Updated results from a Phase 2b clinical trial continue to support Karyopharm Therapeutics‘ investigative oral therapy selinexor (KPT-330) as a promising approach for heavily-treated multiple myeloma patients who have exhausted all approved therapies.
In the trial, STORM (NCT02336815), more than a quarter of patients responded to the treatment, with responses lasting a median of 4.4 months. Median overall survival was 8.6 months, but reached the 15.6-month mark in patients who achieved minimal disease or better.
The findings were recently presented at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting, Sept. 13 in Houston. The study, “Phase 2b Results of the STORM Study: Oral Selinexor plus Low Dose Dexamethasone (Sd) in Patients with Penta-Refractory Myeloma,” was presented by Sundar Jagannath, MD, principal investigator of the STORM study.
Selinexor, an inhibitor of the XPO1 protein, works by preventing tumor suppressor proteins from exiting the nucleus. These proteins prevent abnormal cell proliferation and induce the death of malignant cells, but tumors work their way around this by increasing the levels of XPO1, a protein that exports proteins from the nucleus into the cytoplasm.
By preventing XPO1 from functioning, tumor suppressor proteins accumulate in the nucleus, which cause cancer cells to die while leaving healthy cells unharmed.
STORM was designed to study selinexor in combination with low-dose dexamethasone, in a population of heavily treated multiple myeloma patients. In a first part, the study included 78 patients, including 48 with quad-refractory disease and 30 with penta-refractory disease.
Quad-refractory patients are those who received prior treatment with two immunomodulatory drugs —Revlimid (lenalidomide) and Pomalyst (pomalidomide) — and two proteasome inhibitors — Velcade (bortezomib) and Kyprolis (carfilzomib) — and have not responded to at least one proteasome inhibitor and one immunomodulatory drug.
Those with penta-refractory disease are similar to patients with quad-refractory disease, but also are refractory to an anti-CD38 monoclonal antibody, such as Darzalex (daratumumab), or isatuximab.
Initial results showed that 21% of quad-refractory patients and one in five penta-refractory patients responded to selinexor. The findings were so strinking that Karyopharm decided to expand STORM to include 120 additional penta-refractory myeloma patients.
The most recent results from Part 2 fo the study, presented at the SOHO meeting, have shown that 26.2% of patients responded to Selinexor, including two complete responses, six very good partial responses, and 24 partial responses.
An additional 52.6% of patients achieved stable disease after selinexor treatment, leading to a disease control rate of 78.6%.
Minimal residual disease is a measure that determines whether a patient still has myeloma cells in the blood or bone marrow that could lead to relapse. The two patients with complete responses were negative for minimal residual disease.
Patients lived without disease progression for a median of 3.7 months, and survived for a median of 8.6 months. But for the 40% of patients with minimal response or better, overall survival was 15.6 months, which contrasted largely with the 1.7 months seen in patients whose disease progressed while on selinexor.
Safety data was consistent with that obtained in Part 1 of the STORM study, with side effects being predictable and manageable with adjustments in dose or supportive care. Treatment-related adverse events were mostly mild-to-moderate, and included fatigue, nausea, anorexia, and weight loss. Low platelet levels and anemia were the most common severe or very severe side effects.
“The additional Phase 2b clinical results presented today are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Jagannath said in a press release. Jagannath is director of the Multiple Myeloma Program, professor of medicine (Hematology and Medical Oncology) at the Tisch Cancer Institute at Mount Sinai School of Medicine.
“Patients with highly resistant myeloma have very few treatment options available, which underscores the urgent need for the advancement of therapies with novel mechanisms, like selinexor,” said Sharon Shacham, PhD, founder, president and chief scientific officer of Karyopharm.
Karyopharm has submitted an application with the U.S. Food and Drug Administration (FDA) requesting selinexor’s accelerated approval for heavily treated myeloma patients, and expects to fill a conditional approval request with the European Medicines Agency in the beginning of 2019 for the same indication.
If the medicine is approved, the company will need to confirm the benefits of selinexor in additional studies. To this end, the company is already conducting the BOSTON Phase 3 trial (NCT03110562), testing selinexor in combination with Velcade and low-dose dexamethasone, in patients who received one to three prior treatments.