Phase 2 Study of Teclistamab-Based Induction Regimens in Patients with Transplant-Eligible (TE) Newly Diagnosed Multiple Myeloma (NDMM): Results from the GMMG-HD10/DSMM-XX (MajesTEC-5) Trial

Introduction: Teclistamab (Tec), a first-in-class B-cell maturation antigen × CD3 bispecific antibody, has demonstrated deep and durable responses as monotherapy and in combination regimens for the treatment of MM, leading to its approval for triple-class exposed relapsed or refractory MM. Daratumumab, a CD38-targeting monoclonal antibody, has shown deep and durable responses and prolonged survival outcomes in combination with lenalidomide and dexamethasone (DRd) and in combination with bortezomib plus lenalidomide and dexamethasone (DVRd), in patients with NDMM. The addition of Tec to these regimens aims at eradicating MM cells early to achieve long-term disease-free survival. MajesTEC-5 is a multi-cohort, phase 2 study evaluating Tec-based regimens in patients with TE NDMM. Here, we report the combined outcomes of the induction therapy phase of TE NDMM treatment in 3 study cohorts who received Tec-DRd or Tec-DVRd.

Methods: Patients aged 18-70 years with TE NDMM received Tec-DRd (Arms A, A1) or Tec-DVRd (Arm B) induction therapy. Patients received subcutaneous (SC) Tec in Cycles 1-6; in Cycle 1 only, patients received step-up doses of 0.06 and 0.3 mg/kg on Day 2 and 4 followed by treatment doses of 1.5 mg/kg on Days 8 and 15. In Cycles 2+, Tec 1.5 mg/kg was given QW in Arm A and 3.0 mg/kg Q4W in Arms A1 and B. SC daratumumab (1800 mg) was administered QW in Cycles 1-2 and Q2W in Cycles 3-6. Lenalidomide (25 mg) was given orally on Days 1-21 from Cycle 2+ and dexamethasone (20 mg) was given orally or intravenously on Days 1-2, 8-9, 15-16, and 22-23 of Cycles 1-2. Patients in the Tec-DVRd cohort also received SC bortezomib (1.3 mg/m²) QW in Cycles 1-6. Per protocol, the use of intravenous immunoglobulin therapy was advised to maintain serum IgG levels of ≥4 g/L. Primary endpoints were adverse event (AE) and serious AE rates in each cohort; secondary endpoints included response rates and minimal residual disease (MRD)–negativity rates (10^–5 threshold; next generation flow cytometry). First post-treatment MRD assessment per protocol was planned following completion of Cycle 3.

Results: A total of 49 patients were enrolled in Arms A (Tec-DRd, n=10; first dose December 2022), A1 (Tec-DRd, n=20; first dose October 2023), and B (Tec-DVRd, n=19; first dose October 2023). In the combined population, 8 (16.3%) patients were aged ≥65 years, 31 (63.3%) were male, 49 (100%) were Caucasian, and 47 (95.9%) had an ECOG PS score of 0-1. Two (4.1%) patients discontinued all study treatment due to refusal of further treatment. Three (6.1%) patients discontinued lenalidomide and no patients discontinued Tec or daratumumab. At data cut-off, median (range) duration of induction study treatment was 2.6 (0.03-7.66) months; median relative dose intensity was 99.3% for Tec, 92.4% for daratumumab, 87.2% for lenalidomide, and 83.1% for bortezomib.

Of the 36 patients who completed Cycle 3, 35 had MRD assessments and all achieved MRD-negativity (10^–5). In the 10 patients who thereafter completed Cycle 6 (Arm A only), all maintained MRD negativity. Among the 23 patients who completed stem cell mobilization, median stem cell yield was 8.7 × 10⁶/kg; 10 (43.5%) patients received plerixafor. Grade 3/4 treatment-emergent AEs (TEAEs) occurring in ≥10% of patients were lymphopenia (38.8%), neutropenia (28.6%), leukopenia (12.2%), increased lipase (10.2%), and increased gamma-glutamyltransferase (10.2%). Grade 3/4 infections occurred in 13 (26.5%) patients; serious TEAEs occurred in 23 (46.9%) patients, most commonly (≥10%) due to pyrexia (10.2%). One patient (2.0%) reported Grade 3 pancreatitis. No TEAEs led to study treatment discontinuation or death. A total of 32 (65.3%) patients experienced cytokine release syndrome (CRS) events, all were Grade 1/2 (Grade 1, n=26; Grade 2, n=6). No patient experienced immune effector cell-associated neurotoxicity syndrome (ICANS).

Updated data with longer follow-up across the 3 individual cohorts will be presented.

Conclusions: In summary, Tec combined with DRd and DVRd as induction therapy demonstrated manageable safety profiles and unprecedented clinical efficacy in patients with TE NDMM. Of the patients with MRD assessment at data cut-off, all achieved MRD-negativity (10^–5) by the first MRD assessment. Additionally, stem cell mobilization was feasible with Tec-DRd and Tec-DVRd.