FDA Approves Selinexor Triplet in Multiple Myeloma For Second Line and Beyond

The FDA has approved selinexor (Xpovio) in combination with bortezomib (Velcade) and dexamethasone (SVd) for the treatment of adult patients with multiple myeloma who have received at least 1 prior therapy.^1,2

This new indication expands the uses for the oral selective inhibitor of nuclear export (SINE) drug to the second-line setting. Previously, the FDA approved selinexor in 2019 for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior treatments and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

Approval for selinexor in this indication was based on findings from the phase 3 BOSTON trial (NCT03110562).

"New treatments for multiple myeloma remain a critical need for both patients and their treating physicians," Paul Richardson, MD, clinical program leader and director of clinical research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and co-senior study author of the BOSTON trial, said in a statement. "As the only approved nuclear export inhibitor that has demonstrated a strong synergistic effect with a proteasome inhibitor such as bortezomib, selinexor has, in my opinion, the potential to meet a current treatment gap for our multiple myeloma patients in need of new therapeutic options."

The randomized, open-label BOSTON study explored the use of once-weekly SVd in comparison with a twice-a-week combination of bortezomib and dexamethasone (Vd) alone in patients with multiple myeloma who have received 1 to 3 prior treatments, including proteasome inhibitors. Patients were randomized 1:1 to either the once-weekly triplet arm or the twice-weekly doublet arm.³

A total of 402 patients were randomized. In the investigational arm, patients received selinexor at 100 mg plus 1.3 mg/m² bortezomib and 20 mg of dexamethasone twice per week. In the control arm, bortezomib and dexamethasone were administered twice per week for the first 24 weeks and then once a week thereafter.

The median age of all patients was 67 years (range, 59-73) and 20% of patients were 75 years or older. Almost half of the patients (48%) had high-risk cytogenetics.

Patients had received a median of 2 prior treatment regimens (range, 1-2) including prior lenalidomide (Revlimid) in 38% and prior bortezomib in 69%. Thirty-five percent had undergone prior stem cell transplantation.

Median progression-free survival by International Myeloma Working Group criteria, the primary end point of the study, was 13.93 months (95% CI, 11.73–not evaluable [NE]) with SVd compared with 9.46 months (95% CI, 8.11-10.78) with Vd alone (HR, 0.70; 95% CI, 0.53-0.93; P = .0075).

The objective response rate was 76.4% in the triplet arm versus 62.3% in the doublet arm. Stringent complete responses (CRs) were observed in 10% of patients who received SVd and CRs in 7%. Five percent of patients who received SVd were negative for minimal residual disease (MRD). In the control arm, stringent CRs were reported in 6% of patients who received Vd and CRs in 4%; 4% of patients achieved MRD negativity.

Median duration of response was 20.3 months versus 12.9 months in the SVd and Vd arms (HR, 0.81; 95% CI, 0.56-1.17; P = .1364), respectively.

The median overall survival was not yet reached as of the data cutoff in the SVd arm compared with 25 months in the Vd arm (HR, 0.84; 95% CI, 0.57-1.23; P = .1852).

“Selinexor with once-weekly bortezomib-dexamethasone demonstrated encouraging and highly significant results in the phase 3 BOSTON study, including a 47% improvement in progression-free survival versus standard twice-weekly bortezomib-dexamethasone. Patients receiving SVd had approximately 35% fewer clinic visits compared to those receiving the standard, twice-weekly Vd regimen, thus receiving 40% less bortezomib and 25% less dexamethasone as compared with the control arm in the first 24 weeks of therapy. This once-weekly dosing feature helps makes the SVd regimen attractively simple,” Richardson added.

The most common hematologic adverse events of any grade reported in the investigational arm were thrombocytopenia (60%), anemia (36%), and neutropenia (15%), which all had higher incidences compared with the control arm (27%, 23%, and 6%, respectively). Common nonhematologic adverse events included fatigue (42% with SVd vs 18% with Vd), nausea (50% vs 10%), diarrhea (32% vs 25%), peripheral neuropathy (32% vs 47%), decreased appetite (35% vs 5%), weight loss (26% vs 12%), and asthenia (25% vs 13%).

“Adverse events with SVd were important but generally self-limiting, reversible, and proved manageable with dose modifications and aggressive supportive care, as well as generating significantly lower rates of peripheral neuropathy compared to the control group,” Richardson noted.

"Today's US approval broadens the existing label for Xpovio and allows Karyopharm to offer a new, highly active, treatment option to a significantly expanded patient population," said Sharon Shacham, PhD, MBA, Founder, president and chief scientific officer of Karyopharm, in a statement. "We believe the expanded reach of Xpovio will address a critical need for patients with multiple myeloma given its novel mechanism of action, convenient oral administration, and established rapid and sustained efficacy profile.”

Selinexor is also FDA approved for the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma, not otherwise specified, after at least 2 lines of systemic therapy.

_References:

_{1. FDA approves selinexor for refractory or relapsed multiple myeloma. News release. FDA. December 18, 2020. Accessed December 18, 2020. https://bit.ly/3myEb8S}

_{2. Karyopharm Announces FDA Approval of XPOVIO® (Selinexor) as a Treatment for Patients with Multiple Myeloma After At Least One Prior Therapy. News release. Karyopharm Therapeutics. December 18, 2020. Accessed December 18, 2020. https://prn.to/2WuO5y2}

_{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): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3}