Micrograph of myeloma neoplasm from bone marrow biopsy
Micrograph of myeloma neoplasm bone marrow biopsy.

Mount Sinai researchers have for the first time identified genes that predict a good response to Selinexor, a new therapy for multiple myeloma, but one that can have serious side effects for some patients.

Karyopharm’s selinexor (XPOVIO) is the first selective inhibitor of nuclear export to be approved for multiple myeloma. It inhibits karyopherin XPO1. Selecting patients who would benefit the most has remained elusive until now, but a study published this week in JCO Precision Oncology points to a solution for that.

The Mount Sinai scientists sequenced RNA of CD138+ cells from the bone marrow of 100 patients with MM who participated in the BOSTON study of selinexor, followed with differential gene expression and pathway analysis.

They identified a signature of three genes, WNT10A, DUSP1, and ETV7, that were activated in patients who had positive responses. They validated the signature in an independent group of patients who participated in an international clinical trial that led to Food and Drug Administration (FDA) approval of the drug. They also found the three-gene signature in patients with the brain cancer glioblastoma who responded well to selinexor.

The genes involved in the signature, the authors note, reveal a potential mechanism through upregulated interferon-mediated apoptotic signaling that may prime tumors to respond to selinexor-based therapy.

“This signature has important clinical significance, as it could identify patients who are most likely to benefit from treatment with selinexor-based therapy, especially in earlier lines of therapy,” said one of the senior authors, Alessandro Lagana, PhD, Assistant Professor of Oncological Sciences at The Tisch Cancer Institute at Mount Sinai and Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai.

Members of the same Mount Sinai team published in Science Advances last year on “the first multiomics patient similarity network of myeloma” to identify patient subgroups of the disease. As Inside Precision Medicine reported at the time, the researchers identified three main groups and a dozen subgroups. They also identified new classes of high-risk patients.

Samir Parekh, MD, Director of Translational Research in Myeloma at The Tisch Cancer Institute at Mount Sinai, the other senior author of the study, added, “Our findings provide the basis for improving patient selection for targeted agents using a small panel of genes to guide precise application of these drugs in real world scenarios, including relapse following CAR-T, an increasingly important clinical challenge in Myeloma.”

Selinexor has proven helpful for patients who failed other FDA-approved therapies for multiple myeloma. However, the majority of patients who take the drug experience side effects, sometimes severe, so it is important to identify patients who will respond positively and potentially expand the use of the drug into patients who haven’t failed other therapies.

As a result of this study, Mount Sinai has begun to further study tests for this signature to identify patients who may benefit from selinexor in patients who qualify to use the drug as well as patients who participate in a precision medicine clinical trial launching soon.

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