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Published on December 11, 2020
Myeloma Expert Shares New Research and Hope for a Cure
Are we close to a cure for multiple myeloma? What is the latest news in myeloma research? Multiple myeloma expert and member of Mount Sinai's myeloma division, Dr. Josh Richter, MD, joined Patient Power co-founder Esther Schorr for an informative live Q&A for patients with multiple myeloma. The discussion included encouraging news for patients from the world’s most comprehensive hematology event of the year, the 62nd American Society of Hematology Annual Meeting (ASH 2020). Dr. Richter shared updates on immunotherapy for multiple myeloma, addressed concerns about taking a COVID-19 vaccine, answered your questions about stem cell transplants and spoke about hope for a multiple myeloma cure.
This program is sponsored by GlaxoSmithKline. This organization has no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.
Transcript | Multiple Myeloma Answers Now: Is a Myeloma Cure on the Horizon?
Esther Schorr: Hi there. This is Esther Schorr with Patient Power and I'd like to welcome all of you to ASH 2020 and our myeloma Answers Now program. ASH is a little bit different this year, as it's completely virtual. Under normal circumstances, there are hematologists and researchers coming from all over the world together, many thousands of them in one place to talk about their research and new findings and this year it's all virtual. And so the goal of our live event today is to ask one of our esteemed multiple myeloma specialists to ask as many of the questions as you've already posed to us, either in email or will during this program and try to get some expert advice.
Just so you know, this program is sponsored by GlaxoSmithKline and we really appreciate their support, but as with all Patient Power programs, our sponsor has no editorial control over the content. Now I would like to get started by welcoming our wonderful expert, Dr. Joshua Richter. And Dr. Richter, are you there?
Dr. Richter: Absolutely. Hi out there in virtual land.
Esther Schorr: There you are. Dr. Richter, we debated about how to introduce you and I've decided that the way we need to introduce you is two ways. One way is the Lord of Plasma Cell, which was your suggestion. And the more formal way is as an Assistant Professor of Medicine at the Tisch Cancer Institute at Mount Sinai School of Medicine. We're so grateful to have you here today with us, albeit virtually. Dr. Richter has extensive clinical trial experience and has been published in esteemed publications, such as the New England Journal of Medicine, Blood, and the Journal of Clinical Oncology. I'm not sure how many more things we can put after your name, Dr. Richter, but we're really pleased to have you here today.
I just do want to let those of you who are live and watching our program know that if you have questions during the program, that you might want us to try to ask Dr. Richter, take a look at the Q and A button at the bottom of your screen and go ahead and put your question in there and our producer will do the best to share them with me and as we have time, we'll try to get to as many questions as possible. Let's get to the first question. Tell us Dr. Richter, what is the big headline at ASH this year for multiple myeloma patients?
What Are the Key Takeaways for Multiple Myeloma at ASH 2020?
Dr. Richter: The fact is, and this is actually the best thing. There's not one, there's many. And I think that is actually the most encouraging thing that I could say about this is that in years past, I can remember showing up at these meetings and exactly, as you said, what's the one thing? Is it this new drug? What is it? There are so many things in myeloma this year that I can't pick just one. There are updates on the CAR Ts, which we're all so excited about that are going to be approved probably within the next two to three months.
There are the new cell mods, so the next generations of drugs beyond Revlimid (lenalidomide) and pomalidomide (Pomalyst). The thing that I'm most excited about is the bifunctional antibodies and it's not just the bifunctional antibodies, but what we call non-BCMA targeted bifunctional antibodies. BCMA is this new, great target for drugs like belantamab (Blenrep), therapies like CAR Ts and even bi-functionals, but where do we go after that? And there are two presentations this year about looking at targets beyond BCMA. I'm just excited for all of these.
Esther Schorr: Wow. You really can't pick one thing and that is exciting because I know in years past, when we've spoken to experts like yourself at ASH, there wasn't quite as much. This year, I think in some of the questions that people are asking today, you'll probably be able to cover some of these things in more depth, but that is exciting news. Before we dig into those questions, I just wanted to touch base on something that is relevant to basically all the blood cancers right now and anybody who's immune-compromised, we're closing in on God willing, on a COVID vaccine here in the States and I know just last week in the UK, they approved a Pfizer vaccine. What should myeloma patients know about COVID vaccines? And what advice would you give them regarding a vaccine?
What Should Multiple Myeloma Patients Know About the COVID Vaccine?
Dr. Richter: Sure. I think this is of course, one of if not the most important question at the moment. A slight personal side note, the physician in charge, the top person who's deciding whether or not the vaccine moves forward in this country is my former professor at Yale, a man by the name of Peter Marks and for whatever it's worth, there is no better person on the planet to be the arbiter of what moves forward and what doesn't. He is one of if not the smartest person I've ever met or worked with or for. Unbelievably kind, unbelievable breadth of knowledge so the first thing I would say is, trust in whatever comes out, because if he's at the forefront, that's a big thing.
The Pfizer one is probably going to be the first one approved, it appears to be a two dose of vaccine. How and when we're all going to get it, who knows. In general, it appears that it's going to be safe for myeloma patients to get. Now, when I say safe, they obviously didn't test it in myeloma patients, but we believe it to be safe in myeloma patients. The issue of course is one of timing. When you give a vaccine, giving vaccines and the way vaccines protect us to me is the exact same way when you're planting vegetables in a garden. It doesn't matter if you've got great seeds, you have to put them in good soil to grow. It's really about timing. If you just got a stem cell transplant, giving you the vaccine the couple weeks later may not be the ideal time because it's like planting those seeds in the desert. You need to speak with your own healthcare team, not just in terms of safety, but in terms of when is the right timing to be efficacious.
Now, people are going to ask, "Will this work in myeloma patients?" And of course we don't know, but we have strong suspicions that it would. One of the reasons is we did some research in our institution about patients with multiple myeloma who developed COVID. And we found that the overwhelming majority of them developed an antibody response to the disease itself, which indicates to us there's a high likelihood that people with myeloma will develop antibodies if they receive the COVID vaccine. The take home points, really close to getting it, at least in this country, but when are the individuals going to get it? My guess is sometime in first quarter of 2021. It appears to be safe. It'll likely work, but work with your healthcare team to figure out the best timing.
Esther Schorr: Okay. But let's say that the vaccine, a myeloma patient gets the vaccine and it doesn't work, then what happens?
Dr. Richter: That's a really, really great question. And one of the possibilities is that after you get the vaccine, you check for antibodies to COVID and you don't mount them either because of your myeloma or because of the treatment you're on. And that's going to be something to discuss with your myeloma team on an individual basis. And the reason is we simply have no data yet on sequential vaccinations. Meaning if you get the Pfizer vaccine and for some reason you don't develop an antibody response or you develop it and then lose it, we don't know then getting the Moderna or the J&J Janssen vaccine is going to make a difference. If you ask me, if I had a patient show up in my clinic who received one of the vaccines and it didn't work and by that point we had another, I would try to get them the second one to attempt it with a different vaccine, but we don't really know.
Esther Schorr: Okay. We'll move on from COVID to our email questions. I just have one other question for you related to COVID. There are going to be myeloma patients that either have just started some sort of treatment for their disease or just come off it and you just spoke about the timing issue for somebody who say, just went through a stem cell transplant or something where their immune system is at a kind of nadir or not functioning well. What kind of discussion does there need to be between somebody like yourself, a hematologist and a myeloma patient if they're about to start chemo, for example or one of these other treatments? Is there a something they should be aware of?
Can You Share Insight on COVID Outcomes in Myeloma Patients?
Dr. Richter: We do know that unfortunately, people with myeloma if they get COVID will tend to have a more aggressive course that they can become sicker. It's definitely patient by patient. I think that for patients who are just post stem cell transplant, the type of precautions we recommend are the same precautions most people are taking in the setting of COVID. Limiting going out involving crowds, things of that nature. The more difficult question is when you ask, what about just every other patient who's just starting their frontline therapy or their disease came back, they started something else? I think taking a little extra precaution is never a bad thing until all of this settles down. The rule of thumb that I have for what it's worth and most of this comes from the fact that my wife gave birth a few months back and in the preceding months, my mantra was, if whatever you're thinking about doing if you do it and then you're going to worry about it after, don't do it.
Esther Schorr: Sounds like good advice at any age. If you're really worried about it, maybe you shouldn't be doing it. Very good. Let's move on to some of the questions that we've gotten from our audience. Corrin Ponder asked an interesting question. She says, "I'm a 34-year-old and was recently diagnosed with high-risk genetics due to multiple copies of 1q duplication, 1p deletion and trisomy 13. There's so much out there about other abnormalities, but not a lot about chromosome 1. What is the prognosis like with these I guess more rare or different abnormalities?" And she asks about average life expectancy.
What Is the Prognosis of High-Risk Multiple Myeloma?
Dr. Richter: Sure. First of all, chromosome 13 data has changed. Trisomy 13 actually is not a concern. In older data sources or deletion of 13 or 13q deletion was considered a high-risk lesion. When that data was analyzed, it seemed that there was some confounding variables and now 13, we kind of cast off as not the most important. You're absolutely right though, that chromosome one abnormalities are becoming a hotter and hotter topic to look at. We know a few things. We know that not all 1q's are created equal, meaning the more copies you have of 1q, the worse the prognosis is. Having three copies is not as bad as having four or five copies. The other component is in how many cells? Do you have five extra copies and 1% of cells? Or do you have six extra copies in all the cells? And that makes a difference.
The two things I would say are one, in terms of average life expectancy, this is not the end all be all. It's one of many prognostic factors and there are people that can have the worst cytogenetics and still do amazingly well for other reasons. I wouldn't be hung up on the one thing.
For whatever it's worth, there's really exciting data about a new line of therapy in a trial that we are opening at our center with drugs called MCL-1 inhibitors. And it turns out that for the majority of these genetic abnormalities, we don't have therapy specifically focused on it, but we actually have a therapy that we are opening within the next month or so, specifically for people with 1q amplifications. It's a drug that goes by the very fancy name of AMG 397, doesn't have a full name yet and it's a pill that specifically targets this MCL-1, which is thought to be one of the main issues at chromosome 1. We're on the cusp of maybe making a large dent into the adverse outcome of 1q amplifications.
Esther Schorr: It really sounds like the profiling that more and more people are getting done now early on in any of these conditions, blood related cancers especially, that understanding what the abnormalities are from, would it be a genetic standpoint or genomic? I sometimes get those mixed up. I know one is one and one's the other, that those are really critical so that you guys can figure out what's the combination that's right for that set of abnormalities.
Dr. Richter: First of all, that couldn't be more true in general. Genetic or genomic are both completely acceptable. We believe in what's called the multi-omic approach, genomics, proteomics, meaning proteins, immune profiling and really the crux of this is at some point along your myeloma journey, you ought to be evaluated at a myeloma center. It does not have to be mine, but the reality is that the average hematologist oncologist only sees zero to 10 cases of myeloma per year when on Thursday, I had 24 in my clinic and there are many other myeloma centers throughout the country and throughout the world.
Especially in the day and age where we're doing this over Zoom, if you have not yet seen a myeloma specialist at one of these great centers, you can reach out to any number of them to have a consultation over Zoom and have that physician communicate with your local physician to really get granular with the details that we focus on every day.
Esther Schorr: Yeah. And that's the message that we preach every day too, to make that connection if needed. Two part question from Bonnie McDonald, "What are the evolving pros and cons of stem cell transplant now that we have more and more promising novel agents?"
What Is the Role of Stem Cell Transplants in Myeloma Treatment Today?
Dr. Richter: This is only one of the hardest questions in all of myeloma. And this is a question that has been asked for many, many years and it's not just now. In the old days, the standard of care was a regimen called VAD, infusional vincristine (Marqibo), Adriamycin (doxorubicin) and dexamethasone (Decadron). And if there's anyone on the call who's received that, I apologize. It was the best we had at the time and they did this great study showing that transplant was better than the greatest of the day, but that's when the greatest of the day wasn't that good. Now we have such great drugs, is it still better?
There's two really interesting studies that give a little bit of conflicting information. One is a study that was presented recently called the IFM/DFCI2009 study. And with this data is look at patients getting upfront RVD, Revlimid, Velcade (bortezomib), dexamethasone, probably the most common regimen people get and it split them. And half of them got transplant and half didn't. And overall, if you compare the two arms, both did very well.
The people who got the transplant seemed to have a higher rate of deeper responses, so more complete responses, a trend toward staying in remission longer but at the end of their initial induction phase, they did bone marrow biopsies looking at something called MRD, minimal residual disease, a very sensitive technology to find one cancer cell in a million or 10 million. And if at that point after induction, you had no detectable myeloma, people did the same, whether or not you had a transplant or not. Some of us are trying to say, "Well, if you get such a deep remission with your upfront therapy that we don't detect any myeloma, you don't clearly benefit from the transplant."
On the flip side, there's a study called the FORTE study and the FORTE study, which was presented again by Dr. Francesca Gay, compared three different types of upfront regimens for myeloma patients, carfilzomib (Kyprolis), cyclophosphamide (Cytoxan), dexamethasone, and then a transplant, carfilzomib, Revlimid, dexamethasone and then a transplant or just getting 12 cycles of carfilzomib, Revlimid, dexamethasone, no transplant. And in the three arms, both regimens with Revlimid did better than the Cytoxan. And at first, it looked like both, transplant or transplant did the same, but people with high-risk cytogenetics did significantly better when they had the transplant compared to when they didn't.
And even more consilience to that was an updated data from what's called the STaMINA trial, another three-arm trial that compared people to getting one transplant or no transplant or some extra induction. And initially it looked like people who got one or two transplants did exactly the same, but in a specific subset called the intention to treat analysis, the people with high-risk disease had longer remissions if they got two transplants as compared to one.
The short answer is we have very conflicting data. It appears that the real benefit for transplant may be in those people with higher risk cytogenetics and for people who have really high-risk cytogenetics, even considering doing two transplants, but we still don't know at the patient level so that's why ultimately decisions like this needs to be made with your care team.
Esther Schorr: Right. Okay. What I heard out of all of that brief explanation.
Dr. Richter: Sorry.
Esther Schorr: No, no, no. It's great. Is that stem cell transplants are not going away, but that for potential group of myeloma patients that it makes sense for, but that there are a lot of different scenarios of combining that transplant with novel agents or other agents to make it more durable. I want to follow up with a question from somebody who's listening right now, Edwin Lasanta who says, "After a stem cell transplant, what timeframe does it take for a relapse to develop? And at what level of disease you have in your bone marrow, should you be considered for another transplant or other treatments?" That's kind of an example that maybe you can elaborate on.
What Information Can You Share About Relapse after a Stem Cell Transplant?
Dr. Richter: Oh of course. Yeah, I think we're getting more selective with who we transplant. In the old days we just transplant everyone. Now we're getting more selective. In terms of when can people relapse after a transplant? I've seen everything from a week later to a decade later and everywhere in between. The bone marrow assessment is difficult to say, because myeloma is very heterogeneous. You can get a marrow here that says 5% and here that says 10, here that says 30. It's difficult if your bone marrow beforehand said 5% and the one after says 15, it doesn't necessarily mean that you progressed. It could've meant that that 15 was previously 30. Marrows are a little bit hard to say.
In terms of when you would do another. There's two ways we can do transplant. One is tandem. One transplant and then another. The other is called salvage. We do one and then we do another if and when the disease comes back. The timing for tandem, it's been studied by the group at the University of Arkansas, and three to six months is the optimal time where you've recovered enough, but still get the most benefit from the second one. In terms of when we would do it down the road if your disease came back, the classical data says, every time you do the same transplant, we expect about a 40 to 50% remission as the first. If you got one and your disease came back a decade later, you're going to get four to five years minimum. That's a way to go. If your disease comes back in one year, we're not likely to do another one right away.
Esther Schorr: Got it. Got it. Okay. Another question that's come in is about the use of venetoclax (Venclexta) for myeloma patients. What promise do you see in that? Because I know that's a drug that's being used in a variety of settings.
Does Venetoclax (Venclexta) Treatment for Myeloma Show Promise?
Dr. Richter: Enormous promise actually. This was a big trial called the BELLINI trial and the BELLINI trial compared people with relapsed myeloma to get Velcade and dexamethasone versus Velcade, venetoclax and dexamethasone. And this was just published on November 14th in the Lancet Oncology and the data had showed immense response rates, deep and durable responses for two specific types of myeloma patients. One is people who have translocation t(11;14) and the other is people who have high expression of something called Bcl-2. And there are a number of ways we can assess if your myeloma cells really express Bcl-2 and the reason why that kind of makes sense is that venetoclax is a Bcl-2 inhibitor. If you have a lot of it, it blocks it very well.
The issue with the BELLINI trial was the FDA had put it on hold because of some increased toxicities in people who got venetoclax. We're still trying to figure out who venetoclax is perfect for and who may be in that subset that may be at higher risk, but ultimately if you have a translocation 11;14, that drug bubbles up to our surface very high for using it, as soon as your disease comes back, either once or twice, because you are likely to do very, very well on the drug.
Esther Schorr: Again, that sounds like you got to know what the profile is, the genetics, in order to know which cocktail and isn't a Bellini a cocktail?
Dr. Richter: A Bellini is a cocktail. I believe it's a peach liquor with champagne maybe? I think that's what a Bellini is.
Esther Schorr: Yeah. All right. Thank you. I thought that was right. Angela Herman is one of our community members listening and she's obviously following some of the latest research and she asks a good question, "Can you comment on the change in efficacy with Janssen's BiTE?" You might have to explain BiTE therapy to some of the other folks. BiTE therapy, as they move patients from weekly to every other week so less often.
What is BiTE Therapy?
Dr. Richter: Janssen actually has two BiTEs and I'll talk a little bit about both of them and these are some very exciting drugs. What is a BiTE? People may be familiar with monoclonal antibodies, drugs like daratumumab (Darzalex), rituximab (Rituxan), elotuzumab (Empliciti) and these are just like our body makes antibodies to fight infection, we've engineered antibodies to attack myeloma and they classically have one arm and we tell them what to target and they grab onto that target and they try to kill it. What a BiTE is, it's a bispecific antibody. BiTE is an abbreviation for bispecific T-cell engager. And basically it has two arms and one has a target on it that grabs the myeloma cell, the other target grabs onto your own T-cells, your own immune cells and it makes your immune cells fight your cancer. It's a way to activate your own immune system separate from giving you something a little bit more aggressive, like a CAR T.
Now Janssen has two extremely exciting drugs that are in the pipeline that are both BiTEs, same target for the T-cell, different target for the cancer cell. One drug is called teclistamab. Teclistamab is a CD3 and BCMA - and BCMA is the target for a lot of these CAR Ts and it's on all myeloma cells. That's a very exciting drug. And then there's another one called talquetamab, which also targets CD3, except the other target is something called GPRC5D, it's another marker that's on all myeloma cells. Both of these drugs are extremely efficacious, but one of the things that we're still trying to figure out and that whoever brought this up is absolutely right and this is one of the key problems is how do you dose these drugs?
Do you give them IV or subQ? Obviously, subQ is nicer, but IV has a higher peak when you give it so that may be better. And then the issue of once weekly or twice weekly is getting rather interesting because on one hand, we want to space out if we can so that people don't have to get drugs every single week, but does that drop the efficacy? At the flip side does giving it every week ramp up your T-cells so much that maybe it'll throw your immune system into overload. We're still trying to answer these questions with the trials and the data presented is really interesting. I just don't know that we're quite there yet with the stamp of approval of the best way to give it.
Esther Schorr: Stay tuned, we could keep working on it. I just want to, before we have to wrap up, I want to talk a little bit about CAR T-cell therapy. There've been a number of questions about that. Do you have some idea when CAR T-cell therapy will be approved as a first line treatment for newly diagnosed, multiple myeloma patients?
Any Updates on CAR T-Cell Therapy?
Dr. Richter: That's a really great question. And unfortunately, it's going to take a little bit of time, because we don't know yet if that's better than the standard. Probably by February or March, we will have approval of CAR Ts for people who have been through a lot of other treatment. There's an ongoing study called the KarMMa-3 study, which looks at people when they first relapse, should they get a standard regimen or a CAR T? Now we hope that CAR T's are even better, but there's a potential that the earlier you use a CAR T in someone, even though it may be more effective, it may also be more dangerous. And the reason is, CAR Ts activate your T-cells. If you activate T-cells that have been kind of beaten up by other therapies for years, they're not as robust so they may not work as well, but they're also not going to kick into overdrive as much.
We have a little concern that if you use it up front, that you take a T-cell that's so angry and ready to go, that when you engineer it and give it back as a CAR T, it may be so aggressive that the side effects may be too much for people. Those studies are ongoing, the KarMMa-3 study and now the KarMMa-4 study looking up front and we need to learn a lot about, is it better than the therapy we have? And the answer is maybe, but unfortunately, we're probably a couple years off at minimum from using CAR Ts up front on people.
Esther Schorr: As a first line. Okay. Are there at this point, any specific criteria for the possibility of using CAR T as a therapy for a patient? Or are there any immediate, specific disqualifiers?
Dr. Richter: At the moment, they're all on trial. Every trial has its specific list. And to your point, when it gets approved, the devil's going to be in the details. The FDA is going to give specific language of who can get it and who cannot. And part of this may be a little restrictive because CAR Ts are expensive. The government may say, "Well, these cost half a million dollars or more," they don't want to give it everyone until we have proof it's good for everyone. The likely approval language, and again, we don't know until it's there, is going to be in triple class refractory patients, meaning you've had a proteasome inhibitor like Velcade and IMiD drug-like Revlimid and an antibody drug-like daratumumab and then your disease has come back.
Esther Schorr: That's a lot to take in and as we get to the end of our time, out of all of that, and out of all of this research that's going on, what would you say to the patients and their loved ones who are listening today and following what's coming out of ASH? What would be your sort of parting gift to them?
Is There a Multiple Myeloma Cure on the Horizon?
Dr. Richter: The parting gift is I've been focusing in myeloma solely as a career for a little over a decade. And when I started and the inevitable question would come up is myeloma curable? And I would say, "No." And over the last year or so with some of the new technologies that have been approved, technologies about to be approved and then the next generation, that is no longer what I tell people. What I tell people is, "My job is to keep you alive until there's a cure, because I think there's going to be one within some period of time that is palpable. We can see the cure down the road." And perhaps we have the tools in front of us today if we can get a little bit smarter about sequencing and combination in an individual, we may be able to get people into such long remissions that by the time the disease does come back if it does, we'll have a whole new generation of therapies. We have so many options coming down the road, nothing but excitement and stay tuned for what's clearly going to be a very exciting 2021.
Esther Schorr: Wow. And I know across many of these conditions being discussed at ASH, that word that wasn't spoken about just a few years ago, the potential for cure is coming up over and over again this year. That is very, very encouraging. Dr. Joshua Richter, thank you as always for being such a beam of light in all of this. We really, really appreciate it. And I want to thank all of you who have logged in today and asked us questions. And please, please discuss with your doctor what you learned from our program that could improve your care. And don't be shy, there's going to be a transcript and a replay coming soon to our website so you can review what you've heard today.
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