Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk

Abstract

In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1-3 prior regimens were randomized to once-weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib-dexamethasone (XVd) or twice-weekly bortezomibdexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high-risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of amp1q21) cytogenetics (XVd, n = 70; Vd, n = 71), and 261 (64.9%) exhibited standard-risk cytogenetics (XVd, n = 125; Vd, n = 136).Among patients with high-risk MM, median PFS was 12.91 months for XVd and 8.61 months for Vd (HR, 0.73 [95% CI, (0.4673, 1.1406)], p = 0.082), and ORRs were 78.6% and 57.7%, respectively (OR 2.68; p = 0.004). In the standard-risk subgroup, median PFS was 16.62 months for XVd and 9.46 months for Vd (HR 0.61; p = 0.004), and ORRs were 75.2% and 64.7%, respectively (OR 1.65; p = 0.033). The safety profiles of XVd and Vd in both subgroups were consistent with the overall population. These data suggest that selinexor can confer benefits to patients with MM regardless of cytogenetic risk. ClinicalTrials.gov identifier: NCT03110562.

A Case Report of a 58-Year-Old Woman with a Diagnosis of High-Risk Myeloma Refractory to Multiple Line of Therapy and Treated with Selinexor, Bortezomib, and Dexamethasone Prior to Allogeneic Stem Cell Transplantation

“…Moreover, when each of the high-risk cytogenetic abnormalities were examined separately, patients with del(17p) (as in our case) receiving the XVd regimen were found to have a median progression-free survival of 12.2 months compared with 5.9 months for those treated with Vd (hazard ratio, 0.38; 95% CI, 0.16–0.86; 1-sided P =0.008) and an ORR of 76.2% vs 37.5% (1-sided P =0.010). Additionally, the median time to next therapy was significantly improved in patients with del(17p) receiving the XVd regimen compared with those on Vd (14.8 vs 7.6 months; hazard ratio, 0.30; 95% CI, 0.12–0.75; P =0.003), with a not statistically significant trend toward improved duration of response (14.8 vs 6.8 months; P =0.008) [ 16 ]. Notably, due to transfusion-dependent thrombocytopenia, our patient was treated with a selinexor dose lower than the initial dose used in the XVd combination in the BOSTON trial [ 6 ].…”

Selinexor: Targeting a novel pathway in multiple myeloma

“…In an analysis of patient subgroups with high‐risk (defined as t(4;14), t(14;16), del17p, or 1q21 amplification [≥4 copies]) or standard‐risk cytogenetics, the benefit of selinexor‐Vd versus Vd was maintained in terms of ORR (high‐risk 79% vs. 58%; standard‐risk 75% vs. 65%) and PFS (high‐risk: median 12.9 vs. 8.6 months, HR 0.73; standard‐risk: median 16.6 vs. 9.5 months, HR 0.61), albeit that there was evidence of the poor prognostic impact of high‐risk cytogenetics on outcomes in both arms [63]. Of particular interest was the maintained efficacy benefit in patients with del17p, with an ORR of 76% versus 38%, median PFS of 12.2 versus 5.9 months (HR 0.38), and median OS of 22.2 versus 21.2 months (HR 0.43), suggesting specific activity associated with the selinexor mechanism of action in the context of the loss of at least one copy of p53 [63]. 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.…”

“…Of particular interest was the maintained efficacy benefit in patients with del17p, with an ORR of 76% versus 38%, median PFS of 12.2 versus 5.9 months (HR 0.38), and median OS of 22.2 versus 21.2 months (HR 0.43), suggesting specific activity associated with the selinexor mechanism of action in the context of the loss of at least one copy of p53 [63]. 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).…”

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.…”