IntroductionMultiple myeloma (MM) is a malignant neoplasm characterized by clonal proliferation of plasma cells in the bone marrow (BM). This disease accounts for approximately 2% of all cancer deaths and nearly 20% of deaths caused by hematologic malignancies. 1 Although allogeneic stem-cell transplantation 2-5 occasionally cures these patients, and drugs such as thalidomide, lenalidomide, and bortezomib have improved outcomes, 6 high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) 7 still appears to be the best treatment for patients up to 70 years of age. However, the great majority of patients with MM are incurable due to the persistence of minimal residual disease. 8,9 Thus, novel modalities complementing or improving current treatment options are needed.Natural killer (NK) cells are cytotoxic lymphocytes that lyse certain tumor-and virus-infected cells without any prior stimulation or immunization. 10 The cytotoxic activity of NK cells is tightly controlled by a balance between activating and inhibitory signals from receptors on the cell surface. A main group of receptors that inhibit NK-cell activation is the inhibitory killer immunoglobulinlike receptors (KIRs). Upon recognition of self-MHC class I molecules on target cells, these receptors deliver an inhibitory signal that stops the activating signaling cascade, sparing cells with normal MHC class I expression from NK cell-mediated lysis. Activating receptors include the natural cytotoxicity receptors (NCRs) and NKG2D, all of which push the balance toward cytolytic action through engagement with separate ligands on the target cell surface. 11,12 This role of NK cells indicates their possible use for adoptive immunotherapeutic strategies, in particular against malignancies that express low levels of MHC class I molecules. 13 The aim of this study was to investigate whether, and under what conditions, NK cells from patients with MM can be expanded numerically using good manufacturing practice (GMP)-compliant components. Furthermore, we aimed to investigate if NK cells expanded ex vivo could target autologous MM cells and thus prove to be favorable candidates for immunotherapeutic approaches against MM. Methods Patients and acquisition of patient materialPeripheral blood and BM samples from 7 newly diagnosed patients at different stages of MM were included in this study. The patients were admitted to the Department of Hematology, Karolinska University Hospital Huddinge, Stockholm, Sweden. The study was approved by the south Stockholm research ethics committee. Informed consent was obtained from all patients in accordance with the Declaration of Helsinki. Patients' characteristics at the time of blood and BM sampling are given in Table 1.Peripheral blood mononuclear cells (PBMCs) as well as BM mononuclear cells (BMMCs) were isolated by gradient centrifugation, using Lymphoprep (Axis-Shield, Oslo, Norway). PBMCs and BMMCs were washed twice with phosphate-buffered saline (PBS; Gibco, Grand Island, NY), and cell viability was assessed...

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