These findings suggest that while MPO inhibition may not enhance efficacy of bortezomib induction therapy, it holds promise as a maintenance strategy to improve long-term outcomes in MM. Collectively, our data support further investigation of AZD5904 as a novel maintenance therapy targeting the BM microenvironment, with potential to enhance and sustain the effectiveness of existing, standard of care regimens.

Our findings highlight ABCB1 promoter hypomethylation as a potential epigenetic driver of CFZ resistance in MM. These results underscore the clinical relevance of epigenetic regulation in drug resistance and the potential of targeting DNA methylation as a therapeutic strategy to overcome resistance in MM.

In addition, GAS significantly inhibited aberrant NF-κB signaling and upregulation of NLRP3 inflammasome-related proteins of BIPN mice. GAS may alleviate BIPN by suppressing microglia-mediated neuroinflammatory responses, and the NF-κB/NLRP3 inflammasome signaling pathway appears to be involved in this process.

In vivo experiments confirmed that WYC-209 potentiated the antitumor efficacy of CFZ by upregulating ZMYND8, thereby ameliorating tumor burden in NSG mice. These findings establish that targeting ZMYND8 with the novel retinoid WYC-209 potently enhances the efficacy of CFZ and holds translational promise for improving clinical outcomes in patients with MM.

Notably, 7n displayed the strongest inhibitory activities against JAK3 in 76 kinase profiles with the inhibitory rate of 96.87% at the concentration of 5 nM. Altogether, these findings suggest that JAK3 is a potential target to develop the inhibitor for treating Bortezomib-resistant multiple myeloma and 7n can be considered a promising candidate for further research.

Post-ASCT2 maintenance, particularly with lenalidomide or carfilzomib-based regimens, significantly prolonged disease control in randomized and real-world studies. In the modern treatment landscape, second or salvage autologous transplantation remains a valid, safe, and effective strategy for carefully selected patients with relapsed multiple myeloma, particularly those with chemosensitive disease and prolonged initial remissions. ASCT2 should be integrated in a risk-adapted manner alongside maintenance therapy and emerging immunotherapies, serving as a durable consolidation or bridging approach rather than routine therapy for all relapsed patients.

High plasma cell-like phenotype signatures were linked to poorer progression-free survival (PFS) but greater benefit from R-CHOP plus bortezomib, while low-signature patients achieved better PFS with R-CHOP alone. These findings characterize the transcriptomic features of distinct plasma cell-like phenotypes in DLBCL, providing new insights into its prognostic relevance and potential for individualized treatment strategies.

Co-treatment of BoHV-1 with either bortezomib or lenalidomide increased anti-MM cytotoxicity. Finally, BoHV-1 upregulated CD38 on both MM cells and immune effectors, thereby increasing sensitivity to the anti-CD38 daratumumab. These findings establish BoHV-1 as a promising immunovirotherapy agent, effective as a single agent and in combination strategies, by coupling direct oncolysis with broad immune remodeling of the BM microenvironment.

Venetoclax-based regimens, combined venetoclax with either hypomethylating agents or low-dose cytarabine, have markedly improved treatment outcomes in elderly patients with acute myeloid leukemia (AML). Importantly, the combination of bortezomib and venetoclax significantly prolongs the survival of mice inoculated with venetoclax-resistant AML cell line harboring BAX mutations, which are commonly observed in relapsed AML following venetoclax-based regimens and confer resistance to venetoclax by inhibiting BAX-dependent apoptotic pathway. Collectively, this study provides a rationale for venetoclax-bortezomib combination as a potential strategy to overcome venetoclax resistance in certain AML subsets.

Cycloheximide (CHX) chase and MG132 treatment showed that FMR1 depletion reduced FTO protein abundance and accelerated FTO turnover in an MG132-sensitive manner, consistent with a post-translational regulatory relationship. Collectively, our data support an FMR1-FTO module associated with the immune-excluded phenotype and nominate this axis as a potential vulnerability for disrupting stromal immune barriers. The FMR1-FTO axis may represent a candidate target for strategies aimed at relieving immune exclusion and improving immunotherapy sensitivity.

In contrast, the methylation status of histone H3 lysine 4 (H3K4me1/3) on the PERK promoter remains unaltered, regardless of the complex state. Taken together, the findings of this study underscore the key role of KDM5C as a driving force behind MM progression and BTZ resistance, indicating that KDM5C represents a novel and promising therapeutic target for the treatment of BTZ-resistant MM.

Furthermore, the modulation of p16INK4a expression by MUS81 was abolished by pretreatment with cycloheximide or MG132, suggesting that MUS81 stabilizes p16INK4a by preventing proteasome-mediated degradation. Collectively, these findings indicate that MUS81 works as a tumor suppressor in BC by inhibiting proliferation and migration through post-translational stabilization of p16INK4a.