Page 206 - Haematologica Vol. 109 - July 2024

ARTICLE - S-DVd in RRMM patients Introduction
The translation of innovative drugs from bench to patient has allowed continued improvement in survival in multiple myeloma (MM) patients.1 Despite this benefit, many patients with MM will eventually relapse and become multi-drug resistant highlighting the need of developing new drugs and combinations based on drugs with novel mechanisms of action.
Selinexor is a first-in-class oral inhibitor of a nuclear export protein called exportin 1 (XPO-1). By blocking this protein, most tumor suppressor proteins remain in the nucleus, resulting in cell cycle arrest and death of malignant plasma cells.2,3 Selinexor showed anti-MM activity in preclinical studies leading to the development of several clinical trials evaluating selinexor in combination with different antimy- eloma drugs.4 Currently, selinexor is approved in different settings and combinations. Selinexor in combination with dexamethasone (Sd) is approved for penta-refractory MM adult patients who have received at least four prior lines (PL) of therapies, based on the positive results of the STORM trial.5 In addition, selinexor is approved in combination with bortezomib and dexamethasone (SVd) for relapsed and refractory MM (RRMM) patients who have already received at least one PL of treatment based on efficacy and safety results of the BOSTON trial.6
Current treatment guidelines for RRMM patient, particularly in those lenalidomide (len)-refractory, recommended the use of proteasome inhibitors (PI)-based combinations together with anti-CD38 monoclonal antibodies, such as daratumumab or isatuximab.7,8 Mechanisms of action of daratumumab in- clude induction of apoptosis, immune-mediated actions and immunomodulatory functions, resulting in deep responses and prolonged survival when combined with immunomod- ulatory drugs (IMID), or PI, allowing even its combination in quadruplets with an acceptable toxicity in the upfront set- ting.9,10 One of the approved combinations for RRMM after one PL is daratumumab plus bortezomib and dexamethasone (DVd), based on results of the phase III CASTOR trial, where an improvement in the progression-free survival (PFS) as compared with bortezomib and dexamethasone (Vd) was demonstrated.11 Based on this background, we hypothesize that the addition of selinexor may improve the efficacy of DVd in a well tolerated manner. Here we present the results
Table 1. Treatment schedule in the clinical trial GEM-Selibordara.
V. González-Calle et al.
of a phase II clinical trial conducted by the Spanish myeloma group (GEM/PETHEMA) to investigate the efficacy and safety of the quadruplet selinexor plus DVd (S-DVd) in RRMM patients.
Methods
Trial design
An open-label, non-randomized, multicenter, phase II study to evaluate the efficacy and safety of S-DVd in RRMM pa- tients (GEM-SELIBORDARA trial). The study was designed by GEM/PETHEMA and carried out in 14 Spanish hospitals from July 2018 to March 2021. The cut-off date was February 6, 2023. The study had two different parts. In part 1, eligible patients had to have received at least three PL of therapy, including a PI (bortezomib) and any IMID and to be refrac- tory to the last line of therapy or double refractory as per IMWG definition.12 In part 2, eligible patients had received at least one PL. Prior treatment with PI was allowed if prior response, no grade ≥3 related-toxicity, and a washout of at least 6 months. Prior therapy with selinexor or anti-CD38 monoclonal antibodies was not permitted (see protocol in the Online Supplementary Appendix).
Patients received DVd (with intarvenous daratumumab) at the approved dose and schedule, in combination with selinexor days 1, 8, 15 and 22 (100 mg in part 1 and 60 mg in part 2) (Table 1). Treatment was given until disease progression or unacceptable toxicity. Recommended sup- portive treatment to minimize nausea was 5-HT3 receptor antagonists (Online Supplementary Appendix).
All patients provided written informed consent. The pro- tocol was approved by the Spanish Health Authorities and a central ethical committee. The study was conducted ac- cording to the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice (ICHGCP). The trial was registered at clinicaltrials gov. Identifier: NCT03589222.
Endpoints and assessments
The primary endpoint of the trial was to evaluate the efficacy of the combination S-DVd in terms of overall response rate (part 1) and complete response rate (CR) or better in part 2, according to IMWG criteria.13 Additional study endpoints are included in Online Supplementary Appendix.
PART 1
PART 2
Daratumumab (16 mg/kg IV/SC) weekly C1 and C2, C3-C6 Q2W, C7+ Q4W Bortezomib (1.3 mg/m2 SC): d1, 8, 15 & 22 (C1-C8), d1 & 15 (C9+). Dexamethasone 40 mg d1, 8, 15 & 22
Selinexor 100 mg d1, 8, 15 & 22
Selinexor 60 mg d1, 8, 15 & 22
4-week duration cycles
5-week duration cycles
Treatment was continued until disease progression or unacceptable toxicity
IV: intravenously; SC: subcutaneously, C: cycle; Q2W: every 2 weeks; Q4W: every 4 weeks; d: day.
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