bortezomib

Overview

Bortezomib (trade name Velcade) is a first-generation, reversible inhibitor of the 26S proteasome and one of the most pivotal agents in modern hematologic oncology. It functions by blocking the ubiquitin-proteasome pathway, which cells rely on to degrade misfolded, damaged, or regulatory proteins. By preventing this degradation, bortezomib triggers the accumulation of pro-apoptotic factors and disrupts the nuclear factor-κB (NF-κB) signaling cascade, ultimately inducing programmed cell death in malignant cells. Its selective cytotoxicity against rapidly proliferating tumor cells — particularly plasma cells — established it as a cornerstone drug in the treatment of multiple myeloma and, subsequently, mantle cell lymphoma.

Beyond its established hematologic indications, bortezomib continues to be investigated in a broad array of solid tumors and rare hematologic malignancies, including AL amyloidosis, diffuse large B-cell lymphoma (DLBCL), colorectal cancer, and uterine leiomyosarcoma. Its mechanism of action — inducing proteotoxic stress and activating the unfolded protein response — provides a rational basis for combination strategies with immunomodulatory agents, monoclonal antibodies, and novel Targeted therapies. Resistance to bortezomib, driven by mechanisms including proteasome subunit mutations, upregulation of survival pathways, and alterations in the tumor microenvironment, remains a central challenge motivating ongoing drug development efforts.

Focus of Latest Publications

Recent publications on bortezomib have focused primarily on multiple myeloma, where it continues to be evaluated both as part of standard regimens and as a partner in novel combinations. In a longitudinal observational study of newly diagnosed multiple myeloma, the bortezomib-lenalidomide-dexamethasone (VRd) regimen was associated with a transient expansion of circulating monocytic myeloid-derived suppressor cells during induction, with levels normalizing after autologous stem cell transplantation. The increase in M-MDSCs correlated with shallower response depth, although it did not remain an independent predictor after adjustment for disease stage. A separate real-world FAERS analysis comparing first-line regimens reported that VRd was associated with elevated neurological disorder signals, supporting regimen-specific safety monitoring and neurological surveillance during bortezomib-based therapy.

Several recent studies explored mechanisms that may influence bortezomib response or toxicity. In multiple myeloma cells, MYBL2 knockdown enhanced ferroptosis and increased bortezomib sensitivity through transcriptional regulation of CDKN3 and inactivation of the PI3K/Akt signaling pathway. Another study examining bortezomib-induced peripheral neuropathy used whole-exome sequencing and transcriptomic integration to identify genetic susceptibility patterns and inflammatory pathways, suggesting that inflammation-driven neuronal dysfunction contributes to bortezomib-related neurotoxicity. These findings point to both potential biomarkers of response and a molecular basis for adverse-event risk in patients receiving bortezomib.

Bortezomib was also investigated in combination strategies aimed at improving anti-myeloma activity. In a murine model of advanced multiple myeloma, the syndecan-1-targeting peptide chimera SSTNIV showed the greatest survival benefit when combined with bortezomib, reducing bone marrow tumor burden, alleviating extramedullary disease, and restoring hematopoiesis. In newly diagnosed multiple myeloma with extramedullary disease, the phase 2 SVRD regimen combining selinexor with bortezomib, lenalidomide, and dexamethasone produced deep hematologic responses, high rates of extramedullary disease regression, and manageable toxicity. In relapsed/refractory multiple myeloma, the DREAMM-6 arm B trial evaluated belantamab mafodotin with bortezomib and dexamethasone, reflecting continued interest in bortezomib-containing combinations for difficult-to-treat disease.

Beyond multiple myeloma, bortezomib has been studied in other malignancies and in safety-focused preclinical work. In uterine leiomyosarcoma cell lines, bortezomib induced cytotoxicity, apoptosis, mitochondrial dysfunction, cell-cycle arrest, and altered autophagic processing. In colorectal cancer cells, bortezomib was examined in combination with 6-O-carboxypropyl-α-tocotrienol to enhance anticancer effects. Together, these publications reinforce bortezomib’s role as a proteasome inhibitor with broad investigational use, while also highlighting ongoing efforts to optimize efficacy, overcome resistance, and better define toxicity across disease settings.

Key Publications

• NEWJul Circulating M-MDSC Expansion During Therapy Associates With Treatment Response in Multiple Myeloma: A Longitudinal Observational Study. (Clinical and translational science, 2026, PMID 42374568): "VRd, but not daratumumab-based regimens, significantly expanded M-MDSCs (median +0.98%, p<0.0001), which normalized after ASCT."
• NEWJul MYBL2 Knockdown Enhances Ferroptosis and Bortezomib Sensitivity by Transcriptionally Regulating CDKN3 and Inactivating PI3K/Akt Signaling in Multiple Myeloma. (Journal of biochemical and molecular toxicology, 2026, PMID 42345518): "MYBL2 knockdown also enhanced the bortezomib (BTZ) sensitivity of MM cells."
• May The safety profile of lenalidomide, dexamethasone, daratumumab, and bortezomib combinations in multiple myeloma: a retrospective analysis of the FAERS database. (Naunyn-Schmiedeberg's archives of pharmacology, 2026, PMID 42171749): "The current study aimed to compare the real-world safety profiles of first-line multiple myeloma regimens-lenalidomide plus dexamethasone (Rd), bortezomib plus lenalidomide and dexamethasone (VRd), and daratumumab plus lenalidomide and dexamethasone (DRd)-using the FDA Adverse Event Reporting System (FAERS) database."
• May SSTNIV, a syndecan-1-targeting peptide chimera, reverses immune suppression and inhibits myeloma progression. (Signal transduction and targeted therapy, 2026, PMID 42115585): "When combined with the frontline MM chemotherapy agent bortezomib, SSTNIV conferred the greatest survival benefit, substantially reducing MM cells in BM, alleviating extramedullary disease, and restoring hematopoiesis."
• May Genetic Susceptibility and Inflammatory Mechanisms in Bortezomib-Induced Peripheral Neuropathy: Insights From Whole Exome Sequencing and Transcriptomic Analysis. (Journal of applied toxicology : JAT, 2026, PMID 42055794): "Inter-individual variability in patient susceptibility to bortezomib (BTZ)-induced peripheral neuropathy (BIPN) suggests a potential role of genetic predisposition."
• May 6-O-Carboxypropyl-α-Tocotrienol Enhances the Anticancer Effects of Bortezomib Without Suppressing NRF1 and NRF3 in Colorectal Cancer Cells. (Anticancer research, 2026, PMID 42049351): "Bortezomib, a proteasome inhibitor, exhibits limited efficacy against colorectal cancer (CRC); therefore, strategies to enhance bortezomib sensitivity in CRC are required."
• Jun Digital spatial profiling uncovers transcriptomic features of distinct plasma cell-like phenotypes in diffuse large B-cell lymphoma. (Blood advances, 2026, PMID 41886633): "Using phenotype-associated genes, we constructed a random forest model to predict bortezomib response."
• May Proteasome inhibition by bortezomib induces stress-response-mediated cytotoxicity in uterine leiomyosarcoma cells. (Biochemical and biophysical research communications, 2026, PMID 41861709): "In this study, we investigated the cytotoxic effects and underlying mechanisms of bortezomib in Ut-LMS cell lines SK-LMS-1 and SK-UT-1B."
• May Efficacy and Safety of Belantamab Mafodotin with Bortezomib plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: The DREAMM-6 Arm B Trial. (Clinical cancer research : an official journal of the American Association for Cancer Research, 2026, PMID 41770089): "The phase I/II DREAMM-6 arm B study (NCT03544281) explored belantamab mafodotin combined with bortezomib/dexamethasone (BVd) in relapsed/refractory multiple myeloma (RRMM)."
• Apr Frequency-adjusted daratumumab-based regimen versus bortezomib/dexamethasone in newly diagnosed AL amyloidosis: a matched-cohort study. (Annals of medicine, 2026, PMID 41560662): "This real-world study compared the efficacy and safety of a frequency-adjusted, cyclophosphamide-free Dara-based regimen with bortezomib/dexamethasone (BD)."