Experts Share Updates on Clinical Trials and Re-Testing

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Andrew Schorr:

Greetings from Orlando, Florida. Andrew Schorr here with…

Esther Schorr:

…Esther Schorr. I’m also in Orlando.

Andrew Schorr:

Yes, you are. And I get to be with her all the time—34 years now. Another one of our daily wrap-ups from the American Society of Hematology. I’m wearing my daily wrap-up sweater if you watched last year. It’s kind of comfy. It’s like Mr. Roger’s.

Dr. Pemmaraju:

Wow! Very nice.

Andrew Schorr:

Anyway, I want to tell you that across the way, there are like 25,000 hematologists, and blood cancer researchers, and blood researchers from all around the world at the Orlando Orange County Convention Center. If you’re from central Florida, you know that. And they talk about the latest studies and important issues that affect us patients. Okay. I’m living with two conditions: an MPN, myeloproliferative neoplasms the last seven or eight years and chronic lymphocytic leukemia 23 years. But we all wonder what’s next for us. And, Esther, care partner?

Esther Schorr:

Yes.

Andrew Schorr:

You’ve been with us. So, you’ve been over at the convention center.

Esther Schorr:

Yep. I have spent…

Andrew Schorr:

…what have you been doing?

Esther Schorr:

Yeah. I spent the entire day today getting this head filled with all of the exciting stuff that’s going on in a lot of different areas. So, I know we’re going to talk, in a little while, about two—two…

Andrew Schorr:

…two of our guests. We have a third guest coming.

Esther Schorr:

Yeah. In other areas. But I spent some time with some ALL experts. And…

Andrew Schorr:

…at Brown from Johns Hopkins?

Esther Schorr:

Exactly. And some time with James Berenson who talked a lot about progress in multiple myeloma.

Andrew Schorr:

And Waldenstrom’s.

Esther Schorr:

And Waldenstrom’s. And Michael Wang from MD Anderson and Joshua Brody from Mount Sinai who talked to me…

Andrew Schorr:

…he’s sort of a comedian, right? He had you in stitches.

Esther Schorr:

Oh my gosh. He had me in stitches. And very exciting stuff especially—in all those areas. But in mantle cell lymphoma there’s just a tremendous amount of—of good stuff going on that wasn’t there before.

Andrew Schorr:

So, we have two more days of this. So, we’re going to be covering a lot more in-depth chronic lymphocytic leukemia. We’re going to be talking about Hodgkin's and non-Hodgkin's lymphoma. Oh my God. So, much here. And generally, there’s a lot of progress, but today we’re going to have a little bit more of an orientation on multiple myeloma and on the MPNs, okay? And so, let’s show you who we have with us. So, first of all, to my immediate right is Naveen Pemmaraju. What’s your title from MD Anderson?

Dr. Pemmaraju:

Andrew, thanks for having me. Associate Professor of Leukemia.

Andrew Schorr:

Okay. And to his right is Rafael Fonseca from the Mayo Clinic in Scottsdale, right?

Dr. Fonseca:

That is correct.

Andrew Schorr:

Okay. Noted myeloma specialist. And I should tell you folks these guys are like the kings of Twitter. So, if you are—so many physicians now—not many…

Dr. Pemmaraju:

Right.

Andrew Schorr:

…but these are leaders in reaching out in digital media both to patients and to physicians around the world. Thank you for doing that.

Dr. Pemmaraju:

Thank you.

Dr. Fonseca:

Thank you.

Esther Schorr:

Well, that’s truly a stream for information. That’s another channel. These are experts in their area. So, if you’re not on Twitter, I think it’s a great thing to be on. They also retweet things that are from your associates. Correct?

Dr. Pemmaraju:

Right on. Right.

Andrew Schorr:

Sometimes we retweet things we’re doing.

Esther Schorr:

I can’t account for that.

Andrew Schorr:

So, Dr. Fonseca, let’s start with you for a minute.

Dr. Fonseca:

Sure.

Andrew Schorr:

Multiple myeloma—We had—earlier today, I did a live broadcast. Some of the myeloma patients saw it with Dan Vogl from Penn. and Frits van Rhee from Arkansas. And we talked about a lot of things, but it seems like you continue to have more options in myeloma. So, help us understand from the buzz here where we are now to get people hope, even starting with people who’ve had—with so-called smoldering myeloma.

Dr. Fonseca:

Right. Well, thank you for the opportunity first of all. It’s great to be here with you. And we can start from the beginning. Let’s start with smoldering. So, as you know, smoldering has been this provisional category we have. I say it’s an artificial taxonomy where we place patients who obviously seem to have a process that looks like myeloma, but don’t have the complications for the disease. And this year was particularly important, because a second randomized study tested the idea of early treatment for these patients. Historically, we—we said, “There’s no need for treatment.” We always said, “You don’t want to treat too early.”

But then the question came back in the other side of that argument that’s, “Are you treating too late?” So, we have been very closely looking at parameters that might allow us to start treatment early. Just recently, there’s—there’s a study published that—the ECOG study E3A06 that looked at lenalidomide (Revlimid) versus observations alone. And what we learned in that trial is that there would be justification for considering starting treatment in high-risk, smoldering multiple myeloma. Now this is not a widely accepted concept, but we saw a very significant difference in outcomes for patients. So, I think this is a conversation we’re going to have more and more with patients.

Andrew Schorr:

So, how do you know who’s high-risk?

Dr. Fonseca:

So, that is really the crux of the matter: “How do you define high-risk?” The most recent iteration of that stratification includes a model that’s called the 20/20/20 that looks at the number of plasma cells—the 20 percent or greater—the M spike—2 grams per deciliter greater, and—and the ratio of 20 as well too. So, with those three markers, you’re trying to make an approximation for patients who would have any one of those—two out of those three markers that would be considered high-risk smoldering. Now, there’s still some debate about this, and there’s some question whether you can monitor patients, and follow them closely, and decide if they need treatment later. But I think a study was just presented—the E3A06—would say that if you had a patient that clearly emits criteria and one is concerned about treatment initiation, now would be a reasonable consideration.

Andrew Schorr:

Okay. And you have more treatments than ever before?

Dr. Fonseca:

Correct.

Andrew Schorr:

So, and—and this goes all the way through to some of the sickest people. I mean, and there was a drug approval: selinexor (Xpovio).

Dr. Fonseca:

Sure.

Andrew Schorr:

So, and—and I think there are combination studies you’re looking at—whether drugs can be used earlier. So, where are we now with your sort of armamentarium?

Esther Schorr:

And I would like to hear too because what I heard today was it’s these combinations but it’s also combinations of older drugs that are already standard of care with a lot of new stuff...

Dr. Fonseca:

Absolutely.

Esther Schorr:

…that worked differently.

Dr. Fonseca:

Absolutely. So, one of the things we’ve learned is usually that teaming up makes sense when it comes down to multiple myeloma, because you approach it from a multi-pronged perspective trying to prevent resistance of those cells.

Esther Schorr:

Mmmm.

Dr. Fonseca:

I mean, two things are notable that are moving forward. One was the recent approval of selinexor, which has a punitive mechanism of action that would enhance the activity of tumor suppressors genes. So, it would somehow create vulnerabilities for those cells. And for instance, that is one that is being combined with other medications. Just to 80 percent of the study, a combination with pomalidomide (Pomalyst) and dexamethasone (Decadrom). All patients have prior lenalidomide exposure. Not all of them have prior pomalidomide. And all—then the lenalidomide patients were—were resistant to lenalidomide. Ans they were able to show response in this patient population. Now, the trick with selinexor has been that as it was approved—proved to be quite challenging with regard to the side effects.

Andrew Schorr:

Side effects.

Dr. Pemmaraju:

Right.

Dr. Fonseca:

But the dosing modifications and the schedule modifications very specifically going to once per week is what’s being explored with these new clinical trials. And I think that—that the signal is interesting. So, we have to see if we can find the right dose and the right combination, but that might provide an option for patients who—who may not have additional therapeutic options.

Dr. Pemmaraju:

Yeah.

Andrew Schorr:

I want to ask about one other drug. So, I have CLL, and our CLL folks know that one of the drugs that has come on strong there is venetoclax (Venclexta).

Dr. Fonseca:

Sure.

Andrew Schorr:

There was thinking early on that that would have a place in myeloma as well. And then it sort of took a pause, but I understand—what you’re hearing here—is it’s back.

Dr. Fonseca:

Absolutely. I—I think what we just have to be very clear—from what we know, venetoclax will be a great tool. At first glance, we can tell that’s for the patients who have the t(11;14) translocation—the chromosome translocation between chromosomes 11 and 14, which is 15 percent of myeloma patients. Perhaps there may be a second group looking at genes such as Bcl-2 and their expression level. But for starters, the data for the t(11;14) is very, very powerful with very deep responses.

In this particular meeting, they’re presenting an update of what’s called the BELLINI trials. So, that’s the venetoclax combined with bortezomib (Velcade)—one of the drugs we've had for a while—with really—a very, very good results. I’ll give you an example that has a ratio for the experimental arm—that—that is the one with venetoclax versus a control—came out that .095.

Andrew Schorr:

That's good.

Dr. Fonseca:

I mean, when see clinical trials where we see a 30 percent drop—that would be .7—people are ecstatic. We see .3, it’s great. In this case, it he was .095 for those patients the with t(11;14). So, I think we—we’re going to see this move forward pretty quickly particularly for patients who have t(11;14).

Andrew Schorr:

So, the name of the game for myeloma now is getting the treatment that’s right for your situation, right?

Dr. Fonseca:

Correct.

Andrew Schorr:

Okay. So, this is going to bridge with Dr. Pemmaraju—is—let’s just talk about testing to know what version of myeloma you have or at that point in your journey. We've heard about genomic testing and MRD testing and whatever—just apply that to myeloma today.

Dr. Fonseca:

Well, we’ve known for sometimes there's different versions of myeloma—different flavors, if you may if one thinks about this—mostly described by the specific genetic changes that those cells have. And for patients that are listening to us, when I talk about genetic changes, I'm talking about changes exclusively in those cells, not changes that you have in the rest of your body.

Andrew Schorr:

Not your eye color or whether you have hair.

Dr. Fonseca:

And not—or things you’re going to pass on from generation to generation. Right. Very restrictive to the cancer cells. And I think we've talked about risk just thinking about outcomes, but we really need to talk about biology. So, venetoclax is the first agent that targets one specific—one of those markers We do that classification through mechanisms such as FISH. It can be done through gene expression profiling, which is quite powerful at discerning outcomes for patients. But most recently, we’re moving towards the sequencing-based methods, which can give you most of the information with fish plus the mutation analysis

Andrew Schorr:

Next generation sequencing.

Dr. Fonseca:

Next generation sequencing. Correct

Andrew Schorr:

Okay. And one last thing is minimal residual disease or measurable disease—that has a role in myeloma now too—kind of know where you are, right?

Dr. Fonseca:

Sure. I think one of the themes of this meeting is that you want to get those patients who are in the—starting treatment—if at all possible little possible to the lowest burden of their disease. And in our mind, this is not measured by the test that would call minimal residual disease. It can be tested by fluid. It can be tested by generation sequencing. But what we're seeing for those patients that achieve that very deep response, the long-term outcomes are—are better. As we see patients who go through some of those modern therapeutics, we see that an increasing number of patients are becoming MRD-negative.

So, we're using this to establish prognosis. We're thinking about using this in the future to decide about stopping maintenance treatment in patients who remain MRD negative—what we call we called sustain MRD negativity for a while. And then I think we're reaching the point where—even allow us to do monitoring because we can quantify the number of cells at levels that we could never detect protein analysis.

Andrew Schorr:

Sounds good.

Esther Schorr:

Yeah, it does. But I have a question then.

Dr. Fonseca:

Sure.

Esther Schorr:

We have these—you have all these different combinations that could be used. Somebody's treated. They've been tested so you know which combination to use. Do they need to be retested if they need to be treated again if they need to be treated again? I know I've been asked that question.

Dr. Fonseca:

Sure. That is—that is an excellent question. So, there are some core features of a myeloma cell that will never go away. So, if you're a myeloma patient and you're t(11;14), every single cell of that person’s myeloma now and, in the future, will always be t(11;14).

Esther Schorr:

Okay.

Dr. Fonseca:

So, those are the drivers or key genetic factors. We have that pretty well established. What we test for now are for secondary things such as mutations—mutations of P53, abnormalities of MYC, abnormalities of other genes like chromosome 1, abnormalities that are more prevalent with progression. So—so, the testing is different from when we baseline versus when you do it down the line. But that may hold important information as we continue to select treatments.

Andrew Schorr:

You’re looking for other passengers that are affecting the...

Dr. Fonseca:

That is correct.

Esther Schorr:

…affecting the ride.

Dr. Fonseca:

I could say—we’ve—we've built the story of this subclone analysis for multiple myeloma, which is a beautiful story that tells you that there are all these difference subclones. But they' hold some core identity that is unique to older myeloma cells. So, I sometimes say that this is like those games that they show you two pictures and you can find the differences. They're almost identical even though there are subtle differences and they might allow you to differentiate outcomes, but the core elements of that genetics will remain the same.

Andrew Schorr:

Okay. Let's change horses a little bit in that—now let's talk about MPNs, I have myelofibrosis. People, just to remind you, there are others—essential thrombocythemia, polycythemia vera, myelofibrosis. Some people progress from one to another. I started “boom” right with myelofibrosis 7 years ago. My genomic test showed that mine was driven by JAK2V617F, and there was one JAK inhibitor to inhibit that. And it’s done well. And I'm going scuba diving with Esther believe it or not after this.

Esther Schorr:

I’m a glutton for punishment.

Andrew Schorr:

So, I have energy. Okay. So, Dr. Pemmaraju, one was approved not long ago, right?

Dr. Pemmaraju:

Yeah. Thank you, Andrew. So, ruxolitinib (Jakafi)—the JAK1 and JAK2 inhibitor that we've known really has been around for quite a while now. FDA approved 2011 into 2012 clinical trials before that. But now we have a second JAK inhibitor that's on the market FDA approved as of August of this year 2019. And that's called fedratinib (Inrebic). This is a new drug for a lot of our colleagues and folks out there. So, I want to give you a little bit of information on that. This also hits this JAK pathway—importantly not the mutation. So, that's important to say these are JAK inhibitors. So, that's why these drugs can and do work in patients who have the other mutations: CALR or MPL. So, I think that’s one important point. As the second in class JAK inhibitor, it also has a broad label approval. And so, it theoretically can be given in the frontline setting or after the ruxolitinib has stopped working. There were two clinical trials we're done that back up both of those points. The first one was called the JAKARTA study—frontline patients—they have not yet received ruxo—any therapy. There were three arms in this study. Interestingly, 500 milligrams—400 milligrams daily. And then a placebo, because this was done right around the time of the COMFORT trials for ruxolitinib.

That met its primary endpoint. The spleen size reduction—that’s in the frontline setting. There was a second trial called the JAKARTA 2, which was in ruxolitinib—after ruxolitinib failure patients. That's an important study. That was close 100 patients. That also met its primary endpoint. There was some reanalysis done by our friends Dr. Claire Harrison, Dr. Rubin Mesa that showed that that's the case. The only problem with this drug development was that there was some closing suspension for quite a while because there was a fear and worry of something called Wernicke’s encephalopathy.

Andrew Schorr:

Changed drug companies were behind it.

Dr. Pemmaraju:

It changed hands. And our good friend, Dr. Catriona Jamieson, was instrumental in helping the resurrection of that. And here's what happened. Out of hundreds of patients—800 patients across all the trials of the fedratinib—there were approximately eight cases that were at least felt to be, at the time, Wernicke’s encephalopathy. That’s important. The drug was suspended. Upon reanalysis by Dr. Jamieson, Dr. Mesa, Dr. Harrison, and others, it looks like not all of those cases actually held up for Wernicke’s, which turns out to be a pretty complicated diagnosis. However, they did represent some form of encephalopathy.

So, the new drug on the block—fedratinib– has some sort of encephalopathy that we have to watch for. That's called a black box warning. It's there. And so, the guidance is check thiamine levels at baseline, replace them if needed. If this Wernicke’s develops, we need to hold the drug and give IV thymine. But the second signal is that there is some GI toxicity gastrointestinal. So, nausea, vomiting, diarrhea. So, I think we need to be on the watch for that. This represents the second drug that's FDA-approved. The story doesn’t end there. There's actually a few other JAK inhibitors that are exciting and development.

And I can tell you that they are now into the Phase III testing, which most of our viewers know now that that's the later stages. One is called pacritinib, which you both have followed that development for a long time. That's entering into the phase called the PACIFICA trial. And that's really targeting patients who have platelets below 50, which has been an urgent unmet medical need for us.

Andrew Schorr:

Which is low.

Dr. Pemmaraju:

Right.

Esther Schorr:

That is low.

Dr. Pemmaraju:

Which—which is so low that the ruxolitinib and the fedratinib—the two approved drugs—don't—you're not supposed to go past that. So, that's a—that’s a Holy Grail marker. The second one is momelotinib. And by the way, a lot of these JAK inhibiters have had a start and stop as you both have chronicled. This drug is also now back into a Phase III trial. That's called the MOMENTUM Study, and that one will be against danazol.

So, what's old is new again as Dr. Fonseca knows from myeloma. And that one will strategically try to go for the anemia of myelofibrosis. So, it's a new era. JAK inhibitors that can be given in the setting of thrombocytopenia low platelets or anemia—low hemoglobin. These were the problems with the prior JAK inhibitors. It's an exciting time.

Andrew Schorr:

Go ahead please. I’m excited.

Esther Schorr:

So, I have a question then. If patient care partners are hearing this now—which they are—and there's this whole range of potential things. What questions does a patient need to ask when they're at a point where they need treatment and they're all these choices? What should they be thinking about?

Dr. Pemmaraju:

Absolutely. This is the important question as we head 2020.

Esther Schorr:

That’s so confusing.

Dr. Pemmaraju:

Because we didn't have this question.

Esther Schorr:

Right.

Dr. Pemmaraju:

You guys know better than most that we didn't have this dilemma five years ago.

Esther Schorr:

Right.

Dr. Pemmaraju:

It's a good dilemma to have I'll start off with. I guess I have two points to say. One is that as you guys have always said at Patient Power, knowledge is power, right? So, that this concept of having knowledge—I think some doctors are worried about patients reading. They—they call it in a derogatory term Dr. Google, but what Dr. Fonseca, myself and our colleagues think is actually we encourage it. I want you to read up on social media online. Just discuss it with us. So, whatever you're reading, don't just sit there and internalize it yourself and worry about it. Bring it up in the clinic visit.

So, be informed if you can—if you're able to—you and your caregiver. The second concept is that some of these things are on clinical trials, and they’re publicly available on something that you guys have helped to publicize, which is ClinicalTrials.gov—freely available in the comfort of your own space—patients, community, providers, anybody can look up these clinical trials. And it tells you who’s the contact person, where the site’s available, how close are they to you. So, I think those are two things that can help our patients.

Esther Schorr:

That’s great. Okay. Thank you.

Andrew Schorr:

Okay. This is a busy, busy time for these experts who are with us. We're going to let Dr. Fonseca go, because he has data that he has to present. We’re going to bring in another one of our favorite guests—another really very famous myeloma specialist Dr. Raje. So, stay with us. You’re going to stay?

Dr. Pemmaraju:

My pleasure, Andrew.

Andrew Schorr:

Dr. Fonseca, thank you so much.

Dr. Fonseca:

Thank you very much. Again, thank you for the work you do.

Andrew Schorr:

We’re going to take a quick break. We’ll be right back. We have a new superstar with us, and that is our dear friend Dr. Noopur Raje—from Mass. General—myeloma specialist. Thank you for scooting over here.

Dr. Raje:

Thank you for having me.

Andrew Schorr:

So, earlier Dr. Fonseca was with us, and we spoke about the whole range of new medicines and—and ways of thinking from smoldering myeloma to high-risk advanced. We talked about selinexor as a new option, combined managing side effects, new combinations. But now, we get in this world of immuno-oncology. So, help us understand that for a little bit, because I think it's pretty instructive. We've heard across a number of conditions—CAR T-cell therapy. I'll get to that next. But first I want to ask you, what are BiTEs?

Esther Schorr:

Yeah.

Dr. Raje:

No, I think with every ASH, I keep telling you this. Every year is an exciting year. This year specifically, we’re seeing finally the effects of immuno-oncology really playing a very significant role not just in myeloma, but hematologic malignancies in general.

Dr. Pemmaraju:

Yeah.

Dr. Raje:

And that makes it a very, very exciting time. So, immuno-oncology covers a lot. It covers—starts out with antibody-based treatment. We’ve always had antibodies. And multiple myeloma started off with elotuzumab (Empliciti) and daratumamab (Darzalex).

Andrew Schorr:

Targeted therapy.

Dr. Raje:

Targeted but also engage the immune system in different ways. Antigen-dependent cytotoxicity engaged the T cells. And that's how most of these monoclonal antibodies work. We’ll get into BiTEs, but what was interesting to me today was actually listening to another new CD38 monoclonal antibody. And when I first started listening to the presentation, I said, “I don't think we have the stomach for one more daratumamab.” But really the drug which was presented today was TAC-O79. And this is a new CD38 monoclonal antibody. And amazingly, we're seeing great response rates with very good tolerability in patients who have already been exposed to a prior CD38.

So, they had patients who had had daratumamab still responding to this TAC antibody. So, I think the monoclonal antibody space is still not saturated. We still have a little bit of work to do. Now focusing more on your question of the other immuno-oncology approaches, which is—we do have conjugates—conjugated antibodies. And the one which is furthermost in its development and hopefully will get approved is the GSK conjugated antibody. And although we don't have a lot of that data presented at this year's ASH meeting, we've seen that over the years. This year’s ASH meaning, like you said, the excitement is around BiTEs. And BiTEs essentially stands—it’s Bi-Specific T-cell Engagers. And what they do is essentially what CAR T-cell are made to do outside of the human body, where we actually genetically modify them, and get them activated, and then go put them back into patients so that they get expanded with Bi-Specific T-cell Engagers, you have a monoclonal antibody which recognizes the target with one arm. And then the other arm activates your T cells in vivo. So that's why they have this dual…

Andrew Schorr:

…so, let me see if I get this right. So, CAR T-cell…

Esther Schorr:

…so, it’s cooking it inside rather than cooking it outside.

Andrew Schorr:

So, rather than cooking takeout, if you will.

Esther Schorr:

Yeah.

Dr. Pemmaraju:

Right.

Andrew Schorr:

It’s the restaurant or whatever you want to say—sorry, I don’t want to say it that way. The manufacturing, if you will, is pulling power from your immune system, and doing it within your body.

Dr. Pemmaraju:

Right.

Dr. Raje:

That’s exactly…

Esther Schorr:

…you don’t have to create that effect…

Dr. Raje:

…that’s…

Esther Schorr:

…outside.

Dr. Raje:

That’s exactly…

Esther Schorr:

…it happens inside.

Dr. Raje:

Inside the body. That’s exactly right. And the other benefit of that—because of this, this is an off-the-self technology, which you can use as opposed to getting cells from a patient, then generating those CARs, which typically takes—depending on whichever CAR you look at—right now, it's about three to four weeks that we have for manufacturing time before we can put those cells back into people.

Esther Schorr:

Is still too early to tell whether there’ll be less toxicity—less side effects?

Dr. Raje:

So, you saw data presented this morning from—Bi-Specific T-cell Engagers. I'm not using the word BiTE because Amgen has sort of—BiTE is an Amgen sort of—of…

Andrew Schorr:

…trademark.

Dr. Raje:

Trademark. So, we call them Bi-Specific T-cell Engagers. And in this case, the Celgene BiTE Bi-Specific T-cell Engager was presented this morning. And the reason I bring up the issue of toxicity is they do essentially work—CARs do. So, they go in target—we’re still using the same target, which is BCMA and myeloma. B-cell maturation antigen. And we know that BCMA is generally expressed on all plasma cells. And in fact, on all mature B cells. And the T-cell engager compartment—component of this antibody, activates your T-cells in vivo—in a patient’s body. And with the cell gene, BiTE, we did see pretty much the same toxicity that you can see with CARs, maybe a little bit less.

But you still see cytokine release syndrome. No neurotoxicity was seen, but CRS was definitely seen. But along with that, we are seeing very deep responses very similar to what we see with CARs. It’s almost analogous to what you see with blinatumomab (Blincyto)…

Dr. Pemmaraju:

…exactly.

Dr. Raje:

…with the lymphomas. It's a very similar kind of a story with myeloma now.

Andrew Schorr:

Okay. So, let me see if I ger this right and help everybody understand. These are new discussions—okay—for we patients are hearing about. And that is we've talked for a little bit about CARs: chimeric antigen receptor T-cell therapy, and taking your cells and making a drug in a lab, and then—maybe in two or three weeks, giving it back to you to target your sickness and activate your immune system, right? And now, you’re saying can we do it within the body. Okay. But these are super powerful therapies. And so, there's no free lunch. There are side effects. So, you have to learn that. So, where are we, not just in doing it, but making it easier on patients?

Dr. Raje:

This is certainly—so, this is still a work in progress, and we're really very early in the development of all of these. I think the good news here is we are seeing remarkable efficacy in patients who were given these drugs too. What we are doing early on with some of the Bi-Specific T-cell Engagers, is initially, we do hospitalize people for about 3 days. It's 72 hours of hospitalization, because typically the CRS and the toxicities are seen with that first infusion.

Andrew Schorr:

Cytokine release syndrome.

Dr. Raje:

Release syndrome. CRS is cytokine release syndrome. It’s a little more muted compared to what you see with CARs. We haven't had to use a lot of drugs like tocilizumab, which is an aisle six receptor antibody, which we typically use in CAR T-cells when they end up with these toxicities. I think what CAR T-Cells have allowed us to do is learn about some of these toxicities, and we’ve become pretty good at managing them. So, at least in the myeloma world, the first thing I think we've learned is how do you manage them? And it's fairly well tolerated in the majority of patients.

So, that I don't hesitate giving CARs two people who are a lot older as well, which is something that people don't appreciate enough. We have people in their 70s actually tolerate CAR-T cells quite well. Similarly, we can do that with things like these Bi-Specific T-cell Engagers as well. And that may just be a matter of us having learned how to manage toxicity better. Again, I do want to underscore the fact that it is not a free lunch. It comes with toxicity. But after your first infusion, most of these treatments happen outpatient.

Andrew Schorr:

All right.

Dr. Pemmaraju:

Wow.

Esther Schorr:

But these are both being used at this point when somebody is further down the line in other treatments have not worked. Is that correct?

Dr. Raje:

That’s exactly correct.

Esther Schorr:

So, it’s not first-line treatment.

Dr. Pemmaraju:

Right.

Andrew Schorr:

So, where is transplant? And transplant has been a staple for so many people. If you have myeloma, you know a lot of people correspond with others—maybe yourself. You’ve had transplants. Some people have had double transplants.

Esther Schorr:

Yep.

Andrew Schorr:

So, where is that?

Dr. Raje:

So, one transplant is still considered a standard of care treatment for the treatment of multiple myeloma even today. We are looking to bring these technologies early, because honestly in my mind, using an immune-based approach earlier is going to be even more effective as opposed to using it very late in the disease state where your immune system is actually quite beat up. So, bringing these technologies earlier would be the thing to do. We do have clinical trials, at least in the CAR T-cell space where we—in the high-risk patient population, we are using CAR-T cells instead of transplant early on.

We’re also doing studies. If you failed an autologous transplant within the first year of getting the transplant, that biologically high-risk patient. We would consider something like CAR-T cells. So, they've already moved early on and I can see the same thing happen with the Bi-Specific T-cell Engagers as well.

Andrew Schorr:

Well, I was telling Naveen, you’re a hematologist and I knew your area is MPNs in particular and those conditions, but when you listen to what myeloma docs are saying…

Dr. Pemmaraju:

…mmmm. You read my mind, Andrew.

Andrew Schorr:

What are—what are you thinking?

Dr. Pemmaraju:

You read my mind. So, I wear the two hats. On the MPN side, we're not there yet. We're not there yet for a number of reasons. What are colleagues in multiple myeloma and in lymphoma, right? Where—where the approved CAR-T cells first came in—the relapsed/refractory lymphoma—this is amazing translational science. From the time of the lab studies to the first patients—pediatric patients, older patients—all the stories you've heard to now we're hearing about this into multiple myeloma. The couple of caveats for us is—in general for our MPN patients—they’re usually on the spectrum of what's considered a chronic disease rather than—at least what multiple myeloma starts out as because of her work and others—they’ve turned it into a more of a chronic disease. So, the acceptability of toxicities, risks is not really there yet right now with the current technology that we have. A second thing is what's the target? Multiple myeloma, lymphoma—they have defined and identified—brilliantly, in my opinion—nice targets, which meets certain criteria. Should not be too much expressed on the normal cells, should be accessible to the new technology, and then can be followed or tracked over time.

Andrew Schorr:

You don't have those hooks.

Esther Schorr:

So, not so much. Yeah.

Andrew Schorr:

You don't have those beacons.

Dr. Pemmaraju:

We don’t have those beacons. Now you both follow the literature very closely. The leads are in the early stages for the MPNs. The big breakthrough—at least that was mentioned—this might be of interest—is the CALR. So, CALR was the new kid on the block. 2013, ASH—this meeting—late-breaker abstract—New England Journal that day—that was only less than six years ago really to the moment. And that showed that that was the second most common mutation among patients with MPNs—myelofibrosis and ET in particular, So, that’s fine. Maybe there's a prognostic element which tells us and our patients how you might do overtime.

But Dr. Annamalai and colleagues in Europe have shown that maybe—possibly there's an antigenic element to CALR. So, this might be new to a lot of people. And this research is applicable to acute leukemias as well as their MPNs. So, maybe you have to start way—way further away from here. So, I think toxicities, finding the target, and then the acceptability of the risks—that has to be weighed out in an acute versus chronic disease.

Andrew Schorr:

All right. So, we asked Dr. Raje about transplant. So, there—I know some people who progressed with MPNs who’ve had transplants.

Dr. Pemmaraju:

Yes.

Andrew Schorr:

And I have a friend—you know her: Sandra—and she was speaking, “I see the transplant as a nuclear option.” She's really afraid of it and I wouldn't look forward to myself. Does that still have a role for people where these JAK inhibitors and things are no longer working?

Dr. Pemmaraju:

It does. My colleague at MD Anderson would—would not be pleased unless I said this which is “In 2019 and 2020 stem cell transplant—allogeneic stem transplant remains, the only curative option for patients with myelofibrosis.” There. I said it. That means that by definition, all of our JAK inhibitors, all of the novel agents, the clinical trials—we have not yet found a curative therapy. Contrast that would say AML, acute myeloid leukemia, where I do have the ability to cure my patients with cytotoxic chemotherapy or other agents. I'm going to repeat, because it’s very important. Stem cell transplant from another person—allogeneic—appears to be the only curative therapy.

So, it does have a role, but patient selection is everything. The European and the American data sets agree on a few things. It should be someone who has the so-called intermediate to high-risk myelofibrosis. They've either responded to the JAK inhibitor but have such a high-risk disease, that they will likely relapse. They—they can be considered. Or as Andrew nicely mentioned, the patients who are not responding to upfront therapy get a second-line therapy, and then now can be considered. Age has to be a factor.

Fine, but it's more the performance status. And then the donor type matters. It used to be restricted to those donors who were a full match, either a related sibling, for example, or an unrelated donor. Now, our colleges have pioneered the haploidentical stem cel transplant that's gaining data in the MPNs and acute leukemias. So, the thinking and teaching here is all of the excitement with JAK inhibitors and novel agents, the stem cell transplant the only curative action for a fraction of our patients.

Esther Schorr:

But it's the kind of thing you don't go into lightly, because you have to be the right profile.

Dr. Pemmaraju:

Yeah, you called it a nuclear option. As side effects, risks—it, unfortunately, has a rate of mortality. That means a death rate in the first 30 days; in the first 60 days; first 100 days. And so, as you both astutely noted, this is not something that can be offered easily or quickly. It has to be a discussion. And really, to be honest, the patient has to qualify for it by organ system and function. So, I think that's important.

Andrew Schorr:

Right. You mention organ system. Earlier, we did those several earlier live programs today. And one of the patients wrote in. He asked about “Well, if I have poor kidney function”…

Dr. Pemmaraju:

Yes. Good point.

Andrew Schorr:

…“can I have a transplant?” And it was a peer of yours, Catriona Jamieson, saying “Well, probably not because it's not like we just want to have the transport be successful. You're going to be on a lot of medicines after the transplant. And your body needs to be able to clear this. If you have poor kidney function, you'll have great difficulty.”

Dr. Pemmaraju:

I want to comment on that. You're exactly right. Kidney function as one factor here—I often counsel my patients when we're thinking about going for allogeneic transplant, it is an effect like getting another full body tune-up. And in some senses, it’s a bit more rigorous then when a patient starts on either oral or IV chemotherapy. For example, it's very common before stem cell transplant to get a dental consult. That may not be a part of our normal armamentarium on the oncology side.

So, a kidney function that's insufficient or abnormal or not quite normal, sure. It could prevent it because, like you said, the medicines. Graft versus host disease, the preventative medicines, the treatment—if it is deemed by the team that you can't tolerate it beforehand, then you won't even go in the first place. And that does knock out quite a few of our patients from contention.

Andrew Schorr:

Right. Let's go back to you Noopur. Are these new areas even talking about immunotherapy, other conditions people might have—comorbidities. Does that limit them getting their immune system to fight the cancer?

Dr. Raje:

Always. I think it's really important to see what's going on with the patient, and really design treatment personalized to the patient. Having said that, I think these immune strategies are probably the most sort of patient specific, patient directed therapies. And in general, some of the things—and this is something which I do like to kind of educate people on. What we use as transplant eligibility criteria are not the same for some of these other therapies at least in myeloma. So, we don't do the kind of transplant that we were just talking about, which is an allogeneic transplant.

Dr. Pemmaraju:

Right.

Dr. Raje:

That is rarely done in myeloma.

Andrew Schorr:

You do an oncologist.

Dr. Pemmaraju:

Right.

Dr. Raje:

We do and autologous transplant. And generally, the timing of doing an autologous transplant is it's almost a consolidated approach. And patients are extremely well at the time they go into an autologous transplant. And then we get them into a hospital and get them quite sick from the transplant, and then make them better after. Whereas some of the treatments that we're talking about in the immune oncologist space are done at a time when a patient requires therapy. So, they are relapsed. They are refractory from their disease in itself. And they do have a lot of disease burden on board. And they are not as well as they would be at the time of transplant.

Having said that, because we’ve gotten a little bit comfortable with the experience, we have with the CAR-T cells, with these now Bi-Specific T-cell Engagers, we will offer it to patients who are older. You do have to have relatively normal renal functions. Because some of the drugs we use—especially with CAR-T cells—we do use drugs like cyclophosphamide (Cytoxan) and fludarabine (Fludara)—wherein you have to have a certain level of renal function to be able to tolerate those drugs and then go in with these technologies. So, it’s a little bit different, but managing comorbidities is critically important. We have to have good organ function to be able to tolerate all of these treatments.

Andrew Schorr:

So, we’re hearing all these reasons why our patients should have a consultation with a specialist like that.

Esther Schorr:

Absolutely. But I have—that’s true—I have one other question. You’re both talking about immunotherapy. And that all seems like the success of these current ones…

Andrew Schorr:

…because a transplant is immunotherapy.

Dr. Pemmaraju:

Right.

Esther Schorr:

Right. All—it all depends on your immune system being able to be engaged or…

Andrew Schorr:

…or rebooted.

Esther Schorr:

Or rebooted. So, are there any things that patients should talk to their doctors about in terms of boosting their immune system before they go into this kind of treatment? I mean, I know some of the diseases impact how your immune system works, and it might not be working right. But is there anything that can be done to boost it?

Dr. Raje:

So, that’s a really good question.

Dr. Pemmaraju:

Yeah.

Dr. Raje:

And I don’t think we know the answer to that.

Dr. Pemmaraju:

Right.

Dr. Raje:

But I will say, at least in the disease that I treat, when you have symptomatic active myeloma, your immune system is already compromised.

Esther Schorr:

Right.

Dr. Raje:

So, what we do believe right now is if you can get immuno-oncology coming in earlier, it’s going to be even more effective than what you’re seeing. So, at this very late stage—at the very late stages, we’re seeing close to 100 percent of our patients respond to this. What we are not seeing is sustained response. Right. We are seeing people still relapse after getting the CAR-T cells—after getting the BiTEs. And that’s why I think if we can move these earlier on in the disease paradigm, we’re probably going to get a more robust response. In terms of how you can boost your immune system, I don’t think we know. We usually use sort of more prophylactic strategies. So, make sure you’re up on your vaccinations. At least in the myeloma world, we do use drugs like immunoglobulin to help boost up peoples’ immune systems.

Esther Schorr:

Right.

Dr. Raje:

So, if you are at risk for infections, things like that, but nothing else that I know of.

Andrew Schorr:

I get immunoglobulin or IVIG.

Esther Schorr:

IVIG.

Andrew Schorr:

Esther sits with me for three hours. They do it monthly for the CLL because my IG’s are not great. Anything you’d say about people—your patients. But let’s say, what can I do…

Dr. Pemmaraju:

Yeah. I was thinking about that.

Andrew Schorr:

…to help me be stronger? What do you tell me? Is there a diet? Or what can you…

Dr. Pemmaraju:

…there’s—there’s only two things I can bring to this discussion on the myelofibrosis side and the MPN. One is the diet. So, before a year or two ago, I would have not been able to bring it up. But both of you know are my good friends and colleagues—Dr. Angela Fleischman at UC Irvine.

Andrew Schorr:

She’s studying it.

Esther Schorr:

Yeah.

Dr. Pemmaraju:

Yeah. Dr. Robyn Scherber in San Antonio. They’re studying this actively. Some of the data that’s coming out of the lab and the surveys that they’re doing. And now going into the patients, is there are some leads. What I’m going to present to you—as always—is cutting edge. So, the work has to be done. But not to our surprise, they’re finding that diets that are so-called low inflammatory diets. Some people know them as Mediterranean diets or—or these types of diets. So, not the traditional Western diets. They found in the lab and now starting in people that this may correlate with decreased inflammation.

Well, if we think of these diseases—heart disease, MPN—as disorders of inflammation, this is a whole new field. And to both of your interest and our viewers, there is a study being presented at ASH this year that I’m eager to see the data, which is the fibro met study, which is patients with myelofibrosis, and they're given metformin (Glucophage) for this exact thing that you’re asking. Not necessarily from glycemic control. None of these patients have diabetes.

Andrew Schorr:

Metformin is for diabetes.

Dr. Pemmaraju:

That’s right. It’s also an anti-inflammatory drug too. And so, there have been other tests for metformin in breast cancer and in other cancers. And they’re going to show the data—the preliminary data on 11 patients that they’re seeing exactly this: decrease in some of the key MF pathways through inflammation. Not just through that. And then there was a recent blood paper on controlling glycemic levels that may have to do with this. Two, quickly, this concept of can you have chemotherapeutic intervention that may boost up the immune system. Not a surprise to either of you, but there is data now on JAK inhibitors—just ruxolitinib—prior to the stem cell transplant improving outcomes. But they’re tied to the things that we already know—decreasing the spleen size, people feeling better going in. Some of these symptoms. However, there is data now. So, European data sets and ours that decreasing the spleen and JAK inhibitor is not only safe, but maybe improves the outcome. So, those are two of the things.

Andrew Schorr:

Wow.

Esther Schorr:

Those are great answers. Thank you.

Andrew Schorr:

So, we’ve gone quite a while. Thank you for being here. And I think as hematologists who are on the leading edge. These are exciting meeting for you guys, right?

Esther Schorr:

Definitely not boring

Dr. Raje:

Every year. Absolutely.

Dr. Pemmaraju:

Yes. Yes.

Dr. Raje:

Absolutely. And you keep saying, “Maybe next year’s ASH is going to be slow.” It doesn’t turn out that way.

Andrew Schorr:

Okay. All right. Thank you for being here with us. And remember to look for these other events. And what do we always say, Esther?

Esther Schorr:

Knowledge can be the best medicine of all.

Andrew Schorr:

Thanks for watching.

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