Irene Ghobrial, MD
Dana Farber Cancer Institute
Interview Date: December 16, 2020

How will COVID-19 affect multiple myeloma precursor condition patients compared to black Americans or myeloma patient family members? Dr. Irene Ghobrial of the Dana Farber Cancer Institute is expanding her study of precursor conditions to address the IMPACT of COVID-19 on precursor condition patients vs. "control" groups. How will MGUS and smoldering myeloma patients respond to the COVID-19 vaccine? Will the responses be durable? Are the genetic changes that happen at earlier myeloma stages affecting a patient's immune system so they have a better or worse outcome to COVID? These important studies are being asked in the IMPACT study. Please consider joining this study if you are: 

• An MGUS or smoldering myeloma patient
• African American
• A family member of an MGUS, SMM or myeloma patient

Thanks to our episode sponsor

Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects myeloma patients with researchers. I’m your host, Jenny Ahlstrom, and we'd like to thank our episode sponsor, Bristol Myers Squibb, for their support of this program.

We've just completed one of the busiest times of the year with the American Society of Hematology or the ASH meeting. This is a once a year event where global experts in hematology get together to discuss recent findings and their discoveries and their papers. You'll notice on the myelomacrowd.orgwebsite, we have a lot of that content, and will continue through the rest of December and likely through January because there was a lot of information there, so please check out those ASH articles and stay up-to-date on the incredible progress being made in the multiple myeloma space. 

We are very excited to have a show talking about COVID-related things and also other studies that are expanding things to the myeloma community and really trying to understand what's the impact of COVID on multiple myeloma and precursor conditions in patients. Also, how do we prevent myeloma from happening in the first place? For that, we have Dr. Irene Ghobrial of the Dana-Farber Cancer Institute with us today. Welcome, Dr. Ghobrial. 

Dr. Ghobrial: Thank you, Jenny. Happy holidays to everyone, and thanks again for having me on your radio show.

Jenny: Let me introduce you before we get started, and then we'll just launch in with our questions. Dr. Ghobrial received her medical degree from Cairo University School of Medicine in Egypt, and she's an attending physician on Medical Oncology at the Dana-Farber Cancer Institute. She is professor of Medicine at the Harvard Medical School. She's director of the Clinical Investigator Research Program at Dana-Farber and director of the Michele and Steven Kirsch laboratory. 

Dr. Ghobrial is a physician scientist who specializes in the field of multiple myeloma and Waldenstrom's, and does a significant amount of work on precursor conditions like monoclonal gammopathy of undetermined significance or MGUS and smoldering multiple myeloma or smoldering myeloma. She focuses on the role of how these precursor conditions progress to active myeloma, and is very intent on shutting that down before it becomes active myeloma.

She created the Center for Prevention of Progression of Blood Cancers where patients with these precursor conditions can be monitored for different evolution to see why they progress and how, and that is something that patients -- we’ll talk about that today in today’s show --that's a study that patients can join but don't need to travel. 

She is the lead primary investigator for these PCROWD and PROMISE studies, and the PROMISE study, which has been significantly funded by Stand Up To Cancer, so it's very important award that she received for that. She's now launching this IMPACT study. 

So, Dr. Ghobrial, maybe you want to explain what you've learned so far from the PCROWD and the PROMISE studies. We can go into more detail about what those studies are a little bit when you talk about who's eligible to join the IMPACT study, but what have we learned so far from your prior work? Then please share more about the IMPACT study.

Dr. Ghobrial: Absolutely. Maybe I'll start with PCROWD first and then move to PROMISE and then move to the new study, IMPACT. PCROWD started a few years ago. The whole idea was we have a lot of databases and we have a lot of information about myeloma, but we don't about precursors, about MGUS, monoclonal gammopathy of undetermined significance, and smoldering myeloma. 

THE PCROWD STUDY

What we hope to do is if we can understand better who will truly progress in their lifetime to myeloma if you have MGUS or if you have smoldering myeloma. Instead of doing the watch-and-wait or, as people say, watch and worry. Why don't we understand together as a community, what causes progression - is it the genetics, epigenetics, the immune system? Once we know that, we can develop better biomarkers. We can tell you in a more predictive way if you will progress in your lifetime or not, and that can help you make a better decision. Do I need to be treated early or not? 

The hope is that we truly prevent progression. We never have anyone wait until they develop myeloma and then we treat them. We never wait for you to have fractures, bone lesions, anemia, renal failure. We always treat you earlier to prevent all of these end organ damage or damage, basically, of your organs. 

The hope was that instead of having you come to Dana-Farber or come to one of us in big cancer centers, why don't we bring it to you? So this is a truly patient-empowered, direct-to-patient access, nationwide and actually now, internationally, where you click online to log into pcrowd.org. You can enter your information, and you become part of the study. You consent online. You don't need a physician. You don't need anyone. 

Basically we send you a kit for your blood or for your bone marrow biopsy, and we ask you, are you okay that we ask your doctor to give us your clinical data, your information? Actually, HealthTree now that Jenny's doing, is wonderful because it can give us access also to that clinical information or gives you access to that clinical information. As we do that, we get thousands of people who serially give us their blood or bone marrow sample. When you have 2,000, 3,000, people who have precursor conditions, now we can ask the big questions. Now we have enough numbers to say, okay, now we can understand who progresses. 

Actually, when we launched that, four, five years ago, we had 3,000 people. We are serially following them. We hope to get actually more and more. The hope is we get up to 10,000 and more so that we can understand this better. We already have shown several new studies within the last year that made an impact already for our community to understand mechanisms of progression. 

We know that if we sequence, we do something called next generation sequencing, and we look at your own sample from the bone marrow or from the blood, what we call liquid biopsy, we can define certain markers that can predict for us who will progress from smoldering myeloma to active disease, and potentially use those markers to be even more predictive than clinical markers to tell us who should be treated early. We’re hoping to bring that into the clinic immediately so that we can order that test, and we can help you immediately. For now, it's research level only, but I'm hoping within 2021, this will be one of the initiatives we want to bring. 

We also learned that your immune system even at the MGUS stage is not normal completely. You may be prone to certain infections, and we'll come back to that with the COVID-19, in a second. We did something called single cell sequencing where we look at all of the single cells as each individual cell from your immune system, and we found that indeed, even at the MGUS stage, not only as myeloma, your immune system is not completely normal, and then it starts getting worse as we go to myeloma. That helps us also develop therapies. We can develop immunotherapy early on and so on.

That's with PCROWD. It's precursor crowdsourcing. We're crowdsourcing for patients, basically, and telling you, this is your community, please help us. I would encourage everyone who's listening now, if you have MGUS, if you have smoldering myeloma, please sign up. We would love to have everyone on it.

THE PROMISE STUDY

Now, a few years ago, two years ago, we applied to Stand Up To Cancer, to say, well, something doesn't make sense. Why are we waiting for people to develop myeloma? Why are we not screening for it? We know that cancer screening saves lives. We know that breast cancer screening with mammography, colon cancer screening with colonoscopy makes a huge difference. Why can't we just get a blood test, a simple blood test, and look for myeloma, which is the protein level, the monoclonal spikes, as we call it. 

So we launched a study to look in high-risk individuals. This is not for everyone. This is for people who are at very high risk of developing myeloma. We will look for their monoclonal protein, but instead of doing it by the usual serum protein electrophoresis, we're doing it by a more sensitive test called mass spectrometry which was developed recently by Binding Site in collaboration with Mayo Clinic, and we give you that results back for free. So this is the PROMISE study. Again, while people are looking at that, please log onto promisestudy.org. 

What we said is we will screen 30,000 individuals. This is a big study, nationwide again. They're either family members of people who have a blood cancer, so your own sister, brother, mom, dad and kids over the age of 40 to age 75. If you have a blood cancer, so if you have myeloma or a precursor like MGUS or smoldering or any blood cancer, lymphoma, leukemia; you are eligible, or your family members are eligible, and they can sign up. 

We send them a kit. They go to Quest Diagnostics, any Quest Diagnostics nationwide, and they get that blood draw. Part of it will go to Mayo Clinic where we get the results. This is the clinical results, whether you have the monoclonal protein or not. We call you with the information, and we help you. If you do have MGUS, we work through the system. We actually see you virtually. 

We now have this to offer for you, a virtual clinic or telemedicine clinic with me or with any members at Dana-Farber, or we refer you to someone else, if there's someone local. We want to make sure that if you are diagnosed with this, we provide the best care possible. We call it white glove care for anyone who goes on PROMISE. If you're negative, we re-screen you back again in three years. That's the PROMISE study. 

Now, of course, when COVID started March of this year, we said, well, we have no idea how COVID will affect our patients with MGUS or smoldering, and especially that PROMISE study is trying to recruit people who are black Americans. Actually, the other recruitment part is other high-risk individuals.  If you are black or if you are of African descent, you have a two to three times higher chance of developing myeloma, and we still don't know why. So, for PROMISE, you're either a family member, or you are black or of African descent. 

THE IMPACT STUDY

We said, well, we don't know if COVID will affect you worse or not if you have a precursor condition. We know that your immune system is not normal, but you're not all the way to myeloma, and people may not know that you're truly at risk. Now that we have the vaccines rolling in, we don't know if you will respond as well as a normal person, if your immune system will give you that sustained immunity against COVID, once you get the vaccine. So we said well, why don't we launch a study called IMPACT? It's theimpactstudy.org. Again, you can look it up right now while we're speaking. Anyone who signed up to PCROWD or anyone who signed up to PROMISE, you can also sign up to IMPACT.

Now we can draw your blood, tell you if you have a COVID-19 antibody test. That's through Quest Diagnostics. They're doing it for free for us. We'll give you your results to get to know if you had the infection or not, which is important. Then when you get the vaccination or when we follow you for the next year, we will ask you to give us samples every three months for one year, so that we can see, how does your immune system look like after getting the vaccine? Or if you got infected, what does your immune system look like at three months, at six months?

So we're doing all of this single cell sequencing of your immune system in your blood. We're also looking for inflammation, cytokines, we're looking for CHIP mutations, which is certain mutations that can predispose people to have the worse infection. We're hoping to do that and release the information immediately back to you. So, everyone who's on the portal, that data would be available immediately for them every three months, as we sequence the samples. That's the IMPACT study. 

We know that it's hard, especially now with COVID, so we said, people who are signing up for the first time for PROMISE, they get two in one. They can sign up for PROMISE and get IMPACT, and we also can give them a $50 gift card because they're spending the time and effort, to compensate for their time and for going to Quest Diagnostics. So they get both kits in one, for PROMISE and IMPACT, at the same time. 

Jenny: Okay, that makes a lot of sense. If they get the kit and they're already going to their facility, can they draw it there, and then they mail it off? Or do you to have to do it through Quest?

Dr. Ghobrial: For the COVID antibody test, because it's a Quest Diagnostics test, they have to go to a Quest Diagnostics. That's why it's important to go there. If it's PROMISE, because the kit has to go to Mayo Clinic and it has to be drawn by a certain phlebotomist, it also has to be through Quest. If they don't have a Quest Diagnostic, local or near them, we can send them a phlebotomist at home. There is a service that we can send them at home, a phlebotomist. 

Jenny: Either way, it'll be just convenient to your local area, and you don't really have to travel anywhere. I think Quest has a lot of facilities that you can find in your community. Is there a major website that you can go look at, to find where your closest facility would be? 

Dr. Ghobrial: Yes, absolutely. There is a link, so once you put in your area code or your address, it actually will tell you where’s the local facility. We’re also trying to see if we can even work with pharmacies and Walmart and anything else. Quest is also in Walmart right now. So we're trying to make it as easy for you as possible, but again, let us know, if you have any problems, we are always happy to help and try to send a phlebotomist at home. 

Jenny: I've done that before to just get labs run, gone to just the local Quest Diagnostics without having to go to my facility. It's really simple. Usually there aren't that many people in there. They take your blood, and they're done. It’s very fast.

Dr. Ghobrial: Well, thank you, Jenny, for giving that. It's important to know that feedback. That's wonderful. 

Jenny: Yes, it was easy when I did it. We have so much to learn about COVID, I think, and I'm sure you've had COVID-positive myeloma patients now. Is there anything you want to share about what you've learned? Because what you mentioned before is really important. We don't know how myeloma patients are going to respond to the vaccine. I think everyone's very excited that there is a vaccine now available and starting to be rolled out. I would imagine that you, as a healthcare provider, will probably be one of the first to to get it, but also myeloma patients might be some of the first to get it. There's so much we don't know yet about that.

I think Dr. Raje at Mass General was mentioning that as well. Will myeloma patients, just because they are already immunocompromised, will they have the same type of responses? Will they have durable antibodies? How will they react? What's been your experience so far, I guess, in your clinic, with COVID-positive myeloma patients, and then those with precursor conditions?

Dr.Ghobrial: Absolutely. We've had, of course, like many others, a few cases of patients with myeloma who are on therapy, who had also COVID, and many of them were hospitalized. I had one of my patients who was in the intensive care unit for a long time, and he recovered wonderfully, and other patients. He actually received the Regeneron antibody, so we were very lucky that that was recent. It was on clinical trial.

Again, you've seen some of the publications that some of the patients with myeloma did not do well, but that was early on, in the early setting when we didn't have access to many new drugs. I think now, we still should be very careful. We still should be cautious with everything. Hopefully, as we get the vaccine, as we get to understand better the immune system and the response of the immune system to COVID, we can give you more advice. 

I will say that's why we're doing the IMPACT study to truly understand what is the response of the immune system to COVID, not only the infection, but also the vaccine in our own patients, and give you back that information. Instead of giving you a hypothesis, maybe they will respond well or not, I can actually give you data in a few months from now. 

Jenny: I'm glad that you're doing the blood-based test. I think Dana asked this question in a prior show with Dr. Richter  -- she was asking which type of blood test is actually the best to determine if you have COVID, also to determine if you have the antibodies, and he was noting that it was the blood test. How does this test that you're running at Quest compare to the other tests we might be more familiar with, for antibody testing or COVID? Does it test to see if you have it and if you've developed antibodies? Or what does the test actually do? 

Dr. Ghobrial: That's an important question. There are two different types of tests. There are some that are to see if you have currently the active infection. These are usually PCR-based, not antibody-based. This just says the virus is there, and I can detect the virus. These can be, of course, from the nasal swab or from the saliva or from tissues and so on, or blood, of course. That's not what we're doing in the IMPACT study. That's very important too, if you think you have the infection, currently, you should be tested, of course.

The antibody test asks the question, did you get infected in the past? That could be in the recent past or in the long, you know, several months ago, because there are different types of antibodies, IgM or IgG. That's the one that we're testing right now in the blood. We chose Quest Diagnostics because we have a relationship with them and because they have an FDA-approved test, and their data shows that it's a very sensitive and specific test. 

At the same time, we have here at Dana-Farber, a much more sensitive test, but it's research level only. It's 10 times or 20 times more sensitive than the ones out there, the FDA-approved ones, but it's research level. We can run 1,000 samples per day, and we will be doing that, in collaboration with one of our doctors here, Eric Fischer, who developed that new test, on all of the samples. So, at the research level, we will also be repeating it again, with all the different types of antibodies here. 

Jenny: Okay, great. That's amazing. Essentially, in this IMPACT study, you're going to have a group with precursor conditions from the PCROWD study, so, MGUS or smoldering myeloma patients. You'll also have this control group or non-myeloma related group from the PROMISE study. Then you'll be able to compare the two really well. I think that's a really neat study design because you'll have both people who are impacted already. 

Dr. Ghobrial: You're right, and they're almost all of the same age. They were at risk of developing myeloma, but they don't have it. Like we said in PROMISE, we're hoping to have 20% black Americans, so we can ask the question, why is race playing a part in this? So, absolutely, we're going to be asking a lot of big questions, not only of COVID, but also in general, of our immune system in many of our patient population or population at risk.

Jenny: I think in COVID, you’re looking at things like diabetes or heart conditions or other things that might make you more vulnerable to COVID, or having worse outcomes if you get COVID. Some of those same things are present in some precursor condition patients, and it might give you the opportunity to look at these, what they call, comorbidities or other diseases that might be adjacent to the precursor condition or not, and just see, is there a difference? You might be able to identify something truly unique, in comparing these two precursor condition groups and, what you call, normal population, as you're going to look at this. So, it might not just be how we're going to respond to the COVID vaccine, but it might be even something deeper than that.

Dr. Ghobrial: Yes absolutely, Jenny. We should collaborate on all the research together because you're right. This is going to be beyond COVID. We're collecting samples for circulating free DNA, for circulating tumor cells, for metabolomics, proteomics. We're keeping it wide open to ask big questions in the long run too, and not only the specific question that's currently important which is the COVID-19 question. 

Jenny: Right, and I think that's an important question. When it comes to things like the flu vaccine, I know sometimes, the doctors will say, definitely get the flu vaccine this year, but you might need to get booster shots because myeloma patients have more depressed immune systems or things like that. When you think about this COVID-19 vaccine, I think everybody's curious, will it help me develop antibodies if I'm immunosuppressed? Will I need booster-type shots? 

I guess, over time, because you're watching patients, what, three months, six months and one year, you're going to be able to see trends and patterns. Do you have any ideas or hypotheses now, before you start the study? I'm sure you’ll have more later, as you have more people participate, but what would be your guess? Everything's so new. That's a hard question for me to ask. 

Dr. Ghobrial: Well, it's hard to guess. Sometimes we go in with one hypothesis, and that's the best part of research, that we are surprised that we are not correct. We have to be very open-minded and saying the research would tell us the answer, and not what we want to say as the answer. 

I really don't know. I'm hoping that we will mount a good enough immune system that lasts for a long time, but maybe that will not be true. Maybe MGUS will mount to a certain immune system, almost as healthy control, but maybe not. Maybe smoldering myeloma, maybe it's stage-wide. As you get more progressive in myeloma, from MGUS to smoldering to active disease, you have less and less of an immune response. I might be wrong about that. 

We don't know until we get to answer those questions and have the longitudinal samples every three months for one year to really see what will happen. Do we need booster vaccines, like you said? Do we need serial vaccines every year? Do we need two shots more than anyone else? There are lots of questions there that we need to understand better. 

Jenny: We've had a lot of patients ask, if they have this or immunosuppressed, should they be taking IVIG? How do you see IVIG relating to any of this? Especially with, do precursor condition patients need IVIG ever? Do they use that? I'm not very familiar with if they do or don't.

Dr. Ghobrial: IVIG is basically that you're given an immunoglobulin gene to people who have a very low level of immunoglobulin G. That happens when your normal immunoglobulins are suppressed because, either you have the myeloma and it's secreting bad, nonfunctional antibodies, immunoglobulin, or because you've been on therapy and dexamethasone or daratumumab or Velcade or any of the therapies kill the plasma cells. By doing that, you're killing also the good normal plasma cells that make antibodies. 

We usually know that people who have a low immunoglobulin, especially immunoglobulin G, may be prone to recurrent infections, pneumonia, sinus infections and so on. By giving you IVIG, we’re trying to help you get some of that protective effects from someone else's immunoglobulin. Now, those will not protect you from COVID-19 because we do not have prior antibodies to COVID-19 because this is a new virus. No one has been previously exposed to it. 

So, currently, IVIG that you get right now would not be protective to you for COVID-19, and that's why the studies that are ongoing right now are using convalescent plasma which is plasma from people who recovered from COVID-19, and giving it back to them to see if that can help. That will be something, hopefully, available in the future as more and more people have COVID antibodies.

For smoldering myeloma and for some MGUS patients, their immunoglobulin may also be suppressed, what we call immunoparesis. That just means that already their plasma cells, the good normal plasma cells are suppressed, and that's a sign that the bad plasma cells are already acting up. It's one of the best prognostic markers of progression from smoldering myeloma to active myeloma in one of the studies like the Spanish studies that have been done. We sometimes give IVIG but usually not. If you don't have recurrent infections in smoldering myeloma, we wouldn't say that you need IVIG in those patients. 

Jenny: Just a question about this COVID vaccine as it comes out, are you recommending that all your patients get it, and even precursor patients, MGUS and smoldering myeloma patients?

Dr. Ghobrial: Yes, absolutely. We hope that everyone should get it. I don't know when we will have the roll-out for every patient. This is something that we're waiting to get answers at Dana-Farber, but I encourage everyone to get it. 

Jenny: The small amount of patients that you've seen that have gotten it, do they develop strong antibodies, and do those antibodies last? You probably don't have enough information, not enough patients to determine that yet, because it's probably a very small number of patients. I’m just curious.

Dr. Ghobrial: I wish we had the answer. We all want to have that answer. So far, since approval, it has been approved to healthcare workers. I guess the first vaccinations were, what, two days ago? 

Jenny: Yes. 

Dr. Ghobrial:  Then we will start giving it to patients, and then we will start seeing the effects. We don't have data, of course, on the clinical trials, whether they had certain number of patients who are immunocompromised or not, they have not released that data, and who was on placebo and who was on the vaccine. I think this coming year, and that's why the impact study is so timely, we will get all of those answers, hopefully, within the next three, six months, and so on.

Jenny: Right. Well, we'll have to do another program so you can share what you've learned from the study.

Dr. Ghobrial: Absolutely. 

Jenny: Earlier in the show, you mentioned that we know that the patients with precursor conditions like MGUS and smoldering myeloma, have immune system changes. Do you want to share what you've learned -- what you mean by that? Do you just want to share what immune system changes you see happening earlier at these different stages, these precursor stages? 

Dr. Ghobrial: So, we did a paper, and I'm happy to share the paper with anyone who wants it. It's The Nature of Cancer, in this year, 2020, where we did something called single cell sequencing of the bone marrow cells from healthy people, MGUS, smoldering and multiple myeloma, and we're hoping to extend this beyond what we've done so far. 

What was interesting is, I thought that we will have different levels where, from normal to MGUS, you'll have a little bit of a change but not much because MGUS might look like a benign normal thing. You might have a normal immune system, and then it starts getting worse. We were surprised that, actually, some of the MGUS bone marrow immune cells looked exactly like myeloma, that it was this sudden change from healthy to MGUS. Your immune system is already changing. That's what's interesting because I did not expect MGUS to be that abnormal in the immune system. 

Then you do see further changes, further progressive changes in the NK cells and the T cells as you go to smoldering myeloma and then to active disease, but there was this one jump from normal to MGUS that definitely affected it. I think that's critical for us. I don't mean to scare anyone who has MGUS because maybe those changes are not in any way going to affect your progression or going to affect your response to infections, but I see it in many of my patients who tell me, I get recurrent infections or I have autoimmune diseases, or I have something weird. You go, ah, we never thought of it. Or when we think of vaccinations in our patients with MGUS, we have to start thinking, will they really mount a good response to vaccine if their immune system is not working well? 

You can also start thinking, should I think of immunotherapy, of activating T cells and NK cells, as early as smoldering myeloma as a way to prevent myeloma progression? If we know there is something already altered, can we harness the immune system to improve it before it goes to active myeloma? That's what we're doing in some of the clinical trials that we're launching in 2021, is we're bringing in bispecific antibodies and other immunotherapies like NK cells, early on, in the smoldering setting.

Jenny: Well, I think that's such an important idea because if you can shut it down and boost your immune system to be able to fight it, you may never progress. That's been your goal for many years, to shut down the progression. 

Dr. Ghobrial: Right.

Jenny: That's amazing. I think this is so important, though, in the context of COVID because one of the reasons I'm asking that is, if you do have MGUS and you are seeing these early changes, then we really need to know, how does COVID affect you? How does it affect you over the long term with a different, “different” immune system that you have as, not only just a myeloma patient, but as a precursor condition patient? That's what you're trying to learn in this IMPACT study.

Dr. Ghobrial: Yes, you're right. It's not just how MGUS or smoldering affects your COVID response, but also how COVID affects you, and affects your immune system and your inflammation environment, and will that make you progress faster or slower to myeloma? 

Jenny: Yes, that would be a little alarming. It's what you said before, patients should still take whatever precautions they can and try not to get it. I think we're all so tired of COVID. 

Dr. Ghobrial: We are, indeed, all of us.

Jenny: At times, it's easy to just go, okay, never mind, but you really still have to stay vigilant even though you don't want to. Especially during holidays, it's hard, but it's important. 

So, if you can help me review, let's say somebody has not yet participated in the PCROWD study, or they haven't joined the PROMISE study yet, or their family members haven't joined, or if you're African American, you haven't joined yet, but you want to join those studies; and then can you just walk me through the logistics, again, of how the kits would be mailed to you? Because you can decide to join PCROWD or the PROMISE study right now, right? It's not just for people who are already in it, but you can join those two studies and join the IMPACT study at the same time. Correct? 

Dr. Ghobrial: Correct and that's what we're encouraging. We're telling everyone, if you have MGUS or smoldering myeloma, sign up to PCROWD anytime. It's P and then crowd, you can look it up, it's pcrowd.org. You can look up Dana-Farber at PCROWD or my name in PCROWD, and you'll find the link. Again, if you have any problems, please email us anytime. 

PROMISE is for anyone who is a relative or black American. So, if you have MGUS or smoldering or myeloma or any blood cancer, lymphoma, leukemia; your first degree relative is eligible. So while you're in the holidays, and you're talking to family, encourage them to look for it. Cancer screening can make a huge difference. I personally signed up for PROMISE because I'm of African origin. I'm from Egypt. I would highly encourage everyone to sign up for it because why wouldn't you want to know early what could potentially be preventable? 

That's what I hope in the future, all of us can do a blood test to know if we have early cancers, and we can prevent them. In fact, this is what we're hoping to do in general, not only for myeloma, but to all the other cancers. If I can detect it early, and I can prevent it; I hope, in the future, I never develop an active cancer. Again, yes, it could be a little bit scary to know, but I'd rather know than wait two, three years, four years from now and have vaccine and get diagnosed with myeloma. 

So, if you are of African origin, or if you're black, or if you have a first degree relative of any blood cancer, you can go on promisestudy.org and sign up. Once you sign up, it's very simple. It takes five minutes to sign up. You can also sign up to the IMPACT study, so theimpactstudy.org, and the same kit, it's basically two-in-one, the same kit can be used. We mail it to you. You can then get an appointment at Quest. They're very good. They're very organized. You don't have to go in and stand in line. You can just get an appointment. You go get your blood drawn, and that's it. You get to know if you have MGUS or smoldering myeloma, and we call you, and we help you. Or if you're negative, it's a good thing to know. We also tell you if you had the COVID-19 antibody test or not, and we're also doing the $50 gift card to everyone who goes for PROMISE.

For PCROWD, you don't need to go to Quest Diagnostics you because you're already an established patient with an oncologist already. So, whenever you're going next time to your doctor, just take the kits with you and have them draw it for you, whenever they're drawing your blood count, as usual. Again, you can go to Quest Diagnostics at that time.

Jenny: Okay, that makes sense. I think sometimes it needs reviewing because sometimes it can be confusing for patients to know. What do I take with me? Or where do I need to go and when? I think the important thing that you're learning from the PCROWD study is that, what you said earlier, you have had thousands of patients participate now, and you do know -- you're learning important things from those studies. Those are both blood samples and bone marrow samples, right? So, if you're already going to your doctor's office, you can, like you just said, invite them to just -- 

Dr. Ghobrial: Yes either blood, or if you're doing a bone marrow biopsy, of course, we would ask you to give us some of your bone marrow. I think it's important for everyone to know that your blood sample, which is easy and simple, can give us a lot of information as much as your bone marrow sometimes, so it's important to give us that blood sample too.

Jenny: Well, with a more detailed blood testing that you're doing, I think, like using mass spectrometry instead of the regular test for the monoclonal or the SpaP, I guess it’s called, that that gives you more information. 

Dr. Ghobrial: Absolutely, it's a much more sensitive test, and for the first time, we're using it for screening in this PROMISE study. In fact, we were expecting to have only three to 5% of the population to be positive, when we screen them. We found that we are up to 10%, screen positive. That's a very high number of those high-risk individuals we are screening. That tells us that we are actually targeting the right population if we're getting 10% positive rates. 

Jenny: I know you worked a lot with Dr. Kyle. Do you want to just go over a little bit of some of the history there with MGUS? Because if this is true and 10% of the population that you're screening has MGUS, then there's a lot we don't know about these precursor conditions and what we can and can't do. I was looking at some of the ASH data that you referred to a little bit earlier in the show, that reviewed the genetic changes patients can have even in these earlier conditions and they were being separated into two different risk groups. 

Dr. Ghobrial: Yes. So let's talk about Doc Kyle because he's truly the grandfather of multiple myeloma and a pioneer. Doc Kyle, and he’s 95, I think, now, and still leads many of the studies. He actually coined the name monoclonal gammopathy of undetermined significance, MGUS, as well as the name smoldering myeloma. He's truly the one who made all of those discoveries. It's wonderful because I trained with him at Mayo Clinic, and I always look up to him as my guiding physician who has really made everything possible for us. Hopefully, we would move on with his research to understand this better and better. 

He came up with idea that there are indeed people who have this monoclonal protein, the M spike, but they don't have myeloma. Jan Waldenstrom, who was another physician who was wonderful. He's the one who actually described the disease Waldenstrom’s macroglobulinemia. Jan told Dr. Kyle “Well, this is likely just a benign thing. That's not cancer. Let's not worry about this.” Dr. Kyle was smart enough to say, “Well, what if they can develop myeloma in the future? What if this is a precursor to myeloma, and it's not just a benign condition? Let's not ignore it. Let's follow those patients.” 

He actually started the first screening study in Olmsted County, Minnesota, which is very close to the Mayo Clinic in Rochester. He sent a letter to all of the people who lived in that county and said, “Do you mind giving me your blood draw, and I will see if you have this M spike?” It's exactly like PROMISE, but done 50 years ago.

Indeed, he found that 3% of the population over the age of 50, if you just screen them randomly, you will find 3% of the people have this MGUS, and the rate of progression to myeloma is 1% per year. Every year, you only have a 1% chance and 99% chance of having nothing. You may have already a change in your cells, you have this pre-cancer cell, but it doesn't go all the way to myeloma. Now we're trying to understand why and what happened. 

That's happened in many other cancers. All the time, as we get older, many of our cells can change, can mutate and become abnormal. In fact, as we get older, there's something called CHIP mutations, stem cell mutations that happen in our own blood stem cells. Again, 3% of the population over the age of 50 may have those CHIP, clonal hematopoiesis of indeterminate potential, and that in the future can go on to develop MDS or leukemia. We now actually are finding correlation or work that can make any myeloma come together and happen together. 

So, we're all getting older with mutations happening in ourselves, the question is, can we detect them early so that we can prevent them from going all the way to leukemia or myeloma? Can we understand who developed them, and why would you develop them? Why would I develop MGUS or CHIP while my brother does not or my sister does not? Or why do black Americans have two to three times higher chance of developing myeloma compared to Caucasians? What's so high in that? There must be some, also, underlying germline. We are born with certain DNA or epigenetic changes that predispose us to getting those. 

All of those factors, plus other factors like the environment, exposures to pesticides, OBC, so many other factors can contribute into the rate of progression. If we can understand them better, we can, one, give you better markers so that we can be more precise in why you developed it, but also, when will you have problems from it. We can also prevent it in the future. Maybe we can develop a vaccine for MGUS, just like we developed a vaccine for COVID, and we prevent MGUS from going on to myeloma for everyone. That's truly not something that can happen in 20, 30, 40 years. It can actually happen within the next five to 10 years if we work hard on understanding it and developing it. 

Jenny: Well, yes, you and Dr. Kyle have done so much work on this. That name, monoclonal gammopathy of undetermined significance, I guess, the question would be, what research obstacles do we have to overcome to get a monoclonal gammopathy of determined significance? You're working on that, right?

Dr. Ghobrial: Exactly, exactly. We should have that name changed. 

Jenny: What do you see are those key barriers? You've talked about some of it. It's just having enough data, right? 

Dr. Ghobrial: Correct. This is truly research by the community, by everyone. We cannot do that on our own. We cannot do it in cell lines or mouse models. This is truly work by the patients for the patients, and we cannot get it unless we have large cohorts to ask those big questions. Because if we do it on only 100, 200 patients, it's not high powered enough to answer the big questions. 

So, I would truly encourage everyone. It's a blood sample. If you want to really give back to the research community, help us understand what causes myeloma in many of us, help us understand what causes progression from MGUS to smoldering. If you have myeloma, encourage your family members. Because by understanding why they are at risk, if they are your first degree relatives, we can then understand what causes myeloma in the first place. 

Jenny: I think a perfect Christmas present to ask your family, if you are a myeloma patient, to give you is to participate in the PROMISE study. I think that's a perfect gift to ask them. They don't have to buy you anything. They just have to sign up and go to Quest. That will be the Christmas present that I ask for, from my sisters. My parents are not -- they don't qualify because they're over the age range, but my sisters are available to do that.

It's truly, like you're saying, this group effort. If we really want to come to conclusions faster, we need to invite our families to contribute and our friends to contribute. Sometimes they are willing to take us to appointments and sit with us in the infusion clinic. I think it's just an easy ask to say, and I'll go with you too, if you want me to, then we'll go to lunch afterwards and make it a family affair. This is something that we can do as families. Even during the holidays, we can do it during the holidays to do this together. I just think it's really important.

Dr. Ghobrial: I totally agree with you. I think it is, like you said, it is a gift to help us understand, to help yourself and your family understand who’s at risk and why, and define things that we can do in our own hands rather than wait for it to happen. It's such an important gift for all of us. Thank you for encouraging your sisters and your family to participate 

Jenny:  I think it's absolutely critical. While we have a few minutes, do you want to review any important data from ASH? I think there's so much happening in the precursor condition space that I think it would be helpful if you pointed out important things. I also want to note that you participated on one of our Myeloma Crowd Round Tables and revealed a lot about MGUS and smoldering myeloma, so we'll include a link to that in the transcript for this show. I think that'd be helpful. Then we'll open it up for some caller questions. 

Dr. Ghobrial: Absolutely. I think ASH, this year, has surfaced two themes in the MGUS and smoldering area, but we can also talk about regular myeloma therapies. One was, again, trying to define who would progress from smoldering myeloma to active disease. What is this high-risk smoldering? Many of you already know the clinical markers, something called 20/2/20, which is 20% plasma cells, 2 grams M spike, 20 light chain ratio. 

All of us said that's good, but not good enough because it's a one-time point, while a patient is not one-time point. A patient has continuous numbers, and a 20% plasma cell number is not so accurate. You can have a bone marrow biopsy, and on one side, it's 10%. If I do it again, on another side, it will be 30%. Did you suddenly change in your own prognosis? The answer is no. Those numbers that we use may not be the most accurate numbers.

So we're trying to change it into more of a continuous variable, something that, every time you come in, we adjust the prognostic markers. We can change and be smarter in how we can prognosticate things so that we can give you more accuracy in your decision. That was done by something called circulating tumor cells by the Spanish group. We had done it by the genomic markers. As I said, we have identified three markers that can predict progression, and we're hoping to add to them more. 

The other thing that is important is understanding therapy. Should I be treated if I have high-risk smoldering myeloma? I think there were two studies that we know of, done, of Revlimid, or lenalidomide versus nothing, and then the ECOG study. These are good but, again, being careful that we don't over-treat or under-treat. What I mean is, if you have really high high-risk smoldering myeloma, I would rather treat you like real myeloma than treat you only with lenalidomide because it may be under-treating you, and that may not be good. Vice versa, if you are high-risk smoldering by 20/2/20 but you really don't have that marker, maybe lenalidomide is not a good idea for you either. 

Jenny: Yes, if I knew I was going to progress with high-risk smoldering myeloma to active myeloma and it’s coming, then I wouldn't even do a doublet like Revlimid amd dex. I'm not sure how that would help me a whole lot. I would probably want to just jump into full myeloma treatment. That idea that your longest remission is going to be your first remission, you might want to do something more like the ASCENT study or something like that. 

Dr. Ghobrial: Yes, so what we're hoping to do is something called precision interception. Not every patient has the same disease. We should not be treating you the same way. What we hope to do is, if you have 11;14, we put you on venetoclax. If you have a p53, 17p, something bad, we put you on a bispecific antibody, or something more aggressive. If you have something mild or if you have almost myeloma, you can go to ASCENT or, we're opening soon, daratumumab-RVd, like the GRIFFIN study. We're bringing active myeloma therapy early. If you have, in the future, we will think of, if you have KRAS mutation, BRAF mutation, we put you on those. 

Again, come to us and talk to us. Again, this, Jenny, really brings it to the point of having a second opinion because not only myeloma is sub-specialized, smoldering myeloma is even more sub-specialized. You need to really talk to people who do it for a living, and can give you a second opinion, and we're happy to see you. We launched PCROWD as an all virtual. You don't have to come to Dana-Farber to see us. You can get a second opinion without stepping out of your own house. 

Jenny: I think that's fantastic. I know, you've done telemedicine. I've referred patients to you before, who you've done telemedicine visits for. and what a blessing. That, to me, is a gift. I know a lot of good things haven't happened out of COVID, but that's one thing that has happened that has been helpful for patients who are older and immunocompromised and don't really want to get on a plane all the time to join studies like this and get second opinions without having to travel. Thank you for doing that because that's a gift to us as patients.

It's true. It's very hard, knowing what to do. Especially in the smoldering myeloma space, you're like, is it time? Is it time? Patients who are relapsing, and I personally understand the psychology around that, it's tough to know, what do I do? When do I do it. I feel like I'm playing chess with my life. It's hard. I just am so grateful for you and for people like you who are willing to specialize, and really help us, as patients, know what to do and know what all the options are, so, thank you. 

Dr. Ghobrial: Oh, absolutely, and thank you, Jenny. I agree with you. There is one blessing that came from COVID-19 is for us to innovate, for us to change the way we practice medicine. I agree that telemedicine or virtual visits, hopefully, are here to stay where you don't have to travel all the way to Boston to get a second opinion. 

Jenny: Yes. Well, it would be worth going, but it's much better if you don't have to fly if you don't need to. 

Dr. Ghobrial: That’s true, especially that we have a winter storm coming up. 

Jenny: Yes. Well, I would like to open it up for caller questions. If you have a question for Dr. Ghobrial, you can call 347-637-2631. You can push 1 on your keypad. I'm sure she'd be happy to answer questions around precursor conditions, the studies, or COVID, as well. We'll start  go ahead with your question. 

Caller: Oh, thank, you, Dr. Ghobrial. The HealthTree profiles have a robust amount of information in them. Is there any way that you can access existing HealthTree profiles? Or are there any additional questions or things that could be added to HealthTree to benefit the studies that you're doing? 

Dr. Ghobrial: Yeah, it's a great question. In fact, Jenny and I were just talking about collaboration between our studies together that anyone who's on HealthTree who wants to sign up to PCROWD or PROMISE, or vice versa, anyone who's on PROMISE and PCROWD, could sign up to HealthTree. 

In general, we have an epidemiological questionnaire that we ask patients. It includes not only your family history, do you have strong family history of cancers or smoking and all of those things, but it also includes certain questions of diet and nutrition and exposure. Then we ask you to give us a consent to get your medical records from your doctors because we want to double check M spikes and bone marrow biopsies and cytogenetics. 

I think the HealthTree is also doing that, and I think one of the things we can do is really work together with HealthTree to have this database available, as well as also, what we're building, available for HealthTree so that everyone can access their data on an app on their phone. That's truly what we're hoping for is that you can just open your app, see your numbers, but also be able to communicate with us. It gives you reminders of when is your next blood draw. It gives you more information. 

We're also going to hopefully work soon with a company called Vibrant Health. They're the ones who actually are doing All of Us, which is this big study from the NIH. We're hoping that we will also launch wearables where you can wear a Fitbit or your Apple Watch. It will give us more information about your health and fitness and exercise, and can potentially push out clinical trials to people, like an exercise trial or an intermittent fasting trial, things that are easy that you don't have to come to see us to get access to those.

So, the future of using, whether it's HealthTree or whether wearables or whether information on your phone, is here to come, and we're hoping to use that. Again, if you guys have any ideas, please send it to us. This is really an area where we ask people to give us advice and help. 

Caller: Thank you. 

Jenny: Yes, that's great. Okay, thanks so much. Our second caller, go ahead with your question. 

Caller: Oh, hi. Thank you for taking the call. I have a question to the doctor there. Thank you for taking the call. A few days ago, Imperial College in London announced that they have -- and there's a press release which I can send you. The team has developed a new drug, which they're rolling out in six universities for testing, that selectively kills myeloma cells in the bone marrow without impacting healthy tissue. 

In the past, the research has been focused on the NF-kB pathway. The team from Imperial College took a different approach. They've kind of effectively got by that issue. They've developed a new drug, and it's called DTP3, which kills the myeloma cells and, importantly, lacks the toxic effect on healthy cells. So far, it's been established that this has the same cancer-killing efficiency as Velcade, a drug that you're probably familiar with. However, DTP3 is 100 times more selective. As they're rolling it out, the clinical evidence so far shows, it selectively kills myeloma cells in bone marrow. Of course, I'm not a scientist or a doctor. 

My question to you is, first of all, could you get yourself conjoined to that roll-out and test this, if you think it's worthwhile? They're rolling it out in six universities after Imperial College announced it. If you wish I can show you the -- I can send you the press release. I'm sure you're familiar with Imperial College. So, could you just comment on that? 

Dr. Ghobrial: Yes. We're definitely open to any new ideas and any new clinical trials. Usually we wait for seeing safety in phase one and phase two in active myeloma, and then we try to bring it earlier in the smoldering setting, but we're definitely open to all innovative ideas and all new drug development, and not just what's available right now. 

Jenny: Okay. I can send her a link because we just wrote an article on that, actually, yesterday.  

Caller: Okay, thank you.

Jenny: That looks interesting. Yeah, thanks a lot. 

Caller: I know some volunteers that would be happy to sign up. 

Jenny: Okay, sounds great. Thanks. 

Caller: Thank you very much. 

Jenny: Good question. Okay, our next caller, go ahead with your question.

Caller: Yes, hi, hello. Thank you. I have MGUS, and I’m reading something about the vaccine having to do with spiked protein. I wanted to know if there's a risk in taking the vaccine because I already have a spike in my blood protein. 

Dr. Ghobrial: Yeah, that's a great question, different spikes, but they’re both spikes, I guess. So, a spiked protein is basically the protein on the surface of the virus, and that's completely different than the monoclonal spike which is basically your antibodies, immunoglobulins that you secrete from the plasma cells of MGUS or smoldering. When we run it on a gel, they all show up in one area, and we call this the monoclonal spike or the area where all the monoclonal proteins show up. Completely different spikes, unrelated to each other at all. 

Caller: Okay, great. Thank you so much. 

Jenny: Thanks, great question. Okay, our next caller, go ahead with your question.

Caller: Hi, Dr. Ghobrial. Thank you for all that you do in this field. I have smoldering myeloma. I'm a part of the PCROWD study, and I've also signed up for the IMPACT study. My question is on the IMPACT study. I'm a little confused. Once we've had the initial blood draw, and we know if we've tested negative or positive for COVID, does everyone continue on for the next three months, six months, 12 months, or just people that have tested positive?

Dr. Ghobrial: It's a great question, and thank you so much for your contribution on PCROWD and IMPACT. Originally, we had said we will only follow up the positive cohort, but we're actually amending the protocol, so you will be getting an email soon, in the next week or so, to ask you to continue and get the three months, six months, nine months samples. Because we noticed that even if you're negative, we may want to capture the data of your vaccination, we may want to capture the data of, what if you get infected between now and a year from now. We don't want to lose that information, so we will ask you, again, if you're willing, to continue to give us samples even if you're negative. 

Caller: I signed up, maybe a week-and-a-half, two weeks ago. How long is it taking to get the initial kits out to people? 

Dr. Ghobrial: That's a great question. We had wonderful results. We had 280 people sign up within the first 10 days, and because my lab cannot process all of the samples safely, at the same time, so we're trying to time it as we get 40, 50 samples back. So, you will find us actually not sending kits on time, and the only reason is that we're trying to time it out so that not everyone is sending it back, the samples, and then we have 200 kits at the same time. We try to process everything, and the technicians are working day and night on this. 

Caller: One final assurance that it's alright for those of us in the study to just go ahead and get a vaccine when it's available, correct? 

Dr. Ghobrial: Absolutely. What we will do in that new amendment, so when you sign up again on IMPACT, is we will ask you, have you -- we're adding a questionnaire about the vaccine because all of this is changing as we change. The trial was approved, our IMPACT study was approved before even vaccination was available. Now that it's available, we're adding a questionnaire to say, if you're receiving the vaccine, can you give us the date, so that we know the immune response, how it is linked to the date of vaccination. So you will find a few amendments which means people will sign up again and get the content again. Hopefully, it will be very simple, for us to ask you, when did you get the vaccine, give us the date, and then if you can continue on giving us blood samples. 

Caller: All right, thank you so much. 

Dr. Ghobrial: Absolutely.

Caller: I'm looking forward to being part of it.

Dr. Ghobrial: Thank you again for the questions and for the clarifications.

Caller: Thank you.

 Jenny: Thanks for joining the study. It’s so wonderful. Dr. Ghobrial, thank you so much for sharing this important study with everybody. I think it will help us understand just so many things, on a precursor status, but on COVID status, really for everybody, not just these precursor patients, just for everyone. So, I would encourage everyone to please consider joining both these PCROWD, PROMISE and IMPACT studies, invite your family members, ask them to do it as a Christmas gift for you. It's just so important. 

I also want to remind everybody that this Saturday, we are having a round table, online, interactive webcast on side effects solutions. So, if you have the side effects, we will have two key myeloma specialists participating on that. You can look forward to that, but, Dr. Ghobrial, thank you so much for participating today and for sharing your important work. 

Dr. Ghobrial: Absolutely. Thank you, Jenny, for having me, and thank you, everyone, for listening in.

Jenny: Okay, and thanks to our listeners for listening to Myeloma Crowd Radio. We invite you to tune in next time to learn more about the latest in myeloma research and what it means for you.