The Vk*MYC Mouse Model of Myeloma Accurately Reflects Clinical Efficacy of Established and Novel Drugs.

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. 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. 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 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. 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.

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. 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 M-spike represents a very useful marker to monitor tumor burden by periodic bleeding, as is done in patients. We have re-evaluated the anti-myeloma activity of novel compounds that have passed extensive pre-clinical characterization and are currently in clinical trials. We have utilized “naïve‘, untreated Vk*MYC mice at early stages of myeloma disease. Response rates were calculated by comparing the M-spike levels after treatment to the levels observed at d0. 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. In contrast, only a minor response was observed to a CDK inhibitor (SNS-032) or the AKT inhibitor perifosine. No response was observed to the HSP-90 inhibitor AUY-922, or to the PI-3K inhibitors BEZ-235 and GDC-0941, or statins. The summary of the results with all tested agents is given in Table 1.

Table 1

activity of single agents in Vk*MYC mice

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Although the modest activity of SNS-032 and perifosine in the Vk*MYC mice mirrors the results of phase-I and –II trials, where disease stabilization was observed, the efficacy of HDACs inhibitors in the Vk*MYC mice is somewhat surprising, since no clear single agent activity had been reported in advanced MM patients. With all the limitations of a mouse model, our data, however, suggest that untreated, earlier stage myeloma patients may be more sensitive to HDAC inhibition.

As more mice are treated and more compounds are screened to further validate the clinical predictive value of the Vk*MYC mice, we would like to propose a new approach to the introduction of novel compounds in the treatment of MM, in which they are tested alone in the Vk*MYC model, and the ones that clearly induce a complete response are then prioritized for testing in a small cohort of earlier stage/untreated patients for one cycle, accelerating the evaluation, and limiting the toxicity. For those compounds that generate a partial response, combination studies can be easily performed in the mouse to assess drug pair efficacy. Finally, drugs that do not show any response in the Vk*MYC mouse should be given a lower priority for further clinical development in MM.

No relevant conflicts of interest to declare.