 The HORIZON study is a particularly important trial because it’s the largest single-arm experience of Melflufen of its kind, in which we enrolled 157 patients with relapsed and refractory multiple myeloma in whom other treatments have failed. Most important, they had to be resistant to pomalidomide or daratumumab, or another CD38-targeting antibody, or both. As a result, the majority of patients were what we call triple-class resistant, and we were enriched for very adverse features, such as extramedullary disease.

At context, Melflufen was given once every month with dexamethasone given weekly. It should be noted that we’ve demonstrated in the laboratory that Melflufen is synergistic with steroids, and so all these patients were already steroid-refractory. Nonetheless, when you combine it with Melflufen, you’re able to demonstrate excellent response rates. We’ve been able to show this in the previous study called the O-12-M1 trial published in 

 last year. With that, the HORIZON study has completed, and we have mature follow-up in being able to show very a solid response rate of around 30% in patients in whom all other approved drugs have failed. In that context, because they were triple-class resistant, for example, and enriched for extramedullary disease, we were very encouraged to see a clinical benefit was apparent.

To understand whether the signal from the HORIZON trial—in terms of clinical benefit compared with other studies in this setting—was really tangible, there was a very nice comparison done by my colleagues looking at HORIZON vs MAMMOTH. It was an indirect comparison of efficacy outcomes for patients with relapsed/refractory myeloma to anti-CD38 monoclonal antibodies vs patients who were antibody-refractory treated with Melflufen plus dexamethasone vs conventional or approved agents.

In this particular study, they were able to show very nicely that for patients who were refractory to anti-CD38 monoclonal antibody therapy, there was longer survival outcome with Melflufen and dexamethasone than was typically seen with other drugs in the MAMMOTH study. To be precise, the median progression-free survival for Melflufen plus dexamethasone was 4.6 months, and the overall survival was 15.4 months. Unfortunately, the MAMMOTH trial, which was looking at salvage therapies after daratumumab-based treatment had failed, showed substantially shorter progression-free survival intervals and overall survival, making this an attractive comparison. This analysis really underscored the high burden of disease and unmet medical need for patients with relapsed/refractory myeloma and the importance of novel combination therapy in this setting.

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HORIZON vs MAMMOTH Explored in R/R Multiple Myeloma

 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 

, 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.

INN Melphalan Flufenamide in Triple-Class Refractory/Relapsed MM

 The treatment landscape for triple-class refractory multiple myeloma has improved dramatically the last couple of years. We’ve come to recognize that patients who are refractory to not only immunomodulators but also proteasome inhibitors were an exquisite unmet medical need. Then we had the advent of the CD38 monoclonal antibodies, which transformed that therapeutic landscape and dramatically improved outcome.

We face the challenge of patients who have become resistant to an immunomodulator such as lenalidomide and meet that challenge with pomalidomide, but now we have the challenge of patients who are resistant to lenalidomide and pomalidomide. In the past when you’ve been resistant to a proteasome inhibitor like bortezomib, it was obviously the tremendous results from carfilzomib-based therapy and the ixazomib-based treatment. Then of course daratumumab and most recently isatuximab.

When you put all that together, what do you do when all those drugs have unfortunately failed your patients? That becomes a huge challenge.

The very good news is that with the approval earlier this year of isatuximab in combination with pomalidomide, we were given an important new option. We then had real excitement around belantamab mafodotin, which targets 

 and provides an off-the-shelf ability to deliver monoclonal antibody-drug conjugate to patients. That was really exciting as a monotherapy, and clearly in combination has done the same thing. We got some great data at the ASH [American Society of Hematology] Annual Meeting on combinatorial strategies with belantamab mafodotin. They’re both particularly promising.

The challenge of belantamab, of course, is the keratopathy, and there’s been lots of work going into that process to figure out how to manage the ocular toxicity and minimize it. We have some very nice strategies for doing so, not least of which is the ability to combine the drug with other agents. So change the dose and frequency in a way that allows to hopefully minimize the ocular toxicity or make it as manageable as possible.

Against that backdrop, we’ve got the excitement of not only the incredible data around cellular therapies and BiTEs, or bi-specific T-cell engagers—which are phenomenal—but also the advent of a targeted peptide-drug conjugate called Melflufen. And Melflufen is really interesting because it’s a truly targeted cytotoxic drug that has been developed with the goal of providing a novel mechanism of action in addition to those we’ve already talked about.

Beyond Melflufen, it’s also important to note that at this meeting, in addition to what we saw with bispecific T-cell engagers, CAR [chimeric antigen receptors] T cells, isatuximab, and belantamab mafodotin, we also had some very exiting data on a new mechanism of action: the XPO1 inhibition or the exportin inhibition, or the exportin inhibitor selinexor, which is a first-in-class drug, is orally bioavailable, can be given to patients in combination with other drugs, and can be very effective.

As we think about the relapsed/refractory landscape, we have in the approved space in the last year the isatuximab and belantamab mafodotin. Because we’re recognizing selinexor was approved last year, we also have selinexor in combination with new drugs really making an impact. The best data in that regard are BOSTON, in which we combined selinexor with bortezomib and have been able to show real clinical benefit in the gold standard, which is a randomized phase 3 trial.

As we think about the triple-class refractory landscape, we’ve got lots of exciting new drugs. Selinexor is an XPO1 inhibitor, a totally novel mechanism of action. We’ve got belantamab mafodotin, as I’ve mentioned, most recently. We’ve got obviously the really exciting data around Melflufen, as well as important options to offer our patients.

In the contest of triple-class resistant disease and relapsed/refractory myeloma, another very exciting example of novel targeted therapy that’s coming very rapidly through the development pipeline is that of the CELMoDs—the cereblon E3 ligase inhibitors. At the ASH meeting, we had an outstanding presentation from Dr Niels van de Donk on the combination of iberdomide with a variety of other backbone agents in the treatment of relapsed/refractory disease. We also had a presentation on some of the mechanisms of action of another CELMoD that’s even more potent, we believe, than iberdomide: so-called CC-92480. This particular orally bioavailable drug is particularly promising, not only as a single agent but also in combination.

We have an array of opportunities now for our relapsed/refractory multiple myeloma patients. But obviously in the interest of this evening, I want to specifically focus on just a few. In that spirit, I’d particularly like to talk to you about Melflufen, or as it’s called by medicinal chemistry name, melphalan flufenamide. That sounds like a very conventional chemotherapy. It isn’t.

As just discussed, we’ve got this array of new agents. And as I just mentioned and described some of the real excitement around the CELMoDs, for example, there are a whole variety of approaches going into targeting triple-class resistant, relapsed, and refractory multiple myeloma.

Paul Richardson, MD, Dana-Farber Cancer Institute

Articles

HORIZON vs MAMMOTH Explored in R/R Multiple Myeloma

INN Melphalan Flufenamide in Triple-Class Refractory/Relapsed MM

Treatment Advances in Triple-Class Refractory/Relapsed Myeloma