Analysis of Repeat Step-up Dosing and Cytokine Release Syndrome Events Following Prolonged Dosing Intervals of Teclistamab in the Phase 1/2 Majestec-1 Study

Introduction: Teclistamab is the first approved B-cell maturation antigen × CD3 bispecific antibody for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma (MM), with weight-based dosing and the longest study follow-up data of any bispecific antibody in MM. Teclistamab demonstrated rapid, deep, and durable responses in the pivotal phase 1/2 MajesTEC-1 study (NCT03145181/NCT04557098). After 2 step-up doses (SUD) to mitigate the risk of cytokine release syndrome (CRS), teclistamab is dosed QW with the option to transition to Q2W dosing based on response. Prolonged dosing intervals (>28 days) may result from delayed dosing due to adverse events (AEs), changes in dosing frequency, or other reasons. Serum teclistamab concentrations after prolonged dosing intervals, compared with those after SUD, have been used to inform whether SUD needs to be repeated. Here, we report a retrospective clinical assessment of repeat SUD and the impact on CRS following teclistamab dosing intervals >28 days in MajesTEC-1 informed by a population PK (popPK) modeling approach. Methods: Eligible patients received teclistamab at the recommended phase 2 dose (RP2D; 1.5 mg/kg subcutaneous QW, preceded by SUD 1 [0.06 mg/kg] and SUD 2 [0.3 mg/kg]). A previously described popPK model was used to simulate teclistamab serum concentrations following prolonged dosing intervals and to evaluate time to reach levels similar to the estimated trough concentrations (Ctrough) achieved after SUD 1 and SUD 2 administration. PopPK estimations were then used to inform a retrospective analysis of clinical data with prolonged dosing intervals, repeat SUD, and CRS events. Results: PopPK modeling showed that following 1.5 mg/kg QW and Q2W doses at steady state, estimated median teclistamab serum concentrations after dosing intervals of 62 days and 111 days were around Ctrough of SUD 2 and SUD 1, respectively. To inform a PK-based rationale for the timing of repeat SUD, these intervals were applied to retrospective MajesTEC-1 clinical data at >28-62 days, ≥63-111 days, and ≥112 days. Of the 165 patients who received teclistamab at the RP2D as of Aug 22, 2023, 61 patients had a total of 128 dosing intervals >28 days. Fifty-two patients had 102 dosing intervals >28-62 days, 78.0% of whom did not repeat SUD when restarting teclistamab. Fifteen patients had 18 dosing intervals ≥63-111 days; most of these patients repeated SUD 2 only (50.0% of intervals) or SUD 1 and SUD 2 (38.9% of intervals). Seven patients had 8 dosing intervals ≥112 days, all of whom either repeated SUD 2 only (50.0% of intervals) or SUD 1 and SUD 2 (50.0% of intervals). Two of the 61 patients with intervals >28 days had a total of 3 CRS events occurring after intervals of >28-62 days. One patient had delayed the start of cycle 2, repeated both SUDs, and had 1 event of grade 2 CRS after repeat SUD 2. The second patient had delayed cycle 6, repeated both SUDs, and had 2 events of grade 1 CRS after repeat SUD 2 and the subsequent full treatment dose. Conclusions: Incidence of CRS upon restarting teclistamab after dosing intervals of >28 days was low. Two of 61 patients experienced CRS (grade 1-2) with restarting after >28-62-day dosing intervals with repeat SUD. Among 61 patients with prolonged dosing intervals, 59 did not experience CRS on restart. These retrospective clinical analyses show that teclistamab treatment can be restarted with minimal risk of CRS after prolonged treatment interruption when repeat SUD is implemented for interruptions of >62 days. These analyses were successfully informed using popPK modeling to recommend the appropriate intervals to repeat SUD when restarting teclistamab treatment, consistent with the European Medicines Agency-approved product label: if maintenance doses are delayed 8-62 days, continue teclistamab at the last maintenance dose and schedule; if delayed 63-111 days, restart teclistamab at SUD 2; if delayed >111 days, restart teclistamab at SUD 1.