A Phase II Study Measuring MRD Negativity after Bispecific T-Cell Redirectors Talquetamab and Teclistamab Consolidation Used in Sequence As Part of First Line Treatment in Transplant Eligible Multiple Myeloma Patients (TALTEC), Nordic Myeloma Study Group

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Background Induction with CD-38 monoclonal antibody, proteasome inhibitor, immunomodulator and dexamethasone, and maintenance with lenalidomide are part of the standard treatment for transplant-eligible patients with newly diagnosed MM (NDMM). Most patients relapse and require several lines of treatment during their lifetime. Optimisation of treatment strategies with the aim of obtaining higher minimal residual disease (MRD) negativity and possibly cure remain the goals of research efforts. T-cell redirectors (TCR) to target GPRC5D (talquetamab) and to target BCMA (teclistamab) are new standard treatment options in the triple-class exposed, relapsed refractory MM (RRMM) patients. Sequentially targeting two surface proteins instead of one, may show better efficacy by overcoming a mechanism of resistance due to single target antigen loss. This study will evaluate efficacy and tolerability of sequenced TCRs as consolidation after first line induction treatment as potential replacement for high-dose melphalan and autologous stem cell transplantation (ASCT). Methods This is an open-label, multicentre, interventional phase II study in NDMM patients with measurable disease, eligible for high-dose therapy, with standard exclusion criteria. Fifty participants will be treated in seven centres in Denmark, Norway and Estonia. Due to exploratory nature of this study, descriptive statistics will be utilised. Participants will be evaluated by Revised International Staging System (R-ISS) and cytogenetics, standard risk or high risk as defined by presence of del 17p, t(4;14) and/or t(14;16), additional cytogenetic abnormalities t(14;20), gain/amp 1q21 and del 1p32 will be assessed. The study consists of three parts: Induction, Consolidation, and Follow-up. Induction will comprise of daratumumab, bortezomib, lenalidomide and dexamethasone (Dara-VRd) with stem cell collection. Consolidation Part I will include 6 cycles of talquetamab and Part II will include 6 cycles of teclistamab. Treatment will continue as Follow-up Phase according to standard of care. Participants may receive ASCT and lenalidomide maintenance or only lenalidomide maintenance. Treatment response will be evaluated by serum/urine electrophoresis; by serum/urine immunofixation, and bone marrow morphology and immunophenotyping when complete response (CR) / stringent CR (sCR) is suspected. Response assessments will be based on International Myeloma Working Group (IMWG) criteria as defined in the protocol. MRD will be evaluated by next generation sequencing (NGS) and [18F] fluorodeoxyglucose positron emission tomography computed tomography (FDG PET-CT) at protocol-defined timepoints. Participants' health related quality of life (QoL) and general well-being will be captured using three patient reported outcome measures: PRO-CTCAE, EORTC-QLQ-C30 and FACT-Cog. Aims Primary endpoint is to determine MRD negative complete response rate at a sensitivity level of 10-6 measured by NGS and FDG PET-CT after talquetamab and teclistamab consolidation therapy. Secondary endpoints are to evaluate proportion of participants achieving MRD negativity (10-6) after induction treatment, conversion from positive MRD to negative MRD (10-6) after talquetamab and teclistamab consolidation, sustained MRD negativity, overall response rate, overall survival, progression free survival, duration of response, time to next anti-myeloma treatment, safety and QoL during the treatment with TCRs. Exploratory endpoints will describe effects of induction therapy on the T-cell compartment defining biomarkers of an effective TCR treatment response; migration, clonal expansion and functional transition of T-cells, epigenetic changes of T-cell exhaustion, methylation status of resistant MM cells and detect proteomic signatures from MRD positive and MRD negative patients by mass-spectrometry. Conclusion The role of TCR in the treatment of transplant-eligible patients with NDMM needs to be explored. The TALTEC study assesses the safety and efficacy of sequential consolidation with talquetamab and teclistamab after D-VRd induction, which in the future may become an alternative to ASCT. The TALTEC study opened in June 2024 and is currently enrolling patients. The study is sponsored by North Estonia Medical Centre in collaboration with Janssen Pharmaceutica NV (EU CT 2023-508212-38-00; ClinicalTrial.gov NCT06505369).

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