P868: MEZIGDOMIDE (MEZI) PLUS DEXAMETHASONE (DEX) IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): RESULTS FROM THE DOSE-EXPANSION PHASE OF THE CC-92480-MM-001 TRIAL
Notice bibliographique
Résumé
Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: MEZI, a novel oral cereblon E3 ligase modulator (CELMoD™) with enhanced tumoricidal and immune-stimulatory effects compared with IMiD® agents, induces maximal Ikaros/Aiolos degradation, leading to increased apoptosis in MM cells. Preclinically, MEZI demonstrated potent synergy with DEX, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs). In phase 1 of CC-92480-MM-001 (NCT03374085), the recommended phase 2 dose (RP2D) of MEZI + DEX (Mezi-d) was selected at 1 mg once daily for 21/28 days. Aims: To report results from the Mezi-d dose-expansion cohort in pts with heavily pretreated RRMM. Methods: Eligible pts had: RRMM; ≥3 prior lines of therapy; refractoriness to lenalidomide (LEN)/pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb; disease progression in ≤60 days of last myeloma therapy. MEZI 1 mg was given on days 1–21 of each 28-day cycle, with weekly DEX (40 mg; 20 mg if >75 years of age). Primary objective was to evaluate efficacy by overall response rate (ORR); secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. Results: As of September 16, 2022, 101 pts had received MEZI-d at the RP2D. Median age was 67 (range 42–85) years, median time since initial diagnosis was 7.4 (1.1–37.0) years, and 20.8% of pts had ISS stage III at study entry. Plasmacytomas were present in 39.6% of pts and 37/101 pts had high-risk cytogenetics (56/101 pts not evaluable). Median number of prior regimens was 6 (range 3–15). Prior therapies included stem cell transplantation (77.2%) and anti-B-cell maturation antigen (BCMA) therapy (29.7%). All pts were refractory to last myeloma regimen and triple-class refractory, and 39.6% of pts were refractory to LEN, POM, ≥ 2 PIs, and an anti-CD38 mAb. Median follow-up was 7.46 (range 0.5–21.9) months, with a median number of 4 (1–20) cycles received; 10 (9.9%) pts continued treatment, with the main reason for discontinuation being progressive disease (60.4%). ORR was 40.6% in all pts (Table). While data are not yet mature, median progression-free survival (PFS) was 4.4 (95% confidence interval [CI] 3.0–5.5) months and median duration of response was 7.6 (95% CI 5.4–9.5) months. In pts with plasmacytomas, ORR was 30.0% (n=40) and median PFS was 3.0 (95% CI 2.1–4.9) months. In pts with prior anti-BCMA therapy, ORR was 50.0% (n=30) and median PFS was 5.4 (95% CI 2.1–9.4) months. Grade (Gr) 3/4 treatment-emergent adverse events (TEAEs) were reported in 92 (91.1%) pts. Most frequent (≥20% pts) hematologic Gr 3/4 TEAEs were neutropenia (75.2%, with 14.9% febrile neutropenia), anemia (35.6%), and thrombocytopenia (27.7%). Gr 3/4 infections were seen in 34.7% of pts, including Gr 3/4 pneumonia (15.9%) and COVID-19 (7.0%). Other Gr 3/4 non-hematologic TEAEs were generally low, including gastrointestinal disorders (5.9%), fatigue (5.0%), and rash (1.0%). Due to TEAEs, 76 (75.2%) pts and 29 (28.7%) pts had MEZI dose interruptions and reductions, respectively. MEZI induced substrate degradation and increases in activated and proliferating T cells in all pts, including in pts refractory to POM-containing therapies, demonstrating the efficacy of MEZI in this heavily pretreated population. Summary/Conclusion: MEZI-d had a manageable safety profile with encouraging efficacy in pts with triple-class refractory RRMM, including pts with prior BCMA-targeted therapies. These results support the development of MEZI in MM. MEZI is being evaluated in combination with standard therapies in MM in an ongoing phase 1/2 trial (NCT03989414); phase 3 trials in combination with PIs are planned.Keywords: Clinical data, Multiple myeloma, Immunomodulation
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 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 ».