No response was observed to the HSP-90 inhibitor AUY-922, or to the PI-3K inhibitors BEZ-235 and GDC-0941, or statins. In contrast, only a minor response was observed to a CDK inhibitor (SNS-032) or the AKT inhibitor perifosine. We found that, in addition to the demonstrated single agent clinical activity of alkylating agents (melphalan), cortico-steroids (dexamethasone) and proteasome inhibitors (bortezomib and carfilzomib), the histone deacetylase (HDACs) inhibitors vorinistat and panobinostat showed strong anti-myeloma activity, inducing a dramatic reduction of the M-spike after only two weeks of treatment. Response rates were calculated by comparing the M-spike levels after treatment to the levels observed at d0. ![]() We have utilized “naïve‘, untreated Vk*MYC mice at early stages of myeloma disease. We have re-evaluated the anti-myeloma activity of novel compounds that have passed extensive pre-clinical characterization and are currently in clinical trials. The M-spike represents a very useful marker to monitor tumor burden by periodic bleeding, as is done in patients. Specifically, the Vk*MYC myeloma is indolent (with a very low proliferative index), confined to the bone marrow, and secretes a monoclonal protein detected by serum protein electrophoresis. The immuno-competent Vk*MYC mouse model of myeloma has already demonstrated high biological fidelity to the human disease, making it a better model to study the behavior of myeloma cells in the context of a native microenvironment. Unfortunately, without a large randomized trial, it is often difficult to interpret the response rates observed in these patients, and determine the contribution of the novel compound to the response observed to the combination treatment. ![]() One solution to this problem is to treat patients earlier in the course of their disease, which has been done by using the novel drug in combination with an approved drug. Another reason may be that to be able to test novel compounds, only relapsed and refractory patients are studied, at a stage in their disease that is unlikely to respond to any drug. One reason for that may be an intrinsic inadequacy of pre-clinical models to predict activity, since for the most part they do not represent the complexity of human MM in an endogenous micro-environment. With the increasing availability of novel compounds, a number of drugs that have shown promising anti-myeloma activity in extensive pre-clinical studies failed to demonstrate clear efficacy in subsequent clinical trials.
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