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Creating Your Myeloma Treatment Path and Factors to Consider

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Published on May 8, 2020

Key Takeaways

With so many available treatment options for multiple myeloma, how can you and your doctor determine which path is best for you? In this segment from our recent virtual town meeting, our panel of myeloma experts explain the factors they consider when creating a patient treatment plan and what therapies are currently available.
 
Dr. Frits van Rhee and Dr. Guido Tricot, both from the University of Arkansas Medical Science (UAMS) Myeloma Center, start by discussing transplant eligibility and risk levels and explain why those are the first two factors they consider. Dr. Shebli Atrash from Levine Cancer Institute at Atrium Health explains induction therapy.
 
The panel also discusses consolidation therapy, maintenance therapy, immunomodulatory drugs, monoclonal antibodies and testing. Watch now to learn from leading myeloma experts.

This program is sponsored by Takeda, Janssen and Karyopharm. These organizations have no editorial control, and Patient Power is solely responsible for program content. It is produced by Patient Power in partnership with UAMS Myeloma Center. 

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Transcript | Creating Your Myeloma Treatment Path and Factors to Consider

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

Maddie Hunter:
Dr. van Rhee, I'm wondering if you can talk a little bit about once you've thought about the factors that you need to consider in terms of building a treatment plan with someone one of the first questions that I know you entertain is, "Is this person transplant-eligible or not?" Can you talk a little bit about what factors you consider when deciding which path to take with a patient?
 
Dr. van Rhee:

We subscribe to the idea that a fit and somewhat younger patient can be actually cured of their disease with a comprehensive treatment approach. So usually they get some form of induction chemotherapy to bring the disease under control. If they're medically fit enough to receive a transplant, we will do at least one transplant. Very often we actually do two transplants. There're three European studies, randomized studies, with more than 10 years follow-up, showing the patients who get two transplant doing better. And I think even myeloma physicians who are not that enthusiastic about stem cell transplantation tend to veer, now, to the notion that patients with high-risk disease may benefit from two transplants. And then there is some form of consolidation and maintenance. Whether somebody goes forward with transplant depends on their physical fitness to some extent or age, as well.
 
Maddie Hunter:
So it sounds like the decision to either transplant or not has to do with fitness, has to do with age, perhaps other co-morbidities that are present. Dr Tricot, Dr. van Rhee just mentioned something about the 
factor of risk and whether a person is high risk or notThat also helps to determine a path. Can you talk a little bit about what makes someone high risk versus standard risk?

Dr. Tricot:
The three most important factors to decide on risk is, most important is genetics. The information we get from that is much more important than anything else. For example, if you look at an ISS stage I you look at the patients who have a good gene profile versus the one that have a high-risk gene profile, there's a major difference, even in the stage I disease. So genetics is by far the most important. The second important factor is how much disease do we have? And to assess that, the best ways to do that, is by PET scan and MRI. Myeloma is a focal disease in contrast to leukemia. In leukemia, it doesn't matter where you do your bone marrow, it will show that you have leukemia, because it's spread evenly all over the bone marrow.
 
Myeloma cells have the tendency to cluster together in small or larger clusters, and they do that because they can survive much better if they are clustering together. And it's in those clusters that you also see the bone destruction and the bone destruction is a bad thing, but not only that, we used to think that bone is an inert organ, but actually it has a lot of cytokines. And those cytokines are released by bone destruction and cause the myeloma cells to grow better. So the extent of disease is second most important factor.
 
And then the third most important factor is the light chains. The higher the ratio is in patients who have kappa light chain disease or the lower the ratio is in patients who have lambda light chain disease, the higher risk the patients have. So those three factors, in my opinion, are by far the most important factors.
 
Maddie Hunter:
So, Dr. Tricot, the genetic testing, the FISH tests that you described, the PET scans, the ways that we evaluate what the extent of the myeloma is in the bone marrow and the genetic makeup, these are all things that are done typically at diagnosis. I want to ask Dr. Atrash a follow-up question about the extent to which you make decisions based on those pieces of information. So we talked about induction as the first thing one is exposed to, the first type of treatment. Tell us a little bit about some of the choices that patients have in that early phase, whether they're a high risk or a standard risk.
 
Dr. Atrash:
For induction, once we determined a patient is transplant-eligible or transplant-ineligible we use the MAIA clinical trial regimen that was presented by Dr. Usmani from our group. And it included daratumumab (Darzalex) added to lenalidomide (Revlimid) and dexamethasone (Decadron)—very nice, very well-tolerated regimen. It's triplet. It showed better progression-free survival than lenalidomide and dexamethasone alone by a far margin. I think hazard ratio was close five, 0.5.
 
If the patient is transplant-eligible, we move on to a quadruplet regimen at this point, we try to follow up the steps of the GRIFFIN trial which was presented by our own doctor as well, Dr. Voorhees, Peter Voorhees, and showed that daratumumab added to bortezomib (Velcade), Revlimid and dexamethasone is an excellent choice and very well-tolerated.
 
Maddie Hunter:
So it sounds like there are many options.  Dr. van Rhee, back to this sort of evolution of steps in a treatment journey. So we've talked a bit about induction. Talk to us a little bit about consolidation, where that fits in. What does that actually mean, and what are some of the treatments that people use with consolidation?
 
Dr. van Rhee:
Consolidation is done after transplant or sometimes also in non-transplant-eligible patients to first further reduce the disease burden. Very often people use some of the drugs which are also used during the induction chemotherapy, so there can be VRd, KRd with or without daratumumab, for a number of cycles and then patients go on to a maintenance regimen. The classical maintenance regimen is single agent, lenalidomide. More and more centers are doing more than one drug, particularly daratumumab together with lenalidomide is being explored but also for patients with higher risk, triplets are being used as a maintenance therapy. In our center, we've been doing triplet maintenance therapy since 2003 with three drugs, and we typically stop at three years.
 
And obviously there are a lot of new developments. There is the development of the MRD measurements, the minimal residual disease for which different methods exist, and one of the big questions is whether we can tailor our maintenance therapy depending on minimal residual disease assessment—and also what we call functional imaging, MET imaging. And there are a lot of different clinical trials going on there, about whether we can use minimal residual disease as an indicator to stop therapy. And in terms of minimal residual disease, what is probably important is not only whether it's absent or negative, but also what type of minimal residual disease there is.
 
There are certain types of myeloma from certain molecular subgroups where the disease is really very indolent, and it's not very important that you're MRD-positive. It doesn't impact on your outcome. On the other hand, we know that if you've got high-risk disease and you're MRD-positive, you're very likely to relapse. So these are all areas which are presently undergoing active exploration.
 
Maddie Hunter:

There's so much in what you just said. I had never heard that before and that some of the same regimens can be used in induction and in consolidation. So I just want to poke at that just a little bit and ask Dr. Tricot, there is this class of drugs that Dr. van Rhee has just mentioned called immunomodulatory drugs. The drug I'm taking is Revlimid. Can you talk a little bit about that class of drug, and what does it really do? What do those drugs do in that class?
 
Dr. Tricot:
The IMiDs basically group three drugs that the first one was thalidomide (Thalomid), and then the derivatives of thalidomide, Revlimid or lenalidomide and then pomalidomide (Pomalyst). Of those drugs thalidomide and Revlimid are probably equal in strength but have different side effects, while thalidomide causes constipation and causes neuropathy and causes people to be drowsy. The main side effect of Revlimid is that it suppresses the counts much more than thalidomide does. But we saw that also already with thalidomide in our Total Therapy II trial where half of the patients were started on thalidomide, and half were not started on thalidomide but otherwise had the same treatments. We were able to collect many more stem cells in the patients who were on the non-thalidomide arm than on the thalidomide arm. So thalidomide was already myelosuppressive to some degree, but certainly Revlimid is much more.
 
So, in terms of what do those IMiDs actually do? Well, they have four functions. The first one is they kill myeloma cells directly, but in killing myeloma cells directly, the IMiDs are much less effective than our typical cytotoxic treatments. But what they have different than our typical cytotoxic treatments like melphalan (Evomela) and cyclophosphamide (Cytoxan) is that they integrate the attachment of myeloma cells to the stroma. Myeloma cells, just like a hematopoietic stem cells, are closely attached to the microenvironment of cells, the stromal cells, and by that attachment they become much more drug-resistant. If you break that attachment, the cells become much more sensitive to chemotherapy.
 
The third thing that happens with the IMiDs is they inhibit the cytokines, such as IL-6 and IL-11 and IL-15, which are actually growth factors for the myeloma and make myeloma cells survive better and grow better. So if you can inhibit that, it will be a detriment for the myeloma cells. And the fourth function is that it increases the immune system and that's why the immunomodulatory drugs, it makes the host better in defending against the cancer by increasing the immune system. So four different functions, it kills directly, it inhibits the attachment of the myeloma cells to the stroma, it inhibits cytokine secretion, and lastly, it also enhances the immune system and that's how the IMiDs are working and have a major effect in the treatment of myeloma.
 
If you, for example, give a monoclonal antibody and you add an immunomodulatory drug like Revlimid to it, you will see that it will increase the activity of the monoclonal antibody, because it enhances the immune system. It makes the immune system more powerful and the combination is better than the monoclonal antibody alone. So in any type of treatment where you really want to have the immune system helping you, it's important that you include immunomodulatory drugs.
 
Maddie Hunter:
Thank you. So those four factors in combination both with thalidomide and Revlimid make them very commonly used. I think this is one of those realities that we all say, and I wondered, Dr. Atrash, if there were things you could say about another class of drugs that sometimes partners with the IMiDs as Dr. Tricot just described, which are the monoclonal antibodies.
 
Dr. Atrash:
So the monoclonal antibodies are simply as the name says is an antibody that goes and attach to the plasma cell. So one of the reasons why we have multiple myeloma is that our immune system does not recognize those cancer cells as cancers. So they let them go. So one of the ways to wake up our immune system is by creating a drug with an arm that can go and attach to one of the markers on the surface of the plasma cells, and that's called monoclonal antibody. There are two monoclonal antibodies already in the market, isatuximab (Sarclisa), which was recently approved and daratumumab. Even with those two drugs, I see a lot of questions about, they are giving IV now, but it looks like soon they will be giving subcutaneous injections.
 
So they are very convenient drugs. They are very important. They change the way we treat multiple myeloma perhaps forever, and they are a platform, in my view, they are a platform for more drugs that can come again later on.
 
Maddie Hunter:  
When we have this treatment regimen and journey and whether we do a transplant or not, and we have some sort of consolidation or ongoing treatment, some of us, and whether we're in a trial or not, have access to getting this test that determines what's the myeloma load left. So, Dr. van Rhee, can you just give us a brief synopsis of where we are with the testing? You've begun to talk about it, but can you give us a sense of where we are and where it's being used?
 
Dr. van Rhee:
It is mostly being used in academic centers, but it's also available to community oncologists. There are essentially two types of tests. One is called a flow cytometry test, so the bone marrow gets labeled with antibodies which recognize myeloma cells, and a machine detects them, and typically this type of test has a sensitivity of 100,000, which means that one myeloma cell in the middle of 100,000 cells can be detected. And there's also a test in which genetic materials extracted from the bone marrow and examined by sequencing technique. That test has a longer turnaround time, but it has a sensitivity of one in a million. In other words, it can detect one abnormal cell in the middle of a million normal cells. The big question is what to do with the information of the test. There's presently no data to suggest that alteration of therapy based on an MRD test definitely improves outcome. However, there are a number of trials going on and we will address that question in future.
 
Maddie Hunter:

So like everything in myeloma, the number itself doesn't necessarily say the story. It's all of these other aspects of that.
 
Dr. van Rhee:

 It needs to be interpreted in context.
 
Maddie Hunter:

Thank you, and I want to say goodbye again. Thank you for your attention. Thank you for your participation. I'm Maddie Hunter and remember, knowledge is the best medicine of all. Have a great, great day.

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

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