A phase II study of selinexor(KPT-330) combined with bortezomib and dexamethasone (SVD) for induction and consolidation for patients with progressive or refractory multiple myeloma: The selvedex trial

Selinexor is an oral selective exportin-1 (XPO-1) inhibitor that forces nuclear retention and activation of many tumor suppressor proteins (TSPs) and IkB and is active as monotherapy and combined with dexamethasone in multiple myeloma (MM). Addition of proteasome inhibitors to selinexor increases levels and activity of TSPs/IkB leading to synergistic MM cell death.AimsA dose escalating phase I/II study was performed in patients with progressive and/or refractory MM, evaluating feasibility (phase I) and efficacy (phase II) of selinexor at 3 dose levels combined with twice weekly (BIW) bortezomib and dexamethasone (SVd).MethodsThe maximum tolerated dose (MTD) and recommended dose level (RDL) were determined using a a3+3a dose escalation scheme. Patients could be included if they had received at least one prior anti-myeloma regimen, and were not refractory to bortezomib. Selinexor on days 1,8,15,22, bortezomib 1.3mg/m2 subcutaneously on days 1,4,8,11, dexamethasone 40mg on days 1,8,15,22 in a 28-days schedule.ResultsSeven patients were treated at the first selinexor dose level of 45mg/m2. The median number of prior treatments was 3 (range 2-7). Three patients were lenalidomide refractory during their last treatment. Two patients were deemed ineligible after inclusion, one patient had a transformation to plasma cell leukemia, one was bortezomib refractory. Two out of 5 eligible patients completed treatment as planned. Only one patient completed selinexor at the preplanned dose of 45mg/m2. Reasons for discontinuation were excessive toxicity(n=1), progressive disease(1), other reasons not specified(1). Two patients experienced a DLT, one grade 4 thrombocytopenia with epistaxis, one patient had an ischemic cerebrovascular event. Adverse events (AE) CTC grade 3-4 were observed in all treated patients (table 1). The study continued with a lower dose level of selinexor of 30mg/m2 with adjustment of bortezomib frequency to once weekly on days 4 and 11. The median number of prior treatments was 3 (range 1-7). Three patients were lenalidomide refractory. Two out of 6 patients who started treatment completed treatment as planned. Reasons for discontinuation were neuropathy grade 4(1), pneumonia(1), progressive disease(3). Six patients were treated of whom 4 patients experienced a DLT: hyponatremia grade 3(2), polyneuropathy grade 3(1), syncope grade 3(1).The study was stopped prematurely due to unacceptable toxicity observed in the 2 different dosing schedules of SVd. In the 45mg/m2 group 4 out of 5 (80%) patients achieved aPR, including 2 VGPR, and 1 sCR. Median follow-up (FU) was 27 months (range 0.6-31.5). Median PFS was 17 months, OS at 1 and 2 years was 100% and 75%, respectively. Four out of 6 (67%) patients in the 30mg/m2 group achieved aPR, including 1 VGPR; no CRs were seen. Median FU was 10.1 months (range 0.6-17.9). Median PFS was 10 months, 1 year OS was 75%.ConclusionWe found that both 30 and 45mg/m2 of selinexor in combination with either twice or once weekly bortezomib resulted in unacceptable toxicity. However, in those patients in whom the regimen was feasible we observed remarkable ORR, PFS and OS in this pretreated, predominantly lenalidomide-refractory MM population. This is consistent with results recently presented for once weekly SVd regimens. This regimen, which also showed high ORR and PFS, is currently being evaluated in the international Phase 3 randomized BOSTON study of SVd vs Vd (NCT 03110562).Session topic: 14. Myeloma and other monoclonal gammopathies - ClinicalKeyword(s): bortezomib, Multiple Myeloma, Refractory, TherapyCode of conduct/disclaimer available in General Terms Conditions