S194: Teclistamab (Tec) + Nirogacestat (Niro) in Relapsed/Refractory Multiple Myeloma (Rrmm): The Phase 1b Majestec-2 Study

Background: Tec is the first BCMA-directed bispecific antibody approved for the treatment of triple-class exposed RRMM. Niro, a gamma secretase inhibitor, has been shown to potentiate BCMA-directed therapies in vitro and in clinical trials. Aims: We report initial results from one arm of the multicohort, open-label, phase 1b, MajesTEC-2 trial, which investigates tec with niro or other anticancer therapies in pts with MM. Methods: Pts were enrolled in the tec + niro cohort (age ≥18 years), had RRMM per International Myeloma Working Group (IMWG) criteria, had received ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and triple exposed to a PI, an IMiD, and an anti-CD38 antibody, with progressive disease within 12 months (mo) of their last LOT. All pts provided informed consent. Three dose levels were evaluated: 1) tec 720 μg/kg weekly (QW) + concurrent niro (100 mg twice daily starting with first dose of tec; n=8); 2) tec 720 μg/kg QW + once daily (QD) delayed low-dose (LD) niro (100 mg QD starting after tec step-up dosing; n=7); and 3) tec 1500 μg/kg QW + QD delayed LD niro (n=13). Primary objectives for this cohort were to evaluate the safety and tolerability of tec + niro and identify optimal doses. Responses were investigator-assessed per IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0. Cytokine release syndrome (CRS) and ICANS were graded per ASTCT criteria. Results: As of Dec 16, 2022, 28 pts received tec + niro. Median (range) prior LOT was 4 (2–12). Median (range) duration of treatment (tx) was 9.4 mo (0.03–19.7) for tec and 4.7 mo (0.16–13.0) for niro. 67.9% of pts had International Staging System stage II/III disease; 20% had high-risk cytogenetics. Most frequent (>20%) tx-emergent AEs (TEAEs) for all doses were neutropenia (82.1%), CRS (75%), diarrhea (64.3%), injection-site erythema (53.6%), decreased appetite (50%), fatigue (42.9%), and anemia (35.1%). Of 8 pts who received tec 720 + concurrent niro, 2 dose-limiting toxicities (DLTs; 1 grade gr 3 GI bleed and gr 3 diarrhea; 1 gr 3 ICANS) were reported. In addition, 1 pt had gr 3 CRS and 1 had gr 3 confusional state. These AEs led to evaluation of delayed LD niro in the subsequent cohorts. In the tec 720 + QD delayed LD niro and tec 1500 + QD delayed LD niro groups, no DLTs or gr 3 CRS or neurologic AEs were reported. TEAEs led to delayed/skipped doses in 24 pts (85.7%). Six treatment-emergent deaths occurred: 3 with primary cause of death as AEs (septic shock, COVID-19, and cardiac arrest), 2 due to other causes, and 1 due to disease progression. The overall response rate was 71.4% (5/8 pts) for tec 720 + concurrent niro, 57.1% (4/7 pts) for tec 720 + QD delayed LD niro, and 92.3% (12/13 pts) for tec 1500 + QD delayed LD niro. Additional response data are shown in the table. Pharmacokinetics and pharmacodynamics were generally comparable to tec monotherapy. No anti-drug antibodies were detected. Summary/Conclusion: The combination of tec + niro yielded response rates of 57–92% across 3 dose levels assessed. This initial experience with tec + niro provides insights on the combination of BCMA-directed therapies with a gamma secretase inhibitor.Keywords: Phase I, Bispecific, Multiple myeloma, B-cell maturation antigen