IKZF1 (IKAROS Family Zinc Finger 1)

P1, N=10, Completed, Zhejiang University | Recruiting --> Completed | N=16 --> 10 | Trial completion date: Aug 2025 --> May 2025 | Trial primary completion date: Aug 2025 --> May 2025

P2, N=20, Active, not recruiting, Pharming Technologies B.V. | Recruiting --> Active, not recruiting

Mechanistically, Tazemetostat appears to reduce IKZF1 binding to the IRF4 promoter and super-enhancer, explaining how the combination with IMiDs/CELMoDs which also have this effect may reach the threshold required to suppress IRF4 expression and ultimately inhibit MM cell growth in resistant cell lines. Our findings highlight a potential strategy for treating MM patients with IMiD resistance.

Oral administration of BMS-986458 results in dose-dependent pharmacokinetics, pharmacodynamics, and significant antitumor efficacy in mouse models of lymphoma. A potential first-in-class agent, BMS-986458, is currently being evaluated in a phase 1/2 clinical trial (NCT06090539) for patients with relapsed/refractory NHL.

The B-ALL patients with concurrent RB1 and IKZF1 deletions had worse outcomes compared to cases without any of these deletions. The RB1 deletion increased the risk of early events in patients with the IKZF1plus profile.

This suggests that IKZF3 is a good biological indicator for tumors and may become a new therapeutic target for tumors. A systematic elaboration of the latest research progress on the IKZF3 gene structure, physiological functions, tumor regulation, and treatment resistance can provide reference and scientific basis for future tumor therapy.

Importantly, dasatinib-based therapy (n = 27) demonstrated superior 3-year OS (100% vs. 66.7%) and EFS (100% vs. 60.0%) compared to imatinib-based therapy (n = 15) (both p < 0.05). Our study indicates that pediatric Ph + ALL has male predominance and frequent genomic aberrations. p190 and p210 have distinct baseline features but comparable outcomes in the TKI era, and dasatinib is a superior first-line TKI.

With frontline therapeutic strategies increasingly employing quadruplet induction regimens and prolonged lenalidomide maintenance, resistance to traditional IMiDs has become more prevalent, creating an urgent need for next-generation cereblon E3 ligase modulators (CELMoDs) capable of overcoming IMiD refractoriness and enhancing the immunologic microenvironment. Iberdomide (CC-220) and mezigdomide (CC-92480) are rationally engineered CELMoDs designed to achieve deeper degradation of Ikaros (IKZF1) and Aiolos (IKZF3), restore cereblon-mediated activity, and potentiate immune effector responses...We examine how their pharmacodynamic properties differ from classical IMiDs, their relevance in triple-class and penta-refractory MM, and their integration into emerging combination strategies with monoclonal antibodies and T-cell-redirecting immunotherapies. Special emphasis is placed on ongoing and future trials that may refine their therapeutic positioning, alongside a critical appraisal of the limitations and future directions of this rapidly advancing drug class.

This finding highlights the functional relevance of IMiD's inherent polypharmacology in circumventing primary resistance mechanisms at the cellular level. Together, our results identify the ARID2-containing PBAF complex as a critical vulnerability in resistant myeloma cells and provide a mechanistic rationale for designing combination strategies that co-target this complex, with the potential to enhance therapeutic efficacy by overcoming drug resistance.