1. A once-per-week regime of selinexor, bortezomib and dexamethasone was associated with significantly improved progression-free survival versus current standard of care.
2. Although the once-per-week regime with selinexor was associated with higher rates of adverse events overall, it demonstrated significantly decreased rates of peripheral neuropathy.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Multiple myeloma, an incurable disease, has seen a considerable increase in treatment options over the past few decades. The prognosis, however, remains poor, and many patients must endure debilitating toxicity from their respective treatment regimes. The current standard of care is a combination of bortezomib, a first-in-class proteasome inhibitor, with dexamethasone. Selinexor, an oral selective inhibitor of nuclear export that selectively activates tumor suppressor proteins, has been approved in the USA for use with dexamethasone in patients with multiple myeloma who have failed at least four previous therapies. Preliminary early-phase myeloma trials of patients on a regime of selinexor, bortezomib and dexamethasone showed a promising safety and efficacy profile. This phase 3, randomized, controlled trial (BOSTON trial) compared the current standard of care, bortezomib with low-dose dexamethasone twice-weekly, with a regime of selinexor, bortezomib and dexamethasone once per week in patients with treatment-refractory multiple myeloma. Overall, the selinexor regime was associated with an increased progression-free survival, higher objective response rate, and longer median duration of response. Although the selinexor regime was associated with higher overall rates of grade 3-4 treatment-emergency adverse events, most were considered reversible. In addition, the selinexor arm had a significantly lower rate of peripheral neuropathy, a major impactor on quality of life for those taking bortezomib. This was a well-powered, robust study that gives considerable evidence to support the use of selinexor as a treatment for refractory multiple myeloma. Although the study was open-label, given the difference in dosing regimes (i.e., once per week versus twice), this limitation was understandable, and efficacy assessments were done independently from physicians administering the regime.
In-Depth [randomized controlled trial]: This phase 3, open-label, multicenter, randomized, controlled trial took place at 123 sites in 21 countries across the globe. A total of 402 patients with treatment-refractory multiple myeloma were assigned to the once-per-week selinexor, bortezomib and dexamethasone group (n=195) and the twice-per-week bortezomib and dexamethasone group (n=207). The primary endpoint of the study was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response (DR), safety profile of trial treatment, and incidence of grade 2 or higher peripheral neuropathy events. Overall, median PFS was significantly longer in the selinexor group (13.93 months [95% CI 11.73-not evaluable] vs. 9.46 months [95% CI 8.11-10.78]; HR 0.70, p=0.0075). ORR was significantly higher in the selinexor group (odds ratio [OR] 1.96 [95% CI 1.3–3.1], p=0.0012), while median duration of response was numerically higher (HR 0.81 [95% CI 0.56–1.17], p=0.1364). Significantly more grade 3-4 treatment-emergent adverse events occurred in the selinexor group; however, most were considered reversible and could be treated with standard supportive care. In contrast, the incidence of any grade peripheral neuropathy, an important concern in bortezomib treatment, was significantly lower in the selinexor treatment arm. Analysis of Kaplan-Meier curves demonstrate a 30% reduction in death risk or disease progression in the selinexor regime compared with current standard of care. The selinexor regime also involves a 37% reduction in hospital visits for patients, an important consideration during periods of global pandemics such as that seen with COVID-19. Taken together, this trial provides strong evidence for the efficacy and safety profile of selinexor, bortezomib and dexamethasone in the management of treatment-refractory multiple myeloma.
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