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What If I Become Resistant to Lenalidomide (Revlimid)?

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Published on December 18, 2020

Doctors Share Treatment Options for Revlimid-Resistant Myeloma Patients

One of the long-standing backbones of the multiple myeloma treatment regimen is lenalidomide (Revlimid). That being said, what happens when a myeloma patient becomes resistant to this widely used oral drug? 

Follow along as host and patient advocate Cindy Chmielewski guides this Answers Now segment with multiple myeloma experts Dr. Craig Cole, MD, Hematologist at the Michigan State University Breslin Cancer Center and Dr. Rafael Fonseca, MD, Hematologist at the Mayo Clinic Cancer Center. They will discuss treatment options and the course of care for “life after Revlimid.” 

This program is sponsored by Sanofi Genzyme. This organization has no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.

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Transcript | What If I Become Resistant to Lenalidomide (Revlimid)?

Cindy Chmielewski: My name is Cindy Chmielewski and I'm coming to you from Lawrenceville, New Jersey. I am a fifth-grade teacher who was diagnosed with multiple myeloma back in 2008. Over time, I became an advocate in the myeloma community and some of you may know me as the Myeloma Teacher. Today, I will be the host of this episode of myeloma Answers Now, and our topic today is going to be about Revlimid (lenalidomide) and what happens if you become resistant to Revlimid.

Joining me today, we have Dr. Craig Cole, who is from Michigan State University's Breslin Cancer Center. Welcome, Dr. Cole. And we also have Dr. Rafael Fonseca, who is coming to us from Arizona and he's a myeloma specialist and the Interim Director at the Mayo Clinic's Cancer Center in Scottsdale, Arizona. Welcome, Dr. Fonseca.

Dr. Fonseca: Thank you.

Cindy Chmielewski: Yeah. Thank you for joining us today. Before we get started with our questions with Dr. Fonseca and Dr. Cole, we are going to start off with a special clip from Dr. Karina Patel, who's a myeloma specialist at the MD Anderson Cancer Center in Texas.

Dr. Patel: The way I discuss it with my patients is that the induction treatment that you had, usually the triplet that includes the proteasome inhibitor, lenalidomide and dexamethasone (Decadron), is there to knock the myeloma down as much as possible. Then the transplant is there to get as many of those cells, that are deep rooted in that bone marrow... however many more we can get, that's the goal there. And then afterwards, once your immune system's back, our goal now is to... it's not the greatest analogy, but I'm in Texas and a lot of my patients have farms and ranches, we talk about weed killers.

We've knocked it down to its lowest, we've gotten a great response, we're putting it into hibernation, and now we want to add something that keeps it in hibernation longer. What we call progression-free survival. And so, our goal is to minimize your toxicity, but increase your efficacy. And what we know is that, by adding that lenalidomide after transplant, you actually can increase that hibernation period or that progression-free survival period, by 19 months compared to if you don't do the maintenance.

And so, when a disease is incurable, our goal is to give you the best therapy upfront and give you the longest time before it comes back, because it's actually going to give you the best quality of life too, and in your younger years.

Cindy Chmielewski: Okay. That was a great starting off point. Now, Dr. Cole, do you think you can start off with a brief overview about Revlimid. For example, what class of drug does it belong to? And what are some of the current indications?

What is Lenalidomide (Revlimid)?

Dr. Cole: I really do think that Revlimid is a drug of divine intervention. The reason I say that is, the drug came from, originally from thalidomide (Thalomid). Thalidomide was a sedative, hypnotic that was used to treat patients with PTSD after World War II, because it was a non-addictive sedative. That then bled it over to being used for nausea associated with pregnancy. And that actually led to, of course, terrible birth defects that were seen in the '60s.

But also, there was a small paper that was written in 1965, where they gave a bunch of patients with different types of cancer, including with myeloma, thalidomide. And actually, those two myeloma patients in 1965, actually clinically had an improvement of their disease with thalidomide. And, when thalidomide was given to refractory myeloma patients in 1997, it had a dramatic effect as compared to chemotherapy. That drug was then refined to Revlimid, and then further into pomalidomide (Pomalyst).

And so, the drug name is the immunomodulatory drugs, and that's a fraction of what it does. An immunomodulator, it uses the immune system to fight the myeloma, but also it affects multiple points of growth, proliferation, adhesion... inside the myeloma cell, to kill it. And the thing is, that thalidomide was never designed to do that. It was not known to do that, and somehow that drug found its way to myeloma, which then somehow, found its way into creating pomalidomide, which really changed the landscape of myeloma.

Cindy Chmielewski: And now we have had a little bit about the science background, the mechanism of action... On this program we're going to be talking a little bit about drug resistance. So Dr. Fonseca, can you define what it means to be resistant to a drug?

What Does it Mean to Become Resistant to a Drug?

Dr. Fonseca: First of all, when we talk about drug resistance, we're talking about the phenomena. And most of the time we're talking about the clinic, where a patient gets a medication and, for whatever reason, the cancer still seems not to respond to that. So the cancer grows or, in the case of myeloma, we see an increase in the proteins that we detect in the serum.

Now, understanding why someone becomes resistant is of paramount importance, as we develop clinical trials, and as we do what we call translational research. People ask the question, "Okay. Well, if you look at the protein, does it happen that over time, that protein evolves and develops some mutations that will make it resistant to the effect of the Revlimid?” Maybe the binding is not there and that's going to be something that, clinically, we will tell patients it seems not to work, and maybe that there is a mutation in the protein.

It turns out that this happens, but it is not very common. There is a recent publication that looked at a very large number of cases, and they did a very deep and detailed genomic analysis. And when you look at numbers, not even half of patients have mutations. So the question then, Okay, that's not what's happening. What are some of the other factors? And some of the other factors are still being elucidated. Our group and others are working to try to understand how that works out, but at the end of the day, what we would love to see is, can you, in advance know, who is likely to respond or not to the medications we're going to give? And of course, Revlimid would not be an exception because, as it stands right now, when we talk to patients about the treatments, we start saying, “We'll start this. It has X-percentage of likelihood of being helpful, but we really don't know until we test that out a month later."

And we need to get better. We need to find ways that we can predict, in advance, who's likely to benefit and not. And as you heard from Dr. Cole, Revlimid and similar drugs are such an important backbone for what we do, for the treatment for myeloma. Not only upfront, but also when the disease comes back. Having that information will become critically important.

Cindy Chmielewski: That's great. And is that information that you have upfront to determine... are they called biomarkers? Is that what you're trying to find?

Dr. Fonseca: Yeah, that's a word we use. Biomarkers, that would allow us to make those predictions. There are multiple ways, but there is not a commonly accepted way, by which I could meet with someone and tell them, you're likely to respond or not. And we do that on a research basis. We do that at our center. We do mutation analysis for cereblon, and the related proteins... neighborhood. We can test functionally, so we can test the cells against exposing them to drugs like Revlimid, and there's a number of assays we do for that. But it's still something that it is in the research world. It's not something that has been validated, or in any way approved, for use in the clinical setting.

Cindy Chmielewski: So now, if I am a patient, how would I know if I'm becoming resistant to Revlimid or any particular drug? Is there a test that lets you know?

Dr. Cole: That's an excellent question. I talk to my patients upfront. When I sit down with a new patient, I make sure to tell them that, when you have myeloma, the one thing about myeloma that is different from a lot of other cancers, is that there is a blood test, usually, we can follow. That the M protein is the protein, the anti-body that is secreted by the myeloma cells.

And when we do a bone marrow biopsy, we count the number of plasma cells, and then we equate the number of to the M protein. And then we know that, that M protein is where the disease is. And we do a scan, like a bone x-ray or a PET scan, to get an idea of how much disease is there? And what does that protein mean?

 And then, as we begin therapy, we see the protein decrease, and it goes down. If there's a 50% reduction, we call that a partial remission. If it's 90%, a very good partial remission, and a complete remission is when it disappears.

Once it disappears, now we know that if it begins to go up... what we call a biochemical relapse, that there's some activity of the disease. And if it goes up by 0.5 or 25%, then we say, “Gosh, something's happening to the disease.” And someone's becoming resistant to a drug, such as Revlimid, if they're on maintenance Revlimid.

Then the important this too, as you see that protein going up, is there anything else that is going on with the disease? Because usually, patients don't feel anything when the protein goes up. We then do more lab work. We may repeat the PET scan to see there are new bone lesions. And then, when the protein goes up, and we see, yes, it's seriously going up, and confirmed. Then, we may change therapy at that time.

So usually, people don't feel any different when they're becoming resistant to Revlimid. It's usually the laboratory studies. You see that protein going up, either the light chains or the M protein, and then we would act then.

Cindy Chmielewski: Okay. So, when we're relapsing, that's becoming resistant to a drug, it seems.

Dr. Cole: Yes.

Cindy Chmielewski: Okay. And Dr. Fonseca, we mentioned before that Revlimid is in the IMiD class of drugs. So drugs such as thalidomide and Pomalyst are in that class too. So if I become resistant to Revlimid, would that make me resistant to thalidomide and Pomalyst? Or should I try those drugs to see if they're successful?

If I Become Resistant to Lenalidomide (Revlimid), Would I Also Be Resistant to Thalidomide and Pomalidomide?

Dr. Fonseca: A lot to unpack from that question but let me just try to put it as simple as possible. In general, if you are resistant to a drug, in a class of drugs, it's a higher likelihood that you will be also resistant to similar drugs.

However, we know that patients who have failed historically... and we knew more about this in the thalidomide era, who were progressing after thalidomide can sometimes show a response with Revlimid, and the same is true in patients who were becoming refractory to Revlimid might respond to pomalidomide. However, if you take 100 patients who have been exposed to Revlimid, and 100 patients who have not, and you were to start treatment with the next drug, pomalidomide. Much more likely, that those who have not been exposed, will have a good response to that treatment. So, it can be tried, and it depends on the specific situation. It is very hard to make a blanket statement, for all patients in that regard.

Now, there's a couple of aspects here that are very important. First of all, based on the comments that I made about the mutation, it is not clear to me that resistance to any one of these drugs is binomial or black and white. On and off. There might be degrees of resistance with it comes down to the IMiDs.

So sometimes a drug that achieves a certain amount of pressure on those cells... it's trying to make them die... may not be enough. And then, the next drug might be able to do that. So that's what we see when pomalidomide, for instance, helps with Revlimid.

Second, this is a critically important question when we started talking for patients who have been on chronic low doses or Revlimid in the form of maintenance. In 2020, it's pretty well accepted now that maintenance therapy is the standard of care. And there are reasons why a patient may not get it, but it should be offered to all patients.

But then you asked a question. When someone is on a low dose for a prolonged period of time, what is the likelihood that, if you increase the dose or if you switch to the next class of drug, that patient will now respond? That is one of the most important questions we have to address, in the short term, in the myeloma community. Because knowing the answer to that, will allow us to select the next line of treatment better. Because right now, we're putting pieces of information, from different studies, and getting them together, but we don't know as of yet what the likelihood is that someone becomes resistant, or is resistant in a detailed way, after maintenance therapy. So that's something we need to work on, from myeloma community perspective.

Cindy Chmielewski: Dr. Cole, it looks like I am becoming resistant to Revlimid. Is there a possibility if I was on five milligrams of Revlimid a day, that if I increased that dose to 10 or the full dose of 25, I might start seeing a response? Or how about, if I add steroids to the Revlimid? Would that help? Are there ways that, maybe that resistance isn't completely gone?

Dr. Cole: So, you can. The one point that's important to make is how heterogeneous the myeloma population is? That this is not a disease that is the same in everyone, and the biology of myeloma is very different from person to person.

Usually when people are on the low doses of Revlimid, like 5, 10 milligrams every 21 days... Yes, increasing the dose can retard that relapse. It can retard the protein a little bit. Adding the dexamethasone, which alone was, decades ago, was one of the treatments for relapsed myeloma... it'll retard that a little bit and then, it might bring it down briefly. But eventually, because the cells have already been exposed to Revlimid, both high dose remotely, before transplant, and then load doses for frequently years as maintenance... they've already figured out a way around the Revlimid.

Increasing the dose, does engage some of those other mechanisms of action, but it's not going to last very long. The dexamethasone may help a little bit, but definitely compared to all of the new therapies that we have, just changing that drug around, compared to all the new things that we happen to have incredible response rates. We usually change drugs, and sometimes we'll increase as dose as a bridge to, then, move onto better therapies.

Cindy Chmielewski: Okay. Makes a lot of sense. Dr. Fonseca, talking about some of the new drugs... If I do become resistant to Revlimid, what are some of the other drugs that are available for those relapse refractory patients?

What Drugs Are Available for Relapsed or Refractory Myeloma Patients?

Dr. Fonseca: When you look at all the clinical trials that have been published, on combinations of monoclonal antibodies plus, say the Revlimids and the Pomalysts, it's worth noting that many of those trials have been done globally, oftentimes in patients that don't have prior exposure to these drugs. So how those results will translate to a population in the United States, we don't know as of now.    

Now then, you would say, well, let's say we had a magic wand and I could tell you, from the get go, who's refractory to something like the Revlimids. What would you do? Well, there's a number of options. One is, there's a number of trials now that are looking at the combination of monoclonal antibodies and proteasome inhibitors. You know, for instance, with carfilzomib (Kyprolis), and not use what we call, those drugs, the IMiDs. So that's one.

Now, one of the very interesting aspects of drugs like Revlimid is that it's oral, and while certainly, patients will sometimes need to get injections, subcutaneous injections or infusions for some of the other medications, that helped a lot, and helped to transition to maintenance down the line.

Another oral drug that will come down the line, and needs to be explored more in this population, will be selinexor (Xpovio). We also have conjugated antibodies now. We just had recently, the approval of an antibody that is conjugated with a toxin. It's kind of like a Trojan horse. It's called belantamab mafodotin-blmf (Blenrep) and has a good degree of activity.

And lastly, we will have a whole array of immunotherapies, different from the standard monoclonal antibodies, in the form of CAR T-cells and bispecific antibodies. So, we'll need to see all of that lines up, for that patient that is coming off of maintenance. And if we could know which of those patients are refractory to a drug like Revlimid, what would be the proper next step?

Cindy Chmielewski: So we have great news to be hopeful. If we become resistant to Revlimid, there are lots of other things that we could try. One of the audience questions we have Dr. Fonseca is, “Are there factors that are related to dosage or scheduling that can make a person more or less resistant?” For example, they were thinking about maybe skipping a dose, or varying the schedule, or maybe taking a break and then coming back on it?

Dr. Fonseca: First of all, there's an ideal world, what we see in textbooks. And then the real world, what happens in the clinic. In the ideal world, I will tell you that, using lower doses of medications, in general, increases the risk that one would develop resistance. In fact, for those of us who do experiments in the laboratory, if you use tiny doses, almost like homeopathic doses of medications, you can almost always induce resistance in Petri dishes, when we use things like cell lines. So, it just stands to reason... and we know this is something that happens in nature, the lower the dose, the more likely one is to have some emergence of resistance.

Now, there is the real world too, as well. In the real world, if you start giving higher doses, then you start running into problems too, as well. With people developing low blood counts... I see that in some of the questions. Or having more difficulty tolerating the drugs. Sometimes patients just cannot complete a full cycle. Sometimes the fatigue or some of the other side effects are just too much for a person. And people like Dr. Cole and myself, trying to find a happy in between where we go, well maybe, we apply a little bit of the art of medicine, if you may. We might say we're going to use it every other day, or we're going to do two weeks out of the four. And people should know, there are no scientific studies that will ever cover, every single one of the possibilities, but we prefer patients to stay on treatment if we can. 

Now what I would say... What I would not advise is, using a few doses here, then stopping for some time, and then assuming, “Ah, I will restart it once the disease comes back.” In general, you have to keep some pressure. I know that's very non-descriptive. It's very subjective, but you have to keep some pressure on those cells to try to avoid that resistance.

Cindy Chmielewski: Okay. Dr. Cole, anything you would like to add?

Dr. Cole: Yeah. I tell my patients that it's like taking an airplane to the next big city versus taking an airplane across the country. So I am six foot, five. And when I get in an airplane, I'm taking a one hour flight. I can tolerate quite a bit of discomfort. I can be put in the middle seat and feel... because I know this flight is going to end. That's like induction therapy. It's uncomfortable but you know that there's an endpoint.

Maintenance therapy is like taking a cross country trip, in an airplane. Because then, I want to make sure my seat is comfortable. I want to make sure I have my headphones. I want to make sure that I have my little snacks. And so, when we're looking at doing maintenance therapy, we really try to make that... because that's a long flight. We try to make that as comfortable as possible.

So, we go over all of the little things that would make that flight uncomfortable. One is diarrhea. That diarrhea can occur when people are on low doses of Revlimid as maintenance therapy. So, we a conversation, “Here's what we're going to do if there's diarrhea.” That we may hold the drug for a brief amount of time. That we may use some antidiarrheals, and that we may use cholestyramine, which has been found to be very effective in treating the diarrhea associated with Revlimid. So we some come up with game plans, of all the things that could interrupt what's going to happen, to try and make that flight as comfortable as possible.

And we also work on dosing. We may have a dose wax and wane. Just as Dr. Fonseca said, we try not to stop it for long periods of time. We really stress compliance of it, but we try to find that sweet spot where the best dose for that patient that will, again, maintain the pressure on the disease, so it takes much longer to come back.

Cindy Chmielewski: Right. So it seems to me, there is no one size fits all. And it's so important to be seeing a myeloma specialist so you can almost get this precision treatment, based on how your disease is responding, and what side effects you're experiencing. Yeah. There's a lot. There's no one answer to many of these questions. Okay, so as we wrap up. Do you have any parting thoughts Dr. Fonseca?

What Should Patients Know About Advances in Multiple Myeloma Treatment and Research?

Dr. Fonseca: My parting thought would be a commitment to... and we are highly engaged in that research that, hopefully, could give us that answer into the future, of determining who's really in a situation that they would be refractory. And that we could do two things. One is that we could select different therapy, if that's the case. But number two, if you know where your pipes are clogged, so to speak, then you might be able to find workarounds. And if there are other ways by which we can achieve the same response as we get with the Revlimids, overcoming some of these mechanisms of resistance, that would make me very happy. So you have a commitment from us to continue working on that particular topic.

Cindy Chmielewski: Thank you so much for spending time with us and enjoy your newborn little girl.

Dr. Fonseca: Thank you.

Cindy Chmielewski: And Dr. Cole, your parting thoughts? Anything?

Dr. Cole: The one thing is that it's an incredibly exciting time. And really, I forgot to mention that, when people are resistant to Revlimid, the first thought is clinical trials. That where we are going, and where we have been, is standing on the shoulders and brains of patients that have done incredible work, by helping us discover and work towards a cure for this disease. And so, every time when we see a patient who is resistant to Revlimid, the first thing we say is, clinical trials. What clinical trial do we have available for you? Because, not only is that becoming the best care that is available, but it's pushing the needle forward for everyone, for us to get to the cure of this disease.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.


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