![]() To evaluate whether the transgenic or transplant versions of the Vk*MYC mouse model would replicate our clinical findings, we examined a cohort of aged transgenic Vk*MYC mice with spontaneous onset tumours and two of the more commonly used transplant clones in our laboratory: Vk#4929 and Vk#31. In order to establish whether T cell aberrancies that are seen in relapsed/refractory disease are present in newly diagnosed MM, we analysed peripheral blood mononuclear cells (PBMCs) from patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), and compared with healthy blood donors from Australian Red Cross Blood Service (ARCBS). We investigated the immunological relevance of different models of myeloma utilizing the Vk*MYC mouse and compared those findings to our analysis of T cells in human MM. When assessing the role of novel immunomodulatory drugs in mouse models, it is important to understand their effects in context of the immune microenvironment. Research using these models has been mainly concentrated on the development of new tumouricidal agents however, the role of the host immune response to malignancy is increasingly being realized, particularly in the context of immune therapies such as immunomodulatory drugs and checkpoint blockade inhibitors. However, the injected malignant cells are potentially quite different from their original BM resident counterparts, in that the transplanted model more readily develops extramedullary disease. The advantage to this method is the greatly reduced time to disease state (weeks as opposed to 12–18 months with the transgenic model). It is also possible to induce a plasma cell malignancy in congenic C57BL/6 mice by transplanting cryopreserved cells from the spleen of a diseased transgenic Vk*MYC mouse. Others have delineated a transition from “smoldering” to active myeloma period based on differences in BM vascularization. It has been argued that there is no true “MGUS” period in the Vk*MYC model, rather the slow accumulation of malignant cells. The disease mechanism involves spontaneous AID-dependent activation of MYC in post germinal B cells an event that is not required for MM development in humans, although complex c-myc gene rearrangements and translocations often occur with disease progression. The Vk*MYC mouse model has been established as an investigative tool for anti-myeloma drug therapy. Less is known about the immunological similarities and differences between human disease and the Vk*MYC mouse models. It is understood that, unlike human MM, the mice used for these models are genetically uniform and the tumours often have a low mutational burden. These mouse models are useful tools to study anti-myeloma therapies however, a deeper appreciation of their relevance to clinical disease is required. By utilizing knowledge of driver mutations, mouse models of disease have been developed. These include immune-editing and oncogenic mutations, which both promote evasion from immune surveillance and resistance to apoptosis. Numerous factors in MM are involved in the velocity of disease progression and they are acquired in a non-stochastic but cumulative fashion over time. ![]() Although MM is largely incurable, the advent of immunomodulatory agents and proteasome inhibitors has significantly increased the life expectancy of patients with this disease. Acquired immune paresis complicates advanced disease due to residual hypogammaglobulinaemia, B cell hypoplasia, the effects of cumulative chemotherapies and an ageing and exhausted T cell population. With evolution of disease, patients variably develop organ damage that can result in lytic bone lesions, hypercalcaemia, renal failure and anaemia. The majority, if not all, patients have a pre-malignant phase of monoclonal gammopathy of undetermined significance (MGUS). Multiple myeloma (MM) is a malignancy of plasma cells that reside within a supportive niche in the bone marrow (BM).
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