Background <p>Teclistamab is a B&#xa0;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.</p> Objective <p>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.</p> Patients and Methods <p>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 (<i>C</i>_trough) 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 (&gt; 28 days).</p> Results <p>Median teclistamab serum concentrations were estimated to drop to levels comparable to the simulated SUD 2 median <i>C</i>_trough after 62 days and SUD 1 median <i>C</i>_trough 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.</p> Conclusions <p>These analyses suggest teclistamab can be safely restarted without repeat SUD for delays ≤&#xa0;62 days, and at SUD 2 for delays 63–111 days. For delays &gt; 111 days, both SUDs should be administered as instructed per label before resuming treatment at 1.5 mg/kg.</p> Clinical Trial Registration <p>NCT03145181 (phase 1, May 9, 2017); NCT04557098 (phase 2, September 21, 2020).</p>