Abstract Topic: 14. Myeloma and other monoclonal gammopathies - Clinical
Background: Treatment of multiple myeloma (MM) is evolving leading to significant improvements in survival, although many patients relapse and become resistant, especially to lenalidomide (Len-refr). New combinations are needed. Daratumumab plus bortezomib and dexamethasone (DVd) is an approved combination for relapsed-refractory MM (RRMM) after 1 prior line (PL). Selinexor is an exportin-1 inhibitor also approved in combination with Vd for RRMM after 1 PL. The combination of selinexor may improve the efficacy of DVd, as it was initially reported by the GEM group.
Aims: To update the results of efficacy and safety of selinexor with D-Vd for the treatment of RRMM in a phase 2, multicenter, open label study (GEM-SELIBORDARA trial) (NCT03589222).
Methods: 57 patients were enrolled between July 2018 and March 2021. The study had two parts. In part 1, patients with ≥ 3 PL, previously treated with proteasome inhibitor (PI) and IMIDs and refractory to the last line or double refractory (to Len and PI) were included. In part 2, patients with relapse or progressive disease after ≥ 1 PL were included. Patients received IV daratumumab (Dara, 16mg/kg) at the approved schedule switching to the subcutaneous (SC) formulation when approved, plus bortezomib (1.3 mg/m2 on days 1, 8, 15 and 22 in cycle (C) 1-8 and days 1 and 15 from C9-onwards) and dexamethasone (40mg days 1, 8, 15, 22), in combination with selinexor days 1, 8, 15 and 22 (100mg in Part 1 and 60mg in Part 2). Cycles of 4-wks duration in part 1 and 5-wks in part 2, until disease progression or unacceptable toxicity. Study was conducted following Declaration of Helsinki and ICHGCP guidelines. Primary endpoint was complete response (CR) rate. Key secondary endpoints were ORR and safety evaluation. Cut-off date: 6 Feb 2023.
Results: In part 1 (n=24), 96% percent were Len-refr, 71% of patients (pts) were double refractory and 96% refractory to the last line. ORR was 50%, with 2 pts (12%) achieving CR (1 MRD-ve and 1 MRD+ve by flow). After a median follow-up (f/u) of 39 months (12-50), 21 pts discontinued treatment, 17 of them due to disease progression. Median PFS was 7.0 months (95% CI 3.1 – 10.8), and OS 28.0 months (95% CI 0 – 57.3).
In part 2 (n=33), median PL was 1 (range 1-3), 20 pts (61%) received 1 PL. 15 pts (45%) were Len-refr; 8/20 (40%) were Len-refr after 1PL; 12% were double refractory and 36% were refractory to the last line. 4 pts had del17p, 1 (4;14), and 3 R-ISS 3. ORR was 82%, with 11 pts (33%) achieving CR (8 MRD -ve and 3 MRD+ve by flow). After a median f/u of 26 months (19-31), 19 pts have discontinued treatment, 14 of them due to disease progression. Median PFS was 24.0 months (95% CI 14.2 – 33.8) for the whole cohort 2, 22.1 months (95% CI 10.9 – 33.1) for the Len-refr group, and 27 months for those relapsing after 1PL. Median OS was still NR (95% CI NE-NE).
Regarding adverse events (AEs) reported with longer f/u, hematological AEs were the most frequent ones [thrombocytopenia (70.1%; G 3-4 in 45%) and neutropenia (36.8%; G3-4 in 29.8%)]. Followed by GI-Tox [diarrhea (38.6%; G 3-4 in 2 pts) and nausea (35.1%; G3-4 in 5 pts]. 41 pts had infections during treatment (G3-4: 39%). The dose of selinexor was the most frequently one modified (15 cases in part 1 and 23 in part 2) and discontinued in 8 pts (5 in part 1 and 3 in part 2). Only 1 pt discontinued the trial due to treatment toxicity.
Conclusion:
In this updated analysis of GEM-SELIBORDARA ph2 trial, longer follow-up did not result in new safety signals with selinexor-DVd. Efficacy is encouraging, especially for early relapses and Len-refr patients. Selinexor-DVd might be considered when a rescue treatment based on daratumumab is needed, as an alternative when cardiovascular comorbidities are present, and the SC and oral formulation are preferred.
Keywords: Myeloma, Treatment, relapsed/refractory