NEWTON, Mass.—Karyopharm Therapeutics Inc. has just announced that the results of the Phase 2b STORM study evaluating Xpovio (selinexor) in patients with heavily pretreated, triple class refractory multiple myeloma. The data have been published online in the New England Journal of Medicine. The STORM study evaluated Xpovio and low-dose dexamethasone in patients with triple class refractory multiple myeloma who were previously treated with all five of the most commonly prescribed anti-myeloma therapies currently available.
“We are pleased to have the STORM study results published in such a highly esteemed, peer-reviewed journal and this publication further supports the potential utility of oral Xpovio in patients with highly refractory multiple myeloma,” said Sharon Shacham, Ph.D., MBA, president and chief scientific officer of Karyopharm. “With the recent accelerated approval of oral Xpovio, patients with heavily pretreated myeloma now have a new therapeutic option to treat their disease.”
Xpovio is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound. Xpovio functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). Xpovio blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion.
Xpovio received accelerated approval from the U.S. Food and Drug Administration (FDA) on July 3 for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval, based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
“Despite the availability of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents and monoclonal antibodies for the treatment of multiple myeloma, most patients will, regrettably, have disease that continues to progress. An increasing number of patients are developing highly refractory disease and have no remaining treatment options of known clinical benefit,” added Paul G. Richardson, M.D., Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, and co-lead author of the manuscript.
The published results are from Part 2 of the international, multi-center, single-arm Phase 2b STORM (Selinexor Treatment of Refractory Myeloma) study, which enrolled 122 patients with heavily pretreated, triple class refractory multiple myeloma in the U.S. and Europe. These patients had a median of seven previous therapeutic regimens, including a median of 10 unique antimyeloma agents. Patients in the STORM study had rapidly progressing myeloma, with a 22% increase in disease burden in the 12 days from screening to initial therapy.
For the STORM study’s primary endpoint, oral selinexor achieved an overall response rate of 26%, including two (2%) stringent complete responses (sCRs), six (5%) very good partial responses and 24 (20%) partial responses (PRs). Both patients who had relapsed after CAR-T therapy achieved PRs. Minimal response was observed in 16 (13%) patients and 48 patients (39%) had stable disease. Median time to partial response or better was 4.1 weeks. Clinical benefit rate (≥ minimal response), was 39%. All responses were adjudicated by an Independent Review Committee.
Median duration of response was 4.4 months. Progression-free survival was 3.7 months, and overall survival (OS) was 8.6 months. In the 39% of patients who achieved a partial or minimal response or better, median OS was 15.6 months, compared to a median OS of 1.7 months in patients whose disease progressed or where response was not evaluable (p<0.0001).
The adverse events observed in the study were a function of dose, schedule and baseline clinical characteristics (e.g., cytopenias). The most common treatment-emergent adverse events (AEs) were thrombocytopenia (73%), nausea (72%), anemia (67%), and fatigue (73%). The most common Grade 3/4 treatment-emergent AEs were thrombocytopenia (59%), anemia (44%), neutropenia (21%) and hyponatremia (22%). Most non-hematologic AEs were limited in severity to grades 1 or 2, with only 10% experiencing grade 3 nausea and 3% experiencing grade 3 emesis.
18% of patients discontinued study treatment because of an AE considered by the investigator related to study drug. AEs leading to dose modification or holds occurred in 80% of patients, with the majority occurring in the first 2 cycles. The most common AEs leading to dose reduction or interruption were thrombocytopenia (43%), fatigue (16%), and neutropenia (11%).
“The data from the STORM study demonstrate that oral selinexor, a first-in-class XPO1 inhibitor, combined with dexamethasone twice weekly, resulted in a response rate of 26% in heavily pretreated patients,” noted Sundar Jagannath, M.D., Tisch Cancer Institute at Mount Sinai School of Medicine, principal investigator of the STORM study and co-lead author of the manuscript. “The characteristics of the patients in the STORM study, including being heavily pretreated, yet still experiencing rapidly progressing disease, are consistent with the growing population of patients who have exhausted available myeloma therapies, but still desire to continue therapy. Of particular significance, for the 39% of patients who had a minimal response or better, overall survival was 15.6 months, compared to 1.7 months in patients whose disease progressed or where response was not evaluable.”
In addition to receiving accelerated FDA approval of Xpovio in combination with dexamethasone in July, Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency with a request for conditional approval of selinexor. Karyopharm expects to receive a decision on the MAA by the end of 2019 or early 2020.