Robin Tuohy:
Welcome everyone, and thank you for joining us for the International Myeloma Foundation's Living Well webinar series. Today, we will focus on living well, ways to improve your bone health as a Myeloma patient. I'm Robin Tuy, vice President Support Groups.

Before we get started, on behalf of the IMF, I'd like to thank our sponsors for supporting this educational program and tonight that is Bristol Myers Squibb, GlaxoSmith Klein, Janssen, and Sanofi.

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It's now my pleasure to introduce you to our speakers. Dr. Beth Faiman began her career in 1994 at the Cleveland Clinic in Cleveland, Ohio where she is employed and immediately became involved in the care of patients and their families living with multiple myeloma. She's also involved in clinical trials to improve numerous drugs to treat myeloma and remains an active member of the healthcare team and the diagnosis and management of patients with multiple myeloma. Dr. Faiman is also a founding member of the IMF Nurse Leadership Board in 2006, and she is passionate about side effect prevention and management. We're also grateful to have joining us this evening Dr. Jens Hillengass, a professor of oncology and chief of myeloma and amyloidosis service at Roswell Park Cancer Center Institute in Buffalo, New York. Prior to joining Roswell, he was the deputy of the multiple myeloma section of the University Hospital of Heidelberg, Germany, the leader of its autologous stem cell transplant program and heads of the Hemat Oncology Imaging Research Group at the German Cancer Research Center. Dr. Hillengass is also a member of the International Myeloma Foundations International Myeloma Working Group where he co-chairs the bone and imaging group.

So at this time it's my absolute pleasure to turn this program over to Beth Faiman to start us off. Beth.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Thank you so much, Robin. I really appreciate and I'm always honored to be invited to speak to patients about side effects and even more so today with Dr. Hillengass who is a co-chair of one of the most important groups in the International Myeloma Working Group. So today we are going to be focusing on bone health. This is one of the most important ways you can keep yourself healthy and we'll give you some strategies and tips. One of the things I recognized when I started caring for patients with multiple myeloma was how many of them presented in wheelchairs and all hunched over, and now we have so many good strategies, medications, supportive care techniques to prevent that from happening. So now people can stand upright and tall as we treat their myeloma. So we'll go through the guidelines and also review bone health is so important.

Now, most of you on this call know that multiple myeloma is a cancer of the bone marrow plasma cells. The healthy plasma cells responsible for protecting you from getting sick unfortunately make one clone of an abnormal protein called a monoclonal protein. Those proteins will continually secrete cytokines, chemicals, and all different kinds of things that want to dissolve the bone and can attack the kidneys. And so treating that protein when appropriate is very important.

When you have an abnormal protein in your blood or urine, this slide shows that there's really three different phases. The first phase is monoclonal gammopathy of unknown significance. Many of you here on this call might have MGUS or had MGUS before you were treated with myeloma. There is actually good evidence that shows even people with MGUS can have ongoing bone loss from the chemicals that want to dissolve the bone in the bone marrow environment. And we'll talk more about that later.

That second level is smoldering myeloma. Patients with smoldering myeloma have a higher level of circulating proteins in their blood or urine. This is a perfect time to find out whether or not you as a patient are a candidate for a well-designed clinical trial. Because if your protein's just high enough that you don't quite qualify for a myeloma diagnosis, you still might be able to participate in a clinical trial so we can find out when we should start treating patients and when we should just continue to observe.

And then finally, active myeloma. That's the top of the tier. That's when you have CRAB: calcium elevation, renal dysfunction, anemia, or bone lesions. So you can see part of the myeloma diagnosis includes bone, and that's why it's so important to talk about. In 2014, as you probably know, the International Myeloma Working Group also suggested that if you had a bone marrow percentage of greater than 60%, a free light ratio of greater than a hundred of this capita Lambda and a low creatinine clearance and an MRI with greater than one focal lesion greater than five millimeters usually found on MRI and Dr. Hillengass will talk more about that later on, then those patients should qualify possibly for earlier treatment.

Dr. Hillengass.

Jens Hillengass, MD, PhD:
Thank you so much, Beth. Great introduction. Thank you so much for having me, and it's a real honor to give this talk with you. Myeloma bone disease, as you mentioned, is a very important part in myeloma, obviously. And as you can see here, what's going on in myeloma is that the myeloma cells are interacting with their environment. They're very depending on the environment, when we do research and we take the myeloma cells out of the environment, they're oftentimes they die, right? And so they need this interaction with other cells, and some of those cells are the eating of the bone building cells. All of us have those cells, they're called osteoblasts and osteoclast. The osteoclasts are the eating cells and osteoblast are building cells, so usually they're in a balance and our body repairs itself by eating bone and then building bone at the same time or almost at the same time.

In myeloma, the bone eating cells, the osteoclasts are overactivated and that leads to this bone loss. And the osteoclasts, they are increased in number and in activities. So it's not only more, they're also more active. And that's important, especially when we look into how can we treat or how can we prevent further damage to the bone. The osteoblasts, the bone building cells are more active and this oftentimes happens in a very close proximity to the myeloma cells themselves. So there's a very close interaction between those cells. Osteoblast activity is usually normal in other regions or sometimes even increased. So showing that the body tries to counteract this overactivation of the bone eating filter osteoclast. And there's this theory, it's not to my knowledge, it's not really proven, but there's this theory that when the bone is destroyed that it builds a scar, because that's oftentimes a question that my patients ask me if I have a little lesion, will it ever go away?

So that's something that is still not really clear. Maybe you, Beth, know more about it, but I think it is difficult, and I will show later slides where I go into what happens to the osteolytic lesions later on.

This is a very complex slide, and these don't go into any details. It's just showing you this complex interaction between the bone eating cells, the bone billing cells to myeloma cells and the stromal cells which are other cells in this area. And there's a lot of research going on, still going on. This is research as you can see from over 10 years ago. There's still a lot of research going on right now to figure out what's really going on. What can we do to prevent this destruction of the bones?

A young colleague from Heidelberg who came to Roswell Park in Buffalo for two years did really great work where we did biopsies of an o osteolytic lesion of this, punched out lesions that cause all this trouble with fractures and pain and all that. And we did a biopsy of that, and we did a random bone marrow biopsy as we usually do on the pedal as most of you I guess have experienced. And you can see maybe on the upper right side, we found that in the osteolytic lesions there are more cells most of the time, and in the bone marrow sometimes the cells are less. So just a mere amount of myeloma cells seem to have an impact of this bone eating process that's going on there. And when looked with very, we call it deep sequencing, we looked what genes in the myeloma cells are overactive. So the genes are the blueprint of our cells and certain genes can be up and when they're upregulated this process that this gene is the blueprint for is more active. And what we found is that in some of these cells in the osteolytic lesions, the bone turnover genes were very high. So we think that the myeloma cells have some genes activated that lead to this bone destruction and that stimulates this osteoblast.

So it's a very complex interplay of these different cell types. And this is what we still try to figure out. We are now looking into immune cells surrounding the myeloma and the osteolytic cells and we see that there's even there an interaction between those cells.

As we mentioned, myeloma bone disease is very common. Almost 90% of patients have some kind of lesions in the cause of their disease. 80% have fractures. It increases the mortality because there are things, obviously, patients who are in pain cannot move that much. They have a higher risk of thromboembolic events, blood clots can rather, get pneumonias because they cannot be active as they should be. And so there are a lot of things going on that are connected with the bone disease that are not even manifest itself in the bone but in other areas of the body.

But pain is obviously a big topic. Fractures, hypercalcemia is also related because these bone eating cells get calcium out of the bone into the bloodstream, which then can cause other symptoms.

For the diagnosis, and it was already mentioned by Beth earlier, we have different ways to diagnose the disease. And I could talk about, I would say without interruption five hours about imaging in myeloma because that's what I have done for the last over 20 years. We have done a lot of skeletal surveys for many, many years and that was okay at the time when we had nothing better available. But nowadays, we have more modern techniques. And there was a question in the chat asking about MRI. I want to go through those techniques briefly. The whole, the WBLDCT is a whole body low dose CT, which is a CT scan of the whole body, low contrast H needed and that is the most sensitive technique to detect bone lesions, because CT is based on x-ray, and the X-ray is not going from one direction just in one area from one side to the other how it's case in skeleton surveys, but it goes around the body. So we get a 3D image of the skeleton because the skeleton, obviously, the bone is very dense and this dense bone kind of blinds out the x-rays. And if we do that from a 360 perspective, then we get the 3D image.

PET CT is giving a radioactive dye, which basically is sugar, that's radioactive, and cells that are very active like myeloma cells eat up this sugar and then the sugar lights up in the area where we have this accumulation of the myeloma cells, and then we combine this with the CT and then we have this benefit to see the bones, so a combination of metabolic activity of the cancer cells, finding them in the body, and then we can see if they have led to this bone destruction.

If this is so awesome, why do we need MRI in the first place? An MRI is very sensitive. MRI is based on the water content of a tissue. Bone doesn't have a lot of water, so the bone itself is not very well displayed in MRI, but the bone marrow which is inside the bone, and you might remember the steel needle going through your bone into the bone marrow, that's exactly where we have our bone marrow, which is the organ that builds our blood. But that's also the organ where the myeloma is actually sitting because that's this interaction that I mentioned earlier, this bone eating, bone building cells, stromal cells and all that of that, that's a whole family of cells sitting there and interacting with each other.

And this is a slide actually from Beth, and I really like it because it also mentions DEXA scans bone density, which is very important. Osteoporosis, when we get older, our bones just get a little bit weaker and DEXA scan shows that. But in multiple myeloma, the problem is as I mentioned, that oftentimes these lesions are very focal and punched out and if you do DEXA scan of the left hip, you will not see what's going on in the right arm. So DEXA scans are interesting for a general diffuse loss of bone, but it's not really helpful for multiple myeloma or detection of [inaudible 00:15:49] lesions.

Coming back to this question about the whole body MRI. We would like to see a whole body MRI. Sometimes the insurance companies are giving us a hard time to get this, but there are good reasons to do that, because MRI shows the changes in the bone marrow before the bone is destroyed. Once the bone is destroyed, it still shows the changes, but there can be changes before the bone is destroyed. And that's very important in early stages like MGUS and smoldering myeloma.

In a low risk MGUS, I don't think we need imaging, but in a higher risk MGUS or smoldering multiple myeloma, whole body MRI is very helpful. And the patient who asked this question talked about diffusion weighted imaging and just briefly, that's a technology that also measures the water content of the tissue and it is very sensitive to detect changes before the bone is destroyed, which we obviously want to do. We don't want to see when it's done. We want to see before it's happening. The problem is that not every center or not every hospital, not every doctor's office has access to this diffusion weighted imaging, and the patient asks here if there's a list of centers, to my knowledge it's not. So you would have to ask your provider if they have access to this kind of imaging.

And let's just go to one last question regarding the diagnostics. It asks about PET CT and yeah, so that's a very specific question. So again, as a summary, CT shows the bone the best. PET CT includes CT, so it shows the bone and it shows metabolic, the pet part shows the metabolic changes. And MRI is very sensitive to show changes before the bone destruction has happened. I think that's a brief summary of that. And then we have compared these different techniques and we have found that CT is about 25% more sensitive than skeletal survey, because they did a long time ago they did a study where they drilled holes into the bones of a corpse, filled it with water, did an x-ray, and they found you that they have had to destroy 50 to 75% of the bone until they even found any changes. So that's the reason why we would really recommend to CT instead of skeletal surveys. And now I hand over back to Beth.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Thank you so much. This has been such a wonderful thorough review of bone imaging, and I've been studying this for years, but the way that you've shared how these techniques are done has been very helpful to me as well as I'm sure, you, on the line. So what do you do about these bones to treat them? Is it always going to be this ongoing damaging of bone? The osteoclast are going to always nibble away at the bone, and it depends on how well controlled the myeloma is, number one, and how active these cells are.

There are three main medications that are given to patients with multiple myeloma. The first one according to the updated guidelines is zoledronic acid. This is really now the preferred agent. It's also indicated for multiple myeloma related hypercalcemia. So it's recommended at diagnosis to receive about 12 months of these bone strengtheners. And then at that time, the physician or the treating team can say, how well controlled is your myeloma? How bad are your bones? Do you have bone disease? And consider whether or not you want to give it on a quarterly basis, twice a year, once a year, et cetera. So that discussion goes between you and your treating team.

Denosumab is a wonderful drug and we'll talk about that in a moment and why we would use that that may be used, especially if you have kidney impairment. It's a monoclonal antibody against this ranked ligand and so that's really an important piece of bone turnover. There's all these different parts in the bone turnover process in that interaction between the tumor cells and the bone marrow microenvironment where these cells live, but the denosumab is very helpful. It's a shot in the arm than given once a month in patients with myeloma. The important thing to remember about denosumab if you've always been prescribed it is we can't just stop it. So there's some data that suggests that you can have reversibility of that bone building benefit and there are some studies that say maybe we should have you get a dose of zoledronic acid before we stop, or just give it once or twice a year.

And then pamadronic acid is one of my favorite old drugs. I actually just stopped recommending it routinely in the last five years. This is a drug that was approved in 1996. In 2002, there was a study that said it was non-inferior to zoledronic acid, which is then when we started using zoledronic acid for myeloma routinely. But anyway, there have been some quality of life studies in Europe that showed that 30 milligrams versus 90 milligrams really helped improve quality of life, decreased skeletal related events. So as much as I like the drug, I think that there are better drugs out there, which is what we're using these days.

So let's go talk some more about the mechanism of action of these bisphosphonates. As much as I love these adorable graphics, I think the highlight of this slide is that there is an interaction between the tumor cells and the bone marrow environment. Look at this blue cell, that's your osteoclast. I call that the scrubbing bubbles guy. He nibble away bone and the osteoblasts which are responsible for rebuilding bone unfortunately in myeloma are silenced. And that's why we need these drugs such as bisphosphonates to wake up the osteoblasts to stimulate the growth factors to rebuild bone the way it should be.

When you're looking at some studies that support the use of these bone strengtheners, this one study that is referenced from 2010 and Gareth Morgan, and this is from what's called an MRC trial. This looked at zoledronic acid versus clodronate, which was the standard of care at the time, and it showed that there was a significant improvement in people living longer when they were given zoledronate, which is the zoledronic acid versus the clodronate, which we don't actually use in the United States. What's also really important to think about is the drug denosumab. I recently mentioned that we had this [inaudible 00:22:18] pamadronic acid from 1996, and then we had a study that said it was non-inferior to zoledronic acid. Now in modern times, Dr Napor Raj and colleagues looked at a study and compared the denosumab, that shot that you can get monthly and then less often versus the zoledronic acid. So this is what's called a non-inferiority trial. We're not trying to say one is better than the other, but both were really good at strengthening bones and decreasing what's called skeletal related events. And that's a common endpoint of these clinical trials, making sure you're not breaking another bone.

Looking at the side effects of the denosumab, it's a different class of drug, it's a monoclonal antibody, it's not a bisphosphonate. So now we call these bone-modifying drugs. The side effects are pretty similar among both of the groups. Most patients did pretty well. Little bit of diarrhea, nausea, and constipation, but that can be seen in anything. Really, I try to advise patients to make sure that they're getting good dental exams and we're checking their urine because these medications, well the zoledronic acid, can affect the kidney tubes and so stay hydrated. The other thing we want to make sure about is that you're taking oral calcium. Now many oncologists will say, don't take that because then if your calcium's high, what do we do? But when you're on drugs like denosumab or the zoledronic acid, it can drop your serum calcium down and make you tired and have other side effects. So talk with your provider about whether or not taking extra calcium supplements are right for you.

I've seen some very low calcium levels, but again, some of the major side effects we worry about is the jaw necrosis. This was described years ago in a medical journal where it was actually breast cancer patients were coming into Florida and they identified that patients were having more of this jaw complication. So it's important to make sure you have a good dental exam and good dental hygiene during this. We know zoledronate can affect the kidneys. I mentioned stay well hydrated, avoid anti inflammatories, and then acute phase reactions. That's kind of like some people feel like they're getting flu-like symptoms, so I recommend to take Tylenol on the days before or in the evening if you have that.

This is a very graphic representation of the John necrosis, and in the early two thousands I saw a lot of this. We weren't very good about recommending dental care. It can be a festering infection that doesn't clear. There are some studies in the late two thousands that were suggesting that antibiotics is how we should treat this and that's still what I do, but I want to prevent it by good dental hygiene and a good dental exam to start.

Going through these quickly now because I keep talking, I could talk for five hours about bone just like Dr. Hillengass, but we have other things to do. Drug related toxicity is something that we really worry about. So again, look at the dose, discuss this with your treating physician or your treating team. If you're going to have dental surgery or invasive dental procedures, make sure you have that discussion. Do you need antibiotics before or after, and is it safe? And then looking at the age and your race, there might be more risk factors for osteonecrosis in the jaw as well.

Again, the duration of treatment, this is your alphabet soup of all the different guidelines. The important thing to know is that there is not a clear agreement as to how long. I saw some questions in the chat. How long should I be on it? Well, the International Myeloma Working Group recommends every month for one year, and then you can decrease the frequency long term to minimize your risk of this jaw necrosis and minimize your risk of kidney problems if you're on the zoledronic acid. But have that discussion with your treating team.

Dr. Hillengass, back to you.

Jens Hillengass, MD, PhD:
Yeah, I agree. I could also talk about, and the questions in the chat are just great. They really reflect one short of two short answers, zoledronic acid, the brand name is Solmeta that was asked several times. It's the same drug, just a brand name. And there's also question about can bone heal? And that's exactly what I want to show in this slide. You can see on the left, that's a CT scan that's basically a cut through the body with a CT scan, and you can see there's a big hole in this virtual body. And then on the right side after treatment, this patient had a regrowth of bone. You can see this whiteish rim of the osteolytic lesion and the body tries to rebuild bone.

We did a study, a retrospective analysis, and in about 75% of patients, we saw these attempts of the body to regrow the bone. That's not a guarantee, and it's obviously large lesions take much longer, but since we have such good treatments, it is definitely beneficial.

Then local therapies, obviously for pain and for fractures, what we can use is something called kyphoplasty. In kyphoplasty is well, when there's a fracture, as you can see in this cartoon. We can go in, usually our radiologist or other surgeons, surgeons can do that. And you can see here we go in with the catheter, we pump up a balloon. This is a very optimistic cartoon to be honest. That the body becomes upright again is unfortunately not really happening. That the balloon basically presses the particles of the fracture to the rim of the bone to make it stronger there. Then we take the balloon out and then what we do, we fill it up with bone cement. And I have spoken with a lot of people who do that actively. Our radiologist do it in Germany. It was actually a dentist who did it and he did a really great job. And what we see here is that this bone cement, when it becomes hard, it becomes hot as well. And this heat basically cooks the nerve endings which then helps with pain.

And we did an analysis later on to see is this kyphoplasty really helpful? Another name is Vertebroplasty. It's a little bit different technique, but very similar from the concept. And you can see here the bone around it heals. And we looked if the kyphoplasty has really a benefit. And you can see here the height of the vertebral bodies stayed high in the same level as compared to when radiation, which is another option to treat because it kills the myeloma cells and it leads to a local inflammation which leads to a calcification, which is kind of a replacement of bone. And then we can also see systemic treatment alone. And you can see this upper line shows that the kyphoplasty helped to keep this vertebral bodies in the same height or that they don't fracture any further.

The problem is, and that's still a discussion, and there's more like an opinion debate if the other vertebral bodies, because this one vertebral body is stronger, if the other vertebral bodies have a high risk to fracture, that's unfortunately unclear. But for pain management, a lot of patients have a really good benefit from a kyphoplasty.

And again, the summary here, we need to test. We need to test for calcium, we need to test for other markers in the blood to figure out if a patient has bone disease. Obviously, radiological imaging is very important and I mentioned that MRI shows the bone marrow involvement, CT and PET CT showed the bone involvement. Then the treatment is bisphosphonates or denosumab, which are two different approaches with the similar end effect.

We recommend calcium. I completely agree with you Beth. As soon as a patient is zoledronic acid and or denosumab, not and but or denosumab, then they should also get calcium and vitamin D. And my practice is in Buffalo, New York. We are not really tortured with too much sun, so we do need vitamin supplements. And my wife and I take them too, even though we have no myeloma yet. Nutrition, there's no really good recommendations for that, but obviously there can be an uptake of calcium as well with cheese and milk products if they're tolerated. And then functioning, obviously we have to make sure that we keep our patients active, and I will talk about that a little bit more in detail later on.

Emergency, obviously new pain, new pain in the area where there was no pain or severely more pain in an area there was pain before is of course an alarm sign. Back pain is unfortunately the most common one. And the changes in mental status can be a sign of hypercalcemia if the calcium is too high. I mentioned that's coming out of the bone as well is also related to the bone disease. Constipation, nausea, vomiting in very high calcium levels, that can be a symptom. Falling is obviously a problem and when the patients have very high calcium, that can also be a risk that they lose their balance.

And I think, I know I go on with the physical activity, and because I saw that some patients also asked this in the chat, should I be physically active? The answer is yes and no. So a long time we told patients because of the risk of fractures, please don't do anything. Don't do any sports. Sit on your couch and don't move. And that's what I did initially because I was afraid that the patients get more fractures, which is of course horrible and I won't avoid it. But these images so that you see here are images of astronauts and as you know, when astronauts go into outer space, they are not exposed to the gravity of earth anymore. So they're bones, they actually get osteoporosis, and those guys and girls of course too, they are in the best shape you can imagine those are really very well trained individuals, and they get bones like a very old and very sick person. So they have to do very sophisticated training because gravity is something that keeps our bones strong. So we know that.

Do we need resistance for our bones to grow? And one patient asked that in the chat. Of course, it's very important that you don't do weightlifting if your bones have a fracture risk. And that's what way you have to really interact closely with your provider. But in general, this question was, is strength training good? Yes, strength training is good, but it has to be supervised. It has to be very, very careful.

And just one trial that I picked out of many, running and that was actually in rats, so that gave rats myeloma or weakened their bones and then they let them run swim, and they had a control group that did nothing and they found that running this impact and the effect of gravity was very helpful, but running is also a risk for fractures in the spine. So please talk with your doctor before you do any of these interventions. But in general it's right. And here you can see a big little lesion. If this patient gets more impact on their spine, that can lead to a fracture. Therefore, please talk with your doctor, or nurse practitioner, physician assistant, whoever is in reach, please ask them before you do any exercise but aim to do exercise, aim to be active. That's very important.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
And back to me.

Jens Hillengass, MD, PhD:
Going to hand it back to you. Yes.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
I just have two more slides. We really wanted to make this just a brief presentation to have so much time left. We have such wonderful questions. I just wanted to highlight and echo everything that Dr. Hill Gas had said years ago. We really restricted therapy. We used braces to brace the pain instead of now we have an internal cast with the balloon hypoplasty, which can help prevent that and treat that pain and radiation and then systemic therapy.

But what else can you do? Physical therapies often recommended by insurance companies, but I don't think many people take as much advantage of it. It can come to your house if you can't leave. You can go in a swimming pool if you don't want to do land exercises. But learning the right exercises to do because some people say, oh, I'm so active, but learning the right exercises to strengthen the muscles to support your spine or reduce the hip pain through the appropriate exercises is important. So discuss the physical activity with your provider.

Try to avoid an inactive lifestyle. Maybe you have to set your timer and go around your apartment or your room for five or 10 minutes at a time, twice a day. If you continue to build on that activity, then all of a sudden you've reached the main cardiovascular recommendations for the daily exercise. Don't exercise though if you don't feel up to it. If you're suffering from anemia or you just started a new treatment, be kind to yourself. Listen to your body and maybe take some breaks. Always plan to try to be active. Even just sitting up and getting out of the chair works those large muscle groups and helps to keep you fit. Trying to do a few stairs at a time also works those large muscle groups to keep you healthy and active. Try to avoid the public gyms and pools if you have a lower immune system, but if you have a good immune system or you're protected or you're protecting yourself, then definitely try to go about that.

There are numerous resources as you know available at the International Myeloma Foundation. They are free. The IMF info line, if we don't get to your questions during this, feel free to call 1-800-452-CURE from 9:00 AM to 4:00 PM pacific standard time. Visit myeloma.org. Listen to IMF TV conferences and get the newsletter. All of these are important things to consider if you're living with myeloma, to live well with myeloma. I think at this time, I think Dr. Hillengass, he's going to stay on for questions with me. How do you think we should do this, Dr. Hillengass? Should we start from the top and make sure we've hit all the questions?

Jens Hillengass, MD, PhD:
That was exactly what I was thinking, and we can just take turns if that's okay for you.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Perfect. [inaudible 00:37:06].

Jens Hillengass, MD, PhD:
I already started. Yeah, it started with the imaging. I think most of them responded to MRI sensitive, not available in all areas, but you should be able to reach someone who has access to that. Bone lesions can heal. It takes very long. They usually, because it's the scar, oftentimes they don't completely disappear. I have seen patients where the lesions completely disappeared when they were small, but it's unfortunately not a guarantee. We have to get even better with our treatments so that the body has more time to heal. I think these are the most important factors there.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Great. And then I think it's really important this one question. How is myeloma bone disease different than bone tumors that represent metastasis in other kinds of cancers? Again, it's the makeup of the cells and the chemicals that are secreted by that tumor in many ways, again, the myeloma is that two-way interaction between the myeloma tumor cells and the bone marrow microenvironment where the plasma cells and the healthy cells live. And so through that two-way interaction, metastases occurs, but based on the makeup of the tumor, they can cause what's called sclerotic lesions in certain cancers of solid tumors. But again, that bone, it varies according to the type of cancer, the lung, the breasts or the prostate, et cetera.

Dr. Hillengass, do you have any more insights to share with that topic?

Jens Hillengass, MD, PhD:
No, it's some are growing bone, some are dissolving bone, and mechanisms are similar. Not exactly the same, but yeah, not exactly what you said. Oh.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
I'm going to point this question to you, Dr. Hillengass, I get this all the time. The primary care providers want bone density screens in myeloma and they're on bone builders and we know they have liver disease. What do you tell your patients?

Jens Hillengass, MD, PhD:
Yeah, so as I mentioned, the DEXUS scan in myeloma is very challenging because it doesn't really reflect what's really going on. The DEXA scan is very good for diffuse bone loss and to be honest, our dexamethasone, our beloved steroids that most patients hate, is unfortunately has a long-term side effect bone weakening. But we used the denosumab or we used the [inaudible 00:39:30] acid to counteract that and the calcium and the vitamin D. So I don't feel that excess scans are very important. If there are other reasons like hormonal changes, postmenopausal, that's a different question, but then again, it is not enough to do that for the myeloma itself.

One brief question about sugars. I personally don't feel that patients have to cut out sugars because it's like when I would smoke a cigarette and tell them to stop smoking, because I love sugar. I love cookies, so my team knows that already, so they tease me with that. Now you don't have to avoid sugars, but you should definitely eat healthy. You should have to buy a high plant-based diet with a lot of plant-based products, but to completely avoid sugars I don't think is necessary. We do some studies at Rosa Park right now where we do intermittent fasting, but that's a different approach and has not really anything to do with sugars.

What do you think, Beth? Patient has hypocalcemia and cramps, they're posttransplant. I personally think that might be the Revlimid. What's your experience?

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Absolutely. They're likely, likely on Revlimid posttransplant. Again, you might be on bone strengtheners and not taking calcium supplements, so discuss this with your treating physician, your treating team and maybe you can have some additional testing. So there was also hormone changes that can occur after transplant or after or just for any reason. So checking thyroids, parathyroid and other hormones might be a good idea.

Another question, I think we had answered this, Dr. Hillengass actually looked like the body builders and there's a heavy weightlifter that likes to strengthen bones and is there any reason why it should be concerned. And that's an individual discussion. I've had people with very strong bones and very strong spines in excellent remission who've always worked out, and I will oftentimes clear them for lifting moderately heavy weights and I know I might get in trouble for saying that, but it's a discussion with the treating team. It's taking into account that individual person and if that is where you find your joy and you really want to be a heavy weight lifter, we work with the orthopedics, oncologist, and the patient to discuss the risks and benefits and protect you the best way we can with bone strengtheners. Dr. Hillengass, what do you think? You can disagree.

Jens Hillengass, MD, PhD:
 Yeah, absolutely. Yeah, again, be careful, but we are doing a trial where we do actually resistance training with our myeloma patients and this patient who asked actually has moldering myeloma, no bone lesions so there's even less concern, but we have not seen any patient having any harm, but my wife is the personal trainer, and she's supervising them very strictly. So that's very important. The technique is very important. Knowing which exercises are okay, which are maybe dangerous, that is very important. And please stay in touch with your providers.

Then there are questions about PET scan and kidney damage. Not a problem. The PET scan, the dye that we use in PET is not a problem for the kidneys. In case of CT, we really want to avoid CT dye because that is not good for the kidneys. With MRI, if the kidney function is good, it's not a problem. If the kidney function is impaired then we should not give MRI contrast agents, because they can cause longer term bad effects on uncertain systems in the body. So PET scan not a problem. MRI with good kidney function, not a problem, but with bad kidney function, don't do it. And CT dye as if you can avoid it, please avoid it. There are some situations when it's about a pulmonary embolism for example, you need the dye, that's important. But if it can be avoided, let's not do it.

And PET MRI as someone is asking, that's not very well investigated yet. It has obviously the benefits of the MRI with the sensitivity of the PET with the information about the metabolism, but it lacks information about the bones and we are talking so much about the bones. So the CT is the best technique for the bones.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
I agree. We use the PET CT and feel that that's the best for the bones. But as you'd mentioned, the MRI is so helpful. We have these high-risk smoldering studies, and it's included that you have to have the PET CT and then if that's negative or the whole body scan, and if that's negative then you have the whole MRI and sometimes we find lesions, but usually if you have a good PET CT scan, I think a majority of people will have a negative MRI findings, which is good news.

I'm going to skip over to what can patients in the MGUS stage do to improve bone health? Exercise, exercise, exercise. Weightbearing exercise. I'm going to steal that about the rats and how when they ran that helped to build the bone. I think walking is a very good exercise as well. And there are some other studies that show that weightbearing exercise can include swimming, so you have to do a lot of swimming, but swimming can be considered a weight bearing exercise if it's done right. Dr. Hillengass, what do you think?

Jens Hillengass, MD, PhD:
Yeah, absolutely. 100% agree that's what we have to do and that's why I showed the astronauts in my myeloma talk. So that's definitely important.

There's many questions about how long do with Zometa, and Beth you mentioned that we don't really know what currently do just based on experience not on science is we stop after five years if the patients are still in remission, because we know that especially zoldronic acid stays in the system for a very long time. So that it stays in the bones and it still has this effect that we talked about. At one point there is a risk. I had one patient after 10 years where this kind of slowing down of the bone turnover led to actually fragility of the bone. So the bones actually were more fragile than they were without, but that was after 10 years in complete remission. So in this patient we should have stopped earlier and unfortunately sometimes we learn by doing that, by be making mistakes. The osteonecrosis of the jaw is obviously a problem. I personally am very hesitant to restart the zoledronic acid. What do you do, Beth?

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
We do not restart zoledronic acid if you have a osteonecrosis of the jaw episode. We also do not give denosumab. I optimize the calcium and vitamin D. We encourage weightbearing exercises, but we do not restart it. So yeah, I agree.

There's a question about a class I think that refers to reclass. So there are a lot of different names for similar drugs. Reclass is the FDA-approved treatment. It's zoledronic acid five milligrams on a yearly basis, and that's given for osteoporosis to postmenopausal women. It's approved for, but for Zometa or zoledronic acid, that's four milligrams and that's given monthly. Just like I saw in the chart, one of the respondent questions was they wanted to know if denosumab was daratumab and no, they're two different things, but denosumab is the same as XGEVA and Prolia. Again, it's what it's approved for by the FDA is to what that is. And I apologize for the confusion, but on the IMF website, you can see the list of all the drugs if you go to myeloma.org under resources. Would you like to take the next question?

Jens Hillengass, MD, PhD:
Yeah, I'm scrolling through some of them we already mentioned. And I think because there are 38 new messages, so I think we have [inaudible 00:47:30].

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Thank you for all the questions.

Jens Hillengass, MD, PhD:
Dose of calcium, I say between 500 and 1,000. Do you agree? That's usually what we do.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
The World Health Organization has recommendations for if you have osteopenia on bone density or osteoporosis and so that kind of varies, but we look at the prescribing information for the drug. So on the denosumab, it's so funny, I have people I work, with the doctors, they say, oh just take a couple of tums on the day of the treatment, which equals about 500 milligrams of elemental calcium. You can chew it so it's not an extra pill. It's relatively inexpensive. But I find that the calcium can really drop down low if you have effective control of the myeloma. So you have to be very careful about low calcium levels. You can get this [inaudible 00:48:18] knee and it can cramp up and be very uncomfortable.

Jens Hillengass, MD, PhD:
Yeah, that's another really good question that I would like to answer about. Why would a patient who has no OS osteolytic lesion still get so made from zoledronic acid or denosumab? So the point is what we mentioned with these very complex graphs. The problem is so the bone, the myeloma cells stimulate the bone-eating cells, but the bone eating cells get substances out of the bone, kind of nutrients that feed the myeloma cells. It's a little bit too easy, but that's unfortunately what's happening. So that's a vicious circle. And to break through this vicious circle, we kill the myeloma cells with our treatment and we kill the bone eating cells that are too active and too many, they're not sick by themselves such as too many and too active. We kill them with the bone limiting drugs, or the bone turnover limiting drugs. There different ways to say that. I would say it's still important to get the zoledronic acids also what the guidelines say. So I would still recommend that.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Hundred percent.

Jens Hillengass, MD, PhD:
Other important questions here?

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
There is one about three compression fractures and two were treated with hypoplasty. Then a third was found and they were told they were too old. I think we still try to focus on fitness and frailty and sometimes people are very sick from the fracture and in a lot of pain. So one of the cutoffs though in my institution is the height. So you worry about that leakage. So it's polymethylmethacrylate is the cement that's often used, and it's the thickness of soft whip ice cream. So it tends to stay in that cavity. Pardon me. But unfortunately sometimes it can leak out. So many people that do the procedure don't want to go too high up in the spine into the cervical spine or the thoracic spine . Sometimes it's the location, and I would have that conversation with your treating team as to really why, and age should not necessarily be an issue unless they're really worried about anesthesia risk associated with that outpatient or short stays procedure. I don't know what your thoughts are?

Jens Hillengass, MD, PhD:
Yeah, no, no, absolutely. I've found some questions about MRD about treatment and those are really important and really good questions, but I think that would really go far beyond our bone talk today, and I'm sure there will be very good talks and maybe they're already online when you can get answers to these questions. So I would like to stick to the bone and imaging questions. There's the question, after a patient is in remission after stem cell transplant, should they get another PET scan? Should they not get one? Our recommendations is to get yearly PET CT scans. One reason is that obviously when we had some patients where the diseases came back without any production of monoclonal protein in the blood or urine. So the imaging can be very helpful. We should not do it too often, but once a year I think it's reasonable, or maybe every other year if a patient is in a remission for longer period of time. And unfortunately a lot of our drugs can also cause secondary cancers and the PET scan helps us to identify those cancers early. Not all of them but some of them. And so that's another reason why I personally prefer to do PET scans if possible yearly or maybe every other year. What do you do in Cleveland?

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
So again, it varies. So one of the challenges we have in my institution is that as you mentioned, skeletal surveys have been the standard of care. Those are plain x-rays from head to toe. They're easy to obtain, they're relatively inexpensive, but unfortunately you have to have anywhere from 20 to 40% bone loss depending on what study you look at as to whether or not you have damage to the bone or not. And so we have these people that for years we've getting regular bone surveys because that's what the guidelines used to recommend. Now what do we do? Do we do a whole body low dose CAT scan to better understand where the disease is, or do we do a PET CT scan? What do you do for your patients that have been in remission for years, Dr. Hillengass? Maybe you can answer my question.

Jens Hillengass, MD, PhD:
Yeah, so as I mentioned, we do PET scans once a year. It might be a little bit of an overkill, but we are also looking what the outcomes will be if that is really helpful. And again, in individual patients it helps, in other patients... I mean it's also radiation exposure. It's not super much, but it's still there. And if we do that for a longer period of time and we know we hope that our patients live very long. So what we have done now is that we do a PET CT, and then we switch to MRI because MRI has no radiation exposure, which then can be beneficial. But we are privileged that we have this whole body MRI with distribution weighted imaging. So that's something that we can do. If the center where you are being treated can provide this, that's definitely also a good option. And because we would see changes there also before we have actually the bone destruction. To be completely honest, we did an analysis in smoldering myeloma where we did every six months MRIs, which was very sensitive and still some patients in these six months in between developed new disease. So we cannot do MRIs before and after meals even though I would love to do that. So there are limitations, but of course the more we can do this on the safer side we are.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Great. Another question that came through is I thought myeloma can cause hypercalcemia. Now you're telling me to take calcium supplements. I'm confused. And so again, what you're doing with these medications, these bisphosphonates or the denosumab, the bone building drugs, you're taking calcium from the blood and putting it back into the bone to strengthen the bone. So the blood calcium goes low as you're rebuilding the bone. So if you are in a remission or your myeloma's under control, you will not have hypercalcemia. We need to give you calcium supplements. Again, have this discussion with your treating team, but the goal is to, because your blood calcium will go really low on these bone-building drugs. So have that discussion with your treating team. And what do you think Dr. Hillengass about vitamin D I very much believe in checking vitamin D levels and replacing vitamin D if it's low, is that something you do or do you have a team of people you work with like primary care doctors, endocrinologists? Who does that in your practice?

Jens Hillengass, MD, PhD:
We don't do it on a regular basis, but we definitely do it at first diagnosis and will want to replace. We know that in our area and your area, which is not so far away.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Three hours away.

Jens Hillengass, MD, PhD:
We have a chronic vitamin D deficiency. It can be checked and we work together as you mentioned with our primary care doctors in the community and they can help with that as well. So I think this definitely makes sense because we should, especially our myeloma patients, should protect themselves from too much sunlight, but then on the other hand keeps them from building their own vitamin D. So that's a little bit of a problem there. So therefore we recommend to check the vitamin D levels and to definitely replace vitamin D.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Excellent. Well I want to thank you Dr. Helen Gas. I think I'm going to turn it to Robin. I really wish we could have answered all of your numerous questions in the chat. Please feel free again to call the 1-800-452-CURE if you have additional questions. There's also additional great resources on myeloma.org website for patients, prior videos, and there have been other bone health discussions as well. Robin, are you still there to close out our call?

Robin Tuohy:
I am, and I've been sitting here listening with both ears. The two of you have been amazing as always. We know that bone health is so important and to learn how and when and what to do and to have these better conversations with our healthcare team so that we can each make the best decisions for ourselves. So I'm sure everyone on this call is grateful, and there's even so much more we can delve into I'm sure, as far as bone health. And Dr. Hillengass, you had said that there are questions in the chat there that were outside of bone health, and I just wanted to share with everyone on this Saturday, believe it or not, we're having another webinar, and that is going to focus on a much broader scope. And Beth, you'll be joining us again for that on Saturday. So if you didn't get enough tonight, come on back. And so go to myeloma.org to see how to register for the Saturday presentation is, and you will learn even more.

So for tonight's program. We'll wrap it up and thank our sponsors. Again, that's Bristol Myers Squibb, GlaxoSmith Klein, Janssen, and Sanofi. And please don't forget that we tried to answer your questions and they did such an excellent job. But if you still have questions, don't forget the IMF info line 1-800-452-CURE. Missy, Paul, and Deborah are happy to take your calls, and we thank you again for taking the time to join us to learn more about bone health, to help you live well with myeloma. And thank you so much Dr. Faiman and Hillengass. This is such excellent and much appreciated information. So thank you and I wish you all a good rest of your day or evening.

Jens Hillengass, MD, PhD:
Thank you very much everyone.

Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN:
Bye. Thank you.