Ask the Multiple Myeloma Experts

Ask the Multiple Myeloma Experts

July 16, 2020  Part of the Virtual Celebrating a Second Chance at Life Survivorship Symposium 2020

Panelists:

• Jens Hillengass MD, Chief of Myeloma, Roswell Park Comprehensive Cancer Center

• Elizabeth O'Donnell MD, Director of Lifestyle Medicine and Medical Oncologist in the Multiple Myeloma Disease Center, Massachusetts General Hospital

• Muthalagu Ramanathan MD, Medical Co-Director, Blood and Marrow Transplant Program, UMass Memorial Medical Center

59 minutes Question & Answer Session

Summary:  The current standard of care for patients with multiple myeloma is high dose chemotherapy and an autologous stem cell transplant.  Although an autologous transplant is not a cure, maintenance therapy with various drugs can control myeloma in many patients for several years.

Highlights:

• Anyone with multiple myeloma up to age 80, who is otherwise in good health and can tolerate chemotherapy, is a potential candidate for an autologous stem cell transplant.
• Having a second autologous transplant is a common treatment strategy. The period of remission after a second autologous transplant is usually less than that obtained after the first autologous transplant.
• A new strategy for treating patients with multiple myeloma that is showing great promise is CAR T-cell therapy.

Key Points:

03:46     A secondary cancer sometimes occurs in patients treated for multiple myeloma.  The cause of these secondary cancers is not clear.

10:32     CT, MRIs and PET scans are all used to monitor myeloma lesions but provide different types of information that can help guide treatment decisions.

13:23     CAR T-cell therapy has been tested on patients with multiple myeloma with encouraging results.

15:41     The safety and effectiveness of an allogeneic transplant (transplant using donor cells) after an autologous transplant is still being researched.

19:48     The cytogenetics of multiple myeloma can change over time which can affect treatment decisions.

25:32     Some therapies used to treat patients with multiple myeloma can cause peripheral neuropathy.

34:40     Some myeloma patients experience “chemobrain” or changes in cognitive abilities as a result of treatment.

42:44     Multiple myeloma and therapies to treat it can cause changes in body composition such as weight loss and change in muscle mass. Remaining active and maintaining physical fitness are important during treatment.

52:29     Amyloidosis can co-exist with multiple myeloma. Treatment is similar to that for myeloma patients.

Transcript of Workshop

00:00     [Moderator] Welcome to the Ask the Multiple Myeloma Experts panel. My name is Sue Stewart, and I will be your moderator for this session. Today we're honored to have a panel of distinguished experts who are ready to respond to your questions about multiple myeloma.

It's my pleasure to introduce to you Dr. Jens Hillengass. Dr. Hillengass is the Chief of Multiple Myeloma at Roswell Park Comprehensive Cancer Center in Buffalo, New York. He is also a member of the Black Swan Research Initiative of the International Myeloma Foundation, and the International Myeloma Working Group. He is currently investigating the effects of physical activity on pain, quality of life, and skeletal events in myeloma patients.

Also with us today is Dr. Elizabeth O'Donnell. Dr. O'Donnell is an oncologist in the Multiple Myeloma Disease Center at Massachusetts General Hospital and she's the Director of the Lifestyle Medicine Clinic. She created this clinic to offer patients the opportunity to address survivorship needs such as physical deconditioning and weight loss.

Finally, we have with us Dr. Muthalagu Ramanathan who is an Associate Professor at the University of Massachusetts Medical School and Medical Co-Director of the Blood and Marrow Transplant Program at UMass Memorial Medical Center. Her research interests include developing novel transplant and non-transplant therapeutic strategies to treat multiple myeloma patients and to make stem cell transplantation less toxic and available to all who can benefit. Please join me in welcoming our experts.

01:49     [Moderator] So I'd like to begin with the first question that we get from several people. Dr. Ramanathan, perhaps you can answer this. How do you know if you're eligible to have a transplant for myeloma? If you are, what is the correct timing for an autologous or for an allogeneic transplant?

02:11     [Dr. Ramanathan] Hi. Welcome to the panel. So multiple myeloma, the current standard of care is autologous stem cell transplant in everybody who's eligible. Eligibility is actually not necessarily based on age. It's based on performance status and ability to tolerate chemotherapy and transplant. So anybody up to the age of 80 and in good performance status is able to undergo a transplant.

The typical timing of transplant is after initial induction chemotherapy. The induction chemotherapy can be anywhere from four to eight cycles, followed by a collection of stem cells, and then transplant. The current standard is to do autologous stem cell transplant in all myeloma patients because of the progression-free survival benefit that has been noted.

03:14     [Moderator] All right. Next question. "I've been on maintenance therapy for over four years. First with RVD and then just Revlimid. What are the risks of staying on this drug for more years? The original plan was for three years, but I've already exceeded that. I'm wondering if there comes a point where the drug becomes more toxic rather than helpful. If I were to switch drugs, what are my options, assuming I stay in remission as I am now?" Dr. Hillengass, would you like to take that?

03:46     [Dr. Hillengass] Yeah, absolutely. Hello. This is a great question. It's also a good thing to have, a good problem to have to be on maintenance for such a long time. That's really good to hear. There is some scientific data showing that some patients develop, unfortunately ... The worst that can happen, unfortunately, develop a second cancer, another cancer, and there is some hints that it might be caused by the lenalidomide, Revlimid, or also by the combination of having had an autotransplant [autologous transplant] with high-dose chemotherapy together with the lenalidomide later on.

At the moment, there's still discussion going on. When we first learned that this happens, this secondary cancers after myeloma treatment, there was a panic in the myeloma world and people said, "Oh, we cannot do that anymore." But then further and more thorough research showed that the benefit of the lenalidomide treatment outweighs the risk of second primary malignancies, as we call them, by far.

So, at the moment, the consensus of most experts is to go on with the treatment until it either doesn't work anymore, it's not tolerated anymore, or the disease progresses, which is basically that the treatment is not working anymore.

There are discussions, because a lot of our patients now achieve a so-called minimal residual disease negativity in the bone marrow. With very advanced techniques, we can measure that, showing a very, very low level of disease. Then there are studies that are planned where we would stop the treatment in those patients and see if they have a benefit from stopping the treatment.

At the moment, we don't have any scientific data. My personal recommendation to my patients who ask this question is to go on as long as they tolerate it and be monitored by an expert or by a hematologist-oncologist for side effects for possibly secondary cancers.

To answer a second question that might come up is there doesn't have to be an additional screening for secondary cancers. It's basically you see your hematologist-oncologist anyway and should just follow the screening recommendations that are out there for everyone. So that would be my recommendation at the moment, to go on with the treatment as long as you tolerate it and as long as it is working. Then maybe in a few years, we have more ideas and more research about this question.

06:20     [Moderator] All right. Thank you. Dr. O'Donnell, perhaps you can respond to this question. Is it safe to have an autologous stem cell transplant for myeloma in this COVID environment? For those who have survived, are there any special precautions we need to take that are different than the general public to protect ourselves against COVID?

06:42     [Dr. O’Donnell] That's a really great question. It's such an important one at this time. I think initially, particularly at our hospital, which saw a lot of COVID cases in March and April, there was a concern about the risks of doing transplant, and we temporarily suspended our own program until we better understood the virus and had more experience with it.

It is safe. We have resumed doing transplant and we continued to do them in diseases like leukemia throughout COVID. That's given us the confidence to say that you can safely do transplants during COVID. Like anything, you have to abide by the precautionary measures that are recommended such as wearing a mask, being very careful about hand hygiene, and avoiding contact with people who maybe puts you at a greater risk of exposure.

I think within the myeloma community in general, not just the transplant community, there's concern about increased risk of infection. Depending on what therapies you've had or what therapies you are on, the degree of immunosuppression or not having as competent an immune system is variable, but you may be at an increased risk of infection.

The best thing that you can do is to talk to your provider and think about the strategies that you can employ to avoid putting yourself in a position for any unnecessary risk or exposure. Then truly just abiding by wearing a mask if you have to be out and limiting those exposures.

08:19     [Moderator] Thank you. Dr. Ramanathan, I think this next one is for you. "I've heard that you can expect your remission to last about half as long after a second autologous transplant compared to the first. I do know two people in my local support group who had failed their first autologous transplant, but had a successful second autologous transplant. What things should a patient consider before undergoing a second autologous transplant?"

08:47     [Dr. Ramanathan] So that is true. The longest remission is typically the first autologous stem cell transplant. What is more important about undergoing the second autotransplant is what is the duration of remission of the first autotransplant? The longer the remission, the higher the benefit of getting another sustained remission with the second autologous stem cell transplant.

What is good about the current situation is we have more and more myeloma drugs available, which are less toxic. So, the deeper remission you get, the higher the progression-free survival even with autotransplant. So more and more that we're involving novel agents upfront, then less and less of chemotherapy. The transplant is the only source of chemotherapy, so to speak. So, there is always benefit to doing the second autotransplant.

The key criteria, though, is organ function, your heart function, lung function, and performance status. There is going to be cumulative toxicity, but as long as you have adequate organ function, you can certainly undergo a second autotransplant.

The good thing is you're usually collected for two transplants upfront. So, you shouldn't have to undergo a second collection. As long as the insurance approves it, and currently Medicare doesn't approve a second autotransplant, but if you had private insurance for the first one, then you're certainly going to be able to undergo a second autotransplant.

10:32     [Moderator] All right. Dr. Hillengass, I think this one is for you. Can quicker CT scans be used instead of MRIs or PET scans to monitor myeloma lesions?

10:48     [Dr. Hillengass] It's dangerous to ask me about imaging because I don't stop talking about it. So please cut me off if I talk too long. So, yes, to a certain degree, the CT gives you similar information than the other imaging techniques. But the CT is the fastest, so it can be done within a few minutes. The MRI's the longest, which can take up to more than an hour, which for some patients, especially if they have bone pain anyway, can be really bothersome.

There are two things that we have to differentiate when we do imaging. One is the bones, where the holes in the bones, osteolytic lesions, are one of the major symptoms of myeloma as, unfortunately, all of the patients will know, almost all of the patients. So, this is very important.

The CT shows us the bones with the highest resolution. MRI and PET, and I mean PET includes CT, so that's true for the CT part as well, but MRI and PET show us changes in the bone marrow before the bone ... They can show changes in the bone marrow before the bone is changed.

So, the MRI is very sensitive, but takes longer. So my recommendation, and also the guideline recommendations, are in early stages where the patients don't have holes in their bones, the MRI has the highest sensitivity, so we might be able to detect something even though there might not be a change in the bones already. So, the MRI has a high sensitivity and shows the bone marrow best.

For the PET CT and for the PET part, we know that patients who have changes in the PET after treatment, especially after autologous stem cell transplant, if they still have changes there that are connected to the multiple myeloma or showing multiple myeloma activity, that's, unfortunately, not a good prognostic marker. So, the achievement of a deep remission should be accompanied by also a deep remission in imaging, meaning that there are no residual changes anymore.

We don't have any scientific data showing that we should change or should adjust any treatment based on these findings, but there are also studies ongoing to investigate that. So, CT shows different things than PET and shows different things than MRI. That's basically the answer to the question.

13:07     [Moderator] Thank you. Dr. O'Donnell, perhaps you can handle this one. Can you talk about the new CAR T-cell therapy that is out there for patients with multiple myeloma? Any other therapies on the horizon that you're excited about?

13:23     [Dr. O’Donnell] So this is a really exciting topic. CAR T-cells stand for chimeric antigen receptor T-cell therapy, for those who are unfamiliar with this new mode of therapy. What happens in this type of therapy that's similar to an autologous stem cell transplant, patients will be pheresed, they'll have an IV put in, and their own T-cells will be filtered out and sent to a company who will manufacture them, reprogram them to hone to a specific protein that exists on the outside of the myeloma cells called BCMA, or B-cell maturation antigen.

Patients are given a little bit of chemotherapy several days prior to their CAR T-cell infusion. Then these cells are infused. These are live cells, so when they go into the body, they bind to that target and start to expand and grow so that they can bind to even more of the plasma cells that they target.

This is not an FDA-approved therapy yet. There are CAR T-cells that have been submitted to the FDA and will be, hopefully, approved, but will be reviewed within the next year. They have unique toxicities that are unlike some of the ones we're familiar with with chemotherapies. As cells die and their contents are released into the bloodstream, it can cause an inflammatory response known as cytokine release syndrome. There are some neurologic toxicities that are temporary and usually completely reversible that can be seen.

But the exciting part of this mode of therapy is that we are seeing deep and long-lasting responses in people who are refractory, meaning the drugs no longer work, from the five major drugs, immunomodulatories such as lenalidomide, pomalidomide, the proteasome inhibitors such as bortezomib and carfilzomib, and daratumumab.

In heavily pretreated patients who've seen multiple lines of therapy, these CAR T-cells can be very effective and get patients into remission that lasts close to one year without needing other additional treatments as maintenance.

15:41     [Moderator] All right. Thank you. Dr. Ramanathan, perhaps you can handle this question. Could you comment on the success of using autologous stem cell transplantation followed within a few months by a reduced intensity allogeneic transplant as far as its impact on disease-free progression or overall survival?

16:04     [Dr. Ramanathan] So allogeneic stem cell transplant is still considered research at this time, primarily because of the toxicity associated with allogeneic stem cell transplant. Even with all the treatment options we have currently for myeloma, we still don't have a cure for myeloma. Maybe CAR T-cells will get us close to that, but it's still not perfect.

So, allotransplant currently provides the only curative option for myeloma, but it's not 100% guaranteed. Though it improves progression-free survival, it improves the duration and the depth of response, because of the toxicity associated with allotransplant it is not considered standard of care.

We've done research on patients, especially younger patients with high-risk myeloma where allogeneic stem cell transplant is used right after the auto called tandem allotransplant. In that situation, the benefit seems to outweigh the risk, but it's only done under research at this time, under research protocol. In summary, it is an effective treatment, but because of the possibility of risks associated with it, it is only done under a study.

17:41     [Moderator] All right. Dr. Hillengass, perhaps you can take this one. What is the relative effectiveness of treatment using Ninlaro and dexamethasone with Revlimid versus without Revlimid for a patient with complete stringent remission of multiple myeloma?

18:00     [Dr. Hillengass] Well, that's a very specific question, and there's no data that we could base an answer on. The experience is that, especially those proteasome inhibitors like ixazomib (Ninlaro), bortezomib, and carfilzomib, together with these immunomodulatory drugs, which are the lenalidomide and the pomalidomide mostly, they work very well together. So they do more than just adding the efficacy. They improve each other. So, the combination is definitely better.

I am not aware of any study comparing ixazomib-dex with ixazomib-dex and lenalidomide, so I cannot give a very qualified answer to that. But the general experience is that those two different drug classes, the proteasome inhibitor and the immunomodulatory drug, work very well together. So, I would expect that there's definitely a higher efficacy of the three drugs compared to the two drugs.

There have been a lot of studies mostly comparing an immunomodulatory drug, mostly lenalidomide or pomalidomide, together with dexamethasone compared to something else plus those two drugs. Almost all of these studies have shown that three is better than two. But, of course, factors like side effects and depth of remission, which is in this question, also play a role.

Again, the efficacy is better, but it's very difficult to say if a patient who is in a very deep remission like stringent CR really benefit for more treatment or if the side effects outweigh the benefits. So, in general, I would recommend to discuss that with the doctor who knows the patient best, and the risks and the benefits can be balanced and a decision can be made based on that.

19:48     [Moderator] All right. Dr. O'Donnell, do the cytogenetics of myeloma change over time in response to therapy? Is it important to look for all cytogenetics upon relapse or just the original mutations?

20:04     [Dr. O’Donnell] So that's a really good question, and this has been studied. First of all, we like to have a baseline cytogenetic report. For those less familiar with the term, this is looking for a specific mutation that can give us a little bit of a better appreciation of the biology of one's myeloma and if it has certain high-risk factors.

Sometimes we identify mutations that are able to be targeted with specific drug therapies. So, cytogenetics can be used for that purpose as well. What we've learned from some of our more basic science research is that as myeloma progresses through lines of therapy, it evolves, and the cytogenetics, with the types of mutations, can evolve as well.

How does that impact your treatment? As I alluded to, there are only certain treatments that can target specific mutations. BRAF would be an example of that. There are data and basket study published in the New England Journal looking at the use of BRAF inhibition in different cancers.

But more so, what cytogenetics are used for when patients are initially diagnosed is assigning them to one of two groups being standard risk or high risk. Where that can come into play is how we use maintenance therapy, using a single agent versus a double agent.

21:32     [Moderator] Dr. Ramanathan, what is the single most significant quantified parameter measuring the effectiveness of cancer treatment?

21:44     [Dr. Ramanathan] In myeloma, it really depends on what your original diagnostic criteria were. In some patients, it could be the M spike or the monoclonal protein. In some patients, it could be the light chain in the serum. In some, it could be light chain in the urine. In some, it could be none of these, but the plasma cell percentage in the marrow. For some, it could be plasmacytoma. So, it's really variable based on what your initial diagnostic criteria were for you to be able to assess response.

So, whichever is the most significantly elevated is usually followed to assess treatment response. Most of the patients have some kind of M spike or light chain that can be followed. This can also be followed as MRD in the flow. Plasma cell percentage and the bone marrow flow can be used as well. It depends on what the significant fact was and following that to MRD levels of detection to assess effectiveness of response.

Again MRD is something which is evolving and continuing to be standardized. That can vary from institution to institution. So, the sensitivity of 10 power minus five, meaning one in 100,000-cell positivity is the current accepted MRD specification.

23:25     [Moderator] For the listeners who are not familiar with MRD, MRD is minimal residual disease. Correct?

23:32     [Dr. Ramanathan] Yes.

23:34     [Moderator] Okay. Dr. Hillengass, can kappa light chains increase only because of myeloma growth, or could it be from stress or viruses, even dormant or reactivated Epstein-Barr, strep, et cetera?

23:49     [Dr. Hillengass] Yes. I mean we all have kappa and lambda light chains independent of if we have a myeloma or not. They can be elevated because of other reasons. For example, they also are excreted through the kidneys. If the kidney function is not good, then the light chains can also go up compared to a normal measurement.

But it depends also on the lambda light chains. If the kappa are the relevant ones in a patient, and it's either kappa or lambda usually, if the kappa are the relevant ones and the lambda also go up, that it's usually a sign that it's something else going on like an immune effect, as it's mentioned in the question, or the kidney function or other factors.

If only one of the light chains goes up, it's more likely to be related to the multiple myeloma because then it's, as we call, monoclonal even though we also see that patients have sometimes more than one clone. Even though the disease is called monoclonal disease, it might be more than one clone.

But, basically, there are other factors that can elevate the kappa and all the lambda light chains, but the ratio of both is very important. So, the ratio between kappa and lambda or lambda and kappa is relevant. If it's a very strong increase, then it's most likely the multiple myeloma.

25:05     [Moderator] All right. Dr. O'Donnell, I think we have a couple of questions that we can put together for you. Does the chemotherapy used to treat multiple myeloma and multiple myeloma itself affect neuropathy in hands and feet only, or can it also affect things such as the feeling of the sensation with urination?

25:32     [Dr. O’Donnell] That's really a two-part question. There are therapies that we use for the treatment of myeloma that do cause peripheral neuropathy. Some do so more consistently, bortezomib being a known example of such, and some of the chemotherapies used during transplant can as well. But a lot of the other treatments we use do include this, and we see it less commonly but still do see it with many of our standard FDA-approved therapies.

In general, peripheral neuropathy can begin with a change in sensation or numbness and tingling in the fingers and toes and march backwards and up. It can also cause pain. Some patients may describe a painful neuropathy.

To your question about urinary symptoms, that is not one that I have had my patients report to me, so I'm less familiar with that as a manifestation of peripheral neuropathy that I have seen in my experience.

26:34     [Moderator] Okay. Dr. Ramanathan, does neuropathy increase the longer you are on maintenance Revlimid?

26:41     [Dr. Ramanathan] There is a 5% to 10% chance of developing neuropathy with Revlimid. So, the longer you are on Revlimid, there is a possibility of neuropathy increasing. As the previous speaker pointed out, the neuropathy is usually from other drugs, but it can be worsened the longer you're on treatment. So, if the neuropathy is getting worse while in maintenance, then maybe cutting down or decreasing Revlimid dose will help.

27:20     [Moderator] All right. Dr. Hillengass, if M protein begins to increase while on a triplet or quadruplet regimen, how do you know which of the individual drugs you might have become refractory to?

27:34     [Dr. Hillengass] That is very difficult to say because, as you say, it's a combination of drugs. But on the other hand, if it's rising while on a quadruplet, it's most likely that none of these drugs is very effective anymore because it's not very likely that one of the drugs makes the others work less. So, they were developed to be combined, and the combinations have been evaluated.

And so, if the M spike goes up despite triplet or quadruplet treatment, usually all of those drugs are not very effective anymore. There might be other combinations of one or two of these drugs that might have a benefit because of interactions of drugs, but it's not very likely. So most likely, if the M spike goes up, the disease is refractory to all of those drugs.

28:25     [Moderator] All right. Dr. O'Donnell, I understand that carfilzomib is a very effective proteasome inhibitor, but with a potential cardiac event risk. When is carfilzomib a good therapy choice and what can be done to manage the cardiac risk?

28:46     [Dr. O’Donnell] Again, a really great question. Carfilzomib is a proteasome inhibitor that is commonly used in the treatment of multiple myeloma, particularly in the second line of therapy. It does have known cardiac risks. Those risks seem to be more pronounced in people who have a cardiac history such as those with a history of congestive heart failure, atrial fibrillation.

So, there are two strategies of which to approach this. One is just how you escalate the dose. There's a very standard starting dose, no matter what in carfilzomib, that's below what the target dose is. So, if you have concerns about a patient's cardiac function and the potential for toxicity, first start with a good understanding of what the patient's cardiac capabilities are, with an EKG and an echocardiogram. Start at a low dose and escalate relatively slowly if you have concerns.

Carfilzomib is also given with fluids. If someone has a history of congestive heart failure, give it with less fluid potentially and monitor your patients. Let them know what symptoms to expect and what to do should they have those symptoms. If a patient does experience cardiac toxicity at a higher dose of carfilzomib, you can back down the dose and retry it at a lower dose as well.

30:15     [Moderator] Dr. Ramanathan, what percentage of allogeneic transplants, that's transplants using donor cells, following an autologous transplant for multiple myeloma have been successful? What are the risks for an allogeneic transplant after an autologous transplant?

30:34     [Dr. Ramanathan] Again, the success rate, so to speak, allotransplant almost always engrafts. That's usually not the concern. The concern is what is the chance of relapse even after undergoing transplant? That (risk of relapse) is the least of all the treatment options we have available. The risk of relapse after allotransplant is about 30%. But, of course, it will depend on what your initial starting point is, whether your disease was in good control or not at the time of transplant.

The toxicity of allotransplant is primarily graft-versus-host disease. Graft-versus-host disease can be both acute or chronic. Acute GVHD can be up to 25% of the time typically, which is primarily the reason why we are hesitant about doing allotransplant.

The other risk associated with allotransplant is risk of infection, both due to the underlying disease and treatments that the patient has received, but also due to immunosuppression that patients have to undergo after transplant, at least for the first six months. So primary risk is risk of graft-versus-host disease and infection, not so much the risk of chemotherapy for allotransplant.

32:03     [Moderator] All right. Dr. Hillengass, how would you interpret a plateau in the reduction of M proteins after 30% decline? How long would you persist with the same drug regimen before changing? What do these results portend for using the same regimen in a future relapse?

32:22     [Dr. Hillengass] So achieving a plateau is ... It depends very much on where this plateau is. If it's a very high plateau, then I would rather change the treatment, because I mean a reduction of 30% is not much. In myeloma, we try to achieve deeper remissions. But this also depends on where in the disease journey this patient is.

If it's very early in the disease, then we have a lot of options. I would rather switch the treatment if it's a patient who had a lot of treatment before and can stay in this remission ... We call it not even a remission. It's a minimal response. We call it clinical benefit. So, if the patient has no symptoms and had a lot of treatments before, not many options left, then I would be okay with such a response.

But if a patient is very early in the treatment journey and, for example, stem cell transplant is planned, I would rather switch to treatment to achieve a deeper remission as preparation for further treatments.

To give the same treatment again is similar to the question we had earlier. If we have other options, then I would rather you choose the other options because this treatment seems to be not too effective for this patient.

But on the other hand, we have also seen that there's a so-called clonal tiding also based on what we have heard earlier. We treat different clones of the disease differently without knowing it. We give the same treatment, but some clones, some parts of the disease respond better, others don't.

So, it might be worth a try in later disease. But, again, this was not very effective in this patient if it's only, as I would say, a reduction of 30%. So, I would not encourage using that if there are other options.

34:22     [Moderator] All right. Dr. O'Donnell, does autologous stem cell transplant or Revlimid or myeloma itself have any effect on memory or the ability to focus, for example, when there's music or other background distractions?

34:40     [Dr. O’Donnell] There is something that you'll hear patients describe as chemo brain, which is a slowing of your typical cognitive function, so harder to balance a checkbook, harder to execute tasks that normally were much easier or that came more naturally to you. And so, we do see that with different treatments, and patients do describe that with Revlimid and also with the medicines given for transplant.

The myeloma itself, I think, is less likely to be a factor there. But even medicines such as dexamethasone, which is a part of almost all therapies for myeloma, have effects on patients which can alter mood and also can alter sleep patterns, which it can also affect cognitive function. So, it's very often multifactorial.

35:31     [Moderator] Dr. Ramanathan, perhaps you can answer this one. "I'm interested in being part of the CureCloud, but I was told it is only for people with active disease, and I'm in remission. I would like to know from the CureCloud what others in remission are doing about maintenance therapy and what their results were? Is it true that if the disease comes back, it's often in an altered form and not with the same characteristics as it had at the time of diagnosis when it was deemed high risk?"

36:03     [Dr. Ramanathan] So CureCloud is a new platform which is being developed by the Multiple Myeloma Research Foundation. The idea is really to collect blood samples from patients and do genomic testing to see how we can improve on current treatment regimens.

So, it's a work in progress, and I think it is something new to evolve as we learn more and more. As far as I understand, it is primarily to get blood which can be collected at home and sent for genomic testing, to see if we can learn from this and improve.

I don't know how much it's going to change within the next few months to years. I'm not exactly sure if it has to be only newly diagnosed. It could be at any point in the myeloma treatment course.

37:10     [Moderator] All right. Dr. Hillengass, perhaps you can address this targeted question. Is it true that if the disease comes back, it is often in an altered form and not with the same characteristics as it had at the time of diagnosis?

37:26     [Dr. Hillengass] Yes, that's true, especially in later lines of treatment. Every treatment kills a certain part of the disease. Then as we know, unfortunately, most of the time the disease comes back. So those cells are selected. It doesn't really change a lot, but it selects, or most likely it selects, the different clones that are more resistant to the former treatment.

What we also see, in later lines of the disease, when the patient's already had several relapses, when the disease came back and they got treatment again, as it's describe in the question, sometimes the characteristics change, that the patient who, for example, had these regular multiple myeloma with the well-known symptoms can develop all of a sudden swellings of lymph nodes or infiltration of organs that we have seen in later lines of treatment.

So, the theory is a little bit that we basically treat the different clones, and some respond and some don't. Some grow up again, some disappear completely because they really died from the treatment. But, yes, the disease characteristic can change.

Some patients have the same characteristics over time. It's very difficult to predict. Sometimes we see in high-risk patients that the change of the characteristics of the disease occur more. Very rarely, fortunately, patients develop a so-called plasma cell leukemia, which is then a very aggressive version of the multiple myeloma, that can also occur very late in the disease state, for example. So, yes, there are changes over time.

39:09     [Moderator] Dr. O'Donnell, can you explain what BCMA is and how it relates to the various forms of myeloma?

39:16     [Dr. O’Donnell] Sure. So BCMA stands for B-cell maturation antigen. If you were to look on the cell surface at a microscopic level, they're little protein strands that are attached to the top, and almost like hairs extend from the plasma cells, the myeloma cells themselves.

BCMA is a common protein that's on the cell surface of myeloma or plasma cells. It's not on a lot of other types of cells, so it makes it a very attractive target for myeloma therapies. The reason being if it can bind only to the bad cells and not affect the good cells in the body, you'll have less toxicity.

We see BCMA being targeted in a lot of our new therapies, including CAR T-cells, antibody drug conjugates, and by specific T-cell engagers specifically.

40:09     [Moderator] Dr. Ramanathan, do we know why multiple myeloma tends to affect African Americans at a greater rate than Caucasian people?

40:21     [Dr. Ramanathan] Cancer, in general, seem to be affecting African American patients at a younger age and more severely. This is not only specific for multiple myeloma. It is true of all cancers, and I'm not exactly sure we understand why that is the case.

40:49     [Moderator] Okay. Dr. Hillengass, what treatment do you recommend for myeloma that's migrated to the lymph nodes?

41:01     [Dr. Hillengass] What I have used ... And, again, this is, unfortunately, not really based on a lot of scientific information. It's more personal experience. If it's really in the lymph nodes or the soft tissues, then I have rather used more old school chemo drugs that have worked good in patients. What I have also done in patients, doing a biopsy of such a lymph node, which we oftentimes do just to really confirm that it is myeloma and not another cancer.

We have then stains for certain markers on the surface. As Dr. O'Donnell said, BCMA is a very common marker in myeloma. But, for example, CD20 and CD30 are other proteins on surfaces of cells that can occur in such patients. Then sometimes we can apply to insurance [for permission] to give a treatment directed against such surface markers. So, these are things that I usually do in those patients and try to do a more individualized approach and more classic chemotherapy agents that have shown to be effective in such patients.

There are newer drugs that have been shown in some studies that they're also effective in soft tissue tumors, but this is rather fresh out of the press information. So, we will have to see if that is really true and if that is really confirmed.

42:25     [Moderator] All right. Dr. O'Donnell, two years after transplant, muscle tone and a tendency towards weight loss are being noted. Are there specific diet and/or exercise recommendations to counter these tendencies? The patient is currently on maintenance Revlimid.

42:44     [Dr. O’Donnell] So there are a lot of factors that can contribute to changes in body composition. Body composition is really composed of how much lean muscle or good muscle you have and then how much fat you have, with the kind of appreciation that more fat is not good for you.

And so, what happens to a patient as they go through therapy for myeloma? Often patients present for the first time with the doctor with pain or a bone lesion that may be immobilizing or quite painful that limits their activity and causes new restrictions. So maybe their activity level goes down when they begin therapy.

There are side effects of the therapy. As I mentioned before, dexamethasone can have some side effects, including loss of lean muscle mass, gain of visceral fat, so belly fat. Going through a transplant with a prolonged, two-week hospitalization, decreased activity, and being housebound for several weeks thereafter can all cause loss of physical function.

So, really, it's two separate things. One, how do you gain back physical function? There are two answers to that. One is to avoid inactivity. To the extent you can, try to continue to be active throughout your cancer treatment. Then two is to work on getting yourself in shape or maintaining physical fitness throughout your treatment.

So, the American Cancer Society recently revised their recommendation. But, historically, the goal had been 150 minutes of moderate intensity exercise per week. There are more recent data that say even three half-hour sessions per week would be better for you than none at all. The guidelines also recommend some strength training twice a week. This is a little bit harder for the myeloma population where your bones are vulnerable. It's important to talk to your doctor about the safety of exercise.

But it's important over time, as myeloma is a disease that patients will live with for many years, to ensure good quality of life, good physical function throughout the duration of the illness, and also to lower cancer-related fatigue.

In terms of diet, there is no one size fits all diet. We don't have any specific research or data within multiple myeloma about what the best diet is. In general, a plant-based diet where 60% of your diet comes from fruits, vegetables, and whole grains is recommended, and minimizing red meat consumption to no more than once per week.

45:29     [Moderator] All right. Dr. Ramanathan, question about second autologous transplants. Is anything different done in a second autologous transplant than what was done in the first autologous transplant?

45:46     [Dr. Ramanathan] So by way of chemotherapy, it's the same drug, melphalan, that is used in transplant. For various reasons, the dosing can change from transplant to transplant. For example, if the first transplant, because of renal insufficiency, a lower dose of melphalan could have been used. When the kidney function improves at the time of second transplant, for example, then we may be able to use the full dose of melphalan. But it's the same drug.

As I had mentioned, there is cumulative toxicity. So, the more and more melphalan we give, we do run into problems with organ toxicity. But the second transplant is relatively well-tolerated.

The other factor that determines the outcome after a second transplant is what is the remission status at the time of transplant? So if you're able to get into a deep remission with salvage chemotherapy and then undergo a second transplant, the outcomes tend to be very good.

46:57     [Moderator] Okay. Dr. Hillengass, what is the form of leukemia or lymphoma that occasionally occurs late in the progression of myeloma that you recently mentioned?

47:09     [Dr. Hillengass] Yeah, that's called plasma cell leukemia. It's basically a very advanced version of the multiple myeloma. Usually myeloma cells are very dependent on the bone marrow microenvironment, the area where usually in the bone marrow the myeloma grows.

Usually they need those supporting cells around them, but in some cases, and very rarely, patients develop this plasma cell leukemia where the myeloma cells have a quiet ability to survive in the peripheral blood or similar with lymphoma, like in the soft tissues or lymph nodes. It's not a different disease. It's just a further advanced stage or further advanced version of the multiple myeloma.

47:53     [Moderator] All right. Dr. O'Donnell, would you expect organ or bone injury from M protein levels of 0.5 g/dL or less?

48:08     [Dr. O’Donnell] Again, Sue, this is a two-part question. So, organ injury in multiple myeloma, specifically kidney dysfunction, occurs when there's so much of this extra protein, particularly the free light chain, circulating in the blood that it clogs the kidneys. Kidneys are really just a big filter.

And so, the amount can matter in terms of organ dysfunction. A level of 0.5, that's really not typically ... Unless there's already significant renal compromise or kidney compromise, that's not a level where we would typically see organ damage. However, if there is a small residual M protein, that speaks to the fact that within the bone marrow, there's still a plasma cell process going on.

As Dr. Hillengass just alluded to, within the bone marrow, there's a microenvironment, meaning there's very special cell signaling going on that regulates the building and destruction of bone. When you have multiple myeloma, that relationship or that balance can be thrown off.

So we don't really say that a specific amount of protein reflects exactly what's going on in an organ or a bone level. But I think we can appreciate that if there is residual disease, there's still a perturbation of that homeostasis going on within the bone marrow microenvironment with your myeloma.

49:38     [Moderator] Okay. Dr. Ramanathan, "My arms and legs fall asleep more readily than they did before transplant two years ago. Is this a progression of neuropathy?"

49:50     [Dr. Ramanathan] It's hard to say. Again, neuropathy tends to be tingling, paresthesia, or pins and needles. Sometimes you get the feeling of walking on pebbles or having your socks on all the time. Those are the features of neuropathy in the feet. Neuropathy in the fingers, there'd be numbness. But again this is persistent. It could wax and wane, but it's persistent.

What you're describing sounds to be going to sleep, and there could be various reasons why. It could be blood circulation-related, activity-related. So, we need to identify what exactly is going on. It may or may not be neuropathy.

50:39     [Moderator] All right. Dr. Hillengass, you've been asked to comment on T-cell leukemia development in the course of the myeloma journey.

50:47     [Dr. Hillengass] Yeah. It can happen. We discussed earlier during this session that second cancers can develop. A T-cell leukemia is biologically different from myeloma, so I don't want this to be confused with the plasma cell leukemia I was talking about which develops out of the myeloma, the same disease. A T-cell leukemia can develop as a result of the treatments that we give our patients, or completely independent of that, of course.

It's, fortunately, very rare, but it can happen. We have seen several patients now developing an acute leukemia, either myeloid leukemia or lymphatic leukemia like a T-cell leukemia, that developed in the patient. But, also, we have seen patients developing solid tumors. Again, fortunately, it's very rare, but it can happen.

51:39     [Moderator] Dr. O'Donnell, does Revlimid itself lead to chemo brain, or is that more likely due to the melphalan?

51:47     [Dr. O’Donnell] That specific term is not something that is truly well-studied in the drug trials that we have. But I think very commonly patients complain of the symptoms that we described earlier in this call. It's hard to distinguish, particularly when they've had both, which is the more likely one to contribute to this.

52:11     [Moderator] All right. Dr. Ramanathan, how does amyloidosis present with multiple myeloma? What symptoms of amyloidosis should a patient watch for? Are there certain types of myeloma more likely to also exhibit amyloidosis?

52:29     [Dr. Ramanathan] Amyloidosis is typically primary amyloidosis, which is AL amyloid, lambda light chain amyloid. Sometimes amyloid coexists with myeloma. Usually when patients present with symptoms suggestive of amyloidosis, such as cardiac symptoms or kidney symptoms, more so than what we would typically see with myeloma, then amyloidosis is suspected.

It can be detected even in organ biopsies like in kidney biopsy or cardiac biopsy, or it can be detected in the bone marrow. Then we have to do specific stains to identify amyloidosis. Like I said, it's typically lambda light chain-associated.

The treatment for amyloidosis is very similar to the treatment of myeloma. So, what treatment that you get for myeloma tends to also help amyloidosis. More specific treatments such as bortezomib and daratumumab seem to have a better treatment effect in a patient with amyloidosis and multiple myeloma.

Amyloidosis means excess deposition of these light chain proteins in multiple organs. So, it could be the heart, it could be the kidneys, it could be liver, it could be several other organs, skin, and other organs.

54:17     [Moderator] All right. Dr. Hillengass, does the time at which myeloma is diagnosed impact the likely success of an autologous transplant?

54:26     [Dr. Hillengass] I have to admit I don't know what is meant with time. If it's meaning earlier or later in the disease, we think that a lower tumor burden, which is not a nice word but it's summarizing the activity of the myeloma and the amount of cells of multiple myeloma, we know that if a patient achieves a deeper remission, which is easier when the disease burden is lower, then the autologous transplant tends to be more effective.

If the time is meaning smoldering multiple myeloma, I am rather hesitant at the moment to treat patients with smoldering myeloma outside of clinical trials. That's what I think might have been meant with time. If someone wants to explain the question a little bit more, I'm happy to answer again.

55:25     [Moderator] Okay. Dr. O'Donnell, what therapy for multiple myeloma is best if your insurance will not cover a transplant?

55:36     [Dr. O’Donnell] So for our newly diagnosed patients with multiple myeloma, it a little bit depends on your age, as alluded to before. But the combination that we've heard referenced before of RVD, or Revlimid, Velcade, dexamethasone, for many is the standard of care. And so, this can be given for at least eight cycles with excellent effect.

This past year, at one of our major conferences, there was a study presented looking at the combination of carfilzomib, Revlimid, and dexamethasone with or without transplant. It actually showed very similar results for both of those arms.

So, it's about using the combination of therapy to achieve a deep response, as deep response as you can go, will bounce with toxicity, and then transitioning to maintenance based on disease response.

56:35     [Moderator] Okay. Dr. Ramanathan, is there any type of myeloma for which an autologous transplant would not be the appropriate therapy?

56:46     [Dr. Ramanathan] Not necessarily. I'm not exactly sure if they have a specific subtype in mind, but any myeloma will benefit from an autologous stem cell transplant, because truly autotransplant is high-dose chemotherapy followed by stem cell rescue. The more chemotherapy you get, the more cancer kill that is gotten. That is the principle of transplant. Every myeloma will benefit from an autologous stem cell transplant.

57:22     [Moderator] Okay. There was a question just texted in about CT scans being used instead of PET scans and MRIs to see myeloma lesions. That was answered earlier in this workshop. So if the person who typed that question would like to go back afterwards and listen to the earlier questions, you will find your answer there.

57:45     [Moderator] Are there any other questions from folks who are interested in having the doctors address a myeloma issue? We have one last question, which is actually not a myeloma questions, but perhaps Dr. Jens Hillengass would like to answer this. "I'm two years out of allotransplant for myelodysplastic syndrome. Does MDS fall under the umbrella of multiple myeloma conditions? If not, how are they different?"

58:13     [Dr. Hillengass] Yeah, so the answer is, no, they are not the same. They're different in the sense that both are hematologic diseases coming from cells of the immune system of the bone marrow. But the MDS is coming from the myeloid lineage, which is one part ... It divides very early in the development of our blood cells. It divides into the lymphatic and the myeloid lineage.

The MDS is a myeloid and the myeloma is a lymphoid malignancy. So very, very early, the cells are the same, but in the further development and where the cancer actually develops, the multiple myeloma develops, these are two completely different diseases.

58:56     [Moderator] So unless there are other questions, I think that brings us to the end of this session. If you have additional questions, you can certainly email them to help@bmtinfonet, and we'll be happy to try to get the answers for you. On behalf of BMT InfoNet and their partners, I would like to thank our panelists today for their very helpful remarks and to thank you, the audience, for your excellent questions.