MajesTEC-9: A phase 3 randomized study of teclistamab monotherapy vs investigator’s choice of pomalidomide, bortezomib, and dexamethasone or carfilzomib and dexamethasone (PVd/Kd) in patients (pts) with relapsed refractory multiple myeloma (RRMM).

Abstract

7507 Background: Triplet and quadruplet regimens have greatly improved outcomes in newly diagnosed multiple myeloma, yet a high unmet need remains for more effective, broadly accessible treatments for anti-CD38- and lenalidomide- (Len) exposed/refractory RRMM. Teclistamab (Tec) is the most widely used BCMA×CD3 BsAb in heavily pretreated RRMM, with improved outcomes in earlier lines of therapy (LOTs). In MajesTEC-3, the synergistic Tec-daratumumab combination significantly improved progression-free and overall survival (PFS/OS) as early as first relapse. MajesTEC-9 (NCT05572515) is the first phase 3 study of Tec monotherapy in pts with 1–3 prior LOTs. Methods: Pts with RRMM and 1–3 prior LOTs including anti-CD38 and Len were randomized 1:1 to receive 28-day cycles (C) of Tec (C1–2: 2 step-up doses then 1.5 mg/kg QW; C3–6: 3 mg/kg Q2W or Q4W depending on response; C7+: 3 mg/kg Q4W) or investigator’s choice of PVd/Kd (21/28-day C). Primary endpoint was PFS by IRC; secondary endpoints included OS, complete response or better (≥CR), and safety. Results: 593 pts were randomized (Tec, n=296; PVd/Kd, n=297). Median (range) age: 70 (34–86) yrs; number of prior LOTs: 2 (1–3); Len refractory: 80%; anti-CD38 refractory: 85%; refractory to last LOT: 92%. With 17.3-mo median follow-up, Tec significantly improved PFS vs PVd/Kd (HR, 0.29; 95% CI, 0.23–0.38; P <0.0001); mPFS: NR vs 8.2 mo; 18-mo PFS rate: 69.8% vs 26.9%. OS was significantly improved with Tec vs PVd/Kd (HR, 0.60; 95% CI, 0.43–0.83; P =0.0020). Of 174 PVd/Kd pts who received subsequent treatment, 68.4% received BsAb or CAR-T. PFS favored Tec across all prespecified subgroups, including anti-CD38-refractory pts and Len-refractory pts. ≥CR rate was significantly higher with Tec vs PVd/Kd (65.9% vs 16.8%; OR, 10.42; 95% CI, 6.89–15.76; P <0.0001). At data cutoff, 65.3% of pts remained on Tec vs 24.0% on PVd/Kd (safety set: Tec, n=291; PVd/Kd, n=283). TEAEs were similar for Tec and PVd/Kd (99.7% vs 97.9%). Grade (Gr) 3/4 TEAEs (84.9% vs 76.3%) and Gr 5 TEAEs (6.5% vs 3.5%) were higher with Tec vs PVd/Kd, noting the median treatment duration was nearly doubled with Tec (13.1 vs 7.0 mo). Treatment discontinuation due to TEAEs was lower with Tec vs PVd/Kd (10.7% vs 13.1%). Gr 3/4 infections were higher with Tec vs PVd/Kd (41.6% vs 29.0%). Any-onset Gr ≥3 infections decreased over time. CRS occurred in 66.0% of pts with Tec (Gr 1/2: 48.8%/16.5%) and ICANS in 4.1% (Gr 1/2: 2.4%/1.4%). Conclusions: Tec monotherapy significantly improved PFS/OS vs standard of care (SoC) in this high unmet need population. CRS and infections were managed with established protocols. Results of phase 3 studies support Tec-based regimens as a SoC as early as second line, across all treatment settings and regardless of prior anti-CD38/Len exposure. Clinical trial information: NCT05572515 .