All about bisphosphonate therapy. So you know, in multiple myeloma, the bones are affected quite frequently. And things that happen are things like skeletal pains or fractures or bone thinning like osteoporosis. So bisphosphonates are a type of medication that actually helps to stop that process or retard the process, slow it down by various mechanisms. And so that's what they do. The whole class of agents is called something osteoclast inhibitors and bisphosphonates are one of them. It's not the only kind of drug that does this. We also have another medication called dinosumab that does this. They all do similar things, but by slightly different mechanisms. What drugs are part of bisphosphonates that myeloma patients may take? The most common ones that we use in myeloma are two intravenous medications. One of them is called zilidrinic acid, or you might have heard of them as Zomata. And the other is called pomidrinate. Pomidrinate is the same as iridia and was the older drug. And now Zomata is just a more potent form of the same medication. It can be given in a much shorter time, but it's the same medication essentially. How do bisphosphonates work? They're synthetic medications. They're analogs to a compound that we have in our bone matrix. So what they do is they directly inactivate these cells called osteoclasts. And osteoclasts are the cells that are part of bone remodeling. They are what destroys the bone. These are the cells that cause a lot of havoc in myeloma and start creating all those problems with loss of integrity of the bone. And these medications, bisphosphonates, help to stop it by directly killing the osteoclasts and preventing their differentiation and maturation and all the things so that they can't work anymore. I don't consider bisphosphonates traditional chemotherapy. They're really more an adjunct to, you know, necessary chemotherapy treatment of myeloma. Really the primary way that they work is on these bone destroying cells called osteoclasts. I wouldn't call them chemotherapy. The experts are going to differ slightly on this particular topic. Personally, I treat everybody who has newly diagnosed myeloma with bisphosphonate therapy along with their chemotherapy, whatever we use to treat the myeloma. Most newly diagnosed myeloma patients have some evidence of bone damage. Whether it's actual fractures or, you know, just osteoporosis, you know, some evidence of bone damage is present in most patients. If you have a new, if there's a newly diagnosed patient who does not have any evidence, has normal bone density and no evidence of fractures or lytic lesions or any of these things, some experts may say we can defer the bisphosphonates. Others, you know, would prefer to use it up front. And most of the ASCO guidelines and other guidelines do call for use of bisphosphonates up front with the newly diagnosed myeloma treatment. There's no evidence that in smoldering myeloma or any of the precursor conditions for myeloma or any of these conditions that bisphosphonate is needed. We don't treat these patients for the most part, but there's no evidence that bisphosphonates is required in this. However, if somebody with smoldering myeloma has osteoporosis, for instance, which is quite common and can happen to all of us or any of us as we get older, then it can be used in a similar way as you would in osteoporosis patient. One would have to be cautious when we use bisphosphonates. Zometa can cause renal insufficiency. The ways to handle it if somebody has mild kidney damage might be to either dose reduce it, give it over longer infusion times. These are possible. Similar things with pomidrinate. They can both damage the kidneys in different ways. Pomidrinate can cause glomerular damage and cause proteinuria, whereas Zometa can cause direct renal insufficiency. So all of these have to be used more cautiously when there is renal damage, not that it cannot be used. Would be particularly difficult to use it if the creatinine clearance is less than 30. This is where dinosumab is a good alternative because those are not metabolized and does not damage the kidneys. So I always make sure that I check the kidney function. Other tests that are very important to do are the calcium level, the vitamin D level. One of the side effects of these kinds of therapies is a drop in the calcium level. So we do want to check what the level is so that they may need, sometimes patients need supplementation and you may want to do that. Vitamin D is also an important part of bone integrity and it's another thing that is important to check so that can be replenished and patients frequently have to be on a maintenance vitamin D with all of these things. The other thing that I do check is a urine test, just to see if there's any proteinuria, albuminuria in the urine because that also would be important to know. So on the blood test, it's going to show up as a serum creatinine. That tells you what kind of kidney function you have. And so the higher the serum creatinine, the less optimally the kidneys are functioning. So that's a good way of looking at kidney functions. So the dose of Zometa is four milligrams. It's given intravenously at least over 15 minutes or more. It's given every four weeks. So initially when starting myeloma therapy, if this medication is being used as an adjunct for the bone part of the myeloma therapy, then giving it every four weeks is optimal and ideal. What is the duration of bisphosphonate therapy? Here again, if you talk to three different myeloma specialists, you get like four different answers. For the most part, I tend to give it for two years straight. After that, some people may continue and most people will agree that you give it upfront for the two years on a monthly basis. Following that, if they're just on maintenance treatment at that point, if there's no active bone damage going on and things are pretty stable, it can be reduced to every three months or so. And there's no absolute evidence on how exactly to do this. Do you dose reduce? Do you reduce the schedule and things like that? But that's something that frequently a lot of experts will do. Others continue the monthly treatment indefinitely maybe or for three years. These things are all over the map. The other thing that I would do is let's say the schedule has been reduced to a less frequent schedule. And if the patient progresses or relapses, then at that point, you know, to go back to the monthly schedule is something also that is frequently done, unless the bones are not a particular part of that progression. Can Zomata be given every 12 weeks instead of every four weeks? Is it any worse to get Zomata less frequently? There are so many of these different kinds of studies that are being done. They're very difficult to do. The information that we really want from all of this, is it any worse to do it less frequently? That kind of study is hard to do because you have to follow the patients. And a lot of things can contribute to a worse outcome in one patient versus, you know, bones not being. The biology of myeloma is just different and everybody to start with. Sometimes these studies may be hard to interpret. You do need large numbers of patients to be able to get reliable information from that. A randomized trial giving Zomata every four weeks versus every two weeks was conducted at 269 academic and community sites in the United States. 1,822 patients with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least one site of bone involvement were enrolled. Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zolagranic acid every 12 weeks compared with the standard dosing interval of every four weeks did not result in an increased risk of skeletal events over two years. This longer interval may be an acceptable treatment option. The updated ASCO guidelines state, for patients without active myeloma who are receiving maintenance therapy, receiving dysphosphonates every three months rather than monthly is an option. They also note that there is insufficient data to recommend a specific duration of dysphosphonate therapy beyond two years. Monthly treatment should be restarted upon relapse with new onset skeletal-related events. What is the dose and schedule of iridia, and how long should it be given? Permidrinate or iridia is given usually in a dose of 90 milligrams. That's the standard dose for permidrinate, and it's usually given at least over two hours. So the infusion time is much longer. If there's any evidence that the kidneys are not in the best shape, prolonging the infusion time is one way to reduce further damage to the kidney. So in that case, it may be prolonged to four hours or even longer, depending on the kidney function. The scheduling is the same as the meta. It's also given every four weeks or monthly. What are the side effects of dysphosphonate therapy, and how are they managed? Dysphosphonate therapy has a few side effects. Simpler ones are things like fevers, some bone pains, muscle pains. People can drop their calcium levels. So these are some of the more common side effects. The side effect that most people are aware of or should be aware of is something called osteonecrosis of the jaw, because that is potentially a serious and can be a disabling side effect. What is ONJ, and what are some symptoms of ONJ? ONJ stands for osteonecrosis of the jaw. It happens when, you know, because the way these medications act, over time the osteoclasts, which are the... So for bone remodeling, we need two kinds of cells, osteoblasts and osteoclasts. So the osteoblasts are forming bone, osteoclasts are destroying bone, and this constant turnover is important to maintain healthy bones. So the dysphosphonates act by just inhibiting the osteoclasts, which causes this imbalance, which results eventually in, because these bones are not constantly turning over the way they're supposed to be, they can outstrip their blood supply and you can have like avascular necrosis, which basically means that the bone is not healthy anymore. It's not receiving those good healthy blood supplies, which makes them prone to bone overgrowth and just necrotic bone, and therefore just non-healing chronic bone problems. That's called osteonecrosis of the jaw. If you have like a persistent, like an ache or a pain or sometimes a swelling, sometimes you can feel a protruding maybe bone or something in your mouth that, you know, shouldn't be there, you know, things like that. So a lot of these non-healing sore or wound or something in that nature generally happens around the face area, in the jaw, in the maxilla, you know, in those bones, the upper jaw, the lower jaw. And so that's why it's really important to have the dentist look at it. But those are some of the common things that people experience. Other things that can happen are atypical fractures that can sometimes happen with these kinds of medications. Rare ones with bisphosphonates include things like cardiac arrhythmias, like atrial fibrillation or ocular toxicity, eye toxicity. These are less common side effects and less known side effects with Zometa or any of the bisphosphonates. A main concern of bisphosphonate therapy relates to kidney side effects as discussed earlier. All bisphosphonates are potential toxins to the kidneys. How are side effects associated with bisphosphonates managed? With things like the fevers and the bone pains and things like they should take, you know, even just Tylenol or something like that, the problem with the muscular and bone pains that can happen with Zometa is that they can set in at any time and then they can even happen after somebody has been on it for months and then you start it. And then even if you discontinue the Zometa sometimes, that particular side effect may not go away. That can be sometimes challenging. It's not the most common thing that happens. In terms of calcium and things like that, you know, just checking the calcium, the kidney function, because that's, you know, obviously these can cause kidney damage. So checking the kidney function every time, the calcium level every time before dosing, that once a month dosing. And periodically checking the vitamin D level just to make sure that the maintenance doses are on target for where we want them to be. So these are ways to mitigate those kinds of toxicities. Now, in terms of the osteonecrosis of the jaw, it is not a common thing that can happen. The incidence of it is less than 1%. But it's very important to be aware of this particular toxicity and to work with an interdisciplinary team. So you really need either oral surgeons or dentists who are aware of this issue, who know how to manage it. We always have the patients have a dental clearance first before even starting this therapy. Having a good overall dental checkup and addressing any issues that need to be addressed prior to being exposed to this drug would be a very good idea. Let's say there is a tooth that really just cannot be salvaged. Well, if you need that tooth out, the best time is before you're ever exposed to bisphosphonate therapy. Maintaining good oral hygiene, mouth washes and brushing the teeth, flossing, simple things. But just maintaining that good oral hygiene is very important. And I also highly recommend continuing close follow-ups with the dentist every six months so that any problems can be caught early and taken care of. How is ONJ treated? So the treatment depends very much on the stage, how bad it is. If it's something simple in earlier stages of osteonecrosis, good oral hygiene, mouth washes, keeping the area clean, antibiotics. If there's a chronic infection, sometimes you may need a prolonged course of antibiotics. Sometimes, you know, limited resections. Let's say there's a part that just needs to be taken out, you know, small areas, and the dentist or oral surgeon will decide how invasive this needs to be. More extensive surgery is generally not preferred because then can cause this vicious cycle of creating more issues from bones that are just not healing. If ONJ develops, should bisphosphonate therapy be stopped and not restarted? If the patient has never been exposed to bisphosphonates before but has osteonecrosis of the jaw from some other reason, you know, of course, bisphosphonates can just potentiate it. However, the more common scenario is somebody who's had bisphosphonate therapy and then developed this problem. And then the question is, now what do you do? They're still prone to all of the bone issues from myeloma. But now with this complication, you know, and so one thing that can be done is if the osteonecrosis has healed, which happens in, you know, more than 50% of patients, you can actually, it takes its time, but eventually it can be, it'll heal. And if it does that, then it is okay to go back on bisphosphonate therapy, but perhaps, you know, with very cautious follow-up and really being very meticulous about that oral hygiene, et cetera. Again, opinions may differ a little bit on this. The other, you know, issue is somebody is on bisphosphonate therapy has a lot of skeletal issues, but now has developed osteonecrosis. Do you stop the bisphosphonate? Do you continue it? And there are schools of thought for both. The fact is once these bisphosphonates have gone to the bone matrix, that binding tends to be reversible and it just stays there for long periods of time. So not taking it, you know, at that, not receiving it anymore at that point really doesn't do a whole lot to reverse the problem. Should extensive dental work be avoided when taking bisphosphonates? Again, if you've never been exposed to bisphosphonate therapy, if as long as you wait until the bone and the mucous membrane, everything in that area is completely healed, which generally is at least about two, three weeks, then it's okay to start at that point. However, if you've been on bisphosphonate therapy and then you need some dental work done that was unavoidable, then most people would hold the bisphosphonates for at least three months before and three months after the procedure. What is the role of hydration in regards to side effects from Zomeda? So hydration is very beneficial, you know, right before or after Zomeda therapy. Again, because of its potential to cause kidney damage and especially if there is some evidence of mild damage to the kidneys, hydration goes a long way in trying to, in preventing further damage. So hydration orally, just drinking fluids before and after is very useful. Sometimes you can receive it while you're getting the Zomeda. You can get some hydration prior to the Zomeda, a little bit of hydration post, which I do. Someone who has somewhat borderline kidney issues and I need to use the Zomeda, that's how I normally would do it. Is bisphosphonate therapy covered by insurance? It's hardly ever been an issue in terms of, you know, having any kind of bisphosphonate therapy at all. In other words, you know, maybe they don't approve Zomeda, but you know, most insurances do approve at least the pimadrinate and, you know, and that's fine. When it comes to dinosumab, we do have a little bit more problems in getting insurance approval because it is a more expensive drug. But among these three choices, something or the other is feasible for the majority of patients. Can bisphosphonate therapy be given on the same day as other myeloma therapies? Absolutely, it can be given on the same day. There's no need to go back for another visit just to get this. And we, you know, it is very, very commonly done that way to avoid an extra, you know, the inconvenience of an extra visit. If you are a patient with commercial insurance and are finding it difficult to afford your medicines, the Novartis Co-Pay Assistance Program may be able to help. If you have limited or no insurance coverage, the Novartis Patient Assistance Foundation, Inc., provides medicines at no cost to eligible U.S. patients who are experiencing financial hardship.