Three-gene signature predicts selinexor response in patients with multiple myeloma

ByJennifer R. Southall

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Patients with multiple myeloma tumors that featured a three-gene signature demonstrated a higher likelihood of achieving a durable and deep response to selinexor, according to study results published in JCO Precision Oncology.

Rationale and methods

Selinexor (Xpovio; Karyopharm Therapeutics) is an oral selective inhibitor of nuclear export compound. The drug binds with and inhibits the nuclear export protein XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus.

“Selinexor is an approved therapeutic for patients with relapsed or refractory multiple myeloma. However, not all patients respond and some may experience severe side effects,” Alessandro Laganà, PhD, assistant professor of oncological sciences at The Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai, told Healio. “We, therefore, sought to investigate the molecular mechanisms that could help us identify who would benefit the most from this treatment.”

Laganà and colleagues sequenced RNA data from bone marrow of 100 patients treated with selinexor for multiple myeloma included in the BOSTON study and identified a novel three-gene signature — ETV7, DUSP1 and WNT10A — activated in patients who responded positively to treatment.

They then validated the gene signature in an independent cohort of 64 patients included in the STORM trial and in an external cohort of 35 patients treated in a real-world setting.

Key findings

Results showed the three-gene signature identified deep and durable responses to treatment with selinexor. Researchers found the signature revealed a potential mechanism through upregulated interferon-mediated apoptotic signaling that may aid in tumor response to selinexor.

Results of a subcohort of patients with recurrent glioblastoma further validated the three-gene signature.

Implications

“These results have important clinical implications, since we now have a tool to guide the use of selinexor in patients with multiple myeloma in a more precise manner, particularly in advanced disease settings such as in patients who relapse from [chimeric antigen receptor T-cell] therapies,” Laganà said.

“We are launching a clinical trial soon, where we will evaluate the use of targeted therapies recommended based on specific genetic and molecular markers, including our novel signature for selinexor,” he said. “We are also investigating the molecular mechanisms underlying the activation of these genes in patients who respond to the treatment and how we can leverage this information to identify possible therapeutics that could synergize with selinexor to ultimately expand its benefits to a larger group of patients.”