Selinexor ( Xpovio ) 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-multiple myeloma activity in patients with proteasome inhibitor ( PI )-sensitive and PI-refractory disease.
While twice weekly ( BIW ) Bortezomib in combination therapy is efficacious, prolonged use is limited due to peripheral neuropathy ( 50-60% ).
The BOSTON study was designed to determine if SVd regimen improves progression free survival ( PFS ), overall response rates ( ORR ) and reduces the rate of peripheral neuropathy versus Vd regimen.
BOSTON is a global, phase 3, randomized study of QW SVd versus BIW Vd after 1-3 prior anti-multiple myeloma regimens.
The primary endpoint is progression-free survival. Secondary endpoints include overall response rates, overall survival ( OS ) and peripheral neuropathy ( rates and EORTC QLQ-CIPN20 outcomes ).
Randomization was stratified by treatment with prior therapies with proteasome inhibitors, number of prior anti-multiple myeloma regimens, and Revised International Staging System ( R-ISS; stage III vs I or II ).
Following confirmation of progressive disease, patients on Vd regimen could cross over to either: 1) SVd for patients able to tolerate continued Bortezomib or 2) Selinexor and Dexamethasone for patients with Bortezomib intolerance.
402 patients were enrolled; 195 and 207 to SVd and Vd, respectively. Median age was 67 ( range: 38-90 ). Most ( 59.6% ) patients were 65 years and 57.1% were male.
R-ISS stage at the time of multiple myeloma diagnosis was III for 18.5% of patients.
Baseline characteristics were balanced across the two arms.
SVd regimen has significantly prolonged progression-free survival versus Vd regimen ( median 13.93 vs 9.46 months, HR = 0.70, P = 0.0066 ).
SVd regimen is associated with a significantly higher overall response rates ( 76.4% vs 62.3%, P = 0.0012) .
Median overall survival was not reached on SVd regimen versus 25 months on Vd regimen ( 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. Peripheral neuropathy rates ( grade 2 ) were significantly lower with SVd vs Vd ( 21.0% vs 34.3%, P = 0.0013 ).
In conclusion, BOSTON is the first phase 3 study to evaluate the clinical benefit of SVd for relapsed / refractory multiple myeloma. T
he study met the primary endpoint: once weekly SVd regimen has significantly improved progression-free survival and overall response rates compared to twice weekly Vd regimen.
Rates of peripheral neuropathy were significantly reduced with numerically fewer deaths on SVd regimen versus Vd regimen.( Xagena )
Source: American Society of Clinical Oncology ( ASCO ) Virtual Meeting, 2020