Selinexor in Combination with Daratumumab-Bortezomib and Dexamethasone for the Treatment of Relapse or Refractory Multiple Myeloma: Initial Results of the Phase 2, Open-Label, Multicenter GEM-Selibordara Study

Background: Treatment of multiple myeloma (MM) has significantly evolved in the last decade leading to significant improvements in survival. Still, cure remains elusive and new combinations incorporating drugs with novel mechanism of action are needed to rescue patients becoming resistant to standard of care. Selinexor is an exportin-1 (XPO1) inhibitor approved in combination with dexamethasone for the treatment of penta-exposed relapsed-refractory MM (RRMM) and showing superior PFS and ORR combination with weekly Vd versus standard twice weekly Vd in RRMM after 1-3 prior lines (PL). Dara-Vd is also a combination approved in RRMM after 1-3 PL. Here we report the initial results of a phase 2, multicenter, open label study (GEM-SELIBORDARA trial) (NCT03589222), based on the combination of Selinexor with D-Vd (SELIBORDARA) for the treatment of RRMM.

Patients and methods: Between July 2018 and March 2021, 57 patients were included. The study had two different parts. In part 1 patients with ≥ 3 PL, previously treated with proteasome inhibitor (PI) and immunomodulatory drugs and refractory to the last line or double refractory were included. In part 2, patients in relapse or with progressive disease after ≥ 1 PL were included. Patients received intravenous daratumumab (Dara, 16mg/kg) at the approved schedule, plus bortezomib (1.3 mg/m ² 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 were of 4 weeks duration in part 1 and 5-weeks duration in part 2. Treatment was continued 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 profile. Cut-off date: 1 June 2021.

Results: Patients included in part 1 (n=24) had a median age of 65.5 years. Median number of PL was 3 (range 2-3). 96% and 71% of patients had MM refractory to lenalidomide (Len-Refr) and PI. 71% had double refractory and 96% had MM refractory to last line. 21% had high-risk cytogenetics (HR-CA) and 12.5% had R-ISS 3.

Part 1 ORR was 50% with 3 patients (12%) achieving CR/sCR. After a median f/u of 28.3 months, 18 patients have discontinued treatment, 14/18 due to disease progression. Median PFS and OS were 7.1 (95% CI 3.4 - 20.0) and 27.5 months (95% CI 10.6 - NE), respectively.

In part 2 (n=33) median age was 69 years. Median PL was 1, 61% with 1 PL. Forty-five percent of patients were Len-refractory and 12% were double refractory. 36% were refractory to the last line. 5 patients had HR-CA and 3 patients had R-ISS 3.

After a median f/u of 9.8 months, 8/33 patients have discontinued treatment, 5/8 due to disease progression. ORR was 82% with 8 patients (24%) achieving CR/sCR. Median PFS is not yet reached (95% CI 12.1 - NE). Median PFS in Len-Refr patients included in part 2 (n=15) was 12.1 months. Median OS is NR (95% CI NE-NE).

Adverse events (AEs) were manageable. Recommended supportive care to prevent Selinexor associated nausea (± anorexia) included ondansetron for 2 days and daily olanzapine. Hematological adverse events (AEs) were registered in 77% of the patients. Thrombocytopenia was the most frequent (68.4%; grade 3-4 in 34%). Neutropenia was reported in 33% (grade 3-4 in 25%). Non-hematological adverse events (AEs) were registered in 75% of the patients. GI-Tox was reported in 22 patients (38%), with nausea as the most frequent GI event (16/22, only 2 grade 3-4). Overall, 35 patients (61.4%) required dose modifications. Selinexor was the drug most frequently modified, and was reduced in 24 (15 in part 1 and 14 in part 2) and discontinued in 5 patients (4 in part 1 and 1 in part 2), respectively. Only 1 patient discontinued the trial due to AEs.

Conclusion: In this phase 2 single arm, open label study, the combination of Selinexor plus DVd showed encouraging efficacy and manageable safety profile both in the setting of late and particularly early relapse MM, although data in this second cohort is still immature and requires longer follow-up.