Multiple myeloma (MM) is the second most common hematological malignancy, predominantly affecting the elderly. With the development of an aging society in China, the incidence of MM has been steadily increasing, becoming a significant concern for public health and a considerable socioeconomic burden. Over the past two decades, breakthroughs have been achieved in both clinical management and basic research on MM. However, the field now stands at a crossroads for the next phase, facing numerous developmental directions and challenges.

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells within the bone marrow, with pathological features including abnormal secretion of monoclonal immunoglobulins, osteolytic bone disease, and multi-organ dysfunction. Despite significant advancements in therapeutic approaches that have markedly extended patient survival, primary drug resistance and relapse remain major obstacles to clinical cure. The pathogenesis and progression of MM are intricately regulated by the bone marrow microenvironment (BMME), a dynamic network composed of diverse cellular and non-cellular components. The BMME not only supports the survival and proliferation of MM cells but also plays a pivotal role in disease progression by modulating bone metabolic homeostasis, mediating immune escape, and promoting drug resistance. In recent years, groundbreaking therapeutic strategies targeting the BMME have emerged, including immunomodulatory drugs, bispecific antibodies, CAR T-cell therapies, and microenvironment-modulating agents. These approaches have significantly improved objective response rates and survival outcomes in relapsed/refractory MM by disrupting cytokine signaling, reprogramming the immunosuppressive microenvironment, or inhibiting tumor-stromal interactions. However, challenges such as drug resistance, treatment-related toxicity, and tumor heterogeneity persist in clinical practice. This review systematically delineates the roles of BMME components in MM pathogenesis, analyzes the molecular mechanisms underlying MM cell-BMME interactions, and explores innovative strategies to enhance therapeutic efficacy and prognosis through targeted modulation of the BMME. These insights provide a foundation for developing novel therapeutic paradigms aimed at overcoming current limitations in MM treatment.

Multiple myeloma (MM) is a hematologic malignancy characterized by the malignant proliferation of plasma cells. Currently, proteasome inhibitors (PIs),immunomodulatory drugs (IMiDs), and autologous hematopoietic stem cell transplantation (ASCT) are the primary approaches used to improve the survival outcomes of MM patients. However, as treatment advances, most patients still face refractory and relapsed diseases, and the path to a cure remains challenging. In recent years, monoclonal antibodies (mAbs), chimeric antigen receptor T cells (CAR-T),antibody-drug conjugates (ADCs), and bispecific antibodies (BsAbs) have all demonstrated promising efficacy in clinical studies and applications. These antibody and cell-based immunotherapies have brought new hope to patients with refractory and relapsed MM (RRMM). Each type of immunotherapy offers unique advantages in activating immune cells, targeting tumors, and improving patient outcomes, yet they also encounter challenges related to safety and resistance. In the future, with continuous advancements in molecular biology and antibody engineering, novel immunotherapeutic products are expected to achieve synergistic effects through combination strategies, thereby providing longer survival benefits and improved life quality for RRMM patients. This article aims to review the latest progress in immunotherapy for MM, systematically discussing the mechanisms of action, current clinical applications, and future development trends of mAbs, CAR-T, ADCs, and BsAbs. It is intended to serve as a comprehensive reference for researchers and clinicians and promote advancing precision immunotherapy for MM.

UBE2O is a distinctive ubiquitin-conjugating enzyme characterized by its large size (1 292 residues) and dual E2/E3 enzymatic activities, enabling diverse ubiquitylation types. Unlike typical E2 enzymes (150~200 residues), UBE2O’s multifunctionality allows it to regulate substrate degradation, subcellular localization, and functional modulation. Emerging studies highlight its critical roles in protein quality control, erythroid differentiation, metabolic regulation, and maintenance of circadian rhythm. Dysregulation of UBE2O is implicated in various diseases, including cancers, neurodegenerative disorders, and metabolic diseases. This review extensively discusses the unique structural features, diverse biological functions, and pathological roles of UBE2O, as well as its therapeutic potential for associated diseases.

Multiple myeloma (MM) is a hematologic malignancy originating from plasma cells in the bone marrow. In recent years, the use of novel drugs and hematopoietic stem cell transplantation (HSCT) has significantly improved the prognosis of MM patients. However, MM remains challenging to cure and is prone to relapse and resistance. For patients with relapsed/refractory multiple myeloma (RRMM), there is an urgent need to explore novel therapeutic approaches. Bispecific antibodies (BsAbs) are a promising class of immunotherapeutics that functions by simultaneously binding to tumor cell antigens and endogenous effector cells, thereby forming an immunological synapse. This interaction facilitates the activation of effector cells, leading to the targeted lysis of tumor cells. Numerous clinical studies have demonstrated the significant efficacy of BsAbs, either as monotherapy or in combination with other treatment regimens, in patients with RRMM. This article summarizes the mechanisms of action, efficacy, and safety of BsAbs, and discusses optimal sequencing strategies in immunotherapy, aiming to provide new perspectives for the treatment of MM.

Although teniposide (VM26) is widely used in the treatment of lymphoma, its poor water solubility, low bioavailability and systemic toxicities still limit its clinical application. Nano-delivery systems are effective in increasing the bioavailability and reducing the toxicity of VM26, but there is an urgent need to overcome the problem of its non-specific targeting. Therefore, in this paper, we designed and constructed a hyaluronic acid-modified teniposide-targeted nano-delivery system (VM26-TNDS), and characterised its drug encapsulation rate, particle size and zeta potential. We also investigated the effects of VM26-TNDS on B-cell lymphoma cells with different expression of CD44 receptor, in terms of cellular targeting, inhibitory effect of proliferation, and induction of apoptosis and necrosis. The results showed that the drug encapsulation efficiency of VM26-TNDS exceeded 85%, and its liquid formulation could be stably stored at 4 ℃ for more than 6 months without precipitation. Based on CD44 receptor expression, Granta-519 (high expression), Raji (medium-low expression) and SU-DHL-4 (almost no expression) were screened for cellular experiments. Compared with VM26-NDS, the targeted modification could effectively reduce the uptake of VM26-TNDS by RAW264.7 and increase the uptake of VM26-TNDS by CD44 receptor-expressing lymphoma cells. The inhibitory proliferative effect and apoptotic necrosis-inducing ability of VM26-TNDS were stronger than those of VM26-NDS for Granta-519 and Raji cells, whereas there was no significant difference in the inhibitory effect on proliferation and ability to induce apoptosis and necrosis between VM26-NDS and VM26-TNDS in SU-DHL-4 cells, reflecting the targeting advantage for VM26-TNDS, as expected. However, its toxic effect on B-cell lymphoma cells only reflected the targeting advantage at some concentrations (0.25 μmol/L and 0.5 μmol/L), which met the expectation. The above results indicate that a teniposide-targeted nano-delivery system, VM26-TNDS, has been successfully prepared in this study. VM26-TNDS improves the delivery efficiency of VM26 by targeting human B-cell lymphoma cells expressing the CD44 receptor, thus killing human B-cell lymphoma cells more effectively and overcoming the problem of non-specific targeting in drug delivery to improve the therapeutic effect. Its biological therapeutic effects and mechanisms still need to be proved by more in vitro and in vivo experimental evidence.

Acquired resistance to the proteasome inhibitor bortezomib (BTZ) poses a significant challenge in the treatment of multiple myeloma (MM). During the acquisition of BTZ resistance, metabolic reprogramming is actively engaged in MM cells. However, the key regulatory genes and molecular mechanisms mediating bortezomib resistance through this metabolic rewiring have not been fully elucidated. This study aims to investigate the regulatory role of pyrimidine metabolites in drug resistance of MM and their underlying molecular mechanisms. Screening via CCK-8 assays demonstrated that the pyrimidine metabolite uridine is associated with BTZ resistance in MM (P<0.05). In vitro experiments, including CCK-8 assays, Western blotting, and flow cytometry, demonstrated that uridine partially suppresses bortezomib-induced apoptosis in MM cells (P<0.05). In vivo, experiments utilizing Vk*MYC mouse models, subcutaneous tumor models, and intramedullary bone marrow transplantation models showed that the combination of BTZ and uridine significantly accelerated tumor growth, exacerbated bone destruction, and increased tumor cell infiltration in tumor-bearing mice (P<0.05). RNA sequencing analysis revealed that uridine primarily affects mitochondrial translation in MM at the transcriptional level. Seahorse energy metabolism assays demonstrated that uridine enhances mitochondrial oxidative phosphorylation without significantly altering glycolysis. Transcriptomic analysis further identified a significant upregulation of cytochrome c oxidase subunit 5B (COX5B) transcription in uridine-treated groups (P<0.05). Functional studies confirmed that COX5B is a key molecule mediating uridine’s effects on mitochondrial function in MM cells. In conclusion, uridine promotes BTZ resistance in MM by upregulating COX5B transcription and protein expression, thereby enhancing cytochrome c oxidase activity and regulating mitochondrial oxidative phosphorylation. This study delineates the role of uridine in the development of bortezomib resistance in MM and elucidates its COX5B-mediated metabolic reprogramming mechanism, providing a theoretical foundation for developing targeted therapies against relapsed/refractory MM.

A subset of patients with multiple myeloma (MM) present with reduced serum vitamin B12 levels at initial diagnosis; however, its clinical significance and underlying mechanisms remain unclear. Vitamin B12 plays a crucial role in hematopoiesis and immune regulation. This study aims to elucidate its association with extramedullary diseases, immune function, and prognosis in MM patients. A retrospective analysis was conducted of 92 newly diagnosed MM patients, who received treatment at the Second Affiliated Hospital of Soochow University between January 2020 and December 2023. Patients were classified into a low vitamin B12 group (n=37) and a normal vitamin B12 group (n=55) based on their serum vitamin B12 levels. The findings revealed that the incidence of extramedullary infiltration was significantly higher in the low vitamin B12 group than in the normal group (26.5% vs. 17.0%, P=0.031). Survival analysis demonstrated that patients with low vitamin B12 levels had significantly shorter overall survival (OS) and progression-free survival (PFS) (OS: P=0.0123; PFS: P=0.0136). Additionally, these patients showed a decreasing trend in peripheral blood total T cell, CD4⁺ T cell, and CD8⁺ T cell counts, with serum vitamin B12 levels showing a significant positive correlation with the total T cell count (R=0.2717, P=0.0135) and CD4⁺ T cell count (R=0.2175, P=0.0497). In conclusion, reduced serum vitamin B12 levels at initial diagnosis are significantly associated with poor prognosis in MM patients and may serve as a potential prognostic biomarker. Furthermore, vitamin B12 deficiency may contribute to immune dysfunction, particularly impaired T cell immunity, and a higher incidence of extramedullary diseases.