689 Pharmacodynamic results with talquetamab and daratumumab in patients with relapsed/refractory multiple myeloma in TRIMM-2
Notice bibliographique
Résumé
<h3>Background</h3> Talquetamab is a T-cell redirecting bispecific antibody targeting G protein-coupled receptor family C group 5 member D and CD3. Daratumumab is an anti-CD38 monoclonal antibody with direct on-tumor and immunomodulatory actions. The phase 1b TRIMM-2 (NCT04108195) trial showed that talquetamab + daratumumab had deep (overall response rate [ORR] of 71–84%) and durable responses, with promising ORRs in unmet need subgroups (anti-CD38 refractory and prior T-cell redirection exposed), and a manageable safety profile in patients with relapsed/refractory multiple myeloma (RRMM). We present pharmacodynamic results from TRIMM-2 to support and elucidate the potential immunomodulatory mechanisms of action (MOA) of talquetamab + daratumumab. <h3>Methods</h3> Patients had MM, ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and IMiD and had not received anti-CD38 therapy in ≤90 days. Patients received the recommended phase 2 doses of talquetamab, 0.4 mg/kg weekly or 0.8 mg/kg biweekly with step-up doses, + daratumumab 1800 mg per the approved schedule. Whole blood from patients in TRIMM-2 was analyzed for immune populations by flow cytometry. T-cell clonality was analyzed by T-cell receptor sequencing. <h3>Results</h3> Patients who received talquetamab + daratumumab demonstrated T-cell redistribution (early reduction in peripheral CD3+ T cells) and subsequent T-cell recovery, consistent with the MOA of each agent. A high level of clonal expansion was observed at cycle 3, day 1 vs baseline, including a significant increase in the fraction of newly detected clones, indicative of antigen-specific T-cell activation. Talquetamab + daratumumab led to a moderate increase in effector memory CD8+ T cells and induction of T-cell activation, as evidenced by an increase in LAG-3+, TIM-3+, and PD-1+ CD8+ T cells in the first cycle. An initial reduction of CD38+CD8+ T cells was observed after daratumumab administration; however, following talquetamab administration, induction of CD38+CD8+ T cells was observed, indicative of T-cell activation. Consistent with daratumumab’s MOA, there was a notable reduction in immunosuppressive CD38+ regulatory T cells (Tregs) with the combination and a sustained reduction in natural killer cells. There was no reduction in total CD19+ B cells. <h3>Conclusions</h3> The pharmacodynamic profile of talquetamab + daratumumab was consistent with the respective MOAs and showed induction of T-cell activation, an increase in T-cell clonality, and reduction of immunosuppressive CD38+ Tregs. These data support the promising efficacy of this off-the-shelf immunotherapy combination in patients with RRMM. <h3>Acknowledgements</h3> This study was funded by Janssen Research & Development, LLC. Medical writing support was provided by Rachael Smith, PhD, of Eloquent Scientific Solutions, and funded by Janssen Global Services, LLC. <h3>Trial Registration</h3> NCT04108195 <h3>Ethics Approval</h3> Conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonization’s Good Clinical Practice guidelines. Protocol/amendments were approved by each site’s Institutional Review Board. All patients provided informed written consent.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| 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 | 0,001 |
| 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 ».