STOMP Trial Analysis Reveals Immunomodulatory Effects of Selinexor in RRMM

Analysis from a retrospective, post hoc examination of samples from patients with relapsed/refractory multiple myeloma (RRMM) enrolled in the multi-arm, open-label, phase 1b/2 STOMP trial (NCT02343042) show that selinexor (Xpovio)-based regimens positively modulate the T-cell compartment in the bone marrow of responding patients.^1,2

The objective of the trial was to identify biomarkers predictive of response to selinexor-based regimens and to determine the impact of these treatments on the bone marrow microenvironment, specifically on T-cell activation and fitness.

In post-treatment samples from patients who responded to therapy (achieved partial response or better), CD3-positive T cells showed a significant upregulation of proteins associated with T-cell activation, proliferation, survival, and effector function. Key upregulated markers included:

• Epidermal growth factor receptor (EGFR)
• CD127 (IL-7 receptor alpha chain)
• Granzyme B and Granzyme A
• Phosphorylated ERK1/2 (pERK1/2)
• STING
• CD14
• CD44
• Phosphorylated AKT1 (pAKT1)

A critical observation was the lack of induction of inhibitory immune checkpoint molecules on CD3-positive T cells after selinexor-based treatment. This holds true for samples taken during response and, importantly, for samples taken at the time of disease progression. This indicates that the development of resistance to selinexor is likely not mediated by T-cell exhaustion. The study confirmed no significant increase in the following markers:

• PD-1
• Cytotoxic T-lymphocyte associated protein 4 (CTLA4)
• Lymphocyte activating 3 (LAG3)
• T-cell immunoglobulin mucin family member 3 (TIM-3)
• Forkhead box P3 (FOXP3)
• V-set immunoregulatory receptor (VISTA)

Interestingly, the coinhibitory molecule TIM-3 was upregulated in samples from patients responding to therapy, particularly in the selinexor plus pomalidomide (Pomalyst) plus dexamethasone (SPd) arm (n = 3). However, its expression was positively correlated with the effector molecule granzyme B and was not associated with a shorter time to disease progression. This suggests TIM-3 may have a context-dependent costimulatory function or reflect a transiently activated T-cell state rather than terminal exhaustion.

The study identified several proteins whose baseline expression levels in either myeloma cells or T cells were associated with patient outcomes.

Analysis of CD138-positive myeloma cells from pretreatment samples revealed a link between proliferation signaling and treatment efficacy.

Phosphorylated MEK1 (pMEK1)<br>Phosphorylated AKT1 (pAKT1) was associated with poor progression-free survival (PFS). Proapoptotic BAD protein was associated with improved PFS, but this was not statistically significant. Granzyme A was associated with poor PFS. Patients with a higher baseline expression of <br>- CD45<br>- pan-AKT<br>- STING had improved PFS. Patients with a higher baseline of <br>- BAD<br>- Ki-67<br>- Cleaved Caspase 9<br>- Phosphorylated-p90 RSK had poor PFS. 

By comparing protein expression in CD138-positive myeloma cells from pretreatment samples to those taken at disease progression, the study identified a potential mechanism of acquired resistance.

The DNA damage repair protein PARP1 was significantly upregulated in myeloma cells from patients who developed resistance to selinexor. High PARP1 expression is independently associated with poor prognosis in MM. Resistant cells also showed downregulation of the antiapoptotic protein BCL-2 and the immunogenic protein HLA-DR.

A total of 34 bone marrow biopsy samples from 17 patients treated at Duke University were assessed. These patients were enrolled in 3 arms of the STOMP trial:

• Arm 1 (SPd): selinexor + pomalidomide + dexamethasone ((n = 3)
• Arm 5 (SDd): selinexor + daratumumab (Darzalex) + dexamethasone (n = 9)
• Arm 6 (SKd): SEL + carfilzomib (Kyprolis) + dexamethasone (n = 5)

The study employed NanoString GeoMx Digital Spatial Profiling to perform a spatially resolved, quantitative analysis of 79 immuno-oncology-related proteins. The analysis was conducted on specific cell populations, primarily CD138-positive myeloma cells and CD3-positive T cells, isolated from archived patient bone marrow biopsies taken before and after treatment.

The discovery of PARP1 upregulation in resistant myeloma cells suggests that combining selinexor with PARP1 inhibitors may be a viable strategy to prolong treatment efficacy.

Kang Y et al, authors of the study, note that the concepts generated by this study are already being explored. Retrospective studies show promising outcomes for patients treated with selinexor-based regimens prior to chimeric antigen receptor (CAR) T-cell apheresis or after CAR T-cell relapse. Clinical trials are underway or being launched to investigate selinexor in combination with next-generation immunomodulatory drugs and with bispecific antibodies.

“This study may provide some rationale for the clinical use of [selinexor]-based regimens as bridging therapy or maintenance therapy to T-cell–engaging therapies such as CAR T-cell therapy or bispecific antibodies treatment,” said Kang Y et al. 

Kang Y et al acknowledge several limitations, including the retrospective nature of the analysis, the small sample size derived from a single institution, and the use of available convenience samples rather than a mandated collection protocol. The results require validation in an independent patient cohort.

REFERENCES

1.Kang Y, Neff J, Ellero A et al. Selinexor-based treatments are associated with increased expression of T-cell activation markers in multiple myeloma. Blood Immunology & Cellular Therapy (2025) 1 (3): 100009. doi:10.1016/j.bict.2025.100009

2.Selinexor and backbone treatments of multiple myeloma patients (STOMP). ClinicalTrials.gov. Updated October 3, 2025. Accessed November 24, 2025. https://clinicaltrials.gov/study/NCT02343042