Myeloma Maintenance Strategies after Transplant or CAR T cell Therapy

[00:04] Moderator: Welcome to the workshop, Myeloma Maintenance Strategies After Transplant and CAR-T-cell Therapy.

My name is Michelle Kosick, and I will be your moderator this afternoon. It is my pleasure to introduce today's speaker, Dr. Tara Gregory.

Dr. Gregory is the co-director of Plasma Cell Dyscrasia Program at the Colorado Blood Cancer Institute, where she treats patients who have diseases such as multiple myeloma, amyloidosis, monoclonal gammopathy, and plasma cell leukemia.

Her research focuses on multiple myeloma treatments, including CAR-T-cell therapy.

Dr. Gregory is passionate about educating patients to ensure they understand their disease and partners with patients to make treatment decisions that honor both quality of life and outcomes.

Please join me in welcoming Dr. Gregory.

[01:02] Dr. Gregory: Thank you, Michelle, for the very kind introduction, and thank you to BMT InfoNet for having me back again this year.

I always look at my picture here and think, man, I got to get a new headshot because I stopped dying my hair after COVID.

Today, what we're going to talk about are maintenance strategies in multiple myeloma specifically, and we'll walk through some different concepts of how maintenance therapy started. How that landscape is changing; the goals of treatment, and we are going to get into a concept called minimal residual disease assessments because that's becoming more important and an evolving field in myeloma. So, we will go ahead and get started.

[01:49] First of all, today we will be talking about why we do additional treatments after an initial treatment such as a transplant for multiple myeloma patients.

We will go through some of the maintenance therapies that are currently available after transplant and then what we call CAR-T-cell therapy, and I'll be explaining what that is as well.

We will talk about how long patients need to stay on myeloma therapies and how long they typically keep the myeloma under control before the myeloma needs a different treatment, and we call that progression when that happens.

Then we will get into some of the side effects of the current maintenance therapies. With maintenance, the longer we can keep patients on some treatment is better, and understanding the side effects and how to deal with those side effects or prevent them really do allow our patients to continue on therapy for as long as possible.

[02:45] First of all, what I'd like to start with is a history of myeloma treatments, and really, myeloma-directed therapy started back in the 1940s. Things were pretty similar from the 1980s until about the 2000s for 20 years before our field really has started to just jump off and change in the 2000s and 2020s.

When we start to talk about myeloma therapy for patients, when patients are initially treated, we call that a first line of therapy. Classically, in the United States, that includes when patients are diagnosed with myeloma, they have a disease that we decide, okay, this myeloma patient needs to be treated.

The initial four months of treatment or around their four to six cycles of treatment, we call an induction therapy, and that is classically followed by a stem cell transplant, and that's where we give high-doses of chemotherapy that are really good at mopping up myeloma. But it's also really good at killing your bone marrow.

I spend a lot of time teaching my patients what your bone marrow is and what it does for you and how it's very important for day-to-day life, like keeping you from bleeding and getting infections. That high-dose chemotherapy is very good for killing extra little myeloma cells that we can't see, but it's good for killing bone marrow.

So, what we do ahead of time is we collect the blood maker stem cells from the bone marrow, and we do this through a blood procedure where the stem cells are moved from the bone marrow into the blood with shots and then collected with a machine that looks like a dialysis machine, and it's called an apheresis machine. Those are frozen.

I basically say, those are like the healthy seeds from your garden. We're going to come in and give you this big chemotherapy and wipe the entire garden out, like the grass, the trees, you know, not only just the weeds, and then we're going to reseed that garden with your own blood maker stem cells, and that is the transplant part.

[04:56] Then patients go on to, there's some different phases of treatment afterwards, consolidation and maintenance. That treatment can stretch for years, ideally, and that is considered one line of therapy because it was all one big planned treatment altogether, even though there were different phases to it.

That transplant came about in the 1980s, and we used to do those for patients when, you know, the chemotherapy that they were getting didn't work anymore.

[05:28] In the 1990s, we said, well, okay, it looks like maybe we should do this from the get-go, and that's the model that we've kept today where we get patients' myeloma under control, and then we mop it up with a transplant.

And then it was in the mid-2000s when we said, hey, maybe we should be keeping people on some treatment to prevent this myeloma from coming back so fast. That concept is called maintenance therapy. That really took off when we had these new, what we call immunomodulatory drugs, like lenalidomide come onto the market in the mid-2000s.

That's where that concept of maintenance started. And that's what we're going to dive into.

[06:11] What I want to show you here and what my patients are very familiar with is what we like to refer to as the myeloma iceberg, and we think about our goals of treatment. Where do we want to get people?

When patients are diagnosed with myeloma, you can see this top dotted line at the very tip of the iceberg.

You've got all this myeloma underneath the water level, the ocean, but it finally showed up at that very tip top of that iceberg, and that's when patients are newly diagnosed and treated. As we start to make the myeloma better, we have different criteria to say how much better it is.

In patients whose markers and, you know, the blood markers that you get done to check the myeloma and the bloodstream, those are protein levels. If we can make those protein levels better than 50%, you know, more than 50% down from where they started.

[07:10] Let's pretend that somebody got diagnosed, their monoclonal protein or their M spike was three grams per deciliter. If that goes down to 1.5 or less, we call that a partial remission or a PR.

As we start to say, okay, all the blood tests are looking normal. The M spike is zero. The test called immunofixation isn't present anymore. That's negative. There's less than 5% cells in the bone marrow, the light chains are normal. That's called a complete remission.

Our goal really used to be with treatment, well, if we could get you into a near complete remission or at least 90% better than when you started, that was good enough. We said, all right, that's where patients are going to do well.

It makes sense, but there was a lot of research behind this, that the more you can push the myeloma down into a deeper and deeper response or the more you can melt that iceberg, the longer patients are going to go without needing a change in treatment, the longer patients are going to go without having a problem related to their myeloma.

[08:25] As we continue to have better and better tests to look at myeloma, we've gotten into this concept of minimal residual disease. We're going to talk about that later, but you can see at the very, very bottom, the second to bottom dash line is can you detect even the teeny tiniest little bit of myeloma down there? If you can't, we call that being minimal residual disease-negative.

We have a new definition of cure in myeloma, which is really exciting this year because ultimately we used to say this was a disease that we couldn't cure. Now we're saying we do think we can cure this disease if we can make that test negative for five years running straight. So, I want to talk about those goals of treatment so that you know really what we're headed with these different studies.

[09:21] Now we will get into the point of the talk, which is maintenance. In the beginning, the first study that was really done about maintenance therapy was done by the French myeloma group, and I can't speak French. My partner, Dr. Mattis, can. But Intergroupe Francophone du Myélome is the IFM, and this study was done in 2005.

So that's how they do their studies, and it was study two.

What happened with these patients is that these patients got their stem cell transplants. And within six months, they received the lenalidomide. Everybody did for two months.

What they saw after the two months is that they really did push these patients into more complete remissions. So, remember that iceberg that we're talking about, we're getting the iceberg about halfway melted down.

Then after the two months of therapy, some patients went on to get a sugar pill, which is called a placebo, and other patients went on to a lower dose of the lenalidomide.

What happened was things were so much better at the two-year mark for people who were getting the maintenance therapy, the lenalidomide, that they decided that they should let patients who were getting the placebo or the sugar pill cross over, and we still saw a benefit.

Ultimately, patients who got maintenance therapy were able to go almost five years before they needed a different treatment for their myeloma compared to under three years for patients that just did a sugar pill.

The other thing of note is that these patients didn't receive treatment with lenalidomide forever. They did this for about a year. So, it was limited treatment.

[11:05] Now, what happens is that, you know, in the United States, we don't believe anybody else. We always have to repeat all these studies ourselves. So, we did our United States version. And there have been quite a few studies with maintenance in these structures. We're just going to go through the nice big ones.

This is called the CALGB-100-104 study. In the United States study, patients were started on maintenance therapy within three months of their transplants.

They were either randomized to receive a sugar pill, which is the placebo, or they went on to the low dose of Revlimid. Again, things were so much better at the six-month mark that patients were allowed to unblind if they wanted to.

So, they would say, would you like to know if you've been receiving the sugar pill or not? Some people said, yes, I do, and say, okay, well, it looks like you haven't been receiving the medication. Would you like to receive the medication? Because we're seeing already patients are doing better within just six months of starting maintenance therapy. So, patients were allowed to choose if they wanted to go over and receive the medication.

Again, on average, patients were going six years, about five years, before we saw a relapse compared to about two and a half years if they didn't take the maintenance therapy.

[12:28] These two studies combined really said to us there is a real benefit to keeping patients on a little bit of myeloma treatment, a low dose, no steroids. Generally speaking, this would start out at about 10 milligrams and patients did better and were going on to better therapies with more time under their belts.

Now, one of the things that we can do is we can look at studies that were done.  In medicine, we typically don't like to say, well, these people did this over here and these people did that over here, and let's compare the two because it's a little bit apples to oranges. So, it's hard to get a good idea of, you know, is that really a true comparison?

We'll do what are called meta-analysis. So, these are when we pool data and we use statistics from the studies to see if we can combine some of these bigger studies together to get a bigger answer.

We really do like meta-analysis of three really important maintenance studies.

[13:38] Ultimately, what you can see in these two pictures is that the blue lines are where patients were receiving lenalidomide maintenance, and the yellow lines are where they didn't.

Now, the first box, the box in the middle, is talking about how long did people go before they needed to have a different myeloma treatment, and how long did they go before they relapsed? And we call that progression-free survival, meaning how long did you go without your myeloma being active?

[14:13] We get really excited when we look at these curves. Say I could get my thumb in there, I could fit my thumb between those two curves. You can see here, there's a big spread between the blue line and the yellow line, which goes along with the French study and the U.S. study that we were talking about.

[14:34] Now, the next thing about myeloma is that typically our patients do so well over time because when the myeloma comes back, we have another good treatment and another good treatment and other good treatments. So, people live a very long time with myeloma, and I'm going to show you some of that.  This is older data, but we're going to go through some of the newer stuff.

It can be very hard to say that what I'm doing for someone is going to make them live longer overall, and we call that a survival benefit. How long are people living in general?

What was really exciting about this meta-analysis is that it did show us that when patients do maintenance therapy, they overall live longer better than people who don't do maintenance at all.

That's what that second graph is showing us there. You can see at the end, you can start to get your thumb between those lines.

[15:35] Now, we talked a lot about lenalidomide maintenance. And lenalidomide, I think a lot of people are familiar with, is a pill.

The way that it works is that it is an immunomodulatory drug. What these drugs do is they rev up the immune system. So, then you have more healthy immune cells that can see the cancer is foreign and come eat it. So that's one of the things it does.

The other thing that it does that's really important, it prevents a protein from working that helps keep the myeloma cell alive, and that protein is called cereblon. So, we're starting to see new drugs that we've been waiting for to come on the market that worked real specifically on that protein. Those are called CELMoD inhibitors. But that's what lenalidomide does. So that came out in 2005.

[16:33] Now, if we hit the mid-2000s, in about 2015, we got a new type of drug on the market for myeloma, and these were called the anti-CD38 antibodies.

I like to say Dara makes everything better because there's a drug called daratumumab and my name is Tara, so Tara and Dara, and one day, maybe there will be a daratumumab who knows.

But this is not the only drug. There's also a drug called isatuximab. So, there are multiple different kinds of anti-CD38 antibodies, and they work very similarly. Just some of our initial data was done with the one drug.

But I like to say Dara makes everything better because every time we added Dara to something that we were already doing, outcomes got better and patients really tolerated the medication well.

[17:19] The way that these drugs work is that the myeloma cell, bad green little myeloma cell there, have these little proteins that stick up on the surface. Those would be those little CD38s.

Basically, cells have a lot of these CDs on them, and we number them based on what they are. Myeloma cells make a lot of these CD38s.

Daratumumab, the yellow little antibody there, goes and can stick on to that little protein that lives on the surface of the myeloma cell, and a couple things happen.

It says, yo, immune system over here, you missed this. Like signal flare, come eat this. It's kind of like shooting off a signal flare to the immune system.

If you have something like lenalidomide that's revving up those immune cells, and then you've got the antibody, those guys can work together to help the immune system target in on that cancer cell.

The other thing that happens is that when the daratumumab stick or the anti-CD38 antibodies stick to the myeloma cell, they hold hands and they tighten up and they rip the myeloma cell wall apart.

[18:31] Then lastly, what they're able to do is they recruit a series of proteins. This is how doctors are nerds and how you know when this came out, when we learned about this part of the immune system. It's called a Mac attack, like McDonald's.

It's a series of proteins that come in and they drill a hole in the myeloma cell wall. The daratumumab helps those little proteins come over and find the myeloma to help pop it.

[18:54] Those drugs came out in the mid-2000s. Since Dara makes everything better, we started to do studies where we said, well, maybe we should be incorporating these antibodies as part of the treatment in maintenance therapy. One of the big studies that was done was called the AURIGA study.

Again, in typical fashion, patients did a stem cell transplant. Within three months, half the patients got the daratumumab and the lenalidomide together. The other half of the patients only got the lenalidomide.

The Dara group stopped the Dara after two years, so this is one of the initial studies. They stopped after two years.

[19:44] When we looked at almost a three-year mark to see how patients were doing, because it takes so long to watch patients over this long, long period of time, and this is a newer study. At the 30-month mark, 83% of the patients hadn't relapsed when they got the Dara compared to 66% without. So, we're saying, okay, now we can add in this second drug. And man, you know, now we're really getting nice responses where patients are going longer and longer and longer before their myeloma is coming back.

[20:16] Now we're going to start to get into some of the newer data. And what I want to do is take a minute to talk a little bit about that MRD or that minimal residual disease response.

So, we talked about how in the beginning that near CR was we were happy if we could get patients there. And then we knew CR and stringent CR were more important.

But wouldn't it be better to melt that iceberg even further down where you can't even see the tip of it anymore? That concept is called minimal residual disease-negative.

What we're going to start to see is the outcomes of a lot of studies are not just how long people live without their myeloma being active and how long they live overall. But the goal is going to be, are they MRD negative at the end of this treatment or not?

[21:16] I want to go into that testing a little bit.  Now, this is just to drive that point home. How do patients do when they become MRD negative?

So that top blue line is when patients are MRD negative compared to other responses. That purple would be the complete remission, the green line or the stringent complete remission. The CR is that 100%. The VGPR, that's going to be our 90%. And the PR is kind of that like maroonish brown line, and that's 50%.

You can see that patients are doing the best when they hit that MRD negativity rate up there in terms of how long they're living without their myeloma being active and how long they're living overall. Because if you look at that overall survival on the right side and the MRD negative, I mean, that's fantastic, right?

[22:14] If we look at some of our old data on myeloma patients from years and years in the past, we didn't see survivals that were like way over 95%. Now we really are because our treatments are helping patients become minimal residual disease-negative or MRD negative.

Okay, so how do we do this test? Can you have this test done?

Unfortunately, right now it's a bone marrow test. I'm sorry. It does have to be in the bone marrow.

We have other cancers where we've been able to change the test to a blood test. We can do a blood test in patients with acute lymphoblastic leukemia. We can do that in chronic lymphocytic leukemia.

So, we're working on it and we're testing it in myeloma, but right now it's still going to be a bone marrow test.

You can send the test on blood, but it doesn't match up with what's happening in the bone marrow right now.

[23:06] What the test is, is it is a type of next generation sequencing or NGS, and the company that does the test is called Adaptive Biotechnologies and they have named their test clonoSEQ. So, the type of testing is next generation sequencing or NGS. The Company who's doing it for us largely in the United States is Adaptive Biotechnologies, and the brand name of the test itself is called a clonoSEQ test, and this is currently the only FDA approved MRD test with myeloma or for myeloma in the United States.

The way that this works is that when there's a lot of myeloma in the bone marrow, and from when you were diagnosed with myeloma, so if you're diagnosed back in 2012 with myeloma, we got to go find that sample that's hopefully of your bone marrow that's hopefully sitting in a box in a file cabinet with your bone marrow just kind of sitting in a piece of wax.

Every time I explain this, I feel like it's almost kind of like Jurassic Park with the mosquito and the amber.

[24:23] What we do is we ship that sample off to the company. They are able to take the DNA out of that old myeloma sample specifically and only from the cancer cells, the myeloma cells.

There's a chromosome, chromosome six, with a very unique DNA sequence or strand of DNA that comes only from the cancer cells, and it says, I am your cancer DNA. And over time, as the myeloma changes, that DNA strand stays very consistent. So it doesn't change.

So ultimately, what that is, is that's us finding what is your needle look like.

[25:09] Later on, when you do treatments and we get bone marrow samples, we say, can we find that needle in a haystack anymore? And if we cannot find that needle in a haystack, then that's called being MRD negative. So again, it doesn't need to be sent fresh. It can be done on old samples.

A lot of what happens with our patients now is that I'll meet a new patient who didn't have this test done when they were initially diagnosed. I can request that the company go find the old samples from when the patient was diagnosed years in the past and see if they can get that DNA done, that DNA testing done for me. And then they say, OK, we've identified the clones. Then I have that to compare to samples moving forward.

That is a test that you can ask your physicians for that can be sent and then used moving forward in the future. Sorry, that's really confusing. I hope it made sense to everybody. It's a lot of DNA testing.

[26:16] Okay, so now that we know what MRD is and we are back to our maintenance story, this is one of our studies called the Perseus study, that looked at MRD as an end point in the management of myeloma. So, this is Perseus and we know he went and cut the head off Medusa. Medusa is our myeloma cell today, and daratumumab is going to be our special shield because we know how important that was for Perseus to knock Medusa out. One of the things about myeloma is that when we do these studies, we think we're very clever.

[26:49] We like to name them after Greek mythology, Roman mythology, constellations, that sort of thing. Or we like to do studies and put two Ms in it. For example, there's a study called the IMAGINE trial with two Ms.

In the Perseus study, when patients initially started getting their treatment before they ever got a transplant, some groups got Dara, bortezomib, lenalidomide, and dex, so four drugs. We call that a quadruplet.

The other group didn't get daratumumab at all, because at that point, it wasn't a standard thing that we would do. At that point, we hadn't proved that Dara made everything better in the very beginning. We're there now because of this study.

[27:35] Then both groups went on and got a stem cell transplant. Then patients went on to get an additional two cycles more of treatment. And then either if you were in the non-DARA group, you just went on your Revlimid maintenance, compared to patients who were in the Daratumumab group, they got the DARA and the low-dose Revlimid. They got an MRD assessment later.

If the MRD test became negative, then the DARA could be stopped, and if the MRD test was positive, then patients stayed on the Dara and the lenalidomide until their myeloma got worse again.

[28:09] And so what did we see? So, in a four-year follow-up, the number of people without active myeloma, so this is our progression-free survival, with Dara 84% compared to no Dara 68%.

We kind of knew that. We saw that in our other study, right, in the AURIGA study that we talked about.

Complete response rates, how deep was the response? 88% with Dara compared to 70% without. 

But minimal residual disease testing, 75% compared to no Dara at 48%.

If you look at this study and then a similar study that's being done called the Griffin study, at every time point, at every time we check after the initial induction therapy, after the transplant, after the consolidation therapy, on maintenance, the MRD just keeps getting better and better and better and better.

So again, Dara makes everything better. More people are MRD negative, and we're starting to see us use that outcome of MRD negativity.

[29:14] This might bring up some questions for you. Well, what if I didn't get daratumumab and I got the other one, isatuximab?That's great. They've done very similar studies between these two different drugs and the results look very comparable.

But what if I only got lenalidomide maintenance? That's okay. We didn't know how to do this stuff a long time ago. Some people got treatments back in the 2000s and they're still doing fantastic.

That doesn't mean that you don't ever get to have a CD38 antibody. We can always bring those up the next time that you get treatment.

Now, I do have a lot of patients that say, well, what if I can't stay on maintenance because it makes me sick? It gives me a rash. I vomit. My blood counts drop.

That's okay, too. If we go back to that French study, remember, even just a little bit of treatment really got patients great outcomes. So that's fantastic. And we also have fantastic options for future treatments as well.

[30:16] So I just talked about how great maintenance is. What are the bad parts? And I had already mentioned that it's important to be able to stay on treatments. The more manageable that we can make them, the longer your patients are going to stay on.

And, you know, a low dose is way better than no dose is kind of what we say.

These treatments, both lenalidomide and the anti-CD38 antibodies, they can cause low blood counts. And so, a lot of times what we'll do as we're treating you is we'll be watching the blood counts to see what's happening. And if we think that they're starting to get a little too low, then we'll go ahead and change the dose.

And, you know, we're not talking about like we don't let them go so low that you need a blood transfusion. We don't really want to get there in maintenance therapy. So we'll be pretty quick to drop things if we feel like it's hurting you.

[31:10] Risk of infections. Anytime we treat myeloma, we give people a 30 percent risk of upper respiratory infections, colds, that kind of thing. 

Really, with these anti-CD38 antibodies, they're so good at fighting off bad myeloma cells and dropping antibody levels that they can drop the good antibody levels too.

And so, a lot of times we have to give infusion of healthy antibody to help protect infection.

That's called intravenous immunoglobulin or IVIG.  And classically, we really should be keeping those IgG levels greater than 400. If you're running under 400, you should really be getting this IVIG infusion, and typically, it's given about every four to six weeks.

[31:54] Treatments can make you tired. If a patient tells me that they go out and mow the lawn and they're done for hours after that, that's too tired. You should be able to go out and do those extra things in life and enjoy them. So, we'll adjust doses for that.

When you're on those drugs like lenalidomide for long, long periods of time, they keep your intestine from absorbing what we call bile acid salts. And bile acid salts are what bind fat, so we absorb it. So, if you don't absorb the salt, you don't absorb the fat, and everything's going to shoot straight through.

There are drugs like cholestyramine that'll help bind that up, and that's a powder that physicians can prescribe for you.

[32:30] There's this weird shortness of breath thing that people can get, and they feel like, like, I'm just sitting here, and I'm panting, and I can't catch my breath. And what's wrong with me?

Well, nothing's wrong, but the drug does, can make you feel like you're short of breath.

There is a risk for blood clots with lenalidomide. Based on you and your history, do we just need a baby aspirin or do we have to put you on a real big blood thinner? Cause you've shown us you like to make blood clots. So, you got to step up.

[33:00] There is a risk for other cancers on maintenance therapy, and so we'll kind of get into this, But that's why we're thinking, you know, maybe not everybody needs to be on all the maintenance all the time. Maybe there's a place to kind of back off early.

That's where research is coming up. So, you know, we really have to be careful about our skin, wide-brim hats, men like baseball caps, not enough because the back of the ears. That's the important place in the back of the neck where I see men get a lot of skin cancers, blood cancers, smoking. It'll increase your risk of lung cancer, big drinker, head and neck cancers, that sort of stuff.

Those are all things that while your physician's keeping a tight eye on you or your nurse practitioner or PA while you're on these drugs.

[33:43] So future directions, where are we headed?

We are headed towards stopping treatment if we can be MRD negative. That's really exciting.

[33:56] One of the studies that we're using to do this is called the MASTER trial. So, what you can see here is that patients are getting their initial treatment with four drugs again. They're getting a pretty strong drug compared to the bortezomib.

They're getting a drug called Kyprolis or carfilzomib with Revlimid and dex, and then they get an MRD test. Then they get a transplant, and they get an MRD test.

If you have two MRD tests that are negative, those patients stop treatment, and they just get monitored.

[34:31] Now, if we start to see the MRD test come back up to just a tiny little bit positive, they go back on a maintenance strategy, and we're calling this MRD-SURE. These patients do go on to a Dara-KRD consolidation. They get a couple cycles. They can get the MRD test repeated, MRD test repeated, and then go on to a maintenance strategy with just the lenalidomide maintenance.

So, we don't have data. This is really new. We don't have the data yet to have us change what we're doing with patients. But this is where we're headed. This will be really interested to keep an eye on people and see what to do.

[35:14] The next area that we're going into are drugs called bispecific antibodies. To quote my partner, Dr. Mattis, he likes to say that the next best treatment is available to you on a clinical trial.

We have a lot of these clinical trials available here at the Colorado Blood Cancer Institute. A lot of big myeloma groups do, too.

What these drugs are is they're what bispecific antibodies. So, if we remember the anti-CD38 antibodies, they're just going to go stick to one thing. They're sticking to that CD38.

These antibodies grab two things. One side is going to grab the myeloma cell. That's the green cell right there.

The other side is going to hold on to the cancer cell, and it's going to drag that immune cell called a T cell and the myeloma cell together. And then the T cell can release little inflammatory toxins and pop the cancer cell.

[36:01] So it's a way to actually push them together. Whereas with the anti-CD38 antibodies, they're like, hi, immune system, I'm over here. Do you see me? As opposed to like, let's get together here.

We have a lot of studies looking at, can we replace a transplant by going on to a bispecific antibody for a couple of years? Should we use a bispecific antibody as our maintenance strategy? Should we use a bispecific antibody plus an anti-CD38 antibody together as a maintenance strategy? Should we add in lenalidomide in there somewhere? So those are some treatments as well that we're looking for at maintenance.

Then can we become MRD negative? If we become MRD negative, can we stop? And how long is it going to be before patient's myeloma comes back?

[36:57] Next thought is maybe we should use CAR-T-cells, and what CAR-T-cell is saying, okay, let's not just give you an antibody that's going to link the two together. So, you have to keep getting these shots. Let's go ahead and just change your immune system.

Let's take out those T cells from the blood, and the lovely thing about a T cell is it doesn't live in the bone marrow. It already lives in the blood, so you don't have to move it there with all the shots.

[37:23] Go on the machine, collect those T cells out, set it for T cells, ship those off to a company. You can see this little blue spiky guy over here at the top next to the green cell. And that's a viral particle that goes inside your T cell and goes into the DNA of the T cell and says, why don't you grab a new pincher, some new prongs? And that's that little yellow thing sticking out. And that's called a receptor.

[37:51] That receptor can stick to a protein that's called an antigen on the cancer cell, and the cancer cell there is that purple big Goomba thing.

The T cell, when it sticks, releases all those inflammatory proteins called cytokines that help pop the myeloma cell.

[38:10] Right now, the big one that we use in myeloma sticks to a protein called B-cell maturation antigen or BCMA. With that cell, there are a lot of different proteins right now. That's a big one that we use.

[38:26] So, can we replace a transplant with a CAR-T? Should we do a transplant and then a CAR-T as our mop-up and then leave people off stuff?

I think the other question is, well, what if I get a CAR-T because my myeloma came back and then I go on maintenance therapy? So, is there any maintenance after a CAR-T?

[38:42] The answer is right now, no. It's not standard to put patients on maintenance therapy if they get a CAR-T after their myeloma's come back. We call them one and done.

We do have some clinical trials that are asking that question. Should patients go on a little bit of maintenance like lenalidomide or something like that?

Right now, the answer is no. Don't do maintenance after CAR-T, but that might change.

[39:03] Some final thoughts. Maintenance therapy after stem cell transplants help patients live longer and live longer without myeloma.

The current standard would be to get maintenance therapy with an anti-CD38 antibody and the lenalidomide.

Talking to your physician about how you're feeling to help make treatment manageable over a long time is very important. You don't just have to get beat up and stick with it.

[39:26] Then hopefully I just lied to you that people are getting transplants all the time because maybe and hopefully we won't need stem cell transplants in the future. It could be possible because I lied to you last year. I did a talk on CAR-T-cell and I said, does CAR-T-cell cure cancer? And the answer was probably not.

[39:47] Well, that was wrong. It looks like CAR-T-cell therapy in patients with really, really bad myeloma is probably curing about 40% of those patients. Now because of that, we have that new criteria for curing myeloma therapy. So that is really, really exciting.

And with that, I will go on to opening us up to questions.

Q&A

[40:14] Moderator: Thank you, Dr. Gregory, for this very informative presentation.

[40:14] Now let's take some time for the questions. If you have a question for Dr. Gregory, please use the question box on the lower left side of the screen. We will answer as many questions as possible.

Our first question is if I have kidney failure caused by my myeloma, can I still have these treatments?

[40:44] Dr. Gregory: That is a wonderful question.

The question is, when patients have myeloma, there can be a lot of that extra immune sticky protein that the cancer makes that gums up the works in the kidneys and can make the kidneys fail and not filter very well.

So, some people, they get treated for their myeloma, their kidneys can get healthier. Some people end up on dialysis and can come off, and some people, unfortunately, get stuck on dialysis. Some people's kidneys aren't so damaged that they need dialysis, but they're still not functioning at 100%.

The answer is yes, you can do all these things. We just have to adjust the doses of our medications that we give you to make it safe.

These drugs can all be given when patients are on dialysis. We just have some rules about when you take it related to dialysis and how much you can take.

Stem cell transplants can happen in patients who are on dialysis. We just have to adjust the dose of the chemotherapy that we give people as well.

Great question. Yes, we just have to pay attention to the kidney function and give you the right doses.

[41:50] Moderator: Thank you.

How long will you need to be on maintenance? Is it better to be on it indefinitely or should we be getting bone marrow biopsies and utilize

[42:00] Dr. Gregory: MRD testing to guide treatment? That is such a good question.

I think a lot of doctors don't know the right answer. And maybe one day we'll have a very firm, this is the answer. It's a little loosey-goosey right now.

I think the first thing is the longer you can be on maintenance, the better. There's another meta-analysis that said how long, and so we know that on maintenance, the most bang for your buck is the first year.

Then it's definitely somewhat better to get the second year. Third year, a little bit better. Fourth year, smidge better. After the fourth year, we're probably not getting as much bang for our buck off maintenance.

So, if I'm with my patients and we're really pushing to try and tolerate it and stay on it, we really try and hit that two-year mark. And then if at four years they're like, my quality of life is terrible, we've done all the dose reductions, they just really don't want to be on the medication, I'm like, hey, you know what? It's probably okay at this point to come off because we've got so many good treatments for you next round.

Now, I do think doing those MRD tests are going to be very, very helpful moving forward to know how long you have to stay on. So, I do think that's coming, that we're going to use that test to say you can stop maintenance now.

One of the things that we're learning out of the MASTER trial is that if we have a patient with what we call standard risk myeloma, and they went into MRD negativity at the beginning of maintenance, and they stayed MRD negative for a year, those good standard risk patients probably can come off maintenance and do just as well as somebody stays on.

That's not a standard decision right now, but it's definitely where we're headed.

[43:40] Moderator: It's not clear to a member of our audience why we go back to look at an old sample to look for MRD. Isn't it better to look at the latest sample to know how good the treatment is working?

[43:57] Dr. Gregory: That's a great question.

So, we have to have the old sample to know what we're going to look for in the future.

We have to find out what is your needle look like first, and when you have a lot of cancer cells in the bone marrow, that's when it's the easiest to find what your myeloma DNA signature is.

Then we use that as to go look for it in the future off the future samples. So that's a good question.

On a future sample, if I have a patient, when they're diagnosed, if in the very beginning of their diagnosis, they had 70% myeloma cells in the bone marrow, well, that's a lot of cancer for me to be able to go figure out what makes that cancer look like that cancer so I can go search it in the future.

Ideally, when my patient's myeloma comes back, I don't let it get so bad that they have that much cancer. So, there'll probably be less cancer cells in there, like 5% or 10%. And when you have less cancer cells, it's harder to find that DNA signature off that new sample. The test just isn't as good as figuring out a clone, and we don't need that clone or that DNA signature is not going to change over time. It's something that stays pretty tried and true.

Now, there are situations where we can't find the old sample, or they're just not able to get the DNA out of the old sample. We are at the point where we have to see if we can try to get it off a new sample.

But again, we're really dependent on there being a lot of cancer cells there. So, there's a lot of cancer DNA to help us figure out what's your specific DNA signature so that we can go hunt it in the future.

[45:51] Moderator: Do we have any idea about using Dara for long-term utilization in patients?

[45:59] Dr. Gregory: We do.

If we go back to that Perseus study, those patients stay on the daratumumab if they were MRD positive. We do know that the longer patients are on daratumumab, the more and more we see that the healthy antibody levels go down. And so it's important to keep patients on that intravenous antibody or the IVIG to help out the immune system.

But that is the trade-off, is that that medication really can make it hard to prevent infections.

We do have patients now where those drugs, the anti-CD38 drugs, are being used continuously because the myeloma was under control for a long time. It came back, and that's where a lot of patients are dealing with getting daratumumab, is that their myeloma came back.

So, we had to put them on their second line or their third line treatment. In those situations, once the myelomas come back, we do keep you on treatment indefinitely.

Where we're talking about stopping some of these therapies is in the very beginning. Can we push you so low in the very beginning that we have the opportunity to stop? 

When it's relapsed, a lot of our therapies still are to just stay on the drugs for long periods of time until they don't work anymore.

[47:27] Moderator: Dr. Gregory, can you talk about what DEX adds to the mix when it's part of a triplet or quad therapy?

[47:36] Dr. Gregory: Oh, that is such a good question because that's really changing.

So, dexamethasone is a type of steroid. For those who, I'm sure anybody who has myeloma, unless you haven't been treated yet or you're a myeloma caregiver, you know what DEX is. But it's a really, really, really strong steroid.

Most people have taken prednisone, like 20 milligrams for a rash or something like this. Typically, the dose to treat myeloma is a 40 milligram dose. That's like taking 120 to 160 milligrams of prednisone all in one fell swoop. So that is a massive dose of steroid.

When patients are over the age of 70 or they have bad diabetes or something else is going on, then we think we should drop that dose to 20 milligrams. And some patients need to go lower than that. But there is an age period where we say dex needs to cut in half.

The dexamethasone, the way that it works is it actually pops a hole in the myeloma cell wall and makes it explode. So, it's really good at doing that in lymphoma, and it's really good at doing that in myeloma. Those are the two diseases where you'll see us use a lot of steroids.

Now, in the initial treatment, in that first four months, on average, that patients are getting therapy, we like to keep that drug around. But we know that over time, that dexamethasone just leads to toxicity and it doesn't really help the drugs work any better over time in that maintenance strategy. That's why we get rid of the dexamethasone.

What you're going to start seeing, two things. 

First off, is that if people are older and what we call frail and not able to do a lot of these big therapies. There was a study that was done about, I think it was about two or three years ago, and they only gave the dexamethasone in combination with lenalidomide and Dara for one month, and then they got rid of it. And the patients did great. So, it doesn't look like we really need the steroid around long now that we have these great drugs that focus on myeloma.

The other thing that you're starting to see is that we're doing a lot more CAR-T cell therapy for patients. It's more available, so more patients are able to get it.Not only that, but patients are getting it sooner in their treatment course.

So, it used to be that you had to go through four separate lines of therapy before you could qualify for a clinical trial. Now you can have a CAR-T as your second therapy if Revlimid stopped working for you. Not if you didn't tolerate Revlimid. If it gave you a rash and you stopped and then your myeloma got worse two years later, that doesn't count. But if the Revlimid stopped working for you, you can have the CAR-T.

In CAR-T, we don't want to give you any steroids because steroids kill T cells. So, I don't want to put any of those new juicy T cells that are going to go chomp on myeloma and then kill them with a bunch of steroids. We don't do that either.

You're starting to see more of those bispecific antibodies that link the immune cell to the cancer cell. Since we're trying to use a T cell to fight off cancer, we are going to use a little bit of steroid, like even lower than the 20 milligrams, somewhere around like 16 milligrams for the first couple doses just to prevent fevers and that kind of stuff.

But after that, we get rid of the steroids because we don't want to have steroids around that are killing our healthy T cells that we're trying to get to fight off cancer. So, steroids are starting to go away, which is really, really, really exciting for anybody who's taken them. They know how they're no fun.

[51:11] Moderator: Do CAR-T treatments target any other things besides BCMA? Do they target things like GPRC5D?

[51:21] Dr. Gregory: That's a great question.

BCMA is currently the target that we use in myeloma. If you get CAR-Ts for other diseases like acute leukemia, CLL, that kind of stuff, they use different targets.

So right now, the two FDA products that we have are ide-cel and cilta-cel are the two CAR-Ts. They both target BCMA. The FDA should be approving a third CAR-T for myeloma that's also targeting BCMA, and that one's called anitocabtagene autoleucel.

The PDUFA date, I think, is right before Christmas. I think it's December 23rd this year.So that one will be coming on the market.

In research, we are looking at other proteins. So, in research, there are a couple products that target another protein called GPRC5D. GPRC5D also is on our skin cells, skin cells, our hair follicles, our mouths, so like our tongue, the back of our throat.

Those CAR-Ts can go attack those areas too, so you can see some rash and kind of yucky nails. Hair can get kind of coarse and definitely have issues with dry mouth and taste. In the CAR-T studies that look at GPRC5D, that seems to be pretty limited, and then it goes away, which is nice.

The other thing that we're looking at in myeloma is making a CAR-T that just doesn't hit one thing on the myeloma cell, but it hits a second thing. So that CAR can go in and it can lock on to two separate things.

There's a product in study, and the studies are called the DURGA studies, D-U-R-G-A. And those hit both BCMA, but they hit something else called CD19. And there's a whole story there, but basically it hits those two.

It's thinking maybe there's a more immature myeloma cell can grab if it grabs the CD19. Those studies are looking really fantastic.

There are other studies that are looking at CARs that hit the GPRC5D and the BCMA, and so those are what we call dual CARs because they hit two things. So that's where we are right now with CAR-T-cell therapy and myeloma.

[53:33] Moderator: Can you tell us a little bit about the decision tree that is used to determine which bispecific drug you utilize in a plasma cell patient?

[53:43] Dr. Gregory: Oh, getting fancy.

We were just talking about how myeloma cells have different proteins on their surface. I'm going to try not to put the wrong finger up and down so I don't flip everybody off.

But ultimately, right now, if our patient wants to get a CAR-T, the only CAR-T we have is to BCMA on outside of a research study, so standard of care.

 Now, there are bispecifics that can hit BCMA. There's a bunch on the market.

There's linvoseltamab, elranatamab just came out, teclistamab. Oh gosh, I hope I'm not leaving somebody out. Those are our main three.

Then we have something called intentamig that should be coming soon. We have a bispecific that hits talcatamab. That's the GPRC5D.

Those are the two that we have out on the market.

Now, if I ever want to give somebody a bispecific to CD or to BCMA, I cannot give the bispecific first because it's going to take that protein away.

When the myeloma comes back after being on that treatment for so long, because it's a continuous treatment, the myeloma is going to come back without the BCMA and then there's nothing for the car to work against. So, I'll never give a patient the car or the bispecific treatment to BCMA before a car if they ever want to use a car.

Now, if you give a CAR-T and it targets this, the CARs are gone and out of the system within about six months, they're dead and gone. They do the most bang for their buck in the first month to melt that iceberg real low.

So, if the myeloma grows back after a CAR-T, it didn't keep getting hit by the car to knock this guy out.  When the myeloma comes back, it still has that protein. So now I can use my bispecific again. That's still an option.

But if I need to use a bispecific before CAR-T, I'm probably going to go for the GPRC5D and stay away from this or hit this one so that I have that available for my car. Hopefully that was not too confusing.

[55:52] Moderator: That was an awesome explanation.

Dr. Gregory, can you tell us about some new strategies to reduce infection in plasma cell patients, particularly with IVIG?

[56:06] Dr. Gregory: Sure. The first thing is that we know that patients do get a lot of infection within their first month of treatment.

There's a lot of studies saying that we should have patients on a general antibiotic for that first month to prevent bacterial infections.

There was a study specifically done with a drug called levofloxacin. That's not the right drug for everybody, but that was what the study used. So that's one idea.

The other thing is really watching those IgG levels. So, if your IgG level is normal is over 600; if you're under 600 and you're getting a lot of infections, like at least two or three infections per year, like colds, that kind of stuff, or colds that you just can't kick that lasts a long time, that's a person who should be getting IVIG.

If your IgG level is under 400, regardless of if you're getting infections or not, you should be getting IVIG. Because that's a protein, immune proteins live on average for four to six weeks.

It is an IV treatment, and it's something that is just given routinely as long as that level is low. There is data showing us that in patients who are on bispecific antibodies, they should be getting IVIG regardless of their IgG levels, that they do better and get less infections.

CAR-T-cell therapy will keep those IgG levels low for about a year in most patients. So, they can plan after a CAR-T that they'll need to be on that IVIG therapy. And most patients on the anti-CD38 antibodies need it as well.

Another big thing is getting vaccinated. It's hard to make good antibodies to vaccines when you have myeloma because all of our therapy was trying to kill your ability to make an antibody.

But what's more important with these vaccines is that they give a T cell response. And the healthier your T cells and the more happy ones you have, the better off you're going to be at not only fighting off infection, but fighting off myeloma.

It helps create a more active, robust immune system that's good at keeping your cancer at bay as well.

[58:05] Moderator: Wow, as always, this group has the best questions.

This presentation, Dr. Gregory, has been really incredible and informative.

On behalf of BMT InfoNet and our partners, I'd like to thank you for your presentation, and thank you, audience, for your excellent questions.

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