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Benefit of selinexor dose reduction on outcomes with selinexor, bortezomib and dexamethasone in patients with lenalidomide‐refractory multiple myeloma: Subgroup analysis of the BOSTON trial

Year: 2026

Type: article

Abstract: A subgroup analysis of efficacy, safety and QOL in patients who received selinexor in combination with bortezomib and dexamethasone (SVd) with and without selinexor dose reduction and who had lenalidomide-refractory disease in the phase 3 BOSTON trial showed improvements in efficacy, quality of life (QOL) and safety outcomes with selinexor dose reduction in this difficult-to-treat population. These findings demonstrate the benefit of selinexor dose reductions in optimizing the treatment of patients with lenalidomide-refractory multiple myeloma (MM) receiving SVd. Lenalidomide is a cornerstone of first-line therapy for newly diagnosed multiple myeloma (MM), and regardless of eligibility for haematopoietic stem cell transplant, regimens typically include a combination with dexamethasone and anti-CD38 monoclonal antibody, with or without bortezomib.1 Consequently, lenalidomide-refractory MM is encountered with increasing frequency in the clinical setting and is challenging to treat.2 As more MM therapies have become available, refined guidelines and expert recommendations for relapsed/refractory MM (RRMM) have stratified treatment choices by prior exposure and sensitivity or refractoriness to previous treatment.1, 2 Specifically, international guidelines recommend using more than one drug and/or switching to a new drug class as the preferred second-line treatment for patients with lenalidomide-refractory disease.1, 2 Selinexor, a first-in-class, orally available inhibitor of exportin 1 (XPO1), is a rational second-line option for lenalidomide-refractory disease due to its unique mechanism of action and approved multi-agent combination for MM. Inhibition of XPO1 results in nuclear retention and functional activation of tumour-suppressor proteins, ultimately suppressing cellular proliferation and tumour growth rates.3 Selinexor is approved in combination with bortezomib and dexamethasone (SVd) for adults with RRMM who have received at least one prior therapy.4, 5 This approval was based on the phase 3 BOSTON trial (NCT03110562) that showed significantly improved progression-free survival (PFS) and overall response rate (ORR) and clinically improved overall survival (OS) with SVd versus Vd in previously treated adults with RRMM.6 A post hoc analysis of all patients who received SVd in BOSTON showed that selinexor dose reductions (vs. no reduction) were associated with longer median PFS (16.6 vs. 9.2 months), higher ORR, longer median duration of response (DOR) and longer time to next treatment (TTNT), with lower any-grade treatment-emergent adverse events and improved quality of life (QOL).7 The management of patients with lenalidomide-refractory MM at relapse is especially challenging as these patients have poor outcomes and rapidly progress through treatments.8, 9 An analysis of patients with lenalidomide-refractory MM in BOSTON, with over 2 years of follow-up, showed a clinically meaningful improvement in median PFS (10.2 months vs. 7.1 months), median OS and ORR with SVd versus Vd in this subgroup.10 Given the improved efficacy observed following selinexor dose reductions in the full BOSTON SVd population and the aggressive biology of lenalidomide-refractory MM, we sought to further determine the impact of selinexor dose reductions specifically in the subpopulation of lenalidomide-refractory patients who received SVd. Our subgroup analysis of the phase 3 BOSTON6 trial included previously treated adults with RRMM who received SVd, with and without selinexor dose reduction (from a starting dose of 100 mg weekly), and who had lenalidomide-refractory disease, defined as progressive disease (PD) within 60 days of lenalidomide or a best response of stable disease or PD. The dose schedule, end-points and statistical analysis information are provided in the Supporting Information. The trial was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation guidelines on good clinical practice, and the institutional review board or an independent ethics committee at each participating centre approved the protocol. All patients provided written informed consent. Of the 195 patients who received SVd in the BOSTON trial, 53 had lenalidomide-refractory disease, 35 of whom had selinexor dose reduction (termed SEL-reduced) and 18 who did not (termed SEL-100). Apart from performance status (PS), high-risk cytogenetic abnormalities and treatment duration, baseline and treatment characteristics were generally similar between SEL-reduced and SEL-100 patients (Table 1). The median duration of study treatment was 7.9 months (range, 0.5–33.2) for the SEL-reduced group and 2.5 months (range, 0.1–10.9) for the SEL-100 group. The ORR in the SEL-reduced group was 74.3% (95% CI, 56.7–87.5) compared with 55.6% (95% CI, 30.8–78.5) in the SEL-100 group (Figure 1A). The rate of very good partial response (VGPR) or better was 48.6% (95% CI, 31.4–66) versus 11.1% (95% CI, 1.4–34.7) respectively. The median time to achieve a best response, defined as partial response or better, was 2.7 months (range, 0.7–11.7) versus 1.4 months (range, 0.7–2.1) respectively. The median DOR for the SEL-reduced group was 15.3 months (95% CI, 12.2 to not estimable [NE]) compared with 4.2 months (95% CI, 4.2 to NE) for the SEL-100 group (Figure S1). The median TTNT was 14.8 months (95% CI, 13.4–26.7) versus 4.8 months (95% CI, 4.2 to NE) respectively. For the SEL-reduced group, who had a median survival follow-up of 28.2 months (95% CI, 23.4–33.4), the median PFS was 13.9 months (95% CI, 6.9 to NE). In comparison, for the SEL-100 group, who had a median survival follow-up of 27.2 months (95% CI, 22.7 to NE), the median PFS was 5.1 months (95% CI, 3.5 to NE; Figure 1B). The median OS was 26.7 months (95% CI, 16.9 to NE) for the SEL-reduced group versus 24.6 months (95% CI, 15.8 to NE) for the SEL-100 group (HR, 0.91; 95% CI, 0.37–2.28). QOL scores, as measured by the EORTC QLQ-C30 Global Health Status, more than doubled in SEL-reduced versus SEL-100 patients (mean ± standard deviation [SD] best change from baseline, 10.4 ± 23.3 vs. 3.7 ± 26.9; Table S1). In SEL-reduced patients, the mean (±SD) change in QOL score from pre-dose reduction to best score post-reduction was 18.1 ± 21.5, far exceeding the 10-point threshold demonstrating improvement. Any-grade non-haematological treatment-related adverse events (TRAEs) following the first selinexor dose reduction as compared with before dose reduction included nausea (23% vs. 54%), fatigue (14% vs. 31%), diarrhoea (20% vs. 29%), decreased appetite (11% vs. 23%), vomiting (17% vs. 23%) and weight loss (14% vs. 20%), respectively (Table S2). Any-grade haematological TRAEs after first dose reduction versus before dose reduction included thrombocytopenia (63% vs. 71%), anaemia (23% vs. 17%) and neutropenia (14% vs. 11%). Results of this analysis of patients who had lenalidomide-refractory MM and received SVd with a selinexor dose reduction were consistent with the primary BOSTON analysis and dose-reduction subgroup analysis of all patients who received SVd in the intent-to-treat population.6, 7 Our findings showed improvements in efficacy, QOL and safety outcomes with selinexor dose reduction in the difficult-to-treat population of patients with lenalidomide-refractory disease. Patients in the dose reduction group had numerically higher rates of poor PS and high-risk cytogenetic abnormalities compared with patients without dose reduction, underscoring that, despite poorer prognostic features, the dose reduction group performed dramatically well. Selinexor dose reduction allowed patients to receive treatment three times longer than patients without dose reduction. This longer treatment duration translated into improved outcomes: specifically, higher ORR and VGPR or better rates in patients who had selinexor dose reduction than in patients without reduction. Sustained disease control and deep and durable responses were observed in these patients. Median DOR and TTNT more than tripled in patients who had selinexor dose reduction compared with those without dose reduction. Consistent with the 10.2-month PFS seen in all patients with lenalidomide-refractory disease who received SVd,10 PFS in this lenalidomide-refractory population was prolonged in patients with selinexor dose reduction versus those without (13.9 vs. 5.1 months respectively). A numerically higher OS rate was observed in patients with dose reduction, and importantly, OS rates were maintained even with a reduced dose. QOL scores showed greater improvement in the SEL-reduced group versus the SEL-100 group. Gastrointestinal effects and fatigue are known non-haematological adverse events associated with selinexor, and in this analysis, selinexor dose reductions led to a lower proportion of these TRAEs after the first dose reduction. It is very likely that the lower incidence of these events enabled patients to tolerate these adverse events and remain on treatment, hence improving outcomes. In light of our findings, it is plausible that, contingent upon baseline and disease-specific characteristics, certain patients may derive benefit from initiating selinexor at a reduced starting dose. However, this hypothesis has not been evaluated in a controlled clinical trial, and therefore, definitive evidence to support this strategy is currently lacking. Results of this subgroup analysis are limited by their ad hoc nature and small patient numbers. As such, results should be considered exploratory. The goals of lenalidomide-refractory MM treatment at relapse include maintaining disease control, delaying progression, balancing efficacy with tolerability and QOL and prolonging PFS and OS.11 Expanding on the known benefits of SVd treatment at relapse in patients with lenalidomide-refractory MM, our findings demonstrate that selinexor dose reduction allowed patients to remain on treatment longer, hence attaining a 13.9-month median PFS and improving response, QOL and tolerability. These findings corroborate similar improvements in AEs, while maintaining or improving efficacy, that have been observed with selinexor dose reductions in various combinations, including with pomalidomide–dexamethasone, in similar triple-class refractory populations.12, 13 Carfilzomib–dexamethasone (Kd) and pomalidomide–bortezomib–dexamethasone (PVd), two regimens that have shown advantages over Vd in phase 3 trials, showed less robust PFS outcomes in patients with lenalidomide-refractory MM. Specifically, in the ENDEAVOR trial, the Kd doublet was associated with an 8.6-month median PFS in the lenalidomide-refractory population, and in the OPTIMISMM trial, the PVd triplet demonstrated a 9.5-month median PFS in patients with lenalidomide-refractory disease.14, 15 In summary, findings of this subgroup analysis of the phase 3 BOSTON trial demonstrate the benefit of selinexor dose reductions in optimizing the treatment of patients with lenalidomide-refractory MM receiving SVd. Sosana Delimpasi was responsible for the investigation, writing—original draft, and writing—review & and editing. Ivan Špička was responsible for the investigation and writing—review & editing. Jason P. Butler was responsible for the investigation and writing—review & editing. Don A. Stevens was responsible for the investigation and writing—review & editing. Mercedes Gironella Mesa was responsible for the investigation and writing—review & editing. Ceri Bygrave was responsible for the investigation and writing—review & editing. Giovanni Marino Merlo was responsible for the conceptualization, methodology, data curation, formal analysis, software, validation, writing—review & editing. Charles la Porte was responsible for the conceptualization, data curation, formal analysis and writing—review & editing. Meletios A. Dimopoulos was responsible for the investigation, writing—original draft and writing—review & editing. This study was funded by the Menarini Group. Medical writing and editing assistance were provided by Claire Gilmore of Phillips Group Oncology Communications, Inc., and funded by the Menarini Group. This work was supported by the Menarini Group. Sosana Delimpasi: honoraria from Amgen, BMS, GSK, J&J and Menarini; Ivan Špička: honoraria from and participation on a DSMB or advisory board with Amgen, BMS, Johnson & Johnson, Sanofi and Takeda; travel/accommodations/expenses from Johnson & Johnson and Sanofi; Jason P. Butler: consulting/advisory role with Johnson & Johnson; honoraria from Novartis; participation on a DMSC for two phase 1 clinical trials; Don A. Stevens: nothing to disclose; Mercedes Gironella Mesa: honoraria from BMS, J&J, Menarini Stemline, Pfizer and Sanofi; participation on an advisory board with Pfizer and Menarini Stemline; travel/accommodations/expenses from J&J and Menarini Stemline; Ceri Bygrave: consulting/advisory role with GSK, Janssen and Sanofi; honoraria from BMS, GSK, Janssen, Menarini-Stemline, Sanofi and Takeda; travel/accommodations/expenses from Janssen and Takeda; Giovanni Marino Merlo: employment with Menarini Group; Charles la Porte: employment with Menarini Group; stock or stock options with J&J; Meletios A. Dimopoulos: honoraria from participation in advisory boards and satellite symposia with Amgen, AstraZeneca, BeiGene, BMS, GSK, Janssen, Menarini, Regeneron, Sanofi, Swixx and Takeda. 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Source: British Journal of Haematology

DOI: 10.1111/bjh.70479