Teclistamab, Daratumumab, and Pomalidomide in Patients with Relapsed/Refractory Multiple Myeloma: Results from the Majestec-2 Cohort a and Trimm-2 Studies
Authors: D'Souza Anita , Costa Luciano J. , San-Miguel Jesús F. , Berdeja Jesus G , Morillo Giles Daniel , Touzeau Cyrille , McKay John T , Dholaria Bhagirathbhai , Martin Thomas G , Perrot Aurore , Oriol Albert , Sureda Balari Anna , Prior Thomas , Ghosh Debopriya , Kang Lijuan , Larsen Julie S , Ludlage Hein , Vandenberk Lien , Chen Lingling , Koster Bas D , Sun Weili , Kobos Rachel , Searle Emma , Matous Jeffrey V , Chari Ajai , Kampfenkel Tobias 
Published: December 2024

Introduction : Teclistamab (tec) is the first approved B-cell maturation antigen × CD3 bispecific antibody (BsAb) for the treatment of triple-class exposed relapsed/refractory multiple myeloma (RRMM), with weight-based dosing and the longest study follow-up of any BsAb in MM. Both daratumumab (D) and pomalidomide (P) have immunomodulatory effects that may augment the function of tec, potentially enhancing its antimyeloma activity. We present safety and efficacy data for patients with MM who received tec in combination with D and P (tec-DP) in 2 phase 1b studies, MajesTEC-2 (NCT04722146) and TRIMM-2 (NCT04108195).

Methods : Eligible patients in this cohort of MajesTEC-2 had 1-3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and lenalidomide, and in TRIMM-2 had ≥3 prior LOT, including a PI and an immunomodulatory drug (IMiD) or were double refractory to a PI and an IMiD. Patients received weekly doses of tec (0.72, 0.75, or 1.5 mg/kg with step-up dosing [SUD]) and approved schedules of D (1800 mg) and P (2 or 4 mg). P was introduced after SUD was completed. Responses and adverse events (AEs) were investigator assessed per International Myeloma Working Group criteria and Common Terminology Criteria for Adverse Events v5.0, respectively. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per American Society of Transplantation and Cellular Therapy guidelines.

Results : Twenty-seven patients received tec-DP (TRIMM-2, n=10, enrolled Apr 8-Aug 23, 2021; MajesTEC-2, n=17, enrolled Nov 17, 2020-Mar 29, 2021). At the data cut-offs (Apr 9, 2024 [TRIMM-2]; Apr 15, 2024 [MajesTEC-2]), median follow-up was 25.8 months (mo; range, 0.5-39.6) and median treatment duration of tec-DP was 12.0 mo (range, 0.5-33.9). Median age was 62 years (range, 35-79); 59.3% were male. Median prior LOT was 2 (range, 1-16), with 33% having had &gt;3 prior LOT; 40.7% were D exposed. AEs of any grade in ≥50% of patients were neutropenia (77.8%), cough (59.3%), and CRS (55.6%). Grade 3/4 AEs in ≥15% of patients were neutropenia (77.8%), lymphopenia (22.2%), anemia (18.5%), COVID-19 pneumonia (18.5%), and pneumonia (18.5%). All CRS events were grade 1/2 and resolved. There was 1 case of ICANS (grade 1) that resolved. Infections occurred in 25 (92.6%; grade 3/4, 63.0%) patients, most commonly upper respiratory infection (44.4%; all grade 1/2), pneumonia (29.6%; grade 3/4, 18.5%), sinusitis (29.6%; grade 3/4, 3.7%), and COVID-19 infection (25.9%; grade 3/4, 7.4%). Overall, 3 (11.1%) patients discontinued all 3 study drugs due to AEs. There were 7 deaths, 1 due to progressive disease and 6 due to infections (COVID-19 pneumonia, n=4; pneumonia, n=1; pseudomonal bacteremia, n=1]; 4 of these 6 patients with infectious deaths had hypogammaglobulinemia and were not receiving intravenous immunoglobulin (IVIg) before the onset of the infection. All fatal infections occurred before an intensified infection prophylaxis plan was implemented (starting in Feb 2023), which included increased emphasis on recommendations for IVIg supplementation. Since then, no further fatal infections occurred. Overall response rate was 88.5%, very good partial response or better rate was 84.6%, and complete response or better rate was 61.5%. Median time to first response was 0.95 mo (range, 0.9-1.9). Median duration of response was non-estimable (NE; 12.2 mo-NE). Median progression-free survival was 26.5 mo (11.2-NE). Preliminary data showed that tec serum concentrations were generally within the same range of values observed with tec monotherapy in MajesTEC-1.

Conclusion : Tec-DP was feasible and led to promising efficacy in patients with RRMM. Infections, including COVID-19, were common, emphasizing the importance and positive impact of infection prophylaxis, including IVIg supplementation.