All About Alkylating Agents (like Melphalan, Cytoxan, Busulfan and Treanda)

All about alkylating agents. So alkylating agents are one of the oldest types of chemotherapy drugs that we use. What they do is they in turn create some damage to DNA. That's the genetic material that encodes for basically all the cells functions. These drugs include drugs like cyclophosphamide, melphalan, and desulfan. These are some of the very first drugs that were ever tried to treat myeloma back in the late 1950s and early 1960s. They still are a useful group of drugs. Cyclophosphamide and melphalan in particular are still in use for treatment of myeloma today. How do alkylating agents work? Because they interfere with DNA replication, they are really interfering with cells that are in the process of dividing. When you're an adult, the number of cells that are really actively dividing are few. So depending on the amount of an alkylating agent you get, the potential areas where you might interfere with cell growth would be hair cells, cells lining the GI tract, and blood cells because those are three areas where there actually is quite a bit of cell turnover on a regular basis. Now the idea here of using an alkylating agent in a cancer is that those cancer cells are dividing at a much faster rate than normal cells, so they will be preferentially hit by these drugs, but they aren't targeted in the sense that those drugs aren't specifically going, say, to myeloma cells, they will hit other cells as well. What are the side effects of alkylating agents? So again, a lot of it has to do with the amount that's given in over a period of time. So for people who might have received a combination called Cybordy, which uses oral cytokines, those doses are considered relatively modest. And so the side effects that people might encounter might be some mild nausea. They typically don't have side effects like hair loss, mucositis, meaning irritation of the lining of the mouth, and esophagus. Really depends on the dose. And if a person is getting some of the oral cytokines regimens, there may be some. I think there are occasionally, in my experience, patients who find even those lower doses of cytokines not tolerable, you can try to cut the dose to manage that. But there are some, I would say maybe 5% of people who find the cytokines, no matter what the dose, difficult in terms of nausea. And those are people that we usually try to come up with a different plan for treatment. The higher doses, like if a person has a transplant with melphalan, those types of doses, which are given a very large dose over a very short period of time, they are associated with side effects, including total hair loss that we call alopecia. They're also associated with irritation of the lining of the entire GI tract from the nose all the way down to the rectum. And finally, these are those kinds of doses, melphalan during a transplant will create profound myelosuppression. That means it will essentially stop production of your blood cells for a period of time. How are low blood counts managed? So during a transplant, the way we manage a person having very low blood counts, that is, you know, low white count, red cells that drop and platelets that drop is we give you back stem cells. And so those stem cells are designed to replenish the bone marrow production of the blood cells because that dose of melphalan giving a transplant is big enough that it would be very difficult for a person to recover on their own. When you're using smaller doses of alkylating agents, you can use what are called growth factors. And these are drugs, most of these are injected. There's one oral drug for platelets that can help your cells recover. But typically in the doses that are used outside of a transplant, those kinds of steps aren't necessary. But myelosuppression, which is that term for lowering of blood counts, is usually one of the biggest side effects of these alkylating drugs. Does sucking on ice help prevent mouth sores during transplant? This was a terrific idea. And I believe it was a thought from a group of nurses who were taking care of transplant patients and noticing that a lot of people, I mean, a lot, had very severe mouth sores that would appear about a week after they would get melphalan as part of their stem cell transplant. So what they did is they sought, okay, well, if you chew on ice, it's gonna cause some tightening of the blood vessels, what we would call vasoconstriction. And then that drug won't be affecting those lining cells. And ice chipper, some people call it the fancy word cryotherapy, meaning cold therapy. But that seems to be quite effective. And that's really made a big difference for patients. And so we've noticed that really the number of patients who have severe mucusitis during a stem cell transplant is far lower than it used to be. Now you can still get irritation of the esophagus because the ice, you can't really hold ice down here. But that cryotherapy that we use is quite effective. What should myeloma patients know about cold caps or cryotherapy for hair loss? Cold caps are primarily used when women are receiving chemotherapy for breast cancer. And the results have been partially successful. I wouldn't say it's a complete success from what we have seen here with our oncology colleagues and their patients. There has just been a little concern about, do you wanna limit the drug getting to all parts of the body? And so at least we had at one point thought we might look at a trial in cryotherapy and transplants, but we decided that we weren't necessarily comfortable with that idea. How are GI side effects managed? It depends on the context. So if a person is developing GI side effects during a stem cell transplant, we basically try to pull out the stops. And that is using anti-nausea drugs, often in combination, not just one. Some people may know the name Zofran. There's a drug, olanzapine that's used because the nausea can be quite severe and even steroids can be helpful. There hasn't been a lot of innovation in this area over time. So if people are not able to eat well, we support them with IV fluids. Most of the time, this kind of severe gut toxicity is really confined to those people who are undergoing a stem cell transplant and last no more than a couple of days, but it can be quite unpleasant. And I think if you talk to people who've had stem cell transplants, sometimes that is a part of the recovery period they remember vividly when they weren't able to eat very well. We also sometimes to stimulate a person's appetite if they're having anorexia, that means not the loss of appetite, we'll use a drug like mirtazapine, which can stimulate appetite. It's also an antidepressant, but we use that. And also the drug, Megesterol or Megase, that's used sometimes to stimulate appetite. So either one of those sometimes is good if people are really struggling with starting to eat again after a stem cell transplant. How is diarrhea managed? So diarrhea, typically what we use are agents like Imodium, that you can buy over the counter and also another drug called Lamodil is sometimes used. And diarrhea after a stem cell transplant related to melphalan can last several weeks. And so we often, after people have recuperated from the transplant, we have them on these drugs for a period of time afterwards. Cyclophosphamide does not tend to cause diarrhea like that. It can sometimes in people who are getting higher doses, but melphalan is really the big one we think about is causing more of this GI toxicity. Do alkylating agents cause more DNA damage than the newer anti-myeloma therapies? The feeling is, is that's probably correct. And one of the, we assume when we do a stem cell transplant that we are replenishing the bone marrow with healthy cells that haven't been exposed to this drug melphalan. And that's one reason why when you might've had or might've been invited to have stem cells collected, they may have asked you to have stem cells collected enough for two transplants. And one of the hopes is that if you went through that second transplant later, some years later, and had another dose of melphalan, that again, you're using those healthy, non-exposed blood cells to help get around that. Unfortunately, the incidence of secondary cancers is still less of a risk than a person's myeloma in almost every situation. So that if you receive a recommendation to receive an alkylating agent, usually it's for a good reason. So it could be that the most common, probably a stem cell transplant or maybe that's cytoxin recommendation because your kidneys aren't working well. And then sometimes we go back and use these alkylating agents because they're really one of the best drugs, particularly if a person has very, very hard to treat myeloma or has had many, many relapses, bringing those drugs then back again can be quite helpful for people. When are alkylating agents used in myeloma treatment? One alkylator agents can be used actually in all phases of myeloma treatment. And 50 years ago, they were used always in the first steps of myeloma treatment, what we would call induction. Oral melphalan is used still in parts of the world where access to some of the newer drugs is not available. So a combination called melphalan, Velcade and prednisone or the MVP is still used in Europe. It's used in the Caribbean and South America. And in the doses that that drug is given in that combination, it's actually the side effects are relatively mild. There really isn't hair loss. There isn't a lot of GI side effects. But the feeling was, is that you could do somewhat better with the newer drugs. And one concern about alkylating agents is if they're given many, many times over many, many months, we believe that they can cause damage to normal blood cells that can lead to blood problems down the road. So things like even what we call secondary leukemia can develop because of just repeated exposure even to small doses of these alkylating agents. So that's really avoided, but many people, and I'm sure some of your audience probably received oral cyclophosamide, particularly if they had kidney problems when they were first diagnosed because that's a drug we can use very safely when people have kidney failure. Sometimes it's given in very large doses. If people have really hard to treat myeloma in Europe, cyclophosamide is actually given as part of a regimen to mobilize stem cells. That's commonly done as it's called. But again, the idea is that you use these drugs on a limited basis to try to get all the benefit from them and avoid toxicity that comes from using these for too long. Some of you may be aware there's a new alkylator agent that was recently approved, melphelphin. And melphelphin is based on melphalan, but it is basically packaged so that the melphelphin seems to enter myeloma cells more efficiently. And once inside the cells, there are enzymes called endopeptidases that break down the melphelphin into melphalan. And that drug actually was just approved last month for use in people who have, again, more than four lines of therapy. I think people are kind of interested to see how well melphelphin works. And it does have a schedule where it's given once every 28 days, which I think people are very interested in seeing that kind of intermittent schedule, which I think is attractive. What is bendamustine? Bendamustine is a alkylator agent that also has some properties of a different type of chemotherapy, but bendamustine is actually used a lot in lymphomas and chronic lymphocytic leukemia, and even a type of lymphoma related to myeloma called Waldenstrom macroglobulinemia. But bendamustine has been used primarily as a salvage treatment in myeloma. And it's typically partnered with either lenalidomide, pomalidomide, or Velcated. And there's definitely people who, when they are no longer responding to, say, some of those agents by themselves will respond to bendamustine. So that can be quite a useful drug. And again, it's given infrequently, usually one or two days per month. It does have like those other alkylator drugs we mentioned, this myelosuppression, this suppression of normal bone marrow production. And so some patients can be in a situation where they actually need red cell transfusions or platelet transfusions as they're recovering from these drugs.