{"doi":"10.1016/j.ebiom.2020.102716","title":"A pharmacodynamic model of clinical synergy in multiple myeloma","abstract":"BACKGROUND: Multiagent 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. METHODS: A 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. FINDINGS: Combination 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. INTERPRETATION: The proposed framework can inform clinical decisions from ex vivo observations, thus providing a path toward personalized therapy using combination regimens. FUNDING: This 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.","journal":"EBioMedicine","year":2020,"id":97027,"datarank":0.5289540786924243,"base_score":3.5263605246161616,"endowment":3.5263605246161616,"self_citation_contribution":0.5289540786924243,"citation_network_contribution":0.0,"self_endowment_contribution":0.5289540786924243,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":33,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9107,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":480559,"name":"Maria Cláudia Silva","orcid":"0000-0002-4576-0180","position":1,"is_corresponding":false},{"id":480560,"name":"Rafael Renatino Canevarolo","orcid":"0000-0002-8722-8512","position":2,"is_corresponding":false},{"id":480561,"name":"Raghunandan Reddy Alugubelli","orcid":"0000-0002-4314-1204","position":3,"is_corresponding":false},{"id":481799,"name":"Gabriel DeAvila","orcid":null,"position":4,"is_corresponding":false},{"id":481800,"name":"Alexandre Tungesvik","orcid":null,"position":5,"is_corresponding":false},{"id":481801,"name":"Lia Perez","orcid":null,"position":6,"is_corresponding":false},{"id":255974,"name":"Robert A. Gatenby","orcid":"0000-0002-1621-1510","position":7,"is_corresponding":false},{"id":65782,"name":"Robert J. Gillies","orcid":"0000-0002-8888-7747","position":8,"is_corresponding":false},{"id":480562,"name":"Rachid Baz","orcid":"0000-0003-4538-4733","position":9,"is_corresponding":false},{"id":480563,"name":"Mark B. Meads","orcid":"0009-0008-0259-1875","position":10,"is_corresponding":false},{"id":480564,"name":"Kenneth H. Shain","orcid":"0000-0003-4178-8888","position":11,"is_corresponding":false},{"id":480565,"name":"Ariosto S. 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