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Translational Research : the Journal of... Aug 2018Over 2 decades ago, the proteasome was considered a risky or even untenable therapeutic target. Today, proteasome inhibitors are a mainstay in the treatment of multiple... (Review)
Review
Over 2 decades ago, the proteasome was considered a risky or even untenable therapeutic target. Today, proteasome inhibitors are a mainstay in the treatment of multiple myeloma (MM) and have sales in excess of 3 billion US dollars annually. More importantly, the availability of proteasome inhibitors has greatly improved the survival and quality of life for patients with MM. Despite the remarkable success of proteasome inhibitor therapies to date, the potential for improvement remains, and the development and optimal use of proteasome inhibitors as anticancer agents continues to be an active area of research. In this review, we briefly discuss the features and limitations of the 3 proteasome inhibitor drugs currently used in the clinic and provide an update on current efforts to develop next-generation proteasome inhibitors with the potential to overcome the limitations of existing proteasome inhibitor drugs.
Topics: Antineoplastic Agents; Boron Compounds; Bortezomib; Drug Resistance, Neoplasm; Glycine; Humans; Neoplasms; Oligopeptides; Proteasome Inhibitors
PubMed: 29654740
DOI: 10.1016/j.trsl.2018.03.002 -
Blood Advances Sep 2021The expression of CD20 in precursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with poor outcomes. The addition of rituximab to intensive chemotherapy in...
The expression of CD20 in precursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with poor outcomes. The addition of rituximab to intensive chemotherapy in CD20+ ALL has led to improved outcomes in several studies. However, there is no clear evidence regarding the optimal number of doses and its benefit without an allogeneic stem cell transplant. Achieving measurable residual disease (MRD)-negative status postinduction would reduce the requirement for a transplant. Novel approaches are needed to induce a higher proportion of MRD-negative complete remission in patients with high-risk ALL. Given bortezomib's activity in relapsed ALL and its synergism with rituximab in B-cell lymphomas, the addition of bortezomib to rituximab and chemotherapy may provide an incremental benefit in CD20+ precursor B-ALL. We conducted a phase 2 study to test the activity of bortezomib and rituximab in combination with a pediatric-inspired regimen during induction therapy in newly diagnosed adolescents and adults (aged >14 years) with CD20+, Philadelphia-negative precursor B-ALL; bone marrow MRD negativity at the end of induction was the primary end point. From December 2017 through August 2019, a total of 35 patients were enrolled. End-of-induction MRD-negative status was achieved in 70.9% of patients, as opposed to 51.7% in the historical cohort treated with chemotherapy alone. MRD-negative rates improved to 87.5% post-consolidation. At a median follow-up of 21 months, event-free survival and overall survival rates were 78.8% (95% confidence interval, 66-94) and 78.7% (95% confidence interval, 65.8-94), respectively. There was no significant increase in toxicity with bortezomib and rituximab compared with the historical cohort. The incidence of neuropathy was 26% (all less than grade 3). The combination of bortezomib, rituximab, and a pediatric-inspired ALL regimen was active and well tolerated in de novo CD20+ Philadelphia-negative precursor B-ALL. This trial was registered with the Clinical Trials Registry-India as CTRI/2017/04/008393(http://ctri.nic.in/Clinicaltrials).
Topics: Adolescent; Adult; Bortezomib; Child; Humans; Lymphoma, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cells, B-Lymphoid; Rituximab
PubMed: 34461632
DOI: 10.1182/bloodadvances.2020003368 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2021In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved...
Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE.
BACKGROUND
In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status.
PATIENTS AND METHODS
Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients.
RESULTS
Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%).
CONCLUSION
Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone
PubMed: 34344638
DOI: 10.1016/j.clml.2021.06.005 -
Cancer Metastasis Reviews Dec 2017The clinical efficacy of proteasome inhibitors in the treatment of multiple myeloma has encouraged application of proteasome inhibitor containing therapeutic... (Review)
Review
The clinical efficacy of proteasome inhibitors in the treatment of multiple myeloma has encouraged application of proteasome inhibitor containing therapeutic interventions in (pediatric) acute leukemia. Here, we summarize the positioning of bortezomib, as first-generation proteasome inhibitor, and second-generation proteasome inhibitors in leukemia treatment from a preclinical and clinical perspective. Potential markers for proteasome inhibitor sensitivity and/or resistance emerging from leukemia cell line models and clinical sample studies will be discussed focusing on the role of immunoproteasome and constitutive proteasome (subunit) expression, PSMB5 mutations, and alternative mechanisms of overcoming proteolytic stress.
Topics: Acute Disease; Animals; Bortezomib; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Leukemia; Molecular Targeted Therapy; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 29071527
DOI: 10.1007/s10555-017-9699-4 -
Experimental Hematology Sep 2016Allogeneic hematopoietic stem cell transplantation is the standard treatment for a variety of benign and malignant conditions. However, graft-versus-host disease (GvHD)... (Review)
Review
Allogeneic hematopoietic stem cell transplantation is the standard treatment for a variety of benign and malignant conditions. However, graft-versus-host disease (GvHD) continues to present a major barrier to the success and wide applicability of this procedure. Although current GvHD prevention and treatment regimens exclusively target T cells, bortezomib, a reversible proteasome inhibitor, possesses unique immune regulatory activities that span a wide variety of cellular processes of T and dendritic cells essential for the development of GvHD. Herein, we review the current understanding of the effects of bortezomib in vitro and in animal models and summarize the clinical data relevant to its use in the prevention and treatment of GvHD. We conclude with an outline of the remaining challenges and opportunities to optimize bortezomib's potential role in this setting.
Topics: Animals; Apoptosis; Bortezomib; Clinical Trials as Topic; Cytokines; Dendritic Cells; Disease Models, Animal; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Activation; T-Lymphocyte Subsets; Transplantation, Homologous; Treatment Outcome
PubMed: 27224851
DOI: 10.1016/j.exphem.2016.05.005 -
Clinical Lymphoma, Myeloma & Leukemia Mar 2024A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use...
INTRODUCTION
A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use of pomalidomide, bortezomib, and dexamethasone (PVd) for treating relapsed/refractory MM. This subanalysis of OPTIMISMM assessed outcome by frailty and/or bortezomib dose adjustment.
METHODS
Patient frailty (nonfrail vs. frail) was classified using age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. Data from patients requiring a bortezomib dose reduction, interruption, and/or withdrawal during PVd treatment were assessed.
RESULTS
Among 559 patients, 93 of 281 (33.1%) and 93 of 278 (33.5%) patients who received PVd and bortezomib and dexamethasone (Vd), respectively, were frail. Overall response rate (ORR) and median progression-free survival (PFS) were higher in nonfrail vs. frail with PVd treatment (ORR, 82.8% vs. 79.6%; PFS, 14.7 vs. 9.7 months); significantly higher than with Vd regardless of frailty. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were higher with PVd vs. Vd, regardless of frailty. Discontinuations of PVd were lower in nonfrail vs. frail patients (19.2% vs. 30.1%); the median duration of treatment was similar (DoT; 8.8 vs. 8.9 months, respectively). Patients who received PVd with a bortezomib dose adjustment (n = 240) had a longer median DoT (9.3 vs. 4.5 months) and PFS (12.1 vs. 8.4 months) vs. those without.
CONCLUSION
Frail patients treated with PVd demonstrated a higher ORR and a longer PFS and DoT vs. Vd, despite a higher frequency of grade ≥ 3 TEAEs leading to pomalidomide, bortezomib, and/or dexamethasone discontinuation. Therefore, PVd treatment may improve patient outcomes, regardless of frailty.
Topics: Humans; Multiple Myeloma; Bortezomib; Lenalidomide; Frailty; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Thalidomide
PubMed: 38072743
DOI: 10.1016/j.clml.2023.10.009 -
Expert Opinion on Drug Discovery Feb 2017Mantle cell lymphoma (MCL) is an incurable, often aggressive B-cell malignancy. Bortezomib (BTZ), the 20S proteasome inhibitor was originally developed and approved for... (Review)
Review
Mantle cell lymphoma (MCL) is an incurable, often aggressive B-cell malignancy. Bortezomib (BTZ), the 20S proteasome inhibitor was originally developed and approved for treatment of relapsed refractory multiple myeloma, and subsequently approved for treatment of MCL. BTZ's single-agent activity induces clinical responses in approximately one-third of relapsed MCL patients. BTZ-containing combination therapies have further improved the quality and duration of clinical responses compared to standard chemotherapies in previously untreated MCL patients. Areas covered: This review summarizes the discovery, mechanisms of -action and resistance, preclinical- clinical-developments, and FDA approval of BTZ for treatments of MCL. Expert opinion: Preclinical MCL models demonstrated the apoptotic effect of BTZ through multiple mechanisms, as well as synergistic anti-MCL activity between BTZ and other chemotherapeutics. Single-agent and combinational clinical trials have validated the therapeutic potential of targeting the ubiquitin proteasome system (UPS) in MCL. However, inherent and acquired drug resistance remains a significant clinical problem and multiple potential mechanisms have been identified. Next-generation proteasome inhibitors with different pharmacodynamic properties from BTZ may partially address the issue of inherent resistance, with increased response rates noted in some diseases. In addition, upstream UPS components, e.g., E3 ligases or deubiquitinating enzymes, may also be targetable in MCL.
Topics: Animals; Antineoplastic Agents; Apoptosis; Bortezomib; Drug Design; Drug Discovery; Humans; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Proteasome Inhibitors
PubMed: 27917682
DOI: 10.1080/17460441.2017.1268596 -
Journal of Physiology and Pharmacology... Apr 2018Multiple myeloma (MM) is a disease of unknown, complex etiology that affects primarily older adults. The course of the disease and the patients' survival time are very... (Review)
Review
Multiple myeloma (MM) is a disease of unknown, complex etiology that affects primarily older adults. The course of the disease and the patients' survival time are very heterogeneous, but over the last decade, clear progress in the treatment of this incurable disease has been observed. Therapeutics that have proven to be highly effective include the immunomodulatory drug thalidomide and its newer analogs, lenalidomide and pomalidomide, as well as the proteasome inhibitors bortezomib and carfilzomib. However, the administration of some of the treatments, e.g., thalidomide or bortezomib, has also been associated with the occurrence of a serious and common adverse effect, drug-induced peripheral neuropathy. The mechanism of the development of the peripheral neuropathy is poorly understood. Nevertheless, one of its potential causes could be inadequate concentrations of crucial trophic factors, including neurotrophic and/or angiogenic factors, which are responsible for the proliferation, differentiation, survival and death of neuronal and nonneuronal cells.
Topics: Animals; Antineoplastic Agents; Bortezomib; Humans; MicroRNAs; Multiple Myeloma; Nerve Growth Factors; Peripheral Nervous System Diseases; Protease Inhibitors; Thalidomide
PubMed: 29920472
DOI: 10.26402/jpp.2018.2.02 -
Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection.Blood Advances Apr 2021Systemic chronic active Epstein-Barr virus (EBV; sCAEBV) infection, T- and natural killer (NK)-cell type (sCAEBV), is a fatal disorder accompanied by persisting...
Systemic chronic active Epstein-Barr virus (EBV; sCAEBV) infection, T- and natural killer (NK)-cell type (sCAEBV), is a fatal disorder accompanied by persisting inflammation harboring clonal proliferation of EBV-infected T or NK cells. Today's chemotherapy is insufficient to resolve disease activity and to rid infected cells of sCAEBV. The currently established treatment strategy for eradicating infected cells is allogeneic hematopoietic stem cell transplantation. In this study, we focused on the effects of proteasome inhibitor bortezomib on the disease. Bortezomib suppressed survival and induced apoptosis of EBV+ T- or NK-cell lines and peripheral mononuclear cells containing EBV-infected T or NK cells of sCAEBV patients. Bortezomib enhanced binding immunoglobulin protein/78-kDa glucose-regulated protein (Bip/GRP78) expression induced by endoplasmic reticulum stress and activated apoptosis-promoting molecules JNK and p38 in the cell lines. Bortezomib suppressed the activation of survival-promoting molecule NF-κB, which was constitutively activated in EBV+ T- or NK-cell lines. Furthermore, quantitative reverse transcription-polymerase chain reaction demonstrated that bortezomib suppressed messenger RNA expression of proinflammatory cytokines tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) in EBV+ T or NK cells from the patients. Finally, we examined the effects of bortezomib using xenograft models of sCAEBV generated by IV injection of patients' cells. The intraperitoneal administration of bortezomib significantly reduced EBV-DNA load in peripheral blood and the infiltration of EBV-infected cells in the models' livers. Moreover, the serum concentration of TNF-α and IFN-γ decreased after bortezomib treatment to the models. Our findings will be translated into the treatment of sCAEBV not only to reduce the number of tumor cells but also to suppress inflammation.
Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Bortezomib; Endoplasmic Reticulum Chaperone BiP; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans
PubMed: 33787860
DOI: 10.1182/bloodadvances.2020002417 -
Blood Nov 2018
Topics: Bortezomib; Decision Making; Humans; Lenalidomide; RNA
PubMed: 30442746
DOI: 10.1182/blood-2018-10-875138