Abstract 36: Preclinical models of multiple myeloma

Abstract

Abstract Multiple myeloma is a clonal B-cell malignancy characterized by the accumulation of terminally differentiated, antibody-producing plasma cells in the bone marrow. Genetic mutations within the myeloma cells and their interaction with various cytokines and growth factors contribute to the invasiveness of the disease and enhanced drug resistance. Patients are generally asymptomatic until very late-state disease. However, once disease is present, localization in the bones, especially the spine, is common. There are few preclinical models that recapitulate human disease. In this work, we have evaluated the human MM.1S model and the murine 5TGM-1 model. MM.1S was derived from a 42-year-old African American woman and has been documented to express CD25, CD38, CD52, and CD59. It also expresses the glucocorticoid receptor and is dexamethasone sensitive. To more effectively monitor in vivo disease progression, we transfected the MM.1S line with luciferase (MM.1S-pMMP-LucNeo). With bioluminescence imaging (BLI) we track and monitor disseminated disease progression over time and find reproducible in vivo growth in SCID beige mice. The median tumor volume doubling time is ~2 days and median time to morbidity/mortality endpoint is 35-45 days. MM.1S-pMMP-LucNeo was also evaluated in NSG mice which show more aggressive disease onset (staging 7 days post implant vs. 15 days in SCID mice). In NSG mice the tumor volume doubling time is ~1.8 days and median time to endpoint is ~21 days, roughly half the overall survival time observed in the SCID mouse. In all mouse strains we have investigated, the animals are relatively asymptomatic throughout the lifetime of the study and only begin to present symptoms at late-stage disease, similar to how the disease manifests itself in humans. Common, late-stage clinical signs in the mice include lethargy and paralysis. BLI on these animals shows localization of the signal in the spine, long bones, and mandible. As in the clinic, bortezomib (Velcade®) has limited effect on disease progression in this model. Expression of CD138 is a hallmark of plasma cells and multiple myeloma cells. In the NSG study we determined, by flow cytometry, that >85% of the CD45- gate in the bone marrow was CD138+ 21 days post-implant, suggesting significant engraftment of the tumor cells within the bone marrow. 5TGM-1 is a syngeneic model generated from the C57BL/KaLwRij mouse which is predisposed to develop several monoclonal B-cell proliferative disorders, including a low percentage (0.5%) of the mice developing multiple myeloma. From this strain, several cell clones were isolated and called the 5TMM series, which included the 5T33MM clone. 5TGM-1 is a sub-clone of 5T33MM cells and we have used 5TGM-1-luc to monitor disease progression and localization in vivo. The 5TGM-1-luc model is aggressive and BLI has shown localization of disease in the long bones. We have compared this model in both the syngeneic C57BL/KaLwRij strain and the immune-deficient NIH III (triple deficient) strain. Disease progression behaves similarly in both strains of mice, with significant tumor cells localizing in the spine and the long bones. The model is sensitive to traditional chemotherapies like doxorubicin and cyclophosphamide, but bortezomib (Velcade) only produces modest activity and carfilzomib has shown little activity at the dose and schedule tested. A greater understanding of the preclinical behavior of these models, including response to standard of care and molecular profiling, will provide critical insight into designing more clinically relevant preclinical experiments. Citation Format: Erin Trachet, Maryland Rosenfeld Franklin. Preclinical models of multiple myeloma [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 36.