Professor of Medicine, CAR T Program Director Duke University Medical Center Durham, North Carolina, United States
Introduction: Selinexor (SEL) is an oral first-in-class selective exportin 1 (XPO1) inhibitor. SEL in combination with dexamethasone (DEX) and bortezomib is FDA and EMA approved for treatment of patients with multiple myeloma (MM) who have received at least one prior line of therapy. In addition to activating tumor suppressor proteins, non-clinical studies have shown SEL down-regulates immune checkpoints, enhances immune cell surveillance and improves biologic immunotherapies. Herein we investigated the effects of selinexor on MM cell immune markers and the bone marrow (BM) microenvironment in samples from patients with relapsed/refractory MM (RRMM) treated with SEL combinations.
Methods: Samples from patients enrolled in the STOMP trial, a multi-arm, open-label, Phase 1b/2 study evaluating SEL in combinations with different backbone therapies (NCT02343042), at our institute were included in this post-hoc analysis. Paired BM biopsy samples obtained at the time of initial diagnosis (n=12), immediately before SEL treatment (n=20), and at the end of the study (n=20) were assessed, as well as normal control BM samples (n=12). Samples were stained with CD138, CD3 and CD45 antibodies for morphologic identification then probed with the NanoString GeoMx Digital Spatial Profiling (DSP) Immuno-Oncology multiplex antibody panel for quantitative expression of 96 targets with spatial resolution. XPO1 expression was measured by dual color immunohistochemical (IHC).
Results: From January 2017 to May 2022, a total of 47 RRMM patients enrolled in the STOMP trial at our institution. The median age was 66 years (ranging from 50 to 77 years) (males: 21 and females 26; African American patients: 17, Caucasian: 28, Hispanic: 2). Of the 47 patients, 10 were in Arm 1 (SEL+DEX+pomalidomide); 15 in Arm 5 (SEL+DEX+daratumumab); and 12 in Arm 6 (SEL+DEX+carfilzomab); with the remaining in other arms. Patients were treated with SEL-based regimens for a median of 270 days (ranging from 35 to 1709 days). Thirty-one patients (66%) achieved PR or better and 34% patients had VGPR. Thirty-eight patients (81%) discontinued treatment due to disease progression and five patients (11%) discontinued treatment due to toxicities.
DSP and IHC are being performed on normal controls, diagnostic samples, and paired pre/post treatment samples from 4 patients in Arm 1, 10 in Arm 5 and 6 in Arm 6. Myeloma cell signaling pathway activations, BM microenvironment immune activity and XPO1 expression will be correlated with treatment response and drug resistance. Detailed and comprehensive results will be presented at the meeting.
Conclusions: Our study provides insights in how SEL affects the endogenous immune system in the context of MM, with implications for sequencing SEL with immune directed therapies like CAR-T cell treatments. Moreover, our study will identify molecular mechanisms that contribute to drug resistance to SEL, with implications for combination therapies and predictive biomarkers.
