Drug-resistant, true extramedullary myeloma (EMD) presents a major clinical challenge. This aggressive disease subtype is noncontiguous with the bone marrow and carries a high risk for relapse. Furthermore, historical outcomes with existing therapies are generally poor. However, the RedirecTT-1 Phase 2 study offers new hope. This research investigated an innovative dual-targeting approach with two bispecific antibodies. The regimen combines talquetamab and teclistamab as an Extramedullary Myeloma Treatment.
Dual-Targeting Immunotherapy: Mechanism and Design
Talquetamab is an antibody targeting G protein-coupled receptor family C group 5 member D (GPRC5D). Teclistamab targets B-cell maturation antigen (BCMA). Since both BCMA and GPRC5D are highly expressed on myeloma cells, combining these agents offers a dual-pronged attack. The Phase 2 study exclusively enrolled patients with drug-resistant EMD. Investigators primarily tracked overall response using functional imaging. Secondary objectives included the duration of response, progression-free survival (PFS), overall survival (OS), and safety. Consequently, the trial aimed to demonstrate superior efficacy in this difficult-to-treat patient population.
Unprecedented Efficacy in Extramedullary Myeloma Treatment
The RedirecTT-1 study enrolled and treated 90 patients. The median follow-up period spanned 12.6 months. The data demonstrated striking efficacy. Investigators reported an overall response in 79% of patients (95% CI, 69% to 87%). Moreover, the response proved durable. Specifically, 64% of responders maintained their response for at least 12 months. At the 12-month mark, the estimated PFS was 61%. Furthermore, the estimated OS reached 74%. These figures represent a significant improvement over single-agent therapy outcomes in EMD.
Safety Profile and Adverse Events
The dual-targeting regimen showed a high incidence of adverse events (AEs). Common AEs of any grade included oral symptoms like dysgeusia, dry mouth, and dysphagia (87%). Cytokine release syndrome (CRS) occurred in 78% of patients. Nonrash skin effects affected 69% of the cohort. Significantly, Grade 3 or 4 AEs, mostly hematologic events, affected 76% of patients. Therefore, clinicians must carefully manage the regimen’s toxicity. The rate of Grade 3 or 4 infection was 31%. Five deaths during follow-up were considered related to the study treatment. However, the safety profile was generally consistent with the known toxicities of each agent when used as a monotherapy.
Frequently Asked Questions
Q1: What is the primary finding of the RedirecTT-1 Phase 2 study?
The study found that 79% of patients with drug-resistant, true extramedullary myeloma had an overall response to the combination of talquetamab and teclistamab.
Q2: What are the primary targets of the two agents, talquetamab and teclistamab?
Talquetamab targets G protein-coupled receptor family C group 5 member D (GPRC5D), while teclistamab targets B-cell maturation antigen (BCMA).
Q3: What were the most common and serious adverse events observed in the trial?
The most common adverse events included oral symptoms like dysgeusia (taste changes) and dry mouth (87%), and cytokine release syndrome (78%). The incidence of Grade 3 or 4 infection was high at 31%.
References
- Kumar S et al. Dual Targeting of Extramedullary Myeloma with Talquetamab and Teclistamab. N Engl J Med. 2026 Jan 01. doi: 10.1056/NEJMoa2514752. PMID: 41358582.
- Kumar S. Dual-Targeting Immunotherapy Brings Unprecedented Responses to Extramedullary Disease. MediaMedic. 2025 Sep 01.
- Rampling R et al. Bispecific antibodies targeting BCMA, GPRC5D, and FcRH5 for multiple myeloma therapy: latest updates from ASCO 2023 Annual Meeting. J Hematol Oncol. 2023 Aug 3;16(1):92.