Selinexor Combo Yields Strong Responses in Difficult-to-treat Multiple Myeloma

Selinexor in combination with dexamethasone and Pomalyst (pomalidomide) leads to strong and durable anti-cancer responses, without significant side effects, in patients with relapsed or refractory multiple myeloma who received at least two prior therapies, data from a Phase 1/2b trial show.

The findings were presented in a poster titled, “Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma (RRMM),” at the 24th Congress of the European Hematology Association, June 13-16 in Amsterdam.

Selinexor, Karyopharm Therapeutics‘ lead compound, is an oral inhibitor of the XPO1 protein that prevents tumor suppressor proteins from exiting the cell nucleus. This leads to cancer cell death, while healthy cells are mostly spared.

The safety and efficacy of selinexor in combination with low doses of dexamethasone and standard therapies for multiple myeloma — Kyprolis (carfilzomib), Darzalex (daratumumab), or Pomalyst — are being tested in three groups of relapsed or refractory multiple myeloma patients in the Phase 1/2b STOMP trial (NCT02343042).

As of May, 45 patients who had received at least two prior therapies with a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or had failed to respond to both, were enrolled in the SPd (selinexor plus Pomalyst and dexamethasone) arm of the trial.

In this group of patients, the effects of selinexor (60 mg or 80 mg) administered orally once or twice a week, are being assessed in combination with Pomalyst (2 mg, 3 mg, or 4 mg) administered orally once a day, and dexamethasone administered orally at a dose of 40 mg once a week or at 20 mg twice a week.

From the 40 patients who were eligible for efficacy assessments, the overall response rate was 57% among those who had never been treated with Pomalyst and were refractory or had relapsed while on Revlimid (lenalidomide), with 23% of the patients achieving a very good partial response. The median progression-free survival (PFS, the time patients lived without their disease worsening) in this group of patients was 12.2 months.

Conversely, among those who were refractory to both Pomalyst and Revlimid, the response rate was 30%, corresponding to 30% of patients achieving a partial response. The median PFS in this group of patients was 4.2 months.

Among the 45 patients eligible for safety assessments, the most common treatment-related adverse events reported among patients from the SPd arm included abnormalities in blood cell counts (cytopenias), gastrointestinal and constitutional symptoms — those that affect different parts of the body, including weight loss, fever, and headache).

Nevertheless, most of these adverse events were easily manageable with therapy dose adjustments and/or supportive care.

The most common non-hematologic treatment-related adverse events reported during the study were either mild or moderate, and included nausea (56%), fatigue (53%), and anorexia (49%).

The determination of the recommended phase 2 dose (RP2D) for patients enrolled in the SPd arm of STOMP is ongoing.

In another poster titled, “A Phase 1b/2 Study of Selinexor, Carfilzomib, and Dexamethasone (SKd) in Relapsed/ Refractory Multiple Myeloma (RRMM),” Karyopharm presented data from patients who had been enrolled in the SKd (selinexor plus Kyprolis and dexamethasone) arm of STOMP.

In this group of patients, the effects of selinexor (80 mg or 100 mg) administered orally once a week, are being assessed in combination with Kyprolis (56 mg/m² or 70 mg/m²) administered once a week, and dexamethasone administered orally at a dose of 40 mg once a week or at 20 mg twice a week.

According to findings presented at the congress, from the nine patients enrolled in this treatment regimen so far, 78% responded to treatment, including 56% very good partial responses and 22% complete responses. Two patients (22%) had stable disease (SD).

As in the previous treatment regimen, the RP2D for patients enrolled in the SKd arm of the trial is ongoing.

In an oral presentation titled, “Safety and Efficacy of combination of Selinexor, Daratumumab, and Dexamethasone (SDd) in Patients with Multiple Myeloma (MM) Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs,” the company presented data from patients who had been enrolled in the SDd (selinexor plus Darzalex and dexamethasone) arm of the trial.

In this group, the effects of selinexor administered orally at 100 mg once a week or at 60 mg twice a week are being assessed in combination with Darzalex (16mg/kg) administered intravenously once a week, and dexamethasone administered orally at a dose of 40 mg once a week or at 20 mg twice a week.

According to data presented at the meeting, from the 32 patients enrolled in this treatment regimen so far – all of whom had never been treated with Darzalex – the response rate was 73%, including 37% very good partial responses.

Based on tolerability and efficacy data gathered thus far, the RP2D for patients enrolled in the SDd arm of STOMP has been set at 100 mg of selinexor, 16 mg/kg of Darzalex, and 40 mg of dexamethasone, all administered once a week.

“Preliminary data from the Kyprolis arm of the Phase 1b/2 STOMP study show early but encouraging clinical activity, including two patients who achieved a complete response, along with an expected and manageable tolerability profile, in patients with heavily pretreated, double-refractory Kyprolis-naïve multiple myeloma,” Sharon Shacham, PhD, MBA, president and chief scientific officer of Karyopharm, said in a press release.

“Additionally, the Darzalex and Pomalyst arms of the STOMP study continue to demonstrate impressive response rates, including encouraging rates of very good partial responses (VGPR), which indicate a 90% or greater reduction in a patient’s disease burden,” Shacham said.