Abstract Background B-cell maturation antigen (BCMA) directed therapies have demonstrated high efficacy in multiple myeloma (MM). While BCMA is readily cleaved from MM cell surfaces via gamma secretase, pre-clinical studies have shown that adding the gamma secretase inhibitor (GSI) nirogacestat can increase myeloma cell BCMA density, and potentially enhance anti-tumor efficacy of BCMA targeted therapies like belantamab mafodotin. Methods We performed an investigator initiated phase 1b trial (NCT05556798), of belantamab mafodotin in combination with nirogacestat and pomalidomide in MM patients with 3 or more prior lines of therapy. Patients were first treated with nirogacestat for 4 days aiming to increase surface BCMA expression. Patients were then treated with a combination of nirogacestat 100 g twice daily, belantamab mafodotin every 3 weeks for cycle 1-3, and every 6 weeks thereafter. There was a 3+3 dose escalation with 3 dose levels of belantamab mafodotin, 1.0 mg/kg, 1.4mg/kg, and 1.9 mg/kg. Pomalidomide 2 mg day 1-14/21 was added to the belantamab mafodotin 1.4 mg/kg and 1.9 mg/kg cohorts. The trial endpoints were safety, efficacy, and to establish the recommended phase 2 dose. Membrane bound bone marrow plasma cell BCMA expression was assessed before and after the 4 day nirogacestat treatment using 10 color multicolor flow cytometry and BCMA-PE antibody binding (Miltenyi Biotec). Results Nine patients were enrolled on the trial; 7 men, 2 women, median age 68 years (range 66-89 years). All patients had one or more high risk cytogenetic feature (1q gain, 17p deletion, 1p deletion). Median prior lines of therapy was 5; 100% were triple exposed (PI, IMiD, anti-CD38 monoclonal antibody), and 5 patients had prior high dose melphalan with autologous stem cell transplant. Two patients had prior BCMA treatment; 1 patient had received a BCMA CAR T and a GPRC5D CAR T, and 1 patient had received a BCMA CAR T and a BCMA bispecific antibody. The overall response rate (ORR) was 66% including 3 with partial response (PR) and 3 with very good partial response (VGPR). The remaining 3 had stable disease (SD). The ORR for patients in the 1.4 and 1.9 mg/kg cohorts was 100%. In 8 patients with available samples, there was a significant increase in membrane bound BCMA, median fluorescence increased om from 685 to 4228.5, p0.003, after the initial 4 day nirogacestat treatment. Six patients (66%) developed keratopathy, 3 patients had grade 1, 1 patient had grade 2, and 2 patients had grade 3 keratopathy. Belantamab mafodotin was held for 3 patients due to ocular adverse events (AEs), the keratopathy eventually improved to grade 1 and all patients could resume treatment. One patient had grade 2 reduction in best corrected visual acuity (BCVA) without keratopathy in the setting of underlying macular degeneration. Hematological AEs were observed in 4 patients, 3 with grade 3/4 AEs, 1 in dose cohort 2 and 2 in dose cohort 3. The hematological AEs were anemia (N=3), neutropenia (N=2), and thrombocytopenia (N=1). Hematological AEs lead to dose reduction of pomalidomide in 1 patient. There were 10 infections (7 grade 1/2, 3 grade 3) recorded in 6 patients. Four patients developed diarrhea grade 1/2 which resolved or improved with dose reduction of nirogacestat. Other non-hematological AEs included fatigue (N=3), hypophosphatemia (N=1), and infusion related reaction (N=1). There was 1 sudden unexplained death in dose cohort 3. Four patients discontinued trial treatment due to lack of response (SD) or progression of disease (PD), 1 due to prolonged infection, 1 due to withdrawal of consent, and 1 patient due to grade 5 AE. At the data cutoff (July 31, 2025), 2 patients continue on trial treatment. The trial was closed to accrual after the initial 9 patients based on a decision by GSK. Conclusions The combination of belantamab mafodotin, nirogacestat, and pomalidomide showed high efficacy, ORR 66%, in this cohort of heavily pretreated MM patients, using lower doses of belantamab mafodotin than in the DREAMM2 trial. All patients in dose cohort 2 and 3 responded to therapy (ORR 100%) including 2 patients with prior BCMA CAR T and prior BCMA bispecific antibody treatment. The rate of ocular AEs was similar to prior belantamab mafodotin trials and real-world studies. The significant increase in membrane bound BCMA after starting nirogacestat indicates a possible therapeutic synergy between GSIs and BCMA targeted therapies.
Tan et al. (Mon,) studied this question.
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