Paul Richardson, MD, Dana-Farber Cancer Institute, discusses the background and findings of his study on the use of melphalan flufenamide in combination with dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least 4 lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody.
pleasure to join you. And it's actually my privilege to present on behalf of my colleagues are work with mel fluff in as we call it in combination with dexamethasone and the treatment of relapse refractory myeloma. I think just by way of introduction I want to share with you some slides if I may that I think would help frame our conversation this morning. This first slide is simply a description of how malfunction works. I think it's a way to think of it as as a peptide drug. Contradict that leverage is what we call um you know pet today's is and actually borrowed from a very dear friend of mine dr Peter Vorhees who's a co investigator actually in our work here is that it's something of a trojan horse. It basically dives into the myeloma cell and allows the calculator payload to be released in a highly targeted fashion within the cell. And what's really interesting is the fact that this hydrophobic Libya filic platform allows the delivery of a hydra filic lipa phobic calculator warhead into the cell. And this is an important piece of medicinal chemistry because obviously the bone marrow in which myeloma loves to live is a highly fat filled environment and that's a micro environment in which the delivery of a drug that slip a phobic is challenging. That's why traditional male fill in has to be rapidly dose escalated in order for it to do its work. This is very different and it has a novel mechanism action where the calculator warhead is selectively delivered to the do muscle rather like a trojan horse. But most importantly because of this rapid hydrologists driving a concentration gradient and allowing the increased diffusion of Balfe aloof and into the cell. It's almost like the trojan horse in that the Greeks not only get in and start to make mayhem in the city as it were, but they also open the gates and allow more Greeks in. So the analogy to the trojan horse is really a lot more powerful than one might think. Now. Based on that we have pre clinical data led my colleague, Dharmindo chau han, which really shows both in animal models and in bench in vitro model systems, dramatic activity for malfunction even in highly mouthful and resistance cell systems and most importantly, it's able to overcome Melville and resistance very much significantly lower concentrations than we see. For example, in the experiments illustrated in the right of this slide, What's also not shown in this is that we're able to overcome resistance to other drugs as well in similar systems such as partisan MIB and that's an important point because the deployment of malfunction first and foremost has been in the setting of novel agent treatment failure and that's where we've seen some very encouraging results. Now, the first study to share with is the Lance of hematology paper that we published, yo 12 M one, which we published actually just last year. And in this trial we were able to establish a dose and schedule formal fluff in at 40 mg once a month. Now the important thing is that we combined malfunction in this study with dexamethasone. This was a large trial and it was in over 70 patients all told and we established an important cholera bility profile but also showed convincingly that the combination of malfunction index method zone was the direction in which to go recognizing that all our patients were steroid refractory. So the decks methadone wasn't quote unquote making the difference in the absolute sense. But clearly the two drugs together were better than just the one. Now in that context, the 28 day cycle was established. Side opinions were the major issue. We saw a solid response rate, particularly the combination group of 31 and progression free survival was encouraging in the combination group as well. Safety summaries here. I think it's important to emphasize is the side opinions dominated but other side effects were very uncommon. However, in this trial we had a very sick patient population and the number of patients who entered the trial, we had rapidly progressive disease. And in a number of these we saw septic events and in that context two deaths were considered possibly malfunction related. So after this trial we were very alert to the possibility of infection as a problem with malfunction indexing methods own bring into the horizon trial. Now before I get to that I did want to share an important and reassuring signal from the one to um study which was long-term survival. This was 21 months. So whilst we obviously were on the lookout for this infectious signal, we at the same time recognized that for this large cohort of patients, the median overall survival approached 21 months and then a relapse refractory population. That's not only impressive, but it also if you have a major safety issue, you wouldn't necessarily expect that. So based on that the male fluff index methadone combination was taken forward in our relapse refractory trial and this was recently published in the journal of clinical oncology. This was a very large trial of 157 patients in multiple centers across both Europe and the United States. And in that setting were able to demonstrate solid response rate. The investigative based assessment was 29%. The Independent review committee actually confirmed it at 30% and this was in the intent to treat population. If we look at the triple class refractory patients were able to see their very similar response rate and here is summarized the progression free and overall survival data which were again in such a sick, vulnerable population, encouraging with the median overall survival approaching a year and a median progression free survival in excess of four months. What's important to note the side effect profile was reassuring in this regard. We saw side opinions as the dominant issue, but we did not see fatal treatment emergent adverse events that were attributable to malfunction in any case. This I think was important being that the case, the important other side effect we were on the lookout for was myelodysplasia. At the time of this analysis, there was clearly one case documented with underlying by the display stick genetic change. Prior to study entry. When we looked back and interrogated the genetics of the bone marrow sample from. Prior to study entry, Having said that this is a particular side effect. We're on the lookout for which is Dzemal fortunately today, that seems extremely uncommon and rare. But again, because this is a delivery of a very potent calculator warhead, it's something we'll be keeping a very close eye on going forward. What was very good in this trial was that we saw that those patients with extra medullary disease after monoclonal antibody treatment failure in the main actually did remarkably well. We saw a response rate and bone related extra medullary disease of 25 and then the true softest you plasma system as we saw a response rate of 22 and you may say, well how does that compare While other treatment approaches do not achieve that kind of degree of response. Generally speaking, for example, dara to mob given in the dark. Um Ahmad naive population as a monotherapy has been recorded to demonstrate response rates in E. M. D. Of 17%. So to see a response rate of between 22 25% In patients with extra medullary disease that reflects dara to mob or other monoclonal antibody failure is a very important signal in our view and worthy of further study. Further studies are summarized here and the ocean study led by my colleague Peter Sonefeld is comparing ralph lupin and dexter methadone to pommel intermittent. Next method zone similarly, Enrico Ceo, my colleague is leading the fabulous study combining male flew for not only with direct um Ahmad but also with autism IB. This is the direct human map data and the results are very encouraging. Similar. The bore testament. It will also look favorable with enrollment. Ongoing future studies are now including all fluff and dara. Touma mob indexing methods own compared to dara um Ahmad dexamethasone as a backbone with crossover permitted to ensure equal poise. My colleague Marie v. Matias is leading this trial. We're looking forward to results from that. So in conclusion malfunction is the first and only peptide drug. Conjugate leveraging, amina pep. Today's is to date and represents a truly novel mechanism action for patients with relapsed refractory myeloma. Importantly in combination, we've seen meaningful clinical efficacy and manageable safety in patients with heavily pre treated advanced relapse refractory disease And in horizon the overall response rate was approximately 30%. And in that context, the manageable safety profile, we found reassuring ongoing trials include ocean, lighthouse and anchor. And we're very hopeful that this then constitutes an important new treatment option for our patients.