Teclistamab is a B cell maturation antigen × CD3 bispecific antibody approved for relapsed/refractory multiple myeloma. Two step-up doses (SUDs) are used to mitigate the risk of cytokine release syndrome (CRS). For patients who experience dose delays, it is uncertain what length of delay necessitates repeat SUDs. We used modeling simulations and retrospective analysis of the phase 1/2 MajesTEC-1 study to optimize recommendations for repeat SUDs after teclistamab dose delay. Population pharmacokinetic modeling was used to simulate teclistamab serum concentrations after dose delays to assess the duration required to achieve levels comparable to estimated trough concentrations (Ctrough) following SUDs. Quantitative systems pharmacology modeling was used to simulate cytokine dynamics. Modeling-informed time windows were applied to a retrospective analysis of CRS data from MajesTEC-1 recommended phase 2 dose cohorts to further evaluate CRS incidence with prolonged dose delays (> 28 days). Median teclistamab serum concentrations were estimated to drop to levels comparable to the simulated SUD 2 median Ctrough after 62 days and SUD 1 median Ctrough after 111 days. Simulated cytokine peaks at treatment restart during weekly or biweekly dosing at these intervals were lower than those following the initial SUD. Retrospective analysis of clinical data revealed a low incidence of CRS (grade 1–2; 2/61 3.3%) upon resuming teclistamab as recommended following a dose delay. These analyses suggest teclistamab can be safely restarted without repeat SUD for delays ≤ 62 days, and at SUD 2 for delays 63–111 days. For delays > 111 days, both SUDs should be administered as instructed per label before resuming treatment at 1.5 mg/kg. NCT03145181 (phase 1, May 9, 2017); NCT04557098 (phase 2, September 21, 2020). Teclistamab is used to treat patients with multiple myeloma, a type of blood cancer, that has returned after prior treatment (relapsed) or that does not respond to other treatments (refractory). Patients treated with teclistamab first receive two lower doses (step-up doses) to reduce the risk of side effects, including cytokine release syndrome. Cytokine release syndrome is caused by the rapid release of immune-signaling proteins called cytokines into the bloodstream and can result in fever, low blood pressure, and low blood oxygen levels. After step-up dosing, patients are dosed with 1.5 mg/kg once weekly. Patients who achieve a complete response or better and maintain it for at least 6 months can switch to 1.5 mg/kg every other week dosing. Some patients may need to delay teclistamab dosing to help manage side effects or due to other circumstances. We used mathematical model-based simulations to estimate how dose delays would affect serum levels of teclistamab and cytokines; these models suggested that, following dose delays, teclistamab serum levels would be comparable to, and cytokine levels lower than, the levels estimated after step-up doses. Importantly, data from the MajesTEC-1 clinical trial showed that only two of the 61 patients with dosing delays of more than 28 days experienced cytokine release syndrome; all events were low severity. Overall, modeling results and clinical trial data supported an update of the recommendations for restarting teclistamab.
Cardé et al. (Thu,) studied this question.