In the phase III MajesTEC-9 trial, monotherapy with the bispecific antibody teclistamab kept disease under control substantially longer and improved overall survival compared with investigator’s choice of pomalidomide/bortezomib/dexamethasone (PVd) or carfilzomib/dexamethasone (Kd) in patients with relapsed or refractory (R/R) multiple myeloma. However, the benefit came with more serious infections and other toxicities. The interim analysis was reported by Touzeau et al in The New England Journal of Medicine.
Study Details
The open-label, randomized trial was conducted at 162 sites across 24 countries. Eligible patients had received one to three prior lines of antimyeloma therapy, including an anti-CD38 monoclonal antibody and lenalidomide, and had experienced disease progression or had not responded to their most recent regimen. Previous B-cell maturation antigen–directed therapy was not permitted.
A total of 593 patients were randomly assigned to receive subcutaneous teclistamab with step-up dosing or the investigator’s choice of PVd or Kd. Antimicrobial prophylaxis was recommended according to institutional guidelines, and immune globulin replacement was recommended to maintain serum IgG levels of at least 400 mg/dL. The primary endpoint was progression-free survival as assessed by an independent review committee. Key secondary endpoints included complete response or better, overall survival, and time to worsening of symptoms.
Baseline characteristics were generally balanced between groups. The median age was 70 years, and about 29% of patients were aged 75 or older. Patients had received a median of two prior lines of therapy, and nearly three-quarters had disease refractory to both anti-CD38 therapy and an immunomodulatory drug.
Key Findings
At a median follow-up of 17.3 months, the estimated 18-month progression-free survival rate was 69.8% with teclistamab vs 26.9% with PVd or Kd (hazard ratio [HR] = 0.29, P < .001). Median progression-free survival had not yet been reached in the teclistamab group and was 8.2 months in the control group. The benefit was seen across all prespecified subgroups.
A complete response or better was achieved by 65.9% of patients receiving the bispecific antibody vs 16.8% of those receiving PVd or Kd (P < .001). The overall response rates were 84.5% and 54.2%, respectively. Median duration of response had not yet been reached with teclistamab and was 13.4 months with the control regimens.
The estimated 18-month overall survival rate was 79.2% in the teclistamab group vs 68.6% in the PVd or Kd group (HR = 0.60, P = .002). Median overall survival had not been reached in either group. Treatment with teclistamab also significantly delayed symptom worsening.
Safety
Grade 3 or 4 adverse events occurred in 84.9% of patients receiving the bispecific antibody and 76.3% of those receiving PVd or Kd. Serious adverse events occurred in 56.7% and 45.6%, respectively. Fatal adverse events occurred in 6.5% of patients receiving teclistamab and 3.5% of those receiving PVd or Kd; most were due to infection. Neutropenia was the most common grade 3 or 4 adverse event, occurring in 54.3% of patients treated with the bispecific antibody and 22.3% of those in the control group.
Cytokine-release syndrome occurred in 66% of patients in the teclistamab group and was mostly grade 1 or 2. Two patients had grade 3 cytokine-release syndrome, and no grade 4 or 5 cases were reported. Immune effector cell–associated neurotoxicity syndrome was reported in 4.1% of patients receiving teclistamab. Most cases were grade 1 or 2, although one grade 3 event led to treatment discontinuation.
Grade 3 or 4 infections occurred in 41.6% of patients receiving the bispecific antibody and 29% of those receiving PVd or Kd. Fatal infections occurred in 5.5% and 2.8%, respectively. The investigators emphasized the importance of infection monitoring, antimicrobial prophylaxis, and immune globulin replacement.
According to the investigators, the findings support moving teclistamab earlier in the treatment of relapsed multiple myeloma, including into the second-line setting, rather than reserving it for patients who have received many prior therapies. At the same time, the results underscore the need for careful infection prevention and monitoring.
“Adverse events were common; diligent infection prophylaxis and immune globulin replacement are critical for infection management, given the potential for serious infections,” they wrote. They added that results from MajesTEC-3 and MajesTEC-9 support teclistamab-based, glucocorticoid-sparing regimens as second-line and later treatment options across a range of practice settings.
Cyrille Touzeau, MD, PhD, of the Department of Hematology, University Hospital of Nantes, Nantes, France, is the corresponding author of the article in The New England Journal of Medicine.
DISCLOSURE: The study was supported by Johnson & Johnson. For full disclosures of the study authors, visit nejm.org.
