Selinexor in Combination with Pomalidomide and Low Dose Dexamethasone in a Relapsed / Refractory Multiple Myeloma Patient Population with Prior Proteasome Inhibitor and Lenalidomide Exposure
Notice bibliographique
Résumé
Introduction - The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM) with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of 3.6 months in patients (pts) having received a prior proteasome inhibitor (PI) and IMiD. Strategies to improve the ORR and PFS are needed. In murine MM models, the combination of selinexor with IMiDs shows synergistic anti-MM activity and good tolerability. We present the results of a phase I dose escalation study of selinexor in combination with pom and dex (SPd) in RRMM. Methods - The primary objective of this phase 1b/2 study (NCT02343042) is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of SPd. Patients (pts) with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60; 80 mg) or twice-weekly (BIW, 60; 80 mg), with pomalidomide (pom) 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW. Results - As of 15-Jul-2017, 29 pts (14 male / 15 female) have been enrolled. The median age is 61 years, with a median of 4 (range, 2 - 9) prior treatment regimens. Twenty-five patients were IMiD refractory (15 len, 2 pom, 8 pom/len). Three dose limiting toxicities (DLTs) were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (60 mg BIW, pom 3 mg) and 4 missed doses in Cycle 1 (100 mg QW, pom 4 mg). Common treatment related Grade 1/2 adverse events (AEs) include: nausea (55%), fatigue (48%), anorexia (48%) and diarrhea (24%). Grade 3/4 AEs include: neutropenia (48%), thrombocytopenia (31%), and anemia (28%). Doses of 60 mg QW and 80 mg QW are being evaluted to determine RP2D. Twenty-four pts were evaluable for response. Responses rates can be seen in Table 1. Median PFS is 11.6 months with a median follow up of 7.7 months. Eight pts are still on study, (range 1 - 16+ months). Conclusions - Once weekly selinexor can be safely combined with Pd. This all oral combination of selinexor, pom and dex (SPd) has significant clinical activity with an ORR 54% in pts with heavily pretreated MM compared to previously published data of 30% ORR. No additional toxicities over monotherapy with selinexor or the Pd combination were observed. The novel all oral combination of SPd is a well-tolerated regimen and supports further clinical development in RRMM. Disclosures Chen: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sebag: Celgene, Janssen: Consultancy. Bensinger: Bayer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding. Gasparetto: Celgene: Research Funding; Janssen, BMS, Celgene: Consultancy; Janssen, BMS, Celgene, Takeda: Honoraria; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed. Lentzsch: Caelum Biosciences: Other: leadership position and stock; Amgen: Consultancy; BMS: Consultancy. Schiller: Celator/Jazz: Research Funding. Kauffman: Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Shacham: Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Jeha: Karyopharm Therapeutics: Employment. Saint-Martin: Karyopharm Therapeutics: Employment. Shah: Karyopharm Therapeutics: Employment. Bahlis: Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».