Selinexor plus dexamethasone induced objective responses and a significant overall survival among heavily pretreated patients with multiple myeloma, according to results from the phase IIb STORM trial published in <em>The New England Journal of Medicine.</em>
Sundar Jagannath, MD
Selinexor (Xpovio) plus dexamethasone induced objective responses and a significant overall survival (OS) among heavily pretreated patients with multiple myeloma, according to results from the phase IIb STORM trial published inThe New England Journal of Medicine.1
A minimal response or better was achieved in 39% of patients and the median OS was 8.6 months among patients who were triple-class refractory.
“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. 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,” Sundar Jagannath, MBBS, Tisch Cancer Institute at Mount Sinai School of Medicine, principal investigator of the STORM study and co-lead author of the published report, said in a statement.
The findings from the STORM trial come about a month and a half after the FDA granted an accelerated approval to the first-in-class selective inhibitor of nuclear export compound for adult patients with relapsed or refractory multiple myeloma who had received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.2
The multicenter, open-label trial enrolled 123 patients with previously treated multiple myeloma across the United States and Europe to be treated with the combination of selinexor and dexamethasone. All patients had received prior treatment with bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), daratumumab (Darzalex), glucocorticoids, and an alkylating agent. Additionally, patients were refractory to at least 1 immunomodulatory drug, 1 proteasome inhibitor, daratumumab, glucocorticoids, and the patient’s most recent treatment regimen.1
Eligible patients had an ECOG performance status of 0 to 2 and adequate hepatic, renal, and hematopoietic function. Patients were excluded from the trial if they had systemic light-chain amyloidosis, active central nervous system involvement, grade ≥3 peripheral neuropathy, or grade ≥2 painful neuropathy.
Selinexor was administered orally at 80 mg plus dexamethasone at 20 mg weekly on days 1 and 3 of each 4-week cycle until disease progression, death, or discontinuation. Ondansetron 8 mg was also given before the first dose of the study drug as an antiemetic, then 2 or 3 times daily as needed.
The primary endpoint of the study was overall response, and secondary endpoints included response duration, clinical benefit (confirmed minimal response or better), progression-free survival (PFS), and OS.
One enrolled patient did not meet the full eligibility criteria since the patient had not received prior carfilzomib, so 122 penta-refractory patients were included in the intention-to-treat population. The median patient age was 65.2 years and 53% had high-risk cytogenetic abnormalities. The patients had a median of 6.6 years (range, 1.1-23.4) since their initial diagnosis of multiple myeloma. All of the patients had progressive disease at the time of enrollment in the trial, which was rapidly progressing in 88%. The median number of prior therapies was 7 (range, 3-18) and 84% had already received a stem cell transplantation.
As of the data cutoff, 96% of patients had discontinued treatment due, most commonly, to disease progression or adverse events (AEs), with only 4% continuing on treatment. Eighteen percent of discontinuations were due to AEs considered to be related to the study drugs. The median duration of treatment was 9.0 weeks (range, 1-60).
Twenty-six percent of patients achieved a partial response or better (95% CI, 19%-35%), which included 2 stringent complete responses, 6 very good partial responses, and 24 partial responses. This met the trial’s primary endpoint as the lower boundary of the confidence interval was more than 10%. The median time to a partial response or better was 4.1 weeks (range, 1-14).
Minimal responses, defined as ≥25 to <50% reduction in the serum level of myeloma protein, were observed in 13% of patients, and an additional 39% had stable disease.
The median duration of response was 4.4 months (95% CI, 3.7-10.8) and the median PFS was 3.7 months (95% CI, 3.0-5.3). The median OS among patients who achieved a minimal response or better was 15.6 months.
The most frequent AEs observed included thrombocytopenia in 73% of patients, fatigue in 73%, nausea in 72%, and anemia in 67%. The most common grade 3/4 AEs included thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%). Most of the nonhematologic AEs were grade 1/2 in severity.
Serious adverse events occurred in 63% of patients, including most commonly pneumonia (11%) and sepsis (9%).
Dose modification or interruption due to AEs occurred in 80% of patients, mostly within the first 2 cycles of treatment. Twenty-eight patients died during the study with 16 due to disease progression and 12 due to AEs, 2 of which were considered by investigators to be related to treatment.
“Despite the availability of proteasome inhibitors, immunomodulatory drugs, 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,” Paul G. Richardson, MD, from the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, and co-lead author of the published report, said in a statement about the drug’s importance.