Multiple myeloma (MM), a terminally differentiated B cell malignancy, remains difficult to cure. Understanding the molecular mechanisms underlying the progression of MM may identify therapeutic targets and lead to a fundamental shift in treatment of the disease. Deubiquitination, like ubiquitination, is a highly regulated process, implicated in almost every cellular process. Multiple deubiquitinating enzymes (DUBs) have been identified, but their regulation is poorly defined. Here, we determined that TRIP13 increases cellular deubiquitination. Overexpression of TRIP13 in mice and cultured cells resulted in excess cellular deubiquitination by enhancing the association of the DUB USP7 with its substrates. We show that TRIP13 is an oncogenic protein because it accelerates B cell tumor development in transgenic mice. TRIP13-induced resistance to proteasome inhibition can be overcome by a USP7 inhibitor in vitro and in vivo. These findings suggest that TRIP13 expression plays a critical role in B cell lymphoma and MM by regulating deubiquitination of critical oncogenic (NEK2) and tumor suppressor (PTEN, p53) proteins. High TRIP13 identifies a high-risk patient group amenable to adjuvant anti-USP7 therapy.

Background: Zevorcabtagene autoleucel (Zevor-cel, CT053), a fully human autologous anti- B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell

Objective: Multiple myeloma (MM) is the leading indication of autologous hematopoietic stem cell transplantation. The aim of this study was to determine the incidence of mobilization failure and characterize the risk factors associated with poor mobilization (PM) of MM patients in novel therapies era.Methods: We conducted a retrospective study of 211 MM patients who received their first peripheral blood stem cells (PBSC) mobilization at our single center. The following data were collected: age, gender, clinical stage, disease status, complete blood cell count, induction regimen, CD34⁺ cell count in peripheral blood (PB), and PBSC collections.Results: In addition to conventional drugs, 22 (10.4%) patients received daratumumab containing induction, and 33 (15.6%) patients used plerixafor for poor mobilization (pre‐apheresis PB CD34⁺ cells 41 g/L before mobilization, and steady‐state mobilization were risk factors for PM in subgroups of patients treated with lenalidomide for <3 courses. In addition, Hepatitis B virus infection at baseline, thalassemia and measurable residual disease positivity were recognized as predictive factors for PM in subset of chemo‐mobilization patients.Conclusion: In addition to some well‐recognized risk factors, baseline WBC count and daratumumab exposure ≥2 courses before mobilization were revealed as the predictive factors of mobilization failure, providing consultation for preemptive use of plerixafor.

Background: Lenalidomide, an immunomodulatory drug (IMiD), is an effective therapy for the treatment of multiple myeloma (MM). However, prolonged treatment may be accompanied by toxicity, second primary malignancies, and drug resistance. There is an inherent vulnerability in MM cells that high rates of immunoglobulin synthesis resulting in the high level of reactive oxygen species (ROS). This provides a therapeutic potential for MM. Materials and Methods: The intracellular ROS levels, H₂O₂ production and glutathione (GSH) levels were measured using detection kit. Cell viability was evaluated using cell-counting kit-8 (CCK-8) and soft agar colony formation assay. Apoptosis was determined in whole living cells using flow cytometry. Chidamide and its anti-myeloma efficacy in combination with lenalidomide were characterized in MM cell lines in vitro and in a mouse xenograft model. Moreover, Western blotting, immunofluorescence and immunohistochemical studies were performed. Results: ROS levels increased in a time- and dose-dependent manner with chidamide treatment. Moreover, the GSH levels were decreased and the mRNA level of SLC7A11 downregulated after chidamide treatment. The co-treatment with chidamide and lenalidomide increased apoptosis and proliferation inhibition, with combination index (CI) in the synergistic range (0.2– 0.5) using the Chou–Talalay method. The cooperative anti-myeloma efficacy was confirmed in the murine model, and immunohistochemical studies also supported this potentiation. Chidamide enhanced the effect of lenalidomide-induced degradation of IKZF1 and IKZF3 by elevating H₂O₂. In addition, co-treatment with chidamide and lenalidomide increased biomarkers of caspase and DNA damage. Conclusion: Elevated ROS production may constitute a potential biochemical basis for anti-myeloma effects of chidamide plus lenalidomide. The results of this study confirm the synergistic effect of chidamide and lenalidomide against MM and provide a promising therapeutic strategy for MM.

Background: Multiple myeloma (MM) is an incurable hematologic malignancy, requiring sustained therapeutic management to mitigate disease recurrence. Ixazomib, a first‐generation oral proteasome inhibitor, has exhibited substantial clinical efficacy and is widely employed in clinical practice. According to prescribing guidelines, ixazomib is typically administered at an initial dose of 4 mg weekly for 3 weeks, with dose reduction to 3 mg weekly in the event of adverse effects. Prior exposure–response analyses have confirmed that both 3 and 4 mg doses reside within the clinically effective range. This study aims to assess the comparative efficacy and toxicity profiles of 3 versus 4 mg ixazomib in MM. Methods: We performed a retrospective analysis of 207 MM patients undergoing ixazomib‐based therapy across six medical centers. Patients were stratified into three subgroups: initial treatment, in‐class transition, and maintenance/continuation therapy group. Additionally, patients were categorized into two cohorts according to ixazomib dosage: 3 or 4 mg. Demographic characteristics, baseline clinical features, and therapeutic outcomes were compared between the 3 and 4 mg cohorts. Results: Our results indicate that 3 and 4 mg ixazomib demonstrate equivalent efficacy in induction, class‐switch, and maintenance/continuation therapy across most clinical scenarios in Chinese MM patients. Subgroup analysis within the in‐class transition cohort revealed that patients with RISS Stage 3 disease exhibited prolonged progression‐free survival in the 4 mg group. Furthermore, patients with an ECOG performance status of one to two achieved enhanced overall survival with the 4 mg dose. The overall adverse event rates were comparable between the two dose groups. Notably, during the induction phase, the 4 mg group exhibited a significantly higher incidence of Grades 1–2 vomiting ( p = 0.016). Conclusions: These findings suggest that initiating therapy with 3 mg ixazomib is both clinically viable and effective, potentially alleviating the economic burden for MM patients.