated into higher response rates, improved OS and PFS, and a lower frequency of fatal infections compared with the initial pivotal MajesTEC-1 cohort (n=165).