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Results reported from a group of patients with heavily pretreated multiple myeloma who were administered the combination of selinexor plus pomalidomide and low-dose dexamethasone produced positive responses and provided rationale for further investigation into the regimen.
Darrell J. White, MD
Results reported from a group of patients with heavily pretreated multiple myeloma who were administered the combination of selinexor (Xpovio) plus pomalidomide (Pomalyst) and low-dose dexamethasone (Pd) produced positive responses and provided rationale for further investigation into the regimen.1
In patients treated with the recommended phase 2 dose (RP2D) of selinexor plus Pd, the objective response rate (ORR) was 60.0% with most patients achieving a deep response, according to Darrell J. White, MD, who presented the data at the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition. These results compare favorably with historical controls of Pd alone in patients with relapsed or refractory multiple myeloma with response rates of about 30%.2 The median progression-free survival (PFS) in those receiving the RP2D was not reached at the time of data reporting and was over a year in all patients treated with selinexor plus Pd.
“Selinexor once-weekly can be safely combined with pomalidomide and low-dose dexamethasone in patients with heavily pretreated multiple myeloma,” said White, who is a professor in the Division of Hematology, Department of Medicine and senior associate dean at Dalhousie Medical School in Halifax, Canada.
Selinexor is a first-in-class selective inhibitor of the nuclear export protein exportin 1 (XPO1), which is responsible for exporting over 200 cargos including tumor-suppressor proteins such as p53 and Ikb. It moves them from the nucleus of the cell to the cytoplasm, thereby making them functionally inactive. Elevated XPO1 expression has been observed in multiple myeloma and is correlated with poor prognosis and drug resistance. Therefore, use of selinexor induces cell death by reactivation of tumor-suppressor proteins.
Accelerated approval was granted in July of 2019 to the combination of selinexor and dexamethasone in adult patients with relapsed or refractory multiple myeloma following at least 4 prior therapies, including 2 proteasome inhibitors (PIs), 2 immunomodulatory agents (IMiDs), and an anti-CD38 monoclonal antibody based on results of the phase 2 STORM trial (NCT02336815).3
“Selinexor has [also] shown synergistic activity in combination with lenalidomide [Revlimid] in vivo, [which] of course has a chemical structure similar to pomalidomide,” White said. “We therefore hypothesized that the all-oral combination of weekly selinexor with standard pomalidomide and dexamethasone would be an active combination.”
Selinexor continues to be explored as a once-weekly, low-dose regimen for earlier lines of therapy in combination with other agents by way of the multi-arm STOMP trial (NCT02343042). For all arms, including arm 1 of the trial whose results are presented herein for selinexor plus Pd, primary end points were maximum tolerated dose (MTD), RP2D, and the ORR. Secondary outcome measures included safety and PFS.
Patients could be enrolled onto the trial if they had progression on or were refractory to their previous treatment for multiple myeloma and had undergone 2 or more cycles of lenalidomide and a PI. Prior pomalidomide exposure was only allowed in the escalation phase and patients with smoldering or non-secretory multiple myeloma or active plasma cell leukemia were not allowed.
In total, 65 patients were enrolled to different doses of selinexor plus Pd, with a median number of prior therapies of 3 (range, 1-10). All patients had prior lenalidomide and most (87.7%) were refractory to that therapy; most patients had received bortezomib (92.3%).
Similar characteristics were seen in the 20 patients who were treated with the recommended RP2D, which was selinexor at 60 mg on days 1, 8, 15, and 22 plus pomalidomide at 4 mg on days 1 through 21 of each 28-day cycle.
In 46 patients who were pomalidomide naïve or nonrefractory, the ORR was 54.3% with 1 complete response and 9 very good partial responses (VGPR). In those who were pomalidomide refractory (n = 14), the ORR was 35.7% with 1 VGPR.
Median PFS in all patients treated in the selinexor-plus-Pd arm was 12.2 months and was 12.3 months in those who were pomalidomide naïve or nonrefractory. Duration of response was 11.3 months in all patients and was not reached in those receiving the RP2D.
Adverse effects (AEs) of the combination were mostly hematologic, including all-grade and grade 3/4 events of neutropenia (60.3% vs 54.0%, respectively), anemia (54.0% vs 33.3%), thrombocytopenia (54.0% vs 31.7%), and leukopenia (23.8% vs 12.7%). Nonhematologic AEs were mostly low-grade and included nausea (60.3% vs 1.6%), fatigue (50.8% vs 9.5%), decreased appetite (44.4% vs 1.6%), and diarrhea (28.6% vs 0%). These were managed with supportive care and dose modifications.
“These data support a planned phase 3 study [XPORT-MM-031] of the combination of SPd [selinexor or Pd] in patients who have had prior PI, IMiDs, and CD38 monoclonal antibody treatment,” White concluded.