(Guest Lecture): New Approaches to Myeloma Bone Disease | MCRT Webcast: Making Sense of Myeloma Bone Issues

Thank you so much, Jenny, for doing this and thank you all for spending this beautiful day with us. Dr. Gertz has really made my job easy, but I do have some slides to kind of share and we're going to go over those quickly because I see in the chat room you guys have lots and lots of questions. So I'm going to do this quickly so that we can really get to questions. And as Dr. Gertz has very nicely highlighted the importance of bone disease in myeloma, but I just want to give you a little bit of background on what we know about bone disease, what are the treatments out there. So some of it is going to be repetitive, but I've got a few cartoons so that you can picture what we are talking about. As he pointed out with myeloma, the bones tend to be very, bone disease is a very dynamic process and you have two cell types. You have the osteoclasts and the osteoblasts, which in general work in tandem, but in myeloma, we have osteoclasts which work over time, which cause the bone destruction that he was talking about. And what we've done over the last several years is really begun to understand all of the circuitry between the myeloma cell, these significant bone cells, and understand and interrupt some of these pathways so that we can decrease the incidence of bony problems in patients. And again, as he's pointed out, multiple myeloma starts out in the bone marrow and there's a reason why multiple bones can get affected. As you can see, these migrate to different bones, form clusters in different bones, and this is what is representative of the lytic bone disease that Dr. Gertz was referring to. Again, in the old days, we used to do x-rays on all patients and really for x-rays to be positive, you have to have quite advanced bone disease. The good news is with all of the advances we've had in the treatment of myeloma, we've also actually begun to do quite well in terms of diagnostic platforms. So typically we do not do scheduled surveys anymore, but most patients should be getting a whole body low dose CAT scan. And the reason for that is a whole body low dose CAT scan is able to pick up bone disease in more than 90% of patients. So it's unlikely to miss bony disease in patients with multiple myeloma. There's certain other imaging modalities which some of you may have had, and these are more functional, such as an FDG PET scan. I certainly don't do an FDG PET scan in all my patients, but there is a specific patient population who may not have a lot of protein in their bloodstream, and an FDG PET is a good way of picking up disease. And then we also do MRIs in patients specifically when you're focused on spine disease and you're concerned about that bony disease impacting the spinal cord. That's where I do think an MRI of the lumbosacral spine or the thoracic spine is quite important. Based on this now, we as a myeloma working group have come up with recommendations on how to image patients with multiple myeloma. So if you're diagnosed with myeloma, make sure your care provider is familiar with this. It's published. It's something we use to even monitor your bone disease over time. As Dr. Gertz has pointed out, the treatment for myeloma-related bone disease for many, many, many years has just been bisphosphonates. He did talk about surgical procedures such as vertebroplasties and kycoplasties, and I will tell you that if you have pain because of compression fractures in the spine, some of these sort of interventions which are not really very invasive can make a huge difference to your quality of life and really make you feel a whole lot better. The other important thing is if you're on pain medicine and you get a vertebroplasty or a kyphoplasty, it can reduce the amount of pain medications you're on, and that can also make a big difference. I agree 100% with Dr. Gertz in terms of radiation therapy. Minimize the use of radiation therapy because when you radiate, you're also causing stem cell damage in the way of low blood counts, and the key to myeloma bone disease control is the underlying treatment of your multiple myeloma. So if you can get your disease under good control, the chances of you having bone-related problems are going to be a whole lot lower, and that should be our goal, and therefore things like radiotherapy are essentially spot welding, and I would minimize the use of things like radiation therapy. This is the studies which have shown the use of bisphosphonate, so you can use either pomidrinate or zoledronic acid. Both of them are equally efficacious, and they can decrease the incidence of skeletal problems by about 50% or so. We have a new study from the UK group, which is the MRC trial, which has compared zoledronic acid to chlorinate, and what it has shown is something which is quite important, I think, whether or not you have bony lesions or not, if you're getting active treatment for your multiple myeloma, you should be treated with a bone-targeted agent because it has shown to decrease the development of new osteolytic disease. So really important whether you have bone disease or not, is to have a bone-targeted agent. So really important whether you have bone disease or not, I do think a bone-targeted agent is critical. What we have unfortunately seen is, and I look at it more as a good news problem, is we are seeing long-term complications from bone-directed therapies, and this is largely because patients stay on these treatments for a very long time. So osteonecrosis of the jaw and stress fractures have been very important. And stress fractures have been noted. And because of that, I think the chat room, we will talk more about this. We have looked at biomarkers and we've looked to see whether or not we can decrease the frequency of these, as Dr. Gertz was pointing out. We've done the ZMARK study. We've given patients zoledronic acid every three months. And based on this study, it is quite safe to do that. It still controls your bony-related problems and yet decreases the incidence of these long-term complications such as osteonecrosis of the jaw as well as stress fractures. There's another new drug which has been approved recently for the treatment of myeloma. And this is because Rant ligand is a protein which we know is over-expressed in patients with multiple myeloma. We've used a drug called denosumab or XGIVA and we compared this to zoledronic acid in the treatment of multiple myeloma bone disease. This was a very large study, about 1,700 patients. And what we saw here was both zoledronic acid as well as denosumab were equally effective in decreasing the incidence of skeletal-related problems in patients with multiple myeloma. What was also quite interesting to see was denosumab actually was able to control the disease a little bit better compared to zoledronic acid. In terms of safety, both of these agents are extremely safe and efficacious. I think the one important thing to highlight here is patients with multiple myeloma can often have renal abnormalities and in some cases, they have a very high risk of having renal abnormalities. And in situations where your creatinine is not completely normal, denosumab tends to be the safer drug to use in the context of myeloma-related bone disease. So again, we have the IMWG guidelines for the treatment of bone disease. This is not yet published, but will soon be published. You can use either zoledronic acid or denosumab for the treatment of myeloma-related bone disease. One is intravenous, one is subcutaneous, and the frequency initially is monthly, but as Dr. Gertz has pointed out, we do go to every three months. In some situations, you go to every six months or so. The one thing I will note is if you're on denosumab, though, you should not abruptly stop the dosing of denosumab. It needs to be continued because if you do not continue it, you are at a risk for fractures going forward. A few things need to be monitored when you're on these bone targeted agents. That includes your kidney functions, specifically when you're on drugs like pomidrinate and zoledronic acid. Because of the risk of osteonecrosis of the jaw, it's really important that you see your dental health care providers, make sure you do routine cleaning, and make sure that if, you know, we try and avoid you getting things like tooth extractions, but if you absolutely need that, you need to discuss that with your health care providers, and a plan needs to be put in place. Once you're on a bone targeted agent, it's extremely important for you to be on vitamin D supplementation, as well as calcium supplementation, because both of these drugs tend to drop your calcium, down and obviously report any toxicity that you have with any of these bone targeted agents. You know, we do study the bone marrow microenvironment in the laboratory, and this is of special interest to me. We've been studying this for a long time, and Dr. Gertz has very nicely told you that typically when we treat myeloma patients, you don't see healing of those bones. Well, I hope in the future we do, because we are looking at the other cell which can cause bone healing, which is the osteoblast, and we have certain drugs that we can use in this context. And as an example of that, we're using a drug called A011, or cetarecept. This is an actin receptor decoy antibody in combination with antimyeloma. And what you see very nicely is a pet positive patient becomes pet negative. These patients are not getting bone targeted agents, and they are continuing to see benefit in terms of DEXA scans. Other potential targets that we will use in the very near future are drugs against a protein called sclerostin. And our hope is that this will be a very effective treatment for the cancer. So we have a lot of drugs that we can offer, and we're looking at. We are studying the bone niche. We would like to combine these bone healing drugs with the anti-catabolics that you already used to. And we're looking at the anti-catabolics that we can offer. And we're looking at the anti-catabolics that we can offer. So with that, I'll stop here, Jenny, and I look forward to discussion going forward. Thank you. Okay, great. And before we jump into the questions, you've done particularly a lot of work on the bone marrow microenvironment. Do you want to say anything broadly about bone related issues or the bone marrow microenvironment as it relates to myeloma? Absolutely. You know, I showed you a cartoon talking about, you know, how complex the bone marrow microenvironment is. It has, you know, in addition to the bone cells, it has immune cells. And what we are studying in the lab right now is the relationship of these bone cells to these immune cells. They kind of check, keep a check on each other and therefore focusing on this is going to be incredibly important. The other thing I will also mention is we look at these as niches and these are niches where your myeloma cells reside. So if there's anything we can do to try and make these niches unhealthy for the myeloma cells, so to speak, that's going to have an anti-tumor activity as well. And that's something we're studying. We're looking at things like dormant tumor cells. And we know that there are certain bone cells which actually control that. So there's a lot of exciting, interesting things that we're looking at in the lab, which will in fact have therapeutic significance as well. Thank you.