Tag Archive for: refractory

Understanding CLL Treatment Classes

Understanding CLL Treatment Classes from Patient Empowerment Network on Vimeo.

Chronic lymphocytic leukemia (CLL) expert Dr. Seema Bhat explains the different treatment classes available for CLL patients and how the standard of care has evolved.

Dr. Seema Bhat is a hematologist at The Ohio State University Comprehensive Cancer Center – The James. Learn more about Dr. Bhat here.

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Transcript:

Katherine Banwell:

Dr. Bhat, when it’s time to start therapy, what types of treatments are available for CLL patients? 

Dr. Bhat:

So, when we think about treatment for cancer, we think about chemotherapy – the conventional chemotherapy that’s associated with side effects like hair loss, nausea, or vomiting. I’m very happy to say that conventional chemotherapy is no longer the standard of care for patients with CLL. Patients who need treatment for CLL are nowadays treated with what are called, “targeted agents.” 

And we have, in general, two different classes of targeted agents that have been approved for treatment for CLL. We have the BTK inhibitors, Bruton’s tyrosine kinase inhibitors, of which we have three. We have ibrutinib, we have acalabrutinib, and we have zanubrutinib. Then we have BCL-2 inhibitors, of which we currently have one approved, of which is called venetoclax. These treatments can be combined with monoclonal antibodies, which are directed towards the antigen called CD20. For example, rituximab or obinutuzumab. 

Typically, venetoclax is combined with monoclonal antibody as a time-limited therapy. BTK inhibitors usually are not combined with monoclonal antibody. 

Katherine:

What about stem cell transplant, does that fit in there? 

Dr. Bhat:

So, stem cell transplant still has a role for treatment of patients with CLL, but it has moved down the line with such highly effective and well-tolerated oral agents available. 

But, for refractory patients – what we call dual-refractory patients, we definitely are, especially in high – patients who have higher risk features, we do refer them to stem cell transplant. 

Katherine:

And what is a dual-refractory patient, exactly? 

Dr. Bhat:

Dual-refractory patients mean patients who have had a BTK inhibitor, be it ibrutinib, acalabrutinib, or zanubrutinib, and the disease has progressed on that. And then we give them venetoclax, which is a BCL-2 inhibitor. So, these are the two classes of targeted agents that we have available. If they have received ibrutinib, acalabrutinib, or zanubrutinib, and after that, a venetoclax, or venetoclax followed by a BTK inhibitor, and the disease has progressed on both. These patients are called dual-refractory, and currently they tend to be very resistant to whatever treatments we have available. And we looked at other modalities of treatment, be it clinical trials or stem cell transplants for that.  

Expert Advice for Navigating Myeloma Treatment and Care Decisions

Expert Advice for Navigating Myeloma Treatment and Care Decisions from Patient Empowerment Network on Vimeo.

Myeloma experts Dr. Irene Ghobrial, Dr. Omar Nadeem, and Dr. Betsy O’Donnell, review essential testing that may impact the prognosis, care, and treatment options for patients with myeloma. The experts also discuss additional factors that are taken into consideration when choosing a therapy and share updates on new and developing myeloma research.

Dr. Irene Ghobrial is Director of the Clinical Investigator Research Program at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. Learn more about Dr. Ghobrial.

Dr. Omar Nadeem is the Clinical Director of the Myeloma Immune Effector Cell Therapy Program and Associate Director of the Multiple Myeloma Clinical Research Program at the Dana-Farber Cancer Institute. Learn more about Dr. Nadeem.

Dr. Betsy O’Donnell is Assistant Professor of Medicine at the Dana-Farber Cancer Institute specializing in Plasma Cell Disorders.

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Transcript:

Katherine Banwell: Hello and welcome. I’m Katherine Banwell, your host for today’s program. Today we’re going to hear perspectives from three myeloma experts on how to access personalized care for your myeloma. Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you.  

Well, let’s meet today’s guests. I’ll start with Dr. Irene Ghobrial. Dr. Ghobrial, welcome. Would you please introduce yourself? 

Dr. Irene Ghobrial:

Absolutely, and thank you for having us. My name is Irene Ghobrial. I am a professor of medicine at Dana-Farber Cancer Institute in Boston.  

Katherine Banwell:

Thank you. Also with us today is Dr. Omar Nadeem. Thank you for being with us. Would you introduce yourself? 

Dr. Omar Nadeem:

Hi, everyone. Thank you for having me. My name is Omar Nadeem. I’m an instructor in medicine at Harvard Medical School and I work with the faculty at Dana-Farber myeloma program. 

Katherine Banwell:

Okay, lovely, thank you. And last but not least is Dr. Betsy O’Donnell. Thank you for joining us today. Would you introduce yourself to the audience? 

Dr. Betsy O’Donnell:

Sure, and thank you for having us this morning. My name is Betsy O’Donnell. I’m an assistant professor of medicine at the Dana-Farber Cancer Institute specializing in plasma cell disorders. 

Katherine Banwell:

All right. Thank you to all of you for taking the time out of your schedule to join us today. Before we delve into our discussion, let’s start with understanding the types of myeloma. Dr. Ghobrial, what is MGUS? 

Dr. Irene Ghobrial:

So MGUS, or monoclonal gammopathy of undetermined significance, is a precursor or the stage before myeloma happens, and it’s actually a very common disease or entity in many, many of us as we get older. In fact, maybe 5 percent of the population over the age of 50 would have this early MGUS. 

It doesn’t mean that it’s cancer. It’s a precursor to cancer, and we can talk more about it as we go on. 

Katherine Banwell:

All right. Is it the same as smoldering myeloma, or is that something different? 

Dr. Irene Ghobrial:

It’s not. It’s an earlier stage than smoldering myeloma, and it’s hard to actually make the right definitions. But currently what we say is if you have more than 10 percent cancer cells or plasma cells in your bone marrow, then it’s smoldering myeloma. And by the name, smoldering, it’s almost myeloma. It’s ready to go on fire, but it’s not there yet.  

MGUS is before that, and the difference is that the chance of progression from MGUS to myeloma is only 1 percent per year, so many, many people will never progress to myeloma. While smoldering myeloma, just because there are more cancer cells in the bone marrow, has a higher chance of progressing, which is 10 percent per year. And in some people, a very high chance of progression of 50 percent in two years. 

And we want to make sure that we catch those cases early and not wait for myeloma to happen. 

Katherine Banwell:

How would you define myeloma? 

Dr. Irene Ghobrial:

So, myeloma is currently defined as the same thing. The number of plasma cells in the bone marrow could be above 10 percent or more, or you have a protein in the blood. But the problem is that you’ve already had problems. You’ve had symptoms of end organ damage, so we have either high calcium, bone lesions, or bone fractures, anemia, kidney failure.  

And then now or more recently, we added a few more things to tell us these people are going to really develop myeloma soon. So, it used to be part of smoldering myeloma, now it’s part of the definition of myeloma, so that we can treat patients earlier, which is if your light chain level is very high, above 100 for a ratio, or if you have multiple lesions by something called an MRI or a PET CT scan instead of the traditional X-rays, or if your bone marrow has a lot of the plasma cells, more than 60 percent. 

And these were new definitions to make sure we don’t wait too much until people have an organ damage or symptoms and then we treat them. And you’ll hear from us that we think we should be treating people even earlier than that.  

Katherine Banwell:

Well, thank you for that. That’s very helpful. Dr. O’Donnell, let’s move on to testing. What tests are necessary to help understand a patient’s specific disease? 

Dr. Betsy O’Donnell:

Absolutely. So, testing really does depend a little bit on the stage at which your disease is found. In general, we use a very specific blood test that lets us know that there is clonal protein present. Remember, plasma cells are a type of white blood cell, and they make something called antibodies. We use a test called a serum protein electrophoresis, which is a blood test – an SPEP, we call it – that can tell us the difference between normal, healthy antibody and clone that are made from the plasma cells that we see in MGUS, smoldering, and multiple myeloma. 

So, that’s a very important test, and sometimes your primary care doctor may notice that your total protein is elevated and send that test. 

Or there may be other things that tip them off. Perhaps the kidneys are not where they used to be. And so that test is sent, and that’s the first tip-off that someone might have a plasma cell disorder.  

Once we identify that there’s a plasma cell disorder, then that can set in place a workup, depending on the amount of clonal, monoclonal, M-protein that we see. So, sometimes that involves bone imaging. Historically that was a skeletal survey where we took lots of X-rays of your body. Now we have other tests we use. PET scans, CT scans, whole body MRIs. Sometimes it depends where you’re getting your treatment, and also it depends a little bit on your doctor’s degree of suspicion. 

Bone marrow biopsies are a procedure that we sometimes do. We use a thin, hollow needle to take out just a little piece of bone, about the size of an inchworm, and take some fluid with it. There’s actually fluid inside the bone marrow.  

And that can tell us, just as Dr. Ghobrial was defining the spectrum of plasma cell disorders, based on the percent of plasma cells, that can tell us where somebody belongs, which group they might belong in. So, we can use all of these tests to help give us a good sense of how much disease someone has and where in the spectrum or continuum a person is – MGUS, smoldering, or multiple myeloma. 

Katherine Banwell: Okay, great. Thank you. I’m assuming these tests can help with understanding the stage of a patient’s myeloma. So, Dr. Nadeem, how is myeloma staged? 

Dr. Omar Nadeem: Yes. So, myeloma is staged very differently than traditional cancers. Because this is a blood disease, we don’t really think about it like we may in other solid tumor cancers, where if it’s spread to multiple locations it’s four, etcetera. That doesn’t apply to multiple myeloma. It’s actually staged out of three stages, and uses your blood work for the most part, some blood tests, to help identify which stage you are. Historically, that has correlated with how you may do. 

However, now we are learning that it’s far more to this story than just the bloodwork. So, we’re now using our bone marrow test results, particularly a test called a FISH test, which looks at the mutations that are present in examinable plasma cells, and if you have presence of some of these high-risk markers, that can actually either upstage you or downstage you if you don’t.   

So, we’re now I think becoming a little bit smarter how we think about this disease. It’s not just based on some blood test. We’re actually looking at the biology of some of these cells and the amount in the bone marrow. A lot of times patients ask, well, if I have 50 percent, 60 percent, or 80 percent involvement of the bone marrow, that actually does not have anything to do with staging, right? So, I think it’s important to know that it’s actually a very unique staging system in multiple myeloma. 

Katherine Banwell:

Okay. Dr. O’Donnell, the landscape of myeloma has changed significantly in recent years. How have advances in testing changed care from myeloma patients? 

Dr. Betsy O’Donnell:

So, I mean, the landscape has changed incredibly just in terms of the treatments we have, and I think that Dr. Nadeem was talking about something really important.  

In that when we look at FISH, which allows us to know the biology a little bit more, sometimes it helps us to decide kind of the risk that a patient is. We aren’t really at the point now where we do truly tailored therapies, like you see in some cancers, where we can detect specific mutations and pick drugs that align with that, but there are some that we do use. An example would be a drug called venetoclax (Venclexta), which works very well in patients who have a specific translocation, 11;14.  

So, there is some degree in which we use that FISH and those cytogenetics to help define our treatments, but also really we’re just fortunate that we have new and evolving therapies. We’ve changed how we treat myeloma in the up-front setting, and then at the back end we have an exploding field of immunotherapies, CAR-T cells, bispecific antibody that we’re now using that really have tremendously benefited our patients.  

Katherine Banwell:

Dr. O’Donnell, should all patients undergo in-depth testing, like cytogenetics?  

Dr. Betsy O’Donnell:

Yes, so if you’re doing a bone marrow biopsy, absolutely. The question in terms of who needs bone marrow biopsies, if someone has a low risk MGUS, those patients don’t necessarily require a bone marrow biopsy. It’s an invasive procedure, it’s an uncomfortable procedure. But if we’re doing a workup for multiple myeloma or smoldering myeloma that includes a bone marrow biopsy, then absolutely. 

Katherine Banwell:

Okay. Dr. Nadeem, what are you looking for with cytogenetics, and how might test results affect prognosis and treatment? 

Dr. Omar Nadeem:

Yes, so as mentioned earlier, there are some mutations that are considered high risk, I will say with the caveat that we don’t fully understand every single mutation yet or have identified every single mutation yet that may be high risk or low risk.   

But there are roughly five that we have identified that if a patient has one or two or several of those abnormalities, then their disease may behave a little bit more aggressively or may not respond as well to treatment. 

However, I think myeloma is just very complicated, so we look at a lot of these results in the beginning, both whether they may be good or bad. But I think, ultimately, we have to see how patients do, and that by far is the most important prognostic factor, in my opinion. So, if we look at some of these tools, including staging, some of the bone marrow results and cytogenetics, and try to give some prediction in terms of what we may see from this person’s disease, but ultimately the treatments that are so effective now really dictate the course for the majority of the patients. 

Katherine Banwell:

Are there specific tests that patients should ask for that could impact their care decisions? 

Dr. Omar Nadeem:

Yes, I think it depends on where they are in their disease state. So, if we’re looking at whether a patient has a precursor or plasma cell disorder or multiple myeloma, then they need all the testing to help us figure that out. 

So, that includes a bone marrow biopsy, the FISH testing as we just talked about. Advanced imaging like a PET scan or an MRI is now critical to identify patients that may have multiple myeloma versus those that have a precursor condition. So, we used to count on X-rays, as Dr. O’Donnell mentioned, but now really we do prefer one of those advanced imaging techniques for patients to undergo so that we can know. 

So, I think if they have basically those tests completed, that gives us most of the information that we need. 

Katherine Banwell:

Okay. Thank you for that. Let’s go back to asymptomatic myeloma for a moment. Dr. Ghobrial, how are people with MGUS monitored? 

Dr. Irene Ghobrial:

Yes, so how do we even diagnose them, right? It’s a big question because it’s incidentally found. Someone will go to their primary care doctor and have a little bit of a high protein or slight anemia, and it may not be related, and then their doctor will check for serum protein electrophoresis, and that’s pure luck. We want to take away luck from this equation. We want to take away chance from this equation. 

And we want to start screening people who are at risk, and we are doing that with the PROMISE study.  

It’s online available to everyone nationwide, international now, where you can sign up on promisestudy.org and try to ask the question that we do for you research level, the serum protein electrophoresis, and a new test called mass spectrometry that is much more sensitive than SPEP to find it. 

Now, once we find MGUS, we want to know what is my own personal risk of progressing to myeloma? Because I could be 30 years old with MGUS, and likely I will progress to myeloma in the next 10 years, 20 years, and by the time I’m age 60, I would have been diagnosed with myeloma. Just a true case in many, many people. If people are diagnosed today with myeloma, they are going to their doctor because they had back pain or anemia, and they are diagnosed with myeloma. In almost all of the cases, they would have had MGUS and smoldering, but they didn’t know about it three years ago, four years ago because they never got tested  
for it. 

Katherine Banwell:

Right.  

Dr. Irene Ghobrial:

So, we want to change that completely and become proactive rather than being reactive and waiting for symptoms to happen. Once you have MGUS or smoldering, because we don’t know, we start looking for all of the things to help us identify your risk of progression. So, we look at the height of your M-spike. Is it small or big? And then we in many cases say okay, maybe you need a bone marrow biopsy if your M-spike is a little bit on the higher side because we don’t want to miss smoldering myeloma, which will change the prognosis. 

And then we start looking at do you have anemia? Do you have kidney failure? Do you have any of the other things that may predict that you may be actually doing into myeloma? 

We also look at it more as a movie rather than as a snapshot, rather than a picture. If your M-spike is changing or your light chain is changing every three months, every six months, that’s an indicator that the cancer cells are doing something. They’re working in there and growing, and that’s why they’re increasing the M-spike and the light chain. 

And that evolving number is actually a very big predictor of telling us that there is a risk of progressing. Those are all clinical markers that we can do. When we look at the FISH, which we talked about, we can tell the certain markers are chromosomal changes that tell you that those cancer cells want to grow a little bit faster. So, 1q abnormality, 4;14, 14;16, 17p, all of those have been shown that when you have them, the cancer cells are not just sitting around and doing nothing. They’re actually starting to grow, and we want to catch them and understand what is the biology of the disease rather than just how many cancer cells you have. 

We do a lot of research level, and potentially now we’re going to give them back to the patients as clinical level, where we can give you more information about that prediction of your risk of progression. One of my colleagues calls it predicting the hurricane. We know that the hurricane will happen, and it’s a question of how precise could you be? We’re the Weather Channel men here.  

And we could be very precise and tell you it’s going to hit Miami at 2:00 in the afternoon tomorrow, and you could be prepared for it and get out of there. Or, you could be completely unprepared because we were not very accurate in our prediction and tell you it may hit the whole East Coast in the next two weeks. That’s not accuracy. So, we want to be more accurate in our prediction of myeloma because one person will never develop myeloma and can go have fun and enjoy life and not be worried and anxious about their risk, and another person we might say let’s watch you more carefully, or let’s think of interception preventing things. 

So, we do things called next-generation sequencing, taking all of those small numbers of cancer cells, even as little as single cells, and we can do whole genome sequencing and give back that information.  

We look at the immune cells and give back that information. We can do mass spectrometry. And with Betsy and Omar, we’re doing more and more tests so that when we have this prediction model, circulating tumor cells and so on, we can be more accurate in giving you that prediction. 

And help you make the next decision of are we watching carefully, are we preventing and intervening with behavior modification with other things? Are we intervening with therapy to intercept the disease? 

Katherine Banwell:

When are more in-depth tests necessary?  

Dr. Irene Ghobrial:

It depends, of course, on everything. I would probably say for every patient, it is a unique discussion. Some patients will tell me, “Let’s watch again in three to six months, and then I will do more testing,” and some patients want to know everything immediately. And we have those discussions with every patient, and we tailor our therapy as well as our diagnostics workup with every patient, depending on how much they want to know, how much their risk is, and how much they want to be involved in that discussion of how much to prevent myeloma. 

Katherine Banwell:

All right. Dr. Nadeem, as we begin our treatment discussion, would you define personalized medicine as it relates to myeloma care? 

Dr. Omar Nadeem:

Yes. I think we’re getting better and better at really having a personalized treatment plan for each individual patient with multiple myeloma. I think Dr. O’Donnell defined before, we are identifying some of the markers where we have targeted therapy for, and we hope with time we’ll discover more and more targets that can truly lead to personalized medicine for individual patients. 

Right now, though, we have a lot of approved therapies for multiple myeloma, and that list is getting longer and longer basically every month, it seems, nowadays. So, when we have so many tools in our toolkit, we then have to figure out, well, which strategy works for which patient? And the fact that we have effective therapies, we’re able to tailor how much of one particular therapy a patient may benefit from. So, some of the decisions that come into play is which medication should I combine for this patient which will lead to obviously disease eradication? 

And then also, how much do I need to intensify that treatment? Do we need to think about doing a stem cell transplant or not? Yes or no? 

There’s lot of pros and cons, right? So, it’s a very personalized decision that we have, looking at the disease factors, but also a lot of personal factors because transplant interrupts life, and then we have to make sure that that fits with that particular patient’s lifestyle. 

And then we talk about maintenance therapy. You know, that’s the therapy that is designed to kind of keep the disease away usually for many, many years for the majority of patients.  

But what does that look like, right? Does that include just pills? Is it going to be shots plus pills? Is it going to be a combination, etcetera? So, we have all the discussions at each phase of myeloma, and we discuss with them about what the pros and cons are and how that may fit into their particular lifestyle. 

Katherine Banwell:

Dr. O’Donnell, what factors do you consider when choosing a treatment approach? 

Dr. Betsy O’Donnell:

So, I think you’ve heard from all of us that we really try to have an individualized approach. When we’re talking about multiple myeloma, one of the main factors that I think about is really kind of the overall wellness of the patient. Historically we had different categories of transplant eligible, transplant ineligible. 

And so that can influence some of the decisions. Really it comes down to what is the person’s performance does? How well are they doing in their day-to-day life? And that really can dictate the intensity of the therapy. We know that age is just a number, it really is, so there are factors beyond that. What other medical problems do people have? What are the specifics of how well their kidneys are working? 

And so the biggest thing that we can work with is the dose. In fact, we’ve had work that shows that using lower doses from the get-go in older patients allows almost identical outcomes, but really gives patients a tailored dose to where they are at that juncture in their life.  

And so remember, myeloma is much more like a marathon, and so you have to set out at a pace that can be sustained. We treat people continuously. There’s an induction phase where we use a multiple drug combination, but beyond that, as Dr. Nadeem just said, they go on to maintenance, and that maintenance is indefinite. And so you have to set out at a pace or at a dose that you can sustain. 

Different medications have different toxicity profiles, so if someone had, let’s say, cardiac or heart issues, we might steer away from some medications that may exacerbate those. So, every decision is individualized. It’s based on who the patient is, where they are in their life, what other medical problems they have, and what we think they will do best with over time, not just in a short timeframe. 

Katherine Banwell:

Well, as we’ve been discussing, treatment choices vary for individual patients. Dr. Nadeem, what types of myeloma treatment classes are currently available?  

Dr. Omar Nadeem:

Yes. So, we started over three decades ago plus with just having basically steroid medications and some older chemotherapy drugs that weren’t very targeted at all, and that was basically all we had up until about a little over 20 years ago, where immunomodulatory drugs were first discovered to be effective in multiple myeloma, and that included thalidomide and now a commonly used agent called lenalidomide, or Revlimid.  

After that, we had a next class of medications approved called proteasome inhibitors that work differently than the immunomodulatory drugs, and then we combined all of these therapies about a decade plus ago and showed that that was better than anything else that we were doing before that. So, combining the steroids with the immunomodulatory drugs and proteasome inhibitors became the standard of care. 

And then we had the next class of drugs approved in 2015 called monoclonal antibodies, and that’s the first time we have monoclonal antibodies approved for myeloma, and it first started in patients that had relapse myeloma, and then they made it all the way up to front line therapy with a drug in particular called daratumumab.  

And now what we’re going is entering an era of combining all four of these therapies, just like we did 10 years ago with three drugs, and showing that combining four drugs is actually better than three. And the important thing there is that it’s not necessarily adding cumulative toxicity. These are targeted therapies; they all work differently but they all work really well together. So, now combining these agents has allowed us to really treat the disease effectively and allow for patients to tolerate the therapies.  

And then over the last couple of years, we’ve now entered kind of the next renaissance in myeloma where you have immunotherapies, and these are sort of true immunotherapies, in some cases taking the patient’s own T cells and then genetically modifying them to recognize myeloma cells and putting them back into patients. This is called CAR T-cell therapy, and that’s now approved for patients with multiple myeloma.  

And that again, just like the previous drug, sits in patients that have – you know, at a space where patients have had multiple relapses. But we’re now studying that earlier and earlier, and that along with another class of drugs called bispecific antibodies that also use your T cells via a different mechanism. A lot of exciting things going on, and we keep adding to the available agents for this disease.  

Katherine Banwell:

As you say, so many exciting advances. Where do clinical trials fit into a patient’s treatment plan? 

Dr. Omar Nadeem:

Yes. So, clinical trials as a term, a lot of times patients have a lot of questions about what that means. There’s a lot of misconceptions, I would say.  

Sometimes patients think they will get either a placebo and they won’t get the adequate treatment, or that they may not get the right treatment, right, because they’re taking a chance going on a clinical trial. It’s actually the opposite. So, all the trials are really designed to improve upon what we already know works in a particular disease, right? So, when we think about trials let’s say in relapsed myeloma, where the patient has already had some of the approved therapies, we’re looking at the most promising new therapies that have shown efficacy either in the lab or first in human studies and then moving them through the different phases and studying them in more and more patients. 

And that’s how all these drugs get started, right? So, they all get started at that point and then make their way to earlier lines of therapy. 

Then you’re trying to answer different questions as part of clinical trials. So, which one of these therapies can I combine, for example. Which ones can I omit, which ones – so, they’re all sort of getting the standard therapy and getting something either added on top of it or removed, depending on what the question that we’re asking. 

And then in the world that we currently live in with precursor plasma cell disorders, as Dr. Ghobrial mentioned, we have lots of patients that are at high risk of developing multiple myeloma in their lifetime, and that could be in a few years to a decade. And a lot of these therapies are so effective, and we’re now trying to really study some of these rationally in that patient population, so that’s a very different clinical trial, for example, than what I described earlier.  

So, it really depends on what you’re trying to achieve and where you are in the phase of your disease. 

Katherine Banwell:

This next question is open to all of you. Are there therapies in development that are showing promise for patients with myeloma? Dr. O’Donnell, let’s start with you. 

Dr. Betsy O’Donnell:

Yes. So, I think we are so fortunate in multiple myeloma to have so much interest in our disease and so many great drugs developed. So, as Dr. Nadeem was discussing, CAR-T cells are an immunotherapy, the ones that are approved now, we actually are fortunate to have two CAR-T cells approved, target something very specific called B-cell maturation antigen.  

We’re now seeing the next generation where we’re looking at other targets on the same cancer cell, that plasma cell, so those are evolving. 

Same thing is true in the bispecific antibody space. Again, those target BCMA now, but we have newer bispecifics who look at alternate targets, and really what this does is it gives us different ways of approaching the cancer cell, particularly as you relapse through disease. 

Katherine Banwell:

Anybody else? Dr. Ghobrial, Dr. Nadeem? Anything to add about therapies available? 

Dr. Irene Ghobrial:

I would probably say we’re also getting into targeted therapies and more of personalized, so if you have an 11;14 translocation, venetoclax would be an amazing drug for that. And the more we can say my own personal myeloma, what’s the best treatment for me, that’s how we’re trying to do it. So, it may not be exactly precision medicine, but we’re getting closer and closer to precision medicine of my myeloma, my specific drugs. And even if people have a 17p deletion, then we would say let’s think of that immunotherapy.  

It is truly a renaissance for us, and we’re starting to get into trispecifics, into off-the-shelf CAR-T, into so many new things. Into two different antigens that are expressed for the CAR-Ts. I mean, we are really beginning the era of immunotherapy, and we’re excited to see how much we can go into that because it will completely change myeloma, and hopefully we will cure many patients. We think we have already amazing drugs. It’s a matter of when to use them and who is the right person for this right drug. 

Katherine Banwell:

Exactly, yes. Dr. Nadeem, many patients are on maintenance therapy following active treatment. So, how is a patient on maintenance therapy monitored? 

Dr. Omar Nadeem:

Yes, so, majority of the time just with bloodwork. We don’t necessarily need to do a lot of bone marrow biopsies and PET scans for a majority of patients that are on maintenance therapy unless we’re either worried about their blood markers or some symptoms. Generally speaking, any time – it depends on what maintenance therapy they’re on, of course. If they’re just on lenalidomide, which is the most commonly used maintenance therapy, a lot of times we check in with them every one to three months. 

Depending on how their disease status is and how they’ve been doing and whether there’s any side effects that we need to worry about. So, they still have to see their doctors, still have to get the bloodwork. Usually you can get away with having it done no more than once a month or so, unless they are on other medications along with Revlimid, where we then have to check in with them a little bit more frequently. 

And some of that changes, so patients can be on maintenance therapy for five plus years, and we get a very good sense of how they are doing and kind of how their disease is doing, and we can kind of be a moving target in terms of the frequency of the follow-ups. 

Katherine Banwell:

We know that relapse can happen. Dr. Ghobrial, how common is relapsed or refractory disease? 

Dr. Irene Ghobrial:

Yes, and fortunately, we do have amazing remissions. We have very long remissions. Many people are living 10 years, 15 years and longer, which as Dr. Nadeem said, was not something we knew about years ago. I trained 20 years ago as a fellow, and myeloma was a survival of three to five years.  

We’ve come a long way, but we want to change that even better. We want a cure. We want to tell a patient, “You are done. You’re cured,” and we will not stop until that happens. So, when people have a progression again or relapse, then we want to consider what is the next available option. What is the best option to give them yet one more long, long remission? We are failing sometimes, and that’s because the disease is so bad, the biology of the disease is so bad, and the drugs that we’re using may not be the best drugs for that patient. 

And that’s why we need to understand better the biology and pick the right drugs for the right patient up front as much as we can, and also think about earlier treatment. We were just saying we probably have amazing drugs, but we’re waiting way too long until people have almost metastatic disease, and then we treat them. Why not think of an earlier interception when the disease is less mutated, when you have less cancer cells, a better immune system, and use your best drugs then? And hopefully we will achieve cure in many of those patients.  

Katherine Banwell:

What testing takes place after a relapse? Is it different than what has happened before, the testing that was done before? 

Dr. Irene Ghobrial:

No, the same tests exactly. We sort of say it’s restaging. We check everything again – the bone marrow biopsy, the FISH, because you may now develop a 17p that was probably there, but the very, very small number of cells that you cannot detect, and now it grows because of something called chrono selection. The drugs kill the sensitive cells, but they don’t kill the bad cells, and that’s how we can get all of those changes and mutations.  

Katherine Banwell:

Okay. Dr. O’Donnell, is the process for choosing treatment different for a relapsed or refractory patient? 

Dr. Irene Ghobrial:

So, that’s a great question. Yes, it can be. I mean, again, it always depends on how the person is doing at that time. It also depends, there are certain drugs that may not be approved in the front lines, something like venetoclax. If a person has a specific translocation, this 11;14, that’s something that we would like it in a second-line setting, for example. 

Usually one of the big questions people ask is if you’re on a specific class of drugs, should you change classes? So, this example is if you’re on Revlimid, and you have evidence that your disease is progressing, should you change to a different type of drug? A proteasome inhibitor, monoclonal antibody? Should that include one of the same classes of drug, like pomalidomide (Pomalyst), which is the next generation? 

So, there are a lot of different factors that we consider. The number of drugs. So, you know, as Dr. Nadeem said, historically – there’s a lot of history in myeloma therapy, and it’s been an evolution, and so now we’ve had people who were treated with the three-drug combination that are starting, after many years, to progress. So, we might choose a monoclonal antibody for those patients because it wasn’t available at the time they were diagnosed. Versus patients now, who are typically on a four-drug regimen that includes those monoclonal antibodies and all the different classes of drugs. 

We’re looking at different and, if available, novel agents to put those patients on. And again, I think Dr. Nadeem made a really important point that I want to underscore, which is that very often our best therapies are available in clinical trials. And so when and if there is the opportunity to be on a clinical trial, you may be then able to get something that would not otherwise be available to you. So, I encourage people to always have an open mind to being on a clinical trial at any stage in their disease treatment. 

Katherine Banwell:

What therapies are available for relapse or refractory disease? Are they different than other therapies? 

Dr. Betsy O’Donnell:

You know, so that’s a great question. So, yes and no. I highlighted one example that might be a little bit different, but in general, we’re very fortunate that we have multiple classes of drugs, meaning we have different drugs that work differently to kill your myeloma cells. And as Dr. Nadeem said earlier, we use those in combinations to increase the effectiveness of those medicines. Within each class we have a variety of drugs. 

You used the example of immunomodulators, and show that we have three different of those type of drugs. We have two different proteasome inhibitors. Beyond that, we have other classes of drugs that were mentioned. We have monoclonal antibodies, immunotherapies.  

And so very often we make, it’s almost like a mix where we pick what we think is going to be most effective, sometimes based on cytogenetics. The biology. Sometimes based on patient selection. What are their other medical problems, what are their current issues? And we pick the combination that we feel is going to be most effective from the different classes of drugs that we have together, usually trying to use multiple drugs in combination. 

Katherine Banwell:

Well, what newer therapies are available or in development for refractory and relapse disease? 

Dr. Betsy O’Donnell:

So, I think that the greatest interest that I think we’re all most excited about is the immunotherapy space, and I think we’ve seen – for myeloma, we see that this is a relapsing and remitting disease. 

And what’s been so exciting about CAR-T cells and the bispecific antibodies is that in patients who have had, on average, five relapses, we’re seeing tremendous results. So, complete remissions or very good partial remissions that last. In fact, can last up to two years, on average, with one of our CAR T-cell products. 

So, this is really exciting, especially when you compare to what historically has been out there for patients who have had that many relapses. And just as Dr. Nadeem said, the way that drugs enter, they enter from the relapse refractory setting, ethically that’s what makes the most sense, and they march their way forward. And so that process is happening right now as we speak, and I think like Dr. Ghobrial talked about, is the importance in early disease of thinking about using these really exciting therapies in patients who have lower burdens of disease with a goal of cure. 

And so I think all of us on this call are committed to one thing, and that is curing multiple myeloma, and even the precursors that lead up to it so that patients never have to go through the process of years and years of therapy. And so I think we’re very excited about what immunotherapy might be able to offer as we move forward in myeloma treatment. 

Katherine Banwell:

Yes. Thank you for that, Dr. O’Donnell. Let’s take a few questions that we received from audience members prior to the program. Colin writes, “How is it determined as to which patients might be the best candidates for clinical trial CAR T-cell treatment?” Dr. Nadeem, we talked a few moments ago about CAR T-cell treatment. Would you like to answer this question? 

Dr. Omar Nadeem:

Sure, I’d be happy to. So, CAR T-cell therapy is already approved. It’s FDA-approved for patients that have had four or more prior lines of myeloma therapy. So, when we think about a patient coming to us for that particular treatment that have relapsed myeloma, we’re always looking to see how much of the previous therapy they had. 

Whether they meet the indication, the labeled indication for that particular product. And then now, as we’ve discussed today, we’re studying this CAR T-cell therapy in various different phases of myeloma. Earlier lines of therapy, even thinking about studying it in high-risk smoldering myeloma, right? And then kind of looking about how we can best study this therapy in so many different phases.  

So, it all depends on where a patient is in their disease state, and then we kind of look to see whether a commercial approved CAR-T product makes sense for them, or we think about one of our several relapse CAR T-cell trials that are looking at BCMA target, which is what the approved one is, but also looking at newer targets like GPRC5D that we’ve brought up before. 

So, it encompasses a lot of different things, that question, but I think in terms of the candidacy of the patient itself, we do know that these CAR T-cell therapies have some toxicity, so we have to then weigh in terms of what medical problems they have whether they’ll be able to tolerate what the majority of patients with CAR T-cell therapy get, which is this syndrome called cytokine release syndrome, where patients will get a fever. 

And in some cases have changes in their blood pressure or oxygen levels. We have to make sure that the patient’s body can handle that. I will say we’ve gotten better and better at managing a lot of toxicities as it comes to CAR T-cell therapy. When this was first approved, it was all pretty new, but now what we’re learning is if patients are developing a fever, which the majority do, we’re intervening earlier and earlier to prevent them from getting sicker. 

So, these are things we’ve learned now, and the majority of patients get through CAR T-cell therapy toxicity period much better than they did when it was first approved. 

Katherine Banwell:

Okay, thank you for that.   

Dr. O’Donnell, Alex wrote in with this question. “What is the difference between a complete response, VGPR, and PR as it applies to prognosis and maintenance after an autologous stem cell transplant?” And before you answer the question, would you define VGPR and PR for us?  

Dr. Betsy O’Donnell:

Sure. So, we have different criteria that help us understand how well a drug is working, and they’re uniformly used across clinical trials so that we’re all speaking the same language. And so we talk about a PR, a VGPR, and a CR. So, a CR is a complete response, which is 100 percent of that monoclonal protein that we initially detected is gone. We can’t measure it. Or if you have an elevated light chain, which is another piece of the protein, that has gone back down to normal.  

Taking that a step further, astringent CR is if we do a bone marrow biopsy and we can’t find any cancer plasma cells in there. A VGPR is where we see a 90 percent reduction in the amount of protein we can measure, and a PR is anything over – a partial response is anything over 50 percent. 

So, that’s a language we speak really just so that when we’re interpreting clinical trials, we all are using the same criteria. 

And so these are different terms that classify it. If the example that you gave, someone’s had a transplant, what would typically happen 100 days after that transplant is a patient would restart maintenance therapy. The classic maintenance is just lenalidomide, which is the pill that they were probably taking before that. And there’s a lot of controversy now but no good answers about changing therapy after a transplant, if you haven’t received a deep response. 

What we do know is that after a transplant, when someone goes on lenalidomide maintenance, they continue to respond. So, the greatest depth of response is not necessarily achieved in the induction phase or right immediately after transplant, but over time on maintenance. 

There’s another tool that we’re now using and incorporating, both in terms of how we assess treatment but also potentially in how we modify treatment, which is something called minimal residual disease, MRD, which goes a step beyond. When people have astringent CR, a CR, looking for really just traces of the disease on a molecular level.  

And all of those help us understand how well the patient has responded and how long that remission might last, but they’re not definitive in terms of how we should adjust treatment based on those right now. 

Katherine Banwell:

Okay. Thank you for that. Dr. Ghobrial, this is a question we’ve received from Carlene. “Many prominent doctors claim the COVID vaccines suppress the immune system. How can boosters be justified in an already immune deficient myeloma patient? 

Dr. Irene Ghobrial:

Yes, so we think that protecting yourself and preventing COVID infections is so essential and so important. 

Especially in a patient with myeloma and especially when you’re receiving therapy: daratumumab, bispecifics, CAR-T. We want to make sure everyone is protected from COVID infections, and they are real. They are serious, and they cause death in our patients. So, every step, not only getting the vaccine but also sometimes we give tixagevimab co-packaged with cilgavimab (Evusheld) to protect our patients and protect further problems and reinfection. 

Katherine Banwell:

Remind us, what that is, the Evusheld? 

Dr. Irene Ghobrial:

Oh. It’s an antibody to help us prevent the COVID infection, so as a prevention method rather than as a treatment method.  

The other thing that we think of is the immune system is already altered in myeloma. It’s even altered or changed even as early as MGUS and smoldering myeloma. So, when we’re walking around and thinking, “Oh, I have only a benign design of MGUS,” that’s not true. The immune system has already started to change as early as MGUS, and in many of us as we get older. 

So, we have to be more protective and we have to be more careful with our patients. But as we get to even myeloma, before we even treat it, before we use the drugs that kill plasma cells, good and bad plasma cells, which secrete antibodies that fight infections, we are already at risk for COVID infections. 

And then our drugs, unfortunately, don’t only kill the malignant or the bad plasma cells, they also have a small side effect of killing also your normal plasma cells, and these are the ones that make antibodies to fight infections. So, you are at risk and you have to be very protective and careful with yourself. 

Katherine Banwell:

Is there any research on predicting hereditary risk of myeloma? 

Dr. Irene Ghobrial:

Yes, so part of the PROMISE study is trying to understand what is the risk of developing myeloma. So, we’re recruiting people who are either African American because they have a three times higher chance of developing myeloma compared to the White population, as well as people who have a first degree family member with a plasma cell disorder.  

Or even any blood cancer because now we see that CLL and lymphoma and myeloma can actually come together. And we’re now doing something called whole genome sequencing of all of the DNA that you inherit from Mom or Dad called the germ line. Basically, we try to see did you inherit the gene from Mom or Dad that increases your risk to myeloma? 

Now, it’s not as high as something like BRCA1 mutation or 2 mutation, where if you have that, you’re high, high chance of developing breast cancer or ovarian cancer and so on. We probably have several factors that need to be put together. You inherit something and then the environment adds something, and then as we get older, we get the hit. 

Or you inherit something that changes your immune system, and that allows the plasma cells to start proliferating faster because they are reacting as an immune cell, and that allows the hit of myeloma to happen. And we’re working on that, and we would really encourage everyone who has a relative with myeloma, sign up on PROMISE study. 

Because that’s how we can get the answer. That’s how we can say it’s not because you are an African American or you’re White. It’s not because you have a first-degree family member or not. It’s because of this gene. So, taking away race, taking away all of those factors, taking away age and trying to go back to the biology. Is it a certain gene, is it the certain immune cell that makes us go to that risk? 

And then Dr. O’Donnell is really taking it to the next level. Now what is in the macro environment? So, we talked about what we inherit, but it’s like nurture and nature, right? So, nature is the genetics and then nurture, what do we eat? What do we change? Obesity, health, all of those things change our inflammation level and change our ability to basically prevent those myeloma cells from starting or from continuing to progress. And she can potentially talk about her work on microbiome, on the tiny bacteria that are in our body from what we eat. So, maybe, Betsy? 

Katherine Banwell:

Okay.  

Dr. Betsy O’Donnell:

Absolutely. Yes, so one of the things that particularly interests me is the effect of lifestyle on our risk of getting cancer. 

And specifically within plasma cell disorders, and I think there have been other cancers, breast cancer and colon cancer, where they’re a couple steps ahead of us just in understanding the influence of things like obesity and the gut microbiome. So, the specific bacteria that are within your intestinal tract. It makes a lot of sense in colon cancer, but we think that that’s not limited to diseases like that. We actually think that these microbiomes, which are influenced by the foods that you eat, may have a relationship with your immune system. And remember, myeloma is a cancer of the immune system. 

So, we’re all working together on our team here on a very scientific level to understand lifestyle influences and how they may cause or potentiate multiple myeloma. And so we’re excited to kind of bring this piece together. When you think about the spectrum of plasma cell disorders, not everybody goes on to myeloma, but a lot of people sit in these early precursor diseases, MGUS and early smoldering. 

And so are there things that people can do for themselves that might influence their gut microbiome, or if it’s the amount of body fat that we have that’s very involved in cell signaling? Can we modify those things, exercise more potentially, that will decrease our body inflammation levels or alter those pathways that have been set in process that, by altering them, may decrease the risk of going on to more advanced plasma cell disorders? 

Katherine Banwell:

That’s such great information. Thank you for answering that, and thank you all for your thoughtful responses to the questions.  

As we close out the program, I’d like to get a comment from each of you. As I mentioned at the start of the webinar, care for myeloma patients is becoming more personalized, and we’ve been talking about that throughout the program. What are you hopeful about the future of care for myeloma patients? Dr. Ghobrial, do you want to start? 

Dr. Irene Ghobrial:

I’m hopeful that we truly cure myeloma, and no one should ever develop end organ damage. 

We should identify it early and treat it early, and no one should ever come in being diagnosed with multiple myeloma. 

Katherine Banwell:

Okay. Dr. Nadeem? 

Dr. Omar Nadeem:

Yes, I think I definitely agree with what Irene said, and really having a more thoughtful approach to each individual myeloma patient. As I mentioned earlier, we have so many available therapies. I want to be able to know exactly which patients need which path in terms of treatment, and which ones we can maybe de-escalate therapy, right? So, thinking about which patients do well and maybe can get away with not being on continuous therapy, and those that absolutely need it. Identifying them better to give them the best therapy. 

Katherine Banwell:

Dr. O’Donnell, do you have anything to add? 

Dr. Betsy O’Donnell:

I think we all share a common goal, which is cure, and for those who we can’t cure yet, I think really working on making the experience as good as it possibly can be and focusing on the factors that we can control and optimizing those, both for patients and their caregivers who are in this journey together with the patient. 

Katherine Banwell:

Well, I’d like to extend my thanks to all of you for joining us today. 

Dr. Irene Ghobrial:

Thank you. 

Dr. Betsy O’Donnell:

Thank you for having us. 

Katherine Banwell:

And thank you to all of our partners. To learn more about myeloma and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks so much for joining us.  

 

The Benefits of Being Pro-Active in Your AML Care

The Benefits of Being Pro-Active in Your AML Care from Patient Empowerment Network on Vimeo.

Dr. Eytan Stein, an AML expert, discusses the importance of communicating regularly with your healthcare team and shares what makes him hopeful about the future of AML care.

Dr. Eytan Stein is a hematologist oncologist at Memorial Sloan Kettering Cancer Center and serves as Director of the Program for Drug Development in Leukemia in Division of Hematologic Malignancies. Learn more about Dr. Stein, here.

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Transcript:

Katherine Banwell:

Why is it essential for patients to share any issues they may be having with their healthcare team, specifically, sharing their symptoms and side effects?   

Dr. Eytan Stein:

Well, it’s important because we want to help you. I mean, I think that’s what it comes down to. All of us, whether it’s your doctor or your nurses or your nurse practitioner or physician’s assistant or anyone who is part of the healthcare system, we went into this business to help people. I mean, we knew what we were getting into when we went into this, and we want to help people. And one of the ways you help people is you help with their symptoms. So, if you’re not feeling well, you call up, and you say, “I’m not feeling well,” we can help you with that. You shouldn’t suffer in silence.  

I sometimes have patients who will say to me, “Oh, I was going to call you, but I didn’t want to bother you.” You’re not bothering us. This is what – it’s not like you’re calling and asking for mortgage advice, right? This is what we do. So, it’s very important to call us because the other thing is that you’re going to be more – it’s more likely that you’ll be able to complete your treatment if we manage the side effects that you’re having rather than just ignoring them.  

Katherine Banwell:

What advice do you have for patients to help them feel confident in speaking up and becoming a partner in their own care? 

Dr. Eytan Stein:

My advice is, speak up. You just speak up. It’s very important. It’s your – you know, at the end of the day, this is a disease that you are experiencing. Your doctor is there to partner with you and to guide you, but it’s your body. It’s your disease, and you need to be very vocal in what you’re experiencing and advocate for yourself.  

Katherine Banwell:

If a patient has difficulty voicing their questions or concerns, are there members of the support staff who could help?  

Dr. Eytan Stein:

Most centers have a social worker on staff that can help them out. I highly, highly encourage all of my patients to meet with a therapist or a psychologist that specializes in taking care of patients with cancer. I have become more vocal about this that I see really, it’s probably the best thing a patient can do for themselves, and there’s no downside. If you don’t like it, you don’t have to go back. You can do one appointment and not go back. But that can be extremely helpful, extremely helpful.  

So, it’s important in both ways. You need to alert your doctor that you might be feeling one way, but I think it’s also on the doctor to sort of take visual cues from the patient when they see them to understand what they might need and to make those kind of recommendations.  

Katherine Banwell:

Yeah. As we close out our conversation, Dr. Stein, I wanted to get your take on the future of AML. What makes you hopeful?  

Dr. Eytan Stein:

Oh, so many things make me hopeful. I mean, we understand this disease so much more than we understood it even 10 years ago. There are all sorts of new treatments that are being developed. We’re improving the survival of our patients with the new treatments that have already been approved over the past 10 years. And I really think the golden age of AML treatment is upon us, and I really think that – and some people might think I’m crazy – but I really think that by the time I’m done with this, you know, one day, I’ll get too old, and I’ll decide I need to go retire and spend time with my family. But I think by that time, we’re going to be curing the vast majority of our patients. 

Katherine Banwell:

That’s so positive. It’s great to hear that there’s been so much advancement and that there’s so much hope out there for AML patients.  

I want to thank you so much for taking the time to join us today, Dr. Stein.  

Dr. Eytan Stein:

Okay, thank you. It was really nice to be here.   

Disease Monitoring: Is My AML Treatment Working?

Disease Monitoring: Is My AML Treatment Working? from Patient Empowerment Network on Vimeo.

Dr. Eytan Stein explains how AML treatment effectiveness is monitored and why it’s essential for patients to report any symptoms or side effects to their healthcare team.

Dr. Eytan Stein is a hematologist oncologist at Memorial Sloan Kettering Cancer Center and serves as Director of the Program for Drug Development in Leukemia in Division of Hematologic Malignancies. Learn more about Dr. Stein, here.

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Transcript:

Katherine Banwell:

Once treatment has begun, Dr. Stein, how do you know if it’s working?  

Dr. Eytan Stein:

So, that’s a good question. So, the good thing about acute myeloid leukemia when it comes to understanding what’s going on, you know, it’s a disease of the bone marrow cells. And we do bone marrow biopsies to see how things are doing. But no one likes a bone marrow biopsy. It can be a somewhat uncomfortable procedure.  

Katherine Banwell:

How often would a patient need to have a biopsy? 

Dr. Eytan Stein:

Yeah, so they have bone marrow biopsies at diagnosis, and then they often will have bone marrow biopsies two weeks to a month later.  

And then, if they’re in remission, basically any time you think if you want to check to see if they’re in remission or if you suspect the patient is relapsing. Then, you would do a bone marrow biopsy. But what I was getting at is that but you have blood. And the blood is kind of like the bellwether of what’s going on in the bone marrow.  

So, the analogy I use for my patients is, you know, when you’re driving your car and you have – you know, you don’t open the hood every day to make sure the car is running okay. You know, you’re driving your car, and if your car starts making a funny clinking sound, that’s when you open the hood.  

So, the blood is like the clinking sound. If you see something going wrong in the blood, that’s when you know you’ve got to open the hood and look under the hood. If the car is running just fine and you don’t see anything wrong in the blood, using the analogy, maybe you don’t need to do a bone marrow biopsy. 

Katherine Banwell:

What if a treatment isn’t working? What if it stops working or if the patient relapses? What do you do then? 

Dr. Eytan Stein:

Yeah, so when a patient relapses, which unfortunately happens more than we want it to, it’s important number one to do another bone marrow biopsy and at that point, do that mutational testing again because the mutations that are present at the time of diagnosis are not necessarily going to be present at the time of relapse, and sometimes, a new mutation might occur at the time of relapse.  

And again, what that mutational profile shows can help determine what the next best treatment for the patient is. There might be standard-of-care therapies. More chemotherapy might be recommended.  

When a patient relapses, I usually – excuse me – try to get them on a clinical trial because that’s the point where I think clinical trial drugs really have potentially major benefit for the patients, to help get them back into remission. 

How Do Gene Mutations Affect AML Treatment Choices?

How Do Gene Mutations Affect AML Treatment Choices? from Patient Empowerment Network on Vimeo.

Dr. Eytan Stein shares why AML patients should undergo molecular testing when choosing a treatment approach, explaining how targeted therapy works to treat AML patients who have specific genetic mutations.

Dr. Eytan Stein is a hematologist oncologist at Memorial Sloan Kettering Cancer Center and serves as Director of the Program for Drug Development in Leukemia in Division of Hematologic Malignancies. Learn more about Dr. Stein, here.

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Transcript:

Katherine Banwell:

Why is identification of genetic markers essential before choosing treatment?  

Dr. Eytan Stein:

Because when you know the genetic markers, you can target the genetic abnormalities, sometimes with specific targeted therapies, with therapies that fit like a key in a specific lock.  

And those targeted therapies have been shown, in some cases, to improve the survival of the patients, without much cost, without much toxicity. So, I’ll give you an example of this.  

There is a very common genetic abnormality in patients with acute myeloid leukemia called the FLT3 or FLT3 mutation. When you have that mutation, there is a targeted therapy that targets the FLT3 mutation called midostaurin (Rydapt), and it’s been shown in a very large clinical trial that the addition of the targeted FLT3 inhibitor midostaurin in combination with chemotherapy leads to better overall survival than chemotherapy alone.  

So, you need to know that information because you want to give your patient the best chance at beating the disease. And that’s why it’s also important to try to get this information back quickly. You know, no one wants to be sitting around waiting for four weeks to find out if they’ve got a specific mutation. And we’ve gotten better. I think medical centers generally have gotten better at getting this mutational information back to their doctors relatively quickly. 

Katherine Banwell:

Does every patient get this standard testing? 

Dr. Eytan Stein:

It is – does everyone get it? I don’t know. But “Should everyone get it?” is, I think, the important question. Yes, everyone should get this testing.  

It is incorporated into the NCCN and National Comprehensive Cancer Network and European Leukemia Net guidelines. It is important not only because you can think about targeted therapies, but it is also important for prognostic reasons, meaning that certain mutations lead to a higher risk of relapse, and those mutations in a patient might lead me to recommend a stem cell transplant, which is sort of the most intensive thing we can do to help prevent a relapse, while other mutations, which might be “favorable”, in quotes, they might lead me not to recommend a stem cell transplant.  

So, I think this mutational testing is the standard of care and should be done in every patient with newly diagnosed acute myeloid leukemia.  

Considerations When Choosing an AML Treatment

Considerations When Choosing an AML Treatment from Patient Empowerment Network on Vimeo.

AML expert Dr. Eytan Stein reviews factors that should be considered when choosing an AML treatment approach, including potential side effects, age, and patient preference. 

Dr. Eytan Stein is a hematologist oncologist at Memorial Sloan Kettering Cancer Center and serves as Director of the Program for Drug Development in Leukemia in Division of Hematologic Malignancies. Learn more about Dr. Stein, here.

See More from Thrive AML

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Tips for Thriving With AML | Setting Treatment Goals

What Are Current and Emerging AML Treatment Approaches?

How Do Gene Mutations Affect AML Treatment Choices?


Transcript:

Katherine Banwell:

All patients are different, of course, and what might work for one person might not be appropriate for another. How do you choose which treatment is right for a patient? 

Dr. Eytan Stein:

So, it’s an individualized decision. So, what you’re talking to the patient, as we talked about at the very beginning, is you really need to understand the patient’s goals for treatment. You need to understand the anticipated benefit of the treatment that you’re offering and need to understand the side effects of the treatment. 

So, and that sort of becomes the puzzle that you work with the patient at putting together. That is how well do I expect this treatment to work? What are the potential side effects of the treatment, and what are the patient’s goals? And when you sort of lay all those different pieces out, you then usually come up with something that becomes pretty clear what the best thing to do is.  

So, I’ll give you just a very concrete example of this. Sometimes, we have treatments where the medical data would suggest that they might work as well as one another, right? There’s no clear difference between each of the two treatments. But maybe one of the two treatments requires you to be in the hospital, and one of the treatments allows you to be at home.  

So, that’s an important discussion to have with the patient because some patients, believe it or not, want to be in the hospital, because they’re worried about being at home and having to manage this all themselves. Some patients don’t want to be in the hospital. Some patients want to be at home, because they’re scared of the hospital, or they’re worried the food’s going to be terrible.  

And then, that would be important in helping the patient make the decision for their treatment. 

Katherine Banwell:

Right. You mentioned earlier, Dr. Stein, the difference in ages and how you would treat different people depending on their age. So, when you’re choosing a treatment, you obviously look at age. What else? Things like comorbidities? 

Dr. Eytan Stein:

Yeah, so age, so I’m not ageist. So, it’s more that as people get older – and this is just a fact of life – as everyone gets older, their organs don’t work quite as well anymore, right? Things start breaking down as you get older. So, certain treatments aren’t appropriate for older people because the treatments a younger person, because their organs are working at 100 percent, may be able to handle it, while an older person, where their organs might only be working at 60, 70 percent, the treatment might not be as good of a choice for them. 

So, that’s what I mean. So, as people age, their comorbidities increase. So, we always look at comorbidities, and if you had an 80-year-old that was running marathons, I might think about their treatment differently than an 80-year-old who is not running marathons. But most 80- and 85-year-olds aren’t running marathons, so that’s why we sometimes think about their treatment differently. 

What Are Current and Emerging AML Treatment Approaches?

What Are Current and Emerging AML Treatment Approaches? from Patient Empowerment Network on Vimeo.

AML Expert Dr. Eytan Stein provides an overview of current and emerging treatment approaches for people living with AML.

Dr. Eytan Stein is a hematologist oncologist at Memorial Sloan Kettering Cancer Center and serves as Director of the Program for Drug Development in Leukemia in Division of Hematologic Malignancies. Learn more about Dr. Stein, here.

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Transcript:

Katherine Banwell:

What are the treatment types available to AML patients? You mentioned chemotherapy. What else is there? 

Dr. Eytan Stein:

Yeah, so if I was having this discussion with you, even when I first started my career back in 2013, all I would’ve been talking to you about was induction chemotherapy and maybe a lower-dose chemotherapy called hypomethylating agents.  

I think one thing that really needs to be recognized is that the advances we’ve made for the treatment of acute myeloid leukemia, over the past 10 years, have been just remarkable. We’ve had a number up to nine drug approvals over the past 10 years, and those therapies fall into the following categories.  

We now have therapies outside the strong induction consolidation we talked about. We have therapies such as targeted therapies that target specific gene mutations that are present in patients with acute myeloid leukemia. Those are often oral therapies that patients can take at home. And we have very effective therapies for older patients who usually can’t handle the side effects of induction chemotherapy. That’s the combination of a type of drug called a hypomethylating agent with a very, very powerful targeted drug called a BCL-2 inhibitor.  

One of those drugs, that drug is called venetoclax. That’s the one that’s FDA-approved. And the combination of those hypomethylating agents and venetoclax, has really changed the paradigm for how we treat older patients with acute myeloid leukemia, led to many patients who have been able to live much longer than they would have before this therapy came about.  

You know, there are other therapies that are in development, but I don’t know if we’ll end up talking about that a little bit later. But there are therapies such as immunotherapy, which has gotten a lot of press for other kinds of cancers, like one cancer called the rectal cancer, that aren’t yet approved for acute myeloid leukemia but are being developed for acute myeloid leukemia.   

So, the future of acute – the current treatments for acute myeloid leukemia are dramatically better than they were 10 years ago, and I would anticipate that we’re going to continue to see these kind of advances over the next 10 years.  

Katherine Banwell:

What about stem cell transplant? Who might be right for that? Who might be eligible? 

Dr. Eytan Stein:

Yeah, so let’s go back to the discussion a little bit about consolidation chemotherapy. So, when you have a patient that gets induction chemotherapy or gets any therapy – it doesn’t have to be chemotherapy – to put their disease into remission, for a large group of patients, we think that the best way to cure their disease is to do something called a stem cell transplant.  

So, what’s a stem cell transplant? What it is not is like a heart transplant or a liver transplant, which patients often don’t realize.  

So, it’s not a procedure where an organ is being transplanted through a surgical procedure. What it is is it’s acknowledging that the cause of acute myeloid leukemia is that the most primitive cells in the bone marrow, called the stem cells, are the cause of the disease. And the chemotherapies that we give patients to get them into remission don’t always eradicate those bad stem cells.  

So, what we’re able to do once a patient is in remission is we try to get them new stem cells. How do you get a patient new stem cells? Well, you go to a donor, and there’s a donor bank of people who have volunteered to donate stem cells to patients with acute myeloid leukemia. You go to the donor bank, and then you give chemotherapy to the patient to sort of wipe out their bad stem cells, and then you give them new stem cells that will hopefully permanently eradicate the disease. 

What ends up happening is that a large group of patients with acute myeloid leukemia end up being referred for a stem cell transplant. The reason is twofold. You know, it used to be – I keep talking about the past. I’m getting older, and so now I can talk about the past.  

Yeah. So, it used to be that stem cell transplants were really reserved to people less than 65 years old.  

But our advances in our ability to do stem cell transplants has allowed for us to now successfully do stem cell transplants on patients, even into their upper 70s and sometimes even at the age of 80.  

Katherine Banwell:

Where do clinical trials fit in to all of this? 

Dr. Eytan Stein:

Ah. So, clinical trials are extraordinarily important for a variety of reasons. Clinical trials are important because the only way we make advances on a societal level in the treatment of acute myeloid leukemia is by patients who are willing to participate in clinical trials. All of the – because these are trials that are testing new therapies with the goal of improving the survival and the quality of life of patients with acute myeloid leukemia. All these drugs I just talked about that have been approved over the past 10 years, they never would’ve been approved if patients hadn’t agreed to participate in clinical trials. So, that’s something that’s number one that’s very important.  

But on a – forget the societal level for a second. On a patient-specific level, a clinical trial can potentially benefit a patient because it offers a patient access to a new, exciting therapy that may really help in improving their outcome of having acute myeloid leukemia.  

Katherine Banwell:

Yeah. You mentioned emerging therapies. What are some of those? 

Dr. Eytan Stein:

Oh, there’s so many. So, it’s hard to talk about all of them, but I think there are targeted therapies – I think if you sort of break them up into sort of broad buckets, there are new targeted therapies that are being developed for subsets of patients with acute myeloid leukemia. One of the ones I’ve been working on pretty heavily over the past few years is a kind of drug called a menin inhibitor. This is an oral medication that is given to patients of acute myeloid leukemia who have certain genetic abnormalities, specifically either a mutation in a gene called NPM1, or a what is called a rearrangement in a gene called MLL.  

So, that’s a group of – that menin inhibition seems to be extraordinarily effective in treating patients, at least from the early data, for those specific subtypes of acute leukemia.  

The other therapies that are really getting a lot of play now are the immunotherapies, which I mentioned a second ago. There are immunotherapies that work to – called bispecific immunotherapies where what happens is it works to harness the immune system to kill the cancer cells. You may have heard a lot about CAR T-cell therapy, which is another way of harnessing the immune system and engineering immune cells to target acute myeloid leukemia cells. And the other thing I want to point out is that even if you don’t have a new therapy against a new target, you can imagine now that we’ve got all these 10 new approved drugs.  

But what we’re trying to figure out – one of the things we’re trying to figure out over the past few years has been what’s the best way to give these new drugs? What kind of combinations can you put them in that might make things even better? Maybe you should give two of those drugs first and then give another drug afterwards. And a lot of the research that’s being done now is being done to understand the best sequencing and combinations of drugs with the drugs that we already have approved. 

What Are the Phases of AML Therapy?

What Are the Phases of AML Therapy? from Patient Empowerment Network on Vimeo.

Dr. Eytan Stein discusses the phases of AML treatment, defining induction therapy, consolidation therapy, and maintenance therapy.

Dr. Eytan Stein is a hematologist oncologist at Memorial Sloan Kettering Cancer Center and serves as Director of the Program for Drug Development in Leukemia in Division of Hematologic Malignancies. Learn more about Dr. Stein, here.

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Transcript:

Katherine Banwell:

What is induction therapy?   

Dr. Eytan Stein:

Yeah, so induction chemotherapy refers really to a type of chemotherapy that tends to be quite intensive, so strong chemotherapy that patients receive in the hospital setting. That induction chemotherapy typically requires a hospitalization of three to four weeks, sometimes a little bit longer, as the patient gets their treatment during the first week or so and then they’re recovering from the effects of that treatment during the next three weeks in the hospital.  

Katherine Banwell:

Okay. What is consolidation therapy? 

Dr. Eytan Stein:

Ah. So, a patient first gets induction chemotherapy. If they achieve a complete remission, so their disease goes away, that’s great. We know their disease seems to be gone. But we also know that patients relapse. So, if patients relapse, it means their disease wasn’t really gone. It’s just that we couldn’t find it. It was hiding somewhere.  

So, consolidation chemotherapy is chemotherapy that is given after a patient is in complete remission in an effort to kill any residual leukemia cells that may be hiding in the body, that we can’t see in our bone marrow biopsies, in an effort to deepen the remission that we’ve achieved during induction.  

Katherine Banwell:

Okay. Are there any other terms that patients should be familiar with? 

Dr. Eytan Stein:

There are. You know, there are a lot of other terms that patients should be familiar with. I’ll just touch on one because it can get complicated. We now have for acute myeloid leukemia, a type of therapy that goes beyond induction and consolidation called maintenance therapy.  

Maintenance therapy is when a patient is done with induction, done with consolidation, and the question is, can you give them something that is easy to take, relatively non-toxic, that they can take for a prolonged period of time, to also help prevent relapse? Maintenance therapy has been really a backbone of the treatment of a different kind of leukemia called acute lymphoblastic leukemia, which happens primarily in children for many years. Maintenance therapy is also now a backbone of therapy for a different kind of blood cancer called multiple myeloma. And very recently, only within the past year to two years, we’ve incorporated maintenance therapy for AML for certain groups of patients.  

Expert Perspective: Why Myeloma Patients Should Weigh in on Their Care Decisions

Expert Perspective: Why Myeloma Patients Should Weigh in on Their Care Decisions from Patient Empowerment Network on Vimeo.

Myeloma specialist Dr. Abdullah Khan shares key advice encouraging patients to participate in care and treatment decisions and discusses the importance of communicating symptoms and side effects to your healthcare team.

Dr. Abdullah Khan is a hematologist specializing in multiple myeloma and plasma cell disorders at the Ohio State University Comprehensive Cancer Center – The James. Dr. Khan is also an assistant professor in the Division of Hematology at The Ohio State University. Learn more about Dr. Khan.

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The Role of a Myeloma Specialist on Your Care Team

Transcript:

Katherine:

Let’s turn to decision-making, Dr. Khan. What is the role of the myeloma patient when making care and treatment decisions?  

Dr. Khan:

As a provider, my role is to inform the patient of the facts and the need for a decision. The purpose of the discussions is to determine the patient’s goals and preferences, because it’s essential the patient’s values of respected. The best outcomes occur when the medical facts align with the patient’s preferences. And this is a multi-disciplinary team approach.  

Katherine:

Why is it so important for patients to share any symptoms and side effects they’re having with their healthcare team?   

Dr. Khan:

I read something recently on an NIH website titled “What Do I Need To Tell the Doctor?” that I think answers this question well. And I’m quoting the article. “Talking about your health means sharing information about how you feel physically, emotionally, and mentally. Knowing how to describe your symptoms and bringing up other concerns will help you become a partner in your healthcare.”  

I think I really like that end, “partner in your healthcare.” The patient’s symptoms and suggest disease or disorder in the body. If there are concerns, this may prompt a clinic visit or the patient may be advised to go to the closest ER or urgent care depending on the urgency of the situation. But in other cases, the healthcare team may help provide reassurance that the symptom can be continued to be monitored more resolution, or it can be evaluated in more detail if it persists or worsens.  

Katherine:

What about side effects? Why is that important for patients to share any side effects they may be having?  

Dr. Khan:

Side effects may be a result of the disease itself. It might be a marker of the side effects from the treatment. Or I’m focused on the multiple myeloma, but there’s every other organ system in the body that also needs help. So, the myeloma might be doing okay. The treatment might be doing okay. But, for example, we might have a lung toxicity from their pre-existing COPD or a heart toxicity from their pre-existing coronary artery disease. So, it’s very important to share all symptoms So, we can see how to properly assess it.   

Katherine:

And better care for the patient.  

Dr. Khan:

Right.  

Expert Perspective: Advances in Treating Relapsed and Refractory Myeloma

Expert Perspective: Advances in Treating Relapsed and Refractory Myeloma from Patient Empowerment Network on Vimeo.

Dr. Abdullah Khan, of Ohio State University Comprehensive Cancer Center – The James, reviews currently available treatments as well as those in development for patients with relapsed or refractory myeloma. 

Dr. Abdullah Khan is a hematologist specializing in multiple myeloma and plasma cell disorders at the Ohio State University Comprehensive Cancer Center – The James. Dr. Khan is also an assistant professor in the Division of Hematology at The Ohio State University. Learn more about Dr. Khan.

See More from Engaging in Myeloma Treatment Decisions

 

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Relapsed and Refractory Myeloma Defined

Transcript:

Katherine:

Are there any recent advances in treatment for patients with relapsed or refractory disease?  

Dr. Khan:

Currently and in the past 20 years or so, we’ve seen about 20 approvals for new drugs for patients with multiple myeloma. The way the approval process works it typically looks at the effectiveness of a drug in the relapsed refractory setting first. And after establishing the safety and efficacy, the therapies are moved earlier in the disease course.   

The great example of this are the anti-CD38 monoclonal antibodies daratumumab and isatuximab. They were first approved in the relapsed refractory setting in combination with other antimyeloma treatments. And due to their impressive effectiveness and relative safety, they’re already being used in the frontline setting for patients with newly diagnosed multiple myeloma.   

In the newly diagnosed setting, a commonly cited study is the phase two GRIFFIN trial. And that added daratumumab to the BRd, or bendamustine (Bendeka, Treanda), lenalidomide (Revlimid), dexamethasone backbone.  

And Europe, they completed the phase three study of adding isatuximab, the other anti-CD38 monoclonal antibody to the BRd backbone. And what we’re finding what was very effective in the relapsed refractory setting was actually adding to the efficacy of newly diagnosed treatment regiments. As a side note, these trials – there are also trials looking at daratumumab and isatuximab in the smoldering myeloma phase, so moving it even earlier.  

I think one of the most attractive new targets in myeloma is targeting this antigen called B-cell maturing antigen, and a number of therapies are being developed or are already developed for it. The first approved was belantamab mafodotin, and this is an antibody drug conjugate. 

So, when the antibody binds to BCMA on the multiple myeloma cells, it releases its toxic payload into the myeloma cell. And so, it’s very effective towards myeloma, and no other good cells or fewer other good cells are affected by it. To provide some numbers, in patients with a median of seven prior lines of treatments, meaning their myeloma had relapsed that many times, the response rate was about 30 percent. And a fifth of those patients had VGPR, very good partial response, or better response.  

There are also bispecific antibodies that target this myeloma marker, and we anticipate getting one approved soon in the U.S. called teclistamab. Teclistamab is an antibody that binds both CD3 on T cells of the immune system and B-cell maturating BCMA on the myeloma cells. 

So, the way this antibody kills myeloma is by activating the T cells, the immune system, and directly killing the tumor. So, this was recently published in the New England Journal of Medicine. And in people who were treated with at least five prior lines of therapy, the response rate was about 63 percent, and the median progression-free survival, or the time until the myeloma progressed, was about 11 months.  

We were very active in a clinical trial looking at the effectiveness of another antibody, a bispecific antibody, called Regeneron 5458. In a similar patient population, the response rates were 75 percent in the higher-dose level group, and right now it’s actually a bit too early to tell how long the progression free survival is or the duration of response. 

There are also other bispecifics in development targeting other myeloma markers ssuch as talquetamab, that binds to a marker called GPRC5D, and cevostamab, which binds to a marker called FcRH5. The response rates as single agents in patients with relapsed refractory multiple myeloma are 66 percent and 45 percent respectively. These are all incredible numbers for a single drug in the relapsed refractory setting.  

How Does Disease Staging Affect Myeloma Treatment Choices?

How Does Disease Staging Affect Myeloma Treatment Choices? from Patient Empowerment Network on Vimeo.

What are the stages of myeloma, and how does this affect care? Dr. Abdullah Khan, a myeloma specialist, reviews how myeloma is staged, which genetic markers may affect risk, and the impact of staging on treatment decisions.

Dr. Abdullah Khan is a hematologist specializing in multiple myeloma and plasma cell disorders at the Ohio State University Comprehensive Cancer Center – The James. Dr. Khan is also an assistant professor in the Division of Hematology at The Ohio State University. Learn more about Dr. Khan.

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Transcript:

Katherine:

How does staging affect treatment option?  

Dr. Khan:

Staging is done by two methods. The older method is the international staging system, abbreviated as ISS. And then there’s the newer revised ISS, or RISS. 

The patients are assigned stages one to three. To determine the ISS you need lab values for the beta-2 microglobulin and albumin. For the revised ISS, you add on the lab value for LDH, lactate dehydrogenase, and you also add in the chromosome risk profile. So, there are certain genetic changes that predict a more aggressive myeloma. And the ones added to the revised ISS staging system are translocation 4;14, translocation 14;16, and deletion 17p.  

So, that’s the ISS stage and the revised ISS stage. There are also other factors patient providers look into when determining the risk profile for patients. So, that might include other genetic changes. 

One that is gaining a bit more traction right now is something called gain 1q, or amplification 1q, so more than one copy of part a chromosome. Some patients might have myeloma that doesn’t start, and the bone marrow might be found outside of the bones. And that’s called extramedullary disease, and sometimes that’s kind of high-risk. And some people have so much bone marrow plasma cells that it actually spills into their bloodstream. So, they might have high circulating plasma cells. Anyway, this will give information on staging.  

And in terms of how it affects treatment option, I’ll give maybe two examples. Let’s say in case one we have a 40-year-old patient high-risk multiple myeloma. The high risk portends a poorer prognosis, meaning the outcomes might not be as good as someone with a standard myeloma. So, in that case, I might try to do or use the most aggressive treatment option in order to maximize treatment responses because I know the overall outcome is poor. 

I do all this while acknowledging maybe the chances of having side effects might be higher, but that might be an acceptable tradeoff.  

In case two, I’ll flip to an 80-year-old with standard risk cytogenetics.  

So, I predict their myeloma to behave standard. In this case, I might try to use a regimen with a more acceptable safety profile, because the predicted response to treatment is anyways very good. So, I don’t want to hurt them in the process of getting their myeloma in remission.  

I’ll also say this. My practice pattern at The Ohio State University might be a little different than someone on the East Coast or West Coast, and that’s okay. We all have our experiences with the different treatment regimens, but we all have the same goal of being as aggressive as we can while being mindful of side effects. 

How Is CAR T-Cell Therapy Changing Myeloma Care?

How Is CAR T-Cell Therapy Changing Myeloma Care? from Patient Empowerment Network on Vimeo.

Dr. Abdullah Khan discusses how CAR T-cell therapy works to treat myeloma, the currently approved CAR T-cell therapies, and the outcomes related to progression free survival (PFS) for patients with heavily pre-treated myeloma.

Dr. Abdullah Khan is a hematologist specializing in multiple myeloma and plasma cell disorders at the Ohio State University Comprehensive Cancer Center – The James. Dr. Khan is also an assistant professor in the Division of Hematology at The Ohio State University. Learn more about Dr. Khan.

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Transcript:

Katherine:

Let’s talk about CAR T-cell therapy. How is CAR T-cell therapy changing the field?  

Dr. Khan:

Myeloma was a little late to the CAR-T game, but we’re very happy it’s here. The two products approved in myeloma are idecabtagene vicleucel, ide-cel for short, and ciltacabtagene autoleucel, or cilta-cel for short. 

So, the way CAR Ts work, they are customized T cells for each individual patient. You collect the T cell from the patient with myeloma. You reengineer them in the laboratory to produce proteins on their surface called chimeric antigen receptor. That’s CAR portion of the CAR T therapy. And these CARs recognize and bind specific proteins on the surface of multiple myeloma.  

So, these genetically modified T cells are then expanded or multiplied to make millions of cells. They’re sent back to the hospital where they were collected, where the patient is. And they’re infused back into the patient. The hope is that these modified cells, these CAR T cells, will continue to multiply in the patient. And with guidance from that engineered receptor, they will recognize and kill multiple myeloma very effectively. 

So, I can provide some numbers to the outcomes of the two approved CAR T cells – CAR T products in multiple myeloma. The first approved was ide-cel in patients with a median of six prior lines of therapy, a single dose of CAR T was able to produce an objective response rate – that’s how many people responded to the treatment – of 73 percent, and the median, the middle person, progressed after 8.8 months of getting this treatment. The other product, cilta-cel, was also studied in patients with a median of six prior lines of therapy, and the objective response rate was an astounding 98 percent.  

Katherine:

Wow.  

Dr. Khan:

And the median progression-free survival is actually not yet reached. So, these are remarkable results with heavily pre-treated myeloma. And the myeloma community’s very excited to actually bring these treatments to earlier lines of therapy such as a newly diagnosed patient with multiple myeloma. 

Advances in Myeloma Molecular Testing

Advances in Myeloma Molecular Testing from Patient Empowerment Network on Vimeo.

What is molecular testing, and how does it impact myeloma care? Dr. Abdullah Khan from the Ohio State University Comprehensive Cancer Center – The James discusses the specific markers found in cytogenetic analysis that determine a patient’s risk and may impact treatment choices.

Dr. Abdullah Khan is a hematologist specializing in multiple myeloma and plasma cell disorders at the Ohio State University Comprehensive Cancer Center – The James. Dr. Khan is also an assistant professor in the Division of Hematology at The Ohio State University. Learn more about Dr. Khan.

See More From INSIST! Myeloma

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How Do Test Results Impact Myeloma Treatment Options?


Transcript:

Katherine:

Have there been advances in molecular testing for myeloma patients?  

Dr. Khan:

Molecular testing is a broad term and can indicate checking genes, proteins, and other molecules. Even let’s say speaking outside of the world of myeloma, molecular testing can be used to determine in individuals if they have a high chance of developing cancers or other diseases.  

It can be done to confirm so cancer diagnoses using the tissue biopsy specimens. It can also be used to help plan treatment, find out how well the treatment is working, provide prognosis information, and other information. In the world of myeloma, there are – in the world of myeloma, there are researchers looking at all of these molecular changes that can happen with disease.  

Katherine:

So, how do the results of these tests affect treatment?  

Dr. Khan:

There’s a particular cytogenetic change called translocation 11;14 that’s found in maybe a quarter of all patients with newly diagnosed myeloma, and it predicts a high likelihood of responding to a new drug called venetoclax.  

In the clinical trial of venetoclax, when it was given to all patients with multiple myeloma, there was actually higher mortality in patients when given venetoclax in combination with bortezomib and dexamethasone. And this is despite a higher response rate by adding the venetoclax.  

The thought process was maybe those patients were not doing well because of higher chances of serious infections. But when they took the data and they looked at that subgroup of patients with the translocation 11;14, there was no such concern in that subgroup. So, in this case of having translocation 11;14, it actually giving you a new treatment option based on the findings of the molecular testing. 

We participate in a national clinical trial called MyDRUG, and that’s looking at other molecular changes to see if a more targeted treatment when added to the backbone of myeloma therapies translates to better outcomes.  

Another recent development in molecular testing is diagnostic testing for minimal residual disease, and that’s from the bone marrow in patients with multiple myeloma.  

The most commonly used test in clinical trials is the clonoSEQ test; it’s an FDA-cleared diagnostic test. The way it works it looks for specific DNA sequences on the receptors of the cancer cells. So, each cancer cell has like a genetic barcode.  

Using the liquid part of the marrow, we can look for those cells that harbor that genetic barcode. 

And the test is so sensitive, we can find one in a million cells in a patient’s bone marrow aspirate. So, it’s a very sensitive test, but it is not yet approved for making treatment decisions. One way we can use it though is for prognostic information. So, a patient attaining minimal residual disease-negative status or MRD-negativity, probably will do better than someone who has MRD-positive disease.  

And there’s an emerging concept called sustained MRD negativity. So, let’s take an example of someone getting MRD testing at one year and two years after their stem cell transplant. The patient who is MRD-negative at both the one-year and two-year marks will likely do better than the one who is MRD-negative at one year but turns positive at the two-year mark. 

So, these are some of the new developments in molecular testing in multiple myeloma.  

What Tests Are Essential Before Choosing a Myeloma Treatment Approach?

What Tests Are Essential Before Choosing a Myeloma Treatment Approach? from Patient Empowerment Network on Vimeo.

Dr. Abdullah Khan, a myeloma specialist, discusses the types of tests that myeloma patients should undergo before choosing therapy, at diagnosis, and if they relapse.

Dr. Abdullah Khan is a hematologist specializing in multiple myeloma and plasma cell disorders at the Ohio State University Comprehensive Cancer Center – The James. Dr. Khan is also an assistant professor in the Division of Hematology at The Ohio State University. Learn more about Dr. Khan.

See More From INSIST! Myeloma

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Advances in Myeloma Molecular Testing

Advances in Myeloma Molecular Testing

Understanding MRD and What It Means for Myeloma Patients

Understanding MRD and What It Means for Myeloma Patients

How Do Test Results Impact Myeloma Treatment Options?

How Do Test Results Impact Myeloma Treatment Options?


Transcript:

Katherine:

What testing should take place before choosing a myeloma treatment?  

Dr. Khan:

I thought I could answer this question in an indirect way first.  

Katherine:

Okay.  

Dr. Khan:

I just wanted to let the audience know that anyone, including those that are not in the medical field, can create an account with the nccn.org. That’s the National Comprehensive Cancer Network’s website.  

And from there they can download the myeloma guidelines, which are available to all myeloma providers as well. And in the guidelines, there are sections for workup, treatment, how to follow patients with myeloma, and many other things.   

So, going back to the question, the first patient encounter will likely include a thorough history and physical exam. Initial lab work includes blood counts, the serum chemistries so we know about the liver and kidney function, multiple myeloma markers. And patients about get very familiar with monoclonal protein, the serum immunoglobulins, and the serum-free light chains. 

These are used as the surrogates for responses when you’re undergoing treatment for the myeloma. We will also at the first visit probably also do a 24-hour urine collection, and that’s looking for the abnormal protein in the urine.  

There’s imaging. In the past, we used to do x-rays head to toe. That’s sometimes called the myeloma survey or the skeletal survey. But the new recommendations are actually looking for something a bit more sensitive.  

So, at our practice, what we do is a PET scan.  

So, that includes functional information as well the images themselves. And some institutions may do a PET scan head to toe using low-dose radiation. The final test we will do in patients with newly diagnosed myeloma is a bone marrow biopsy and an aspirate. 

So, the biopsy’s looking at the bone itself and the architecture. And the aspirate, you take the liquid part of the bone marrow, and you can ascertain a lot of information including the burden of myeloma when the patient’s newly diagnosed.  

Katherine:

What do you mean by “burden”?   

Dr. Khan:

You can quantify the number of cancerous plasma cells in the bone marrow. So, some of the information says you have a healthy amount of good bone marrow cells, 50 percent, 60 percent, for example, but of that 50 percent, 60 percent, maybe 80 percent is taken over by myeloma. So, you will get burden of myeloma information from there.  

Katherine:

What additional testing should take place following a relapse?  

Dr. Khan:

I’ll start that response by first talking about the types of relapses, and there are two broad categories. If we see the myeloma coming back as just the monoclonal protein going back up from its lowest, or maybe the serum-free light chain going up – and there are very specific criteria for what defiance a relapse. But if it’s just a number, we call it a biochemical relapse.  

On the other side, there’s a clinical relapse. And at that point, there might be new end organ damage. We’ve heard of the acronym CRAB when we’re describing myeloma. That stands for hypercalcemia, renal or kidney insufficiency, anemia, and bone disease. So, these are end organ damage directly from the multiple myeloma. 

So, typically, we’ll try to change the management at biochemical relapse, because a new organ injury may contribute to the patient’s frailty, or it might even limit the treatment options. The testing out of relapse is pretty similar to the first diagnosis. We’ll repeat the history and the physical example, the labs, imaging. And more often than not, I’ll also recommend a bone marrow biopsy to see is that myeloma changing genetically, and does it help me kind of determine new treatment options.  

Myeloma Expert Debunks Common Clinical Trial Misconceptions

Myeloma Expert Debunks Common Clinical Trial Misconceptions from Patient Empowerment Network on Vimeo.

Dr. Abdullah Khan, a myeloma specialist, shares advice for individuals that may be hesitant to participate in a clinical trial, reviews the phases of trials, and explain the informed consent process.

Dr. Abdullah Khan is a hematologist specializing in multiple myeloma and plasma cell disorders at the Ohio State University Comprehensive Cancer Center – The James. Dr. Khan is also an assistant professor in the Division of Hematology at The Ohio State University. Learn more about Dr. Abdullah Khan.

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The Benefits of Participating in a Myeloma Clinical Trial


Transcript:

Katherine:

What would you say to someone who’s hesitant in participating in a trial?  

Dr. Khan:

Well, the decision to participate is complex and personal, but the ultimate decision regarding trial participation rests with the patient. So, some of the reasons why patients might be hesitant, they might have distrust toward the medical community given the history of clinical trials in this country. If we take the example of the abuse of African American patients during the Tuskegee syphilis experiments, that’s just one example.  

Katherine:

Yeah.  

Dr. Khan:

Another reason patients might be hesitant is they don’t like the idea of being randomized to the treatment that they’re going to get. 

So, they might end up getting a placebo. They might get another standard of care. And they might not get that new, fancy drug. So, giving up that level of control does require some compromise. Another reason is the uncertainty of the potential side effects of the chemotherapy drugs, especially if you’re participating in an early-phase clinical trial.  

Furthermore, trials require very defined and frequent monitoring sometimes. So, some patients might not like the time commitment to a clinical trial. Another reason might be that there are concerns for cost. I can alleviate that concern by saying that typically there are mandates that the insurer cover the routine costs of clinical trials.  

Katherine:

You mentioned some misconceptions. Are there any others that patients might have about participating in a trial? 

Dr. Khan:

I guess the two most common things, the first one, and I think all providers have heard this, “I will be treated like a guinea pig.”  

Katherine:

Yeah.   

Dr. Khan:

For me, that is probably the furthest from the truth because of all the safeguards in place. Clinical trial participants are followed the most closely and probably get more medical attention than someone who is not on clinical trial. To participate in the clinical trial, the participant has to voluntarily – and that’s the keyword – sign an informed consent form. And finally, the participant can also leave the trial at any time for any reason.   

Another common misconception is that clinical trials of dangerous because they use untested drugs. There might be some truth to that. There are many phases to clinical trials. And in some early-phase clinical trials it is true that participant may actually be the first to ever get the new therapy. 

So, some of the outcomes are not known. But in late-phrase clinical trials, tens to thousands of patients may have already been treated with the study drug, so there a lot of preliminary safety data and also efficacy data.