Weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in patients with multiple myeloma (MM) after one to three prior therapies: Initial results of the phase III BOSTON study.

Abstract

8501 Background: Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, leading to the reactivation of tumor suppressor proteins. In a phase 1b/2 study, the combination of once weekly (QW) selinexor with bortezomib and dexamethasone (SVd) was well tolerated with anti-MM activity in patients (pts) with PI-sensitive and PI-refractory disease. While twice weekly (BIW) bortezomib in combination therapy is efficacious, prolonged use is limited due to peripheral neuropathy (PN, 50-60%). The BOSTON study was designed to determine if SVd improves progression free survival (PFS), overall response rates (ORR) and reduces the rate of PN vs Vd. Methods: BOSTON is a global, phase 3, randomized study of QW SVd vs BIW Vd after 1-3 prior anti-MM regimens. The primary endpoint is PFS. Secondary endpoints include ORR, overall survival (OS) and PN (rates and EORTC QLQ-CIPN20 outcomes). Randomization is stratified by treatment with prior PI therapies, number of prior anti-MM regimens (1 vs > 1), and Revised International Staging System (R-ISS; Stage III vs I or II). Following confirmation of progressive disease, pts on Vd could cross over to either: 1) SVd for pts able to tolerate continued bortezomib or 2) selinexor and dexamethasone for pts with bortezomib intolerance. Results:402 pts were enrolled; 195 and 207 to SVd and Vd, respectively. Median age was 67 (range: 38-90). Most (59.6%) pts were > 65 years and 57.1% were male. R-ISS stage at the time of MM diagnosis was III for 18.5% of pts. Baseline characteristics were balanced across the 2 arms. SVd significantly prolonged PFS vs Vd (median 13.93 vs 9.46 months, HR = 0.70, P = 0.0066). SVd was associated with a significantly higher ORR (76.4% vs 62.3%, P = 0.0012). Median OS was not reached on SVd vs 25 months on Vd (P = 0.28). Most frequent treatment-related adverse events (grade ≥3) for SVd vs Vd were thrombocytopenia (35.9% vs 15.2%), fatigue (11.3% vs 0.5%) and nausea (7.7% vs 0%). Clinically important differences were reported on the motor, autonomic and sensory scales on CIPN20. PN rates (grade ≥2) were significantly lower with SVd vs Vd (21.0% vs 34.3%, P = 0.0013). Conclusions: BOSTON is the first phase 3 study to evaluate the clinical benefit of SVd for relapsed/refractory MM. The study met the primary endpoint: once weekly SVd significantly improved PFS and ORR compared to twice weekly Vd. Rates of PN were significantly reduced with numerically fewer deaths on SVd vs Vd. Full dataset will be presented at the meeting. Clinical trial information: NCT03110562 .

<p>Clinical Utility of Selinexor/Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: A Review of Current Evidence and Patient Selection</p>

“…The primary study endpoint was met by showing a 4.47 month (47%) increase in the median PFS of patients receiving SVd compared with those receiving Vd (13.93 versus 9.46 months, respectively, p=0.0066). 32 SVd was also associated with a significantly higher ORR (76.4% vs 62.3%, p = 0.0012), whereas no new safety signals emerged. 32…”

“…32 SVd was also associated with a significantly higher ORR (76.4% vs 62.3%, p = 0.0012), whereas no new safety signals emerged. 32…”

“…25 Importantly, the primary results of the randomized phase 3 BOSTON study were recently presented. 31,32 Four hundred and two patients with RRMM and one to three prior lines of therapy were randomized to receive either SVd or Vd. Selinexor was administered at 100mg once weekly, bortezomib at 1.3 mg/m 2 once weekly and dexamethasone at 40mg once weekly.…”

Multiple myeloma current treatment algorithms

“…Importantly, alkylatorcontaining regimens must be considered at this stage. Additional options for second or higher relapses include adding panobinostat to a proteasome-inhibitor containing regimen 58 , or using a selinexor-containing regimen such as selinexor, bortezomib, dexamethasone 75,76 . Bendamustine-or anthracycline-containing regimens are used in refractory settings 77,78 or the addition of panobinostat to a proteasome-inhibitor containing regimen 58 .…”

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy

“…Recent data from the registrational phase III BOSTON trial evaluating selinexor 100 mg in combination with once-weekly bortezomib and dexamethasone (SVd) to a control arm of twice-weekly bortezomib and dexamethasone (Vd) were presented at ASCO 2020 [ 43 ]. In 402 patients with relapsed/refractory MM (RRMM) who previously received between one and three prior treatment regimens (NCT03110562), in spite of 40% lower bortezomib and 25% lower dexamethasone doses at 24 weeks (eight cycles) , the study met its primary endpoint, with a median PFS of 13.93 months and 9.46 months (hazard ratio 0.70; p = 0.0066) for SVd and Vd, respectively.…”