Relapsed or refractory multiple myeloma (RRMM) is difficult to treat, but true Extramedullary Myeloma (EMM) presents an even greater challenge with a very poor prognosis. EMM involves plasmacytomas noncontiguous with the bone marrow, meaning the malignant plasma cells form tumors in soft tissues outside the bone. Historically, existing therapies have struggled against this highly aggressive subtype. Consequently, there is an urgent and significant unmet need for new therapeutic options. A new Phase 2 study, part of the RedirecTT-1 trial, investigated an innovative dual-targeting immunotherapy combination for these high-risk patients.
The dual-targeting strategy combines two first-in-class bispecific T-cell engagers (TCEs). Specifically, investigators used talquetamab and teclistamab. Talquetamab targets the G protein-coupled receptor family C group 5 member D (GPRC5D) on myeloma cells, while teclistamab targets B-cell maturation antigen (BCMA). Both GPRC5D and BCMA are promising immunotherapy targets highly expressed on multiple myeloma cells. Therefore, this dual-antigen approach aims to overcome mechanisms of resistance, such as antigen escape, by engaging two separate targets.
Dual-Targeting Efficacy in Extramedullary Myeloma
This phase 2 study enrolled a total of 90 patients who had drug-resistant, true EMM, with a median follow-up of 12.6 months. The combination therapy delivered a high overall response rate (ORR) of 79% (95% CI, 69 to 87). Furthermore, this response rate surpasses the historical ORR seen with either monotherapy in EMD patients. Patients achieved deep and durable responses. The percentage of responders maintaining a response for at least 12 months was 64% (95% CI, 48 to 76). Importantly, the estimated 12-month progression-free survival (PFS) was 61% (95% CI, 50 to 71), which is a significant outcome, since no prior therapy in EMM had shown a PFS exceeding one year. Overall survival (OS) at 12 months was 74% (95% CI, 63 to 83).
Managing Toxicity: Key Safety Observations
The dual-targeting regimen’s high efficacy accompanies a notable toxicity profile. Common adverse events (AEs) of any grade were consistent with the known profiles of each agent when used alone. Oral symptoms, including dysgeusia, dry mouth, and dysphagia, affected 87% of patients. Cytokine release syndrome (CRS) occurred in 78% of patients, and nonrash skin effects were observed in 69%. Clinicians must therefore manage these common side effects proactively. Moreover, grade 3 or 4 AEs, mostly hematologic events, affected 76% of patients. Grade 3 or 4 infection was a significant concern, occurring in 31% of the patients. Five of the 10 deaths that occurred during follow-up were considered treatment-related, and five were due to infection. Only 6% of patients discontinued one or both agents due to a nonfatal adverse event.
Frequently Asked Questions
Q1: What antigens do talquetamab and teclistamab target?
Talquetamab targets GPRC5D (G protein-coupled receptor family C group 5 member D), and teclistamab targets BCMA (B-cell maturation antigen). Both bispecific antibodies also target CD3 on T cells to redirect them against the myeloma cells.
Q2: How does the efficacy compare to previous Extramedullary Myeloma treatments?
The study demonstrated an impressive 79% overall response rate and a one-year progression-free survival rate of 61%. This significantly surpasses the historical efficacy of monotherapy agents or other prior treatments for this high-risk subtype, which typically show a PFS of less than one year.
Q3: What were the most common adverse events?
The most common adverse events of any grade were oral symptoms (87%), cytokine release syndrome (78%), and nonrash skin effects (69%). Furthermore, a high incidence of Grade 3 or 4 events was noted, primarily hematologic events and infections.
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.
- Bispecific T-cell engagers in multiple myeloma: efficacy, safety, and resistance mechanisms. Blood. 2025 Jan 16;145(3):213-228. doi: 10.1182/blood.2024026365.
- Talquetamab, Teclistamab Combo Yields Deep, Durable Responses for RRMM with EMD. Oncology News Central. June 26, 2025.