Teclistamab Plus Daratumumab Versus Standard Daratumumab-Based Proteasome Inhibitor Combinations for Relapsed/Refractory Multiple Myeloma: An Inverse Probability of Treatment Weighting Analysis

In the phase 3 MajesTEC-3 study (NCT05083169), teclistamab with daratumumab (Tec-Dara) significantly improved progression-free and overall survival (PFS/OS) versus investigator’s choice of standard-of-care daratumumab/pomalidomide/dexamethasone (DPd) or daratumumab/bortezomib/dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma (RRMM) after 1–3 prior lines of therapy (pLOTs). Of the DPd/DVd patients, 85.5% ( n = 253/296) of whom were refractory to an immunomodulatory drug (IMiD), 90.7% ( n = 263/290) received IMiD-based DPd and 9.3% ( n = 27/290) received proteasome inhibitor (PI)-based DVd. We leveraged individual patient-level data (IPD) from other pivotal trials to estimate and further substantiate comparative outcomes of Tec-Dara versus standard-of-care PI-based RRMM regimens: daratumumab/carfilzomib/dexamethasone (DKd; no current comparative evidence) and DVd (to support MajesTEC-3 findings). Inverse probability of treatment weighting (IPTW) was used to adjust for intertrial differences. IPD were available from MajesTEC-3 (Tec-Dara), CANDOR (NCT03158688; DKd), and CASTOR (NCT02136134; DVd). Patient characteristic imbalances were adjusted for using IPTW. Outcomes included PFS, OS, overall response rate (ORR), very good partial response or better (≥VGPR), and complete response or better (≥CR). Hazard ratios (HRs) and risk ratios (RRs) with 95% CIs were estimated. Following adjustment, key baseline characteristics were well balanced across cohorts. Tec-Dara was significantly associated with improved PFS versus DKd (HR 0.22; 95% CI 0.15–0.33; P < 0.001) and DVd (HR 0.11; 95% CI 0.07–0.17; P < 0.001); Tec-Dara was also significantly associated with improved OS (DKd: HR 0.40; 95% CI 0.26–0.61; DVd: HR 0.24; 95% CI 0.14–0.40; both P < 0.001). Patients demonstrated higher rates of ORR, ≥VGPR, and ≥CR with Tec-Dara versus DKd (RR 1.11, 1.33, and 2.84 respectively) and DVd (RR 1.10, 2.20, and 5.17). Tec-Dara demonstrated consistent PFS and OS benefits and deeper levels of response over DKd and DVd in patients with RRMM and 1–3 pLOTs. These results further support Tec-Dara as a new standard-of-care regimen for RRMM as early as second-line treatment.