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Promising Treatments For Relapsed Myeloma

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Published on July 10, 2020

Reports from the American Society of Oncology (ASCO) and the European Hematology Association (EHA) bring exciting treatment news for people living with multiple myeloma, especially relapsed/refractory myeloma. Experts discuss promising results from several major studies including the BOSTON study, the KarMMa study and the ENDURANCE study. Dr. Paul Richardson, Clinical Director, Jerome Lipper Center for Multiple Myeloma; Dana-Farber Cancer Institute and Patient Power co-founder, Andrew Schorr have an in-depth discussion on what the future holds for multiple myeloma patients.

Some important notes from the conversation: "While still in the early days, CC-92480 is headed to phase 2 of a trial for triple class refractory patients, those who have exhausted other treatment options, phase 1 reported a 55% response rate. Car T trials offer an option with well tolerated side effects."

From Dr. Richardson, "These are regimens that can be given with relatively infrequent visits to the office, oral approaches, and the flexibility to offer patients a degree of safety with our therapies is tremendously important in this new era that we live in."

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Transcript | Promising Treatments For Relapsed Myeloma

Andrew Schorr:
Hello, it’s Andrew Schorr, here at Patient Power and joining us once again is a world-renowned multiple myeloma expert from the Dana-Farber Cancer Institute in Boston, and that’s Dr. Paul Richardson. Dr. Richardson, thank you again for being with us.

We've had two major medical meetings where myeloma has been discussed. The American Society of Clinical Oncology, normally in Chicago, virtual this year of course. Then the European Hematology Association meeting, virtual again. Lots of news about myeloma for patients and families affected by myeloma. What would you like to highlight?

Dr. Richardson:
Oh, thank you, Andy. And it's my pleasure to be with you. And it's been an amazing two meetings. In fact, despite the enormous challenges posed by COVID, I would simply say that a real feast of new information and very timely given the challenges we're facing. We already discussed earlier the BOSTON data... I really want to focus on some of the other highlights, recognizing that in the time we have, I can't possibly cover everything.

The things that caught my eye, most importantly, I was very impressed with the CAR-T data presented. Recognizing this is a very specialized approach, but, nonetheless, I think very promising and hopeful for myeloma patients. And my colleague, Dr. [Inaudible] presented the updated results of the KarMMA study, which clearly show that an incredibly vulnerable population there is a meaningful progression, free survival gain in my opinion from the approach.

One of the challenges, however, is that it doesn't appear particularly durable, and this is different from lymphoma and leukemia. I think that's a big area of challenge for us. Having said that, I think it was very promising beginning, and there were a number of other CAR-T study results presented with different platforms, showing that you may be able to achieve longer durations of disease control. Generally speaking was the side effect panel or side effect issues encountered are important, and they're generally manageable.

In that same spirit, we presented some of our own work looking at this very important potent new cell models. It's called a Cereblon E3 ligase inhibitor. And this is an oral agent given once a day, three weeks on and one week off. We did our phase I study first in human reports from our phase I study of 76 patients in a multicenter international trial.

Now the drug is called CC92480, and I'll call it 480 for short. 480 is the most potent cell model that we currently have from preclinical work. And we sought to see how would the drug behave in the clinical setting in treating relapsed and refractory multiple myeloma in patients who have exhausted all available options at their respective treating centers. So that meant our patients would classically relapse and refractory. Unfortunately, immunology immunotherapy has failed them. Proteasome inhibitors have failed them. So had monoclonal antibody treatments. They were enriched for patients who were so-called triple-class refractory or triple-class resistant.

Now in this patient population, we were struck that the drug was generally well-tolerated. We were able to establish a dosing schedule and, very importantly, at the dose that was best tolerated. One milligram daily, three weeks on and one week off. We saw a response rate of 55%. Importantly, in the other cohorts of patients, the response signal, particularly with dose that was determined to be the best dose, the response was very robust as well. And it's still early days and it's still a phase I experience, but we're now expanding into the phase II setting. And in that setting, we're very hopeful we'll see a consistency of benefit.

What we were very struck by was that in the patients in whom we saw extramedullary disease, amazingly, with just a pill and a pill combined with dexamethasone (Decadron), we saw responses and in a significant number of patients. So putting that together, 480 was a very promising, simple new agent that's come on the scene. It builds on the success of another cell mod called Iberdomide (CC-220) and people have said to me, is this just another imid? Is it just like pomalidomide (Pomalyst) and lenalidomide (Revlimid)? No, it isn't. These are specifically designed molecules. They take on the same target, but at the same time, they're in a very different category in terms of potency and efficacy.

We were very pleased to see with 480 echoing the success of Iberdomide from earlier studies, but even going a step further and we're able to see even greater potency in a very, very vulnerable population. That was very exciting. And I think the final study that I really wanted to emphasize had emerged at ASCO, or was presented at ASCO as a plenary session no less by my colleague and the principal investigator, Dr. Shaji Kumar from The Mayo Clinic, Shaji presented the results of the ENDURANCE trial. And this ENDURANCE study was a tremendously important effort. It was an integral effort. Our role as the alliance was to contribute in partnership with ECOG and SWOG to this effort, and especially acknowledge the patients who participated a thousand strong.

We were able to show that what's the best front-line regimen right now in myeloma. We had RVD versus carfilzomib (Kyprolis), Revlimid and dexamethasone and arguably, it was the difference potentially between a Ferrari in the form of KRd and a regular sports car in the form of RVD. And what we found actually was the RVD performed just as well as KRd. And that was very important because until that point, I think many of us had assumed carfilzomib powerful and definitely a more potent proteasome inhibitor would outperform RVD. And we didn't see that in this particular study.

The good news for patients is that both arms performed well. Side effects for a Bortezomib (Velcade) were riddled with neuropathy, but we had to be very careful about carfilzomib and cardio, renal, and pulmonary toxicity and thrombosis. Now that doesn't mean carfilzomib shouldn't be used... Absolutely not, quite the opposite. It just gave us the highest level of evidence in being able to make choices for our patients have best upfront regimens to use. And of course, strategically then to be able to use, for example, if you use bortezomib first, carfilzomib second is an obvious next line of attack if you need it. And this trial really helped us make sense of that concept of sequencing.

Andrew Schorr:
So Dr. Richardson, let me put all this together for patients because people are hanging on every word. Some people really understand the science. Some people are grappling with that, but you are totally immersed in this. And you've had these two really worldwide meetings-

Dr. Richardson:
Right.

Andrew Schorr:
Are you encouraged? So when a new patient comes or even a patient where certain therapies have failed them and they're relapsed, refractory, they've gone through on a longer journey with myeloma that you feel you have something to talk about. Maybe it's a clinical trial, maybe it's a new combination or validation of existing combination, but you have things to offer them.

Dr. Richardson:
Absolutely. I mean, I think that's the beautiful message, Andy, is that we have great options upfront. I mean, for example, the endurance style is a study of two fabulous regiments and the thing is both are great, the question is how do you sequence them? And to your point, the sequencing then becomes everything.

We have lots of new options. We have wonderful data, for example, on Isatuximab (Sarclisa), which is a new CD-38 antibody. We also had great data on daratumumab (Darzalex). So we're seeing a whole array of approaches that are demonstrating to us that our ability to control the disease over the long term will continue to improve. And what was very important was that these were strategies that could be legitimately deployed in the real post-COVID pandemic world that we live in. These are regimens that can be given with relatively infrequent visits to the office, oral approaches and have the flexibility to be able to offer patients a degree of safety with our therapy. That's tremendously important in this new era that we live in.

Andrew Schorr:
It's all good news. Myeloma has really been a poster child for blossoming research that can help people on a much longer journey for most people with myeloma. Dr. Paul Richardson from Dana-Farber. Thank you for shining a light on this, and we wish you well with your continued research.

Dr. Richardson:
Thank you, Andy. It's my pleasure. And thank you for your interest in myeloma and particularly your support of our patients. Thank you.

Andrew Schorr:
Andrew Schorr for Patient Power with Dr. Paul Richardson from Boston. Remember, knowledge can be the best medicine of all.

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