(Guest Lecture): October 2023 - Living Well with Myeloma

As mentioned, I'm Rebecca Silverman. I'm one of the Myeloma faculty members a little bit south of here in Portland. This picture is a stock photo. The leaves aren't actually quite this pretty yet, but I think that we're going to hopefully get there unless the rain comes comes for us and we lose all the all the pretty color. I'm supposed to be talking to you guys about living well with myeloma, which I think is a really important subject. We've been hearing this morning about all of these incredible advances and about how much new treatment opportunity there is for patients. And as you guys know, patients are living longer and longer with this with this disease, and the physicians are really starting to catch up on understanding which treatment factors are the most important in the eyes of patients. As doctors, we talk about treatment effectiveness in the context of is the myeloma protein number going down? Is the PET scan cooling off? Is the patient living for a long time? But we're starting to now really understand that we need to talk to the patients and understand what they define as effective treatment, what they think is most important for them. This figure is a little bit busy and it's a little bit hard to read, but it's a composite of treatment factors identified by patients from large real world databases of myeloma patients over time. And so it's a population that's hopefully a little bit more like everybody in the community in clinical trials. The patient populations are highly selected. We want to know that patients are kind of the same when we start giving them an experimental therapy and try to understand how they might be affected by that therapy in the real world databases. A lot of patients are contributing time and effort to filling out surveys where they're saying, this is the sort of thing that I'm experiencing. This is the sort of thing that seems really important. This talk is mostly going to be about bone health, which is something that's very important for all patients with multiple myeloma and directly impact some of these things in the dark blue on this figure, particularly physical activity, productivity, as well as quality of life and disease symptoms. Bone abnormalities in myeloma are extremely common, and myeloma is actually the most frequent cancer to involve the skeleton. Up to 90 percent of myeloma patients develop bone lesions over the course of their disease, and 70 percent of myeloma patients have bone pain at the time of diagnosis. These pictures are regular old x-rays of a patient's spine. And as I think you can really easily appreciate, there's clear spots in the bone where they shouldn't be there, and those are holes in the bone that are caused by interactions of the myeloma cells with the other cells of the bone marrow. And it's important to realize that bone destruction and myeloma can involve any bone in the body, but also that myeloma bone lesions can be asymptomatic. So this is a picture that is from a patient that I took care of who came to me as a second opinion consultation, and over the course of our discussion, we realized that no one had taken any pictures of her legs or her arms. They'd only taken pictures of her center part of her body. She was someone who was very, very active, was the primary caregiver for her elderly mother, was helping lift her out of bed and into the shower. And this picture was really pretty startling because there's a giant hole in her thigh bone, which was really at very high risk of fracturing if she were to twist the wrong way or to move the wrong way. So what we did was we called up our orthopedics colleagues. They got her into the hospital fairly quickly and were able to do a procedure where they put a metal rod into the bone to stabilize that lesion, put a couple of nails in there. She stayed in the hospital overnight and apparently the only reason she stayed overnight was because she got a little bound up from the pain medications. And then she did not have a fracture of that leg and she was able to go ahead and help take care of her mom and continue to receive treatment. Now, the classic description of myeloma bone lesions is of a moth eaten appearance of these round, very discrete holes in the bones. And it's kind of fun to realize that in x-rays they can be very, very distinctive. Some have wondered whether we could say, oh, let's look at fossils, let's look at artifacts that are found at various sites and wonder if a patient or if a person had had a particular diagnosis. This is a picture of a skull that's in the American Museum of Natural History that was dated back to about 200 A.D. And there's been question about whether this person might have had myeloma. We don't know for sure, but it's kind of interesting to understand myeloma bone disease. We need to understand a little bit about the normal bone remodeling process. If you think about bone as a brick wall, you've got constant activity where osteoclasts, which are these big cells on the left, are kicking away the old bone and osteoblasts. The little guys are laying down new bricks. So in myeloma, we have an uncoupling of that process. The osteoclasts are more active. They're taking away a lot of extra bone, and we no longer have the work of these osteoblasts to lay down new mineral. That results in an overall loss of bone, and in some areas we end up with holes in the bone itself. There's a lot of different cells in the bone marrow microenvironment that have a direct impact on the skeleton, including the myeloma cells. But there's also stromal cells, osteocytes, as well as those osteoblasts and osteoglasts that I talked about. And what we've learned over the years is that the myeloma cells themselves play a direct role in stopping the activity of those osteoblasts. So the myeloma cells keep the osteoblasts from doing their work, and they also increase the activity of the osteoclasts. The presence of the myeloma cells makes the osteoclasts more active. And then the osteoclasts themselves are also releasing factors that are increasing the growth of the myeloma cells. So we end up with this cycle. We have more bone destruction that's leading to more growth of the myeloma cells, which is clearly problematic. Myeloma can also cause thinning of the bones, osteopenia or osteoporosis. And similar to the way that osteoporosis is described in conditions aside from cancer, we talk about dexascans, where a patient's bone density is measured at particular areas of the skeleton and then compared back to what are considered to be normal individuals and reports list something called the T score, which compares an individual's bone density with that of a normal control. Current treatment of myeloma bone disease is OK. In my opinion, it's not perfect. The goals of the treatment are to prevent fractures, for sure, prevent new bone destruction and bone loss, and to hopefully improve a patient's pain. We have two general types of medications that are considered bone-directed therapies in myeloma. We have bisphosphonates, like xylalazonic acid or Zometa, and we have rank-line inhibitors like dinosumab or Xgeva. These work in slightly different ways. They're both given in the infusion clinics. Zometa is taken up into osteoclasts and leads to the destruction of those cells directly. The dinosumab is working in a different way. It's a monoclonal antibody that is working against one of the factors that promotes osteoclast activity. In my opinion, the optimal treatment for myeloma bone disease is going to be here when we have a way to normalize the bone remodeling process. And as I said, we're not there yet. We have to do both eradication of the myeloma cells, which we're getting a lot better at, and then we have to figure out how we can turn those osteoblasts back on so that we can fill in the holes that have already been created in the skeleton. Imaging, as you all probably know, is incredibly important as a part of the myeloma diagnostic process, and in some cases as part of the surveillance of patients with myeloma. We used to use standard skeletal surveys, which were regular x-rays of all of the bones in the body, and that's crossed out here because that's no longer considered to be the gold standard for how we look for bone lesions in myeloma. Patients have to lose about 30 percent of their bone mineral before you can actually see the difference on an x-ray. So now we're using higher acuity or more advanced imaging methodologies like whole-body CT scans, whole-body MRI scans, and in some cases PET CT. It's gotten really confusing. It's a difficult question to say what is the best scan that I can get or what is the correct scan that I can get. Often what I advise people, and that's as doctors as well as patients, is that it depends on what we're looking for. If we're looking for a bone lesion that will allow somebody to have the myeloma criteria or one of those crab criteria, then we want to make sure that we're using a very, very sensitive test. If we want to compare how someone's skeleton looks with how it looked before, it might make sense to just use the same test that we had before so we can compare apples with apples. PET MRI is listed at the bottom of this list, and I think that this is what is coming. We have a PET MRI machine in Portland that we're using largely for research purposes. I have not yet succeeded in compelling an insurance company to let me have a PET MRI scan for one of my patients, but I'm still trying and hopefully we're going to get there at some point. Importantly, bone scans underestimate skeletal involvement in multiple myeloma. You might be aware that bone scans are sometimes used to follow metastatic bone lesions and other kinds of cancers. This is the same patient's scan. I think you can all appreciate it on the regular x-ray that hip bone clearly has something wrong with it. There's nothing going on in the center part of the bone space, but on the picture right next to it, which is the same person, that scan does not show that there's so much bone destruction, and that's because the bone scans rely in part on the osteoblast activity to develop the picture. The International Myeloma Working Group does have recommendations for treatment of myeloma bone disease, and there's a lot going on on this slide. The simplest and most important questions, in my opinion, are which patients should be treated for bone disease, and the answer is for sure anybody who has evidence of bone destruction, for sure anybody who's receiving anti-myeloma therapy, so if someone has crossed that line from smoldering myeloma to active myeloma, and they're now getting treated, they should also be talking to their doctors about getting bone-directed therapy. It gets a little hazy when we talk about osteoporosis and osteopenia. The International Myeloma Working Group took osteoporosis out as part of the definition of myeloma-defining events, but if you have osteoporosis and you also have myeloma based on one of the other criteria, then it is recommended that you should be receiving bone-directed therapy. Which drug, bisphosphonate versus dinosumab, we believe right now that those two are considered to be equivalent. We do know that the stronger bisphosphonates, like zoledronic acid, are recommended over the less potent bisphosphonates, like the pill forms of bisphosphonates. And then the problem of for how long to treat is one that we really don't know the answer to. There are some recommendations that the bone-directed therapy should be continued until the disease is under excellent control. That gets a little bit tricky when we're talking about the zoledronic acid versus the dinosumab. Dinosumab is a reversible inhibitor of the osteoclast activity, which is good and bad at the same time. It's bad in that if you stop it suddenly and don't do anything about it, you can have an accelerated bone loss after the drug is stopped. In my opinion, it's kind of good and exciting because that implies that if you get rid of the myeloma cells and you have this new future way to restart the osteoblasts, that maybe you could actually restore normal bone remodeling. So I think there's more to come on that factor. The MRC-9 trial was a study published several years ago now that showed us that the more potent bisphosphonate is more effective than the less potent bisphosphonate. Newly diagnosed myeloma patients, 70% of whom had bone disease, started treatment and were randomized to either get the IV bisphosphonate or the pill form. The folks who got the IV bisphosphonate had fewer fractures, but also appeared to have improved control of their disease, suggesting that treating a patient's bone disease may also be helping to treat their myeloma. More recently, we had a study that was comparing the zoledronic acid with denosumab. This was a really big study. About 1,700 patients were randomized to get one or the other. And the conclusion from the sponsors was that denosumab is equivalent to zoledronic acid in delaying the time to a first skeletal-related event, so to a new bone fracture or a new bone lesion. And in subsequent analysis, there's suggestion that denosumab might prolong progression-free survival in patients with newly diagnosed disease, and it might be preferable in patients who do have kidney dysfunction as part of their myeloma. So to summarize this part of it, we know that zoledronic acid and denosumab decrease the risk of fracture. They can't prevent fractures in all myeloma patients. There are some situations where the bone is already so damaged and so weak that you do need the help of the orthopedist to try to keep the fracture from happening. They do not allow patients to heal their bone lesions, and they don't build new bone on their own. There are certainly situations where a patient's lesions look like they're improving over time, and the quality of that bone is something that we don't fully understand at this point. We do have procedures and medications that can help to improve the pain associated with bone lesions. At the bottom is the bone-directed therapy I've been talking about, the zoledmeta or the denosumab or exgiva, but other types of therapies can be considered depending on what's going on with an individual. Sometimes someone will have a painful bone lesion, and we refer them for radiation to that bone lesion, and that can be very, very, very, very helpful. Sometimes a patient does need to go to the operating room to have pinning or stabilization of an impending fracture, and we also sometimes refer people for particular therapies to the spine to help correct compression fractures, and those are called vertebroplasty or kyphoplasty. These kind of fall in and out of favor. Right now vertebroplasty is considered to have a category C recommendation, so okay, but not amazing, from the International Myeloma Working Group. Vertebroplasty occurs when bone cement is injected into a fractured vertebrae and fills up the hole to hopefully strengthen it up. Kyphoplasty is a little bit different. In that case, a needle is still put into the lesion, but a balloon is put into that spot and then inflated, and that hopefully helps restore the anatomy a little bit. So it stabilizes the fracture and then kind of opens it up again so that the normal way that the bones are configured can be returned, and hopefully that can be helpful for people. Importantly, there are complications associated with bone-directed therapy, specifically something called osteonecrosis of the jaw. This is rare, but this is a big deal when it happens. So I've told you that these medications are both impacting the osteoclasts. They're stopping the normal remodeling process with the hope that we're going to lose the problem of having accelerated bone loss. This also means that the bone doesn't heal in a normal way if it's injured. And so in the jaw, particularly in the setting of dental procedures, there is a risk that people can have loss of the jaw bone in the setting of inflammation or in the setting of dental work done when they're on these medications. So what I tell patients is that if they have a lot of deferred dental work when they're diagnosed with their myeloma, I want them to see their dentist, get a cleaning done, really understand what needs to be done or what can be pushed aside before we start the bone-directed therapy. If someone has been going to a dentist quite regularly, things are feeling healthy, they don't have any pain, it's usually okay for them to start, but I want them to be in close communication with the dentist and with me about what's going on. If they are riding a mountain bike and they go over their handlebars and they have a tooth knocked out, that needs to get dealt with immediately. But if they have a planned procedure, then we can talk about it. We can talk about how to time the bone-directed therapies with any dental work that needs to be done. Sometimes people will not have pain, but sometimes they will have really significant pain with this problem. And it's really important that they stay in close communication about what's being done to treat it. What else can people do to maintain their bones? Adequate calcium and vitamin D in weight-bearing exercise are always very high up on the list. Vitamin D promotes calcium absorption in the gut and is needed for bone growth and remodeling. Many myeloma patients, even those who had very high calcium levels when they were first diagnosed, do need calcium supplementation, and so it's important to remain in communication with your team about that. Vitamin D deficiency is common in general. It's extremely common in this part of the country. Above the 37th parallel, we are well above that parallel, vitamin D deficiency is really present in a lot of people. It's estimated that overall about 40% of myeloma patients are D deficient, and I think that number is actually much higher, certainly in Portland and probably in Seattle, too. Severe D deficiency can be associated with decreased muscle strength and an increased fracture risk. The Institute of Medicine does have recommendations for D supplementation, but honestly we don't know what the right dose is for everybody, so you just need to talk with your doctor. We generally are checking D levels quarterly or so. Sometimes people do overdose on vitamin D. A lot of patients really like those gummy vitamin D supplements, and I personally like them, too, but they're not snacks. I've had people who just end up snacking on them, and then their vitamin D levels are way too high, and we have to hold them for a bit. Okay, we've only got six minutes left, so I'm going to fly through this bit a little bit. Exercise. Exercise is incredibly important in general. It's also very important while people are getting any kind of cancer care, and I think it's really a very critical thing to talk about in myeloma, where people are often living with some degree of chronic pain, and they've been fully educated about how their bones may be weaker than another person. They might be worried about how to exercise and what is good to do. This set of slides I borrowed from a colleague of mine who is a woman in the nursing school at OHSU who does a lot of work on exercise physiology and how exercise can affect oncology. We know that exercise can be very helpful for symptom management. It can help with side effects, particularly fatigue. We don't know yet whether exercise might also help with making treatments for cancers work better, but we suspect that it could. As all of you acutely know, cancer treatment can accelerate the aging process for many individuals. People have increase in weight. They have decrease in their mobility. They have weakness. They sometimes have cognitive changes associated with treatment, and all of that in combination with other medical problems that someone might have can lead people to live a less full life than they otherwise would if they did not have a diagnosis. Dr. Winter Stone, who's my colleague, her team has been looking at when exercise can be prescribed during the course of a patient's treatment to understand how much can help and at what stages it can be of most use. So they've been testing is exercise safe, testing if it's effective, and testing what is the right amount that people should be thinking about engaging in. Interestingly, until about 2010, cancer patients were told that they should not exercise, that they should really rest. But now we know that it's better for cancer patients to be as physically active as their abilities and as their pain symptoms might allow. And that doesn't necessarily mean going for a run. It really just means avoiding inactivity. Some activity is better than none, and we want people to be able to continue their normal activities as much as possible during and after the non-surgical treatments. There have been suggestions that we should be writing exercise prescriptions that are specific to cancer. This is an example, and this is an example of something that their team is testing. So testing programs where a patient might be encouraged to participate in two or three days per week of some sort of exercise, and they call it a moderate intensity exercise. And moderate is defined by something called the talk test. So moderate exercise means that they could be talking, but not necessarily singing while performing that kind of exercise. So maybe going for a walk around the block would count. Up to 30 minutes is recommended, and the hope is that people can engage in some kind of aerobic exercise as well as some kind of resistance exercise. This has been shown to help improve fatigue, help improve physical function, potentially also help improve mood. Specifically in the setting of transplant, their team has looked at different frequencies and intensities of treatment pre-transplant, during the transplant procedure itself, and after transplant. And what they've shown is that by engaging in some kind of regular activity, patients can maintain their aerobic fitness and muscle strength during the transplant procedure, and they can still improve their symptoms during and after transplant while trying to maintain some physical activity. It's important to realize that you can start anywhere, and the really critical point is that it's beginning to start a habit, and to try to maintain that habit over the ups and downs of a treatment and over a disease course. I think everybody understands that there's going to be highs and lows with this diagnosis. There's the trauma associated with initially being diagnosed and realizing that this is the world that you're now living in. There are periods of time where things are going well, you're feeling very, very normal. And then we unfortunately still have to talk about relapse and intensification of treatments again. And if you can have a habit of having some kind of physical activity, we believe that this really can help overall. The realities are that not everybody's a marathon runner. Many people were never marathon runners, and people have physical limitations that might impact either their ability to participate in exercise or their comfort and their interest in participating in exercise. So it's really important to think about how to get started. If someone has physical limitations, if, for example, they have very significant neuropathy, I'm very frequently referring people to physical therapy for balance training so that they can start understanding how they can work with the equipment that they might have in their home so that they can increase their activity a little bit. For people who have had little activity in their lives, we want them to just avoid sedentary behavior, begin with gentle exercise, stretching, and then finding some way to gain their motivation, particularly working with a care partner can be helpful. Skip all this. One early study that was done showed that even 15 minutes of daily walking can have a big impact on fatigue during radiation and chemotherapy. So I think that's really, really important to keep in mind. And adding strength is also critical, and it doesn't have to be a lot of strength, but we want people to be able to maintain their independence, to be able to get up off the ground if they should slip, and to be able to continue to live as well as they possibly can. I'm going to end with this slide. This is Carrie's 5013C organization. So she's someone who works with exercise specialists, physical therapists, and she's put together this website where patients and their caregivers can be welcomed in to home classes that are given online. And they have stretching classes, they have some gentle cardio classes, they have some yoga classes, and the idea is to help to build a community and to help people to feel comfortable with what they have. So with that, I'll stop. Thank you very much. Thank you.