Belantamab Mafodotin, nirogacestat and Pomalidomide for Patients with Relapsed/Refractory Multiple Myeloma
Authors: Hultcrantz Malin , Hassoun Hani , Tan Carlyn Rose , Korde Neha , Lesokhin Alexander M. , Hashmi Hamza , Maclachlan Kylee H , Rajeeve Sridevi , Shah Urvi A. , Patel Dhwani , Derkach Andriy , Hamid Selena , Shekarkhand Tala , Tran Linh , Caple Julia , Barnett Kelly , Sood Tara , Jenna Blaslov , Konsky Amanda , Murata Kazunori , Roshal Mikhail , Giralt Sergio A. , Usmani Saad Z. , Mailankody Sham 
Published: December 2024

Background
B-cell maturation antigen (BCMA) directed therapies have demonstrated significant efficacy in relapsed/refractory multiple myeloma however treatments can still be optimized to improve the response rates. BCMA is cleaved from the cell surface through the enzyme gamma secretase. Pre-clinical suggest that adding a gamma secretase inhibitor can increase BCMA expression and enhance anti-tumor efficacy of BCMA targeted therapy including belantamab mafodotin (belamaf).
Methods
This is an investigator-initiated phase 1b trial of belamaf (NCT05556798) in combination with nirogacestat and pomalidomide in patients with relapsed/refractory multiple myeloma. Patients with 3 or more prior lines of therapy, measure disease, and exposure to a proteasome inhibitor, an IMiD, and an anti-CD38 antibody were eligible.
Patients were treated with nirogacestat for a run-in period of 4 days to increase the BCMA surface density on the plasma cells prior to starting belamaf. After the run in, patients were treated with a combination of nirogacestat 100 g BID, belamaf every 3 weeks for cycle 1-3 thereafter every 6 weeks during for cycle 4+, and pomalidomide 2 mg day 1-14/21 days.
The trial had a 3+3 dose escalation design with 3 dose levels of belamaf, 1.0 mg/kg, 1.4mg/kg, and 1.9 mg/kg. The primary endpoints are safety, efficacy, and to establish the recommended phase 2 dose (PR2D). Given recent data from combination studies of pomalidomide and belamaf, pomalidomide 2 mg was added to the 1.4 mg/kg and 1.9 mg/kg cohorts. Correlative studies include membrane bound BCMA before and after the nirogacestat run-in, soluble BCMA levels, pharmacokinetics, as well as whole genome sequencing at baseline and at the end of trial.
The study includes a dose escalation part and a dose expansion part based on the RP2D from the dose escalation. Here we report on the dose escalation part of the trial.
Results
Nine patients have been enrolled on the trial, three patients at each dose escalation level. There were seven men and two women, median age was 68 years with median 5 prior lines of therapy.
Three patients were treated on the first dose level belamaf 1.0 mg/kg with nirogacestat 100 mg BID. All patients had stable disease (SD) and one patient developed grade 1 keratopathy.
Three patients were treated on the second dose level with belamaf 1.4 mg/kg, nirogacestat 100 mg BID, and pomalidomide 2 mg. One patient had partial response (PR) and two patients had very good partial response (VGPR). One patient developed grade 1 keratopathy and one patient had grade 3 keratopathy. The grade 3 keratopathy occurred during cycle 4, thus after the dose limiting toxicity (DLT) period.
Three patients have been enrolled on the third dose level with belamaf 1.9 mg/kg, nirogacestat 100 mg twice daily, and pomalidomide 2 mg. One patient achieved a PR so far and 2 patients had SD per the monoclonal protein level. All three patients have had a &gt;90% reduction in the free light chain level. One patient was still within the DLT period at the time of data cut off (7/31/2024).
In total, three patients developed ocular events at the time of data cut-off, one patient had grade 1 keratopathy, one patient had grade 1 with decreased best corrected visual acuity (BCVA) grade 1, and one had grade 3 keratopathy with decreased BCVA grade 2. Belamaf was held for two patients due to ocular toxicity, both patients subsequently improved to grade 1 and could continue treatment. Four patients developed diarrhea grade 1/2 which resolved or improved with dose reduction of nirogacestat to 100 mg or 50 mg per day. Four infections were reports in three patients; three grade 1/2 and one grade 3. Four patients came off trial due to lack of response (SD) or progression of disease (PD) and one patient due to withdrawal of consent because of the ocular event.
Summary
The combination of belamaf, nirogacestat and pomalidomide has been tolerable and effective also at lower doses of belamaf. The overall response rate (ORR) was 44% (4/9 patients) across all dose cohorts. Within the belamaf 1.4 mg/kg and 1.9 mg/kg dose cohorts, 4/6 patients achieved PR or better with the two remaining patients still being evaluated. Updated safety and efficacy data as well as translational BCMA studies will be presented at the conference.