The Phase 3 MajesTEC-3 trial, the first randomized study of bispecific antibody therapy in multiple myeloma, evaluated teclistamab plus daratumumab (Tec-Dara) versus standard-of-care triplet regimens (daratumumab with pomalidomide-dexamethasone or bortezomib-dexamethasone) in 587 patients with relapsed/refractory multiple myeloma after 1-3 prior lines of therapy. With 34.5 months median follow-up, Tec-Dara delivered transformative results with median progression-free survival not reached versus 18.1 months for standard therapy (hazard ratio 0.17, 95% CI 0.12-0.23, p less than 0.0001) and remarkable 36-month PFS rate of 83.4% versus 29.7%. The combination achieved significantly higher complete response rates (81.8% vs 32.1%), overall response rates (89.0% vs 75.3%), and MRD negativity at sensitivity of 1 in 100,000 (58.4% vs 17.1%, all p less than 0.0001), with unprecedented overall survival benefit showing 83.3% versus 65.0% at 36 months (hazard ratio 0.46, p less than 0.0001) and notably over 90% of patients alive at 6 months remaining alive at 30 months. Treatment was well-managed with comparable Grade 3/4 adverse event rates (95.1% vs 96.6%), cytokine release syndrome occurring in 60.1% (predominantly Grade 1-2), ICANS in only 1.1%, and infections decreasing over time with transition to quarterly dosing supported by prophylaxis protocols, establishing Tec-Dara as a new standard of care for relapsed/refractory multiple myeloma as early as first relapse.

Key Points:

• Unprecedented PFS Benefit: Median PFS not reached with Tec-Dara versus 18.1 months with standard therapy (HR 0.17, 95% CI 0.12-0.23, p less than 0.0001); 36-month PFS rates of 83.4% versus 29.7% represent an 83% reduction in progression or death risk
• Deep, Durable Responses: Complete response rates of 81.8% versus 32.1% (odds ratio 9.56, p less than 0.0001), overall response rates of 89.0% versus 75.3%, and MRD negativity rates of 58.4% versus 17.1% demonstrate superior depth of response across all measures
• Transformative Survival Benefit: Overall survival significantly favored Tec-Dara with 36-month OS rates of 83.3% versus 65.0% (HR 0.46, 95% CI 0.32-0.65, p less than 0.0001); over 90% of patients alive at 6 months remained alive at 30 months, indicating durable benefit once initial therapy period completed
• Universal Benefit Across Subgroups: PFS and OS benefits consistent across all prespecified subgroups including patients age 75+ years, lenalidomide-refractory, high-risk cytogenetics, 60%+ bone marrow plasma cells, soft-tissue plasmacytomas, and prior anti-CD38 exposure
• Extended Treatment Duration: Median treatment duration twice as long with Tec-Dara versus standard therapy (32.4 vs 16.1 months); 71.0% of Tec-Dara patients versus 28.3% standard therapy patients remained on study treatment at data cutoff
• Improved Quality of Life: Median time to worsening of myeloma symptoms not reached with Tec-Dara versus 39.9 months with standard therapy (HR 0.50, 95% CI 0.34-0.72, p=0.0002), demonstrating superior symptom control
• Manageable Safety Profile: Grade 3/4 treatment-emergent adverse events comparable between arms (95.1% vs 96.6%); Grade 3/4 infections occurred in 54.1% versus 43.4%, with new onset Grade 3+ infections decreasing over time coinciding with quarterly dosing and supported by antimicrobial and immunoglobulin prophylaxis
• Mild Immune-Related Toxicities: Cytokine release syndrome occurred in 60.1% (Grade 1: 44.2%, Grade 2: 15.9%), ICANS in only 1.1%, with low treatment discontinuation rates due to adverse events (4.6% vs 5.5%)
• Early-Line Population: Study enrolled patients with 1-3 prior lines (median 2), including lenalidomide-refractory patients (those with 1 prior line must have been lenalidomide-refractory), excluding only BCMA-directed therapy and anti-CD38 refractory patients
• Reduced Disease Deaths: Primary cause of death was progressive disease in only 4.6% of Tec-Dara patients versus 20.3% in standard therapy arm, demonstrating superior disease control

Conclusion:
The MajesTEC-3 Phase 3 trial establishes teclistamab plus daratumumab as a paradigm-shifting new standard of care for relapsed/refractory multiple myeloma, representing the first positive Phase 3 study of bispecific antibody therapy in this disease and delivering clinically remarkable results that fundamentally change treatment expectations as early as first relapse. The unprecedented 83% risk reduction in progression or death, with 83.4% of patients remaining progression-free at 3 years compared to 29.7% with standard triplets, combined with the transformative 54% reduction in death risk and 36-month overall survival of 83.3% versus 65.0%, establishes a new benchmark for efficacy in this setting that far exceeds historical standards. The striking finding that over 90% of patients who survived the initial 6-month treatment period remained alive at 30 months underscores the durability of benefit and suggests that Tec-Dara may fundamentally alter the natural history of myeloma for responders, while the 81.8% complete response rate and 58.4% MRD negativity rate at ultra-sensitive levels represent depths of response rarely achieved with conventional therapies in relapsed disease. Importantly, this superior efficacy came with a manageable and well-characterized safety profile, with cytokine release syndrome predominantly mild (60% Grade 1-2), ICANS rare (1.1%), and infections decreasing over time with the transition to quarterly dosing supported by established prophylaxis protocols that have been refined through extensive bispecific antibody experience. The consistent benefit across all patient subgroups, including traditionally challenging populations such as those age 75+, lenalidomide-refractory, and high-risk cytogenetics, demonstrates the broad applicability of this regimen, while the off-the-shelf availability eliminates manufacturing delays and access barriers associated with cellular therapies, positioning Tec-Dara as an immediately accessible, highly effective immunotherapy option that should be considered for virtually all eligible patients at first relapse, fundamentally changing the treatment landscape and raising the standard for what constitutes effective therapy in relapsed/refractory multiple myeloma.

Authors:
María-Victoria Mateos, Nizar Bahlis, Aurore Perrot, Ajay Nooka, Jin Lu, Charlotte Pawlyn, Roberto Mina, Gaston Caeiro, Alain Kentos, Vania Hungria, Donna Reece, Ting Niu, Anne Mylin, Charlotte Hansen, Raphael Teipel, Britta Besemer, Meletios Dimopoulos, Elena Zamagni, Satoshi Yoshihara, Kihyun Kim, Chang-Ki Min, Paulus Geerts, Elena Van Leeuwen-Segarceanu, Agata Tyczynska, Juan Luis Reguera, Magnus Johansson, Markus Hansson, Mehmet Turgut, Mark Grey, Surbhi Sidana, Paula Rodriguez-Otero, Joaquin Martinez-Lopez, Hamza Hashmi, Robin Carson, Rachel Kobos, Weili Sun, Kristen Lantz, Anne Seifert, Debbie Briseno-Toomey, Lisa O'Rourke, Maria Rubin, Diego Vieyra, Lijuan Kang, and Luciano Costa.

Presented at ASH 2025 (Abstract LBA-6).