Irene Ghobrial, MD
Dana Farber Cancer Institute
Interview Date: September 20,2018
Dr. Irene Ghobrial shares the new PROMISE study, the biggest myeloma screening study ever run to help prevent the blood cancer from occurring by catching it at an early stage. The PROMISE study is supported by a $10M Stand Up 2 Cancer award. The study will include patients over the age of 45 with family members of MGUS, smoldering myeloma, multiple myeloma or Waldenstrom’s patients and African American patients, who are 3 times as likely to develop multiple myeloma. Joining the study is easy. You are mailed a kit which you take to a lab and the lab takes care of sending the samples to the researchers. What can we learn from the study of 50,000 people who are likely to be at risk for early myeloma conditions and their family members? Perhaps how to cure myeloma before it begins. Join this important study today!
To watch more videos about the study and find links to join, click here:
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We’d like to thank our episode sponsor today, Takeda Oncology, for their support of the Myeloma Crowd Radio programs. Now, as patients, we’re always asking, how far out a cure might be for multiple myeloma? I’m very excited to share this show with you today to talk with a renowned myeloma researcher who’s trying to prevent myeloma from happening in the first place. So welcome, Dr. Ghobrial.
Dr. Ghobrial: Thank you, Jenny. I’m really excited to be here.
Jenny: We’re excited to have you. Before we get started, let me give a brief introduction for you, and then we can start in with some questions that we have and your study that you’re launching.
Dr. Ghobrial received her medical degree in 1995 from Cairo University School of Medicine in Egypt. She completed her internal medicine training at Wayne State University in Michigan and her hematology subspecialty training at the Mayo Clinic in Minnesota. Dr. Ghobrial is attending physician of medical oncology at the Dana-Farber Cancer Institute and Associate Professor of Medicine at the Harvard Medical School. She’s the director of the Clinical Investigator Research Program at Dana-Farber and director of the Michelle & Steven Kirsch Laboratory.
Dr. Ghobrial specializes in the field of multiple myeloma and Waldenstrom’s, and specifically in the precursor conditions of myeloma including MGUS (or monoclonal gammopathy of undetermined significance) and smoldering myeloma. She focuses particularly on the role of malignant bone marrow niche in disease progression and what’s happening inside that bone marrow microenvironment and why patients are progressing from these early conditions to active myeloma.
Her laboratory research has been rapidly translated to innovative investigator initiated clinical trials. This has included over ten Phase 1 & 2 clinical studies, one of which we’re going to be talking about today. She is a co-leader on the first consortium of clinical trials for blood cancers in collaboration with the Leukemia and Lymphoma Society to form the Blood Cancer Research Partnership, which is a consortium for innovative clinical trials of community oncology sites coordinated by Dana-Farber.
She also initiated the Center for Prevention of Progression of Blood Cancers where patients with these early conditions like MGUS, MDS, and CLL are monitored, even remotely – you don’t even have to go to Dana-Farber to participate in these studies – and the myeloma study, the PCROWD study is a really important tissue bank study that we’ve talked to many of you about before that collects samples from patients with precursor conditions. She’s now the lead primary investigator for a new clinical trial that received a major grant from Stand Up 2 Cancer.
Dr. Ghobrial, we’re so happy that you’re working on these conditions and for your deep, deep research for multiple myeloma patients.
Dr. Ghobrial: Thank you, Jenny. Again, it’s all because of all the support we have from the patients and the excitement that every patient brings to the table so that we can actually change this disease and prevent it.
Jenny: Yes, I agree. Well, maybe you want to give just a little bit of background for people who may not be familiar with your work on your work in precursor conditions, like why did you began investigating this hypothesis to treat earlier potentially? How did you form the PCROWD study? What was the rationale behind that?
Dr. Ghobrial: I trained at Mayo and many of you probably know that the person who coined the name MGUS, monoclonal gammopathy of undetermined significance, is Dr. Bob Kyle. He’s over 90 years old, and he still works and is excited about research. I was trained by him. He’s the first one who actually started not just naming the disease but collecting a large cohort of people who lived near Mayo Clinic in Olmsted County and said, well, those people have a small monoclonal protein, but they have a potential chance of developing myeloma in the long term. We should carefully watch them and see them.
That has been the standard of care for all of these years. For the last 50 years, we see people who have an early precursor condition MGUS or smoldering myeloma. We tell them “watch and wait”. Just keep waiting until you have an organ damage, until you have bone lesions, fractures in your bones, kidney failure, anemia, and then we will treat you. Over the last few years, we’ve realized that, one, we have so many new options of therapies that are amazing in myeloma, yet we never use them until patients progress; and, two, we understand better the disease and we understand better the biology of the disease and that the cancer cells are already formed and have already acquired so many changes early on that just waiting doesn’t make any sense.
It’s a simple question. If I have today early breast cancer and I go to my doctor, they would never tell me, “Why don’t you just wait and leave that lesion where it is until you have metastasis everywhere and you’re fracturing your bones from metastatic breast cancer, and then I treat you.” Obviously, that would be completely unacceptable. Yet we do that every single day for myeloma. We tell everyone, wait until you have lesions and then we treat you.
The reason why I started this, I don’t want us to do this. We want to completely change the way we think of it and treat our patients early and potentially prevent myeloma from happening from the beginning.
Jenny: Well, I understand that and I think it’s a wonderful approach. What have you learned so far? Because I know there’s been so much that you’ve learned over even the last five years. I even saw a recent study talking about how they divided patients into two different smoldering myeloma groups and found one group would progress faster, like one where the genes had already mutated and the other where they were still in that mutation process and took longer. You learned an amazing amount. Can you share some of those findings?
Dr. Ghobrial: Yes, absolutely. So again, thanks to everyone who supported PCROWD. The precursor CROWD initiative that we started a few years ago, we collected many samples from many patients. We were able to understand better how smoldering myeloma genomically is characterized, meaning what are the changes in the cancer cells? That’s just one step. We have so many other steps to try and understand how progression happens. In that study — and we presented it last year in the American Society of Hematology and we’re getting ready to put together the paper and share it with everyone — we found that indeed smoldering myeloma is very heterogeneous, meaning some people may never progress and some people progress very fast and they may actually have the same numbers — 10% plasma cells and M spike that’s three grams. So how can you differentiate it when we don’t have an actual biomarker?
We did all those studies called next generation sequencing where you do something to look at the specific changes at a single point at a single DNA change. We call them single nucleotide variants or mutations. We found that indeed some patients who have specific mutations — KRAS, NRAS, BRAF or translocations or something called MEK amplification or translocation — they progress much faster to myeloma. That adds a lot to the clinical markers that we have and potentially could be used as a better predictor, a better biomarker for who will have a high likelihood of progressing to myeloma.
In the future, we expect that we take a sample from a patient whether it’s the bone marrow or the peripheral blood as we just talked before in one of the prior radio discussions of the blood biopsies, we could detect if those patients have those specific mutations or alterations and say, indeed, you have a high chance. Let’s get started on thinking of early intervention, on early therapy so that we can prevent progression.
Jenny: Okay, wow, perfect. Similarly, I know there’s been a lot that you’ve done with smoldering myeloma. Are you also just looking at MGUS in the same way? Because I know some of these studies include both smoldering myeloma patients and MGUS patients.
Dr. Ghobrial: Yes, absolutely. A lot of the clinical trials are on smoldering myeloma because it’s much more advanced and it makes sense to treat early. However, we said, well, maybe we’re actually targeting a clone that has already progressed. When we say high-risk smoldering myeloma, many people already have changes in their bone marrow that look exactly like myeloma. So can we even go earlier with some novel ways of thinking, like either a single agent daratumumab, which is an antibody that we use for myeloma or vaccine therapy, or something that can alter the immune system and prevent progression even at an early time? We have a clinical trial for high-risk MGUS and low-risk smoldering myeloma that’s open for single agent daratumumab.
We’re hoping to open vaccine trials for smoldering myeloma and then bring them to an earlier stage later on. We’re hoping to start understanding better how to target the immune system early so that we can give the vaccine at an MGUS stage and say to everyone, this is it. We don’t need to think about it in the future, sort of like what we do with infectious diseases and other things, a way of prevention completely. Of course, I think it’s important to talk about the PROMISE study now because that’s really targeting how we can detect early. I don’t know if you wanted to talk about it later on or not, but I’m happy to discuss it.
Jenny: We can start now. Sure, sure.
Dr. Ghobrial: Sure. The whole idea of the PROMISE study — and this hopefully will launch in the next week or so — is we see people who have been incidentally found with MGUS and smoldering myeloma. You go to your doctor when you have a high protein level or some slight anemia, and that’s how you’re diagnosed with MGUS or smoldering myeloma because you’re asymptomatic. You don’t have symptoms. You don’t have bone pain. But we’re missing so many people. So everyone walking down the street who has MGUS and is not diagnosed is potentially someone who will develop myeloma in a few years from now, and we didn’t do anything to find it.
The part that was interesting is that when we go to our regular doctors for screening, we screen for breast cancer with mammograms, we screen for colon cancer with colonoscopy, yet your doctor never tells you, “Why don’t I do just a blood test to screen if you have a myeloma or not,” to look for blood cancers. We do not have a screening test for blood cancer, and we want to change that. So we said, let’s launch a large study, 50,000 individuals. But instead of screening everyone, because the chance of developing MGUS is only 3% at the age of 50 and then it increases with age, let’s look for people who have a very high chance of developing myeloma. That includes an African-American population because there’s three times higher chance of developing myeloma. They may develop it even at an earlier age, so at age 40 or 45, an African-American patient may be at a much higher risk than a Caucasian.
The other thing is let’s get people who have a family member who has myeloma or a lymphoma or B-cell malignancy, meaning if my brother and sister or one of my family members has myeloma or has MGUS, my chances of developing myeloma is also very high, two to three time higher. So let’s ask everyone over the age of 45, so again young population, so that we can potentially find myeloma early and prevent it up to the age of 75 and screen this population.
We were very lucky to Stand Up 2 Cancer believed in this idea that we will screen for a blood cancer. We will change the way we think of primary prevention. We will do this all online. You don’t have to come to Dana-Farber. You can just be wherever you are in the United States. We want you to register online. In fact, you can already start sending us your name and information by email, and it’s firstname.lastname@example.org. Jenny will have it available for everyone again. But in this case, you can register online. We will send you a kit where you can go to a Quest lab anywhere close to you or any of the other institutions where you can get your blood drawn. And it will be tested at Mayo Clinic to see if you have the M spike or not. If you do, we would be calling you. One of our nurses will call and say, “Yes, indeed you have an M spike. Let’s get you connected to a hematologist or oncologist close to you. Let’s make sure that indeed we understand what’s going on with you, do you have MGUS or smoldering and follow you.” If you don’t have it, well, the first thing is you get to know that you don’t have it which is good; and, two, we will follow you again in three years to make sure you don’t develop it again in three years from now.
This close follow-up of 50 thousand individuals, both having it or not, will help us understand why certain people develop it, why certain people are at a high risk. We will ask epidemiology questions like medications, health changes, exercise, diabetes, other things that can lead to progression in people. But we will also do genomic studies as well as studies on the bone marrow samples from the positive cohorts, from the people who test positive, to try and understand how can we prevent myeloma from happening in those people who have MGUS and smoldering.
This will be the first time in the United States. We look at people who are actually screened for this disease and not found incidentally. So we’re very excited about that. It’s truly a promise for us to change the way we think of myeloma and potentially prevent this completely from happening.
Jenny: I think it’s amazing that it just makes so much sense to me as a patient that this earlier screening is not that expensive, it’s not hard to do. I don’t know, it just makes so much sense because it saves you so much time, money, and pain in the long run. So what a wonderful study design. I’m just thrilled. Maybe you want to also talk about the team behind this because I know you’re the primary investigator, and you have this wonderful team in place.
Dr. Ghobrial: We call them the Dream Team. Stand Up 2 Cancer calls them the Dream Team, and indeed it is a dream team. We have six different institutions: Dana-Farber is one of them, but we have the Broad Institute, MIT, The Harvard School of Public Health, Johns Hopkins, Mayo Clinic. All of us together are working on this one idea. Let’s make sure that we get the samples, understand better the disease, call the patients, and follow them up until we understand better how to prevent it.
I can tell you within here at Dana-Farber, we have a huge number of people working on this just to coordinate it, how are we going to have everything streamlined. We’ve worked very closely with many people. Of course, with our advocates — and Jenny is one of them, of course — making sure that everything we do and we develop is discussed with you to make sure that this is really delivering something that patients like and understand and are willing to be part of.
Jenny: Well, it’s fantastic. I have a question too. When you said they’re being tested. They don’t have to send in — I mean they’re sending in samples basically or having a test run at a local facility — how do those results get back to you? Just walk me through the steps that a patient might go through to go get a sample and then get that sample to you?
Dr. Ghobrial: Yes, absolutely. Our website will actually have a very nice animation of the whole process so that people can see it and understand it. But let’s say that you go on the website and register and say that you’re interested, we will send you a small questionnaire. You fill in the forms. And then the kits are being developed by the company called GBF. We’re very lucky and appreciative of all the work that has been developed by many other companies that are working with us not just through the Dream Team, and that includes GBF and Quest Diagnostics and, of course, the Broad Genomics Platform and the Mayo Clinic Labs because they’ve really been instrumental in developing this, as well as the Fred Hutch Team that developed for us the platform for all of this integration of the systems and the IT behind the scenes.
So the patient will log in. We will send them the kit that’s already pre-packed and shows all the information. They would go to a local Quest Diagnostics where they’re already trained to know what to do with those samples. They get their blood drawn within, hopefully, five to ten minutes. Then this sample will be sent, part of it to Mayo Clinic and part of it to the Broad Institute for the research. The Mayo Clinic sample will be tested whether they have myeloma or not. This is the M spike and serum free light chain. That information gets back to us at Dana-Farber.
We have a registered nurse who’s trained to tell the patients whether they are positive indeed or not. If they are positive, then we also help them through our collaborations with the International Myeloma Foundation, the MMRF (find a Myeloma Specialist on the Myeloma Crowd) to get into one of the local oncologists or hematologists in the area. We help them get all the tests that are required to understand better whether they have MGUS or smoldering myeloma. We ask them to still send us more of those research samples as they’re going through their clinical routine studies, and then we follow them every three to six months or every year depending on, of course, the disease status until progression.
This is a cohort of people who are always connected with us. It’s basically like a social media network in a way. They can call us anytime. They can connect with us. We will give updates through the website. We will have information for everyone as we go along. But also, we will offer clinical trials for this specific cohort to tell them about the new advances and the new options they can have.
The people who screen negative, we will ask them if they’re okay to be reconnected with us again in three years, and we get another sample from them. It’s an opportunity for everyone who has a family member with myeloma or who is African-American over the age of 45 to get tested for free and get to know whether indeed they have this or not, and then be part of this community who’s changing the way we think of myeloma and offering us this amazing benefit for everyone else in the future.
Jenny: It’s a very valuable service, I think. One thing that I think is important about this is that if they do test positive — I kind of want to stress this point — that you’re going to help direct them towards an academic facility where they can be appropriately followed and potentially treated if need be by a myeloma specialist versus a general oncologist who might be seeing 20 different types of cancers. Do you want to talk about that a little bit about the importance of being able to follow them with a myeloma specialty team?
Dr. Ghobrial: Yeah, absolutely. I think that myeloma is a rare disease. We’re not saying that you have to go to an academic center, but we’re encouraging especially if someone has advanced disease or something that requires therapy, it would a good idea to ask an expert. That happens for every disease, but myeloma especially is relatively a rare disease. If you are going to get therapy, we’re here available at many academic centers, available to give an opinion and see what are the best options. Then it depends on the patients. Some patients cannot travel too far and want to be treated locally and that’s fine, but it’s a good idea to potentially have just one opinion and have some inputs from the experts.
What we try to do with the BCRP, which is that consortium, is we provide some of that care to all the community sides and some of those clinical trials to all of those community sides who are working with us, so trying to deliver that same expertise care back into the community. That requires a lot of work, but at least it’s a one step forward for that.
Jenny: How many clinical trials are there currently in these early precursor conditions? Why should patients consider joining a clinical trial if they have one of these conditions?
Dr. Ghobrial: So clinicaltrials.gov has the list of all the trials. You can go online and see them and see which ones are available. But, of course, it’s very confusing because you’ll see so many criteria. So that’s why it’s important to talk to us, and we’re happy to help anytime. We have created here a Center for Prevention of Progression. So the whole thing that we’re doing at Dana-Farber is specifically focusing on early prevention. We want to actually see you. Anyone who has MGUS and smoldering and has a question, we’re happy to see you, give you our opinion, give advice on what to do.
For some patients, watch and wait is fine because your risk is very low. But if your risk is very high to develop myeloma, this is when we start telling you about all the potential options we have available. Some of those again are online. I don’t want to discuss them now because either they’re closed by the time someone comes or they’re not available yet. So I’d rather have those very specifically later on. But again, email us, call us, come for a second opinion anytime. We’re hoping to launch soon the physical clinic where not only MGUS and smoldering are seen, but also other precursor blood cancers are seen in the same clinic so that we truly have the first center, the first cancer center that focuses on prevention for our patients.
Jenny: Wow, I think it’s totally amazing. In terms of study length, you mentioned that if patients test negative, they’ll be checked after three years. When is the study complete – does it end after a certain period of time?
Dr. Ghobrial: Well, we’re hoping that this will be something like what Bob Kyle has created 50 years ago and it’s never ends. It keeps giving you more and more information, more help. So the funding is only for a few years, but we expect that this will be so rich and so useful for us and for many other scientists in the world that we keep learning from it in the future. So I hope years from now and I’ll be gone, but this study keeps going on and help everyone.
Jenny: Well, I hope so. I hope you’re another Bob Kyle because he still comes to office every day and does research even at 90. It’s amazing.
Dr. Ghobrial: He is, yes. There’s only one Bob Kyle, though.
Jenny: Well, you’re pretty unique yourself. I think that’s amazing. Can you tell us what you will do with the findings and how long do you think it will take to generate new insights? I know it’s kind of a difficult question when you’re planning a clinical trial and launching it, but I think it’s important for patients to know where you’re headed.
Dr. Ghobrial: Yes, absolutely. It’s important also to have realistic expectations of how fast we can get information because yes, we will sequence all the samples as fast as we can, but sometimes we need long term follow-up to understand the implications. We need the years of follow-up sometimes to understand indeed this changes progression or not. However, what we’re doing in PCROWD is we have the samples of patients who already have MGUS and smoldering, so already we’re learning from what we have now and we can implement it to understand better on the new samples and on the future studies. It will keep changing.
I can tell you the technologies that we have right now may not be the same ones two or three years from now. We’re improving so fast and having so many new ideas and so many new technologies that what we do now could potentially be useless in two or three years from now, and we will have even better and better ideas and better technology to understand the disease better. We’re encouraging people who have MGUS and smoldering myeloma right now, please go on PCROWD and register and give us your samples because today we can do the sequencing, and today we can understand better what’s going on with your disease and that can help us immediately, but also can help the future studies of PROMISE study and for future other patients.
Jenny: Just one thing to point out also is that, so the PCROWD study will be an ongoing study? That won’t really have an end, will it?
Dr. Ghobrial: Correct, yes. We’re ramping up the website for this one so that the PROMISE and PCROWD will be basically sister websites. Patients who have MGUS and smoldering and get to know about PROMISE and we tell them, well, you’re already known to have MGUS. Don’t get disappointed. Just go to PCROWD and you can still help us and you can still participate in it. These are two sister websites, two sisters studies basically for anyone who either will screen and is a high risk but does not have MGUS or for people who have MGUS and smoldering and are already known to have it.
Jenny: Okay, perfect. Well, there’s one other tool that I think might be helpful in this situation. We’ve created this tool called HealthTree that we’ve been talking about. In that tool, you’re able to find a myeloma specialist, and you’re able to see all the active clinical trials that are also available. I know I’ll be talking to you about — because we’ll be providing that data to researchers. So if patients also want to participate in HealthTree, we could share that data back with you for this study that could potentially give more information for patients whose data you’re trying to look at as a whole product. A 360-degree view of the patient I think is important.
Dr. Ghobrial: Yes, absolutely.
Jenny: That’s on healthtree.org if people want to create a profile there.
Now you talked about asking people about their medications, their health, their exercise, their genomics. One thing that you’ve been studying for a really long period of time is the bone marrow microenvironment, what’s happening inside that bone marrow. Also, there’s a lot of work being done, it seems like, on the immune systems status of individuals like why do some people — maybe it’s the immune system that’s holding back the progression of the disease, or maybe it’s something that’s happening in their bone marrow, maybe it’s combination of the two. Do you want to talk about those two factors or what you’ve learned about those two things?
Dr. Ghobrial: Yes, absolutely. The one thing that sometimes intrigued us is that sometimes the cancer cells already have many of the changes and mutations even at an early MGUS stage. But why would those cancer cells not keep growing and develop into myeloma within a year? Why would they sit around for 10, 15 years? What’s holding them off? This is when we realize that cancer cells are not just sitting on their own. They live in an environment. You can think of that ecosystem and how important it is on supporting or preventing cancer cells from growing. We think part of that ecosystem is the immune system.
So within the bone marrow microenvironment, the cancer cells sit but an immune cell can tell it, no, you cannot keep growing. You are sitting there and we will watch you carefully, or you can have an immune system that’s lazy, that doesn’t work very well. In that case, the cancer cells will keep growing and proliferating, and there is no policing basically to prevent this from progressing. Potentially, by understanding how the immune system works and how the microenvironment works, we can understand how to control the disease from growing even if the cancer cells exist. This is very important because we have now something called immunotherapy, like the immune checkpoint inhibitors and the antibodies and all of those things that we have that can target the immune system, and make it grow much faster or make it stronger basically to police those cancer cells.
One of the things we’ve done — and this we’re hoping to present in the American Society of Hematology meeting in a couple of months — is something called single cell RNA sequencing, meaning we take the bone marrow cells and we look, yes, at the cancer cells, but we also look at all the other cells around it. Instead of looking at them in bulk, think of it as looking at a forest versus a tree. If you can look at every single tree and understand better how it looks, it’s very different than looking at the whole forest and not having the specific details of each tree. Single cell RNA sequencing is basically that. You look at every single tree, you look at every single cell and understand the genes that are inside this cell. You can tell, are there more T cells? Are the more B cells? Are there more NK cells? But not only that, are they changing in a myeloma patient versus a normal sample? What has changed in them and can we target that by developing drugs or antibodies that can improve on the immune system to prevent myeloma from growing?
Jenny: Very important. One of my other questions was, just overarching, what other strategies have you seen changed in the past five years or so, five or ten years, or clinical practice changed in learning all these new things? Because it seems like the technology, the advancement of immunotherapy, the technology that you’re using to test, the genomics of the disease are really radically changing the treatment paradigm and influencing that. So what overall strategies have you seen changed?
Dr. Ghobrial: Yes, I think over the last five to seven years we’ve seen a lot of advances in genomics and understanding better at a very, very deep level the mutations and the alterations that happened at the DNA, at the RNA level but also at the epigenetic level. These are all in the cancer cells. Then we look at the immune cells and this has been again a huge change in the way we think of how to target cancer cells by looking at that interaction between the microenvironment immune cells and the cancer cells, all of the new development not only in technology development like single-cell level of studies but also understanding how to develop therapy for them. We also have all the CAR T and all the ways of manipulating the immune system by cellular therapy, by using your own cells to activate your own immune cells and they can kill cancer cells. This is a huge change in how we treat patients. So there are a lot of changes within not just the treatment but also, like you said, technology development.
Jenny: Yes, amazing. It’s amazing the progress and the pace to me because the pace seems to be going so quickly. Going back to basics, we’ve been on this 50-city tour to introduce this new platform called HealthTree. In one of our meetings, we were in New Mexico, one of the patients said, “You know, I went to this general oncologist. I was diagnosed with MGUS. He told me I had one to three years to live. I’d better get my affairs in order.” So I think in general, we need better education about some of these early conditions and for people who are listening that might not be familiar with some of the conditions. Can you just give a brief overview of MGUS and what that means and smoldering myeloma and what that means and high-risk smoldering myeloma? I know we’re kind of seeming to go backwards a little bit, but I think it’s important for people who want to participate in the PROMISE study and might not understand what these conditions are.
Dr. Ghobrial: Yes, absolutely. There are two precursor conditions to myeloma and they’re divided by certain numbers, but those numbers are arbitrary because again a patient is not — if you have a certain number of cells in your bone marrow, any changes by 1%, that doesn’t suddenly change your prognosis. So I will define what are the numbers, but just be careful that a patient is a very unique. Your own progression and your own changes is not because suddenly you’ve change from MGUS to smoldering myeloma.
What is MGUS? MGUS is monoclonal gammopathy of undetermined significance. Long, big name. We know it actually has a determined significance because it can go on to myeloma, so the name should be changed. But having said that, it means that you have a very small number of pre-cancer cells, plasma cells, which are the myeloma cells. They may already have some changes in them, but they cannot keep growing on to develop myeloma. So you would have less than 10% of those cancer cells in your bone marrow, but you do not have any of the other changes, meaning you do not have anemia or bone lytic lesions or renal failure or hypercalcemia. You do not have some of the new criteria we have like a light chain ratio, a serum free light chain ratio that’s very high, over 100, or by an MRI or a PET/CT scan, a couple of lesions in your bones or a significant number of plasma cells in your bone marrow which is that 60%.
If you have none of those, you do not have active myeloma or symptomatic myeloma. Then if you’re less than 10% in your bone marrow or less than three grams protein in your blood, then you have MGUS. Why is this important? Because MGUS, in general, if we put everyone together who has MGUS, the chance of progression is only 1% per year, meaning in ten years you have a 10% chance of progressing to myeloma, in 20 years you have 20% chance of progression to myeloma. This is a very, very small number. If your age is 50 or 70, I’ll tell you when you’re 90, you have 20% chance of developing myeloma. This should be the least of your problems right now. You can have ten thousand other things that are a headache for you rather than the MGUS. This is important to not scare someone and tell them you have only one to three years of survival. That’s completely wrong.
Jenny: Oh, no, I thought it was ridiculous.
Dr. Ghobrial: Yes. I mean that’s really unfair for a patient to have that. When I talk about we see our patients and we do prevention of progression, when we do all of that, that doesn’t mean that we’re changing in any way how low the risk of developing progression. We’re just saying for people who have higher risk — and I’ll talk about that — we can do something to prevent it from happening.
Now, smoldering myeloma is the next step up before it goes on to develop myeloma. I say that but sometimes we never detect exactly the differences. We cannot tell you, “Well, you know next year maybe smoldering, and then the year after you will be myeloma.” We are not very good at predicting who will progress and who will not. That’s why it is very important to go on and keep following your doctor. Even if you have MGUS, even if your risk is very low, keep seeing your doctor once a year because it’s the people who stop following up, they’re the ones who develop myeloma and we don’t know, and then suddenly they come in with bone pain and it’s too late because they’ve developed already the disease. So don’t stop seeing your doctor at least once a year if you have MGUS.
Now, if you have smoldering myeloma, this is when you have more than 10% plasma cells in your one marrow. Again, a lot of my patients will tell me, “I’m at 9% so I’ve MGUS.” But they do another bone marrow biopsy on the other side and “I’m 11% so I have smoldering myeloma.” How is that possible? The answer is yes, we put those numbers but they don’t mean anything for you. Your cells, whether they’re 9% or 11%, won’t make any difference. These are distinctions that we use so that physicians can talk to each other so that we can define better biomarkers, but they do not change your own prognosis as a patient. That’s very important to understand that.
In general, smoldering myeloma has a chance of 10% progression per year, so much higher than the 1% per year. If in five years, you would have 50% chance of progression, and this is when it starts becoming hard to understand. Let’s say you’re 40. When you’re 45, you may have myeloma. That could be a problem. Then a specific subgroup of those people with smoldering myeloma, we call them high-risk smoldering myeloma. They have a very high chance of developing myeloma. Within two years, they have a 50% chance of developing myeloma. There are different criteria for this. There’s the Mayo Clinic criteria, the Spanish criteria, the modified new Rajkumar criteria.
There are different ways so we don’t have to go into those details. But just a subgroup of people when they have those markers, it indicates the cancer cells are ongoing. They’re growing up. They’re changing things. You have a very high chance of going on to develop and organ damage in the next couple of years. You may have no symptoms now but be very, very careful. You may have symptoms very soon. These are the ones that we’re offering now clinical trials to prevent progression because we know, at least by the Spanish study, that some treatment is better than observation in preventing progression in those patients, in preventing the lesions and the kidney failure and so on. This is why we’re doing all those trials to prevent progression in the high-risk group.
So I don’t know if that clarifies it or confuses it more. I know it’s very confusing for many patients.
Jenny: No, it’s a wonderful overview. I think if patients, especially if we’re reaching out to people who have never heard of these conditions before or family members of people with these conditions, it’s really important for them to know the basic, so that was just a great overview. Thank you so much.
Do you have any idea how many people in the United States and maybe a breakout, Caucasian versus African American who might have one of these precursor conditions? Just curious.
Dr. Ghobrial: It’s very important. We know a couple of facts. When the study by Dr. Kyle was done in Olmsted County, he basically screened that whole population. He found that indeed the 3% chance at age 50 for having MGUS, but these were mainly Caucasians in Olmsted County. When the NCI with Ola Landgren looked at a larger cohort of people who had blood samples stored for ten years and they went back to all of those people, they found that indeed that number reflects the whole population and not Olmsted County. So again, 3% chance in general at age 50 to have MGUS, and then it keeps increasing with age. It gets up to 9% at age 70 and so on. As we get older, our chance of developing MGUS is much higher.
However, what he also found in that study is the African American population is three times more common to have MGUS as well they are much younger when we can detect it. At age 40 and 45, you can find MGUS in an African American population. Other studies that Ola Landgren has done as well as the studies by the Icelandic Group have found that the family members also have a very high chance of having MGUS. This is why we picked those two numbers, the African American and the family members, to be the ones that we think will have about a 9% chance of having MGUS or smoldering myeloma when we screen for them.
Jenny: It makes so much sense to identify people early. This study is beginning in about a week. You’ll be able to have open registration. One question that I think is important is how can patients best help you in the study? Because I think patients want to help advance the research. People were really excited when we told them about the PCROWD study, and there were many people that helped to share that information. How do we reach the 50,000 people that you want inside the study?
Dr. Ghobrial: Yes, it’s all going to be driven by patients actually and by healthy individuals. I would say every single patient who has MGUS or smoldering myeloma or myeloma, talk to a family member. That’s the first thing. If they’re interested, give them the website. Give them the information or our email at email@example.com and tell them to register. We would love to see everyone. Of course, if you’re an African American over the age of 45, please consider the study. It’s an easy blood test. It will require minimum amount of time from you to go to the phlebotomy center. But, hopefully, that can change the way we think of following our people and our patients and screening everyone in the future. We hope that this will be a blood test that will be part of the routine care your primary care doctor will do. But we cannot do that, and we cannot change the way we think of screening until you actually participate in the study.
If you have neither of those, please use social media. Please talk to your neighbors please and any of the myeloma events. Talk to people in the churches and anything. If you can just tweet about it, talk about it in Facebook, this is the way we can tell everyone about the study and help get the 50,000 patients’ accrual.
Jenny: Absolutely. Also, inside the HealthTree we also ask a question. We allow researchers like yourself to ask the patient community questions, survey questions. One of the questions in there is would you like to participate in this study that you have this PROMISE study? So, we will share it as much as we can, and we’ll share it in our groups and in social media also.
Dr. Ghobrial: Wonderful.
Jenny: Well, it’s such a key study to learn, how does this even happen? Because when you look at active myeloma, I had so many people say, “Well, myeloma is just not a single incident. It’s something that you’ve probably had MGUS at some point. There were probably certain triggers that triggered it into myeloma.” If we can figure that out and we can see that 360-degree view of the patient, then you can come up with better hypotheses about who should be treated and with what. So, I think it’s just really critical.
Dr. Ghobrial: Absolutely.
Jenny: Yeah, it’s amazing. Well, I want to leave some time for caller questions.
Dr. Ghobrial: We want to thank you, Jenny, again for this.
Jenny: Oh, sure. I think that I’ve just seen so many researchers like you that are very talented and very bright and doing amazing work. I think the patients can help accelerate a cure; I really do I think by even simple things like sharing something on your Facebook page. Yeah, it’s wonderful. So anything that we can help do to help people avoid getting myeloma. This is not a club that any of us want to be in. We don’t want patients to have to go through active myeloma. So if they have early conditions that you can stop progression, it’s fabulous and we just applaud you for all your efforts.
Okay, we have several questions that I would like to — if you have a question, you can call 347-637-2631 and press 1 on your keypad. Go ahead ask your question.
Caller: Hi, Jenny. Hi, Dr. Ghobrial. This is Dana Holmes, proud to be smoldering, couldn’t be prouder for the past 3 and a half years. I have submitted 12 samples of serum to your brilliant researchers and two bone marrow samples. Obviously, there’s more to come. As long as I keep smoldering, you’ll keep getting my samples. Maybe the universe will keep me smoldering for that purpose alone.
Dr. Ghobrial, of course, thank you for everything you do. It’s just such a pleasure to work with you and your team and just the way that you have supported our smoldering and MGUS communities with your willingness to engage in social media. It’s just incredible, so thank you for that.
Dr. Ghobrial: Oh, thank you. It’s really a lot of your work, Dana. So we thank you actually.
Caller: Well, my part is really easy, just kind of getting people excited about your programs. They’re just so terrific and they’re so easy to participate in. This PROMISE study sounds even easier than the PCROWD study. I just want to clarify a couple of things. It would really be for people over the age of 45 who are at the highest risk of potentially having MGUS or smoldering myeloma that being a first degree relative and/or African Americans because we know that patient population has a higher risk. Is that correct?
Dr. Ghobrial: Correct.
Caller: Okay. What about first-degree relatives who have other blood cancers, would they be eligible or is this strictly for myeloma?
Dr. Ghobrial: No, we allow also Waldenstrom macroglobulinemia because it’s very close to it. I don’t recall that we’ve allowed CLL or other B-cell malignancies although they may have a high chance. I have to go back and see if we decided it could be too confusing, so we kept it very strict about just myeloma, MGUS, smoldering, and Waldenstroms.
Caller: Okay, great, because then we’ll be able to encourage the folks who have IGM MGUS and smoldering myeloma to participate.
Dr. Ghobrial: Correct.
Caller: Then just to go over the idea with the labs. We get our kit, which is similar to the PCROWD, we take it to Quest Labs or our own myeloma facility to have that sample drawn, correct?
Dr. Ghobrial: Correct.
Caller: Then how do we send them to you? Are we getting like a FedEx envelope like we got with PCROWD, or is this something that the labs then will send on to the Mayo Clinic? How does that part work? Do you know?
Dr. Ghobrial: We made it even simpler. So Quest has actually agreed that they do the FedEx’ing for you. They’ll take the kit, and they’ll do everything.
Caller: Wow! That’s a big plus. Great. Now, Dr. Ghobrial, I know you guys are going to be testing M spike and serum free light chains. What about for an MGUS that might be too low for these tests to actually detect? Are you guys going to think about adding an immunofixation just to pick up those really small MGUSes?
Dr. Ghobrial: Great question. So actually, we have a very good collaboration with Mayo Clinic. Not only we will do SPEP, serum free light chain, and then reflects with immunofixation. We will have all of the samples getting done by mass spectrometry.
Caller: No way. Wow, that’s exciting!
Dr. Ghobrial: Yeah, it is. Mass spec is a way that can detect an M-spike much, much better and in a much higher sensitivity compared to the routine testing by serum protein electrophoresis. It will still be at a research level, but we believe that that potentially can detect some of those cases where it’s a slight change but we’re not sure, and then the mass spec will give us more information. But it will not be a clinical test; it will be a research test. Then, hopefully, in the future we can switch it to become a clinical test.
Caller: Oh, okay. So mass spec is going to be under the research end of it. Okay, got you. That’s wonderful. Last week, Jenny had an interview with Dr. Steven Lipkin who specializes in clinical genetics at Weill Cornell. He was talking to us about some of his research being done on a germ line gene called KDM1A. He was basically explaining that the data shows that individuals who carry that germ line mutation are predisposed to familial multiple myeloma. Is that something that your work, either in PCROWD or at someplace else, has also supported? Because he also said that he’s working with a genetics company to create an actual multiple myeloma gene panel that would include this amongst other genetic codes, so to speak, to sort that all out. Because that’s really important for any of us that have families and children. This is a big concern whether we get them tested or not. Should we encourage it? Should we wait? It’s always a great cloud over my head personally for my family.
Dr. Ghobrial: Yes, absolutely. One thing and maybe I did not clarify it is because we’re picking only high-risk people, we are asking an important question, why an African American or a family member would have a higher risk of developing myeloma? In fact, we have both: the people who do have it, the positive cohort, as well as the control group who doesn’t have it but has the same high risk for being in individual either first degree relative or an African American. We’re doing germ line sequencing for all of those patients and also comparing it to the general population sequencing that we have at the Broad Institute because there’s a huge effort of cohorts to understand germ line genetics which is what you’re saying exactly. Am I at risk and what am I carrying? What will I give to my offspring as a potential risk? This will be all definitely part of the study and because we have a big number of people, then we will have the confidence to say if this is truly related or not, because you need a large number of samples for something like this.
Caller: Absolutely, you do because you know right now we’re hearing that our children could perhaps have a two to four-fold increased risk which when you think about it it’s not a whole lot, but it might be more because we don’t know enough about it. So this is a wonderful, wonderful initiative. I thank you for it. I thank all of your supporters who were providing with the funding to do this. I’m going to be calling my family members.
Dr. Ghobrial: Thank you so much.
Caller: Well, thanks, Dr. Ghobrial. Thanks, Jenny, for having this wonderful forum once again. Take care, guys.
Jenny: Okay. Thank you for your question. And we have another caller. Go ahead with your question.
Caller: Dr. Ghobrial, thank you very much for this work. It seems to me, while it makes sense to try to treat people earlier, it sees that that concept is premised on a couple of things. One is which is that we can sort of recently accurately identify who the true high-risk patients are. I’d like to get a little bit more color on your thoughts as to whether or not we’re at a stage where we can reasonably feel like we can identify that group of people and also whether or not treating those people sooner rather later is not going to do more harm than good. Are we at a point where the treatment options where that calculus is more favorable to the patient?
Dr. Ghobrial: Yes, great questions. So let me take them into two parts. The first thing, are we at the stage where we can truly understand who is at high risk? Let’s talk just at the high-risk smoldering myeloma. The clinical criteria we use right now which is the M spike, the tumor burden, light chain ratio, and all of those, whether you use the Mayo Clinic criteria or the Spanish or the composite, the one that has all of those, are really good in saying indeed those people have high risk. It may miss some people who are intermediate risk and should actually be in the high risk. That’s why the genomic data could be important in adding this information. If you add the IgA or some other factors into it, it may put someone at high risk who is not. So it’s not a perfect, perfect biomarker, but it’s pretty good in detecting most of the population who’s at high risk of developing myeloma.
We are working on improving it and the IMW, the International Myeloma Working Group, is working on a consensus recommendation of how to truly define this group. I think as we develop better genomic markers, meaning the MEK translocations, the map kinase pathway, all of those things, we will refine this a little bit to be even better in predicting who’s at high risk. So at least the criteria of high risk that we have right now may not be perfect but are not that bad. They’re pretty good in detecting most of the people who will be developing high risk.
The second question is should I really treat or will I cause more harm? That’s actually a very important question. I get that every single day. There are several things for this. The first thing is the tumor clone, meaning the cancer cells, by waiting for them to grow on into symptomatic myeloma, there’s nothing that will help them improve. They will just get worse and worse and will acquire more and more mutations. There’s nothing beneficial from allowing them to go on to eat your bones and cause kidney failure. There’s no benefit from waiting basically.
However, what we want to know, especially at high-risk myeloma, is we do not want to sub-treat those patients. If you’re at high risk, doing a little bit of Revlimid, doing a little bit of therapy is actually potentially more harmful because as if you’re treating active myeloma with a single drug instead of the combination of drugs that we think are good. So one thing is if we treat, we treat with effective therapy. We want to treat with drugs that we know are active combination therapies, things that we know indeed will make a difference, at least for high risk smoldering. For lower risk and things like this, yes, it could be very different. We can use the immune system to harness things and improve on it. We don’t have to kill everything.
So the idea right now is if you have high-risk smoldering myeloma, you may have basically everything that an active myeloma has, and we should consider real therapy for those patients to kill as many cancer cells as we can. That should make a difference in progression-free survival. The other thing is there is already clinical data from the Spanish group that sees treatment with lenalidomide and dexamethasone (Rev/Dex) versus observation changed the progression-free survival and the overall survival of people. Those that progressed later on, they had no harm. They did not develop a worse myeloma after they stopped therapy.
The one thing that’s important to remember is in the smoldering studies that we do, we treat for certain number of months and then we stop, and that’s important. We do not keep treating you forever because that’s when you may acquire resistance by maintenance therapy for a very, very long time. We treat for two years and then we stop. If you had an excellent remission and we stopped, there’s no more that drug effect that could potentially develop resistance. Basically, we’re allowing the system to restart from scratch and allowing it to go back into an MGUS-like stage or potentially if it is in a great remission, hopefully, that doesn’t come back for years and years and potentially may be cured.
The idea is that effective therapy that restarts the system from scratch potentially helps the immune system to recover, so using immunotherapy, using vaccines, using other things will be very important. Not sub-treating it and stopping therapy and not considering on forever are steps to make sure that indeed we can make a difference in the survival.
Caller: So I just want to follow up quickly. The thought is that we’re not creating necessarily resistance by treating early because — I mean that’s sort of an important point. Is that right?
Dr. Ghobrial: Correct, yes, yes. If I told you I will give you only 5mg Revlimid and you have high-risk smoldering, that can cause resistance as if I’m treating active myeloma with a very small dose, but we’re not doing that. We have not seen a single case of resistance because of those therapies that we’re doing. You’re basically saying, instead of treating a patient with active myeloma when they have lesions in their bones and kidney failure, I’ll treat them a year before or a year and a half before when they have the exact same kind of cancer cells, the exact changes, but they have not caused damage of the bones and damage of the kidneys. At least this is true for the high-risk disease.
Caller: Thank you.
Dr. Ghobrial: Absolutely.
Jenny: Okay, great. Thanks for your question. We have another caller question. Go ahead with your question.
Caller: Hi, yes, my name is Jill and I’m a myeloma patient. I was actually interested about things that trigger myeloma because it seems like in our patient support groups online that there are fair number of people who have autoimmune conditions. I actually do have an autoimmune condition, Graves’ disease. I also had a car accident, a severe one that caused a lot of inflammation about three years before I was diagnosed and where I got my compression fractures. So since I’m the mother of four, I guess I’m wondering about risk factors for my kids and just in general, whether stress or inflammation is a common risk factor that could trigger smoldering or MGUS condition turning into myeloma.
Dr. Ghobrial: Great question. So we don’t have all the answers. That’s why actually part of the PROMISE study we’re doing all this epidemiology work. So we will have a long questionnaire for everyone to answer question like this. Have you had autoimmune diseases? Are you on specific therapy? Is diabetes or medications — any of those things that we think could allow the system to change. So I talked about the microenvironment, but there is also a big environment, which is inflammation of the body, immune dysregulation which is these autoimmune diseases, other triggers that allow the immune system to become in disarray and that allows the cancer cells to grow or could allow that first hit to happen. Why would the B cell or plasma cell become a cancer cell? Maybe something allowed it to grow so fast because of an infection or an inflammation or an autoimmune disorder. By growing so fast they get this mutation, they get this mutation. They get this adder while they’re dividing. We don’t know all the answers, but part of this large cohort study is we will start some of those questions answered and then they would require further research, of course.
Caller: Yes, that’s very interesting. I am actually a researcher, and I study proteins involved in misfolding that relates to ALS and other diseases. Definitely, it seems like there often this second hit for the initial stress that somehow gets enhanced by a secondary stress like the head trauma and other things, for example. It’s very interesting though that there seems to be these common themes that as we learn more about the body and how it works. But I’m glad to hear that you guys are looking into health histories and everything else to help us out as well. We appreciate your wonderful work.
Dr. Ghobrial: Yes, absolutely. Thank you.
Caller: We really appreciate the work you’re doing. It does seem that there is a plus side on having an autoimmune condition because I certainly responded very well to therapy. So I don’t know if maybe my hyperalert immune system also went on attack pretty well, so I’m doing quite well now. Thank you.
Dr. Ghobrial: Yes, that could be very interesting. Absolutely.
Caller: Thank you very much for your time.
Jenny: And thank you so much for your excellent question. I love that question about autoimmune disorders. I think as you accumulate patients into this study with such a big cohort, you’re going to be able to see some of these patterns. It’s also a question that we are asking in HealthTree because more rapidly maybe we can aggregate a whole population of myeloma patients’ family members and then contact people and say, “Hey, you have a family incident of myeloma. Would you like to participate in this study?” So, we look forward to helping you through that tool.
Well, Dr. Ghobrial, we are so grateful that you have helped us better understand this study, this important PROMISE study. We know that it was going to help identify amazing things for us as myeloma patients and for people with those precursor conditions to avoid this disease as much as possible and for as long as possible. So thank you so much for all you’re doing. We just really appreciate your time today.
Dr. Ghobrial: Absolutely. Thank you, Jenny. Thank you again, everyone. It’s really a pleasure and an honor really to work with everyone. It’s truly this is driven by patients, so I actually want to thank you all for this.
Jenny: Well, thank you so much. We will be posting a link for registration on our website as you have that available. Any other materials to help patients learn more about the study, we’ll be posting that as well on the website. So just watch for that on the myelomacrowd.org website. We’ll just keep you up to speed on this PROMISE study.
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