t(4;14) Positive Multiple Myeloma Is Chemosensitive to Dexamethasone and/or Thalidomide but Not Alkylating Agents: Rapid Relapse and Not Primary Drug Resistance Explains Poor Outcomes.
Notice bibliographique
Résumé
Abstract The t(4;14) simultaneously dysregulates expression of fibroblast growth factor receptor 3 (FGFR-3) and MMSET and has been detected in 15% of MM patients. Despite being an early event in the genesis of clonal gammopathy the t(4;14) is somewhat surprisingly reported as a poor prognostic factor in patients treated with both conventional chemotherapy and those undergoing autologous stem cell transplantation (ASCT). Presumably either primary drug resistance or, alternatively, rapid relapse following treatment must explain this outcome. To address this clinical issue we analyzed 128 patients who were treated with induction chemotherapy followed by melphalan 200 mg/m2 at our institution between 1998–2000. Using FISH analysis we identified 16 of these patients with a t(4;14). These patients had a predominance of the IgA isotype (56.3%) compared with t(4;14) negative patients (17.7%) (p = 0.0019). Otherwise baseline characteristics including sex, age, B-2 microglobulin, CRP, calcium, creatinine, Hb, albumin or percentage of bone marrow plasma cells were indistinguishable from the general MM poulation. Fifteen t(4;14) patients received induction chemotherapy with 4–5 cycles of vincristine, adriamycin and dexamethasone(VAD) with one receiving pulsed dexamethasone alone. Thirteen of the sixteen (81%) responded with > 50% paraprotein decrease. However 3 of these 13 patients demonstrated early progression of disease during later cycles of VAD or during stem cell collection and required further salvage prior to ASCT. Use of high dose melphalan and ASCT resulted in a further 54% of patients achieving a >50% paraprotein decrease with a mean paraprotein reduction of 49% (range 0–99%). Nevertheless the median progression free survival (PFS) post ASCT was only 9.9 months, significantly shorter than for t(4;14) negative patients (p=0.0001). Given the surprisingly short PFS following high dose alkylating agents we next examined all salvage regimens employed. Ten patients at some point received a conventional dose alkylating agent as salvage (cyclophosphamide or melphalan). Response was dismal with stable disease in 6 patients and progressive disease in 4 patients. In contrast 14 patients at some point received salvage thalidomide or high dose dexamethasone either as a single agent or in combination. Five patients demonstrated a partial response (>50–90% reduction), 4 patients a minor response and 5 patients had stable disease for an overall response rate of 64%. Two patients treated with Bortezomib demonstrated partial responses. We conclude from this preliminary analysis that t(4;14)+ve MM is poorly responsive to alkylating agents, including high dose melphalan and thus that use of these agents (including ASCT) is generally of no long term value in this patient population. Given the high response rates of 81% at induction and 64% at salvage, induction and maintenance regimens containing high dose dexamethasone and/or thalidomide are favored. Nevertheless, since response to these agents is often short lived novel therapeutic regimens are required. In this regard the early clinical study of targeted FGFR-3 tyrosine kinase inhibitors which have shown pre-clinical promise is encouraged.
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 | 0,000 | 0,001 |
| 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) | 0,002 | 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 ».