(Guest Lecture): September 2023 - Making Watch and Wait Obsolete

So I'll just talk a little bit about why we care about precursor conditions of multiple myeloma. I would say that as a physician I trained at Mayo Clinic and so I trained with Bob Kyle, Maury Gerst, Rafael Fronseca, many doctors who really have started all the work of multiple myeloma. And as we see patients, the first thing we do is they went to their doctor because they had bone pain or they fell and they had a fracture or I have anemia when I'm seeing my doctor. And it's basically you're going to your doctor first, having the symptoms, trying to figure out what happened and then we diagnose you with myeloma. And it's rarely the other way around where your primary care doctor saw a little bit of a high protein or a little bit of a change and diagnosed you with the precursor condition which is MGUS. And the problem with that is once you're diagnosed with myeloma you're on the journey of myeloma and we're very fortunate. I'm the oldest one of those physicians who's going to talk today so I can tell you that 20 years ago when I was still a fellow at Mayo Clinic we didn't have the drugs we have now. We had dexamethasone. I'm sure a lot of you have tried it. It's awful. And then we basically had thalidomide and dexamethasone, the best combination we had at that time. And that was the randomized trials, Thaldex versus Dex and we were very excited. Oh, we're in the novel era. That was the time that we were starting to use the new drugs. And that's the problem. Now we have all those amazing drugs. We have bispecific antibodies that you'll hear about from Dr. Nadim. We have CAR-T therapy that you heard Jenny has used. We have really a new era, the new revolution of immunotherapy along with all those amazing drugs that we have. So our responses are better and better. Many of you would have minimal residual disease. In the old days we didn't even have complete remission. We were lucky to have some patients have some response. So over the last 20 years everything has changed. The one thing that hasn't changed is we're not treating you earlier. And if you think about it, millions of people have the precursors of myeloma. Millions of people have MGUS and small ring myeloma and they go to their doctors and their doctors will say, watch and wait until you have fractures in your bones, anemia, lytic lesions, kidney failure and then I treat you. Now that would have made sense 20 years ago or 30 years ago when I only had dexamethasone or melphalan and when palliative care was perfectly fine. But it doesn't make sense these days for us to tell you watch and wait until you're falling apart and then I treat you. So I'll try to convince you, although many of you may not be in the MGUS and small ring era, but your family members could be screened. You can talk to other people because screening saves lives and we can change the trajectory of myeloma. We can change the survival of myeloma by thinking of it earlier. So with that in mind, what is MGUS? MGUS actually was described by Dr. Kyle over 50 years ago because he was finding those proteins in the blood but those people didn't have myeloma. And we were lucky enough that Dr. Jan Waldström, his colleague, said this is benign gummopsy, let's not do anything about that. But Dr. Kyle was very good in thinking, well some of those actually go on to develop myeloma, let's not call it benign when it could actually have some significance and that's why he called it monochloral gummopsy of undetermined significance so that we don't just dismiss it. And he started following those people. In fact, he sent letters to everyone who lived in Olmsted, Minnesota. Every person, do you mind if you give me your blood? That was the good old way of doing things. I don't think it was IRB approved even. I don't think there was IRBs at that time. And then they all were, again, Minnesota nice, right? So everyone was sending blood samples and he kept sending them letters every year. How are you doing? Are you starting to get myeloma or not? Give me another blood sample. And that's how he collected this data. This data is real. That over the years and years, people do end up sometimes progressing. The risk of progression is very low but they do progress. How common is MGUS? If I take everyone walking around, right now it's hard to find people walking around in Boston because of the weather, but if I take people walking around in Boston and just take over the age of 50, 3 to 5% of the population. Now that was mainly in Caucasian populations and that was also shown from the new study called the I-STOP study in Iceland. Unfortunately we do not, or fortunately we do not look like the Icelandic people. We have more diversity than all the Icelandic people. That means that we have more African Americans, we have more racial diversity, and we have people who have strong family history. And that indicates that we have a higher prevalence. Our numbers are much higher than that 5%. Likely it is 3 to 4 times even higher in African Americans or people of African descent. And that's going to be shown by Katherine Maroneck soon. Now if you have MGUS, your risk of progression is actually very, very low. One percent chance per year. So we see you, we talk about life, we talk about kids and grandkids in our clinic, and we really don't worry most of the time. But if you're progressing and we've seen it, some people have MGUS for 20 years and then we start seeing it progress. That's why we want to see you every year. It's not because we're not doing anything, it's because we want to actually find it and when it starts progressing we can catch it early and do something about it. Now if you have smoldering myeloma, and that was also described by Dr. Kyle, and the word smoldering is actually the perfect word for it because it tells you it's almost on fire. It's getting there, be careful with it. The current definition of smoldering myeloma is a little bit arbitrary. It's because you have 10 percent cancer cells in your bone marrow, we would put it in that category. Now we all know that the bone marrow biopsies are patchy, so if you get one area of a bone marrow it will be 5 percent, another area it will be 15 percent. So we take that with a grain of salt. But in general, if you have enough cancer cells in your bone marrow, it means that they're starting to grow, they're starting to cause enough problems that they will likely cause myeloma in your lifetime. And this is when we start talking about all of the things we do of, can I prevent that? Because in most patients with MGUS we can do studies to prevent long-term problems, but once you're in smoldering myeloma we want to be a little bit faster, and this is what we call interception. So you'll hear from Dr. Marinek a lot about prevention, more of lifestyle modifications, and other things. You'll hear from Dr. Nadim, if you're on the high-risk, smoldering myeloma side, let's actually do interception, let's actually treat you early before you have disease. And we differentiate those words from how intense our treatment will be. So I like to use this slide, and I've actually had this slide for over 10 years now, and it's really to say what we're doing in myeloma may be wrong. In breast cancer, we screen for breast cancer because cancer screening saves lives, and we do mammographies. For colon cancer we do colonoscopies. However, for myeloma, which could be a simple blood test, we don't do a cancer screening program. And I can tell you from personal experience that a blood sample is much easier to do than mammography and colonoscopy. So we should be doing cancer screening by blood tests. And when we find it, when we find an MGUS or a smoldering myeloma or even high-risk smoldering myeloma, you end up seeing many physicians who will tell you watch and wait, wait until you have those end organ damage. That's like telling a woman with breast cancer who has stage one breast cancer, not just DCIS, you're perfectly asymptomatic, wait until you have metastasis everywhere, fractures in your bones, and then I treat you. And I'm sure that that woman will have a lawsuit against that physician and will go like, you're crazy. So why are we not telling our myeloma doctors, you're crazy, do something about it now. Don't go telling your physicians you're crazy. I want you to be upset with us, challenge us, tell us why are we still doing standard of care, watch and wait. So we started seven years ago or eight years ago a Center for Prevention of Progression or CPOP. We're changing the name very soon to Center of Early Detection and Interception by next month. And you can see many of the physicians who are here are part of it. And it's a team effort to really say not just for myeloma but in general for all blood cancers let's screen early, find who's at risk and let's really intercept early or prevent it. And you can see that we don't only work in the leukemia or pre-leukemia and the pre-myeloma and the pre-lymphomas but we also have an amazing team of population scientists, of genetics, of cardiologists because it's not just when you have MGUS you don't just think of pre-myeloma, you think of osteoporosis and cardiovascular risk and other things. So this is really a comprehensive approach. So I'll take you very fast and we screen early because we want to find it early. We don't want to wait for it to incidentally be found although many of you could be found that way. We want to risk stratify because some patients will never develop their myeloma in their lifetime and that's good but those who will develop it in their lifetime we want to know about it. So we want to differentiate it and not just based on your M-spike or your life chains. And then we intercept because if we don't do anything about it then what's the point of finding it early other than making you anxious. So the CPAP and the CPAP clinic that we started, for us to answer those questions we said we need to have data, we need to have proof because that's how you change science and you change clinical practice. And we started collecting data and clinical information but also samples from patients and many of you really empowered us to do that. So the first trial that we did was called P-Crowd because we're crowdsourcing patient information. Our power here and we were able to get over 3,000 people signing up online giving us their clinical information and then sending us samples or when they come to clinic they give us samples every three months, every six months, every year. We're hoping to work with Jenny now to merge our data and work with her amazing work on getting that information from the health records so that we can really empower our information. And we have over 10,000 samples and then the PROMIS study was another study that I remember Catherine Marek and I sitting down and trying to design it was to screen people and she'll tell you more about that study but we said let's not wait for you to be incidentally found, let's screen you if you're at risk and that's if you are of African descent or if you have a family member with blood cancer. And you can see that with that we have large numbers of data that we can start asking those questions. So PROMIS and I don't have the brochures but it's online, promisestudy.org. If you have a family member, sister, brother, daughter, son who is eligible over the age of 30 or over the age of 40 if they're not very high risk then please consider it. If you're of African descent please consider screening because it matters for us to find it early and we're screening online and you can see the QR code and we do a lot of health fair events. In fact we're working now with Jenny on many of those events so that we can do that. Now Catherine will show you the data much more but what we found which is very important is that when you are at risk it's 13% of the people are positive for monoclonal gummopsy and even some more are positive for a very small number of monoclonal protein, what we called monoclonal gummopsy of indeterminate potential. Now once you have this MGUS or small-dream myeloma you want to know what is my personal risk of progressing not what everyone else's risk because I care about what I will go on to develop and unfortunately it's not linear. I cannot just put two of your measures and then just draw a line and say well your progression then will be in 10 years or in 5 years. What happens is this, you could be completely stable and then suddenly it goes up or it suddenly goes up after I saw you for a couple of times. In fact one of the patients who's going on one of our trials screened on the PROMIS study, her mother had myeloma, her grandfather had myeloma so she screened on our trial, she's 50 years old, she has a small monoclonal protein and I said you'll be fine, it's tiny and within that first year she started progressing and we said ah it's not really that fine, it's actually progressing and now it's progressing fast enough after two years of monitoring her that we're considering that she's high risk small-dream myeloma and going on our clinical trials. That shows you the power of screen and detect early before she gets myeloma. Likely if we had not screened she would have started having symptoms and would have had myeloma by now. And then Catherine Maranek will show you what we've done on trying to risk stratify patients and what it means to risk stratify is to try and collect all of your data and understand why it matters for you whether you will progress or not. So we put the clinical data, your M-spike, your light chain, your age, your hemoglobin, your kidney function but then what we're hoping to do is not only use that in a calculator that calculates for you every single time, we want to add more information. Are your genes that are in your cells bad genes or good genes? Is your immune system working well or not? And once we put all of that data together then it gives us a bigger picture. So I'll show you what I mean by are your genes changing or not. In the lab, so my lab is across the clinic, we basically cross the street and we find the lab and we can do a lot of things that clinically we cannot do these days so that's why it's called research based data. We can take your cells whether they're from your blood sample or from your bone marrow biopsy and instead of just looking at fish which is what we do clinically which is the big pieces of the chromosomes, we can go down all the way to the small little changes in your DNA what we call next generation sequencing. So we can sequence every single piece of your DNA inside the cells and now we can do it on every single cell. So the technology is getting so much better that I can do something called single cell sequencing. Every cell I can get all of the DNA or all of the RNA and I can find every single change in it. Now why would that matter? You can see this colorful thing, that's how the genome, that's how all those DNA changes happen when you have myeloma. You have a lot of changes. You have P53 and MIC and 1114 and 414 and tons of changes but when you're earlier in MGUS or small ring, not all of those changes are happening and we want to know which ones really lead to progression. We know now for example that one of those like MIC or if you have KRAS or NRAS, those are likely going to progress to myeloma but that's from data that we developed thanks to people like you who gave us samples and helped us answer that question. So this is the data. We took 250 patients with small ring myeloma and we took their samples and we followed up if they had progressed or not and we found indeed three changes, KRAS and NRAS make alterations as well as something called ATM or ATR or P53 or 17P and if people have one of those, we know that those are going to likely progress to myeloma very fast. We don't do that clinically. We need to do that on the genomic level and we're hoping to actually bring that to the clinic so that you don't just do FISH, you can do it also in the clinic. The next thing we do is in the blood, you have small numbers of circulating tumor cells and that's critical because one, we would love to stop doing bone marrow biopsies. I'd like to see how many of you want to raise their hand to say yes, I want to do a bone marrow. None of you. No one wants to do a bone marrow biopsy and that's true for us too. We don't want to do bone marrow biopsies. We would like to be able to collect your cells that are the bad cells in your blood and now we can do that in a very sensitive way so not only we can count them, which is fine, we can do that by flow cytometry, but we can sequence them and this is data where we did something called minimum seek. Even if you had 50 cells, I can sequence them and get everything much better than FISH. We now can do it even less than 50 cells, which is the single cell sequencing. This is the data that tells you whole genome sequencing on circulating cells is much better than FISH. All of you are now scientists because you can show this data and say even from the blood, we can get data better than FISH. The next thing of single cell sequencing and I'll show you this slide because it really helps us understand why it matters to look at single cells. If you drink a smoothie, and actually there is a very good smoothie place right by here, it tastes really good, but you can't tell the difference between a strawberry and a raspberry. They're mushed together. However, if you really want to tell the difference, you need single cell sequencing. That's like eating fruits. You can tell this is not just a raspberry, this is a bad raspberry. It's a mutant raspberry and that's the power of single cell sequencing. We're even moving to the fruit tart, what we call spatial sequencing. I can look at the whole bone marrow and see where are those cancer cells and are they sitting beside the immune cells and are they talking to each other or not? This is what we do in the lab with all of those samples. What we first did with the MGUS and small ring myeloma samples that we take from the bone marrow or from the blood of patients is we looked at the cells that are in that. Instead of looking at only the myeloma cells or the MGUS cells, we said, well, we have now the power of single cell. Let's look at the normal cells, the normal plasma cells within the same patient and why are they different than the cancer cells? This is called intrapatient, not interpatient. I don't just compare a patient to a patient. I compare within your own sample why some cells are bad and some cells are good. I can learn from that because now I have that power. It can tell me which genes are bad, which genes are good and how can I develop drugs for that, but how can I use that for the prognosis of a patient? Now we've done over 245 samples and we're hoping to do more of that. You can see the machine takes each single cell and puts on it a barcode and then we can tell if your B cells have that VGJ sequencing, the MRD that we use, so we can sequence every cell with its own VGJ. We can tell if this cell is malignant or not and we can answer big questions like what are the genes on malignant cells? Can I develop something better than the BCMA CAR T because BCMA is expressed on all the And then in the last few slides I'll tell you why it matters to also look at your immune system because cancer cells don't just live alone. They live in an environment. It's the neighborhood and Ken Anderson, our leader, has always talked about it's the neighborhood. It's not just the cells alone. So immune cells are truly your part of your neighborhood and if you have a bad neighborhood, you know what happens there, right? So that's what the immune system is. And your immune system is very important to protect you from progression, also to protect you when you're getting therapy. So we did the same thing. We did immune single cell sequencing on healthy individuals, MGUS, small ring and myeloma, and we were surprised that even as early as MGUS, some of your cells may not be normal. And that's why it's important for us to watch even MGUS, especially with COVID, especially with other things, infection may be at risk. So you may actually have some changes happening as early as MGUS. And now we've done this on over 370 samples comparing blood to bone marrow, finding signatures, finding which immune cells are bad and how can we develop new therapies to prevent that. And we also do something called T cell receptor, which is telling us which T cells are the ones that can respond to the cancer cells and which ones cannot and that can help us develop new vaccines potentially against MGUS. So my last slide, and I have six seconds to go through it, is really to try and understand how can we intercept. Now, Dr. Nadim will tell you why it matters for us to treat, especially if you're really high risk. If you're almost going to get myeloma in the next two years, we want to intercept. And we are lucky that 10 years ago, some studies were done using Revlimid and DEX versus nothing that show us that indeed people with small-dream myeloma will benefit. But now we're smarter than this, so we can do things that are very specific to your own mutations or your own changes like 1114. Or we can use the best drugs, immunotherapy, as early as possible. And Dr. Nadim will show you how much some of those immunotherapies, the bispecifics and the CAR-Ts, are showing us amazing responses in small-dream myeloma. And we're hoping to bring that even earlier in the lower-risk small-dream myeloma. So with that, I'll stop and say we want to screen early. We want to risk stratify because not everyone needs treatment. And we want to intercept the disease so that no one ever develops myeloma in their lifetime. And I'd like to thank, of course, amazing teams who work with us at Dana-Farber, our collaborators and our funders. Thank you.