Teclistamab monotherapy significantly extends progression-free and overall survival compared with standard chemotherapy combinations in patients with relapsed or refractory multiple myeloma (RRMM), a phase 3 trial has found.

Findings from the MajesTEC-9 trial, evaluating the BCMA- and CD3-targeting bispecific antibody, were presented at the 2026 ASCO Annual Meeting in Chicago and published concurrently in the New England Journal of Medicine [link here].

The study compared teclistamab against investigators’ choice of pomalidomide, bortezomib and dexamethasone (PVd) or carfilzomib and dexamethasone (Kd) in 296 patients from 24 countries, including Australia, who had previously received one to three lines of therapy including an anti-CD38 monoclonal antibody and lenalidomide.

Key results

Associate Professor Roberto Mina, from the Winship Cancer Institute of Emory University in Atlanta, told the meeting MajesTEC-9 was the second positive phase 3 study to show a survival benefit with teclistamab-based therapy compared with standard of care in patients with RRMM.

He noted the PFS benefit was consistent across all clinically relevant subgroups, including patients refractory to lenalidomide, patients refractory to daratumumab, and those with high-risk disease.

Notably, 79% of patients in the teclistamab arm were alive at 18 months compared with 69% in the PVd/Kd arm, despite two-thirds of control patients going on to receive a T-cell redirecting therapy, either a bispecific antibody or CAR-T, in a subsequent line.

The trial included patients with a median age of 70 years, with around 29% aged 75 or over. High-risk features were common: 15% had ISS stage III disease, 35% had high-risk cytogenetics and 20% had extramedullary disease. Half had previously undergone autologous stem cell transplant.

Safety

Grade 3 or 4 adverse events occurred in 84.9% of teclistamab recipients and 76.3% of PVd or Kd recipients. Infections of grade 3 or higher were more frequent with teclistamab (41.6% vs 29.0%), predominantly upper respiratory tract infections and pneumonia.

Cytokine release syndrome, mostly grade 1 or 2, occurred in 66.0% of teclistamab recipients. Immune effector cell-associated neurotoxicity syndrome occurred in 4.1%.

Treatment-related deaths occurred in 6.5% of the teclistamab arm and 3.5% of the control arm, mostly from infections and hypogammaglobulinemia, and predominantly within the first six months.

Associate Professor Mina said most patients who died had not received immunoglobulin replacement therapy and many had hypogammaglobulinemia at the time of the event.

“This really reinforces the recommendation that the guidelines have put out about the use of immunoglobulin replacement therapy, to be very rigorous with that even at the beginning of treatment, and the importance of antimicrobial prophylaxis,” he said.

Professor Hang Quach from St Vincent’s Hospital Melbourne was among the investigators.

Context

In an NEJM editorial [link here], Professor María-Victoria Mateos from the University Hospital of Salamanca said MajesTEC-9 represented a pivotal step forward, particularly given the changing biology of early relapse in an era where most patients now receive proteasome inhibitors, immunomodulatory drugs and anti-CD38 antibodies as frontline therapy.

She noted that findings should be interpreted alongside the MajesTEC-3 trial, in which the combination of teclistamab plus daratumumab produced outstanding results, though approximately only 5% of those patients had prior anti-CD38 exposure.

“For patients who were eligible for the MajesTEC-3 trial, combination strategies may be preferred, whereas the MajesTEC-9 trial addresses a more challenging and increasingly common population for which effective interventions are needed,” she wrote.

Professor Mateos said the increasingly crowded therapeutic landscape, which now included multiple BCMA-targeted strategies such as CAR-T therapies, bispecific antibodies and antibody-drug conjugates, meant treatment selection would likely depend more on patient characteristics, access and sequencing than on intrinsic differences in efficacy.

MajesTEC-9 was funded by Johnson & Johnson.