I have been asked to talk about the newest phase II trials that are exciting in the management of myeloma. What I have decided to talk is more about the difficulty of integrating new agents in the era of new molecules. Now that we have proteasome inhibitors and immunomodulators and monoclonal antibodies and histone deacetylase inhibitors all approved now the patients who are eligible for clinical trials find a very difficult time in identifying drugs that are actually effective. Similarly the regulators are finding difficulty in finding a space for the new molecules.
So the first goal is to try to find a way to alter the resistance to the known agents, particularly there are new drugs and old drugs that have been shown that can modify the response once there is a refractory state. Interesting on that are in the IMiD arena; we and others have shown that clarithromycin can change the responses and salvage patients once they have gone through a relapsed state. More importantly, when we add it to pomalidomide the responses have doubled to the standard pomalidomide and dexamethasone. In the same vein, in this meeting and in the last ASH nelfinavir, which is an anti-retroviral drug, has also shown activity in people who have resistance to bortezomib. Although the mechanism has not been clearly defined, their responses have been outstanding and it’s suggested that it could be overcoming multi-drug resistance or perhaps similar to clarithromycin it could be a pharmacokinetic effect. Being as it may, these agents are available and are cheap and they’re easy to integrate in any country. In the era of cost containment those are two drugs that are important to notice.
In the newer drugs it is promising the new immunomodulators, so I should call them the new cereblon-binding agents which are being designed and developed by Celgene. CC220 or CC122 are two different drugs that have shown potential efficacy in cell lines who are lenalidomide resistant and 220 has shown to be effective in cell lines and animal models who are resistant to pomalidomide. So those two agents are now under development in phase I and phase II trials that have shown promise and possibly will be part of the armamentarium in the near future.
In terms of resistance to bortezomib and carfilzomib we have now also the opportunity to study the next oral proteasome inhibitor which includes oprozomib. Oprozomib is one of the most effective drugs in vitro and it had begun development in the clinic through different phase I and phase II trials. There has been a hiatus on its development but there is a new impetus to try to develop. It has been shown to have efficacy in bortezomib resistant patients and including in carfilzomib resistant patients and it’s an oral drug. So if we can get around the toxicity, particularly the GI toxicity, it will be a very important drug to look at in the future.
Finally, the last part of my talk is going to focus on the histone deacetylase inhibitors and although there has been a panoply of drugs with very broad effect, histone deacetylase inhibitors are more promising, I would say, given the lack of toxicity and the efficacy which would be the HDAC6 inhibitors of which ricolinostat or ACY-1215 is the first one. The next generation of that will give us the option to maybe alter the response to pomalidomide. We have seen some responses even in pomalidomide resistant patients when you combine these agents that may not have single agent activity but in combination may alter their efficacy and improve response.
What is the take home message?
It’s very positive and there is a panoply of drugs that we are looking at and that we are trying to develop. The era is a difficult time for the developers because there are now so many agents but that’s all good news for the patients. So the more we have the better we are.