In Heavily Treated Myeloma Patients, Selinexor-Dexamethasone Combo Shows Positive Results

Patients with heavily treated multiple myeloma have promising response rates when treated with a combination of selinexor (KPT-330) and low-dose dexamethasone, according to the results of a Phase 2b clinical trial.

Selinexor, a first-in-class oral selective inhibitor of nuclear export, is currently being developed for a variety of advanced hematologic and solid tumors, including multiple myeloma, acute myeloid leukemia, B-cell lymphoma, and liposarcoma.

It binds selectively to the XPO1 protein, a nuclear export protein, leading to the accumulation of tumor suppressor proteins in the cell nucleus, and resulting in the selective induction of cell death in the cancer cells.

The Phase 2b STORM trial (NCT02336815) is a multi-center, single-arm study designed to evaluate selinexor in combination with low-dose dexamethasone in heavily treated multiple myeloma patients. The study enrolled 78 patients, 48 of whom had quad-refractory disease, and 30 of whom had penta-refractory disease.

Patients with quad-refractory disease are those who previously received two proteasome inhibitors: Velcade (bortezomib) and Kyprolis (carfilzomib), and two immunomodulatory agents: Revlimid (lenalidomine) and Pomalyst (pomalidomide). Also, their disease is refractory (does not respond) to at least one treatment of each category, and has progressed after their most recent treatment.

Those with penta-refractory disease are similar to patients with quad-refractory disease but are also refractory to an anti-CD38 monoclonal antibody, such as Darzalex (daratumumab) or isatuximab.

“Although treatment of multiple myeloma has improved dramatically, eventually many patients will develop refractory disease, no longer responding to any of the immunomodulatory agents and proteasome inhibitors commonly used (quad-refractory). These patients will also eventually progress on anti-CD38 monoclonal antibodies, which we refer to as penta-refractory disease,” Keith Stewart, MB, ChB, the Anna Maria and Vasek Polack Professor of Cancer Research at the Mayo Clinic and lead investigator of the STORM study, said in a press release. “These are clearly the patients with the highest unmet need, as they have no remaining viable treatment options.”

Importantly, the study’s overall response rate (ORR) was 20.5 percent, with those with quad-refractory disease having an ORR of 20.8 percent and those with penta-refractory disease showing an ORR of 20 percent.

The researchers report that the side effect profile of selinexor was similar to that observed in previous trials, with no safety signals identified.

“We are currently unaware of any other therapy, oral or intravenous, reporting such activity in these difficult-to-treat patients who have exhausted all available therapies,” Stewart said.

Based on these positive top-line results, Karyopharm Therapeutics, which developed selinexor, is now planning on expanding the STORM study to include 120 additional patients with penta-refractory disease. Results of the expanded cohort are expected in early 2018.

Assuming positive outcomes and given the unmet need of heavily treated multiple myeloma patients, the company intends to use STORM data to support a request to the U.S. Food and Drug Administration to grant an accelerated approval for selinexor in multiple myeloma.

In addition to the STORM study, Karyopharm has also started the Phase 1b/2 STOMP multi-arm clinical trial (NCT02343042) to evaluate selinexor and low-dose dexamethasone in combination with currently existing therapies for the multiple myeloma population, including Velcade, Pomalyst, or Revlimid. The combinations will be evaluated in separate arms, and selinexor will be tested in doses of once and twice a week.

Dose escalation has already been completed for the Velcade arm, and the recommended dose has been determined. This will provide information for a new Phase 3 study Karyopharm intends to initiate.

The BOSTON Phase 3 trial will evaluate selinexor in combination with low-dose dexamethasone and Velcade compared to low-dose dexamethasone and Velcade in multiple myeloma patients who have already received one to three previous lines of therapy. The trial is expected to begin in early 2017 and will enroll approximately 360 patients.

“Myeloma continues to be an incurable blood cancer in most patients and our main goal in treating refractory disease is to induce responses and maintain them as long as possible,” said Dr. Sagar Lonial, MD, professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine and chief medical officer at Emory’s Winship Cancer Institute.

“In addition to these new data with oral selinexor and low-dose dexamethasone, the emerging clinical data from selinexor in combination with [Velcade], including in proteasome-inhibitor refractory disease, suggests a synergistic effect and favorable safety profile. These data are quite exciting and will form the basis for future studies,” Lonial said.