Key Points
CD3+ T cells from patients taken after selinexor-based regimen treatment showed up-regulated activation and proliferation markers.
CD138+ cells from patients with acquired selinexor resistance showed enhanced PARP1 expression, but no induction of immune checkpoints.
Abstract
Many currently approved therapies for multiple myeloma (MM) utilize the endogenous immune system. The indirect effects of cytotoxic anti-myeloma agents on the immune microenvironment can impact on the success of subsequent or combined immune-directed therapies. In the current study, we investigated the effects of the exportin 1 inhibitor selinexor (SEL) on the bone marrow (BM) microenvironment and BM myeloma cells, utilizing serial samples from patients treated with SEL-based regimens on the STOMP trial (NCT02343042). Digital spatial profiling of selected CD138+ myeloma cells and CD3+ T cells was performed to assess expressions of 79 proteins involved in immuno-oncology. In selected CD138+ myeloma cells from samples of patients taken at screening before SEL treatment, increased expression of proliferation markers (p-MEK1 [S217/S221], p-AKT1[S473]) was associated with poor progression free survival, and thus might be candidate predictive biomarkers of response. In post-treatment CD3+ T cells from samples taken from patients during response to SEL, upregulation of EGFR, CD127, granzyme B, and pERK1/2 (T202/Y204) was observed, consistent with T cell activation. No induction of the immune inhibitory markers LAG3, PD-1, or CTLA4 was seen in the CD3+ T cells, either at the time of response, or in samples taken after disease progression, indicating T cell exhaustion is likely not a mechanism of acquired SEL resistance. The ability of SEL to exhibit anti-myeloma activity without inducing T cell immune checkpoints may have clinical implications, and future studies are needed to determine if SEL complements CAR T cell therapy and bispecific antibodies for the treatment of MM.
