Selinexor, Bortezomib, Dexamethasone Combination Effective for Patients with Multiple Myeloma

Results from the phase 3 BOSTON study, published in The Lancet, suggested that a once-per-week combination regimen of selinexor (Xpovio), bortezomib (Velcade), and dexamethasone (Ozurdex) is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received 1 to 3 previous lines of therapy.¹

"The results from the BOSTON study published in The Lancet demonstrate that the once-weekly regimen of [selinexor] and [bortezomib], with low-dose dexamethasone reduced the risk of disease progression or death by 30% and induced a higher rate of overall and deep responses compared to patients receiving a standard twice-weekly [bortezomib] and low-dose dexamethasone regimen,” co-senior author Paul Richardson, MD, clinical program leader and director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, said in a press release.² “This was observed despite approximately 40% less [bortezomib], 25% less dexamethasone, and approximately 35% fewer clinic visits on the [selinexor-bortezomib-dexamethasone] arm as compared with the standard [bortezomib-dexamethasone] therapy arm.”

“Encouragingly, the efficacy of the [selinexor-bortezomib-dexamethasone] regimen was consistent and noteworthy across several key subgroups, including patients who were frail or 65 years and older, patients with high-risk cytogenetics, patients with moderate renal impairment and patients who had either prior bortezomib or lenalidomide treatment,” Richardson added.

The BOSTON study was conducted at 123 sites in 21 countries and included 402 adult patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. Participants were randomly assigned 1:1 to receive either 100 mg selinexor once per week, 1.3 mg/m2 bortezomib once per week, and 20 mg dexamethasone twice per week, or 1.3 mg/m2 bortezomib twice per week for the first 24 weeks and once per week thereafter along with 20 mg dexamethasone 4 times per week for the first 24 weeks and twice per week thereafter.

Notably, the BOSTON study allowed for patients on the control arm to crossover to the selinexor-bortezomib-dexamethasone arm following objective progression of disease verified by an Independent Review Committee (IRC).

The primary end point of the study was progression-free survival (PFS) in the intention-to-treat population and key secondary end points included overall response rate (ORR) and rate of peripheral neuropathy, among others. Importantly, the trial is ongoing, with 55 patients remaining on randomized therapy as of February 20, 2020.

Overall, 195 patients (49%) were randomized to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13.2 months (IQR 6.2-19.8) for the selinexor, bortezomib, and dexamethasone group and 16.5 months (9.4-19.8) for the bortezomib and dexamethasone group.

Median PFS was 13.93 months (95% CI, 11.73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9.46 months (8.11-10.78) with bortezomib and dexamethasone (HR 0.70; 95% CI, 0.53.0.93; P = .0075). Those in the selinexor, bortezomib, and dexamethasone arm also demonstrated a significantly greater ORR compared to the bortezomib and dexamethasone arm (76.4% vs. 62.3%, P = .0012).

Moreover, patients who had received only one prior line of therapy demonstrated a higher ORR on the selinexor, bortezomib, and dexamethasone arm as compared to the bortezomib and dexamethasone arm (80.8% vs. 65.7%, P = .0082). Importantly, selinexor, bortezomib, and dexamethasone therapy compared to standard bortezomib-dexamethasone therapy also showed consistent PFS benefit and higher ORR across several important subgroups.

Regarding safety, the most frequent grade 3 to 4 adverse events (AEs) were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs. 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs 2 [1%]), anemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Further, peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; OR 0.50; 95% CI, 0.32-0.79; P = .0013). Forty-seven (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died.

"We believe the successful outcome of this study represents an important advancement for myeloma patients and we are sincerely grateful to all of the patients and investigators who participated in the BOSTON study,” Sharon Shacham, PhD, MBA, president and chief scientific officer of Karyopharm, said in the release. “While [selinexor] received accelerated FDA approval last year for patients with penta-refractory multiple myeloma, a supplemental new drug application requesting approval for [selinexor] as a treatment for patients with multiple myeloma who have received one prior line of therapy has been accepted by the FDA and assigned a PDUFA action date of March 19, 2021. We are working closely with the regulatory authorities in both the US and Europe to make this potential new treatment option, with a completely novel mechanism of action, available to patients as quickly as possible, if approved."

References:

1. 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. The Lancet. doi: 10.1016/S0140-6736(20)32292-3

2. Karyopharm Announces Publication of XPOVIO® (Selinexor) Phase 3 BOSTON Study Results in The Lancet [news release]. Newton, Massachusetts. Published November 12, 2020. Accessed November 13, 2020. https://investors.karyopharm.com/2020-11-12-Karyopharm-Announces-Publication-of-XPOVIO-R-Selinexor-Phase-3-BOSTON-Study-Results-in-The-Lancet