Safety and Efficacy of Selinexor Plus Bortezomib, Lenalidomide and Dexamethasone (XVRd) in High Risk Newly Diagnosed Multiple Myeloma: A Multi-Center, Single-Arm, Phase Ib/II Trial
Authors: Chen Xiaoqin , Wang Yun , Wang Weida , Wang Hua , Wu Bingyi , Liang Yang , Xia Zhongjun 
Published: December 2024

Background: High-risk (HR) cytogenetics is associated with poor outcome in newly diagnosed myeloma multiple myeloma (NDMM). Selinexor is a(SINE) compound that selectively binds and inactivates XPO1. In the phase 3 BOSTON study, the PFS benefit was particularly notable in patients with del(17p), t(4;14) and amp(1q21) abnormalities in the SVd versus Vd regimen. These data support the use of selinexor has clinical activity in the treatment of patients with high-risk cytogenetic abnormalities. We therefore aimed to assess the safety and efficacy of selinexor in combination with VRd as a first-line treatment for NDMM patients with HR cytogenetics (NCT05422027).

Methods: High risk was defined as patients with with at least one of the following abnormalities: del(17p), t(4;14), t(14;16), del 17p, p53 mutation, gain 1q or R-ISS stage 3 or high plasma cell s-phase or GEP for high risk signature. The primary objective of the dose escalation study is to determine the safety, tolerability and recommended phase II dose (RP2D) of selinexor. Subsequently, dose expansion will be performed at the RP2D level to assess efficacy(MRD negative rate,ORR), safety and tolerability. Patients received the XVRd regimen as induction therapy for 4 cycles (28 days per cycle). Following the induction phase, patients received 2-4 cycles of XVRd consolidation therapy after autologous stem cell transplantation (ASCT), while those who did not undergo ASCT received a further 8 cycles of XVRd consolidation therapy. All patients received XR for maintenance until disease progression, death, intolerance or other reasons.

Results: Between Jul 2022 and Jul 2024, 14 patients with NDMM were enrolled in our trial and 4 patients were excluded due to protocol violation and other reasons.10 patients (6 males and 4 females ) with NDMM were enrolled in our trial with a median age of 52.5. ISS stage 3 was present in 5 (50%) patients. Based on the inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n = 2, 20%),1q21 amplification(n = 6, 60%) or extramedullary (n = 1,10%).

In the phase Ib study, the following selinexor dosages were administered: 40mg qw (n=4) and 60mg qw (n=3). Dose-limiting toxicities (DLTs) were not observed.Common treatment-related adverse events (TRAE) included (all grades, Grades 3/4) were thrombocytopenia (60%,50%)，neutropenia (30%, 20%), leukopenia(50%,0%), infection (20%,10%) and nausea (20%,0%), all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 60 mg QW. The trial recommends a triple antiemetics regimen,including 5-HT3 receptor antagonist, aprepitant and olanzapine, to be taken prior to the use of selinexor. Dexamethasone is also recommended to be applied on the same day as selinexor.

A total of 10 enrolled patients were evaluable for response. The ORR was 100%, including ≥VGPR 20% and sCR 60%. Among 8 evaluable patients,the best MRD negativity rate (NGF, 10-5) was 75%（6/8).The safety profile was consistent with previously.

Conclusions:This study established the safety profile of selinexor 60 mg qw in combination with VRd for HR NDMM with an ORR of 100%. An ongoing phase 2 study of dose escalation phase study will further evaluate the efficacy and safety of the combination regimen.