637 results match your criteria bortezomib carfilzomib

Retrospective study of treatment patterns and outcomes post-lenalidomide for multiple myeloma in Canada.

Eur J Haematol 2021 Jun 15. Epub 2021 Jun 15.

Cross Cancer Institute, University of Alberta, Canada.

Lenalidomide is an important component of initial therapy in newly-diagnosed multiple myeloma, either as maintenance therapy post-autologous stem cell transplantation (ASCT) or as first-line therapy with dexamethasone for patients' ineligible for ASCT (non-ASCT). This retrospective study investigated treatment patterns and outcomes for ASCT-eligible and -ineligible patients who relapsed after lenalidomide as part of first-line therapy, based on data from the Canadian Myeloma Research Group Database for patients treated between January 2007 and April 2019. Among 256 patients who progressed on lenalidomide maintenance therapy, 28. Read More

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Prognostic impact of resistance to bortezomib and/or lenalidomide in carfilzomib-based therapies for relapsed/refractory multiple myeloma: The Kyoto Clinical Hematology Study Group, multicenter, pilot, prospective, observational study in Asian patients.

Cancer Rep (Hoboken) 2021 Jun 14:e1476. Epub 2021 Jun 14.

Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Combinatory strategies with carfilzomib (CFZ), a second-generation proteasome inhibitor, plus dexamethasone (DEX) with or without lenalidomide (LEN) have shown promising efficacy for patients with relapsed/refractory multiple myeloma (RRMM) in pivotal clinical trials. However, their effects on patients who were resistance to bortezomib (BTZ) and/or LEN have not been fully evaluated in a daily practice setting.

Aims: To evaluate the real-world efficacy and safety of CFZ-based treatments; that is, CFZ with LEN plus DEX (KRD therapy) and CFZ with DEX (KD therapy), in Asian patients, we conducted a multicenter pilot prospective observational study in the Kyoto Clinical Hematology Study Group. Read More

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Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein.

Sci Rep 2021 May 25;11(1):10883. Epub 2021 May 25.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, PRB, 720 S. Donahue Dr., Auburn, AL, 36849, USA.

Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL-AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Read More

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Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect.

Sci Rep 2021 May 18;11(1):10523. Epub 2021 May 18.

School of Medicine and Surgery, Experimental Neurology Unit, University of Milano - Bicocca, Via Cadore 48, 20900, Monza, MB, Italy.

Proteasome inhibitors (PIs) represent the gold standard in the treatment of multiple myeloma. Among PIs, Bortezomib (BTZ) is frequently used as first line therapy, but peripheral neuropathy (PN), occurring approximately in 50% of patients, impairs their life, representing a dose-limiting toxicity. Carfilzomib (CFZ), a second-generation PI, induces a significantly less severe PN. Read More

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Feasibility of six cycles of lenalidomide-based triplet induction before stem cell collection for newly diagnosed transplant-eligible multiple myeloma.

Hematology 2021 Dec;26(1):388-392

Department of Hematology, Hyogo College of Medicine Hospital, Hyogo, Japan.

Objectives: Achieving a deep response with induction therapy has a major impact on outcomes following autologous stem cell transplantation. Although longer and intensified induction therapy may provide better disease control, longer exposure to lenalidomide negatively affects stem cell yield. We examined the feasibility of 6 cycles of lenalidomide-based triplet induction therapy before stem cell collection in transplant-eligible multiple myeloma patients. Read More

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December 2021

Pegfilgrastim for primary prophylaxis of febrile neutropenia in multiple myeloma.

Support Care Cancer 2021 May 14. Epub 2021 May 14.

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori "Dino Amadori" (IRST), IRCCS, Via Piero Maroncelli 40, Meldola, (FC), 47014, Italy.

Multiple myeloma (MM) survival rates have been substantially increased thanks to novel agents that have improved survival outcomes and shown better tolerability than treatments of earlier years. These new agents include immunomodulating imide drugs (IMiD) thalidomide and lenalidomide, the proteasome inhibitor bortezomib (PI), recently followed by new generation IMID pomalidomide, monoclonal antibodies daratumumab and elotuzumab, and next generation PI carfilzomib and ixazomib. However, even in this more promising scenario, febrile neutropenia remains a severe side effect of antineoplastic therapies and can lead to a delay and/or dose reduction in subsequent cycles. Read More

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KD-PACE Salvage Therapy for Aggressive Relapsed Refractory Multiple Myeloma, Plasma Cell Leukemia and Extramedullary Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Apr 6. Epub 2021 Apr 6.

Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Patients with advanced/aggressive multiple myeloma have limited treatment options to achieve rapid disease control. In eligible patients, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide is often used. However, many patients are refractory to or have toxicities from bortezomib and there is a need for bridging therapy. Read More

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Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/refractory multiple myeloma (RRMM) in the US.

Ann Hematol 2021 May 10. Epub 2021 May 10.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. Read More

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A Systematic Review and Network Meta-analysis of Randomized Data on Efficacy of Novel Therapy Combinations in Patients with Lenalidomide-refractory Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Mar 26. Epub 2021 Mar 26.

Division of Hematologic Malignancies and Cellular Therapeutics, The University of Kansas Medical Center, Kansas City, KS.

Introduction: Lenalidomide use in nearly all induction regimens for multiple myeloma (MM) has led to the treatment of lenalidomide-refractory disease becoming one of the most important clinical questions in its treatment. Given the lack of direct comparisons of treatment regimens for lenalidomide-refractory MM, we used a systematic review to identify randomized controlled trials (RCTs) that included lenalidomide-refractory subgroup analysis.

Methods: We performed a systematic review to identify RCTs for MM that enrolled patients with lenalidomide-refractory disease, then performed a network meta-analysis (NMA) using random effects model to compare regimens. Read More

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G9a/GLP targeting in MM promotes autophagy-associated apoptosis and boosts proteasome inhibitor-mediated cell death.

Blood Adv 2021 05;5(9):2325-2338

Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.

Multiple myeloma (MM) is an (epi)genetic highly heterogeneous plasma cell malignancy that remains mostly incurable. Deregulated expression and/or genetic defects in epigenetic-modifying enzymes contribute to high-risk disease and MM progression. Overexpression of the histone methyltransferase G9a was reported in several cancers, including MM, correlating with disease progression, metastasis, and poor prognosis. Read More

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Targeting Ubiquitin-Proteasome System With Copper Complexes for Cancer Therapy.

Front Mol Biosci 2021 13;8:649151. Epub 2021 Apr 13.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States.

Characterizing mechanisms of protein homeostasis, a process of balancing between protein synthesis and protein degradation, is important for understanding the potential causes of human diseases. The ubiquitin-proteasome system (UPS) is a well-studied mechanism of protein catabolism, which is responsible for eliminating misfolded, damaged, or aging proteins, thereby maintaining quality and quantity of cellular proteins. The UPS is composed of multiple components, including a series of enzymes (E1, E2, E3, and deubiquitinase [DUB]) and 26S proteasome (19S regulatory particles + 20S core particle). Read More

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Carfilzomib or bortezomib in combination with cyclophosphamide and dexamethasone followed by carfilzomib maintenance for patients with multiple myeloma after one prior therapy: results from a multi-centre, phase II, randomized, controlled trial (MUK).

Haematologica 2021 Apr 29. Epub 2021 Apr 29.

Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds.

The proteasome inhibitors (PIs), carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these PIs in combination with cyclophosphamide and dexamethasone (KCd vs VCd) in second line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomised patients (2:1) to KCd (201) or VCd (99); responding patients on carfilzomib were randomised to maintenance carfilzomib (69) or no further treatment (72). Read More

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Survival and treatment patterns of patients with relapsed or refractory multiple myeloma in France - a cohort study using the French National Healthcare database (SNDS).

Ann Hematol 2021 Jul 21;100(7):1825-1836. Epub 2021 Apr 21.

Amgen SAS, Boulogne-Billancourt, France.

Over the past decade, several drugs have been approved for the treatment of relapsed or refractory multiple myeloma (RRMM). This retrospective study, using the French National Healthcare database (SNDS), describes the treatment patterns and outcomes of patients with RRMM treated in real-world clinical practice in France. Patients were adults, with a diagnosis of multiple myeloma, who initiated second-line (2L) treatment approved for use in France between 2014 and 2018; this included bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide, or pomalidomide. Read More

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Current Approach to Managing Patients with Newly Diagnosed High-Risk Multiple Myeloma.

Curr Hematol Malig Rep 2021 Apr 19;16(2):148-161. Epub 2021 Apr 19.

Division of Hematology/Oncology, Department of Medicine, Multiple Myeloma and Amyloidosis Program, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, 161 Fort Washington Ave G, New York, NY, 10032, USA.

Purpose Of Review: With rapid advances in the therapeutic landscape and biological insights in multiple myeloma, it is critical to identify and strategically manage high-risk patients to achieve best outcomes with currently available drugs. The purpose of this review is to summarize the management of high-risk myeloma with a focus on recent advances in the field.

Recent Findings: The most widely accepted definition of "high-risk" is the Revised International Staging System (R-ISS) stage 3 disease, which includes high tumor burden (ISS stage 3) and high-risk FISH cytogenetics or an elevated lactate dehydrogenase level. Read More

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Inhibition of P-Glycoprotein Does Not Increase the Efficacy of Proteasome Inhibitors in Multiple Myeloma Cells.

ACS Pharmacol Transl Sci 2021 Apr 4;4(2):713-729. Epub 2021 Feb 4.

College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia.

P-Glycoprotein is a well-known drug transporter associated with chemotherapy resistance in a number of cancers, but its role in modulating proteasome inhibitor efficacy in multiple myeloma is not well understood. The second-generation proteasome inhibitor carfilzomib is thought to be a substrate of P-glycoprotein whose efficacy may correlate with P-glycoprotein activity; however, research concerning the first-in-class proteasome inhibitor bortezomib is inconsistent. We show that while P-glycoprotein gene expression increases with the disease stages leading to multiple myeloma it does not affect the survival of newly diagnosed patients treated with bortezomib. Read More

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Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial.

JAMA Oncol 2021 Jun;7(6):862-868

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Recently, the benefit of adding daratumumab to the proteasome inhibitor-based, 3-drug combination of bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma who underwent high-dose melphalan chemotherapy and autologous hemopoietic cell transplant was assessed. Here, we examine the addition of daratumumab to the second-generation proteasome inhibitor-based, 3-drug combination of carfilzomib, lenalidomide, and dexamethasone.

Objective: To assess the safety and effectiveness of carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy for patients with newly diagnosed multiple myeloma, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant. Read More

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In-depth proteomic analysis of proteasome inhibitors bortezomib, carfilzomib and MG132 reveals that mortality factor 4-like 1 (MORF4L1) protein ubiquitylation is negatively impacted.

J Proteomics 2021 06 10;241:104197. Epub 2021 Apr 10.

Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125, USA. Electronic address:

Proteasome inhibitors are an important class of chemotherapeutic drugs. In this study, we performed a large-scale ubiquitylome analysis of the three proteasome inhibitors MG132, bortezomib and carfilzomib. Although carfilzomib is currently being used for the treatment of multiple myeloma, it has not yet been subjected to a global ubiquitylome analysis. Read More

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Upfront Carfilzomib, Lenalidomide, Dexamethasone with Transplant in Multiple Myeloma Patients, the IFM KRd final results.

Blood 2021 04 7. Epub 2021 Apr 7.

IUC Oncopole, Toulouse, France.

Bortezomib, lenalidomide, dexamethasone plus transplant is a standard of care for eligible Multiple Myeloma patients. As responses can deepen with time, regimens with longer and more potent induction/consolidation phases are needed. In this phase II study, patients received eight 28-day cycles of carfilzomib (K) 20/36mg/m2 (D1-2,8-9,15-16), lenalidomide (R) 25 mg (D1-21), and dexamethasone (d) 20 mg (D1-2,8-9,15-16,22-23). Read More

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Low-Dose Cyclophosphamide versus Intermediate-High-Dose Cyclophosphamide versus Granulocyte Colony-Stimulating Factor Alone for Stem Cell Mobilization in Multiple Myeloma in the Era of Novel Agents: A Multicenter Retrospective Study.

Transplant Cell Ther 2021 Mar 28;27(3):244.e1-244.e8. Epub 2021 Jan 28.

Hematology Unit, Romagna Transplant Center, Hospital of Ravenna, Ravenna, Italy. Electronic address:

The optimal stem cell (SC) mobilization strategy for patients with multiple myeloma (MM) remains a matter of debate. Possible approaches include low or high doses of cyclophosphamide (Cy), other chemotherapeutic agents, or granulocyte colony-stimulating factor (G-CSF) alone. The scope of the study was to compare low-dose Cy plus G-CSF versus intermediate-high-dose Cy plus G-CSF versus G-CSF alone for SC mobilization in MM, in terms of efficacy and safety. Read More

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Cost-effectiveness of Novel Treatment Sequences for Transplant-Ineligible Patients With Multiple Myeloma.

JAMA Netw Open 2021 03 1;4(3):e213497. Epub 2021 Mar 1.

Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Importance: Although the number of treatments for elderly patients with non-transplant-eligible (NTE) multiple myeloma (MM) has increased substantially, evidence is lacking on the clinical effectiveness and cost-effectiveness of novel treatment sequences.

Objective: To determine the optimal sequence of treatment for patients with NTE MM from the perspective of the patient, physician, and society.

Design, Setting, And Participants: Using data from a Dutch observational registry, this economic evaluation combined evidence from network meta-analyses in a patient-level simulation model and modeled time-to-event and types of events from a hospital perspective with a lifetime horizon. Read More

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Pharmacology differences among proteasome inhibitors: Implications for their use in clinical practice.

Pharmacol Res 2021 May 6;167:105537. Epub 2021 Mar 6.

Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Preclinical and clinical investigation on proteasome as a druggable target in cancer has led to the development of proteasome inhibitors (PIs) with different pharmacodynamic and pharmacokinetic properties. For example, carfilzomib has a better safety profile and a lower risk of clinically relevant drug-drug interactions than bortezomib, whereas ixazomib can be orally administered on a weekly basis due to a very long elimination half-life and high systemic exposure. The purpose of this review article is to elucidate the quantitative and qualitative differences in potency, selectivity, pharmacokinetics, safety and drug-drug interactions of clinically validated PIs to provide useful information for their clinical use in real life setting. Read More

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Daratumumab for the Management of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: Current and Emerging Treatments.

Front Oncol 2020 17;10:624661. Epub 2021 Feb 17.

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Meldola, Italy.

Immunotherapy is changing the paradigm of multiple myeloma (MM) management and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved for the treatment of this malignancy. Daratumumab exerts anti-myeloma activity by different mechanisms of action as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), direct apoptosis, and immunomodulation. After GEN501 and SIRIUS trials showed efficacy of daratumumab monotherapy in heavily pretreated relapsed-refractory multiple myeloma (RRMM), in patients with at least two previous line of therapy, two phase III trials demonstrated superior overall response rate (ORR) and progression free survival (PFS) using triplets daratumumab-bortezomib-dexamethasone (DVd) Vd (CASTOR) or daratumumab-lenalidomide-dexamethasone (DRd) Rd (POLLUX) in relapsed-refractory MM patients; so these combinations have been approved and introduced in clinical practice. Read More

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February 2021

Carfilzomib in Combination with Bortezomib Enhances Apoptotic Cell Death in B16-F1 Melanoma Cells.

Biology (Basel) 2021 Feb 15;10(2). Epub 2021 Feb 15.

Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Korea.

Proteasome inhibitors, such as bortezomib (BZ) and carfilzomib (CFZ), have been suggested as treatments for various cancers. To utilize BZ and/or CFZ as effective therapeutics for treating melanoma, we studied their molecular mechanisms using B16-F1 melanoma cells. Flow cytometry of Annexin V-fluorescein isothiocyanate-labeled cells indicated apoptosis induction by treatment with BZ and CFZ. Read More

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February 2021

The Mitochondrial Protease LonP1 Promotes Proteasome Inhibitor Resistance in Multiple Myeloma.

Cancers (Basel) 2021 Feb 17;13(4). Epub 2021 Feb 17.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Multiple myeloma and its precursor plasma cell dyscrasias affect 3% of the elderly population in the US. Proteasome inhibitors are an essential part of several standard drug combinations used to treat this incurable cancer. These drugs interfere with the main pathway of protein degradation and lead to the accumulation of damaged proteins inside cells. Read More

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February 2021

An Endoplasmic Reticulum Specific Pro-amplifier of Reactive Oxygen Species in Cancer Cells.

Angew Chem Int Ed Engl 2021 05 8;60(20):11158-11162. Epub 2021 Apr 8.

Friedrich-Alexander University Erlangen-Nürnberg (FAU), Department of Chemistry and Pharmacy, Organic Chemistry Chair II, Nikolaus-Fiebiger-Str. 10, 91058, Erlangen, Germany.

The folding and export of proteins and hydrolysis of unfolded proteins are disbalanced in the endoplasmic reticulum (ER) of cancer cells, leading to so-called ER stress. Agents further augmenting this effect are used as anticancer drugs including clinically approved proteasome inhibitors bortezomib and carfilzomib. However, these drugs can affect normal cells, which also rely strongly on ER functions, leading, for example, to accumulation of reactive oxygen species (ROS). Read More

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Burden of Treatment-Induced Peripheral Neuropathy in Patients with Multiple Myeloma in Sweden.

Acta Haematol 2021 Feb 25:1-9. Epub 2021 Feb 25.

Department of Hematology, Lund University, Lund, Sweden.

Introduction: Treatment-induced peripheral neuropathy (TIPN) is a complication of multiple myeloma (MM) treatment.

Objective: This real-world, retrospective study used electronic medical record (EMR) data from 3 Swedish clinics to assess the occurrence and economic burden of TIPN in patients with MM.

Methods: Eligible patients had an MM diagnosis in the Swedish Cancer Registry between 2006 and 2015 and initiated treatment during that period. Read More

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February 2021

Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing.

Nat Med 2021 03 22;27(3):491-503. Epub 2021 Feb 22.

Department of Immunology, Weizmann Institute, Rehovot, Israel.

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Read More

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Post-Transplant Maintenance Treatment Options in Multiple Myeloma.

Oncol Ther 2021 Jun 21;9(1):69-88. Epub 2021 Feb 21.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Maintenance therapy post autologous stem cell transplant (ASCT) is commonly employed in myeloma patients to prolong remission, as relapse invariably occurs after ASCT. After initial diagnosis and risk stratification, patients receive initial therapy with a combination of drugs, typically a proteasome inhibitor and an immunomodulatory imide drug (IMiD), and in those considered eligible, high-dose chemotherapy followed by autologous stem cell transplant. The aim of our study was to review the literature and consolidate evidence regarding different maintenance therapies post stem cell transplant in myeloma patients. Read More

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HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma.

Int J Mol Sci 2021 Jan 29;22(3). Epub 2021 Jan 29.

College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea.

Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Read More

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January 2021