On December 18, 2020, selinexor was approved for use in combination with bortezomib and dexamethasone for treatment of adult patients with multiple myeloma who have received at least one prior therapy.^1,2

Selinexor received accelerated approval in 2019 for use in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who had received at least four prior therapies and had disease refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

Supporting Efficacy Data

Approval was based on findings in the open-label, phase III BOSTON trial (KCP-330-023, ClinicalTrials.gov identifier NCT03110562).^2,3 In the trial, 402 patients who had received no more than three prior therapies were randomly assigned to receive once-weekly oral selinexor in combination with once-weekly subcutaneous bortezomib and twice-weekly oral low-dose dexamethasone in 35-day cycles (SVd; n = 195) or standard twice-weekly bortezomib plus low-dose dexamethasone in 21-day cycles for the first eight cycles and in 35-day cycles thereafter (Vd; n = 207). Treatment was continued until disease progression or unacceptable toxicity. Patients with grade ≥ 2 peripheral neuropathy were excluded from the study.

For the SVd vs Vd groups, median age was 66 vs 67 years (44% vs 36% < 65 years), 59% vs 56% were male, and 83% vs 80% were White. Overall, 10% vs 8% had an Eastern Cooperative Oncology Group performance status ≥ 2, and 60% vs 60% had revised International Staging System stage II disease. The number of prior therapies was one for 51% vs 48%, two for 33% vs 31%, and three for 16% vs 21%. The most common known prior therapies were bortezomib (69% vs 70%), lenalidomide (39% vs 37%), and stem cell transplantation (39% vs 30%). Among those with a known cytogenetic status, 50% vs 46% had high-risk cytogenetics.

Median progression-free survival, as assessed by an independent review committee using International Myeloma Working Group response criteria, was 13.9 months (95% confidence interval [CI] = 11.7 months to not estimable) in the SVd group vs 9.5 months (95% CI = 7.6–10.8 months) in the Vd group (estimated hazard ratio = 0.70, 95% CI = 0.53–0.93; P = .0075). The overall response rate was 76.4% vs 62.3% (P = .0012), with a very good partial response or better in 44.6% vs 32.4% (P = .0082). The median duration of response was 20.3 months vs 12.9 months.

How It Works

In nonclinical studies, selinexor reversibly inhibits nuclear export of tumor-suppressor proteins, growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). XPO1 inhibition by selinexor leads to accumulation of tumor-suppressor proteins in the nucleus, reduction in several oncoproteins such as c-myc and cyclin D1, cell-cycle arrest, and apoptosis of cancer cells.

Selinexor exhibited proapoptotic activity in vitro in multiple myeloma cell lines and antitumor activity in murine xenograft models of multiple myeloma and diffuse large B-cell lymphoma. The combination of selinexor and dexamethasone or bortezomib demonstrated synergistic cytotoxic effects in multiple myeloma cell lines in vitro and increased antitumor activity in murine xenograft multiple myeloma models in vivo, including those resistant to proteasome inhibitors.

How It Is Used

The recommended dose of selinexor in the current indication is 100 mg once weekly on day 1 of each week of a 35-day cycle until disease progression or unacceptable toxicity in combination with bortezomib at 1.3 mg/m² subcutaneously once weekly on day 1 of each week for 4 weeks followed by 1 week off, and oral dexamethasone at 20 mg twice weekly on days 1 and 2 of each week.

Patients should undergo monitoring for complete blood cell count with differential, standard blood chemistries, body weight, nutritional status, and volume status at baseline and during treatment as clinically indicated and should be monitored more frequently during the first 3 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 treatment with a 5-HT3 antagonist and other antinausea agents should be given prior to and during treatment.

Selinexor can be sequentially dose-reduced to 80 mg, 60 mg, and 40 mg once weekly for adverse reactions; treatment should be permanently discontinued if further dose reduction is required. Prescribing information on the current indication provides detailed instructions on dosage modification and management of hematologic adverse reactions including thrombocytopenia, neutropenia, and anemia and nonhematologic adverse reactions including nausea and vomiting, diarrhea, weight loss and anorexia, hyponatremia, fatigue, ocular toxicity, and other grade 3 or 4 nonhematologic adverse reactions.

Safety Profile

Among patients who received selinexor in the BOSTON trial, the median duration of treatment was 29 weeks (range = 1–120 weeks), and the median dose was 80 mg.

The most common adverse events of any grade occurring in at least 20% of the selinexor group with a at least a 5% difference in incidence vs the Vd group were fatigue (59% vs 21%), nausea (50% vs 10%), decreased appetite (35% vs 5%), diarrhea (32% vs 25%), peripheral neuropathy (32% vs 47%), upper respiratory tract infection (29% vs 22%), weight decrease (26% vs 12%), cataracts (22% vs 6%), and vomiting (21% vs 4%). The most common grade 3 or 4 adverse events included fatigue (28% vs 5%), cataracts (9% vs 1.5%), nausea (8% vs 0%), and diarrhea (6% vs < 1%). The most common grade 3 or 4 laboratory abnormalities were decreased platelets (43% vs 19%), decreased lymphocytes (38% vs 27%), decreased hemoglobin (17% vs 12%), and decreased neutrophils (12% vs 7%).

Serious adverse events occurred in 52% of patients in the selinexor group, the most common being pneumonia (14%) and sepsis, diarrhea, and vomiting (4% each). Grade ≥ 2 peripheral neuropathy, a prespecified secondary endpoint of the trial, occurred in 21% vs 34% of patients (odds ratio = 0.50, 95% CI = 0.32–0.79). Adverse events led to selinexor dosage interruption in 83% of patients, the most common causes being thrombocytopenia (33%), fatigue (13%), asthenia (12%), pneumonia (11%), and upper respiratory tract infection (10%). Dose reduction was required due to adverse events in 64% of patients, the most common causes being thrombocytopenia (31%); decreased appetite (8%); and nausea, fatigue, and decreased weight (7% each). Selinexor was permanently discontinued due to adverse events in 19% of patients, the most common causes being fatigue (3.6%) and nausea (3.1%).

Selinexor has warnings/precautions for thrombocytopenia; neutropenia; gastrointestinal toxicity, including nausea, vomiting, diarrhea, anorexia, and weight loss; hyponatremia; serious infections; neurologic toxicity; embryofetal toxicity; and cataracts. Platelet counts, neutrophil counts, and sodium levels should be monitored throughout treatment.

Hydration status and concomitant medications should be optimized to avoid dizziness or mental status changes. Treatment of cataracts usually requires surgical removal of the cataract. Patients should be advised not to breastfeed while receiving selinexor. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves selinexor for refractory or relapsed multiple myeloma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selinexor-refractory-or-relapsed-multiple-myeloma. Accessed January 7, 2021.

2. Xpovio (selinexor) tablets prescribing information, Karyopharm Therapeutics Inc, December 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212306s005lbl.pdf. Accessed January 7, 2021.

3. Grosicki S, Simonova M, Spicka I, et al: Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON). Lancet 396:1563-1573, 2020.