Primary analysis of the phase 3 randomized trial of selinexor and lenalidomide versus lenalidomide alone as maintenance therapy post autologous stem cell transplant for patients with newly diagnosed multiple myeloma (ALLG MM23; SEALAND)

Abstract Introduction Selinexor (S) is an oral selective exportin 1 inhibitor approved in relapsed multiple myeloma (MM) in combination with bortezomib (V) and dexamethasone (d). We investigated whether low-dose S combined with lenalidomide (R) was superior to R alone as maintenance therapy following autologous stem cell transplant (ASCT) in newly-diagnosed MM (NDMM). We report the primary analysis of the randomized open-label phase III SeaLAND (ALLG MM23) study (ACTRN12620000291987). Method Eligible patients were transplant-eligible NDMM who had received 3-6 cycles of VRd induction and undergone ASCT. Patients were screened and randomized from day 75 to 115 post-ASCT. Following a safety run-in, a weekly S dose of 40mg was deemed safe. Patients were randomized 1:1 to receive either low dose S (40mg Weekly) with R (10 mg on D1–21 of cycles 1–3, 15 mg on D1-21 from cycle 4 onward) or R alone. Patients received ondansetron 8mg immediately prior to, and 8-hours following each S dose. Additional ondansetron and low-dose olanzapine were used as required for break-through nausea and vomiting. Measurable residual disease (MRD) was assessed upon achievement of a serological complete response (CR) and reassessed 12 months after the initial documentation of MRD negativity. The study had originally planned to enrol 290 patients but was terminated early after a futility analysis indicated no statistically significant difference in progression-free survival (PFS) between arms. Results As of 11 July 2025, 149 patients had been enrolled and randomized (R: 65, SR: 84). The median age (R: 62 years, range: 34-76, SR: 62, range: 39-75), sex distribution (Female, R: 32%, SR: 26%), proportion of high-risk cytogenetics abnormalities [HRCAs, Del(17p)/t(4;14)/t(14;16), R: 28% SR: 21%), and R-ISS stage III patients (R: 5%, SR: 6%) were balanced across arms. At screening, the CR/sCR rate was 37% (n=31) in the SR arm, and 25% (n=16) in the R alone arm. At best response, the CR rate was higher in the SR arm compared to R alone (64% vs. 51%, p=0.056). The overall MRD negativity rate at any timepoint was 18% in the R alone arm and 17% in the SR arm. Among patients with del(17p), 6 were randomized to R alone and 12 to SR; none in the R arm achieved MRD negativity, compared to 25% (3 of 12) in the SR arm. At a median follow up of 30.1 months for the R alone, and 28.1 months for the SR arms, there was no significant difference in PFS between treatment groups (HR=1.14, 95%CI: 0.59-2.22, p=0.69). Median PFS was 45 months for R, and not-reached for SR. Thirty-month PFS rates were 67% (95%CI 49-79) for the R arm and 71% (95%CI 57-81) for the SR arm. Among patients with del(17p) (HR=1.06, 95%CI 0.54-2.09, p=0.87) or any HRCA (HR=0.68, 95%CI 0.15-3.03, p=0.61), no PFS benefit was observed with SR. The mean number of cycles completed was 17 for R and 15 for SR (p=0.26). For SR patients, the mean number of S-containing cycles was 9 (range: 1-34). The mean relative dose intensity (RDI) of R was low in the SR arm (68%) compared to R alone (81%, p=0.003), while the mean RDI of S was 55%. Grade ≥3 adverse events (AEs) were significantly more frequent in the SR arm compared to R alone (85% vs. 45%, p<0.001). Common serious AEs (SAEs, Grade ≥3) were infection (R: 6%, SR: 19%), gastrointestinal disorders (R: 3%, SR: 14%), fatigue (R: 0, SR: 8%), neutropenia (R: 33%, SR: 62%) and thrombocytopenia (R: 2%, SR: 26%). The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) core 30 (C30) global health status scores were comparable between arms at cycle 6, 12, and 24 (R: 42, 41, 40 vs. SR: 41, 40, 42; p=0.36. Likewise the EORTC QLQ-MY20 side-effect score was similar at the same time points (R: 13, 11, 12 vs. SR: 11, 9, 10; p=0.62). Conclusions In this randomized phase III study, the addition of low-dose S to R maintenance following ASCT did not result in a significant PFS benefit compared to R alone in NDMM. Although a higher CR rate was observed with SR, this came at the cost of increased toxicity, including more infections, cytopenias and gastrointestinal AEs. Quality of life, as assessed by EORTC QLQ-C30 and MY20, was comparable between arms. Although a negative study, these results are important and suggest that due to toxicity, Selinexor may be better suited to induction rather than maintenance. Ongoing follow-up will clarify its role in patients with high-risk cytogenetics.

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