Maintenance Teclistamab Yields Preliminary Activity in NDMM

“Unprecedented efficacy was observed, with all evaluable patients achieving MRD negativity,” according to presenting author Elena Zamagni MD, PhD.

Robust preliminary efficacy and safety occurred among patients with newly diagnosed multiple myeloma (NDMM) who received maintenance teclistamab-cqyv (Tec; Tecvayli) alone or in combination with lenalidomide (Len; Revlimid) after autologous stem cell transplantation (ASCT), according to safety run-in (SRI) data from the phase 3 MajesTEC-4/EMN30 trial presented at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH).

The SRI consisted of 3 maintenance cohorts: 2 administering Tec-Len (cohorts 1 and 2) and 1 administering Tec monotherapy (cohort 3). The main difference behind cohorts 1 and 2 is that the Tec dosing was less intense in cohort 2.

The minimal residual disease (MRD)-negativity rate (10^-5 sensitivity) was 100% among evaluable patients in all 3 cohorts. This was measured at 12 months in cohort 1 and at 6 months in cohorts 2 and 3. Evaluable patients consisted of those with a baseline sample and at least 1 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 Elena Zamagni MD, PhD, associate professor of hematology at the Bologna University, Italy.

Zamagni also reported that responses to treatment deepened during maintenance in all 3 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), 25.0% of patients achieved a CR, and 65.6% of patients achieved an sCR. The corresponding rates were 6.7%, 23.3%, and 70.0%, respectively, in cohort 3.

Regarding hematologic toxicity, the most frequently occurring treatment-emergent adverse event (TEAE) was neutropenia. Across all time points, the overall rate of grade 3/4 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 6 months, we can see that the incidence decreased significantly from 81% in cohort 1—which had a more intense teclistamab 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 Tec 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 lenalidomide, 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 20.0% 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 1 dose of intravenous or subcutaneous immunoglobulin. Infection prophylaxis was also strongly recommended.

Design and Demographics of SRI of MajesTEC-4/EMN30

There were 2 Tec-Len cohorts and 1 single-agent Tec cohort in the SRI. In cohort 1 (n = 32), patients received Tec at 1.5 mg/kg weekly for cycles 1 and 2, and then 3.0 mg/kg every 2 weeks for cycles 3 to 6, and thereafter 3.0 mg/kg monthly for up to 2 years of fixed-duration maintenance. For cohort 2 (n = 32), Tec was given at 1.5 mg/kg on days 8 and 15, and then immediately after it was given at 3.0 mg/kg monthly. In the single-agent cohort 3 (n = 30), the dose of Tec was the same as in cohort 2. For patients also receiving lenalidomide (cohorts 1 and 2), lenalidomide was initiated at 10 mg/day in 28-day cycles from cycles 2 to 4. If lenalidomide 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 2 years; however, for patients receiving Tec-Len who were at least in CR at 1 year, Tec was stopped.

Patient demographics were well balanced between the 3 SRI cohorts. The median age was about 58 years in all 3 cohorts, with cohort 2 having a slightly lower proportion of patients aged 65 years or older. About a quarter of patients in each cohort had high cytogenetic risk at diagnosis. Across all patients, the median time from ASCT to the start of maintenance treatment was 4.7 months (range, 1.8-7.4).

About two-thirds of patients in cohorts 2 and 3 received quadruplet induction therapy, including a proteasome inhibitor (PI), or immunomodulatory drug (IMiD), and an anti-CD38 antibody, compared with about one-third of patients in cohort 1. “This is due to the timing. Cohort 1 started in 2022 while cohorts 2 and 3 started approximately 1 year later,” explained Zamagni.

Overall, 81 (86.2%) of the 94 randomized patients remained on treatment as of September 2024. AEs (n = 5) and patient withdrawal (n = 3) were the 2 main reasons for discontinuation. There were 2 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 SRI now inform the main randomization phase of the multicenter, open-label, 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 4 to 6 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 PR following these initial treatments.

The enrollment goal is 1500 patients. Patients will be randomized in a 1:1:1 ratio to fixed-duration maintenance therapy with Tec-Len, Tec alone, or Len alone.

The dual primary end points of the trial are PFS and 12-month MRD-negative complete remission rate evaluate by next generation flow with a sensitivity level of 10^-5. Secondary end points include overall survival, response rate, MRD conversion rate, sustained MRD negativity, and safety.

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

Reference

Zamagni E, Silzle T, Špička I, et al. 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. Blood. 2024; 144 (suppl 1): 494. doi:10.1182/blood-2024-205608