ArticleBritish journal of haematology2016
A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells.
Article in British journal of haematology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
34 citing papers in PubMed, 58 citations in OpenAlex.
- ANCHOR: melflufen plus dexamethasone and daratumumab or bortezomib in relapsed/refractory multiple myeloma: final results of a phase I/IIa study.Haematologica · 2024Trial
- Efficacy and safety of melflufen plus daratumumab and dexamethasone in relapsed/refractory multiple myeloma: results from the randomized, open-label, phase III LIGHTHOUSE study.Haematologica · 2024Trial
- Patient-reported outcomes in relapsed/refractory multiple myeloma treated with melflufen plus dexamethasone: analyses from the Phase II HORIZON study.British journal of haematology · 2022Trial
- Melflufen plus dexamethasone in relapsed/refractory multiple myeloma: long-term survival follow-up from the Phase II study O-12-M1.British journal of haematology · 2021Trial
- Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2021Trial
- Peptide-Drug Conjugates for Targeted Delivery in Hematological Malignancies: From Design Principles to Clinical Application.Pharmaceutics · 2026Review
- Efficacy of melflufen in multiple myeloma with mutated or deleted TP53.Experimental hematology & oncology · 2025Article
- Optimizing the use of melflufen (melphalan flufenamide) in relapsed or refractory multiple myeloma: recommendations for clinical practice.Annals of hematology · 2025Review
- Outcomes of Melflufen Treatment in Patients With Relapsed/Refractory Multiple Myeloma.European journal of haematology · 2025Article
- Targeted drug conjugates in cancer therapy: Challenges and opportunities.Pharmaceutical science advances · 2024Review
- Recent Advances in the Applications of Small Molecules in the Treatment of Multiple Myeloma.International journal of molecular sciences · 2023Review
- Value in Myeloma Care: Myth or Reality.Current hematologic malignancy reports · 2022Review
- The Role of Belantamab Mafodotin, Selinexor, and Melflufen in Multiple Myeloma.Current hematologic malignancy reports · 2022Review
- Article
- The approval and withdrawal of melphalan flufenamide (melflufen): Implications for the state of the FDA.Translational oncology · 2022Article
- The Peptide-Drug Conjugate Melflufen Modulates the Unfolded Protein Response of Multiple Myeloma and Amyloidogenic Plasma Cells and Induces Cell Death.HemaSphere · 2022Article
- 2021 FDA TIDES (Peptides and Oligonucleotides) Harvest.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Drug resistance in multiple myeloma: Soldiers and weapons in the bone marrow niche.Frontiers in oncology · 2022Review
- Progress and Future Directions with Peptide-Drug Conjugates for Targeted Cancer Therapy.Molecules (Basel, Switzerland) · 2021Review
- A pilot study of 3D tissue-engineered bone marrow culture as a tool to predict patient response to therapy in multiple myeloma.Scientific reports · 2021Observational
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Our prior study utilized both in vitro and in vivo multiple myeloma (MM) xenograft models to show that a novel alkylator melphalan-flufenamide (Melflufen) is a more potent anti-MM agent than melphalan and overcomes conventional drug resistance. Here we examined whether this potent anti-MM activity of melflufen versus melphalan is due to their differential effect on DNA damage and repair signalling pathways via γ-H2AX/ATR/CHK1/Ku80. Melflufen-induced apoptosis was associated with dose- and time-dependent rapid phosphorylation of γ-H2AX. Melflufen induces γ-H2AX, ATR, and CHK1 as early as after 2 h exposure in both melphalan-sensitive and -resistant cells. However, melphalan induces γ-H2AX in melphalan-sensitive cells at 6 h and 24 h; no γ-H2AX induction was observed in melphalan-resistant cells even after 24 h exposure. Similar kinetics was observed for ATR and CHK1 in meflufen- versus melphalan-treated cells. DNA repair is linked to melphalan-resistance; and importantly, we found that melphalan, but not melflufen, upregulates Ku80 that repairs DNA double-strand breaks. Washout experiments showed that a brief (2 h) exposure of MM cells to melflufen is sufficient to initiate an irreversible DNA damage and cytotoxicity. Our data therefore suggest that melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in MM cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.