When should a patient consider changing a therapy?

So, the general principle that most myeloma physicians go by, or, you know, we don't have data when to stop therapy, is that you continue therapy that you've started, and because of two reasons. You continue till progression, that you no longer start responding, and we'll talk about what it means to be progression, or you start to develop toxicity from it, right? And each class of drugs has a specific toxicity that's associated with it, so you are your physician, and you will pay attention to those signs and symptoms. Now, the first principle that you continue therapy until progression is basically, you know, we use the IMWG criteria. You know, if there's a rise in your M component or M spike on your serum protein electrophoresis, more than 0.5 grams per deciliter, as well as a rise in your light chains, or there's a hypercalcemia, your calcium goes up, or new bone lesions, or extra medullary plasma cytomas, which means you have development of tumors that are, you know, related to plasma cells. So these are several criteria that we use to assess if you have progression of disease, and generally we change therapy on that. The second principle is whether you have developed toxicity. Now, you know, each class of drugs, whether it's proteasome inhibitors, I have very low threshold to change therapy, my patients who are in Valcade, if they develop neuropathy, because I think myeloma patients live a long time, and I don't want to have them crippling neuropathy because I want them to go on about their lives and have a good quality of life. That's very, very important to me. A drug like carfilzomib, I think the most common indication, in my opinion, ends up being if they develop new symptoms of heart failure, where they have, and that forces me to, or symptomatic heart failure more, you know, per se, it forces me to send them to a cardiologist, as well as stop therapy, so I don't worsen their cardiac function if they do have a drop in that when it comes to an immunomodulatory agent. Some patients, you know, after they're being on for irreverent maintenance for so many years, they just, you know, the fatigue, the diarrhea, all that catches up, and they're just about done with it. And if they, you know, that's a discussion for you to have with your physician. It's not just because you heard it from somebody, that decision shouldn't be based on that. It should be an assessment of your overall disease and where you are and how far you are from your induction to sort of make that decision when you can come off therapy, if that's what you would like to do. So those are the factors that help me decide changing therapy. In terms of induction therapy, there is a set group of patients who actually, despite you starting them on triple class therapy that includes a PI, IMID, and dexamethasone, they don't respond or their disease is slow to respond. That's when I would consider if you haven't had daratumumab added to it, I would add daratumumab added to it to deepen the response. So there are several reasons why I might make the change to another therapy. The first might be that the patient's monoclonal protein or free light chain is doubling in a period less than three months. So there's no other sign of organ damage, it's just those numbers we check regularly are starting to accelerate. And I use this three month period as a guide to help me decide how fast is it going. So for example, if the M protein was one and three months later it was two, that's a sign that it's doubled in three months. I might check it again in another month, if it's 2.5 it's moving too quickly. So I would think about their prior treatment and deciding what next treatment to give them. I like to change the drug class rather than just to change the same drug in the same class. And I also take into account any medical problems they have. If they have kidney issues, I might choose certain drugs over another. The other reason I might change therapy is that there's an end organ damage event. For example, they developed a new lesion in their spine that creates pain or they have a fracture, progressive anemia. These are examples of how myeloma can progress and even if the monoclonal protein or light chain hasn't changed substantially, I would think that there's reason to switch therapies. And the third reason is toxicity. So sometimes the drugs we give over a long period of time can cause problems. Maybe it's heart disease or maybe it's increased infections. We might switch to another drug that we think will be less toxic. So those are the reasons I would consider changing. So there's two big buckets that I think of when I want to change a patient's treatment. One is the patient isn't tolerating the treatment. Their quality of life is taking a huge hit. They have an allergic reaction to the treatment. They're just not doing well with it. And our goal with patients is to always make sure that we preserve their quality of life while we're treating them. And so certainly if that is compromised, we talk about changing treatment. So that's a first bucket. The second bucket is, of course, disease progression. So if we're starting to see evidence that the disease is starting to escape the medicines that we're giving or the treatment that we're giving, we certainly want to talk about changing treatment to stay ahead of the disease before the disease progresses even more. And at that point, it may be more difficult to regain control of the disease. So evidence that a patient is relapsing or progressing on treatment, on active treatment, would be certainly serum or blood markers like the M protein or serum free light chains. And what we look at there are certain percentage thresholds or cutoffs whereby we expect that these levels would increase above what we call the nadir. And the nadir is basically the lowest these levels will dip on that treatment that we're giving. These percentages are usually 25%. So we look for at least a 25% rise from the lowest level that they have reached while the patient's on treatment. And we like to see at least two consecutive levels. So we'll monitor these labs while a patient's on treatment, usually every cycle. And the cycles differ depending on the treatment. They could be every three weeks. They could be every four weeks. Those usually tend to be the more common cycle lengths. So if we see an elevation that meets evidence or that meets criteria for disease progression once, we'll wait unless it's very high, we'll wait until the next time we see them and we measure their disease. If it's still elevated or even higher, that usually tends to indicate that the patient is progressing. And at that point, we want to talk about changing treatment. Would you consider changing treatment if the myeloma markers are increasing but they haven't increased by 25%? I wouldn't change treatment too early because unfortunately this disease remains incurable. So we want to preserve as many of the medicines that we have that are effective against this disease as we can. So if we treat patients earlier than we expect to or earlier than we want to with newer drugs, then we may be shortening the duration with which we can use all of the treatments we have available. So we really want to keep as many tools in our toolbox as possible so that we always have options. We have this kind of like big supply of options for these people. So if we use treatments too earlier before there's overt evidence of progression, first of all, it may be that the patient's not even progressing. It may be that there's a slight rise for whatever reason. The patient may be more dehydrated or whatever it may be. So it may not be true evidence of progression and certainly we would not want to change treatment unless we have overt evidence of progression to really try to extend the absolute most we can from each treatment that we're able to give each patient.