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Using highly purified myeloma cells from patient bone marrow, we established human-murine myeloma chimeras in severe combined immunodeficiency (SCID) mice and documented secretion of monoclonal human immunoglobulins (Hulgs) in the mice for up to 299 days. Monoclonality of circulating Hulgs was found only when highly purified myeloma cells were injected intraperitoneally. In contrast, injection of unfractionated myeloma marrow led to the development of polyclonal Hulgs in the SClD mice. The criteria for myeloma engraftment included prolonged presence of monoclonal Hulgs in the sera of SClD mice and/or detection of human myeloma cells in their tissues by immunohistochemical examination. Ninety-one percent (10/11) of the fresh HE STUDY of murine models has yielded substantial T information on both the occurrence of asymptomatic monoclonal gammopathies without obvious tumor formation and the development of plasma cell neoplasms.lV2 Most of these studies have used murine plasma cell neoplasms in BALB-C mice3g4 as a model for development of the human disease. Other investigators have also used mouse models in an attempt to reproduce some aspects of other human clinical syndromes associated with monoclonal gammopathies.5p6 However, there have been no prior reports of successful attempts to produce human-murine chimeras with fresh human multiple myeloma (MM) cells. A model of this type would improve the ability to study human myeloma biology and might be of value for studying therapeutic manipulation of fresh human myeloma cells in vivo.Since the initial description of the severe combined immunodeficiency (SCID) syndrome in mice,' several studies have been published related to the use of such mice as animal models for a variety of human disease^,^-^^ including several hematologic malignan~ies.'~-*~ Because SCID mice are deficient in mature T and B lymphocytes,21,22 we hypothesized that they might provide an excellent in vivo model in which to establish human myeloma chimeras. This report documents characteristics of this model. MATERIALS AND METHODS PatientsTumor cells from 11 patients with MM were used in this study. All bone marrows (BMs) were obtained from patients registered in the Southwest Oncology Group myeloma studies, and samples were submitted to the myeloma research and phenotyping laboratories of the University of Arizona. The patients included six women and five men ranging in age from 34 to 76 years (Table 1). Nine of the patients had not received prior treatment. The group included one patient with stage I myeloma, two with stage 11, and 8 with stage 111 by Durie-Salmon staging criteria? BM specimens from 10 patients with MM as well as a tumor biopsy from a breast plasmacytoma in an MM patient were processed for injection into the SCID mice. Peripheral blood lymphocytes from an ovarian carcinoma patient (patient 12) and ascites fluid known to contain malignant cells from a woman with non-Hodgkin's lymphoma (patient 13) were used as nonmyeloma controls for these studies (Table 2). purified myeloma specimens...

Using highly purified myeloma cells from patient bone marrow, we established human-murine myeloma chimeras in severe combined immunodeficiency (SCID) mice and documented secretion of monoclonal human immunoglobulins (Hulgs) in the mice for up to 299 days. Monoclonality of circulating Hulgs was found only when highly purified myeloma cells were injected intraperitoneally. In contrast, injection of unfractionated myeloma marrow led to the development of polyclonal Hulgs in the SCID mice. The criteria for myeloma engraftment included prolonged presence of monoclonal Hulgs in the sera of SCID mice and/or detection of human myeloma cells in their tissues by immunohistochemical examination. Ninety-one percent (10/11) of the fresh purified myeloma specimens engrafted in the SCID mice. Fifty-five percent (6/11) of the patient samples resulted in human B-cell grafts, and 45% (5/11) were identifiable as human myeloma chimeras. Pathologic studies showed that most human plasmacytes were located in the peritoneal cavity but metastatic infiltrates were also found in other organs in 69% of the SCID-human myeloma chimeras. This chimeric model should provide a useful tool for characterization of growth modulation and microenvironmental interactions as well as a means of testing new therapeutic approaches to multiple myeloma.

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