Recuerdo @amniebla que me hizo una clase de linfomas en Vall d'Hebron y me convenció de que esta era mi especialidad soñada.
Hoy soy R1 de Hematología en Hopital Germans Tries i Pujol 🩸 @HematoCanRuti#hematorulers#hematologia
María del Mar Gracia, R-3 del Servicio nos dió la sesión “Dianas Moleculares e inhibidores de Menina en Leucemia Mieloblástica Aguda”. Los Residentes cumpliendo su responsabilidad de formación 👍👍👍
The reason bispecific responses fade in myeloma — T-cell exhaustion — may have a fixable epigenetic switch. New Blood paper (Chiu, Zhao et al, BMS) makes the mechanistic case for mezigdomide + TCE.
Preclinical but kinda neat. Ex vivo Tex model.
The exhaustion phenotype they reproduce is brutal:
• IL2 ↓, CCL17 ↓
• TOX/PD-1/TIM3/CD39 all climbing
• IKZF1 redistributes
• Tex kills BCMA-K562 with Alnuctamab far worse than Tact
What mezigdomide does in Tex:
• Degrades IKZF1/IKZF3 deeper than lena or pom in this system
• Reopens chromatin — Tact-like programming
• Cytokine genes (CCL17, CCL1/2, IFNγ) re-engage;
• >4-fold increase in target cell killing with Alnuctamab — EC50 back to Tact levels
• Same effect carries with teclistamab, talquetamab, and elranatamab
If you remember the how Iber works - Iberdomide degrades IKZF1 too (Tay, Cell Rep Med 2024), but iberdomide's registration program is + daratumumab. Mezig is going the TCE direction — phase 1 with elranatamab is enrolling (NCT06645678), and the companion clinical paper (Chen et al,) already shows PD-1 and TIGIT down on patient T cells in vivo after mezig.
Very intriguing indeed. If a short course of mezi can put exhausted T cells back into a functional state, "progression on bispecific" may not have to mean "switch agent."
Are headed toward CELMoD pulses to extend TCE durability, instead of cycling drug classes?
@BloodJournal @sparekh4 @szusmani@bmsnews@RahulBanerjeeMD@HiraSMian@bhemato
#Myeloma #mmsm #HemOnc
The Immunologic Paradox of BTK Inhibitors in Chronic Lymphocytic Leukemia: Selectivity, Hypogammaglobulinemia, and Infection Risk https://t.co/v6SzaTIZni #mdpicancers via @Cancers_MDPI#cll#leusm
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