Phase 3 Study of Teclistamab (Tec) in Combination with Lenalidomide (Len) and Tec Alone Versus Len Alone in Newly Diagnosed Multiple Myeloma (NDMM) As Maintenance Therapy Following Autologous Stem Cell Transplantation (ASCT): Safety Run-in (SRI) Results from the Majestec-4/EMN30 Trial

Introduction: Len maintenance after ASCT has significant progression-free and overall survival benefits and is considered standard-of-care for transplant-eligible NDMM. However, patients (pts) eventually relapse, supporting the need for novel maintenance strategies to improve outcomes. Tec, a first-in-class B-cell maturation antigen × CD3 bispecific antibody, demonstrated deep and durable responses in multiple myeloma (MM), leading to its approval for triple-class exposed relapsed and refractory MM. Based on preclinical results, Tec and Len may have synergistic antimyeloma effects. MajesTEC-4/EMN30 is a multicenter, randomized, open-label, Phase 3 study evaluating Tec-Len, Tec, and Len maintenance therapy in NDMM after induction and ASCT, ± consolidation. Here, we report initial SRI results. Methods: Eligible pts were aged ≥18 y, had NDMM (per International Myeloma Working Group [IMWG] criteria), received 4-6 cycles of 3- or 4-drug induction that included a proteasome inhibitor and/or an immunomodulatory drug ± an anti-CD38 antibody and a single or tandem ASCT ± consolidation, and achieved a partial response or better per IMWG 2016 response criteria. Three cohorts at different Tec dose frequencies were evaluated: Cohort 1 (Tec-Len) with Tec dosing at 1.5 mg/kg QW for 2 cycles (C), followed by 3 mg/kg Q2W in C3-6, and 3 mg/kg Q4W in C7+; Cohort 2 (Tec-Len) with Tec dosing at 1.5 mg/kg on Days 8 and 15 in C1, followed by 3 mg/kg Q4W in C2+; and Cohort 3 (Tec) dosing at 1.5 mg/kg on Days 8 and 15 in C1, followed by 3 mg/kg Q4W in C2+. All pts received the same inpatient Tec step-up schedule in C1 (0.06 mg/kg; 0.3 mg/kg). Len 10 mg QD in C2-4 (if tolerated, 15 mg thereafter) was given in Tec-Len cohorts. Treatment duration was 2 y for all pts; in Tec-Len cohorts, Tec was stopped after 13 cycles of treatment if complete response or better (≥CR) was achieved. Adverse events (AEs) were graded per Common Terminology Criteria for Adverse Events v5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per American Society for Transplantation and Cellular Therapy guidelines. Investigator-assessed response was based on IMWG 2016 criteria. Results: Across 3 cohorts, 94 pts were enrolled (Cohort 1, n=32; Cohort 2, n=32; Cohort 3, n=30). At a median follow-up of 14.4, 5.0, and 4.9 mo, 97% of pts in each cohort (n=31, 31, 29, respectively) remained on treatment. Baseline characteristics were generally balanced between cohorts with a median age of 58-59 y. Pts in Cohort 1, 2, and 3 had received a median of 15, 6, and 6 maintenance cycles, respectively. Neutropenia and infections were the most common Grade 3/4 treatment-emergent AEs (TEAEs). Compared with Cohort 1, the cumulative incidence of any grade and Grade 3/4 neutropenia at 4 mo showed a decreased trend in Cohorts 2 and 3 with less frequent Tec dosing (Cohort 1: any grade/Grade 3/4 incidence, 69%/66%; Cohort 2: 44%/41%; Cohort 3: 37%/28%). A similar trend was observed for all grade infections with less frequent Tec dosing (Cohort 1: 78%; Cohort 2: 63%; Cohort 3: 61%). Among 68/94 (72.3%) pts who had any grade hypogammaglobulinemia, 63/68 (92.6%) received ≥1 dose of IVIg. The overall CRS rate was 43.6%, with 6.4% Grade 2 and no high-grade events. The CRS rate following the first treatment dose of Tec (1.5 mg/kg) was low at 7.4%. No ICANS were reported. TEAEs led to treatment discontinuations in 2 pts (1 each in Cohorts 2 and 3) and death in 1 pt (Cohort 2; due to COVID-19 during C1, prior to the start of Len). In Cohort 1, all 28 pts with MRD assessments at 12 mo were in MRD negative CR. Among MRD positive pts at study entry, 10 (100%) converted to MRD negative CR during treatment. Among 16 pts who had Conclusions: Overall, Tec-Len and Tec can be safely administered as maintenance therapy following ASCT in NDMM. Cohorts 2 and 3 showed a trend for improved early safety outcomes with less frequent Tec dosing compared with Cohort 1. Tec-Len demonstrated deepening of responses and 100% MRD negative CR rate at 12 mo in Cohort 1 evaluable pts. These data informed the randomized part of MajesTEC-4/EMN30, which is actively enrolling.

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