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.