Dexamethasone Dose Strength Impact in Newly Diagnosed Myeloma | Rahul Banerjee, MD, FACP | ASH 2023

Hi everyone, thanks for taking the time to interview me. Thanks to Health Tree and for everyone listening to this. My name is Rahul Banerjee, Assistant Professor of Medicine at the Fred Hutchinson Cancer Center in Seattle, Washington, also Assistant Professor of Medicine at the University of Washington. And I'm here to talk about one of the topics that's nearest and dearest to my heart as a researcher and the bane of everyone's existence for many of you who are patients, which is dexamethasone. Some of you may remember that Jenny Alstrom had written even a whole song about how much she hated steroids, dexamethasone, and myeloma. I was at Health Tree, kindly invited me last year to speak about dex, the hero or the villain of myeloma therapy. And that's really been a passion of mine because it's obviously like, of all the things that we worry about as researchers, the dexamethasone is kind of a foregone conclusion. We've had dex for 40 years, if not more than that, in myeloma. We continue to use it once per week in our regimen. It actually was a patient-inspired trial led by Vincent Rajkumar as the academic affiliate that actually showed that it used to be dex 40, 40, 40, 40 for four days in a row, and repeat and repeat. Then he showed that dex 40 once weekly was better than that, which makes sense, but we haven't really adjusted anything since then. Even modern studies today continue to use dex 40 milligrams once per week. Many of you listening to this have been on dex 40 milligrams once per week or 20 milligrams once per week for years. And so the oral presentation I'll be presenting tomorrow was the subanalysis or second analysis of SWOG data. SWOG is a very large cooperative group that runs many trials. We looked at two large trials of patients with myeloma, SO777 and S1211, and basically looked at, in those trials that enrolled patients from 2008 to 2016, so well before this modern interest in dexamethasone-sparing regimens emerged, how do those patients do when their dexamethasone was reduced during induction? In real life, hopefully many of you, if you've had side effects of dexamethasone, you've talked to your doctors and they've lowered the dose of dexamethasone accordingly. But in clinical trials, they still can do it. Sometimes it's a little bit more difficult to actually make it happen, but certainly a possibility. And so what we did is we went back and looked and said, look, these patients were getting either in the trials, one of them with dex 40 milligrams once per week, as I alluded to, some were getting dex 20 milligrams, like 20 and 20, pause, 20 and 20, pause, 20 and 20, pause, same principle, what I would call high-dose dex. And basically, we found that even in those patients treated on clinical trials, when people are nervous about adjusting doses, even though these trials were done almost a decade ago, before people really understood the side effects of dexamethasone that all of you tell us about now we know really exists, like cataracts, difficulty sleeping, you know, bone health issues, weight gain, et cetera, we found basically that for patients with dexamethasone dose was reduced during induction, no difference in PFS, no difference in how patients remain disease free or in remission for, no different than overall survival. We did find as a caveat that patients who had major dose reductions, like over 50% dose reductions, we did see a slightly worse signal to decrease the length of remission progression pre-survival. The big caveat there, these are patients on clinical trials a decade ago, so for a clinical trial, investigating a lower some dexamethasone is a big deal and probably the patients were frailer and having a lot more side effects. But I think it shows something that if you were to ask any of us, like, hey, if it was your mother, would you keep them on dex 40 milligrams forever? I would say, no, of course not. I would lower it to 20 milligrams, 12, I would stop when they're in remission. And so we're starting to see that that kind of logic probably is true. We are obviously the study that prospectively, so we are looking at prospective dex sparing regimen, so either starting at dex 20 milligrams and not dex 40 milligrams, so that's five pills of dex and not 10 pills of dex per week, or starting at the higher dose, because honestly dexamethasone does have some benefits, but it's not totally the villain. It does help with bone pain. It does help to prevent injection reactions or infusion reactions from medications like Darzalex, Dertumumab, or Sarkliza, which is Isatuximab, but saying, look, for the first eight weeks, let's get through it, use a dexamethasone to help push down the myeloma rapidly, prevent these side effects, treat the pain, but as soon as we see a response, drop the dex, not just go down the dose, drop it entirely. And so those studies are ongoing. We don't have randomized data there, but I don't think we need it. The other thing I should add for the study is almost two-thirds of patients, even on this trial, did have some level of dex dose reduction. So it's happening. If it's not happening to you and you're having side effects, talk to your doctor about it, because odds are very high that in the era of modern therapies like monoclonal antibodies and newer therapies and CAR-T, the dexamethasone that was the hero of our narrative for the last 40 years, starting to become the villain, I would argue now after the first two cycles, it is the villain.