Investigating Efficacy, Safety, and Biomarkers in a Phase 2 Trial of Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Following Second-Line Lenalidomide-Based Therapy (Tx) in Relapsed or Refractory Multiple Myeloma (RRMM)
Notice bibliographique
Résumé
Abstract Background: Preclinical studies indicate that lenalidomide (LEN) and POM are not cross-resistant (Ocio et al Leukemia, 2015) and that POM remains active in LEN-resistant myeloma cells (Lopez-Girona et al Leukemia, 2012). Likewise, POM + LoDEX showed comparable efficacy in patients (pts) refractory to LEN administered as last prior Tx vs the full population in subanalyses of the clinical trials MM-002 and MM-003 (San Miguel et al Lancet Oncol, 2013; Richardson et al Blood, 2014). To confirm these observations, we initiated a single-arm, phase 2 trial evaluating POM + LoDEX immediately following second-line LEN-based Tx in advanced RRMM (MM-014; NCT01946477). Methods: Eligible pts (aged ≥ 18 yrs) had received 2 prior lines of Tx, with ≥ 2 cycles of LEN-based Tx in the second line. Pts must have had documented progressive disease (PD) during or after their last antimyeloma Tx and Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. POM was administered 4 mg/day on days 1-21 of a 28-day cycle with LoDEX 40 mg/day (20 mg/day for pts aged > 75 yrs) on days 1, 8, 15, and 22 until PD or discontinuation for any reason. Pts received mandatory thromboprophylaxis. The primary end point was overall response rate by modified International Myeloma Working Group criteria (including minor response). Secondary end points included progression-free survival, overall survival, time to progression, safety, and duration of response. Exploratory end points were included to identify molecular, immune, and cellular biomarkers that might inform POM + LoDEX response, resistance, or mechanism of action. Results: As of March 20, 2015, 27 of the 85 planned pts were enrolled and received POM + LoDEX. Twelve pts remain on Tx, whereas 15 have discontinued, due to PD (n = 7) and withdrawal (n = 5), but not adverse events (n = 0). Males comprised 59% of pts; 85% were white and the median age was 69 yrs (range, 44-85 yrs), with 67% of pts aged ≥ 65 yrs. The median time since diagnosis was 3.9 yrs (range, 1.3-13.3 yrs), and 59% of pts received prior stem cell transplant. Most pts (81%) were refractory to the most recent prior LEN-containing Tx, and the median duration of the most recent prior LEN Tx was 8.3 mos (range, 0.3-56.3 mos). The 19% of pts who were not refractory to the most recent prior LEN-containing Tx remain on Tx. Pts predominantly had ECOG performance status 0 or 1 (30% and 63%, respectively) vs 2 (7%). Of the 19 pts with International Staging System assessment reported, most were stage I (n = 7) or II (n = 11) vs III (n = 1). Efficacy and safety data will be presented. Conclusions: The MM-014 study is assessing the efficacy and safety of POM + LoDEX in pts with RRMM who have received second-line LEN-based Tx. MM-014 is designed to confirm and expand the results from MM-002 and MM-003 with translational data. Clonality and biomarkers, including Aiolos, Ikaros, IRF-4, and c-Myc, will be evaluated to determine association with POM + LoDEX synergy, high-risk MM-associated genetic aberrations, clonal evolution, and minimal residual disease. Disclosures Siegel: Celgene Corporation: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Merck: Speakers Bureau; Novartis: Speakers Bureau. Schiller:Celgene Corporation: Research Funding. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stockerl-Goldstein:Celgene Corporation: Speakers Bureau; Onyx: Speakers Bureau. Kaya:Novartis: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Sebag:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Reu:Takeda/Millennium: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Mouro:Celgene Corporation: Employment, Equity Ownership. Sturniolo:Celgene Corporation: Employment. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Research Funding.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,003 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».