Revisiting the role of alkylating agents in multiple myeloma: Up-to-date evidence and future perspectives

Costa, Bruno Almeida; Mouhieddine, Tarek H.; Ortiz, Rosa María Bravo; Richter, Joshua

doi:10.1016/j.critrevonc.2023.104040

Cited by 8 publications

(2 citation statements)

References 249 publications

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“…MM.1s, a multiple myeloma cell line, displayed intermediate sensitivity in our in-vitro testing. This outcome is in line with expectations, given the established e cacy of BEN against multiple myeloma, both as a standalone treatment and as part of combination therapy, particularly in cases of relapsed or refractory multiple myeloma [29,30]. In line with our data, previous studies have reported MM.1s sensitivity to BEN in-vitro at concentrations higher than 100 umol/L at 72 hours [31].…”

Section: Discussionsupporting

confidence: 92%

Comparable Efficacy of Oral Bendamustine versus Intravenous Administration in Treating Hematologic Malignancies

Cracchiolo,

Davis,

Matiatos

et al. 2024

Preprint

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Purpose: The purpose of this study was to analyze potential differences in antitumor efficacy and pharmacokinetics between intravenous (IV) bendamustine (BEN) and a novel orally administered bendamustine agent (PO) that is utilizing the beneficial properties of superstaturated solid dispersions formulated in nanoparticles. Methods: Pharmacokinetics of IV versus PO BEN were determined by analysis of plasma samples collected from NSG mice treated with either IV or PO BEN. Plasma samples were analyzed using liquid chromatography-mass spectrometry (LC/MS/MS) following a liquid-liquid extraction to determine peak BEN concentration (Cmax), area under the concentration-time curve (AUC) and the half-life (t1/2) in-vivo. In-vitro cytotoxicity of BEN against human non-Hodgkin’s Burkitt’s Lymphoma (Raji), multiple myeloma (MM.1s), and B-cell acute lymphoblastic leukemia (RS4;11) cell lines was determined over time using MTS assays. Luciferase-tagged versions of the aforementioned cell lines were used to determine in-vivo BEN cytotoxicity of IV versus PO BEN at two different doses. Results: Bendamustine at a high dose in-vitro causes cell death. There was no significant difference in antitumor efficacy between IV and novel PO BEN at a physiologically relevant concentration in all three xenograft models. In-vivo pharmacokinetics showed the oral bioavailability of BEN in mice to be 51.4%. Conclusions: The novel oral BEN agent tested exhibits good oral bioavailability and systemic exposure for in-vivo antitumor efficacy comparable to IV BEN. An oral BEN formulation offers exciting clinical potential as an additional method of administration for bendamustine and warrants further evaluation in clinical studies.

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Section: Discussionsupporting

confidence: 92%

Comparable Efficacy of Oral Bendamustine versus Intravenous Administration in Treating Hematologic Malignancies

Cracchiolo,

Davis,

Matiatos

et al. 2024

Preprint

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“…Over the past few decades, several non-targeted drugs have been approved for the treatment of multiple myeloma, including alkylating agents [ 40 ], corticosteroids [ 41 – 43 ], immunomodulatory imide drugs (IMiDs) [ 44 – 47 ], proteasome inhibitors (PIs) [ 42 , 48 – 51 ], histone deacetylases (iHDACs) inhibitors [ 37 , 52 , 53 ], and XPO1 inhibitor [ 54 – 56 ] (Table 1 ). While these drugs have significantly extended the survival of patients with multiple myeloma by effectively killing myeloma cells and controlling disease progression, they often come with serious adverse effects due to their non-specificity.…”

Section: Introductionmentioning

confidence: 99%

Multiple myeloma: signaling pathways and targeted therapy

Lu,

Yang,

et al. 2024

Mol Biomed

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Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and the accumulation of malignant plasma cells. The pathogenesis of MM involves the interaction between MM cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules, which activate various signaling pathways such as PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB pathways. Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug resistance of myeloma cells, making them attractive targets for therapeutic intervention. Currently, approved drugs targeting these signaling pathways in MM are limited, with many inhibitors and inducers still in preclinical or clinical research stages. Therapeutic options for MM include non-targeted drugs like alkylating agents, corticosteroids, immunomodulatory drugs, proteasome inhibitors, and histone deacetylase inhibitors. Additionally, targeted drugs such as monoclonal antibodies, chimeric antigen receptor T cells, bispecific T-cell engagers, and bispecific antibodies are being used in MM treatment. Despite significant advancements in MM treatment, the disease remains incurable, emphasizing the need for the development of novel or combined targeted therapies based on emerging theoretical knowledge, technologies, and platforms. In this review, we highlight the key role of signaling pathways in the malignant progression and treatment of MM, exploring advances in targeted therapy and potential treatments to offer further insights for improving MM management and outcomes.

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CAR T‐Cell Therapy for Multiple Myeloma: A Clinical Practice‐Oriented Review

Sadek,

Costa,

Nath

et al. 2023

Clin Pharma and Therapeutics

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The emergence of chimeric antigen receptor (CAR) T‐cell therapy has revolutionized the treatment of hematologic malignancies, including multiple myeloma (MM). Two B‐cell maturation antigen (BCMA)‐directed CAR T‐cell products — idecabtagene vicleucel (ide‐cel) and ciltacabtagene autoleucel (cilta‐cel) — have received Food and Drug Administration (FDA) approval for patients with relapsed/refractory MM who underwent four or more prior lines of therapy (including an immunomodulatory agent, a proteasome inhibitor, and an anti‐CD38 monoclonal antibody). Despite producing unprecedented response rates in an otherwise difficult to treat patient population, CAR T‐cell therapies are commonly associated with immune‐related adverse events (e.g., cytokine release syndrome and neurotoxicity), cytopenias and infections. Moreover, many patients continue to exhibit relapse post‐treatment, with resistance mechanisms yet to be fully understood. Ongoing basic, translational, and clinical research efforts are poised to generate deeper insights into the optimal utilization of these therapies, improve their efficacy, minimize associated toxicity, and identify new target antigens in MM patients.

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Revisiting the role of alkylating agents in multiple myeloma: Up-to-date evidence and future perspectives

Cited by 8 publications

References 249 publications

Comparable Efficacy of Oral Bendamustine versus Intravenous Administration in Treating Hematologic Malignancies

Comparable Efficacy of Oral Bendamustine versus Intravenous Administration in Treating Hematologic Malignancies

Multiple myeloma: signaling pathways and targeted therapy

CAR T‐Cell Therapy for Multiple Myeloma: A Clinical Practice‐Oriented Review

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