Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma

Abstract

Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562.

Selinexor: Targeting a novel pathway in multiple myeloma

“…Also of interest was the efficacy seen in patients with 1q21 amplification (ORR 77% vs. 62%; median PFS 12.9 vs. 8.2 months, HR 0.63; median OS 27.4 vs. 23.5 months, HR 0.85) [63], warranting further exploration in this subgroup of patients. Similarly, selinexor‐Vd showed improved efficacy versus Vd in various subgroups defined according to prior therapy exposure and refractoriness [66] (Table 1), as well as in subgroups of patients with renal impairment [64], although PFS appeared poorer in both arms among patients with more severe renal impairment (creatinine clearance <40 mL/min) (Table 2). Older age and patient frailty are also generally associated with poorer outcomes in patients with MM.…”

Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance

“…Additional phase I studies with selinexor-containing combinations were also initiated but have no results yet, namely to study selinexor plus ixazomib plus low dose of dexamethasone in refractory MM [ 180 ]. Phase II and III studies testing selinexor plus bortezomib plus dexamethasone for refractory MM [ 181 , 182 , 183 , 184 , 185 , 186 ] were also started, and additional phase II trials with selinexor plus bortezomib plus dexamethasone plus daratumumab [ 187 ] and selinexor plus carfilzomib [ 188 , 189 ] in refractory MM were also registered.…”

The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma

“…Based on this study, on December 18, 2020, the FDA approved selinexor in combination with bortezomib and dexamethasone for the treatment of adult patients with RR-MM who received at least one prior line of therapy. Detailed analysis of patient information and clinical parameters demonstrated that benefits of SelVd treatment over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT [ 177 ]. In addition, SelVd conferred benefits to patients over Vd regardless of cytogenetic risk [ 178 ].…”

“…The most common non-hematological adverse events are gastrointestinal disturbances including nausea, vomiting, decreased appetite, and diarrhea, as well as peripheral neuropathy, fatigue, upper respiratory tract infection, weight loss, which are all primarily grade 1 or 2 but can also be grade 3. Electrolyte imbalances, including asymptomatic hypophosphatemia, hyponatremia, and hypokalemia, have also been commonly observed [ [175] , [176] , [177] , 179 , 180 ]. Approximately 19.5% of patients experienced ocular adverse events, including blurred vision and/or dry eye syndrome.…”