Background. Teclistamab is a subcutaneous bispecific IgG4 antibody targeting BCMA on myeloma cells and CD3 on T cells, enabling T-cell–mediated cytotoxicity. Daratumumab is an anti-CD38 monoclonal antibody used in combination with standard agents. The current standard-of-care regimens in elderly patients with newly diagnosed multiple myeloma (NDMM) include the triplet DRd (MAIA) or quadruplet combinations of anti-CD38 antibodies with RVd. These regimens show remarkable efficacy with 32% to 61% MRD negativity at 10-5 and prolonged PFS. However, further optimization of treatment strategies remains a key focus of research efforts for patients with MM. Recently, the combination of teclistamab and daratumumab (Tec-Dara) has demonstrated strong efficacy in the relapsed setting with deep responses. Most trials currently evaluate triplet combinations of BCMA-directed bispecific antibodies with daratumumab and lenalidomide (MajesTEC-7 and MagnetisMM-6). The IFM2021-01 trial is a phase 2 study evaluating the doublets teclistamab-daratumumab (Cohort A) and teclistamab-lenalidomide (Cohort B) in frontline transplant-ineligible patients. Here, we report Cohort A (Tec-Dara), an “all-antibody-based” frontline treatment for patients with NDMM.

Methods. IFM2021-01 is an open-label, multicenter, single-arm phase 2 study enrolling patients aged ≥65 years with NDMM, ineligible for high-dose chemotherapy with autologous stem cell transplantation. Teclistamab was administered subcutaneously with step-up doses (0.06 mg/kg and 0.3 mg/kg) followed by 1.5 mg/kg treatment doses on Days 8 and 15 of Cycle 1. Maintenance dosing continued at 3 mg/kg every 4 weeks thereafter. Daratumumab SC (1800 mg) was given weekly in Cycles 1–2, every 2 weeks in Cycles 3–6, and every 4 weeks thereafter. The primary endpoint was the rate of very good partial response (VGPR) or better after 4 cycles per IMWG criteria. Secondary endpoints include overall response rate (ORR), complete response (CR) rate, MRD-negativity by NGS at 10-5 and 10-6, progression-free survival (PFS), and overall survival (OS). Safety was assessed per CTCAE v5.0. The protocol was approved by the French Agency (ANSM) and an external Ethics Committee. The study is conducted by Lille University Hospital and the IFM French Myeloma group in collaboration and with financial support from Janssen Pharmaceutica NV, a member of the Johnson & Johnson group of companies (EU CT 2024-514101-65; ClinicalTrial.gov NCT05572229).

Results. A total of 37 patients were enrolled in Cohort A. The median age was 73 years, with 11 (30%) patients above the age of 75 years, and 20 (54%) were female. Overall, 33 (89%) patients had ECOG 0 or 1 and 4 (11%) had ECOG 2; 16 (44%) patients were fit, 12 (33%) were intermediate, and 8 (22%) were frail based on the IMWG frailty score. A total of 25 (68%) patients had standard-risk cytogenetics and 12 (32%) had high-risk features (according to the new IMS/IMWG consensus). The primary endpoint - rate of VGPR or better after 4 cycles was 78%. At data cut-off (08/07/2025), the median follow-up time was 7.6 months (13.1 months for 18 patients; 6 months for 19 patients). The ORR at best response was 100%, with 36 (97%) achieving VGPR or better. The MRD negativity rate at 6 months by NGS at 10-6 was 51% in the intention-to-treat population and 100% in the 21 evaluable patients (16 were not evaluable for MRD at 6 months due to missing or invalid samples). Median DOR, PFS, and OS were not reached. No progression or death occurred during the follow up. The rates of PFS, and OS were 100% each. Regarding safety, 28 (76%) of patients had grade ≥3 adverse events (AEs) and 8 (22%) had serious AEs (SAE) – with no grade 5 AEs. The rate of grade ≥3 hematologic AEs was 46%, with 27% neutropenia. Overall, 5 (14%) patients had grade ≥3 infections. All patients received immunoglobulin replacement therapy at inception of treatment. Treatment discontinuation due to AEs occurred in 1 (3%) patient.

Conclusions. IFM2021-01 Cohort A demonstrates that an “all-antibody–based” doublet regimen of teclistamab and daratumumab is highly effective and well-tolerated in elderly patients with NDMM, with deep responses, high MRD negativity, and a favorable safety profile.

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2025
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