Dr. C. Ola Landgren, MD, PhD, Professor of Medicine and Chief of the Myeloma Division at the Sylvester Comprehensive Cancer Center at the University of Miami, talks about how the first responders of the 9/11 tragedy may have developed multiple myeloma.
Interview conducted by Ivanhoe Broadcast News in September 2022.
Can you explain what kind of cancer myeloma is and generally, who it strikes?
LANDGREN: Multiple myeloma is the second most common blood cancer that happens in adults. There are about 150,000 people living with multiple myeloma in the U.S. as we speak. Every year, about 35,000 new cases are diagnosed. Currently, we unfortunately do not have an established cure for the disease, but patients that are diagnosed can live for a very long time. I’ve been a doctor for several years. When I started my career, the average patient lived, unfortunately, only one, two and rarely more than three years. Today, when we treat patients with this disease, patients live 10, 20 or even more years on average.
Could you give me an overview of what you and your colleagues were looking to determine and what you did find in your 2018 study?
LANDGREN: Yeah. I’ve been involved in research around multiple myeloma for many years. I focused on drug development, development of new technologies to rule out minimal residual disease and a lot of other translational questions that tie into genomics. Another area of my interest is to better understand what could potentially cause the disease. I used to be the chief of the myeloma program at the Memorial Sloan-Kettering Cancer Center in New York City for several years. When I worked in New York, I saw several patients in my clinic that were diagnosed with myeloma that had been exposed to the World Trade Center disaster. So, I work together with the fire department of New York City and other groups that were a part of a big network, Einstein University, and there is a big program around the World Trade Center, exposed individuals. In 2018, we published the first study, but we have screened more than 1,000 first responders to the World Trade Center disaster. We screened their blood per the study consent that they have signed for participation in the study. We found that the rate of myeloma precursor disease that put people up for risk for developing myeloma, that risk was about two times higher compared to the general population. We were thinking back and forth how we could continue to validate and expand on these important findings. The one concern that one could raise when you do a study like this would be, are we sure that the exposure to World Trade Center was the true trigger? Could it be that these firefighters are also exposed because they are firefighters and they put out fires for many other reasons and they go other places, as well? So, we work to design a follow-up study that we now published, and that’s what this most recent publication is all about. In this new publication, we have over additional thousand police officers that were part of the protection of these buildings that were attacked, and construction workers that were part of the work after the attack on the building. There were also EMS personnel and others that were part of this disaster. So, in this new study, what we find is that the risk of abnormal proteins, the monoclonal proteins that are myeloma precursor disease, they are equally elevated across these different groups. I think the study overall provides mounting evidence that environmental exposures or risk factors for the onset of multiple myeloma, including exposure to the World Trade Center disaster. There are probably other factors can also trigger multiple myeloma and that’s probably how many different cancers work, that there could be multiple reasons why it could be triggered. But the important finding here, I think, is the finding of an association with an environmental exposure.
I wanted to ask you just for clarification, the first study was just the firefighters, and the second study kind of expanded that to the other first responders who would have been at the site, but not directly in the building, right?
LANDGREN: That is correct. The first study was focusing on the firefighters that responded to the site. The second study included both those firefighters, but had additional more than 1,000 police officers, construction workers and EMS workers. That allowed us to really investigate if there was a consistent pattern. The exposure to the World Trade Center disaster is very different, obviously, for these different groups. So, the firefighters, that’s where they’re at the actual attack on the buildings, they were immediately exposed to very high levels when the buildings came down. The construction workers and many of the police officers, they could be at the site for a very long time, I think over a year, and they were exposed to in the beginning, very high levels and over time, lower levels, but elevated compared to in the normal setting. So, there’s a long-term exposure also part of it. The study shows very consistent about doubling of the rate, putting people at risk for multiple myeloma compared to the general population.
You mentioned myeloma precursor disease. Can you just explain again for our viewers what that is and what that entails?
LANDGREN: Multiple myeloma, as I mentioned, is the second most common blood cancer that happen in adults. It has a lot of unique features. One of the unique features is that it’s one of those cancers that we have a precursor. There are not that many cancers that have that. People know about colon cancer and polyps, and you can do colonoscopy. But other than that, there are not that many different cancers where you have a precursor. But myeloma is an exception from that rule. We published a study over 15 years ago, I led when I used to work at the National Institutes of Health at the National Cancer Institute, where we showed in a very large prospective screening study that multiple myeloma is always preceded by this precursor state. What that means in simple language is that all people that do have multiple myeloma, they previously had the monoclonal gammopathy. It’s very important to know that most people that do have monoclonal gammopathy, they do not go on to develop multiple myeloma. But you need to have the monoclonal gammopathy to develop multiple myeloma. A huge clinical unmet need that we currently have is better technology to answer the question who is at risk for progression and who is not? The standard of care right now is to do repeated monitoring with blood tests. Depending on the level of these proteins, it could be anything from about three months up to an annual blood test. So, people with high levels, the recommendation is to do more frequent testing every three months or so, while people who have lower levels and annual blood tests it would be considered to be standard of care.
If you are detected with the precursor disease, is there anything that doctors can do to stem the tide or to prevent this from turning into myeloma?
LANDGREN: I think from all we know, from the treatment of most cancers, treating it earlier rather than later is usually associated with a better prognosis. But also, we know that if there are people that have semi-benign conditions, if you treat all those individuals and there are many of them that would not go on and develop the disease, that will mean that you would overtreat those individuals. I think if the therapies are toxic, they have side effects that could cause other problems, that’s where the practical dilemma kind of is. So, when it comes to this condition, we currently do not have an established early treatment in place. There is not yet an FDA-approved therapy for these precursor states. I think the future probably will change that and I think there will be drugs approved for earlier initiation. This will also be driven by access to newer technologies to identify those individuals that are preprogrammed to go on and develop multiple myeloma. I run a large research laboratory and I took a lot of the work with me when I came from Sloan-Kettering, and I have established a large group here in Miami. We have set up a large study pool to transform study where we could test individuals that have monoclonal gammopathy, or also so-called smoldering myeloma. We think that we probably have close to 95 percent prediction of developing myeloma within two years. So, we are running a very large study, the transform study, that is open here in Miami. This needs to be completed and we need to confirm this with the final analysis. It probably needs to be validated beyond the study. But the goal is to develop technology that reliably can identify individuals that are preprogrammed to develop the disease. If you can find out early on, then you know which patient really needs to be treated. We are also working on interventions with new immunotherapies. So, these are chemotherapy-free treatments that we are working on.
What treatments are there for these patients who are developing multiple myeloma?
LANDGREN: There is not yet any FDA-approved treatment for myeloma precursor or conditions, the monoclonal gammopathy or smoldering myeloma. There are no drugs approved in that space. So, for now, the standard of care is to monitor individuals over time. And if someone, God forbid, were to start progressing, if the markers would indicate rising levels of these abnormal proteins, if there are new symptoms, if radiology testing would reveal changes, destructions of the bone, if the patient were to have symptoms and additional workup is done, and such things would confirm the diagnosis of multiple myeloma, then there are multiple new treatments approved by the FDA for the treatment of multiple myeloma. In a nutshell, most of these therapies are given, if not all of them these days, outpatient. Many of these regimens are very well tolerated, and that has really changed over the past 10 or so years. Patients would typically receive the combination of oral medications and either injectables or infusions. And after a certain number of months of therapy, a very high proportion of patients could achieve what’s called a minimal residual disease negative state. That means that although we use very sensitive technologies, we could look for, say, one cell in a million and we can still not find any disease. So, those patients, we will call MRE negative. When patients are in these deep responses, we would put these patients on what’s called maintenance therapy – that could be either oral drugs or combinations with quite infrequent injectables with oral drugs. Patients can stay on this for a very long time. I have patients I followed for over 10 years with these medications, and they continue to do very well.
What are the implications of having this information? And were you working in New York on September 11, 2001? Were you at Sloan-Kettering at that point or did you come after?
LANDGREN: I was not in New York City working at 9/11, but I joined later and then we formed a collaboration. I do think that the importance of these results includes multiple facets. One important finding is that the study – because it looks at firefighters, police officers, construction workers and EMS workers – shows that there is a consistent association between this exposure of these groups. I think that’s a very important finding by itself. It strongly suggests that environmental exposures are risk factors, including the exposure to the World Trade Center disaster. I think that’s an important finding by itself. I also think that important deliverables here because of that is people who lived in this area who were exposed, although they may not have worked in these different jobs, a lot of people are wondering about these things. Although there is no firm guideline yet, I think it’s reasonable to consider doing a blood test to make sure that there are none of these proteins in the blood. This is not an official recommendation or preprinted guidelines, but I think it’s reasonable clinical judgment to consider that. If an individual were to be found to have these proteins testing, as I mentioned, longitudinally, would be for standard guidelines to do anything from three to six- or 12-months intervals. Additional testing could be done if the markers indicate so based on these guidelines. Additional important deliverables here are from this study that if we show that there is this association with this exposure. Well, we don’t really understand what the true carcinogens are. People that are exposed to these types of things – burning buildings or dust and things like that – is very important if this is part of the job that individuals have that they will be provided with appropriate protection devices and that they use these devices. I think that’s a very important thing going forward. To me, it’s like if we know that lung cancer can be triggered by smoking, if people do less smoking, there would be less lung cancer. It’s the same logic. If we can minimize the exposure to things that trigger the onset of diseases, we would have fewer people with cases of disease. And lastly, I also think another important deliverable with this study is that if we now show that these exposures can turn into these diseases, we could study that also in the laboratory. We have organoid system. We have cell lines. We have mouse models. There are different types of model systems we have. We could trigger these types of processes in the laboratory. And if we do that, we can then study exactly on a molecular level what happens. And if we see how things happen stepwise, we now could identify targets. That is how new drugs will develop. So, these could also be treatment targets that we will use to stop and prevent the disease going forward. That would be much more work to counter that point, but that could also be part of the deliverables.
Is there anything I didn’t ask you that you would want to make sure people know about this study or about where your research goes from here, where you want it to go from here?
LANDGREN: We study diseases like multiple myeloma and other so-called complex diseases, when it comes to the causation, it is quite complicated. Although the study we have conducted shows there is an association between the exposure to the World Trade Center disaster and the onset of myeloma precursor disease putting people up for risk for developing multiple myeloma, it should also be emphasized that there could be multiple reasons why these conditions could happen. I’ve been involved in many studies over the years. For example, in 2015, we showed in a very large study in collaboration with the United States Air Force, the VA, the CDC and the National Institutes of Health that patients or individuals that were exposed to Agent Orange had a higher risk of developing these conditions. I was the lead investigator for a study where we showed that that could also double the risk for onset of these conditions we are talking about. I’ve also been involved in other studies. There is something called the Agricultural Health Study in the United States looking at people who work at farms with pesticide application. I was the lead investigator for a large study where we showed a pesticide application also could put people at a higher risk. Unfortunately, there are probably other factors as well that we are not aware of. So, it is not a one straight road to these conditions. There could be multiple reasons why these conditions could happen. So, an individual who is exposed to one or many of these, there could still be another reason why that particular individual developed the disease. It’s going to be very hard to prove in individual cases what was the real causative reason for this person to develop the disease.
END OF INTERVIEW
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