Less Frequent Teclistamab Dosing in Responders: Modeling and Simulation Data from the Majestec-1 Study in Relapsed/Refractory Multiple Myeloma

Introduction: Teclistamab is the first approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody for the treatment of triple-class exposed relapsed/refractory multiple myeloma (RRMM), with weight-based dosing and the longest study follow-up of any bispecific antibody in MM. In the phase 1/2 MajesTEC-1 study (NCT03145181/NCT04557098) in patients with heavily pretreated RRMM, rapid, deep, and durable responses were observed over a median follow-up of 30.4 months, including in patients who switched to less frequent dosing schedules according to depth and duration of clinical response. Based on these results, teclistamab dosing at 1.5 mg/kg every other week (Q2W) was approved by the US Food and Drug Administration and European Medicines Agency in patients who achieved and maintained complete response (CR) or better for ≥6 months. Using population pharmacokinetics (PK), exposure-response (E-R), and quantitative systems pharmacology (QSP) approaches, this analysis assessed the PK and pharmacodynamics of teclistamab in patients who switched to less frequent teclistamab dosing, which supported the approval of the Q2W schedule in responders.

Methods: Patients enrolled in MajesTEC-1 received subcutaneous teclistamab at the recommended phase 2 dose of 1.5 mg/kg weekly (QW) after step-up dosing, with the option to switch to the Q2W schedule if they achieved a partial response or better after ≥4 cycles (phase 1) or ≥CR for ≥6 months (phase 2). Teclistamab PK following less frequent dosing (1.5 mg/kg Q2W) was assessed using a population PK approach. E-R analysis was performed for duration of response (DOR), progression-free survival (PFS), and overall survival (OS) based on individual estimated serum trough concentration (C_trough) after the first Q2W dose in the 63 patients who switched to the 1.5 mg/kg Q2W dosing schedule. A QSP model was used to generate a virtual RRMM population with sustained response for ≥6 cycles to estimate the impact of teclistamab dose switching (QW to Q2W) on TBE complex formation (simultaneous engagement of target antigen on MM cells [BCMA; T] and effector antigen on T cells [CD3; E] by the bispecific antibody [teclistamab; B]) and antitumor activity. Additionally, teclistamab PK metrics were estimated for the approved 1.5 mg/kg Q2W dosing schedule and 3 mg/kg monthly (Q4W) dosing based on simulation of the teclistamab population PK model.

Results: The median predicted teclistamab C_trough was lower after the first and fourth Q2W doses (14.4 and 11.7 µg/mL, respectively) than that prior to the first Q2W dose (20.4 µg/mL) but remained above the 90% maximal effective concentration (6.039 µg/mL). No statistically significant E-R relationship was observed for DOR, PFS, or OS in patients switching to Q2W dosing, suggesting that the range of exposure observed in the 63 patients who switched to Q2W dosing did not lead to a difference in maintenance of response. The QSP model estimated comparable TBE complex formation, tumor volume reduction, and DOR for responders who switched to Q2W vs those who remained on QW dosing. Based on PK simulations, teclistamab exposure (steady-state PK parameters [C_trough, maximum concentration, and area under the curve]) at the 3 mg/kg Q4W dose was estimated to be comparable with that of the 1.5 mg/kg Q2W dose.

Conclusions: These modeling and simulation results from the MajesTEC-1 study support the approved switch to teclistamab 1.5 mg/kg Q2W in patients who have maintained ≥CR for ≥6 months. Furthermore, results from the population PK model indicate that teclistamab PK at the approved 1.5 mg/kg Q2W dosing schedule is comparable with that at 3 mg/kg Q4W.

Guo:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Niu:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Cardé:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Wu:Janssen R&D (previous), Jazz Pharmaceuticals (current): Current Employment, Current equity holder in publicly-traded company, Ended employment in the past 24 months. Miao:Jazz Pharmaceuticals: Current Employment. Hanson:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Su:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Pérez Ruixo:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Vishwamitra:Johnson and Johnson Innovative Medicine: Current Employment, Current equity holder in publicly-traded company. Chastain:Janssen: Current Employment, Current holder of stock options in a privately-held company. Samtani:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Wang:JNJ Innovative Medicine: Current Employment. Haddish-Berhane:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company.