Teclistamab Significantly Improves OS, PFS vs Standard Regimens in RRMM

Teclistamab (Tec) monotherapy demonstrated significant and clinically meaningful improvements in both progression-free survival (PFS) and overall survival (OS) compared with investigator's choice of pomalidomide, bortezomib, and dexamethasone (PVd) or carfilzomib and dexamethasone (Kd) in patients with relapsed/refractory multiple myeloma (RRMM) who had received one to three prior lines of therapy (LOTs), according to data from the phase 3 MajesTEC-9 trial (NCT05572515) presented at the 2026 ASCO Annual Meeting.^1,2

At a median follow-up of 17.3 months, Tec achieved a statistically significant and clinically meaningful improvement in the primary end point of PFS by independent review committee (IRC). The median PFS was not reached (NR) in the Tec arm vs 8.2 months with PVd/Kd (HR, 0.29; 95% CI, 0.23-0.38; P < .0001), representing a 71% reduction in the risk of disease progression or death. The estimated 18-month PFS rate was 69.8% with Tec vs 26.9% with PVd/Kd. PFS favored Tec consistently across all prespecified subgroups, including patients refractory to anti-CD38 monoclonal antibodies (HR, 0.32; 95% CI, 0.24-0.42), patients refractory to lenalidomide (HR, 0.30; 95% CI, 0.23-0.40), those with high-risk cytogenetics (HR, 0.27; 95% CI, 0.18-0.41), and patients with ISS stage III disease (HR, 0.46; 95% CI, 0.26-0.83).

Tec also demonstrated a significant OS benefit vs PVd/Kd. Median OS was NR in both arms; however, the estimated 18-month OS rate was 79.2% with Tec vs 68.6% with PVd/Kd (HR, 0.60; 95% CI, 0.43-0.83; P = .0020). This OS advantage was achieved despite more than two-thirds of PVd/Kd patients who initiated subsequent therapy receiving a bispecific antibody or CAR T-cell therapy.

“This is the second positive phase 3 study [along with MajesTEC-3 (NCT05083169)] to show a significant PFS and OS benefit in the second line setting and beyond with teclistamab-based therapy for patients with RRMM,” said presenting author Roberto Mina, MD, Winship CancerInstitute, Emory University, Atlanta, GA.

Response and Depth of Response

Tec demonstrated substantially higher overall response rates (ORRs) and deeper responses than PVd/Kd. The ORR was 84.5% (250/296) with Tec vs 54.2% (161/297) with PVd/Kd (odds ratio [OR], 4.62; 95% CI, 3.13-6.83; P < .0001). The rate of complete response (CR) or better (≥CR) was 65.9% with Tec vs 16.8% with PVd/Kd (OR, 10.42; 95% CI, 6.89-15.76; P < .0001), a fourfold difference. The rate of very good partial response or better (≥VGPR) was 80.1% vs 36.4%, respectively.

Responses with Tec were also more durable. The median duration of response (DOR) was NR (95% CI, 25.2-NE) with Tec vs 13.4 months (95% CI, 10.4-17.3) with PVd/Kd. The estimated 18-month DOR was 80.6% (95% CI, 74.1-85.5) with Tec vs 40.1% (95% CI, 30.8-49.1) with PVd/Kd.

Tec also drove markedly deeper responses at the molecular level. The MRD-negative ≥CR rate in the intent-to-treat (ITT) population was 38.5% with Tec vs 6.7% with PVd/Kd (OR, 8.56; 95% CI, 5.14-14.26). Among MRD-evaluable patients, the MRD-negative ≥CR rate was 86.4% with Tec (n = 132) vs 45.5% with PVd/Kd (n = 44; OR, 6.80; 95% CI, 3.05-15.16).

Patient-Reported Outcomes and Safety

Tec preserved health-related quality of life (HRQoL), significantly delaying time to worsening of multiple myeloma symptoms as measured by the MySlm-Q Total Symptom Score. Median time to worsening was NR (95% CI, 23.85-NE) with Tec vs 19.48 months (95% CI, 16.13-NE) with PVd/Kd (P < .0001; HR, 0.50; 95% CI, 0.36-0.71). The estimated 18-month event-free rate was 73.5% (95% CI, 66.5-79.2) with Tec vs 55.1% (95% CI, 45.2-64.0) with PVd/Kd.

The safety profile of Tec was consistent with its known profile.¹ Treatment-emergent adverse events (TEAEs) of any grade occurred in 99.7% of Tec-treated patients (n = 291) vs 97.9% with PVd/Kd (n = 283); grade 3/4 TEAEs occurred in 84.9% vs 76.3%, respectively. The most common hematologic TEAEs with Tec were neutropenia (any grade 62.5%; grade 3/4, 54.3%), anemia (37.8%; 17.9%), thrombocytopenia (27.5%; 10.7%), and lymphopenia (24.4%; 20.3%).

Cytokine release syndrome (CRS) occurred in 66.0% of Tec patients and was predominantly low grade: grade 1/2 in 48.8%/16.5%, grade 3 in 0.7%, and no grade 4/5 events. All CRS events resolved with no treatment discontinuations due to CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) was infrequent and generally low grade, occurring in grade 1/2 in 2.4%/1.4% and grade 3 in 0.3% of patients. Discontinuations due to TEAEs were 10.7% with Tec vs 13.1% with PVd/Kd, and grade 5 TEAEs occurred in 6.5% vs 3.5%, respectively.

Infections were common, occurring in 82.8% of Tec patients (grade 3/4, 41.6%; grade 5, 5.5%) vs 68.2% with PVd/Kd (grade 3/4, 29.0%; grade 5, 2.8%). The most frequent infections with Tec included upper respiratory tract infections (26.5%), pneumonia (22.0%), COVID-19 (15.5%), and nasopharyngitis (12.7%). Hypogammaglobulinemia was common, occurring in 69.1% of Tec patients vs 50.2% with PVd/Kd; among patients with fatal infections in the Tec arm, 5/16 had no immunoglobulin replacement therapy (IgRT) and 8/16 had a last IgG of less than 400 mg/dL, reinforcing the importance of diligent IgRT use and antimicrobial prophylaxis. Grade 3 or higher infections declined substantially after 6 months, from 33.0% in the first 6 months to below 10% thereafter, consistent with disease control following Tec-induced response.

Study Design and Patient Characteristics

MajesTEC-9 is a randomized, open-label, phase 3 trial enrolling patients with RRMM who had received 1 to 3 prior LOTs including an anti-CD38 monoclonal antibody and lenalidomide, with no prior BCMA-directed therapy. A total of 593 patients were randomized 1:1 between April 28, 2023 and April 3, 2025 to Tec (n = 296) or investigator's choice of PVd or Kd (n = 297; 69% Kd). Tec was administered subcutaneously with step-up dosing (0.06 mg/kg and 0.3 mg/kg) followed by 1.5 mg/kg weekly in cycle 1, then 3 mg/kg every 2 weeks in cycle 2, every 2 weeks in cycles 3-6, and every 4 weeks from cycle 7 onward (earlier if ≥VGPR). The primary end point was PFS per IRC; key secondary end points included ≥CR rate, OS, and MySlm-Q total symptom score.²

Baseline characteristics were well-balanced. Median age was 70 years (range, 34-85) in the Tec arm and 70 years (range, 36-86) in the PVd/Kd arm; 28.4% and 30.0% of patients were aged 75 years or older, respectively. High-risk cytogenetics were present in 35.7% of Tec patients and 35.1% of PVd/Kd patients. Soft-tissue plasmacytomas were present in 18.2% vs 21.9%.

The median number of prior LOTs was 2 (range, 1-3) in both arms. All patients had prior IMiD and anti-CD38 exposure; 79.1% of Tec patients were refractory to lenalidomide and 85.5% were refractory to any anti-CD38 agent. Approximately 75% of patients were double-refractory to an IMiD and anti-CD38 monoclonal antibody, and 34.5% were triple-refractory. Median treatment duration was 13.1 months with Tec vs 7.0 months with PVd/Kd, with 65.3% of Tec patients still on treatment at data cutoff vs 24.0% with PVd/Kd. AE-related discontinuations were similar between arms (10.7% vs 13.1%).

Together with MajesTEC-3, “These data support Tec-based therapy as a new standard in the second line and beyond across practice settings [in RRMM],” Mina said in his concluding remarks.

REFERENCES

1. Mina R, Touzeau C, Hungria V, et al. MajesTEC-9: a phase 3 randomized study of teclistamab monotherapy vs investigator's choice of pomalidomide, bortezomib, and dexamethasone or carfilzomib and dexamethasone (PVd/Kd) in patients with relapsed refractory multiple myeloma. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL.

2. Touzeau C, Mina R, Quach H, et al. Teclistamab in multiple myeloma with one to three previous lines of therapy. N Engl J Med. 2026;394(8):739-752.