The trial’s findings were reported in “Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma,” a study published in the New England Journal of Medicine.
Xpovio, Karyopharm Therapeutics‘ lead compound, is a first-in-class oral inhibitor of the XPO1 protein. It works by preventing tumor suppressor proteins from exiting the cell nucleus. This leads to cancer cell death, while healthy cells are spared.
The U.S. Food and Drug Administration (FDA) had previously awarded Xpovio both fast track and orphan drug status. More recently, the U.S. agency granted accelerated approval to a combination of Xpovio plus dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who received at least four prior therapies and failed to respond to treatment.
This type of endorsement allows a medication that addresses an unmet need in a serious medical condition to be used if it shows benefits on surrogate or interim measures made in a clinical trial. However, the treatment’s continued use — and full approval — requires a further showing of efficacy in a confirmatory study.
That study assessed the safety and efficacy of Xpovio (80mg), in combination with dexamethasone (20mg), in relapsed or refractory multiple myeloma patients who had received at least three prior therapies. The treatment was given twice per week until disease progression, death, or unacceptable toxicity.
In Part 2 of STORM, treatment efficacy and safety were assessed in a group of individuals with penta-refractory disease. These patients had received prior treatment with two proteasome inhibitors, namely Velcade (bortezomib) and Kyprolis (carfilzomib); two immunomodulatory agents, specifically Revlimid (lenalidomide) and Pomalyst (pomalidomide); and the anti-CD38 monoclonal antibody Darzalex (daratumumab).
Penta-refractory patients’ disease does not respond to at least one proteasome inhibitor and one immunomodulatory agent, and Darzalex, and has progressed following their most recent therapy.
The study’s primary outcome was to assess participants’ overall response to treatment. This was defined as achieving a partial response — more than 50% reduction in the amount of myeloma protein found on the patients’ serum — or better, by an independent review committee (IRB). Myeloma protein is an abnormal protein fragment that tends to be excessively produced by malignant myeloma cells and is often used as an indicator of disease burden.
The secondary outcome was to assess the therapy’s clinical benefit, which was defined as achieving a minimal response or better. A minimal response is a 25-50% reduction in the amount of myeloma protein found on the patients’ serum.
Key findings from the first 122 patients eligible for treatment response analyses — who had received a median of seven previous regimens — demonstrated that 26% achieved a partial response or better, and 39% achieved a minimal response or better. The median response duration was 4.4 months.
The median progression-free survival, or the time participants lived without their disease worsening, was 3.7 months. The median overall survival was 8.6 months.
Among the 123 participants who were included in the safety analyses, the most common mild (grade) or moderate (grade 2) adverse events observed included fatigue, nausea, and decreased appetite.
Severe (grade 3) adverse events were reported in 25% of patients, and included low platelet counts (without bleeds), anemia and low white blood cell counts (without fever), and low sodium levels. No life-threatening (grade 4) adverse events were reported.
“This study proved that a novel, first-in-class drug with a new mechanism of action can kill a patient’s cancer cells,” Sundar Jagannath, MBBS, director of the multiple myeloma program and professor of medicine at the Tisch Cancer Institute at Mount Sinai, a senior author of the study, said in a press release. “This proved that the drug worked in patients who had exhausted every other treatment and who would have been placed on hospice care otherwise.”
“This study is meaningful for patients with multiple myeloma who haven’t had success on multiple other therapies,” said Ajai Chari, MD, director of clinical research in the Tisch Institute’s multiple myeloma program, and first author of the study. “An increasing number of patients have resistance to the standard drugs used in the treatment of multiple myeloma, and the overall survival in these patients is short, sometimes less than three months.”
These findings represent a major breakthrough in myeloma research for investigators at the Tisch Cancer Institute, which recently opened a Center of Excellence for Multiple Myeloma. The center’s team of medical experts exclusively treat patients with this cancer.
“The Center of Excellence for Multiple Myeloma is part of The Tisch Cancer Institute and uses the most advanced diagnostic and treatment approaches within state-of-the-art facilities of a National Cancer Institute-designated cancer center,” said Ramon Parsons, MD, PhD, the Institute’s director and the chair of oncological Sciences at Mount Sinai.
“Coordinated care teams include experts from the Bone Marrow Transplant Program, pathology, radiology, immunology, genomics, infectious diseases, orthopedic surgery, cardiology, and nephrology, and patients will have broad access to comprehensive supportive services, including from social workers, financial counselors, and clergy,” Parsons added.
The effectiveness of Xpovio in combination with other approved medications to treat multiple myeloma is currently being explored in ongoing trials. Xpovio also is being investigated for the treatment of other types of cancers, including lymphoma and ovarian cancer.