Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma
Mené sur 42 patients atteints d'un myélome multiple réfractaire ou récidivant, cet essai randomisé analyse la dose maximale tolérée, l'efficacité, du point de vue du taux de réponse globale, et la toxicité du sélinexor utilisé en combinaison avec de faibles doses de bortézomib et de la dexaméthasone (nombre médian de thérapies précédentes : 3)
Selinexor is an oral inhibitor of the nuclear export protein exportin 1 (XPO1). Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) though suppression of NF
κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd. We enrolled 42 patients to receive selinexor (60, 80, or 100 mg orally) plus bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally) once- or twice-weekly in 21- or 35-day cycles. Patients had a median of 3 (range 1-11) prior lines of therapy and 50% were refractory to a PI. Treatment-related grade 3 or 4 adverse events reported in
≥ 10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%) and anemia (12%). Incidence (4 patients, 10%) and grade (≤ 2) of peripheral neuropathy were low. The ORR for the entire population was 63%; 84% ORR for PI nonrefractory and 43% for PI-refractory patients. The median progression-free survival for all patients was 9.0 months; 17.8 months for PI non-refractory and 6.1 months for PI-refractory. SVd treatment produced high response rates in patients with relapsed or refractory MM, including borezomib-refractory MM, with no unexpected side effects. The RP2D is selinexor (100 mg once-weekly), bortezomib (1.3 mg/m2 once-weekly for 4 weeks), and dexamethasone (40 mg once-weekly) per 35-day cycle. The study is registered to https://clinicaltrials.gov as NCT02343042.