Higher Teclistamab Step-up Dosing in Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Results from the Majestec-1 Trial
Authors: Matous Jeffrey V , van de Donk Niels W.C.J. , Oriol Albert , Garfall Alfred L. , Rodríguez-Otero Paula , Chalopin Thomas , Rosinol Dachs Laura , Uttervall Katarina , Mateos Maria- Victoria , Trancucci Danielle , Cardé Natalia Quijano , Hodin Caroline , Stephenson Tara , Zuppa Athena , Chastain Katherine , Karlin Lionel 
Published: December 2024

Introduction: Teclistamab, a first-in-class T-cell redirecting bispecific antibody targeting CD3 and B-cell maturation antigen, has demonstrated deep and durable responses in multiple myeloma, leading to its approval for the treatment of triple-class exposed RRMM. Cytokine release syndrome (CRS) is a common adverse event (AE) among patients (pts) receiving T-cell redirecting therapies. In the phase 1/2, single-arm MajesTEC-1 study, step-up doses (SUDs; 0.06 and 0.3 mg/kg, 2-4 days between each dose) were implemented to mitigate the risk of severe CRS. CRS was reported in 72% of pts treated at the recommended phase 2 dose (RP2D), nearly all Grade 1/2, and 24% experienced CRS after the first full treatment dose. To confine CRS events to earlier dosing, higher SUDs were evaluated. We report the impact of higher SUDs on CRS in exploratory phase 1 cohorts from MajesTEC-1.

Methods: Eligible pts had RRMM and were intolerant to or progressed on available established therapies. Pts received higher SUDs in 2 cohorts: pts in Cohort 22 received doses of 0.1 and 0.5 mg/kg and pts in Cohort 23 received doses of 0.2 and 0.7 mg/kg (2-4 days between each dose). All pts then received 1.5 mg/kg on Days 1, 8, and 15 of Cycle 1 followed by 3 mg/kg Q4W in subsequent cycles. CRS was graded per Lee criteria (Lee 2014) and converted to ASTCT in order to compare with the RP2D. Serum samples were collected to assess teclistamab pharmacokinetics following higher SUDs.

Results: A total of 21 pts were enrolled in Cohort 22 (n=10) and Cohort 23 (n=11). Median age was 69 and 70 years, respectively. Median time from MM diagnosis to first treatment dose was 5.5 years in both cohorts. Extramedullary disease was present in 1 (10.0%) pt in Cohort 22 and 1 (9.1%) pt in Cohort 23. Cohort 22 included 2 (20.0%) pts with ≥60% plasma cells in bone marrow, while Cohort 23 included 1 (10.0%) pt. High risk cytogenetic abnormalities were present in 4 (40.0%) pts in Cohort 22 and 1 (12.5%) pt in Cohort 23.

At a median follow-up of 8.6 months for Cohort 22 and 3.2 months for Cohort 23, CRS was reported in 8 (80.0%) and 8 (72.7%) pts, respectively, all of which were Grade 1/2. CRS events occurred primarily during SUDs, and only 1 pt experienced CRS following the first full treatment dose (Grade 1, Cohort 23). Cohort 22 had 1 Grade 2 event after SUD2; Cohort 23 had 2 Grade 2 events after SUD1, with no further Grade 2 events after SUD2. Median onset of CRS from the last teclistamab injection was 2 days in Cohort 22 and 3 days in Cohort 23, with a median duration of 2 days in both cohorts. All CRS events resolved and none led to treatment discontinuation. Among pts who experienced CRS events, all pts in Cohort 22 received supportive treatment, including 5 (62.5%) pts who received tocilizumab (no pts received corticosteroids). In Cohort 23, 7 pts (87.5%) received supportive treatment, including 4 (50.0%) who received tocilizumab and 1 (12.5%) who received corticosteroids. The pt who experienced CRS after the first full treatment dose received corticosteroids but did not receive tocilizumab.

A total of 6 (60.0%) pts in Cohort 22 and 6 (54.5%) pts in Cohort 23 experienced Grade 3/4 treatment-emergent AEs; the most common (≥20%) were neutropenia (Cohort 22: 3 [30.0%] pts; Cohort 23: 2 [18.2%] pts), anemia (Cohort 22: 2 [20.0%] pts; Cohort 23: 2 [18.2%] pts), and leukopenia (Cohort 22: 3 [30.0%] pts; Cohort 23: 0 pts). No cases of ICANS were reported; 1 pt in Cohort 22 experienced Grade 1 neurotoxicity (dysgeusia, headache, dizziness). Dose-limiting toxicities were reported in 3 pts in Cohort 22 (Escherichia bacteremia, neutropenia, and bone pain) and 0 pts in Cohort 23. One death was reported in Cohort 22 (cerebral hemorrhage related to progressive disease). Based on limited preliminary data, median maximal serum teclistamab concentrations following SUD administration were slightly higher in these higher SUD cohorts compared to the approved SUDs (0.06 and 0.3 mg/kg).

Conclusions: With the higher SUDs of teclistamab, most CRS events occurred prior to the first full treatment dose (1.5 mg/kg), with only 1 pt experiencing Grade 1 CRS after C1D1. CRS events were manageable (all Grade 1/2) and did not lead to any treatment discontinuations. In Cohort 23, both Grade 2 CRS events were confined to SUD1. These results suggest the higher SUDs may improve the pt experience with teclistamab by shortening the time needed for close monitoring of CRS.