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

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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 observ

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.