Advances in Biology and Therapy of Multiple Myeloma: Volume 1: Basic Science

Leukaemia and Myeloma: Essentials for Clinicians
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In both routes models, it is feasible to detect monoclonal component MC in the mouse sera as well as other biochemical markers e.

Both models have been developed in the aim to investigate new drugs and still represent the most common methods to study innovative drugs activity in vivo [ 12 , 13 ]. The s. However, s.

Specifically, in this model, MM cells proliferate in the absence of the peculiar BMM that sustains the expansion of malignant PCs and drives the development of bone damage and drug resistance. Additionally, MM cell lines used for engraftment are mainly derived from extramedullary sites such as pleural effusions or peripheral blood of advanced MM patients. These cells have lost the dependence from the BMM and have changed significantly their genetic background to a late stage disease- instead of intramedullary MM- type.

When considering the i. In these cases, the murine BM can be infiltrated with consequent bone damage as in the human MM. However, along the course of the disease, other mice organs host MM cells, reproducing an in vivo scenario commonly not observed in human disease.

Thus, both models are very useful and easy-to-handle to quickly assess the activity of new cytotoxic drugs, but do not provide insights on the critical interactions between malignant PCs and their own BMM. This information is presently somewhat relevant to allow a successful translation in clinics of innovative drugs with selective mechanisms of action that in most cases involves the BMM.

In these models, the basic idea is to reproduce the human BMM by implanting bone recipients in the flank of mice and then seeding them with fresh primary BM explanted cells or ILdependent MM cell lines. The advantage of this approach is that MM cells grow in an orthotopic full human environment, where BMSCs support MM cell proliferation that in turn triggers osteoclasts OCL activity and suppresses bone apposition, thus reproducing the development of BD as observed in patients. The pictures illustrate different strategies to recapitulate human MM disease in mice.

The yellow quadrant includes models where human MM cells are grown in murine bone marrow microenvironment; the red quadrant includes models where human MM cells are grown in human autologous or allogenic bone marrow microenvironment; each quadrant is accompanied by a table briefly describing the most relevant advantages and limits of each model.

In this model [ 14 ], MM cell lines home exclusively to the human implant instead of murine bone. Furthermore, when a contralateral FBC was implanted, MM cells migrated from the previously injected FBC to the contralateral one, while sparing the murine bone and obviously all other murine normal tissues.

On the other side, administration of human IL-6 induces mice cachexia and therefore these cells cannot be used in vivo without a recipient recapitulating the human bone milieu. In this model, extensive BM infiltration by INA-6 was paralleled by an increased beta 2 microglobulin in mice sera.

Kenneth C. Anderson

The advantages of using the INA-6 implanted SCID-hu model are the unlimited high reproducibility of the data with a cell line that recapitulates more accurately the human disease, growing in an orthotopic environment. The latter is a crucial issue to study mechanistic pathways of myeloma-genesis and to ascertain the effects of new drugs against MM cells and BMM [ 16 , 23 , 26 , 29 — 33 ]. The picture shows the radiologic evidence of a bone lytic lesion within a fetal bone chip.

In the cartoon on the left, the main actors determining the bone resorption activity are reported. Indeed, the use of these models allowed investigators to define the role of key signaling pathways or to investigate several new agents. For example, p38 mitogen activated kinase MAPK is constitutively activated in MM and contributes to tumor growth [ 34 ]. The same model allowed demonstration of the anti-MM effects of thalidomide in vivo [ 35 ].

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The potency of the model to study new drugs has been further tested by Tai et al. MM-dependent OCL activity is clearly reproducible in the SCID-hu model, where zoledronic acid, the most common bisphosphonate routinely used for MM supportive therapy, efficiently attenuates bone damage [ 35 ].

Even if the SCID-hu model proved to be effective in studying MM pathogenesis as well as other plasma cell discrasias such as Waldenstrom's macroglobulinemia [ 37 — 39 ] and the activity of novel drugs, its major limitations rely on FBC availability for many institutions. Alternative methods have been developed in the aim to overcome these issues. In the SCID-rab model human fetal bone chips are replaced by rabbit bones.

MM cells engraft into the rabbit bone reproducing the human disease [ 40 ]. The SCID-rab model has been the backbone for studying the bone-building effects of proteasome inhibitor PI bortezomib, which are independent from anti-neoplastic effects of the PI. Indeed, when mice are exposed to PI, bone mineral density BMD increases in both myelomatous and non-myelomatous bones.

These data represented the basis to further explore bone building activity of novel drugs within SCID-rab. These findings were confirmed and implemented by testing a clinical grade anti DKK-1 Ab in the SCID-hu model [ 30 ], thus demonstrating the close relationship between the two models.


Despite the advances in conventional, novel agent and high dose Advances in Biology and Therapy of Multiple Myeloma. Volume 1: Basic Science. Advances in Biology and Therapy of Multiple Myeloma: Volume 1: Basic Science [Nikhil C. Munshi, Kenneth C. Anderson] on *FREE* shipping on.

The SCID-rab model is a suitable model for preclinical investigation in MM, but it certainly retains its own limits as rabbit bone, although ontogenetically related, cannot be strictly compared to human bone. However, the development of bone chip based models unveiled the potentialities of this approach and prompted investigators to ameliorate this system.

In an effort to reproduce human MM microenvironment in the mouse, synthetic scaffolds, closely resembling the trabecular structure of human bone were developed. In this latter case, the recipient was then engrafted with cell populations from whole bone marrow aspirates directly in vivo. Treatment with i. An intriguing preliminary finding was also the development of neo-angiogenesis in the MM coated PS [ 42 ]. Following-up this observation, Zhu et al.

These data demonstrated that the PS is a powerful platform to recapitulate MM disease and to test a variety of innovative therapeutic approaches [ 29 , 33 , 42 , 44 — 46 ].

Advances in Biology and Therapy of Multiple Myeloma : Nikhil C. Munshi :

Some authors attained successful engraftment of I. However, it should be taken into account, that these models may present an extensive burden of extramedullary disease, thus mostly resembling very aggressive or late stage MM disease more than classical indolent myeloma. Again, the major limitation of this model is due to cell lines, that are better representative of a BMM-independent plasma cell leukemia than a MM. Besides MM cells, patient derived malignant PCs have been engrafted into mice BM reproducing the human disease features.

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The basic mechanism of increased bone resorption in MM is an uncoupling of normal bone remodelling with increased osteoclast activity and decreased osteoblast function [ 26 ]. The role of the EGFR signaling in tumor microenvironment. Multiple myeloma occurs in older dogs, and is not particularly associated with either males or females. Editor: John Damilakis. This leads to analgesic abuse self-medication , most of which are nephrotoxic, hence, worsening the prognosis of the disease. Quick Reference to Critical Care. Ofatumumab is a fully human type I monoclonal anti-CD20 antibody that targets an epitope closer to the membrane, 29 and ofatumumab-opsonized cells bind more C1q even when the concentration of C1q in the medium is low.

In this model, administration of zoledronic acid is effective in attenuating bone disease, while not affecting tumor burden. PIs such as carfilzomib dramatically reduced tumor burden and showed anabolic effects in MM implanted NSG mice, demonstrating that this model is an ideal platform for drug development and testing [ 49 , 51 ]. The advantages of intratibial implants are due to an accelerated and bone confined growth of MM, whose features are strictly related to the human disease.

Early studies demonstrated that IL-6 is essential for MM cell growth in vitro and in vivo [ 55 , 56 ], suggesting that this cytokine is the main supportive factor in mineral oil induced plasmacytomas MOPCs [ 57 ], which develop within the peritoneal cavity following the generation of inflammatory dependent granulomas [ 58 ]. Based on these premises, an IL-6 transgene Tg driven by the promoter of L d gene of the major histocompatibility complex H2-L d was generated in B6 mice and showed the development of massive policlonal plasmacytomas.

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These plasmacytomas carried t 12;15 and c-myc gene rearrangements. IL6 mice spontaneously developed monoclonal plasmacytomas or B cell lymphomas within lymphoid tissues. These early studies were of relevance as they began to unveil the role of IL-6 dependence in MM growth and the importance of tumor microenvironment in promoting MM development in vivo. BM cell line, which is obtained by consecutive i. Interestingly, these tumors shift from a s.

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The lack of pro- apoptotic signals or the enriched survival signals carried by crossed Tg facilitated MYC driven plasmacytoma-genesis by increasing PC frequency in normal mice and increased cyclin D expression. The synergistic effects of MYC and abl can be due to the activation of relevant pro-survival and proliferation signaling pathways such as RAS and PI3K dependent pathways. This synergy seems to be selective for tumorigenesis in PC lineage rather than lymphocytes, although the mechanisms of such selectivity remain not clarified.

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Therefore, these models resemble at best extramedullary MM cases and do not recapitulate the human disease. As discussed, a common element of these models is the rearrangement of MYC gene that drives tumor onset and development. This motif is targeted by somatic hyper-mutation machinery SHM , which can randomly revert the stop codon and promote MYC expression. Antibody production is monoclonal in most cases. Bi- or tri-clonal paraprotein occurs to a lesser extent, indicating the occurrence of different clonal PCs.

These mice have on average lower hemoglobin levels, reduced BMD and MM like kidney damage, thus resembling the human disease. PIs and ImiDs and innovative drugs such as HDAC inhibitors are effective drugs in the model, while standard chemotherapy lacks relevant activity, resembling the human disease. The model is also suitable to study and develop novel combo therapies. This distinctive feature proves to be very helpful to study clonal dynamics of the disease. As for other tumor types, the current hypothesis of MM onset and development is based on the existence of competition among different clones at diagnosis and along treatment, that drives towards indolent or more aggressive disease courses [ 4 ].

Interestingly, transplanted clones can compete out the preexisting tumor clones within the recipient mice, coexist with them or even support these clones to proliferate.

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These different courses resemble the human disease and can be observed also in MM at diagnosis and during subsequent relapses [ 4 ]. XBP-1 is required for PC differentiation as it is rapidly upregulated in B cells upon PC differentiating stimuli, whereas mice lacking XBP-1 retain normal B cell activity but show very low level of antibodies in the absence of PC differentiation.

The same group previously demonstrated that c-MAF upregulation in T cell compartment led to development of T cell lymphomas [ 75 ].