Selinexor (Xpovio) approved for use in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and a CD38-targeted monoclonal antibody.
It is approved for the treatment of patients with relapsed/refractory multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody
The drug inhibits chromosomal maintenance protein exportin-1 (XPO1), a nuclear export protein that mediates the transport of more than 200 cargo proteins, including most tumor-suppressor proteins.
Exportin-1 is the sole known nuclear exporter of tumor suppressor proteins, the glucocorticoid receptor, and oncoprotein messenger RNA’s and is over expressed in myeloma correlating with increase bone disease and shorter survival.
Induces apoptosis is myeloma cell lines.
It works to block the export process by binding to other proteins within the nucleus of the cell and shuttling them through the nuclear pores into the cytoplasm in the rest of the cell.
In an open-label, phase II STORM trial, in which the overall response rate (ORR) was 25.3%.
The complete response rate was 1%, the very good partial response rate was 5%, and the partial response rate was 19%.
Patients were treated with selinexor (80 mg) in combination with dexamethasone (20 mg) on days 1 and 3 of every week, which is the recommended dosage.
The overall response rate was 25.3%, with 1 stringent complete response (CR), no CR, 4 very good partial responses, and 16 partial responses.
The median time to first response was 4 weeks.
The median response duration was 3.8 months.
Common adverse reactions reported in at least 20% of patients include thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.
The recommended starting dosage of selinexor is 80 mg orally on days 1 and 3 weekly until disease progression or unacceptable toxicity, and the dexamethasone dosage is at 20 mg orally on days 1 and 3 weekly.
In the study, patients had undergone a median of 7 prior treatments (range, 3-18), and all were refractory to proteasome inhibitor/immunomodulatory drugs/daratumumab/glucocorticoid.
Additionally, 96% of patients were refractory to carfilzomib/pomalidomide/daratumumab, 84% had undergone stem cell transplant, and 28% had undergone ≥2 transplants.
Selinexor approved in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least 1 previous therapy.
Selinexor addresses a critical need for patients with multiple myeloma given its novel mechanism of action, convenient oral administration and established rapid and sustained efficacy profile.
The phase 3 BOSTON trial, in which the selinexor combination resulted in a statistically significant improvement in progression-free survival (PFS) vs bortezomib/dexamethasone alone in patients with multiple myeloma who had previously received 1 to 3 lines of treatment.
Median PFS was 13.93 months with the selinexor regimen vs 9.46 months with bortezomib/dexamethasone alone,
and translated to a 30% reduction in the risk of disease progression or death (HR, 0.70).
The PFS benefit proved to be consistent across all subgroups analyzed, including age, high-risk cytogenetics, frailty, prior proteasome inhibitor treatment, prior receipt of lenalidomide (Revlimid), and number of previous lines of therapy.
The triplet was also associated with a higher overall response rate (ORR) in the overall population and across patient subsets.
The ORR in the total study population was 76.4% with the selinexor triplet vs 62.3% with the doublet.
The median time to response was 1.1 months with the triplet vs 1.4 months with the doublet, and the median duration of response was 20.3 months vs 12.9 months, respectively.
Adverse reactions occurring in ≥20% of patients included anemia (65.9%), leukopenia (30.9%), neutropenia (38.2%), thrombocytopenia (71.5%), constipation (22%), diarrhea (42.3%), nausea (69.9%), vomiting (37.4%), fatigue (72.4%), weight decreased (48.8%), decreased appetite (53.7%), hyponatremia (35%), and dyspnea (21.1%).3
Almost one-third of patients discontinued study treatment due to adverse effects.
The FDA has approved selinexor as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma, who have received ≥2 prior therapies.
The phase 2b SADAL trial, in which Selinexor demonstrated a 28.3% overall response rate (ORR), including an 11.8% complete response (CR) rate and a median duration of response of over 9 months.
Selinexor is an oral selective inhibitor of exportin 1 (XPO1), which is the major nuclear export protein for tumor suppressor proteins and eIF4E-bound oncoprotein RNAs.
XPO1 inhibition via selinexor promotes nuclear localization of eIF4E and activation of tumor suppressor proteins relevant to non-Hodgkin lymphoma including p53, p21, and IκBα, along with reductions in c-Myc and Bcl-2 oncogenes.
SADAL findings of 127 evaluable patients who had received a median of 2 prior treatment regimens: 28.3% ORR comprised 36 responses, with a disease control rate was 37%.
Deep and durable responses occurred in patients, regardless of DLBCL subtype.
Selinexor induces a clinical benefit in patients with relapsed/refractory diffuse large B-cell lymphoma across age groups.
The complete response (CR) rates were 17.3% and 11.0%, respectively (P = .431); the partial response (PR) rates were 19.2% in younger patients vs 13.4% with older patients.
The median duration of response (DOR) was 9.7 months in patients younger than age 65 compared with 9.2 months in those who are 65 years and older.
Selinexor is an oral option for patients with relapsed DLBCL, including older patients.
In the multicenter, open-label, phase 2b SADAL study, investigators evaluated 60-mg of twice-weekly selinexor monotherapy administered in 28-day cycles.
Previously, shown that selinexor elicited an ORR of 29% including a CR rate of 13%, and a 15.7% PR rate.
A total 8.2% of patients had stable disease and 62.7% had either progressive disease or were not evaluable.
Overall, the median DOR was 9.3 months.
The median time to at least a PR was 8.1 weeks.
In the post-hoc analysis presented at the 2020 ASH Annual Meeting, investigators sought to determine whether there were differences in efficacy and safety of patients with relapsed/refractory DLBCL when stratified by age: younger than 65 years old (39%) or at least 65 years old (61%)
Regarding DLBCL subtypes, patients had germinal center B ([GCB] 53.8%), non-GCB (40.4%), or non-classified disease (5.8%).
The median OS was higher in the younger patient group, at 13.7 months compared with 7.8 months in those aged 65 years and older.
The analysis showed that selinexor is effective in de novo DLBCL, which showed an ORR of 26.2% and in transformed lymphoma (38.7%).
Increase in Progression-Free Survival in Patients with Advanced or Recurrent Endometrial Cancer.
Most common treatment related adverse reactions were: thrombocytopenia, nausea, and fatigue.
Common nonhematologic AEs: mostly nausea (52.8%), fatigue (37.8%), and anorexia (34.6%).
Grade 3/4 AEs include: thrombocytopenia (39.4%), neutropenia (20.5%), and anemia (13.4%).