Fixed-duration teclistamab and talquetamab for frail patients with newly diagnosed multiple myeloma: The EMN37 fitfix study

Abstract Background and Significance . Novel treatments have considerably improved survival of transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Still, the outcome of frail patients remains inferior, even with CD38 antibody-based, triple-class drug regimens. This can be partly explained by a high discontinuation rate due to toxicity, especially induced by lenalidomide and dexamethasone, whereas daratumumab is feasible. Several dose-adjusted lenalidomide and dexamethasone regimens have been proven to be more tolerable. However, continuous therapy is still required. Particularly in frail patients, the introduction of a treatment-free interval (TFI) is of interest. Treatment with the bispecific antibodies teclistamab and talquetamab has been shown to be efficacious in late-line therapy, with high response rates deepening over time, even leading to minimal residual disease (MRD) negativity. Of note, preliminary data on frail NDMM patients receiving teclistamab or talquetamab showed the treatment to be feasible. The combination of daratumumab with bispecific antibodies may lead to deeper and more durable responses that could enable a lenalidomide- and a dexamethasone-sparing regimen including a treatment-free interval (TFI) in the first-line therapy of frail NDMM patients. Therefore, we developed the EMN37 FITFIX, a multicenter, phase II study with two parallel cohorts assessing the combination of daratumumab with teclistamab (Tec-Dara) or talquetamab (Tal-Dara) in frail NDMM patients. Study Design and Methods NDMM patients who are frail according to the International Myeloma Working Group Frailty Index will be included in the study. A total of 150 patients is planned to be enrolled; 75 patients in each cohort. The primary objective will be to determine progression-free survival (PFS) at 18 months in patients treated with Tec-Dara or Tal-Dara. Secondary objectives will include safety and efficacy, including MRD negativity and OS, of the two combinations. Patients will be randomized to receive fixed-duration therapy (18 cycles) with Tec-Dara (cohort 1) or Tal-Dara (cohort 2). Following a TFI of at least 6 months, patients demonstrating progressive disease (PD) may reinitiate treatment with the doublet until PD or until treatment is no longer tolerated. Patients' randomization will ensure equal distribution of patient characteristics in the two cohorts. However, no formal comparison of efficacy or safety between Tec-Dara and Tal-Dara will be performed. To mitigate the risk of potential side effects, dose modifications and adequate supportive care are planned, including prophylactic tocilizumab administration and prophylactic intravenous immunoglobulin (IVIG) supplementation therapy. The study will be conducted in Italy (14 sites), the Netherlands (9), Spain (4), and Norway (2). The enrollment of the first patient is expected by the end of 2025, and enrollment completion in 2027. The updated status of the study will be presented at the meeting. The study is conducted by the European Myeloma Network (EMN), in collaboration with HOVON, NMSG, EMN Italy, and PETHEMA and in collaboration with and with the financial support of Janssen Pharmaceutica NV, a member of the Johnson & Johnson group of companies. This trial is registered with EU Clinical Trials Register (2024-520433-76-00).