Background: Despite the advance in therapeutic options for patients with relapsed/refractory multiple myeloma (RRMM) over recent years, there remains a significant unmet medical need for new, well-tolerated therapies in earlier lines for patients who have previously received an anti-CD38 monoclonal antibody and lenalidomide. Teclistamab is the first B-cell maturation antigen (BCMA)-directed bispecific antibody approved for the treatment of triple class-exposed RRMM. Teclistamab redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells. MajesTEC-9 (NCT05572515) is a phase 3, randomized, open-label, multicenter study comparing teclistamab with investigator’s choice of pomalidomide, bortezomib, and dexamethasone (PVd) or carfilzomib and dexamethasone (Kd) in patients with RRMM. Methods: Patients aged ≥18 years with RRMM (International Myeloma Working Group [IMWG] criteria) must have evidence of progressive disease or failure to achieve a response to last line of therapy and an Eastern Cooperative Oncology Group performance status score of 0–2. All patients must have received 1–3 prior lines of therapy, including ≥2 consecutive cycles of an anti-CD38 monoclonal antibody and ≥2 consecutive cycles of lenalidomide. Those treated with prior BCMA-directed therapy will be excluded. Approximately 590 patients will be randomized 1:1 to receive either teclistamab (28-day cycles) or PVd (21-day cycles) or Kd (28-day cycles). Stratification factors include investigator’s choice of PVd or Kd, stage of disease, number of prior lines of therapy, and anti-CD38 monoclonal antibody refractory status. Treatment will continue until disease progression, death, intolerance, withdrawal of consent, or end of study, whichever occurs first. The primary endpoint is progression-free survival (IMWG 2016 criteria); secondary endpoints include overall response rate, duration of response, and overall survival. Adverse events (AEs) will be graded by Common Terminology Criteria for AEs v5.0; cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome will be graded by American Society for Transplantation and Cellular Therapy criteria. The study opened in January 2023 and enrollment is ongoing. Clinical trial information: NCT05572515.