(Guest Lecture): November 2022 - Steroids 101: Darn that Dex!

So why did we choose this topic? I'm really just excited for you to listen to Dr. Banerjee, because he's come up with a really interactive, fun slide deck about dexamethasone and how it could be the hero or the villain of our story. I feel like I meet with so many patients that are frustrated with the side effects of dex or misunderstanding why dex is used in almost every treatment. I think some people have negative reactions to dex. Some people that I've met love their dex days. They take their friends on shopping sprees. Most care partners hate dex days because then they have to interact with their loved one who is behaving not as they normally do. I just know there's a lot of misunderstanding and hate out there for dexamethasone. There's people that are not compatible with dexamethasone and have to receive other steroids. So finally, I just wanted to sit down with you guys and have a discussion about steroids 101, darn that dex. Let's learn about how it could be the hero or the villain of the story. And here to present us this awesome presentation is Dr. Banerjee. His clinical interests are multiple myeloma, AL amyloidosis, and CAR-T therapy. His research interests are in toxicity management, digital health, and the patient experience. He's an assistant professor in the division of medical oncology at the University of Washington, Go Huskies, and an assistant professor at the prestigious Fred Hutchinson Cancer Center. So that being said, I'm going to stop sharing and turn the time over to you. Thank you for being here, Dr. Banerjee. Of course, thank you, Audrey. It's a pleasure to be here. Let me share my slides first. And then we will get started. Can you see my slides correctly? Not in presentation. Yes, now we can. It just took a moment. Perfect. Absolutely so. OK. So I'll go ahead and start it. Thank you all for taking the time in the afternoon or evening depending on your time zone to check in. Again, my name is Dr. Banerjee from up here, Pacific Northwest in Seattle. I'll be speaking about dexamethasone, the hero or the villain of myeloma therapy. Thanks again to Audrey and to the myeloma crowd or health tree community for inviting me to speak here. Here are my disclosures and acknowledgments. And then I'll note for those of you listening to this or looking at the slides later, anything where I put PMID at the bottom of each slide, that's a study reference. And you can actually search for that PMID PubMed identification in PubMed.gov to look for the actual manuscript or the publication that I'm discussing. So the reason I chose this quote was actually some of you may have seen this video, Dark Knight, one of many, many, many Batman movies, almost as many Batman movies as there are types of therapy in myeloma. This is from the district attorney here who says, you either die a hero or you live long enough to see yourself become the villain. And that kind of journey matches dexamethasone in some ways in myeloma. And my goal is to kind of go through that. And then obviously spend some time to talk about practical tips for all of you when you're on dexamethasone or not on dexamethasone in terms of what to expect. So we'll spend about the next half an hour speaking about these kind of things, including kind of the origin story, where steroids, dexamethasone came from in myeloma, then steroids as the hero, steroids as a villain that many of you are quite familiar with, and then again, practical tips. And we'll spend obviously the bulk of our time answering questions about this thereafter. So let's get started, kind of continue my Batman metaphor here, the origin story. So first, what are steroids? So corticosteroids are hormones that are made by our adrenal glands just above our kidneys. They have quote unquote neuroendocrine effects. So hormones act from afar and kind of change our entire body at once. And all of you may remember this term, fight or flight from high school. That's what steroids are known for, the stress response handling, not necessarily emotional stress, but physiologic stress when your body is revved up. Practically, they do manage our immune response to inflammation. And then glucocorticoids, which are a subtype of steroids, manage electrolytes, so sugar levels in particular. Alluding to that, so two types of corticosteroids or two types of actions by corticosteroids, glucocorticoids, like what we'll be talking about, focus primarily on the immune system and your blood sugar levels. There also are mineral corticoids that focus on your blood pressure and potassium levels. Importantly, some of you know this, most of you have heard this, these are not the same as anabolic steroids. Those are kind of the injections of testosterone supplements to help boost muscle mass. If anything, these are kind of the reverse of that in some ways. In terms of glucocorticoids, again, they are a subtype of corticosteroids, so a type of steroids that focus primarily on blood sugar, hence the word glucose or glucose. So kind of the opposite of insulin in terms of how they work on the body. They generally tend to raise your blood sugar. Cortisol is the all-natural glucocorticoid hormone in our body. Some of you have heard of this idea of cortisol levels corresponding to the surging of stress levels or sugar or anything. There are four synthetic glucocorticoids available in the US. Hydrocortisone is the same as cortisol, prednisone, methylprednisolone, or sodium medrol, and DEX, the beloved DEX that we're speaking about today. Importantly, of course, these can be given in all sorts of ways. Many of you have seen, for example, hydrocortisone cream over-the-counter ointment for kind of topical inflammation to kind of get rid of rashes. Same principle, obviously, but that's generally only for the skin. Systemic steroids are either oral or IV and obviously act on the entire body at once. Then zooming into dexamethasone in particular, it is the strongest glucocorticoid that we have. So I showed you on the right here, not that I am a chemist, but you can see just a couple of changes here. There's a little fluorine here and one of these rings changed and whatever. And all of a sudden, dexamethasone ends up being 20 times stronger than natural cortisone molecule for molecule. Is 100% bioavailable? That's a fancy way of saying that the dosing orally is the same as a dosing IV because all the dexamethasone that anyone takes as a pill gets into their bloodstream 100%. Not all drugs are this way, so we can never assume that medicine, but here, for example, some of you, whether you take 20 milligrams orally or IV in clinic, exact same thing. And thankfully, dexamethasone is relatively affordable. It's been around for a very long time. It's a quote unquote essential medication. And so for example, on GoodRx, it is less than $5 for a 40 milligram for a one week supply of dexas 4-milligram tabs. The steroids have been around for a while. Beth Fame in Cleveland Clinic actually showed me this slide from a study from the 1990s looking at prednisone, for example, that being used as maintenance, which you don't do anymore, improving survival in patients with myeloma. But really, dex has been kind of the star of our show for at least the last 30 years, if not longer. So this is an example of a study of high dose dex from back in the 80s. So this was here, you can see that these patients got dexamethasone 40 milligrams every morning for four days. So they would take it for four days, stop for four days, take it for four days, stop for four days, and so forth as part of a combination drug that included bincristine, it's not Velcade, a drug we don't use anymore for myeloma, and adriomycin or doxorubicin, which you also typically don't use anymore for myeloma. There were some studies of dex literally just by itself. So the same principle, dex here, this was mixed for a meter squared, but practically about 40 milligrams daily for four days and off for four days, daily for four days and off for four days in these patients. And some patients had responses even just with that all by itself. This is also a study from 1992, so very long time ago by modern standards. Some people may be asking, because all of us, we say that our patients are on high dose dex, which is correct. I would call dex 40 milligrams weekly high dose in my mind. So then you might be saying, well, I thought that was high dose, what is this? So that's kind of super, super high dose. And really, until the 2000s, we weren't really sure how best to approach dexamethasone in myeloma. So you can see there actually was a study here, this was an ECOG study. So this was a cooperative group of not funded by a pharmaceutical company, kind of all the researchers and physicians coming together to study this, looking at what was then considered to be high dose dex. So again, four days of straight 40 milligrams, and then four days off, and then four days on, and four days off, and four days on, and so forth, versus what many of you may be more familiar with, which is dexamethasone several pills once per week, for example. This was a randomized study. So patients were randomly assigned to both of them in the newly diagnosed setting, in combination with linalytomide, which is Revlimid. At this time, we tended to use doublets and not triplets or quadruplets for myeloma. So this was a doublet with linalytomide and either high dose dex, meaning four days on, four days off, or one week at a time. And so at first glance, the high dose dex had an overall response rate that was better. Overall response rates mean that the myeloma blood numbers come down at least 50% or more, and that looked better. I have no doubt that the higher the dose of steroids, the more the steroids kill myeloma cells. However, when they actually stopped the study early, because they looked at the data, they found that patients who were getting high dose dex were actually passing away at higher rates, unfortunately. You can see here that at the four month mark, 5% of patients in the high dose dex group had died versus only one patient in the low dose dex group. And you can see here, you'll see a couple of Kaplan-Meier curves that are shown here, and we can talk about these are confusing, but basically on the Y axis here, this is what percent of patients are alive. On the X axis here, you can see this is number of months, and you can see, for example, by one year, maybe only about 90, maybe 85% of the patients in the high dose dex group are alive versus closer to 98% in the low dose group. And this graph kind of looks at that in more detail, and basically long story short, the rates of progression, which is our word for relapse, but the myeloma coming back were similar between them, but the red line is higher than the blue line, which means that patients were dying more for non-myeloma reasons in the high dose group. The main causes of death here really were then blood clots and infections. There was no difference in rates of relapse with that in mind. And so the lessons that we kind of learned from a study like this are two, really threefold. So one is that we very, very quickly stopped using dex, this kind of approach of taking 40 milligrams every day for four days and stopping, then starting, then stopping, for example, move to a once weekly paradigm. We learned that blood clots are very possible and possibly lethal in patients who are getting those kind of ultra high dose steroids. They're not an issue with low dose steroids by themselves. Revlimid with lenalidomide, they are, some of you may be, most of you probably are on blood thinners, for example, but that's not because of the steroids anymore, the doses that we use. And the biggest plug that I wanted to make here, and this is kind of from the International Myeloma Foundation, a tribute that they gave to Michael Katz, who I never had the privilege of meeting, that he was a patient who was both a patient and a patient advocate. So he served on the ECOG, on this cooperative group committee, and he really, really pushed for this study to happen, being like, hey, we just made up our dex doses, let's try a lower dose and see what happens. And really it was thanks to him pushing for this trial that this trial happened. And obviously that our entire practice for all of our patients a decade later has been changed substantially. With that, I'll stop and move on to kind of, in the last decade now, fast forwarding to the year 2022, what do steroids bring to the table? What do they really take away from the table in terms of their side effects as a villain? And then how do we manage things? And then again, I'll spend the bulk of our time answering questions from all of you about how I approach steroids and how it approached them in individual cases. So this is not meant to be a biochemistry talk, so I'm not gonna go into all the details of this. There have been several studies that show that dexamethasone does make other anti-myeloma drugs work better. The word that we use is synergy. Synergy basically means that one plus one equals three, where the combination of drugs works better than you would expect from either drug working by itself. The idea being is that steroids work on many different pathways within myeloma cells and might make them actually promote different proteins intracellularly that makes them more susceptible to other drugs. So here's just some examples here with selenexor, which is a new drug that blocks export of certain proteins. Ortesimib, which is Velcade, that many of you are quite familiar with. This is ibertamide, which is a new cell mod drug, not yet FDA approved, but probably will be a replacement to lenalidomide and pomalidomide someday. And here's one with pomalidomide. A lot of these are preclinical studies, but have shown this principle that in a Petri dish or in a cell model, for example, if you just come put steroids over here and then put some other drug over here and then put steroids and the other drug together over here, the combination effect is the most salutatorious, has the most beneficial effect in terms of killing myeloma cells. There have been clinical studies that have shown this as well. The caveat is that these two studies that I'm showing here, for example, we don't generally use doublets by themselves in most cases, but this was a study of pomalidomide or pomalist, which is a newer version of imid, of revlimid or lenalidomide. I got another Kaplan-Meier curve here, but they looked at palm with dex versus palm alone. And you can see here that basically the dark line looks better. This is progression-free survival. This is how long patients remain in remission without the myeloma coming back, requiring another therapy or unfortunately passing away. And you can see, for example, here that at 10 months, for example, here, not great numbers, but numbers all the same, about maybe 30% of the patients in the palm low dex arm getting palm with dex were still in remission versus closer to only 20% than the patients who were only getting pomalist by itself. This is a study here in the relapse setting. More recently, it was published last year with esatexamab, which is sarclisa, a monoclonal antibody similar to Darzalex or Darro that many of you may be more familiar with. This was a little bit more impressive here where the median PFS, so meaning how long the average patient, 50% of the patients were able to make it without the myeloma coming back, was, if you look at the 50% mark here, was 10 months in the arm that was getting esatexamab with dexamethasone versus only five months in the patients who were getting esa by itself without the dexamethasone. So there is clearly some benefit, even in the modern era, because this is the drug, these are drugs that we do use all the time today of adding dexamethasone in terms of tackling the myeloma. Other things that Stero is bringing to the table. So dex is a very powerful anti-inflammatory drug as I talked about. That's kind of the principle, senaquinon, of why we have dexamethasone in general as a drug. And so for a lot of our medications that are antibodies, what we call monoclonal antibodies, we do require dexamethasone as a pre-medication before them. Just to talk through what that practically means, unlike a classical drug like Velcade or, you know, letalidomide even, for example, a MAB or a monoclonal antibody is actually generally, in most cases, actually mouse-derived. So it's actually a mouse antibody where it's basically, we figured out how to make a mouse antibody that attacks human myeloma cells. And then we started to convert or synthesize that particular antibody in a lab. So this is not, you know, mice are not dying directly to give these drugs, for example, but it was derived initially from a mouse protein. And so you're basically either infusing or injecting a mouse protein directly into your bodies, which sounds terrifying. And your immune system appropriately gets kind of really confused and starts to often attack the actual antibody itself to begin with. And so we often have to give steroids to help calm down that hyper-inflammatory response to begin with. So here are some examples here where this is for Darzalex or DERA, we recommend DEC 20 milligrams beforehand, especially for the first couple of doses, then we can drop it. This is for sarclis or esatexamab, the same principle, 40 milligrams or 20 for older patients. This is for elatuzumab or Ampliciti, which is another type of monoclonal antibody we can see they recommend here a combination of basically 36 milligrams of dexamethasone orally and IV leading to every infusion from the beginning to help avoid these infusion reactions. Dex can help with nausea and with pain. Audrey alluded to this and I have had patients who actually feel their dex days are actually better for them, their pain is better controlled on those days, especially in the beginning of therapy with myeloma, doesn't happen for everybody. But for many times when patients are having uncontrollable pain, I will sometimes use dex 40 milligrams daily for four days, just like the super, super high doses of steroids I'd mentioned 20 years ago. Importantly though, I don't keep doing it again and again, we give it and then we try to taper it. We try to do something else to kind of get control of the pain more definitively, like radiation therapy or starting new drugs for the myeloma and go down on the steroids. The steroids do work both in terms of pain flare as described here, especially for bony pain, but also for, this is an example for all patients with cancer, but for chemotherapy, we often do dexamethasone. So for example, for some of you in the audience may have gotten VD pace or DSEP or CVAD or even a stem cell transplant that we do sometimes use steroids with those regimens, with the high doses of chemo purely as a way to control nausea. But now that I've talked up steroids and how quote unquote awesome they are in some ways, we'll talk to kind of bad blood here. Steroids as a villain in terms of the far more common side effects that people experience that are often negative with these drugs are not positive. So actually myelometry has done some features on this before. So Jenny Alstrom, who I think is either the founder or the CEO of myeloma carotid health tree, if not both, she's wonderful as she's been a tremendous patient advocate and with this side and just in general. So she has several articles on this website. Some of you may have seen specifically about dexamethasone and you can see the very typical story they hear from patients, right? She all of a sudden after being diagnosed, she was lying in bed until 2 a.m., neat freak, going to the laundry all the time, indignant, mad at my kids. My kids are all of a sudden really loud, crying and raged. All of this and her husband was like, what is going on? And we realized, not the myeloma, not anxiety, that's the steroids for sure. She actually wrote a song about it that I encourage you to check out if you'd like. So this is again, not new. It's very common for people to have side effects from steroids to talk through what to expect what many of you are experiencing. So some of this is physiologic. So it's this kind of quote unquote fight or flight response that again, I mentioned that all steroids, all corticosteroids, all cortisol mimics are known for is a stress response. It's kind of like running from a tiger, fighting a tiger kind of response. So jitteriness, anxiety, insomnia. Most patients say that they are able to stay asleep, but it's falling asleep as a difficult part. Irritability and then what Audrey alluded to, the caregiver notices that, oh, my partner is a monster on steroid days. Some patients, some caregivers tell me that, oh, my partner, I love when they're on steroids because all of a sudden they wanna clean the house and cook food and I love that. Most patients kind of a negative thing. That's a stress response in terms of blood sugars and electrolytes. A lot of our patients, this is just how steroids work. They do increase their appetite. They do cause weight gain just from appetite alone. Sometimes can cause blood sugars to go up as well for patients who are diabetic. For most patients, steroids will cause some degree of leg swelling. The medical term for that is edema. So you may notice that your legs are more swollen. Maybe sometimes it's just very subtle at nighttime or in the morning you notice it. Sometimes patients say that the shoes are a little tighter to fit than they were before. That's all leg swelling from the steroids most typically. Steroids do suppress stomach acid. So some patients might notice that they get heartburn or just kind of burning in their stomach afterwards and that can happen as an upset stomach purely from the steroids itself. And then that's on the days that you're on the steroids. Other patients notice that they fear this roller coaster of hormones. So they have what's called a letdown effect or withdrawal effect. So the day after the steroids, for example, they feel very fatigued or in bed all day, for example, and that's all equally problematic. That's kind of acute issues, chronic issues. So kind of for patients who are on steroids for a while, including many of you who are listening to this. So steroids can absolutely impair bone health. Complicated how they do this. They both interfere with the ability of your body to metabolize new bone, but also kind of in some ways may encourage your body to break down old bone from cells that are called osteoclasts. The word for this kind of generalized weakened bones are called osteopenia. Steroids, this is more controversial for weekly steroids. I actually don't think it's that big a problem for steroids once a week, but for those of you who end up being on steroids more frequently than that, you can be at risk of infections like that old ECOG study showed. So some of you, for example, you also have another risk factor like uncontrolled diabetes or low blood counts from some other medications. You may also be on yet another anti-infectious medication called Bactrim or Ceptra. Generic name is sulfamethoxazole trimethoprim. It's also to prevent rare infections, something called PJP. This is different from shingles. So most of you probably are on acyclovir. Acyclovir is to prevent shingles from coming back. And that happens with any proteasome inhibitor like Bortezumib Velcade or Carthalizumab Cyprolis, or from a CD38 drug like Deratumumab Darzalex or Iza-Tuximab Sarkliza. So all of you will be on acyclovir. Some of you may be on Bactrim or Ceptra. And that is a side effect of something else as a risk factor plus being on steroids. Steroids chronically do cause skin and muscle issues. So you can notice acne, easy bruising. Some patients will feel like their core muscles and their kind of upper arms and thighs are a little bit weaker than they were before. Generally, that's not as common with once a week decks as it is with the high dose decks of the days of yore, but certainly can happen. It's something to talk to your doctor if you're experiencing it. And then a lot of our patients may have high blood sugar. So that can manifest in many ways. That can cause blurry vision just from the steroids themselves. That can cause pre-diabetes or tip people who have pre-diabetes over the fence into actual diabetes and more. So just to highlight some practical examples on the showcase that there are researchers who are working on this. This is a study that not published yet, but it was done by Dr. Corday's group at MSK Moral Bone Kettering in New York. And they actually gave patients similar to a Fitbit, like an activity monitor that would wear throughout the day and basically looked, you can see in this diagram here, orange are the dex days, green are the non-dex days. And on this particular graph, the more sleep someone got, the higher the lines are, the less sleep they got, the less. And you can see for some of these patients, some of them you can actually see on dex days that they absolutely are sleeping less objectively by the sleep monitor. You know, like this poor gentleman or lady here, I'm actually not sure what the gender was. You can see that this is the lines here, the boxes are the 25th to 75th percentile of how much you're sleeping. And you can see this patient on the days that they're on steroids, they're sleeping less on average than the worst 25% of their non-dex days, for example. This tends to be more pronounced in younger patients and older patients, we don't entirely know why. Thankfully in the study, when they average things out, the average sleep per night altogether was only six minutes per night on average, less altogether over the entire induction study period. So basically patients probably do sleep more on the other days to make up for this, but still this is a problem. Another example, this was data that was very recently presented at IMS, that our International Myeloma Society meeting two months ago in Los Angeles by Dr. Popa, who kind of gave me these slides, he's based out of the UK. And basically if you look at adults aged 60 to 70 in the US population, cataracts, these are some other studies that show that's about maybe 10 to 30% of patients have cataracts in general, about one to 4% of patients in general have glaucoma. If you look at this study, this is the dream two study of patients who are getting Bilanthamab mafidotin or BlendRep, this is a drug that can cause ophthalmologic or eye toxicities, and so all of the patients were required to get an ophthalmologist to look at their eyes before starting. And you can see here that in this study, 60% of the patients did have cataracts going into this study, 12% of patients had glaucoma going into this study. And in terms of why all these patients suddenly had all these issues way more than the US population, Velcade can sometimes cause some of these, but I would say the big risk factor are steroids, steroids and more steroids in terms of eye issues that these patients had. Again, these are patients, these are not newly diagnosed, these are patients who had at least three prior lines of therapy for myeloma, so it had myeloma for several years, had been on steroids on and off for years during that timeframe. And this is one of the long-term side effects that absolutely we can objectively measure as being a problem. The other side effects for DEX is polypharmacy. That's a very fancy medical word of just saying too many medications that patients are taking. I'm sure all of you will laugh and be like, oh, that's my life right now, living with myeloma. In general, polypharmacy is bad because we've studied polypharmacy in other scenarios and other types of cancer, and it leads to higher out-of-pocket costs, obviously. It's more easy to forget a med if you have so many medications you're juggling around that are sometimes every 12 hours, like a cyclopyr, every day or once a week. Some medications can combine similar to synergy, but in a bad way now and cause side effects in a more pronounced manner like falls or dizziness. And that's just, for all patients with myeloma, again, we generally, as doctors in general, define polypharmacy as five or more meds on someone's list. And just most of you in the audience listening are probably on Revlimid, you're on aspirin because of the Revlimid or a different blood thinner. You're on the dex once a week. Maybe you're on a medication like Ambien or Zolpidem, I'm sorry, the generic name to help with insomnia from the steroids, and you're also on a cyclopyr. So boom, all of you now by default have polypharmacy is not your fault at all, it's the myeloma's fault. And so it's just frustrating. And then of course, separately from this, that definition doesn't take into account the fact that dex only comes in four milligram tabs at the most. So all of you are also kind of chugging five or 10 pills a day, and we're aware of that. That's a problem of note. Recently, there actually is a 20 milligram formulation of dex specifically for myeloma. The brand name is Hemati. And one study showed that a 20 milligram tab of dex was equivalent to taking five of the four milligram tabs, for example. Unfortunately, why aren't more patients on it? I actually don't have any patients who are on it. I think this is why, because insurance companies is very expensive. And so at GoodRx, at least the cost for a one month supply is $200 for this 20 milligram tab formulation versus $15, for example, for dexamethasone. Oh, plenty of issues there, plenty for the talk about in the discussion. What I'll do now is pivot to the final part of this discussion, but just some of the practical tips that I recommend for patients who are on steroids, as they're dealing with them in terms of dealing with the side effects, or maybe even talking to their providers about changing the dosing of it or so forth. So with that in mind, just in terms of lowering the dose of steroids. So since that ECoG study was published a decade ago, most studies now use dex 40 milligrams weekly for most patients. And most studies now have a pivot now where for patients who are age 75 or older, which is a very high cutoff in my mind, they lower the dex of 20 milligrams weekly. For patients who are on trials, I'm often stuck because my hands are tied by the study trial itself. But for patients who I'm just treating in practice, what I tend to do is I counsel patients that, look, this is one of the drugs that you'll have side effects with. I do start patients generally speaking, who are under the age of 75 on 40 milligrams, just because that's what was studied. Any issues whatsoever, no questions asked, we can drop it to 20 milligrams. Any issues with 20 milligrams, I can drop it to 12 milligrams. There are some studies that coincidentally use 12 milligrams and it happened to work. There are no randomized studies here. I can't prove that 12 milligrams works as well as 40 milligrams, but probably does. And people are still having issues thereafter with the steroids. I typically then either stop the steroids or there's some thought, no one has studied in the randomized fashion that other steroids like methylprednisolone or sodium medrol might have lower risks of these. So for example, for our patients who need a steroid pre-medication before Darzalex deratumumab or ethatexumab sarclisa, and you don't like the steroids, I can sometimes use methylprednisolone instead, for example, sodium medrol, and that might theoretically help with some of the jitteriness, but I can't really say for sure. Obviously talk to your doctor, they put the little caveat here about your case because every case is different. That's the total dose of dex per week. Can the timing of the dex be adjusted? Absolutely worth considering. This is a nice publication from the nursing literature about what they recommend that I completely agree with this. So instead of doing dex 40 milligrams weekly, if you're noticing you're just having pronounced difficulties with sleeping on the day of the dex, you could break it to 20 milligrams on day one, 20 milligrams on day two, and then again the week after, 20 milligrams on day eight, 20 milligrams on day nine. Some of you in the audience may already be on that regimen. Some studies, some centers have gone to do that by default by having two days of steroids on, five days of steroids off, no right answer. Has not been said in the randomized study, but that might help a little bit in terms of avoiding these peaks and troughs and roller coasters of being on steroids. Importantly, most of you remember this, but I think it's worth remembering, or I've heard this, but naturally speaking, cortisol levels are highest in the morning, in the early morning at dawn really. So the closest you can take the steroids to dawn, the better. Obviously, please don't wake up at dawn, depending on where you live, to take steroids is not that essential, but the earlier you can take it, the better, in terms of just kind of mimicking what your body is naturally doing and avoiding some of the insomnia and jitteriness that you're going to be feeling in the morning and thereafter. For those of you who are getting dex in clinic, either as part of your myeloma therapy or as an allergy pre-medication, sometimes we can't change that, especially for clinical trials or for the first couple of doses of treatment. Some centers just require for safety reasons that the dexamethasone be given in clinic, but as soon as that's not required, talk to your doctor and say, look, if you trust me, would it be okay if I took the dex at 8 a.m. before driving in, and then by the time that you see me in clinic, I can take the dex at 9 a.m. and then I can get the other medications, for example. That might be helpful both to maximize, again, this kind of dawn effect in terms of when steroids are best dosed and then just making a pledge to my own research. I really am interested in kind of home time and kind of avoiding how much time patients have to spend physically trapped in clinic. And you can imagine some of you have experienced this, right, where the nurse or doctor says, all right, you got the steroids in clinic and now you have to wait 60 minutes by definition until we can infuse the drug. And if there's a way to shift that so you can take the steroids at home orally and with the time that you drive in the clinic, get on the elevator, wait in line, get your blood tests, get room, get your vital signs checked, it's been an hour and now you can just go straight and get your therapy, totally worth pursuing. In terms of whether to stop the dex altogether, so with induction therapy, so for patients, induction therapy means kind of the first four to six months of therapy where we're just trying to get the myeloma into a very good partial response. So 90% reduction of myeloma numbers or ideally a complete response into remission entirely. Yes, it is possible. Generally speaking, we try to lower the dose if we can and get away with it, we can't always. There was a study that was published, a randomized study. I love randomized studies in medicine because they're the best way to prove that anything actually works. But unfortunately, it's very difficult to execute them for a variety of reasons we can talk about. This was an Italian study published last year. These were in patients who were somewhat frail. We have a way to kind of quantify frailty or just how physically fit patients aren't going into things. And these are older patients who weren't quite as healthy as they were 20 years ago. For example, they use doublet induction, which we don't actually do anymore. We typically use triplet or quadruplets, but they gave one arm of patients randomly Revlimid plus just a dex forever. And then, I'm sorry, and then just gave the Revlimid by itself and then, sorry, yeah. Arm one got Revlimid dex and then just got the Revlimid and they dropped the dex. And the other arm got Revlimid plus dex forever. And basically, the two arms performed equally efficaciously and there were fewer issues of low blood counts in the arm that got the Revlimid plus dex than just the Revlimid by itself. So there was some benefit there, or at least there was non-inferiority, meaning that it was totally fine to drop the steroids in these patients after nine months. That's still a lot. Induction therapy often only lasts four to six months. So the jury's kind of still out. For some of you in the audience may have AL amyloidosis, which is a diagnosis where there's a qualitative issue with the M protein in addition to the quantitative issue with the myeloma. For those patients, and if you have amyloid in the audience, I would say strongly drop the steroids as quickly as possible because steroids caused even more issues in patients who have amyloidosis. For those patients, I would probably drop it as soon as I can. For most other patients, I drop it, meaning drop it entirely from the regimen during induction only if the patient's having side effects or issues. Then with regards to consolidation or maintenance, absolutely I would drop it. So for the consolidation, some of you may, for maintenance, basically that's after transplant or after induction therapy. Most of you will not need to be on steroids at all during that time. You're probably just on lanolidamide. Some of you who have quote unquote high-risk disease might be put on the same drugs that you were on during induction, again, during maintenance or consolidation. Even then though, I would say that you can drop the steroids at that point in time and just do the two active drugs and forget about the steroids. And then finally, some real life tips that I would recommend with these two figures who are excited maybe because they're wrapped up on steroids. Some practical tips to tell patients about or I encourage you to kind of consider on your own. So one would be to maximize your quote unquote sleep hygiene on steroid days. Sleep hygiene is our term for basically trying to promote a good night's sleep. So it sounds silly, but try a weighted blanket. Try avoiding cell phones or TV within an hour of bedtime. Try avoiding eating right before bedtime. Try a white noise machine. If you have an Alexa, set that to play white noise. Over-the-counter medications are generally fine for the vast majority of our patients like Benadryl or diphenhydramine or melatonin. Some patients find that topical CBD helps, for example. You can talk to your doctors about that and I would say whatever works, do it for sure. Get your eyes checked out or get new glasses. A lot of my patients tell me that their vision is kind of getting a little bit worse. They tell me that like two years later and I'm like, well, have you seen your eye doctor or your optometrist? And they say, no, I haven't. And again, the steroids will change your vision. Even if you're not gonna get cataracts or glaucoma, just the sugar itself, sugar tends to attract water. And so people's lenses by definition do get a little bit cloudy no matter how old or young they are. So if you have glasses and you feel like your vision is not where it is, talk to your optometrist and if they can adjust your power and that's easy to do, then do it. Take decks with meals. I know I said to take it earlier in the morning if possible. So maybe you can take it with a snack in the morning. It might be ideal to avoid heartburn. Some patients do need antacids like Tums while they're on it and that's totally fine. Make regular PCP appointments for bone health and diabetes screening. So again, independently of all of this, steroids or even MGUS, just anything, or just getting older can cause patients to become osteopenic. That's the word for having weaker bones. We do use zoledronic acid or Zomeda or XG or Dinosamab to strengthen bones in our patients which should treat osteopenia, but it'd be helpful to know. Similarly, if you're at risk of diabetes, it might be worth talking to your doctor and getting an A1C checked for your diabetes or pre-diabetes because that's also something that we can adjust. Or leg swelling, you can elevate your legs at night. You can wear compression stocking, things along those lines. A lot of our patients, especially those who have amyloid, we do often end up starting a diuretic. That's the word for a water pill like Lasix that basically helps to just make patients urinate more. And that sometimes helps with the leg swelling. And then exercise regularly. I mean, you'll hear this from everyone you talk to on this website on myeloma crowd and every doctor, everybody is super important from what's on myeloma in general, just in terms of promoting bone health, but specifically with the steroids and this long-term risk of weakened core muscles, the more you exercise and more in shape you are, it doesn't have to be crazy, but just walking around, staying active, the better you'll do in terms of treatment and the better you'll feel. And then my final piece of advice is to join a patient support group. I have no doubt that by selection by, so if you're listening to this audience are very engaged with your myeloma or your loved ones myeloma and probably are part of the support group like myeloma crowd, but also if you have one in your local community, I know here in Seattle, we have a patient support group, the myeloma fighters, for example, that's often helpful because you may find that just bouncing ideas off of someone who literally has been through this and has been on steroids and has some excellent tip or suggestion that I had no idea was an option like acupuncture or a different CBD topical something or something along those lines might be helpful. And I feel like just talking to people, knowing what to expect and being engaged as part of that journey is super, super important. And I think that helps a lot with this. So in terms of my concluding thoughts with steroids, so Dex was once the hero and now it's very much the villain. And so really, yeah, that's kind of a joke of these, apparently these pharmaceutical ads that all the CNTV, ask your doctor if dropping the Dex or lowering the dose is right for you. For a lot of patients that is entirely appropriate or reasonable to consider if you're having issues with it. And I think it's, you know this better than I do that a lot of times we're running around the clinic thinking about as physicians thinking about the next step, with transplant or CAR T or maintenance or whatever. And we don't really, or if we think about side effects, we're thinking about the Revlimid side effects and not the Dex side effects. So if you notice something, send us a message and talk to us, I promise you that we won't be upset about that. I promise you that there is no study in the world that has shown that Dex 20 milligrams, for example, is any worse than Dex 40. And in my heart, I do truly believe that Dex 20, for example, is totally fine. So that's, it's not, you know, you don't have to be, you know, a super athlete, you know, like fighting your way through this. You don't have to be suffering for no end because I think that if this side effect of Dex is causing you problems, and if Dex 20 versus 40 or 12 versus 20 or no Dex versus 12 could just help you live your life better, that's a very important consideration that your doctor should know about. With that in mind, I will end with one of my favorite quotes from a book called The Emperor of All Maladies about myeloma, how it's not curable yet, but I really hope that we'll get there and I would be very happy to take questions. Thank you all for taking the time to listen in. Awesome. Thank you so much, Dr. Renerjee. That was amazing. I love how actively, how engaging the presentation was. And I'm really excited to get this conversation started. One of the things that I wanted to talk about was this dosing of Dex. So as you were just mentioning, 20 milligrams is just as efficient as 20 milligrams is just as efficient. And we know that kind of this 40 milligram standard has come a while ago. And I say a while ago because even in these past two years, myeloma research has accelerated at an unprecedented pace. I would like to see, and I think you're, I appreciate that you brought up Dex can be the hero and the villain because of its synergy with other multiple myeloma medications. I have a lot of thoughts, obviously, but what I'm trying to say is, do you see another clinical trial happening like soon where the standard of dosing turns to that 20 milligrams or 12 milligrams? I mean, let's talk just a little bit more about that. That's an excellent, excellent question. So yeah, I would love for that to be the case, kind of extension of what you're asking is, well, ECOG did this awesome study of high dose, high, high, high dose Dex versus high dose Dex. Can we do 40 versus 20? It's obviously difficult to get funding for these kinds of studies to be practical. And pharmaceutical companies are not that interested in it. I think the biggest issue is I think, yeah, a lot of our studies that are practice changing are sponsored by industry. And we have to work very closely with industry with pharmaceutical companies. They're the ones who actually make these drugs possible. And I'm not meaning that for any slate to them. And these trials have to pass muster with the FDA, which is also very particular. And so I think by default, what ends up happening is it is very, very slow for clinical trial protocols to change. The example that I would give in this regard is some of you, for example, maybe, and this is a talk for another day about proteasome inhibitors like Velcade or Bortezomib. I tell all my patients that I insist to every pharmacist I meet that all my patients be on Velcade once a week and not twice a week. A lot of our studies are still, they give Velcade day one, day four, day eight, day 11, meaning they give it twice a week as part of their, for the first two weeks, as part of their cycles. There's no evidence in the world that twice weekly Velcade is any better than once weekly Velcade. Several studies, very large studies, have looked at patients who start with once weekly Velcade because the doctors like me who kind of prefer once weekly Velcade for patient convenience reasons and found no difference in outcomes of any sort whatsoever. But yet, literally even today, we had our SWOG, another big cooperative meeting and we were talking about this last week and even then I was like, hey, nudging the people who are presenting a trial and being, hey, do you mind meeting the Velcade once a week and not twice a week? Just because again, it's really annoying to have to come to clinic enough once a week, twice a week, even more annoying. So we're working on it, but I think it's just frustrating that I think the clinical trials are not going to change anytime soon to allow that. I think what would practically happen is just, you know, provider awareness that the docs are aware, the patients are aware, and that's enough for them to say, look, you know, I don't need to worry about the DEX 40, I just rolled with it. Is there a way? Sorry, go ahead. Go ahead, go ahead. It's real world data, right? It's their own patients being able to advocate, hey, we don't need this 40 milligram. It could be just as effective with 20 and having almost the empowered patients bring about that movement. That's exactly right. And the way that I would look at it is with induction therapy, the goal is to get to as deep of a remission as we're going to get to and then we move on. As all of you know in the audience, induction therapy, which is where the bulk of steroids are used in the newly diagnosed setting, is not going to cure myeloma, unfortunately, I wish that it were. And so, you know, if someone, especially if someone's on track and like, you know, they're on four drugs and you can tell that they're already, you know, the myeloma never coming down beautifully, especially for those patients that would feel totally fine with dropping the steroids because whatever synergy the steroids offer might be overkill if it's having side effects and 20 milligrams would be totally fine for those patients if not everybody. But I agree, that advocacy piece I think is super important. I will say that I think in amyloid, amyloid patients, a patient with amyloidosis, they're often much more symptomatic from steroids. Some of those protocols have kind of dropped the steroids more consistently or I've even heard on, I can make a plug for Med Twitter. Some of you in the audience may be on Twitter, I'm on Twitter, it sounds silly and political, but you often hear a lot of patient advocates and physicians talking about things. I've seen a lot of my colleagues like myself for patients with amyloidosis. As soon as we see their light chains going in the right direction, we immediately stop the steroids. Not just lower stop period. I don't think I'm quite there yet for most of my patients with active myeloma, but we might get there someday just by evolution of change, but it won't be soon enough. Yeah, there was a patient that was asking about clarification when it came to your comments on amyloidosis, so thank you for bringing that up again. I think that makes it clear. And how interesting because that's not something that I've heard before even in our amyloidosis chapter. So thank you for sharing that insight. Another question, what's your personal philosophy in including dexamethasone in maintenance therapy? Good question. So my style is definitely not worth it. So for most patients, so maintenance comes in two flavors. So typical maintenance for most patients who don't have these quote unquote high risk features on cytogenetics on their bone marrow biopsy. Again, high risk doesn't mean high risk of death. That just means higher risk of the myeloma coming back sooner after X, Y, Z line of therapy, including transplant. For standard risk patients, I recommend linoleumide by itself, so Revlimid by itself or another drug if that's not tolerated or Velcade if they can't be on Revlimid for kidney issues, for example. The steroids I do not recommend here. For higher risk patients, there is a standard where we either give a drug like Velcade instead of the Revlimid or sometimes combine them both. In that setting, I do lower the doses of all of them because we're playing kind of the long game here. So for example, let's say someone who does have high risk quote unquote myeloma, and I say, I'm gonna put you on VRD after transplant or after your induction therapy until the Velcade being twice weekly or once weekly, I'd make it every other week. The Revlimid, the linoleumide, I would keep only at 10 milligrams, not at 15 or 25. And the Dex, I would absolutely drop. The biggest reason for that in my mind is this cataract study or wherever that was here. That's one of them, and I think the osteopenia, so the long-term issues of bone issues is very difficult to quantify in myeloma because as all of you know, patients have other reasons that they might have weak bones from the myeloma itself and everything else that's going on. And so difficult to say, I just don't think in maintenance that the, again, because with induction, you're trying to slam the myeloma into as close to remission as possible. With maintenance, your goal is preserving a remission. You don't need to intensify things that much with a steroid, especially given their side effects. And the final thing I would tell patients and this, I think the question Astro asked is my personal philosophy, because this is my personal philosophy, is that if the myeloma is going to come back, it's going to come back. And it's not that a couple of extra little things here and there is not gonna change that. I generally bring that philosophy up with regards to, for example, patients are asking, oh, can I take a month holiday from my therapy because I'm going on vacation or something? Or if I'm on DeraTumaMab, can I stop the Dera for the holidays coming up? And I say, yeah, that's probably fine. Or go down on the dose because in the maintenance setting, again, I think the drugs are gonna work for as long as they're gonna work. And when the myeloma becomes resistant to those, it's not gonna be the steroids or that one extra dose of DeraTumaMab that made a difference. And we just have to try something different at that point in time. So for all those reasons, especially for maintenance, I'm very hesitant to recommend anything beyond RevLumid by itself, even for example, Dera. So in the Griffin study, for example, patients were on Dera maintenance as well. And I do not recommend that to most patients because that's Dera, and that study was two years, but in some studies, Dera, people think about putting people on Dera forever. And Dera absolutely does lower your immune system in terms of responses to vaccines and has side effects. Dexamethasone, absolutely, we talked about causes blurry vision. Bone health might actually impair immunity in the long term. We don't really know. And so all reasons in my mind, I feel very strongly about avoiding Dex in the maintenance setting. Interesting. Thank you very much for your thoughts there. I think this highlights the importance, the incredible importance of finding a multiple myeloma specialist that works with you to understand your personal situation, that aligns with your personal philosophies because of the 400 billion medications, that was an exaggeration, that are in multiple myeloma transplant versus not transplant. There's so many differing opinions, almost valid opinions, but I just love your authenticity and your ability to share your personal philosophies. And I just wanna emphasize to our audience today, if these philosophies align with yours, it's worth finding a physician that shares your philosophies. You never wanna be uncomfortable with what's going on in your myeloma treatment. So just wanted to say that. I totally agree. Thank you. Go ahead. Lots of great questions coming in from the audience. So I'm excited to get started with some of them. Susan's wondering about the timing of DECs. When you take DECs, let's say with bortizomib or pomalidomide, do they have to be taken within one hour of each other or 24 hours? It's an excellent question. Yeah, so that synergy I talked to is probably a long-term effect and not a short-term effect. So it's not critical that they be hour to hour time like that. That synergy of them working together is more in the long-term. They do tend to help together, but it's fine. I would encourage, again, taking steroids as early in the morning as possible. And as soon as your clinic allows you to take steroids at home and not an infusion, I would recommend that. Again, because even for the most early risers, our clinics don't open till like 7.30 or 8. And so, again, by then you get there and get everything ready and take the steroids in clinic authority at nine. And so I think earlier in the morning, the better. In terms of the only exception to that rule would be for the first couple of doses of any monoclonal antibody when you're using DEX as a pre-med from an allergic or infusion reaction perspective, like I talked about, which is like a mouse antibody being infused into you. There, most studies and most centers will require that the DEX be taken within 60 minutes of the actual infusion. But honestly, each dose of DEX lasts about four to six hours in your system. So generally speaking, anywhere in that window is totally fine. Interesting, thank you. With what kind of patients would you recommend weekly DEX? We talked about weekly DEX versus... Is it twice a week DEX, for example? Yeah. It's a good question. So it really depends on the patient. It's funny, because if you talk to myeloma doctors about it, we are really bad about assuming we know what patients would prefer. I've had plenty of patients, I've had, like, in my group, I've had like one doc be like, oh yeah, like I always tell my patients to take 20 and 20. I would never ask them to take 40 milligrams once a week. That's insane. And my style is, I, my guess is that more patients might prefer the reverse, because it's just like, they are like, all right, Wednesdays are my steroids. I know this is a day that this day sucks. I know that I have to get my steroids, go into clinic, get my infusions, and the other days I'm free of steroids. So I really don't know. There is no right answer. I'd have no reason to believe that taking DEX, 40 milligrams every Wednesday, as opposed to taking DEX 20 milligrams every Wednesday and Thursday, for example, are any different efficacy wise. I think it's just really up to the patient. And most pharmacies, pharmacists would completely agree with that. For patients who are having issues with insomnia, for example, as a cardinal complaint, I think that maybe splitting the DEX into two days might be more practical, because it's that it's very dose dependent. The higher dose of steroids, the more revved up people get. Conversely, if you're noticing that you're having, you know, a lot of like letdown symptoms, for example, that also, I guess then every other day might be helpful at taking two days, and it might be helpful. But for patients who will be an example, once weekly might be better. For patients who are maybe like forgetful, and I say difficult to remember to do those kinds of things, or for patients where they feel like the DEX was helping with their bone pain, or just helping with their energy level, then once a week is totally fine. Do you ever have patients that take it once a month? There's a question about that. I would say that if you're going to that level, it's probably not synergizing with anything. And my recommendation would just be to stop it at that point in time. There's certainly no harm in doing it. I don't think it's dangerous, but I don't think that it's adding anything at that level, because it's less than once a week, because the total exposure to your body is kind of so fluctuating that it's not probably adding much benefit. So at that point, I would probably say to just stop it, because again, kind of my personal philosophy is that you're going to get a deep of a remission that you're going to get, and then with the myelin was going to come back, it's destined to come back, just bad luck, unfortunately. And at that point, we would do something different entirely that would involve more drugs more commonly. Yeah, some people experience emotional reactions to dexamethasone, extreme anger, extreme depression. Do you have any patients that have experienced this? How do you work with them? Agreed, it's really, really frustrating when that happens for both the patient and their caregiver. It's almost sometimes worse when the patient recognizes and they're just like, I can't help but be so angry and so emotional. So two things that I would recommend. So one is the easiest solution is again, that would be a reason where I would say to just drop the dex entirely, because steroids do have a very, very low risk, but the aracharic risk of psychosis, for example, or mania, I don't expect that to happen to the vast majority of my patients. But if you're having that level of intense reactions, I would say probably there's some dose dependent too, so you probably can lower the dose, or just say, you know what, stop the dex entirely, try methylprednisolone, solimedrill, or just stop and just call it a day, because the other drugs would be the heavy lifting. The other possibility would be, I think a lot of centers, unfortunately with COVID, everything's gotten very difficult, and our behavioral therapists are extremely kind of overworked, understaffed, but sometimes psychotherapy or CBT, cognitive behavioral therapy, has been shown to help. I was telling Audrey earlier, some of my personal research involves the idea of life coaching. So I have a life coaching study open, myeloma crowd health tree actually has a coaching curriculum, and that might be helpful to talk with someone who's been in where you are, kind of walk you through things. Oftentimes patients come and discuss kind of alternative strategies. So that might be complimentary medicine, herbal remedies or acupuncture. Acupuncture used to be very difficult with COVID, but it's gotten easier now, just for a variety of reasons. And I think patients with myeloma are compromised, but not that much so. So if someone's willing to try acupuncture to help with their emotions, with the neuropathy pain that they're having, with any number of symptoms, I don't understand how acupuncture works, but I know that it works for a lot of patients. So I do recommend that, and people might find that to be what they need, or meditation, or integrative medicine, something along those lines. And I think it's all worth pursuing. And that might be something where, the number of hours of all my medical school and training I spent learning about acupuncture was 10 minutes, literally over the last decade and a half of training. So it's not something that most doctors will be able to really answer, but I would say definitely turn to your support network, turn to myeloma crowd, try things that might work for you. And you may find that the solution to that beyond lowering the dextose is trying something more integrative that might actually be helpful. Yeah, thank you. Beth's asking an excellent question. Can you discuss why we're not considered refractory to dexamethasone even when we relapse on it? An excellent question. It's funny you asked that. It's a very pressing question. So the short answer is that dex will always work. By definition, steroids kill lymphocytes. They kill cells of this lineage, and plasma cells are kind of terminal lymphocytes. And so, if you were to give someone, even if they were on their 18th line of therapy, if you were to give enough steroids, it would work. The issue is that it wouldn't work. Durably, steroids don't work by themselves and they don't cause deep responses, but they just will kill off some percentage of plasma cells no matter what. So for example, as an example, one of the critiques of some of the studies of selenexor, for example, so in the storm, or was it Boston? I think it was storm or selenexor was studied with dexamethasone as just kind of a single arm study. And some people, including myself, were kind of like, well, some of the responses you saw might look just from the steroids themselves. You can't really prove the selenexor is adding to dex without doing a randomized study or comparing it to something. So basically, steroids, to the end of the hero question that I'd asked earlier, that I brought up earlier, steroids will always work. And so I don't think that anyone has truly storied refractory in the same way because it will always kill off the myeloma cells versus with daratumumab, which is a targeted drug, the myeloma cells can actually stop expressing CD38 and permanently become refractory to it. Same for lenalidomide, they can engineer the intracellular mechanisms of how they work that block how lenalidomide works. Steroids work in so many different ways at once that I think it's impossible for any myeloma cell individually to become resistant to them permanently. So we don't kind of avoid that word, but I agree with you, it's kind of a weird principle. Yeah, interesting. There's several other questions. Do you have just a couple more minutes if we go a little bit? Yeah, of course, I can save for another five, 10 minutes for sure. Okay, perfect. So there's this last night during our Florida community session, we had an integrative doctor come speak to us. And she mentioned that sometimes she works with oncologists, with patients who are not doing well with dexamethasone, and she actually can use curcumin to be able to synergize, like as almost a steroid replacement to synergize. Have you heard of these kinds of research studies and what are your personal opinions on them? That's an excellent question and also something, because I got 10 minutes of lecture and all of medical school about acupuncture, zero minutes about anything that's kind of herbal or integrative or anything. And so I can't speak to it with expertise. What I would say is that for turmeric in particular, turmeric, however you want to pronounce it, for curcumin, which is curcumin is the active ingredient there, there are definitely preclinical studies that do show that it does work against cancers of lymphocyte lineage that includes CLL, which is lymphoma, as well as myeloma. In my mind, the devil's in the details and the dosing. All these studies, for example, that show that red wine, primose survival, I've heard someone joke that you would have to be taking gallons of red wine a day for that to actually match what was done in the studies. I don't know enough about how curcumin was studied in these particular studies and if it's been studied in humans in that regard. And so we're kind of in an evidence-free zone. What I would say when I tell patients practically, when it comes to herbal remedies or supplements or anything over the counter is that I am fine with trying it because I agree that some of them may help in ways that we don't fully understand, as long as it doesn't cause a particular side effect that I'm already worried about. So in the case of myeloma, any supplement, be that curcumin or people have asked me about green tea or elderberries or anything like that, I actually, and I can put it in the chat or I can remind the audience or if you Google it, Memorial Sloan Kettering Cancer Center has an herbal medicine database. I forgot the name of it, but it's MSK, if you Google like MSKCC herbal medicine, there's actually a tool, their integrative medicine department has come together with this huge list of like all the supplements they've ever heard of and every piece of evidence that's ever been compiled with them and put it together. And so my litmus test is as long as whatever patients are on does not cause or raise the risk of blood clots significantly while they're on ledalidomide or neuropathy while they're on something like bortezomib, for example, totally fine with that. What I sometimes get into issues with is like, some supplements do have been shown to raise the risk of blood clots like estrogen supplements, for example, those that get cautious up if someone's already on Revlimid and already on aspirin as a blood thinner and I say, everything apart from that, I'm fine. So curcumin basically a tumor I gotta be fine with, as long as patients kind of tell me about it so I can put it onto our drug list as long as they've looked at the database and it's fine. And it very well may have a fact very similar to dexamethasone and if that works all the power to them. The only final caveat I would say is that for some clinical trials, they are very, very, very particular. So if you happen to be at a clinical trial before starting anything, before anything entering your mouth that is a medication of any sort, talk to the team about it to make sure that it wouldn't prevent you from getting the study drug, for example. Yeah, thank you. And I would just also add, she really emphasized it was a holistic doctor who had been through medical school who had done her work and she works with very like high quality supplements and she works in partnership with oncologists. So this is not an invitation for anyone to drop their ducks and go to the store and buy some curcumin or turmeric. It's rather, if that is interesting to you, maybe that's something that you look into and speak to your treating physicians about. Agreed. I'll quickly add that many centers have integrative medicine centers built into them or end of oncology. My biggest frustration is insurance companies often don't pay for the consultation, which is supremely annoying, but look, ask your doc. You may well have like a side referral we can place and hopefully insurance would cover that offers, talks about curcumin, talks about lifestyle, talks about yoga, talks about acupuncture and much more. I think it's super important. Definitely, thank you. Laurie's wondering if it's worth it to get cataract surgery because the cataracts are worsening now that she started Dex while she remains on Dex. So like is it worth it? It's an excellent question. It depends on how worrisome they are to your vision is what I would say, because I think the trajectory of steroids and how much they worsen cataracts on like a month to month basis is a little bit unclear. I do think that I would much rather patients preserve their vision because that obviously is supremely important to patients. And if you notice your vision is objectively worsening by your own measure of what you're looking at, then I think it's quite reasonable to take care of it. I would just coordinate with your medical team. Cataract surgery is very, very, very safe. And so there's no issues of systemic ish not have to be what blood clots or any of that, but just time it around your therapy so that you don't inadvertently have to have a delay or a complication and delay your myeloma therapy based around it. But I think it's entirely reasonable, especially for symptomatic from it. Awesome, thank you. I'm gonna go briefly through a couple of questions. Susan's wondering, let's say she's taking 20 milligrams, talks to her doctor about interfering with her quality of life. Doc says it's okay to decrease to 12 milligrams, but without effectiveness data, why would she trade quality of life issues if it might mean lower of efficacy? Honestly, I think this is where it comes to being, again, the personal philosophies. What feels better to you? Does it feel better to have a higher quality of life or does it feel better to you to know that you're doing all that you can in terms of efficacy? So any thoughts on that? Agreed, and I would agree with that entirely. It's a very difficult decision, often depends on the side effects. Having bad swollen legs that can get better with compressive stockings and laces is very different from feeling jittery, not sleeping, feels like a monster, emotionally labile, et cetera. So it really depends on each individual case. What I would say is the benefit of myeloma is that we are never ever, except for CAR-T, I guess, dependent on a single drug working all by itself, we're always tag teaming drugs together. And I would say that if someone's achieved a PR, partial response or better with four drugs, and they ask me, for example, conversely, if someone had an issue with, people with having neuropathy with DERA-RVD, the neuropathy I have from the Velcade, I wouldn't blink twice about stopping the Velcade, period, and just going to three drugs, because we're already starting at four, so four to three is still pretty good. And similarly, if someone's on four drugs and the steroids are causing problems, and we go to three drugs, probably is fine, because each drug works in a different way. And for patients where the therapy's responding to the treatment, I think that that would continue to be the case even without the dex. So again, it's difficult. The other thing I will say is that, I tell patients that this, you know, Velcade is dosed by people's height and weight, DERA is based by people's weight, the IV formulation of it, steroids are not dosed by anything. Same with Revlimid, those two medications, we just give everyone 25 milligrams of Revlimid and 40 milligrams of dex and just kind of see what happens, and that dose is absolutely not for everybody. So I think that it's much better to be on a dose that's manageable and will allow you to stay on therapy for the long call and not cause complications or delay your therapy, God forbid, for example, if you're having, you know, refractory leg swelling or issues that are preventing you from just showing up to therapy on time, that's the problem. And so I think along the dose to where it's manageable is appropriate. Yeah, there's some other questions here, you know, what about 30 milligrams? What about eight milligrams? And maybe this is wrong for me to say and not medical, obviously I'm not a medical professional at all, but if they've found something that works for them within that 40 to whatever range, zero range, is it worth it? Yeah, totally fine. So if you're nervous about going from anything, yes. So Dex does come in two milligram, one milligram, 0.5 milligram tabs. You would have to basically like do the mental math and put the, for 30, you'd have to do like four of the sevens and one of the twos. And, you know, sometimes it just, it gets annoying with pharmacy to prescribe them because you have to remember like that you prescribe both the fours and the twos and get refills of them and so forth. So probably a multiple of four probably is the most practical, I would say. Is 28 milligrams of Dex fine? Totally fine. I suspect that 40 milligrams is a lot for a lot of patients. If 28 as it being a sweet spot and the side effects are manageable, again, some of the side effects of steroids are probably dose dependent, meaning that the higher the dose, the more they happen. Some of them probably aren't. So for example, like the blood sugar going up, probably no matter what, even Dex four milligrams probably is enough to make people's blood sugar goes up. So that is gonna happen no matter what, but like the jitteriness, if 28 milligrams works, all the power to you and just, again, let your doctor know, talk to them about it just so that they can keep track of everything and not mess it up for future cycles, but that's very reasonable. Below 12, yeah, that's where I start to feel like it's, so basically one milligram of Dex is equal to, let's see, HPMD530, five times stronger than Prednisone. So eight of Dex is about 40 of Prednisone. Some of you know Prednisone, that's about the dose that we use for Prednisone for like allergic reactions or contract allergies or whatever. You start going below 12 milligrams into the eight, four range, you're starting to enter like the quote unquote normal range of steroids is probably are not enough to kill cells, they're just enough to suppress the immune system. So for example, eight milligrams of- Sorry for interrupting the patient that was talking about eight milligrams, did it for bone pain because it was really affecting without Dexamethasone, it was about pain. So I think that's definitely a reason to stay. Yes, so the only thing I would say is that if you're on Dex, if you're on Dex for more than once a week and more than twice a week, if you're on Dex every day, even like two milligrams of Dex once a day, indefinitely, you absolutely need to be on Bactrim, on medications to prevent rare infections. And you absolutely need to consider screening for osteoporosis and some of the other side effects of Dex. So this slide I brought up here about susceptibility to infections for patients who are on daily steroids, they absolutely, that's like a life-threatening risk of getting a weird infection. So just for pain, do that and just be wary of this particular side effect and be on the lookout for medication to prevent it. Definitely. Okay, let's hit two other questions. So the first one is let's talk about other steroids briefly. We've talked about Dexamethasone the majority of this time. Are there any other steroids for multiple myeloma that are less bad for bone health than Dexamethasone and what other steroids are available in myeloma treatment? Absolutely, so in terms of systemic theropoids, systemic theropism, sorry, I can be giving either oral or IV, these are the ones, hydrocortisone, prednisone, methylprednisolone, and dexamethasone. For patients who are taking pre-meds of Dex, probably for allergic reactions, for infusions, for monoclonal antibodies, methylprednisolone, we've had a couple patients where we do that and some protocols allow for them, that's fine. Prednisone, there are some studies, so 15 years ago, and my first slide from like 40 years ago, we use prednisone by default here. For lymphoma, for example, which is a similar type of blood cancer, we use prednisone all the time as part of our CHOP therapy. So why pred and not dex in lymphoma? Why dex and not pred in myeloma? It's entirely just a tincture of time. You're welcome to try it and we can do the math. There's a conversion that we can estimate between these. And it's worth a trial. If you're worried about that it's worth a trial. I do think that the class effects of these are pretty typical and the odds are high that if you're having a side effect with one of these, you'll have it with the other ones as well. And then for bone pain in particular, I learned in medical school, I don't know if people have studied this in a systematic way, that dexamethasone is just a little bit better for bone pain just because it has some more anti-inflammatory effects per dose than prednisone does. So I would say probably dex for bone pain in particular over prednisone. But again, if you're having side effects you need to be on a medication. It's worth a discussion with your doctor and the best way to find out is to try it and see what happens. Do you personally use the methylprednisolone with any of your patients? A couple of patients have to have issues with the dex mainly it's kind of like the psychosis or like just a really intense emotional reactions to dex. And if they need it as a pre-med methylprednisolone, so it's called a medrol, we can be given IV in clinic, for example. It's a little complicated because the dosing gets messed up and dex, just to be clear like 40 milligrams of dex is like 200 milligrams of prednisone. And if you've ever been on a prednisone dose pack or something or a medrol pack, it's like 15 times stronger than what you would be getting on a medrol dose pack for poison IV, for example. So it's difficult to kind of convert. A lot of pharmacies don't have enough of those other pills on stock or don't have the IV bag that big on stock. So dex is just practical because we have it. But I think talk to your doctor and they can probably try experimenting with it if needed. Yeah, thank you. Last question here. John's wondering, he's taking pomelists three out of the four weeks. Do you ever recommend that they take dex on the off week of their month? Excellent question. Yeah, because these protocols were all just kind of made up. 15 years ago, I enrolled with them. So just so as many of you know, so with Revlimid, we often recommend taking it 14 out of 21 days or 21 out of 28 days. Same for pomelists, we say, take it for three weeks on, one week off. For example, generally speaking for the off week, I recommend just keeping it as the off week just to really give people a chance to reset and just like make their appointments during that time, live their life during that time. I think dex by itself is a pretty lousy drug, just a single dose here and there. I think it works best when added to other drugs in general. And so I think for off weeks, they generally say make it a complete off week. The antimicrobials that the cyclobutyl need to be on and stuff like that, because of the long-term infectious risks. But on the off weeks, I would say keep them off weeks. It's probably just easier that way. But, you know, are there any exceptions to that rule? Not really. I think I would say that, that if you're allowed an off week, it actually was designed to kind of help mitigate some of the toxicities of that particular regimen. So make the most of that off week. It does no benefit to trying to sneak in some extra pills because they're not gonna add that much bang for their buck. Awesome. Thank you so much. Whoops, one last thing. I just see a lot of comments about, you know, you're talking about taking it in the morning. Sometimes patients feel a lot of success taking it right before they go to bed. And I think, again, it comes back to what works best for you. For some patients, it's gonna be taken in at midnight, right before they go to bed, which kudos to you if you go to bed at midnight. And then some people, it's, you know, at four, five a.m. when they wake up in the morning. So I think, anyway, I really appreciated this discussion. I've appreciated seeing the different views of different myeloma patients and how they're interpreting this and incorporating it into their life. I apologize that we didn't get to all of the questions, but thank you, Dr. Banerjee, for being here with us today. Do you have any closing statements before we finish today? No, I just wanna say thank you all for having me. And I think all of you are obviously self-selecting population. You're very engaged with your myeloma care. You're here on this call, but I would say definitely, yeah. No doctor will ever be upset if you ask a question about side effects. Or I read about this on MyelomaCard or the Convetted website. And there's a lot of things that doctors don't have time to cover, not that we don't know. We just forget to bring it up or don't have time to bring it up. So be proactive, bring it up. And I think that's an important principle. Yeah, it's almost, I don't know if I'm supposed to say this, but it seems a red flag to me if you try to bring up the conversation about lowering decks and they just don't even wanna talk to you about it. I'm not saying it's a red flag that they don't necessarily wanna lower it for specific reasons that they've proven to you. Sorry, that's my mistake. Yeah, no, no, it's about, and what I would say then, and if you're worried that your doctor's just too busy, I would say save it for a MyChart or I shouldn't use brand names. Like a message in between. I would actually much rather a patient tell me about a side effect by MyChart message and then I could deal with it in between rather than when they see me, I only have 30 minutes scheduled for them, but I need to talk about this and about transplant and about MRD and blah, blah, blah. So if you're ever in doubt and you feel bad that the visits are so busy, ask in between. Definitely we don't mind and most of us have centers and nurses who can help us triage questions and figure out a plan in between. Great advice, thank you so much. Of course. All right. Thank you all again for your time and have a wonderful evening. We're gonna finish up with just a couple of outro announcements. Our next meeting will occur in January. We're gonna take a couple of months off and we're gonna be discussing myeloma therapy, what's available for induction therapy. Don't forget to take that exit survey so that we can get your feedback about how you think today went. Join us for other events that you might be interested in. Looks like I forgot to update this slide, so I apologize for that, but tomorrow is gonna be at 2 p.m. Eastern, the Black Myeloma Health Chapter, why Black Myeloma patients and their families should care about the PROMA study. Other upcoming events is found at the link on that slide and will be included in our follow-up email. A special thank you to our sponsors, BMS, GSK, Genentech, Avian Amgen, and thank you so much for taking the time out of your evening to be here with us. We hope that you have a great rest of your day. Thank you, everyone. Bye-bye.