Maintenance Therapy after Transplant: Multiple Myeloma

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Maintenance Therapy After Transplant: Multiple Myeloma

May 3, 2023

Presenter:   Dan Vogl, MD, MSCE, Hospital of the University of Pennsylvania

Presentation is 34 minutes long, followed by 23 minutes of Q&A

Summary: Multiple myeloma is a cancer of plasma cells, which are blood cells that are responsible for producing antibodies to fight infections. Patients with multiple myeloma often undergo a stem cell transplant as part of their initial treatment. Maintenance therapy after a stem cell transplant can enable myeloma patients to live longer but can also cause side effects.

Highlights:

• Although there are many effective treatments for myeloma, as of 2023, there is still not a cure.
• The idea behind an autologous transplant for myeloma is a relatively simple one: If a standard dose of chemotherapy is a good idea, then a higher dose is a better idea.
• The maintenance therapy after a stem cell transplant that has the most proven benefit in myeloma is lenalidomide (Revlimid®).

Key Points:

(03:46): Multiple myeloma causes high calcium levels, kidney injury, anemia, and bone lesions which can be painful and/or lead to fractures.

(05:08): Physicians follow the progression of myeloma by monitoring an abnormal antibody in the blood of myeloma patients called the M protein.

(09:48): An autologous stem cell transplant is part of the standard initial therapy for myeloma because it leads to longer responses, but it still is not a cure.

(10:36): Maintenance therapy is treatment that’s given while the myeloma is in remission to achieve  longer disease control. 

(12:56): The maintenance therapy with the most proven benefit in myeloma is lenalidomide (Revlimid®).

(15:39): Sometimes bortezomib (Velcade®) or pomalidomide (Pomalyst®) is used in combination with other drugs for maintenance therapy.

(18:18): Side effects of Revlimid® can include fatigue, diarrhea, low blood counts, rash, and muscle cramps. A less common side effect is neuropathy (nerve damage).

(20:17): One topic that's gotten a lot of attention is the risk of second cancers with Revlimid® maintenance after a stem cell transplant.

(24:45): Velcade® is used less often for myeloma maintenance therapy and has a higher risk of neuropathy than Revlimid®.

(30:08): The two new treatment options after maintenance therapy are immune therapies called chimeric antigen receptor, or CAR T-cells, therapy and a bispecific T-cell engager called teclistamab (Tecvayli®).

Transcript of Presentation:

(00:02): [Michala O’Brien]: Welcome to the workshop Maintenance Therapy After Transplant: Multiple Myeloma. I'm Michala O’Brien, your workshop moderator.

(00:11): Introduction of Speaker. It's my pleasure to introduce Dr. Dan Vogl. Dr. Vogl is an associate professor of medicine in the division of hematology and oncology at the Abramson Cancer Center of the University of Pennsylvania. He is also the medical director of the Abramson Cancer Center's clinical research unit. Dr. Vogl's research focuses on early phase clinical trials of novel therapies for relapsed and refractory multiple myeloma. Please welcome Dr. Vogl.

(00:43): [Dr. Dan Vogl]: Thank you for the introduction. It's a pleasure to be here virtually with all of you. Today, we'll be discussing maintenance therapy after transplant for multiple myeloma. I'll cover why maintenance therapy is needed, the types and duration of maintenance therapies, disease control expectations, potential side effects, and available therapies when myeloma progresses after maintenance therapy.

(01:25): Let's clarify the scope of our discussion. We're specifically addressing multiple myeloma, a bone marrow cancer. We won't be discussing other conditions treated with autologous stem cell transplants, such as leukemia, lymphoma, amyloidosis, or smoldering myeloma, which is an earlier precursor form of the disease.

(01:52): We'll focus on autologous stem cell transplants, as they are the primary type used for multiple myeloma. Allogeneic or donor stem cell transplants are less common.

(02:05): Our discussion centers on transplant as a treatment for newly diagnosed multiple myeloma. While transplants can be considered for relapsed or refractory myeloma, it's not our main focus for information on maintenance therapy.

(02:28): Specifically, we'll be discussing maintenance therapy, distinct from another post-transplant therapy called consolidation therapy, which is structured differently and has less available information. My emphasis will be on maintenance therapy.

(02:47): Let's begin with an overview of myeloma. Myeloma is a cancer of plasma cells, which are responsible for producing antibodies to fight infections. In myeloma, a plasma cell develops an error and reproduces itself, spreading throughout the bone marrow. These cells are copies of each other, resulting in the production of the same ineffective antibody.

(03:19): Multiple myeloma is diagnosed through the identification of plasma cells in the bone marrow; we can confirm their clonal nature. As these cells produce the same ineffective antibody, it can be detected in the blood or urine.

(03:46): We refer to the disease as multiple myeloma when plasma cells cause issues. The associated problems, known as the CRAB (or CRAB(i)) criteria, include high calcium levels, kidney injury, anemia, and bone lesions, which we call lytic bone lesions. The "I" sometimes refers to the risk of infection.

(04:15): To address these problems, we have treatments to lower calcium levels, reduce fracture risk, alleviate bone pain through radiation and medication, stimulate red blood cell growth to combat anemia, protect the kidneys, administer vaccines for infection prevention, and use antibiotics more liberally to manage infections.

(04:50): Although we have many effective treatments for myeloma, as of 2023, we still don't have a cure. Treatment involves periods of response followed by eventual progression.

(05:08): Physicians follow the progression of myeloma by monitoring the abnormal antibody in the blood called the M protein. You can see in this drawing that we follow the myeloma over time by looking at the level of the abnormal antibody in the blood, the M protein in general. When that goes up, that means the myeloma is growing. You can see in the orange line there the idea that as the M spike goes up or the M protein goes up, you then start a treatment and get a response with the M protein going down.

(05:32): There is then, sometimes, an extended period of response, which we call either a response or a response plateau, or maybe even a remission. But at some point, the disease starts to grow again. You apply another therapy and get another response, and you can actually continue that cycle many times.

(05:50): However, the challenge with myeloma is that, over time, the chance of response tends to get lower, and the duration of the response tends to get shorter What we're trying to avoid is the situation on the right side of the diagram, which we call refractory relapse, where the responses are very short, and the myeloma grows very aggressively and may not respond at all to the next therapy.

(06:17): Many different therapies are available to treat multiple myeloma. We do have a lot of treatments available to get these responses after responses. We use steroid medicines, especially dexamethasone, drugs called IMiDs, or immunomodulatory drugs. Thalidomide was the original one, but we now mostly use lenalidomide and pomalidomide. We use proteosome inhibitors, bortezomib (Velcade®®), carfilzomib (Kyprolis®) or ixazomib (Ninlaro®). We have monoclonal antibodies. Daratumumab (Darzalex®) is most commonly used, but isatuximab (Sarclisa®) and elotuzumab (Empliciti®) are also used.

(06:50): Older chemotherapy medicines, which we often call cytotoxic chemotherapy agents, cyclophosphamide (Cytoxan®) and melphalan, are commonly used, as well as doxorubicin, and a few others that we sometimes use in combinations.

(07:04): There are a couple of newer agents that are each in their own category: selinexor (Xpovio®) and venetoclax (Venclexta®). Most recently, immune therapies, either CAR T-cells or a bispecific T-cell engager called teclistamab (Tecvayli®) are changing the face of how we can treat myeloma. Every one of these therapies can result in good responses, but none of them currently appear to be curative.

(07:34): The idea behind an autologous transplant for myeloma is a relatively simple one: If a standard dose of chemotherapy is a good idea, then a higher dose is a better idea. Since a lot of what we look for is treatments that lead to deeper and longer responses, about 40 years ago, people came up with the idea of doing autologous stem cell transplants for myeloma. That may not be the most brilliant concept in the world, but it happens, especially for myeloma and for older chemotherapy drugs, to be true. As you increase the dose of chemotherapy, it gets better at reducing the myeloma down to a very low level. The flip side is that it also damages the normal cells in the bone marrow that make our normal blood cells.

(08:24): As you can see in this cartoon, when you give higher doses of chemotherapy, that treatment kills the myeloma cells. The normal thing that then happens is that the blood counts, in general, follow the course of that red line and you get low blood counts that last probably for many months. No one would be able to survive that.

(08:52): The idea behind the autologous transplant is that if you remove some bone marrow cells from the body before giving the chemotherapy, put them in the freezer to protect them, and then after the chemotherapy has passed out of the body... in the dotted green line, you can see that when you give the stem cells back, that dashed green line then represents what happens to the blood counts, which, after a relatively short period of time, they reestablish normal ability to make blood cells and the blood counts come back up much earlier than they would if you didn't do the autologous transplant. This is a way of administering a very high dose of chemotherapy.

(09:35): Those of you who have gone through an autologous transplant know that this comes with a lot of other side effects, but it does reestablish blood counts much earlier, making it feasible to give that high dose of chemotherapy.

(09:48): A stem cell transplant is part of the standard initial therapy for multiple myeloma because high-dose chemotherapy has proven to lead to longer responses. This treatment is part of our standard initial therapy for myeloma, primarily because we have a series of clinical trials that definitively show that this intensive chemotherapy leads to longer responses. There is a fair amount of data that suggests that those longer responses also translate into patients living longer.

(10:12): However, this very high dose of chemotherapy, although it knocks the myeloma down to a very low level, sometimes for a very long time, is still not a cure. We've always been interested in the question "should we do something after an autologous transplant for myeloma and give treatment to maintain that response?"

(10:36): Maintenance therapy is treatment given while the myeloma is in remission to achieve longer disease control.  When we talk about maintenance therapy, what do we really mean? It's additional therapy, given in the setting of a response, that contributes to longer disease control, that maintains the response that you've already gotten from a previous treatment.

(10:55):  We can talk about maintenance therapy after standard dose therapies. Often, we might just call that continued therapy because, often, it's just continuing the same medicines that you were on to get your response. However, after high-dose chemotherapy and a stem cell transplant, we call it maintenance treatment or maintenance therapy, and it usually consists of additional therapy that starts several months later after the transplant.

(11:21): Why do we use maintenance therapy? There are many possible reasons. Many of my colleagues have given many reasons to use maintenance therapy. We might want it to deepen the response after the transplant or even eliminate what we would call minimal residual disease, which is the lowest level of myeloma that we think we can detect in the bone marrow.

(11:47): We might want to stimulate immune responses against myeloma. We might want to suppress the development of resistant mutations in the myeloma cells, so that they don't have a chance to become more aggressive. And we definitely want to prolong disease response.

(12:06): Maintenance therapy after transplant for myeloma makes people live longer. In my mind, the main reason that we use maintenance therapy is because clinical trials have shown that not only does it prolong disease response, and maybe do all those other things, but it actually makes people live longer. The reason that we need it to do that is because, after a stem cell transplant, in general, the myeloma is in a good response. It's not that easy to turn a good response into a lower response. In general, myeloma is not causing problems.

(12:36): After patients recover from the side effects of the stem-cell transplant, they're usually feeling good, the maintenance therapy is not going to make them feel better. Since it can't make you feel better, what we really want it to do is make you live longer. Luckily, we have maintenance therapies that do that.

(12:56): The maintenance therapy that has the most proven benefit in myeloma is listed here on the left, which is lenalidomide (Revlimid®). There are four randomized clinical trials that compared Revlimid® either to a placebo or, in one case, to no treatment. Those trials showed improved overall survival, meaning that the patients who were randomly assigned to get lenalidomide on average, lived longer than the patients who were randomly assigned to get a placebo. That was even though the patients who got placebo pills, when their myeloma grew, they generally had access to lenalidomide at the time of progression. That means that the trials were really comparing giving lenalidomide as maintenance after a transplant to saving it for later and using it as treatment for relapsed disease. It turns out that using it for maintenance after a transplant makes people live longer than saving it for later.

(14:03): This improvement in overall survival was confirmed in what we call a meta-analysis. It took the data from all these trials, put them together, and did a larger analysis and confirmed that lenalidomide makes people live longer, when given as maintenance therapy after transplant. Those are powerful data and makes it really something that we would want to do.

(14:27): The other drug that does have some data is bortezomib (Velcade®). Velcade® has had one randomized clinical trial that showed improvement over survival. The only thing that makes us a little hesitant about Velcade® is that, in the trial, it was given both before the transplant and afterwards as part of maintenance. So, it's not completely clear whether it was the Velcade® given before the transplant or after, as maintenance therapy, that really contributed to the overall improved survival. So, the data supporting using Velcade® in maintenance therapy are just not quite as strong as they are for the Revlimid®.

(15:08): Steroids, thalidomide and ixazomib (Ninlaro®) have little or no benefit as maintenance therapy for myeloma. There are some other maintenance therapies that have been tried in myeloma, steroid medicines like prednisone or dexamethasone, thalidomide, which is an older version of lenalidomide, and Ninlaro®, which is an oral proteasome inhibitor very similar to Velcade®. These three medicines have all had clinical trials that showed limited or no benefit to their use in maintenance therapy so, in general, we do not use them.

(15:39): Sometimes Empliciti®, Velcade® or Pomalyst® is used in combination with other drugs for maintenance therapy. Conversely, there are some situations where I or some of my colleagues will use other agents in maintenance therapy, either lenalidomide in combination with other drugs, most commonly Empliciti®, Velcade® or Pomalyst®, which is a newer version of lenalidomide, either by itself or in combination. We tend to use these in situations where we are more worried that a patient's myeloma may have some features that place them at higher risk for early progression and resistance to therapy. While it makes logical sense to use them in these situations, there is limited data that show that there's an actual benefit, so we tend to consider using these, but these combinations or alternative agents are not well proven.

(16:32): For Revlimid® maintenance, the typical plan is to start three to six months (90 to 100 days) following a stem cell transplant, although sometimes we'll start as early as 60 days. The standard dosing, that was used in clinical trials, is to start with a dose of 10 milligrams once a day, and then consider, after a few months of therapy, increasing the dose to 15 milligrams.

(16:56): The idea was that we were worried that some people might not tolerate the higher dose of 15 milligrams, so we started off more moderately, and then increased the dose for people who could tolerate it. We do know that a lot of people don't tolerate the 15-milligram dose and need to return to 10 milligrams. I'm not usually very aggressive about increasing that dose to 15 milligrams, but if people are feeling well after a few months, I generally will increase it.

(17:26): The timing and dosing schedule for Revlimid® maintenance therapy varies. There are two different dosing schedules that have been used in the clinical trials that showed the benefit of lenalidomide (Revlimid®), either three weeks on, one week off schedule, or a continuous schedule with no weeks off. I think either of them can be used and considered to be standard.

(17:42): We then generally plan to use dose adjustments for side effects, decreasing from 15 to 10 milligrams, or from 10 to five milligrams, or even five milligrams every other day. I do tend to be fairly liberal with dose reductions for Revlimid® because that's what we did in the clinical trials. We reduced the doses when people had side effects and still saw improvement in overall survival; we don't have any evidence that it's important to stay at the full dose of lenalidomide during maintenance therapy.

(18:18): Side effects of Revlimid® may include fatigue, diarrhea, low blood counts, rash, and muscle cramps.  What side effects do we see that lead to those dose reductions? The most common ones are fatigue, diarrhea, and low blood counts, especially low neutrophils, which are the white blood cells that help fight off infection.

(18:36): We often see rashes, which are sometimes severe. Sometimes people will just have itching, rather than a rash that you can see. These side effects are usually mild, but they can be severe, and they can make patients miserable. A low neutrophil count can increase the risk of infection. For these, we tend to decrease the dose when these symptoms get bad.

(19:00): We sometimes see muscle cramps in patients on Revlimid® maintenance. Those can be mild, but they can really make people miserable if they're very frequent. We also know that there's a risk of blood clots with Revlimid®. So, in general, we give people something to prevent blood clots, at minimum, a daily aspirin, although sometimes we use other blood thinners.

(19:26): A less common side effect, but still worth paying attention to, is neuropathy or nerve damage that can lead to numbness and tingling in the fingers and toes. This is much more common with Velcade®, but it can also be seen with Revlimid®, especially when used for a long time as maintenance after a stem cell transplant.

(19:47): It’s interesting that some of these side effects will happen even though the patient didn't have them when they were using Revlimid® before the transplant. Sometimes the side effects are more severe, even before the stem cell transplant, when they were using lenalidomide at a higher dose of 25 milligrams. We're not sure why that happens, but we definitely sometimes see different side effects during maintenance after the stem cell transplant than we did beforehand.

(20:17): One topic that's gotten a lot of attention is the risk of second cancers with Revlimid® maintenance after a stem cell transplant. Some of the placebo-controlled trials that showed the benefit of Revlimid® maintenance after transplant, also show an increased risk of malignancies with Revlimid® maintenance after a stem cell transplant. The biggest increase in risk was for cancers of the blood and bone marrow, with leukemia and a preleukemic condition called myelodysplastic syndrome, or MDS, being the most concerning.

(21:03): This is a real concern, although I'm not completely convinced that the trials correctly accounted for the fact that people on lenalidomide lived longer and stayed on the study longer, which means we had more opportunity to see them develop a second cancer. More importantly, it's clear that on these trials, the risk of the myeloma progressing was always higher than the risk of a second cancer, regardless of whether people were on Revlimid® or on placebo medications. There's no evidence that the risk of serious harm or death from a second cancer would outweigh the benefit of Revlimid® in prolonging overall survival, making people live longer with myeloma. Even though this risk is there, we think it's small compared to the benefit of getting lenalidomide (Revlimid®). In general, it does not stop us from recommending Revlimid® maintenance following a stem cell transplant.

(22:05): There's no good data on how long maintenance therapy should be given. How long do we continue? There's no good data on the optimal duration of maintenance therapy. The trials that looked at Revlimid® maintenance generally used a strategy of indefinite maintenance until progression. Concerns about second malignancies have led some experts, especially in Europe, to recommend a fixed duration therapy, meaning continue lenalidomide for one to two years and then plan to stop.

(22:33): For most patients in the United States, we use a strategy of indefinite maintenance therapy, meaning that we plan to continue until the myeloma progresses or the Revlimid® causes intolerable side effects. Or, and I think this is important, that the patient wants to stop, because we don't have good data on the optimal duration of maintenance. That means that once you've gotten through a year or two of Revlimid® maintenance, if you ask the question, "Is there good evidence that I need to stay on the Revlimid® in order to get the benefit of living longer?", the answer is ‘no’. To date, there have not been any trials that looked at that question.

(23:18): In the trials of lenalidomide maintenance that we did, patients had dose reductions and ended up stopping treatment. Thus, we know that the benefit of Revlimid® maintenance was in a group of patients where some people stopped treatment, which means that we're not sure that after any period of time, that it's essential to continue on Revlimid® or to maintain the same dose. If the Revlimid® is causing side effects or it's just getting to be a real bother, it may be reasonable to consider stopping after a period of time, given that we don't know for sure that continuing therapy would provide the same benefit.

(24:02): The average duration of response with Revlimid® maintenance therapy is about four years. How long do these responses last? The average duration of response, which means 50% of people, have their myeloma start to grow by about four years. I'm not sure that number is useful since it hides a wide range. While some people will have a disappointingly short duration of response, some people will have many years, 5, 10, 12 years of response from maintenance lenalidomide (Revlimid®). I certainly would not think of there being any maximum duration of response from Revlimid® maintenance. We always hope that our patients will have a long response after transplant on maintenance therapy.

(24:45): Velcade® is used less often for myeloma maintenance therapy and has a higher risk of neuropathy than Revlimid®. For Velcade® maintenance, I have a lot less data since there are fewer trials, so we use it less often. We generally start therapy about three-to-six months after transplant. Velcade® is given as an injection, usually a subcutaneous, under-the-skin injection, since IV administration has more side effects. Since this is how it was done in the clinical trial showing a benefit, we normally plan to give the Velcade® every two weeks.

(25:18): We're more likely to do Velcade® maintenance for a shorter period of time because most patients tend to get tired of doing the under-the-skin injections, but it can be indefinite maintenance therapy until progression. Velcade® tends to cause similar side effects to lenalidomide (Revlimid®): fatigue and low blood counts, especially low platelet counts, which helps the blood to clot, although rarely to the point of having a risk of bleeding.

(25:47): More specifically for Velcade®, we watch for the risk of neuropathy, that numbness and tingling in the fingers and toes, since that's more common and can be more severe and more permanent with Velcade® .

(26:00): Velcade® increases the risk of reactivating the chicken pox virus as the painful rash known as shingles. Everyone on Velcade® should be on an anti-shingles regimen and an antibiotic. Acyclovir is one of them, but there are others.

(26:16): When myeloma progresses after maintenance therapy, there are a variety of treatment options. What do we do after maintenance therapy? When myeloma progresses after maintenance therapy, there are a variety of options. This cartoon drawing shows all the drugs that I included earlier in my list of agents that we use for myeloma. I put it this way because we usually try to think about combining drugs from different classes together. We often use monoclonal antibodies, immunomodulatory drugs, and proteasome inhibitors together. We then tend to combine them, in some cases, with cytotoxic medications, with steroids, with a medicine called venetoclax (Venclexta®), and/or with selinexor (Xpovio®). We also have, as options, our newer immune therapies, the CAR T-cells and the T- cell engagers. Choosing among all these options and all the various combinations is not easy, but what's good is we do have a lot of options.

(27:22): The general principle is that most people, especially for the first treatment after maintenance therapy, should get a combination therapy, usually a triplet, that is two medications in combination with dexamethasone. Most commonly, we'll use the antibody daratumumab (Darzalex®) or the almost identical drug, Sarclisa®. Darzalex® is the D in these combinations. We have abbreviations for all of our other partner drugs. But in this case with Revlimid®, Velcade®, Kyprolis®, or Pomalyst®, we often will combine immunomodulatory drugs, like Revlimid® or Pomalyst®, with proteasome inhibitors, like Kyprolis® or Velcade®. I'm a big proponent of cyclophosphamide combinations, usually in combination with bortezomib or carfilzomib.

(28:16): In later lines of therapy, we often turn to Empliciti®, which is another of those monoclonal antibodies, usually in combination with Revlimid® or Pomalyst®. We sometimes consider selinexor (Xpovio®), which has an X in the combination because of its brand name Xpovio® and can be combined with a variety of medications. It's important to keep in mind that for patients whose myeloma has this genetic translocation between the 11th and 14th chromosomes, venetoclax, although it's not approved for myeloma, has been shown to be particularly effective in that subset of myeloma patients.

(28:57): Sometimes, a second stem cell transplant is considered after maintenance therapy. In addition to these combination therapies, we sometimes consider doing a second stem cell transplant. This is often a question that I get from my patients. They assume that after their myeloma progresses on maintenance therapy after their first transplant that we would automatically plan to do a second transplant. That approach has relatively limited data, so it's not usually at the top of our list for most patients. It's clear that the duration of a response to a second transplant is correlated with the duration of the response to the first transplant, but it's rarely longer than the response to the first transplant.

(29:38): Most often, I'm thinking about doing a second transplant for my patients who have had a particularly long response to the first transplant, and usually patients whose first transplant, especially with lenalidomide maintenance, gave them longer than the average four-year duration of response. Because with all the side effects of a stem cell transplant, I'd want to make sure that we were really getting a lot of benefit for going through those side effects.

(30:08): CAR T-cell therapy is a new treatment available to treat myeloma patients after maintenance therapy. The last two options that I'll mention very briefly as therapy after maintenance therapy are these newer immune therapies. This treatment called chimeric antigen receptor, or CAR T-cells, involves genetic retargeting of immune T-cells. We are very excited about it. It does require a T-cell collection, and this whole process often looks to patients a lot like a stem cell transplant but ends up being overall easier to go through and very different in how it works. However, it does require a T-cell collection, usually shorter than stem cell collection. It requires some chemotherapy, although generally less than what you would expect to get with a stem cell transplant. And then it gives back to the patient's own T-cells that have been genetically modified to add a protein that targets the myeloma.

(31:13): Those T-cells, when administered to the patient, can cause inflammation in the body that's known as cytokine release syndrome and sometimes confusion that's called neurotoxicity. But when those T-cells go in and start killing the myeloma cells, they can be very effective at doing so.

(31:32): There are two products currently approved, one known as ide-cel (Abecma®), the other cilta-cel (Carvyktii®). Both target an antigen on the surface of the myeloma cells known as B-cell maturation antigen, or BCMA. We can see very high response rates, and sometimes very long-lasting responses with these CAR T-cells.

(31:56): The other newest treatment option for relapsed myeloma is a drug known as a bispecific T-cell engager. The other newest treatment option for relapsed myeloma is a drug known as a bispecific T-cell engager, which is essentially a double-headed antibody that, again, is a way of getting the immune T-cell to attack the myeloma cell. One end attaches onto the T-cell and the other onto a target on the myeloma cell. The medicine that's been approved is called teclistamab (Tecvayli®), and the same target on the myeloma cell as the CAR T-cells, which is the target known as BCMA.

(32:36): The advantage of Tecvayli® over CAR T-cell is that it doesn't require any collection of cells, or chemotherapy; it does, however, require ongoing dosing every one to two weeks on an ongoing basis. There's a trade-off in the way that we get the T-cells to attack the myeloma cells.

(32:58): I think it's important that maintenance therapy after transplant for myeloma is based on clinical trials that show improvements in overall survival and make patients with myeloma live longer. The most common and the most proven maintenance therapy is Revlimid® given as a single agent. Side effects during maintenance therapy are typically mild, but often can lead to dose reductions and sometimes discontinuation of maintenance therapy. And we do have many options available for treatment of myeloma that has progressed after maintenance therapy.

Question and Answer Session

(33:54): [Michala O’Brien]:  Thank you, Dr. Vogl, for this excellent presentation. We'll now begin the question-and-answer session. Our first question is, "Is bile salt diarrhea a result of taking the drug Revlimid®? Is there a good alternative to Revlimid®?

(34:23): [Dr. Dan Vogl]:  I think it's great that this question refers to the diarrhea as bile salt diarrhea because it points out one of the things that we can do about the side effects from Revlimid® maintenance after transplant. I think that we have good evidence that Revlimid® is a good medicine to use as maintenance therapy and limited evidence for other medications. But diarrhea from Revlimid® is a real problem and can make patients miserable. One way to deal with it is to lower the dose of lenalidomide (Revlimid®). Another way is to give medicines to treat diarrhea. We can use standard anti-diarrheal medicines, such as loperamide, which is the generic form of Lomotil®. Both are anti-diarrheal medicines, and both can result in constipation, which often leaves patients flipping back and forth between diarrhea and constipation, which is also miserable.

(35:32): There's some evidence that giving medicines that bind up bile salts or bile acids that are produced by the liver and pushed out into the intestines as part of the normal body process, can be very irritating to the intestines and are implicated in how Revlimid® causes diarrhea in some patients. These bile acid-sequestering drugs are an old class of cholesterol-lowering medicines that were not very effective at lowering cholesterol but are effective at binding up bile acids; there’s good evidence that they can improve the diarrhea from Revlimid®.

(36:21): The one that was most studied is a drug called colesevelam (Welchol®), as well as one called cholestyramine. I've had pretty good experience using these medicines to control diarrhea for patients Revlimid®. What's appealing about them is that, in general, they don't seem to cause constipation and they can be very effective. If you do have diarrhea from Revlimid® and you're trying to avoid reducing or stopping the medicine, then trying these older cholesterol-lowering medicines, are fairly effective with minimal side effects.

(37:12): [Michala O’Brien]:  Can you discuss any long-term side effects there may be from the high dose of chemotherapy given before transplant?

(37:21): [Dr. Dan Vogl]:  In general, the advantage of going through high dose chemotherapy for myeloma is that you get a lot of short-term side effects, but not a lot in long-term side effects. The long-term side effects from the high dose melphalan chemotherapy can be a bit hidden. One side-effect that we worry about is the risk of second cancers. It's clear that melphalan chemotherapy is probably associated with an increased risk of second cancers, but then that gets lumped in with the fact that patients with myeloma also, even without a stem cell transplant, have a higher risk of second cancers.  We worry that the Revlimid® maintenance may contribute to a second cancer, so we never know for sure, if a patient develops a second cancer, what actually caused that increased risk.

(38:18): A lot of patients complain about a sense of mental fogginess, some people refer to it as ‘chemo fog’, that can persist for a long time. We're never sure which part of their treatment causes that problem, but we think that it might be the high dose of chemotherapy. In general, other than those things, we don't expect long-term side effects like diarrhea, low blood counts, nausea, or neuropathy coming directly from the transplant medication itself.

(39:01): [Michala O’Brien]:  What are the best myeloma maintenance therapies to achieve the maximum durable long-term remission?

(39:11): [Dr. Dan Vogl]:  The best evidence that we have is for Revlimid®, by itself, as a maintenance therapy. There are other medications, and some of them have theoretical benefits beyond Revlimid® by itself, but I don't think they're nearly as proven. I think the standard answer for the vast majority of people should be Revlimid®.

(39:44): [Michala O’Brien]:   If you receive a negative MRD (minimum residual disease) test, is that an indicator that you can stop maintenance therapy safely?

(39:52): [Dr. Dan Vogl]:  An MRD test, or a test for minimal residual disease, is a bone marrow test that looks for a very, very low level of myeloma cells. If you can't find even that very, very low level, then we call that MRD, or minimal residual disease, negative. We see that as the deepest possible response that we can identify for patients. There are studies that show that if you get to an MRD-negative response, your duration of response and overall survival are better than if you don't. However, there aren't a lot of studies showing what to do with that information for an individual patient.

(40:50): I've heard it both ways; I've heard experts say that if you get to the point where you are MRD-negative, then your maintenance therapy is clearly working well, and you should continue it. Others have said if you get to that MRD-negative response, then your myeloma's in such a good response that you don't need to continue Revlimid® maintenance afterwards. There are trials starting up and moving through right now that are hopefully going to answer these questions where we're using MRD tests to assign patients to either continue or stop maintenance therapy. I think we're several years away from getting even preliminary results from those trials. We just don't know what to do with that MRD testing. If you have an MRD test and are confused about what it means for you, it means that we're still learning what these tests mean and what we're going to do with them.  This also means that I don't do MRD testing often for my patients in the post-transplant period because I'm not sure how I would use the information.

 (42:11): [Michala O’Brien]:  Can multiple myeloma allotransplant and maintenance drugs cause problems with the parathyroid gland?

(42:20): [Dr. Dan Vogl]:  I don't know of any direct effect of myeloma, stem-cell transplant, or maintenance therapy, on the parathyroid glands. Our parathyroid glands control the calcium level in the blood. That said, it's common, even in people without any of these other conditions, to develop a parathyroid gland disorder, usually an over-functioning parathyroid gland or hyperparathyroidism. This can elevate the calcium level, which in myeloma can be concerning because myeloma can also elevate the calcium level. Evaluating that is very important. There are good treatments available for overactive parathyroid glands so it's usually not a major problem for patients.

(43:18): Right next to the parathyroid gland is the thyroid gland, which produces a hormone that controls the overall metabolism in the body. That can often become under-functioning, called hypothyroidism, which can make people feel very tired and worn out. It can slow down all sorts of processes and lead to changes in the skin, and hair, and nails, and constipation because everything in the body is slowing down due to not having enough thyroid hormone. I do think there's a chance that our myeloma treatments can affect the functioning of the thyroid gland. When my patients have fatigue following stem cell transplant, during maintenance therapy, or even during other treatments for myeloma, I make sure I perform blood tests to evaluate their thyroid function. If it's low, I prescribe thyroid hormone pills that can make people feel a lot better if the thyroid gland is under functioning. However, that's different from the parathyroid gland, so it's important to make sure that you're paying attention to which one your doctor is talking about.

(44:37): [Michala O’Brien]:  Can you discuss T-cell exhaustion and its relationship to immunomodulators?

(44:45): [Dr. Dan Vogl]:   T-cell exhaustion is the concept that when immune T-cells in the blood and throughout the body are trying to fight off either an infection or, in this case, cancer, the T-cells’ job is to destroy other cells in the body when they develop errors inside them. However, when they are constantly stimulated trying to fight something off on an ongoing basis, some signaling inside them changes their instruction to shut down. We refer to that as exhaustion, so they stop being effective at killing the myeloma cells.

(45:39): There are some indications that some of our medicines, and that's particularly the drugs that we call immunomodulatory drugs, which are thalidomide, lenalidomide (Revlimid®), and pomalidomide, that those medicines can stimulate T-cells and may be able to overcome T-cell exhaustion. There are theories that this may be one of the reasons that Revlimid® works after a stem cell transplant during maintenance therapy at a time when we're not giving other medicines, like steroids, that can inhibit T-cell function. Maybe it's really Revlimid® that works by stimulating T-cells and the immune cells, when the myeloma is at a particularly low level, and that that's why Revlimid® is particularly effective during maintenance therapy.

(46:28): There're also the idea to use medicines in this class, like Revlimid® and pomalidomide, after our newer immunotherapies that depend on activating T-cells, like the CAR T-cells and like Tecvayli^®. It's possible that you could see some synergy between the immunomodulatory drugs and the T-cell-redirecting therapies, and that's an area of ongoing investigation.

(47:00): [Michala O’Brien]: Can a patient have CAR T-cell therapy after a kidney transplant?

(47:07): [Dr. Dan Vogl]:  We're going a little bit far field from the topic of maintenance therapy after a stem cell transplant. The answer is that we don’t know the answer for sure. People who have had prior kidney transplants were not included in any of the clinical trials of CAR T-cells. Although you would think that giving a T-cell that is specifically directed against the myeloma cells shouldn't have any danger to a transplanted organ. We know that T-cells are very important in the process of organ rejection. When we give CAR T-cells, we probably do give some other T-cells along with the CAR T-cells that are just regular activated T-cells. The CAR T-cells can set off a lot of inflammation in the body and induce other T-cells to become active. That means that I think we'd worry somewhat doing CAR T-cells after a kidney transplant, that we might see rejection of the transplanted kidney. I think it would require very careful analysis before proceeding with that, as well as consideration of possible alternatives.

(48:33): [Michala O’Brien]:  What treatment would you recommend for a rash, one that specifically broke out on a patient’s chest area?

(48:42): [Dr. Dan Vogl]:  Rash is common with Revlimid® maintenance after a stem cell transplant. The most common treatment that I recommend is anti-allergy medicines; the antihistamine drugs, especially loratadine (Claritin®), cetirizine (Zyrtec®), or fexofenadine (Allegra®). Those are almost interchangeable, although some people feel that one may cause more side effects than the other. Those can be very helpful with fairly mild rash and itching. If itching is a problem at night, then antihistamine drugs, like diphenhydramine (Benadry®l), may be more useful. Those tend to be a little bit sedating, so you don't generally want to use them during the day.

(49:37): Sometimes we'll use steroid creams, like hydrocortisone, for a rash from Revlimid®. If the rash is severe, then we usually stop the medicine, wait for the rash to subside, maybe give the antihistamine drugs, and then restart the Revlimid® at a lower dose to avoid exacerbating the rash. I have seen some patients get a very severe rash with Revlimid®, at least temporarily. If the rash is milder, then I think trying to manage it symptomatically with those treatments is often helpful.

(50:16): With Revlimid® we often see a lot of dry skin and, sometimes, little red, dry, scaly, spots scattered over the arms and the chest. I think those things can be helped by using hydrating skin ointments. The most common ones that I use include Aquaphor®, Eucerin®, or CeraVe®. Those tend not to have any side effects. They can feel a little goopy when you put them on but can be very useful in helping with the dry irritated skin if it's not really a full rash.

(50:57): [Michala O’Brien]:  You talked a little bit about MRD earlier. What treatments are available for a patient who is MRD-positive?

(51:08): [Dr. Dan Vogl]: As I stated previously, we don't know what to do with a test that says that you're still MRD-positive, particularly after an autologous stem cell transplant, when you are on Revlimid® maintenance. Some experts say, "If you're MRD-positive, we should definitely continue the lenalidomide maintenance because you need it to keep the disease under control." Other people say, "If you're still MRD-positive, then it's not working well enough and we should change treatments to try to knock the myeloma down even further, to get it to be MRD-positive." They're making a logical leap that if people who are MRD-positive have shorter myeloma control than people who are MRD-negative, it's a good idea to change treatments to try to make patients MRD-negative. But that strategy has not actually yet been evaluated in clinical trials. I have seen patients go through a lot of different treatments trying to knock their myeloma down to being MRD-negative when we don't know for sure that that's needed.

(52:25): I don't do a lot of MRD testing in my practice. If I did, and if my patient had a positive MRD test but was otherwise feeling well, if their myeloma was at a very low level, if there was no evidence of it growing, I would tend to keep them on their current maintenance therapy, since it has been working. I generally don't have a practice where we perform a lot of MRD tests and attempt to make the MRD test negative. However, some of my colleagues do that in their practices.

(53:00): [Michala O’Brien]:  How can I tell if diarrhea, rash, muscle cramps, or spasms are actually being caused by Revlimid® or by other health issues?

(53:09): [Dr. Dan Vogl]:  That is a question that I often ponder with my patients. In the end, I think there's really only one way to know for sure. You have to take a treatment ‘holiday’ from Revlimid®. In my experience, you have to give it at least two months off treatment and see if you feel a lot better off. treatment. If you feel a lot better, you want to go back on the lenalidomide maintenance at a lower dose to see if you get the same side effects. If you feel better off treatment and get the side effects back when you go back on the treatment, we know for sure that it's related. Otherwise, it can be difficult to tell if the fatigue is mild, if the diarrhea is just intermittent, and if the rash comes and goes. It can be really difficult to tell if it is related to Revlimid® or not. Am I not getting enough sleep and feeling stressed because of a situation at work or with the family? These variables can make it difficult to ascertain exactly what's causing the symptoms.

(54:49): I did see another question that someone had asked about quality of life. I agree that quality of life is really important. We know that starting lenalidomide maintenance from clinical trials is associated with people living longer overall. But because we don't know what the optimal duration of that maintenance therapy is, if there's a significant impact on quality of life, I am very much in favor of dose reductions and, if need be, stopping the treatment completely.

(55:24): [Michala O’Brien]:  Our last question: Does transplant eliminate chromosome deletions p53 and 11;14? Do they get controlled in maintenance therapy?

(55:40): [Dr. Dan Vogl]:  That has to do with the genetic errors that we often see in myeloma cells that can sometimes give us prognostic information about how people are going to do in the long run. These two abnormalities, individually, generally have different prognostic implications.

The 17p deletion, which is where the p53 gene is in our chromosomes, is usually associated with a higher risk, a shorter duration of response, and earlier development of resistance to therapy. The 11;14 translocation, by itself, is often associated with more indolent myeloma, longer time to progression, and generally a better prognosis. When they are seen together, it's usually the higher risk abnormality that seems to control how the myeloma behaves.

Unfortunately, I don't think there's any clear evidence that any of our treatments, specifically, get rid of the cells that have those abnormalities or get rid of the abnormalities themselves. If you start myeloma with a 17p deletion, that 17p deletion tends to stay with the myeloma no matter what we do. However, some of our treatments, especially some of the newer immune therapies, can still provide good responses even if patients have these high-risk abnormalities, and may be independent of whether the patients have these high-risk abnormalities. So, I think there are effective therapies that we can use when genetic changes are present in the myeloma cells.

(57:56): [Michala O’Brien]:  On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Vogl. Thank you, the audience, for your excellent questions. Please contact the BMT InfoNet if we can help you in any way. Enjoy the rest of the symposium.