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Introduction: Multiple myeloma is a plasma cell malignancy that causes extensive osteolytic bone disease. Present treatments target end stage disease but understanding how bone lesions are initiated may offer new approaches to prevent/suppress colonization. It is clear that myeloma cells form specific interactions with the bone microenvironment, where they can remain dormant and protected from current therapy to eventually proliferate and cause disease progression. N-cadherin is an adhesion molecule that has been implicated in the localization of haematopoietic stem cells (HSCs) to ‘niches’ containing osteoblasts on endosteal bone surfaces. In this study, we have tested the hypothesis that myeloma cells utilise N-cadherin to adhere to osteoblasts in vitro and in vivo during the colonization into the bone. Findings: N-cadherin mRNA and protein were expressed by osteoblasts and myeloma cells. We showed focal expression of N-cadherin in myeloma cells, whereas expression was observed contiguously on the membranes of adjacent osteoblasts. N-cadherin expression significantly increased during osteoblastogenesis. Immunohistochemistry demonstrated staining of N-cadherin when myeloma cells were in contact with osteoblasts in vitro and in vivo. Blocking N-cadherin mediated interactions, using specific antibodies against N-cadherin, significantly reduced adherence of myeloma cells to osteoblasts in vitro. Attempts were made to block the adhesion of myeloma cells to bone cells in calvarial bones in vivo. These studies were in conclusion suggested that there may be a role of N-cadherin in these interactions. Conclusion: These studies provide evidence that adherence of myeloma cells to osteoblasts is mediated by N-cadherin in vitro and in vivo, suggesting that myeloma cells may occupy a niche similar to that used by HSCs in bone.

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The BDCA antibodies allowed reliable measurement of dendritic cell (DC) subsets and B cell numbers in the blood of normal subjects, and patients with MM throughout the disease course. The numbers of blood myeloid DC (BmDC) and blood plasmacytoid DC (BpDC) are low throughout the course of the disease, and only improve for a short period of time following autologous HSCT. Thalidomide therapy of patients with relapsed disease was associated with an increase in BmDC1 and BpDC numbers. Monocytes, mobilised at the time of stem cell collection, were used to produce mature DC (matDC) from MM patients and normal donors (ND). The matDC produced from MM patients were of poorer quality as compared to those from ND, despite using combinations of GM/IL-4, GM/IL-13, X4 and MIMIC in the production process. The combinations that contained the X4 maturation cocktail produced the best quality matDC. The DC/T cell system is abnormal in MM patients. Despite this, it is possible to produce antigen loaded mature MoDC from MM patients. When combined with T cell pre-stimulation and IL-2 expansion, these DC are capable of inducing anti-MM cytotoxic T cells, which exhibit considerable anti-MM cytolytic activity. However, the DC from MM patients still display abnormal chemokine receptor expression, which may inhibit their capability to migrate to lymph nodes in-vivo in order to generate these cytotoxic T cell responses. These observations will aid in the optimisation of DC based immune therapies for MM, and suggest that a combined immunotherapy approach using pre-stimulated T cells, MM Ag primed DC and IL-2 may produce better clinical responses in MM patients.