In the Clinic provides overviews of novel hematology and oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On July 3, 2019, the oral nuclear export inhibitor selinexor was granted accelerated approval for use in combination with dexamethasone for adult patients with relapsed or refractory multiple myeloma 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.^1,2

Supporting Efficacy Data

Efficacy was evaluated in 122 patients enrolled in part 2 of STORM (KCP-330-012; ClinicalTrials.gov identifier NCT02336815), a multicenter, single-arm study of patients with relapsed or refractory multiple myeloma who had previously received 3 or more antimyeloma treatment regimens including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti-CD38 monoclonal antibody.² Disease had to be refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and to the last line of therapy. Patients received selinexor at 80 mg in combination with dexamethasone at 20 mg on days 1 and 3 of every week. Treatment continued until disease progression or unacceptable toxicity.

The current approval was based on the efficacy and safety in a prespecified subgroup of 83 patients in the study whose disease was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. The overall response rate was 25.3%, with 1 stringent complete response, 4 very good partial responses, and 16 partial responses. The median time to first response was 4 weeks (range = 1–10 weeks). The median response duration was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing randomized trial in patients with multiple myeloma.

How It Works

In nonclinical studies, selinexor reversibly inhibits nuclear export of tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). Inhibition of XPO1 by selinexor leads to accumulation of TSPs in the nucleus, reduction in several oncoproteins (such as c–Myc and cyclin D1), cell-cycle arrest, and apoptosis of cancer cells. Selinexor demonstrated proapoptotic activity in vitro in multiple myeloma cell lines and patient tumor samples as well as in murine xenograft models.

How It Is Used

The recommended starting dosage of selinexor is 80 mg on days 1 and 3 of each week until disease progression or unacceptable toxicity. The recommended starting dosage of dexamethasone is 20 mg orally, with each dose of selinexor on days 1 and 3 of each week.

Patients should undergo monitoring of complete blood cell counts, standard blood chemistry, and body weight at baseline and during treatment as clinically indicated, with more frequent monitoring during the first 2 months of treatment. Patients should be advised to maintain adequate fluid and caloric intake throughout treatment, with intravenous hydration considered for patients at risk of dehydration. Prophylactic concomitant treatment with a 5−hydroxytryptamine antagonist (eg, ondansetron) or other antinausea agents should be given prior to and during treatment.

The dose of selinexor can be reduced to 100 mg, 80 mg, and 60 mg once weekly for adverse reactions. The prescribing information provides detailed instructions on dosage modification and management of thrombocytopenia, neutropenia, anemia, hyponatremia, fatigue, nausea and vomiting, diarrhea, weight loss and anorexia, as well as other grade 3 or 4 nonhematologic adverse reactions.

Safety Profile

Safety data are available from 202 patients with relapsed or refractory multiple myeloma who received selinexor at 80 mg in combination with dexamethasone at 20 mg on days 1 and 3 of every week. The most common adverse events of any grade in these patients were  thrombocytopenia (74%), fatigue (73%), nausea (72%), anemia (59%), decreased appetite (53%), decreased weight (47%), diarrhea (44%), vomiting (41%), hyponatremia (39%), neutropenia (34%), leukopenia (28%), constipation (25%), dyspnea (24%), and upper respiratory tract infection (21%). The most common grade ≥ 3 adverse events were thrombocytopenia (61%), anemia (40%), fatigue (22%), hyponatremia (22%), neutropenia (21%), leukopenia (11%), lymphopenia (10%), nausea (9%), and pneumonia (9%).

Adverse events led to a reduction in the dose of selinexor in 53% of patients, dose interruption in 65%, and treatment discontinuation in 27%. The most common causes of treatment discontinuation occurring in at least 4% of patients were fatigue, nausea, and thrombocytopenia. Fatal adverse events occurred in 8.9% of patients.

Selinexor has warnings/precautions for thrombocytopenia, neutropenia, gastrointestinal toxicity (including nausea, vomiting, diarrhea, anorexia, and weight loss), hyponatremia, infections, neurologic toxicity (including dizziness and confusion), and embryofetal toxicity. Patients should be advised not to breastfeed while receiving selinexor. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to selinexor for multiple myeloma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selinexor-multiple-myeloma. Accessed July 23, 2019.

2. Xpovio (selinexor) tablets prescribing information, Karyopharm Therapeutics Inc, July 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212306s000lbl.pdf. Accessed July 23, 2019.