Tecvayli Effective Maintenance Therapy in Newly Diagnosed Multiple Myeloma

Patients with newly diagnosed multiple myeloma experienced robust clinical activity when treated with Tecvayli (teclistamab) alone or in combination with standard Revlimid (lenalidomide) as maintenance therapy after induction and autologous stem cell transplantation (ASCT), study results have shown.

Initial results from the safety run-in component of the phase 3 MajesTEC-4/EMN30 trial were presented at the 2024 ASH Annual Meeting. Of note, a safety run-in part of a trial is a preliminary phase designed to assess the safety of a new treatment before it moves into larger-scale studies.

The safety run-in consisted of three maintenance cohorts: two administering Tecvayli-Revlimid (cohorts 1 and 2) and one administering Tecvayli monotherapy (cohort 3). The main difference behind cohorts 1 and 2 is that the Tecvayli dosing was less intense in cohort 2.

The minimal residual disease (MRD)-negativity rate (10-5 sensitivity) was 100% among evaluable patients in all three cohorts. This was measured at 12 months in cohort 1 and at six months in cohorts 2 and 3. Evaluable patients consisted of those with a baseline sample and at least one sample during maintenance. The median progression-free survival (PFS) had not been reached in any of the cohorts.

“Unprecedented efficacy was observed, with all evaluable patients achieving MRD negativity,” said presenting author Dr. Elena Zamagni, associate professor of hematology at the Bologna University, Italy.

Zamagni also reported that responses to treatment deepened during maintenance in all three cohorts. All patients in cohort 1 achieved a complete remission (CR) or better, as did 90.6% of patients in cohort 2 and 93.3% of patients in cohort 3. In cohort 1, the CR rate was 9.4% and the stringent CR (sCR) rate was 90.6%. In cohort 2, 9.4% of patients achieved a very good partial response (VGPR), 25% of patients achieved a CR, and 65.6% of patients achieved an sCR. The corresponding rates were 6.7%, 23.3% and 70%, respectively, in cohort 3.

Regarding hematologic toxicity, the most frequently occurring treatment-emergent adverse event (TEAE, side effect) was neutropenia. Across all time points, the overall rate of grade 3 (severe)/4 (life-threatening) neutropenia was 93.8% in cohort 1, followed by 62.5% in cohort 2, and 46.7% in cohort 3.

Zamagni further explained, “If we look at the cumulative incidence of grade 3/4 neutropenia at six months, we can see that the incidence decreased significantly from 81% in cohort 1 — which had a more intense [Tecvayli] dosing schedule — down to 56% in cohort 2 and 40% in cohort 3.”

Zamagni added that, “Febrile neutropenia, anemia and eosinophilia were very rare, as was the rate of treatment discontinuation due to TEAEs, which was low at 5.3% overall.”

With nonhematologic TEAEs (excluding infection), grade 3/4 TEAEs were rare, with the most frequently occurring being cytokine release syndrome (CRS), which occurred in approximately half of the patients overall. Most CRS cases occurred during Tecvayli step-up dosing, with 37.2% occurring after step-up dose 1, 8.5% occurring after step-up dose 2, and 5.3% occurring after treatment dose 1. There were no cases of grade 3/4 CRS and no discontinuations due to CRS. Also of note, there were no cases of immune effector cell–associated neurotoxicity syndrome. “We also had some diarrhea, mainly related to [Revlimid], and some injection site reaction,” added Zamagni.

Incidents of infections and hypogammaglobulinemia were frequent, according to Zamagni. Grade 3/4 infections occurred in 37.5%, 28.1%, and 20% of cohorts 1, 2 and 3, respectively. The most common infections were 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. All of these patients received at least one dose of intravenous or subcutaneous immunoglobulin. Infection prophylaxis was also strongly recommended.

Design and Demographics of the Safety Run-In of MajesTEC-4/EMN30

There were two Tecvayli-Revlimid cohorts and one single-agent Tecvayli cohort in the safety run-in. In cohort 1 (32 patients), patients received Tecvayli at 1.5 mg/kg weekly for cycles 1 and 2, and then 3 mg/kg every two weeks for cycles 3 to 6, and thereafter 3 mg/kg monthly for up to two years of fixed-duration maintenance. For cohort 2 (32 patients), Tecvayli was given at 1.5 mg/kg on days 8 and 15, and then immediately after it was given at 3 mg/kg monthly. In the single-agent cohort 3 (30 patients), the dose of Tecvayli was the same as in cohort 2. For patients also receiving Revlimid (cohorts 1 and 2), Revlimid was initiated at 10 mg/day in 28-day cycles from cycles 2 to 4. If Revlimid was well tolerated, the dose could be raised to 15 mg/day for cycles 5 to 26. All patients were scheduled to receive fixed-duration maintenance for two years; however, for patients receiving Tecvayli-Revlimid who were at least in CR at one year, Tecvayli was stopped.

Overall, 81 (86.2%) of the 94 randomized patients remained on treatment as of September 2024. Side effects (five patients) and patient withdrawal (three patients) were the two main reasons for discontinuation. There were two patients who discontinued due to progressive disease. Cohort 1 started earlier and thus had a longer median follow-up of 21.1 months. The median follow-up was 9.2 months for both cohorts 2 and 3.

Design of Primary MajesTEC-4/EMN30 Randomization

The results of the safety run-in now inform the main randomization phase of the phase 3 MajesTEC-4/EMN30 Trial.

The MajesTEC-4/EMN30 trial is enrolling patients with newly diagnosed multiple myeloma with an ECOG performance status of 0 to 2, who have received four to six cycles of a triplet or quadruplet induction therapy (PI and/or IMiD with or without an anti-CD38 antibody) and a single or double ASCT with or without consolidation. Patients have to have at least a partial response following these initial treatments.

The enrollment goal is 1,500 patients. Patients will be randomized evenly to fixed-duration maintenance therapy with Tecvayli-Revlimid, Tecvayli alone or Revlimid alone.

The MajesTEC-4/EMN30 trial is actively recruiting patients.

Reference

“Phase 3 Study of Teclistamab (Tec) in Combination with Lenalidomide (Len) and Tec Alone Versus Len Alone in Newly Diagnosed Multiple Myeloma (NDMM) As Maintenance Therapy Following Autologous Stem Cell Transplantation (ASCT): Safety Run-in (SRI) Results from the Majestec-4/EMN30 Trial” by Dr. Elena Zamagni et al., Blood.

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