Preclinical and Translational Biomarker Analyses to Inform Clinical Development of Mezigdomide (CC-92480) in Combination with Dexamethasone and Daratumumab in Multiple Myeloma
Notice bibliographique
Résumé
Introduction: Mezigdomide (MEZI) is a novel, oral cereblon (CRBN) E3 ligase modulator (CELMoD) that induces rapid and potent degradation of lkaros and Aiolos. Reduction of these transcription factors results in direct tumoricidal and immunomodulatory effects in multiple myeloma (MM). MEZI showed promising efficacy and safety in combination with dexamethasone in the phase 1/2 CC-92480-MM-001 trial (NCT03374085) in Relapsed/Refractory MM. MEZI is currently being investigated in combination with daratumumab and dexamethasone (MEZI + DARA + DEX or MEZI-Dd) in the phase 1/2 CC-92480-MM-002 trial (NCT03989414). In MEZI-Dd cohort, MEZI is administered at three different schedules (B1 for 21/28 days; B2 for 14/21 days; B3 for 7/14 days), and at two different doses (0.3mg; 0.6mg). Here we report preclinical data and pharmacodynamic (PD) biomarker analyses from blood and bone marrow samples collected in CC-92480-MM-002 to support dose and schedule optimization of MEZI-Dd. Methods:Preclinical studies on the pro-apoptotic effects of MEZI on daratumumab-mediated complement-dependent cytotoxicity (CDC) and peripheral blood mononuclear cell-based antibody-dependent cell-mediated cytotoxicity (ADCC) were performed in MM cell lines treated with MEZI-D in comparison to single-agent MEZI or DARA. Clinical PD biomarker analyses included peripheral blood samples collected on treatment Cycle (C)1 Day (D)1 and mid C1-C3 for the expression of Aiolos in T-cells and immunomodulation by flow cytometry. Bone marrow samples were collected for immunohistochemistry at screening and mid C2. Serum free light chain (sFLC) and soluble B-cell maturation antigen (BCMA) were analyzed as biomarkers for tumor burden from C1-C6. Results: Preclinically, combinations of MEZI-D induced synergistic anti-tumor activity in MOLP-8 cells. The MEZI-D combination showed greater anti-MM activities across the dosing gradient than either single-agent DARA (~2-4.5 fold) or MEZI (~1.7-2.4 fold) in a CDC assay. MEZI-D also induced significantly more cell apoptosis than POM-D (p<0.05) in an ADCC assay. In the clinic, MEZI-Dd was sufficient to induce rapid Aiolos degradation in the peripheral blood T-cells for doses as low as 0.3mg MEZI, but 0.6mg MEZI was necessary to result in >50% substrate degradation, suggesting 0.6mg MEZI induced deeper substrate degradation. While 0.3mg MEZI-Dd decreased total CD56+/CD16+ NK-cell counts (Median -83.8%) by mid C1 via immunophenotyping analyses, the combination increased %Ki67+ proliferative NK-cell (Median 251.9%). 0.3mg MEZI-Dd also showed consistent trends of schedule-dependent PD immune effects by mid C3, including increased %Ki67+ proliferative CD3+ T-cell (Median B1: 113.1%, B2: 365.1%, B3: 37.4%), decreased CD45RA+CCR7+ naïve CD4+ T-cell (Median B1: -82.0%, B2: -62.3%, B3: -43.9%), increased CD45RO+CCR7- effector memory CD4+ T-cell (Median B1: 142.3%, B2: 82.9%, B3: 13.9%), and increased HLA-DR expressing CD4+ T-cell activation (Median B1: 149.3%, B2: 107.9%, B3: 17.1%). Thus, greater PD immune effects were observed with schedules of 21/28 and 14/21 days, compared to the 7/14 schedule. At 0.6mg MEZI-Dd, greater median changes of PD immune effects were induced with the 7/14 schedule, compared to 0.3mg MEZI-Dd. Conversely, at continuous dosing schedules longer than 7 days, MEZI-Dd PD immune effects of 0.6mg MEZI were similar to 0.3mg MEZI. In addition, greater reduction of tumor burden was observed at 0.6mg MEZI-Dd, compared to 0.3mg MEZI-Dd across different schedules, as assessed by sFLC and soluble BCMA analyses. Conclusions: Our data show dose- and schedule-dependent PD effects of MEZI-Dd. PD analyses at 0.3mg MEZI suggest at least two weeks of continuous dosing may be needed for greater PD activities in combination with daratumumab, compared to one week of dosing. For continuous dosing of one week, a higher dose at 0.6mg MEZI may be needed to achieve greater PD activities. Further investigation of doses at 0.6mg and 1mg MEZI is underway to determine the optimal dose. Moreover, MEZI induction of NK-cell proliferation and/or activation may provide mechanistic rationale for possible MEZI-D synergy in the clinic.
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 | 0,004 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,002 | 0,001 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,002 |
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 ».