Published on March 3, 2021
Melflufen and Dexamethasone Combination Therapy Approved by FDA
The combination of melphalan flufenamide (Melflufen) and dexamethasone offers a new targeted therapy for multiple myeloma patients with fewer side effects. This combination has received FDA approval.
Dr. Paul Richardson, MD, of the Dana Farber Cancer Institute, joins Patient Power co-founder Andrew Schorr to discuss how Melflufen works, and the ongoing studies of Melflufen in combination with other drugs. Dr. Richardson also explains why Melflufen does not impact surrounding tissues when targeting the myeloma cancer cells, resulting in fewer side effects and no hair loss.
Support for this series has been provided by Oncopeptides. Patient Power maintains complete editorial control and is solely responsible for program content.
Transcript | New Combination Therapy Approved for Multiple Myeloma
Andrew Schorr: Hello and welcome to Patient Power. I'm Andrew Schorr in Southern California. Joining us from Boston clear across the country is a quite renowned multiple myeloma expert and that's Dr. Paul Richardson at the Dana-Farber Cancer Institute. Dr. Richardson, welcome back to Patient Power. Just so everybody knows your credentials in myeloma, tell us your title these days.
Dr. Richardson: Well, thank you very much, Andrew. It's a privilege to be with you and thank you for your continued support and interest in our myeloma research. I serve actually as the Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston. I also serve as the R.J. Corman Professor of Medicine at Harvard Medical School, but it's really a privilege actually to be part of a fantastic team where we do translational research from bench to bedside and back for that matter, for our patients.
Andrew Schorr: Dr. Richardson, there's yet another drug and boy we've had a lot fortunately in multiple myeloma, another one that may be approaching approval, melflufen, and there is research that's come out of course, at the recent meetings in blood cancers. Tell us where we stand with this drug. What is it? And who can it help in the myeloma community?
What is Melflufen?
Dr. Richardson: Well, thank you, Andrew. Yeah, we're very excited about melflufen. As you say, it's got an interesting name. It actually is what we call a peptide drug conjugate. It's a highly targeted form of delivering an alkylator warhead to the tumor cell. Why this really matters is because obviously, alkylators have been mainstays of therapy for decades. And in fact, some of our best results are achieved with melphalan (Alkeran and Evomela) and cyclophosphamide (Cytoxan) combined with novel drugs or at least in sequence. And of course, melphalan constitutes the mainstay of autologous stem cell transplant, which of course has been fundamental to improving outcome in younger myeloma patients for many years.
But as we've realized, high dose melphalan is a wonderful older warhorse as it were, in our armamentarium but it carries with it significant side effects that have an impact on quality of life, acute toxicities that can be even very dangerous actually in the peri transplant setting. Although now with supportive care, those are minimal, so the risks are very low. But what we're also realizing is there are long term consequences from high dose melphalan, which include, for example, secondary cancers and for also for that matter, just as we presented at this ASH meeting, what's the secondary cancer risk is really quite low.
What is perhaps more sobering is that when the cancer comes back, there is survivorship from the high dose melphalan and when that cancer comes back, its genetics are really significantly different than if you're not exposed to high dose melphalan early. Efforts to try and circumvent some of the longer-term challenges of melphalan are real.
Melflufen in that spirit is a very targeted approach to try and take the best of melphalan as it were as a warhead, deliver it very specifically to the tumor cell in a way that's highly lethal to the tumor, but most importantly leaves other tissues alone. In that spirit, we've been able to demonstrate preclinically that melflufen is quite different actually in the way it behaves in preclinical models compared to chemotherapy. And in fact, can overdrive resistance to novel agents like proteasome inhibitors, for example, by virtue of its mechanism. It has what we call an anti-angiogenic effect, which is quite striking. And it also has an ability to overcome a very important mechanism linked to 17p deletion, so called p53 mutation. It can overcome that.
Andy, what's so important about this drug is that it is what we call lipophilic. Now, why does that matter? Well, it matters because the bone marrow is packed with fat and lipophilic qualities of drugs are very important to ensure that we get the drug to where it needs to be. Now, for example, by contrast, melphalan is actually lipophobic and it will not go to the bone marrow easily so that's why we have to dose escalate it to get it to where it needs to be. Melflufen is quite different and that I think is one very important distinction.
And what happens is when the drug is delivered to the tumor cell, it's entrapped. And how does that happen? Well, it's entrapped because in tumor cells, they're enriched for things called aminopeptidases. There are loads of these enzymes in a myeloma cell, much less so in normal tissue. And as a result of that, the drug gets in there, the aminopeptidases will cleave it, release the warhead then goes straight to the nucleus to do its damage. And by virtue of that, normal tissues are spared because obviously the drug inertly passes through those other tissues and is excreted from the body. And that this whole concept leads to this therapeutic index.
As a result of that, and this is very good news for our patients, melflufen does not cause hair loss, does not cause alopecia hair loss, I should say and it doesn't cause mucositis, which is another very important side effect. These are properties of the drug that set it apart. Now I do want to also emphasize however that it does cause low blood counts because clearly, it's so powerful that once it gets into the bone marrow, it will affect normal tissue there. We see low platelets or white count and we're very careful about that, but in our trials to date, those have proven very manageable. And what's really interesting is that we've been struck by not only its favorable tolerability profile overall, but also importantly, by its ability to be active when all other treatments have failed. And in this regard, our trials have been really quite exciting.
What are the Clinical Trial Results of the Melflufen and Dexamethasone Combination Therapy?
We were very encouraged that about a third of the patients responded to melflufen and dexamethasone (Decadron) and most importantly, we saw in the high-risk populations a signal. We saw responses of around 25% in patients with high-risk cytogenetics, responses in patients with extramedullary disease of around 24% and we also saw, and this is very interesting that in patients who are truly alkylator refractory, in other words, they'd had prior chemotherapy and coming into the study, they were clearly resistant to that prior chemotherapy, in that population as well. Again, around 24, 25% of patients responding. And these were in turn associated with durability of disease control.
With that early data, we were very excited going forward. And then at this year's ASH meeting we're very pleased that my colleague, Dr. Enrique Ocio, presented the combination study of the ANCHOR trial in which we combined melflufen, both with Velcade or bortezomib in one group of patients and with daratumumab (Darzalex) in another and saw really striking combination effects. We're excited by that. And you may say, "Why combinations?" Well, very much so because obviously long term side effects of melflufen is something we're really keeping an eye on recognizing that with melphalan for example, sometimes you can see secondary leukemia and myelodysplasia. And for that reason, we're being very careful about that. But my own feeling is that in combination with these other drugs, that's where the benefit of melflufen will lie and going forward, we can figure out how to optimize the performance of melflufen in this setting.
Andrew Schorr: Wow. Okay. Well, I'm really pleased to hear this research moving forward and I know people who are patients or have loved ones who are dealing with more advanced myeloma, want to keep hearing this story. And we credit you, Dr. Richardson and your peers who are in research for pushing this along with the cooperation of patients who are in your trials. Thank you so much for all you do and for being with us on Patient Power once again.
Dr. Richardson: Well, Andy, it's really my privilege and I am so grateful for you acknowledging not only all my co-investigators and partners in research, but most importantly, our patients and families because I completely agree. They are really our true heroes. And thank you very much.
Andrew Schorr: Thank you. All right, Andrew Schorr, reminding you that knowledge and as we just mentioned, clinical trial participation can also play a role in the best medicine of all.
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