Abstract
CAR T and bispecific antibody treatment for relapsed/refractory multiple myeloma (RRMM) show promising clinical activity, but most patients (pts) relapse. Emerging clinical data indicate that serial and/or prolonged T-cell–redirecting therapy (TCRT) promotes T-cell exhaustion, which is associated with inferior clinical outcomes. Thus, there is an unmet need to maintain anti-tumor activity between TCRT treatments while promoting a tumor microenvironment facilitating T-cell recovery. Both selinexor (S), an oral exportin 1 (XPO1) inhibitor (approved in combination with dexamethasone (d) in penta-refractory MM and with d and bortezomib in RRMM after ≥1 prior therapy), and mezigdomide (M), a novel and potent cereblon E3 ubiquitin ligase modulator (under investigation in RRMM), have shown T-cell preservation/stimulatory activity. We present preliminary results from Arm 12 of Phase 1 of the Phase 1b/2 STOMP trial (NCT02343042), investigating safety and efficacy of SMd in pts with RRMM for whom TCRT has failed or who otherwise cannot receive TCRT.
Phase 1 of Arm 12 followed a 3+3 design evaluating three dose levels: cohort 1 received S 40 mg/M 0.6 mg/d 40 mg, cohort 2 received S 60 mg/M 0.6 mg/d 40 mg, and cohort 3 received S 60 mg/M 1.0 mg/d 40 mg. Prophylaxis for nausea (dual anti-emetics) for at least the first two months and thromboembolism were required. Study objectives were to determine maximum tolerated dose and recommended phase 2 dose and assess safety and efficacy of SMd. Safety was assessed as per CTCAE V5.0 and response per International Myeloma Working Group (IMWG) criteria.
Thirteen pts were enrolled: 3 in cohort 1, 3 in cohort 2, and 7 in cohort 3. Of all pts treated with SMd, 69.2% (9/13) were male, with a median age of 66 years and had a median of 5 prior lines of therapy. All pts were triple-class exposed to immunomodulatory drugs, proteasome inhibitors, and an anti-CD38 monoclonal antibody. Three pts (23.1%) had relapsed after TCRT (3 cilta-cel; 2 talquetamab; 1 IGM-2644), and 4 after belantamab mafodotin, with 30.8% being refractory to B-cell maturation antigen–targeted therapy.
As of July 8, 2025, no dose-limiting toxicities (DLTs) were encountered in cohorts 1 and 2. Two DLTs occurred in cohort 3. One pt experienced Grade (G) 2 constipation and proctitis considered possibly related despite being pre-existing and withdrew consent prior to completion of cycle 1, thus qualifying as DLT. Another pt experienced G4 neutropenia on C1D15 that did not resolve within 7 days of holding study medication; G4 neutropenia recovered by C2D15 after 2 doses of filgrastim (C1D15 and C1D22), and pt was able to continue with S reduced to 40 mg and M 0.6 mg. Two pts in cohort 3 were not evaluable for DLT determination, due to deviations from protocol dosing in C1, but continued therapy based on the clinical benefit and are included in safety and efficacy analyses. Most common treatment-emergent adverse events (TEAEs) across all pts were neutropenia (69.2%), thrombocytopenia (69.2%), constipation (46.2%), and leukopenia (46.2%). Most common G3/4 TEAEs were neutropenia (38.5%), thrombocytopenia (15.4%), and leukopenia (15.4%).
As of July 25, 2025, 10 patients had at least one IMWG response assessment, disease control (≥ SD) was reported in all pts (10/10). Overall response rate (ORR) was 40% (4/10), 4 pts achieved very good partial response (VGPR). Of note, 2/3 pts in cohort 2 had VGPR.
Treatment with SMd led to an increase in proliferating (Ki-67+), activated (HLA-DR+), and effector memory (CD45RA-/CCR7-) T cells, with a decrease in TIGIT+ T cells by C2D15. The impact of adding S to Md treatment on immune microenvironment is under evaluation and will be presented together with updated efficacy data.
For the all-oral combination of SMd, TEAEs were consistent with AE profiles for S and M, and no new safety signals were detected; DLT of G4 neutropenia was reported but manageable with filgrastim support and dose reduction. Across all dose levels, SMd showed efficacy in pts with heavily pre-treated RRMM in whom TCRT had failed or who otherwise could not receive TCRT. Initial analysis of primary patient samples demonstrated the presence of proliferating cytotoxic T-cells, with decrease in exhaustion markers. These results support continued investigation of SMd in pts with RRMM.
