Data from the safety run-in (SRI) of the phase 3 MajesTEC-4/EMN30 trial indicates that maintenance therapy with teclistamab-cqyv (Tecvayli; Tec), either alone or in combination with lenalidomide (Len; Revlimid), shows robust preliminary efficacy and safety in patients with newly diagnosed multiple myeloma (NDMM) after autologous stem cell transplantation (ASCT). The findings were presented at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH).
Key Efficacy Findings
The SRI comprised three maintenance cohorts: two receiving Tec-Len (cohorts 1 and 2) and one receiving Tec monotherapy (cohort 3). The primary difference between cohorts 1 and 2 was the intensity of teclistamab dosing. Notably, the minimal residual disease (MRD)-negativity rate (10-5 sensitivity) reached 100% among evaluable patients across all three cohorts, measured at 12 months for cohort 1 and at 6 months for cohorts 2 and 3. According to Elena Zamagni MD, PhD, associate professor of hematology at the Bologna University, Italy, "Unprecedented efficacy was observed, with all evaluable patients achieving MRD negativity."
Responses to treatment deepened during maintenance in all three cohorts. In cohort 1, all patients achieved a complete remission (CR) or better (9.4% CR, 90.6% stringent CR [sCR]). Cohort 2 saw 90.6% of patients achieving a CR or better (9.4% very good partial response [VGPR], 25.0% CR, 65.6% sCR), while cohort 3 had 93.3% achieving a CR or better (6.7% VGPR, 23.3% CR, 70.0% sCR).
Safety Profile
Neutropenia was the most frequently observed treatment-emergent adverse event (TEAE). The overall rate of grade 3/4 neutropenia was 93.8% in cohort 1, 62.5% in cohort 2, and 46.7% in cohort 3. Zamagni noted that the cumulative incidence of grade 3/4 neutropenia at 6 months decreased significantly from 81% in cohort 1 (more intense teclistamab dosing) to 56% in cohort 2 and 40% in cohort 3. Febrile neutropenia, anemia, and eosinophilia were rare, and treatment discontinuation due to TEAEs was low at 5.3% overall.
Grade 3/4 nonhematologic TEAEs (excluding infection) were infrequent. Cytokine release syndrome (CRS) occurred in approximately half of the patients overall, primarily during teclistamab step-up dosing (37.2% after step-up dose 1, 8.5% after step-up dose 2, and 5.3% after treatment dose 1). There were no grade 3/4 CRS cases and no discontinuations due to CRS. No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were reported. Diarrhea, mainly related to lenalidomide, and injection site reactions were also observed.
Infections and hypogammaglobulinemia were frequent. Grade 3/4 infections occurred in 37.5%, 28.1%, and 20.0% of cohorts 1, 2, and 3, respectively. Common infections included upper respiratory tract infections, COVID-19, pneumonia, and nasopharyngitis. Hypogammaglobulinemia occurred in 96.9%, 78.1%, and 93.3% of cohorts 1, 2, and 3, respectively, with all affected patients receiving intravenous or subcutaneous immunoglobulin. Infection prophylaxis was strongly recommended.
Study Design and Patient Characteristics
The SRI included two Tec-Len cohorts and one Tec monotherapy cohort. In cohort 1 (n = 32), teclistamab was administered at 1.5 mg/kg weekly for cycles 1 and 2, followed by 3.0 mg/kg every 2 weeks for cycles 3 to 6, and then 3.0 mg/kg monthly for up to 2 years. In cohort 2 (n = 32), teclistamab was given at 1.5 mg/kg on days 8 and 15, then 3.0 mg/kg monthly. Cohort 3 (n = 30) received the same teclistamab dose as cohort 2. Lenalidomide (10 mg/day in 28-day cycles) was initiated in cohorts 1 and 2 from cycles 2 to 4, with a potential increase to 15 mg/day for cycles 5 to 26 if tolerated. Fixed-duration maintenance was scheduled for 2 years, with teclistamab discontinuation in Tec-Len arms after 1 year if patients achieved at least CR.
Patient demographics were well balanced across the three cohorts, with a median age of approximately 58 years. About a quarter of patients in each cohort had high cytogenetic risk at diagnosis. The median time from ASCT to the start of maintenance treatment was 4.7 months (range, 1.8-7.4).
MajesTEC-4/EMN30 Trial Design
The SRI results inform the main randomization phase of the MajesTEC-4/EMN30 trial, which is enrolling patients with NDMM who have received 4 to 6 cycles of triplet or quadruplet induction therapy (proteasome inhibitor [PI] and/or immunomodulatory drug [IMiD] with or without an anti-CD38 antibody) and a single or double ASCT. Patients must have at least a partial response (PR) following these initial treatments.
The trial aims to enroll 1500 patients, randomized 1:1:1 to fixed-duration maintenance therapy with Tec-Len, Tec alone, or Len alone. The dual primary endpoints are progression-free survival (PFS) and 12-month MRD-negative complete remission rate, evaluated by next-generation flow with a sensitivity level of 10-5. Secondary endpoints include overall survival, response rate, MRD conversion rate, sustained MRD negativity, and safety. The MajesTEC-4/EMN30 trial is actively recruiting patients.
