ArticleEBioMedicine2020
A pharmacodynamic model of clinical synergy in multiple myeloma.
Article in EBioMedicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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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
18 citing papers in PubMed.
- Carfilzomib and dexamethasone maintenance following salvage ASCT in multiple myeloma: A randomised phase 2 trial by the Nordic Myeloma Study Group.European journal of haematology · 2022Trial
- Unc-51 like kinase 3 (ULK3) contributes to autophagy and cell survival in multiple myeloma.Nature communications · 2026Article
- Rethinking the role of synergy calculations in the next century of drug combination discovery.Med (New York, N.Y.) · 2026Review
- Human preclinical multiple myeloma in vitro models for disease modeling and therapy screening.Journal of biological engineering · 2025Review
- Acid ceramidase controls proteasome inhibitor resistance and is a novel therapeutic target for the treatment of relapsed/refractory multiple myeloma.Haematologica · 2025Article
- The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma.Cancer research · 2025Article
- 2D and 3D In Vitro Co-culture for Cancer and Bone Cell Interaction Studies.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Combined MEK1/2 and ATR inhibition promotes myeloma cell death through a STAT3-dependent mechanism in vitro and in vivo.British journal of haematology · 2024Article
- Utilizing 3D Models to Unravel the Dynamics of Myeloma Plasma Cells' Escape from the Bone Marrow Microenvironment.Cancers · 2024Review
- Patient-Derived Multiple Myeloma 3D Models for Personalized Medicine-Are We There Yet?International journal of molecular sciences · 2022Review
- CancerCellTracker: a brightfield time-lapse microscopy framework for cancer drug sensitivity estimation.Bioinformatics (Oxford, England) · 2022Article
- Independent Drug Action in Combination Therapy: Implications for Precision Oncology.Cancer discovery · 2022Review
- Glutathione levels are associated with methotrexate resistance in acute lymphoblastic leukemia cell lines.Frontiers in oncology · 2022Article
- Plasma cell dependence on histone/protein deacetylase 11 reveals a therapeutic target in multiple myeloma.JCI insight · 2021Article
- IAP and HDAC inhibitors interact synergistically in myeloma cells through noncanonical NF-κB- and caspase-8-dependent mechanisms.Blood advances · 2021Article
- 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
- The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma.Cancers · 2021Review
- 2D and 3D In Vitro Co-Culture for Cancer and Bone Cell Interaction Studies.Methods in molecular biology (Clifton, N.J.) · 2019Article
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
backgroundMultiagent therapies, due to their ability to delay or overcome resistance, are a hallmark of treatment in multiple myeloma (MM). The growing number of therapeutic options in MM requires high-throughput combination screening tools to better allocate treatment, and facilitate personalized therapy.
methodsA second-order drug response model was employed to fit patient-specific ex vivo responses of 203 MM patients to single-agent models. A novel pharmacodynamic model, developed to account for two-way combination effects, was tested with 130 two-drug combinations. We have demonstrated that this model is sufficiently parameterized by single-agent and fixed-ratio combination responses, by validating model estimates with ex vivo combination responses for different concentration ratios, using a checkerboard assay. This new model reconciles ex vivo observations from both Loewe and BLISS synergy models, by accounting for the dimension of time, as opposed to focusing on arbitrary time-points or drug effect. Clinical outcomes of patients were simulated by coupling patient-specific drug combination models with pharmacokinetic data.
findingsCombination screening showed 1 in 5 combinations (21.43% by LD50, 18.42% by AUC) were synergistic ex vivo with statistical significance (P < 0.05), but clinical synergy was predicted for only 1 in 10 combinations (8.69%), which was attributed to the role of pharmacokinetics and dosing schedules.
interpretationThe proposed framework can inform clinical decisions from ex vivo observations, thus providing a path toward personalized therapy using combination regimens.
fundingThis research was funded by the H. Lee Moffitt Cancer Center Physical Sciences in Oncology (PSOC) Grant (1U54CA193489-01A1) and by H. Lee Moffitt Cancer Center's Team Science Grant. This work has been supported in part by the PSOC Pilot Project Award (5U54CA193489-04), the Translational Research Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center (P30-CA076292), the Pentecost Family Foundation, and Miles for Moffitt Foundation.
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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.