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INN Melphalan Flufenamide in Triple-Class Refractory/Relapsed MM
Paul G. Richardson, MD: Melflufen, or melphalan flufenamide, is what we call a peptide-drug conjugate. It has a novel mechanism of action, just like all the other drugs I mentioned earlier.
What happens is that it delivers its cytotoxic warhead directly to the tumor cell. It does this by virtue of the aminopeptidase targeting effect that is generated by the uniqueness of the chemical structure of the actual molecule. The molecule is highly lipophilic select, and that allows it to be delivered into the bone marrow, which is full of adipose tissue. At the same time as it goes into the circulation, it’s entrapped in tumor cells. Why? Because tumor cells are classically enriched for aminopeptidases—in particular multiple myeloma, but other tumor types as well.
Within the context of myeloma, with Melflufen, it’s trapped within the tumor cell, activated, and cleaved, and the warhead that is essential to the melphalan is then delivered to exactly where it needs to be, which is the tumor cell. This is a unique platform and, from a therapeutic point of view, has been developed first from some really elegant preclinical work that showed was this able to overcome resistance in not only cell lines that were already derived from alkylator-exposed myeloma but also myeloma that was derived from novel therapies. In other words, patients in whom they become resistant to bortezomib, for example, these particular tumor cells are being developed into cell lines. We were able to test that in this setting.
I want to especially acknowledge my colleague Dr Dharminder Chauhan, who led our efforts here at Dana-Farber Cancer Institute to really interrogate Melflufen in the context of these highly resistant cell models. We’re able to show that in the cell models, what Dharminder was able to do was take this into the in vivo setting—ie, in mice—and show that Melflufen was able to overcome resistance to alkylator therapy like melphalan and also able to overcome resistance to some of our backbone agents, like bortezomib and the immunomodulatory therapy. Putting that all together was very attractive.
Dr Chauhan also showed that this is quite different from traditional chemotherapeutics. We were able to show effects on small-vessel formation or neoangiogenesis around tumors, so there was an antiangiogenic effect that we saw that was not seen with conventional chemotherapeutics in the same model system. There were a variety of other mechanisms that became apparent, not least of which is the ability of this drug to overdrive or evade classic pathways of drug resistance, the least of which of course is TP53. The ability of this drug to overcome TP53, which is a very dangerous mutation in myeloma—it leads to very high-risk behavior in patients from the disease—was particularly attractive to us. With all this preclinical information, a series of clinical trials then followed with Melflufen, and these have culminated in the HORIZON study, which we were able to present some data on at this year’s ASH meeting.
Transcript Edited for Clarity
