Learn about all myeloma happenings on the new Myeloma Crowd site: the first comprehensive site for myeloma patients and caregivers. Dr. Vincent Rajkumar, MD Mayo Clinic Rochester Interview Date: May 2, 2014

 How does race and obesity affect the occurrence of MGUS and multiple myeloma? Dr. Rajkumar describes findings on the two to three times increase in myeloma in blacks over whites and his observations that obesity provides a twofold risk factor. He shares the similarities in the African-American and Ghana populations, showing that the incidence is more likely to be genetic rather environmental or socioeconomic reasons. He also discusses how the Hispanic and Japanese (even those exposed to the atomic bomb) had lower incidence of MGUS and myeloma, most likely to be genetic reasons as well. Although there is greater incidence of MGUS and myeloma in the black population, the silver lining may be that the type of myeloma usually found in this group is a less aggressive form and that certain treatments (iMiD-based therapy and transplant) tend to work better for this population. He shares that the precursor MGUS is more prevalent in the obese population, so it is not just a sugar-cancer paradigm. Although there is no determined cause yet identified to link obesity with myeloma, he describes how cytokines like IL-6 or IGF-1 may be higher or hormone level shifts may account for the incidence. He tells us that other genetic factors (like translocations) are more important factors for disease progression than obesity itself. He tells us that those with other states of chronic inflammation, like rheumatoid arthritis, also show higher incidences of myeloma. The live mPatient Myeloma Radio podcast with Dr. Rajkumar

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. This series is in place to help you learn more about the latest research in myeloma so you can make your very best treatment decisions. It's also to make you aware that if patients participate in clinical trials in greater numbers, we can help move the bar. Today, less than 5% of myeloma patients participate and hopefully because of this series, that number is growing. I've had many patients raise their hand to say they want to join the trial and this is wonderful to see. If you'd like to receive a weekly email about past and upcoming interviews, you can subscribe to our mPatient Minute newsletter on the homepage or follow us there on Facebook or Twitter and please share these interviews with your myeloma friends. They're a very deep resource. We also have a site called myelomacrowd.org that's the first comprehensive site for myeloma. Please take some time to explore the links and go deeper than the homepage. There are references and links to the very best myeloma news sources, list of who to follow on social media for all things myeloma, a growing online myeloma specialist directory, and current articles on relevant myeloma topics. You can also contribute what you're learning by clicking on the "Become a Contributor" link. We are very honored to have with us today Dr. Vincent Rajkumar of the Mayo Clinic. Welcome, Dr. Rajkumar. 

Dr. Rajkumar: Thanks so much for having me. I really look forward to this show and I think you're doing a wonderful job. 

Jenny: Well, thank you so much. Let me give an introduction for you before we begin. Dr. Rajkumar is a Professor of Medicine and Chair of the Myeloma, Amyloidosis, and Dysproteinemia Group at the Mayo Clinic in Rochester, Minnesota. He also chairs the Eastern Cooperative Oncology Group or ECOG Myeloma Committee. He has published more than 500 articles and 350 abstracts, and his career was profiled in the November 26, 2011 issue of The Lancet. Dr. Rajkumar has an extensive research program in the field of plasma cell disorders. He has led numerous phase one, two, and three clinical trials investigating the role of new agents in myeloma including the very important randomized trial that led to the approval of thalidomide for myeloma in the US. He also leads several large studies investigating the nature, the prevalence, and progression of various monoclonal gammopathies, including myeloma. His laboratory research has been focused on investigating new agents in myeloma and studying the role of angiogenesis in various plasma cell disorders. He has been continuously funded as an independent investigator by the National Cancer Institute through R01 grants, which is the highest level of grant researchers can obtain. Dr. Rajkumar serves as an Associate Editor for the Mayo Clinic Proceedings, Section Editor for Multiple Myeloma, and related disorders for the journal, Leukemia, and is an Associate Editor for the European Journal of Hematology. He's Deputy Editor of Blood Cancer Journal. He received the "Relentless for a Cure" award from the Leukemia and Lymphoma Society in 2010 and a John Altman [Phonetic] Lecture and Award from the American Society of Clinical Oncology in 2011. Dr. Rajkumar, we're very fortunate to have you on today's show. 

Dr. Rajkumar: Oh my, what an introduction. Thank you. I don't know whether I can live up to all of this, but I really appreciate you having me on the show. 

Jenny: Well, we know you can. We've heard other discussions that you’ve had before and you're excellent. I know for today, we want to focus on your research that you've been doing with obesity and race and how that impacts myeloma. So to begin that, did you start with observations mostly in race or mostly on obesity? How did you start to discover this? 

Dr. Rajkumar: The initial studies were all related to race, so obesity came later on. I must say that a lot of the work that I've done in the last ten years or so looking at racial disparities and monoclonal gammopathies is work that is in close collaboration with Dr. Ola Landgren at the NCI. We work in tandem and teams to address this issue. The fact that multiple myeloma is more prevalent in African-Americans compared with whites is well-known and that has been known for decades. It was worked on by so many researchers before me.

 Jenny: In what percentages is it more prevalent? 

Dr. Rajkumar: Well, generally when you say that a particular race has a greater predisposition to a given cancer, you're talking like a 20% increase in risk or 30% increase in risk. You usually don't see 100% increase in risk or a two or threefold increase in risk. Such kind of disparity is quite uncommon. Multiple myeloma is unique because there is a marked two to threefold higher risk of myeloma in blacks compared with whites, and that level of racial disparity was what got us started because we felt that if we understood the mechanisms of the racial disparity, it would actually provide us with clues on why people get myeloma in the first place for all races.

 Jenny: And in the African-American race, do you see a difference between men versus women or is it consistent also between the genders? 

Dr. Rajkumar: Well, in general, the prevalence of myeloma as well as its precursor conditions is more in men compared with women. It lags about five years in women. As age increases, the prevalence of these conditions goes up. When you look at blacks and whites, the disparity is seen in both men and women and to almost the same extent. The other striking thing is that the younger you go, the disparity becomes even more. I mean, young black patients have a much higher risk of myeloma than whites of comparable ages.

 Jenny: That's really remarkable. You wouldn't think that. I guess when you look at the various stages like an MGUS stage or smoldering or active myeloma stage, you're seeing the same types of things especially if you're seeing younger populations. Are you? 

Dr. Rajkumar: Absolutely. The very first question that we had is if myeloma is more common in African-Americans, is it because there is an increased prevalence of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS)? Since all cases of myeloma evolve from an MGUS, is the disparity because African-Americans have a higher risk of MGUS? Is that the reason or is it because there is a more rapid progression of MGUS to myeloma? Is it the precursor is more or is it the progression rate that's more? So the initial studies looked at the precursor condition to look at the prevalence, and many studies have been done. Most of them are smaller studies and almost all of them are focused on small parts of the US. We did more recently and published this year in Leukemia a study held in conjunction with Dr. Landgren from the NCI, from the CDC Mayo Clinic. It was a study of nearly 15,000 persons from all across the United States who were sampled as part of the NHANES study (National Health and Nutrition Examination Survey). The NHANES is a nationwide sampling that occurs periodically mainly for nutritional evaluation, but we utilize those samples to study the prevalence of MGUS. What we found was that there is a twofold higher risk of monoclonal gammopathy of undetermined significance, the precursor condition, in blacks compared with whites and this is seen in all ages. It's seen in men and women. 

Jenny: That's a very consistent answer, it sounds like. 

Dr. Rajkumar: Yes, it is. It's been known, but this is the first time we've seen it clearly demonstrated in a nationwide study that actually represented the total US population. Now, when you see something like that, you want to find out what kind of monoclonal gammopathies do patients get. We looked at the type of MGUS and we found that the more higher risk MGUS was seen in African-Americans, so it's possible that African-Americans not only have a higher risk of monoclonal gammopathy of undetermined significance, but they may also have a slightly higher rate of progression, and both of those factors probably contribute to the higher risk of myeloma. Now, we have to study the mechanisms in greater detail and those studies are ongoing. We're also going to try and find out if this whole thing happens because blacks get MGUS at a much earlier age than whites, and so we're looking at a population that is age 10 to 50 to try and determine that because depending on the age of onset, the type of risk factors that cause it may be different and we can get clues from that. I must add that we also looked at the differences in MGUS prevalence compared with Hispanics. Now, the NHANES doesn’t -- at least in the times that we sampled -- doesn’t code for ethnicity separate from race, so all we could look at was people coded as Mexican-Americans. And we found that they had a slightly lower risk of MGUS compared with whites, and that has been seen before in other studies as well. 

Jenny: I notice that there were not only lower rates in maybe Hispanic groups or maybe just specifically in Mexico, and then I saw a reference to Japan also that showed lower incidence. 

Dr. Rajkumar: That's correct. The Japanese have published data from survivors of the atomic bomb where there was higher radiation exposure and the initial reason they did that was to find out whether there was an increased risk of MGUS and myeloma and MDS with respective radiation exposure, but later on, that data was used to compare the rates in Japan to the White population of Olmsted County and what we found was that -- what they had found and reported is that even among those exposed to the radiation from the atomic bomb, the risk is still lower than the white population of Olmsted County, so that's a racial thing. Certain races seem to have a much lower predisposition to getting MGUS. Certain races seem to have more and we have to figure out the mechanisms for the racial disparity because then that lies the answer to why people get myeloma in the first place because there are some genetic factors that are predisposing patients to getting MGUS. Actually, Dr. Landgren and I, we had a question about if there is increased risk of MGUS in African-Americans in the US, is this something that you see in Africa as well, which may provide a stronger genetic link, and that was studied in a study from a thousand participants from Ghana. And when you compare the MGUS prevalence in Ghana age-adjusted, it's twofold higher compared with the white population of Olmsted County. What we learned is that increased risk of MGUS in blacks is seen not just in African-Americans, but also in blacks from Africa and that suggests a genetic predisposition. It's not certain. You can still say some socioeconomic factors are at play. Actually, that's how we landed into the obesity story. I think the credit goes to Dr. Landgren for finding this cohort. There is a cohort of patients in the south. We call it the Southern cohort. This cohort was assembled for the study of obesity in poor women from the South and we utilize those samples then to look for MGUS prevalence. We compared roughly 1000 women who are white -- 1000 white women with 1000 black women, which is compared to prevalence of MGUS. They were all of the same socioeconomic status so that you could not attribute any differences to socioeconomic status and we found that adjusting for that, the risk of MGUS in black women is still higher. That told us again it's a genetic thing. It's not socioeconomic in that regard. In that study then, we found that obesity was a clear risk factor for the prevalence of MGUS and that was seen in the NHANES study as well, but we didn't have statistical significance, but it's clearly there. It's a risk factor, close to twofold higher risk. 

Jenny: I did not know that. Now, I have a lot of questions about obesity and I had some people email in questions also. So instead of waiting until the end because they're not going to be able to ask those themselves, I'm just incorporating them into most of the interview. So another question for the African-American population, is there a younger median age for diagnosis in this population?

 Dr. Rajkumar: Yes, I think so. I don't have the data at the tip of my fingers, but again, we are studying the prevalence of MGUS by age right now, but if you look at -- the way it's been looked at is if you look at the age 40 to 50, the probability of getting myeloma in blacks is much higher than whites, and that disparity is higher than what you see in older ages. So there's something going on and there is a silver lining. My suspicion is that the type of myeloma that occurs in blacks is the lower risk type and therefore, when given the exact same therapy, the outcome in blacks is actually better than in whites for similar populations, so that has been seen in the ECOG trial that I did, which looked at high dose versus low dose dexamethasone and lenalidomide where the overall survival of non-whites was higher, was better, again, close to twofold better compared with whites, and that's been seen and recorded by Dr. Landgren as well. So there might be some survival disadvantage to certain portions of the African-American population to access differences, but when access is uniform such as what happens in a clinical trial or when you study an insured population, the outcome is actually better, which leads us to hypothesize that the type of myeloma that occurs in blacks, even though the prevalence is higher, is probably the lower risk type. We are trying to find out if this is because, for example, the trisomy subtype of myeloma is the good risk type and my hypothesis is that is probably what's driving the racial disparity and that we'll find out soon. 

Jenny: Well, that was one of the questions from Dana because she noticed that you spoke about trisomies as being more common in the black population. And although they might have a greater risk of progression from MGUS to active myeloma, they have typically have more bone damage, but more slower-growing type myeloma from other researchers that we've talked to. I don't know if that's accurate or not. Have you looked at the African-American population and tried to separate it out by percentage of the types of translocations? It's mostly t(11;14), from what you're saying? 

Dr. Rajkumar: It's probably mostly trisomies that's driving the disparity. That's still a hypothesis. Well, there have been studies. Dr. Fonseca published a paper in Blood looking at the cytogenetic subtypes. We are doing a study in collaboration with various medical centers in the US looking at the cytogenetic subtypes, differences between the various cytogenetic types in blacks versus whites. Actually, Dr. Greenberg, one of my colleagues here at Mayo who just finished her PhD presented an abstract at AACR on the disparities and prevalence of the various cytogenetic subtypes. The caveat is that a lot of the differences we need to verify because there is no uniform FISH test that is done to look at the cytogenetic subtypes across the US, so any difference we find may be just simply based on what probes were used at the various centers rather than a true racial difference, so centers with a larger African-American population may be using a more limited probe set than what's used at Mayo or MD Anderson. And then when we compare -- for example, we did some comparison with Cook County Hospital and then we found that some of the probes were simply not used. So then, you cannot compare. It's going to take a lot of work because we have to have uniform FISH probes that were used in all patients and then look at the prevalence of each cytogenetic subtype to see what is driving the racial disparity. I think of myeloma as at least seven or eight different diseases and it would be like lightning striking twice if you had increased racial disparity in all of the six types, so I think it's just one or two types at the most that's driving this disparity. The quicker we find it, we'll know exactly how to target it. Right now, I think from all the studies, we have found one that's published by Dr. Landgren, the ECOG trial. I would say that lower risk subtype, probably trisomy subtype, is probably more increased in African-Americans and that is the subtype that responds better to lenalidomide and stem cell transplantation, and that's something that should be out there. 

Jenny: As maybe a standard treatment protocol?

 Dr. Rajkumar: As a treatment protocol that patients are aware of and treating doctors are aware of, that blacks have really done well in certain studies, which utilized IMiD-based therapy and transplant.

 Jenny: Okay. And going back to the FISH test, how long do you think it will take to get a standard FISH test across all facilities? Because when we interviewed Dr. Landgren, he really focused on that point as well. 

Dr. Rajkumar: Yes. See, the problem is that the reason FISH testing is done in many centers is just to identify high-risk myeloma, so then they will be using probes for del(17p), 1q amplification, t(4:16), t(4:14), and del(13p) maybe. So that panel then tells you whether the patient has a higher risk myeloma or not and that's the main reason why people are doing it. And so for that purpose, that probe set is fine, but when you want to classify myeloma into various subgroups, you'll need more than that. You need probes for trisomies. You need probes for t(14;20), t(6;14), t(11;14), and the more probes you use, the more expensive it is. So we have to make a clear case that it's actually important to know what subtype of myeloma patients have before we can generalize that everybody should be using a comprehensive FISH panel. We are moving in that direction. The most recent version of the mSMART algorithm is really dependent on the primary cytogenetic subtype of myeloma and to know that, you have to use a fully comprehensive probe set. I'm just hoping that as we evolve and people start looking at myeloma not as one disease, then we will have this. I don't know how long it's going to take though. The better way to do it is to look at centers that are using similar probes and look at disparities with those cohorts. 

Jenny: Well, it seems to me just as a patient observer that researchers are really handicapped by not having all of the information that they need to be able to make further discoveries. From what we understand, the FISH, you get what you test for and if you don't run those probes, like what you're saying, then you just don't capture that data ever and especially at the beginning when a patient has all those things present and showing up. 

Dr. Rajkumar: Right, and I'm ambivalent only because when I wear my evidence-based hat, if we say to a doctor, "You should be checking for t(11;14)," I have to tell them why and I have to show them data why that is important, so we have to distinguish what's important for research from what's important for practice because then the test is billed to the patient. That's why as we collect data and we show that the outcome depends on certain approaches to treatment, as the approach to treatment varies by cytogenetic subtype, then you can rationally say that it's important for patient care, not research, to actual patient care to get these results and justify the testing because if you're doing it for research and you're paying it with research dollars, that's one thing. If you're billing it to the patient, there's got to be a clear proof that what you're doing is useful for patient care, so I'm torn. I think it's hard to just say what people are doing is wrong unless you have -- or you have a charge that is very similar whether you use one probe or ten, and then you can say yeah, it's better to use everything. 

Jenny: Let me ask you because we've talked to several people about whole genome and whole exome sequencing. Have you used that at all for this population? Has it given you any clues as to maybe some genetic reasons why the black population has a higher incidence of myeloma? 

Dr. Rajkumar: Well, I think again separating research from practice, we have participated in the initial myeloma sequencing that was done and published in Nature from The Broad Institute and the MMRF. And from a research standpoint, trying to understand why people get myeloma and why there is a racial disparity, these tests are going to be invaluable. You're going to get the whole genome sequence and look at the exact differences, that's how you'll get the answers, so yes. However, for practice -- and you hear about companies are offering this or people can get this done for myeloma -- you have to ask yourself exactly what information you will get that is actually actionable. I have not personally ordered a test for a single patient so far. We have the capability now at Mayo and we can order it as a clinical test. I have not done it because I haven't encountered a situation where I felt like this would actually change my plan of care. The probability that a myeloma patient will have a new actionable mutation for which there is a drug that you can use is very low, at least from what we know. We don't know that that action would actually benefit the patient either. I mean, that data is also not out there. So we get a lot of data and then there's not much you can do out of it, and these tests costs several thousand dollars. So I am more evidence-based school of thought rather than rationale-based therapy. I need proof that it works. I actually sent out a tweet asking my colleagues if they ever had a patient on whom they've done it and if they had an action that could be taken as a result of the test and what the outcome was. I didn't get a single response yet. I don't know if people don't have such an experience or they haven't just emailed me, but hopefully when they hear this, maybe you can publicize this. I am looking for an example. Somebody tell me -- and it's not like we found BRAF. I just want to know if you found the BRAF and you used the inhibitor and what actually happened. How many months of response did you get? If I have even a single case where this helped, then it would change my line of thinking. 

Jenny: You're looking at it practically in your practice. 

Dr. Rajkumar: Right, because you have a patient and again, who knows whether the insurance will reimburse this test? Who's going to be stuck with the bill? If you screen 100 patients with a several-thousand-dollar test and perhaps two or three have an actionable thing and you don't know the outcome of that action, how can we justify it? So we are taking it carefully here. It's not like I'm not going to do it. We have a Center for Individualized Medicine at Mayo and they are helping us with this. And so, when we have the appropriate patient where there's no real available therapy right now, they are relapsed and refractory, we refer them to that center and then they will take all the pros and cons, counsel the patients, look at the insurance and then get it. I think in a year or two, we'll have more data on how many people have done it like this and what the outcome was. It's always great to talk about the positive, but the people have to see the other side and then make a decision with eyes open. 

Jenny: Right. I think part of that is doing some of the important diagnostics or discussing with your provider your cytogenetics. I attended an IMF seminar, which was excellent. I asked everybody to raise their hand if they knew their cytogenetics and 10% of the people in the room raised their hand. I think if we're going to demand personalized care, we need to know what kind of profile that we have either through the FISH test or the other diagnostic testing that is available to us. 

Dr. Rajkumar: Yes. I think the FISH is becoming more and more uniform and some of the reason why you don't see that show of hands is because in the older days, we were not doing it routinely. And if you can do it at the very first bone marrow and you had a great outcome after that, you had chemotherapy and transplant and you're in complete response. There's no way to go back and check now. So the patients are doing well and they didn't have the test done at the time, but you would see that maybe a few years from now, as we have patients from this year showing up at these meetings, you'll find more and more people raising their hands, I'm pretty sure. It's becoming more uniform now. 

Jenny: And another question beyond the translocations that might relate to the African-American population, they also have a higher incidence of things like diabetes and renal failure. Are those other things drivers for myeloma? I know you need to do more studies to find out what's driving this, but if you could maybe share your hypothesis about what might be driving some of this. 

Dr. Rajkumar: You know, we pretty much are blind. We don't have any data in terms of ideology. The best hypothesis that you can give is to really look at myeloma as a whole. It's a two-step process. It's analogous to colon cancer. In colon cancer, what happens is that you first have the normal colonic mucosa and then something happens and the patient develops a polyp. The polyp itself is self-limited. It's benign, but there is a risk that the polyp can become cancer when another hit happens. So sometime in the future, a random hit happens and the polyp becomes a cancer. Similarly in myeloma, we all have plasma cells. They're helping us fight infections by making antibodies. Somewhere along the way while they are responding to an infection or an inflammation, there is an error. There's a mistake like a trisomy or a translocation, and you get MGUS, a clone, similar to a polyp, self-limited, doesn’t do much, just sits around, and then 1% of MGUS patients each year get a second random hit. It's like a chance event and when that happens, the MGUS then becomes myeloma. So now that we know that the racial disparity is there at the MGUS stage itself, most likely what is happening is there are some genetic factors like actual gene sequences that might be polymorphisms or mutations that predispose African-Americans to developing this MGUS as they are trying to respond to an infection or an inflammation more readily than whites. That then makes them have a higher risk of MGUS and I think that is more likely than an environmental cause for that. There might be some environmental components to it, but I don't think it's the driver. And then once the MGUS is there at a higher frequency, then the development of myeloma is just driven by that probably. 

Jenny: Well, let's talk about obesity for a little bit because when you talk about that the infection or inflammation might be the secondary trigger basically, I think there's a lot that has to do with inflammation in your study in obesity. So maybe you can help us understand why obesity correlates with myeloma or the findings that you or Dr. Landgren found. Is this just a sugar cancer paradigm or is it something else? 

Dr. Rajkumar: Again, it's not at the cancer stage. We're seeing it at MGUS, so it's more occurring at the transition from a normal cell to a premalignant clone. It's very difficult to just come up with a hypothesis. I know that there must be some cytokines involved. Myeloma cells require IL-6 to grow, insulin-like growth factor and so on. There might be some differences in cytokines, which we all know occur with changes in body weight. And I think, again, when a cell is trying to fight off an infection, it is dividing. And if you have some cytokines that help it divide more or faster, that may increase the chances of an error like a translocation or a trisomy happening, and then that translates into a higher frequency of MGUS. Once you have a higher prevalence of MGUS then from that point onwards to myeloma, it's just that increased prevalence will drive the whole thing, but it's so hard for me to come up with random theories why there might be a different -- I'm pretty sure after looking at all the data that these are not confounding effects, but there are some real effects. If you look at NHANES for example, we looked at so many variables from income to smoking to education status to poverty. None of those made a difference. Obesity, there was a clear trend. Inflammation like rheumatoid arthritis, there was a trend. They all didn’t reach statistical significance, but there was a trend and we're going to study that more. We'll pull it with the second cohort that we're studying right now, another 12,000 patients, so then we'll have more sample sizes to look at these differences. 

Jenny: Have you seen a difference with obesity and myeloma in men versus women? 

Dr. Rajkumar: Yes. The increased prevalence that you see is there in both men and women. However, the study that we did - so that's from the NHANES, if you see the NHAMES, there's a table there which shows you that as the body mass index is going up, there's an increased prevalence of MGUS both in men and women. The study that we published in Blood a few years ago looking at obesity in the South, that was done only in women so we couldn't say anything about men in that. 

Jenny: I know it's controversial even to talk about treating smoldering myeloma early and some people are starting to do that more. Is there anything that could be done early at the MGUS stage to inhibit progression? 

Dr. Rajkumar: Yes. We should just make sure that patients and doctors are aware that it's better to not do anything. You are going to cause more harm by intervening in the absence of solid data. The point to remember is that MGUS progresses to myeloma at 1% per year. 

Jenny: That's so small. 

Dr. Rajkumar: That is again not adjusted for other competing causes of mortality. If you are just for other competing causes of mortality, the risk of progression of MGUS is probably much lower, even 0.5% per year or less. And so, the vast majority of patients with MGUS like 90% approximately will never get myeloma. So if you try to screen and intervene, after ten years of intervention, you may have a prayerof helping two or three people, but you could have given bad treatment to 90 plus percent. So we just have to be more careful. Particularly, I see people wanting to do MRI scan, CT scan with all the MGUS patients. You're just going to increase false positives and cause more harm than good. As in any screening study, whether you take mammography, colonoscopy, prostate cancer screening, HIV treatment, every one of those was backed up by randomized trial showing benefit or absence of benefit. We haven't gotten those kinds of studies. We don't even have interventions to test in those kinds of populations, so we shouldn't come up with ideas on how to screen or how to treat such low-risk patients. Now, smoldering myeloma is a different ballgame because the risk of progression in smoldering myeloma is 10% per year, but even in that, if you go beyond the first five years, the risk drops off. And so, if you look at 100 people with smoldering myeloma, 50 of them will still be fine five years from now and 35 would be fine ten years from now. Then you have to be careful if you use treatments because all our treatments carry actually some life-threatening consequences. There is a certain percent of patients who can die from our treatment. We need to be sure that the risks outweigh the benefits. We need to be looking at what are the implications on quality of life. Again, treating based on rationale has made mistakes in medicine over and over again. We need randomized trials showing that what you hope you will achieve actually happens. And so, even in smoldering myeloma, we are not looking at all patients with smoldering myeloma. We are looking at patients with high-risk smoldering myeloma. The Spanish study looked only at high-risk smoldering myeloma. They looked at a population with a 25% per year risk of progression to myeloma each year. In that population, they found that early intervention may prolong survival, but the test that they used to identify those patients are not available worldwide, so we cannot just take up that study and incorporate it into practice. We are doing a trial right now in the US looking at lenalidomide in smoldering myeloma, high-risk smoldering myeloma, and that'll help us answer some of these questions. We just need more data. The very tip of the iceberg, patients with smoldering myeloma who are ultra high-risk like 40% to 50% risk of progression in the first year, those patients we are willing to treat now because there's hardly any one of those who would not have progressed in two or three years, and that is what people refer to as we start talking about intervening in myeloma early before the CRAB features happen. That would be ultra high-risk smoldering myeloma patients. Dr. Dispenza wrote a paper in Blood looking at exactly what factors we'd be using to decide this. Right now, we can look at three factors -- plasma cell percentage more than 60%, free light chain ratio more than 100, presence of more than one focal lesion on an MRI exam. Any one of those three factors in a patient with smoldering myeloma, you're looking at a risk of progression of 40% per year for two years, so most patients will progress in two years. Those patients are referred to as ultra high-risk and we are ready to call them as myeloma and start therapy. All the other patients with smoldering myeloma are either better off being watched or the higher risk groups are better off enrolling in clinical trials. 

Jenny: I understand the caution and I think it's wise. I know patients with smoldering myeloma. Sometimes it's a hard head game to know that you have something, and even at the MGUS stage, it's a challenge psychologically. 

Dr. Rajkumar: Right, but the treatment we are using is not like aspirin or Tylenol. These are risky treatments and we need to know whether they actually work, not just that they may work, before we start intervening. That’s not easy because if you go lower and lower risk, it will take years before you know the answer. If we're not doing something, it's not because we don't have time or won't make the effort, but it's a judgment call and we are always weighing the pros and cons and wrestling with whatever decisions we make. It's like you want to help people and do it. At the same time, you don't want to harm people. 

Jenny: Can we go back to obesity for a minute? And maybe you're not probably an expert on obesity because you're an expert in myeloma, but can you help us understand what biologically happens in obesity that affects cells either with insulin or IL-6 or other factors like DNA repair or gene functions?

 Dr. Rajkumar: I'm not sure -- again, cytokines like IL-6 or IGF-1 may be higher and may be involved. Another possibility that I've been thinking about is hormonal differences. There is a definite hormonal shift that happens in obesity with greater male hormone levels. And so, it may be something to do with that because there's a clear gender difference in MGUS and in myeloma. If you look at the prevalence of MGUS by age group, women lag behind five years. The prevalence of MGUS in a 60-year-old woman would be the same as a 50-year-old man. The five or ten years difference is always there and it may be that the estrogens are protective and the androgens are more driving the prevalence of MGUS. I think that that may be one of the reasons why there's a discrepancy in obesity. Maybe with obesity, the hormonal shifts affect the prevalence. 

Jenny: Are there hormonal differences in levels between racial communities? 

Dr. Rajkumar: I don't know. I don't think we have measured or checked that, but that's a good idea. I don't know. When we've done the NHANES study, all of the prevalence differences were adjusted for all the factors that you can think of, so we are pretty sure that the racial disparity persists after adjusting for everything else that might be confounding, but not to the detail of hormonal levels whether that drives it. 

Jenny: You may have answered this already, but if you have MGUS or smoldering myeloma, does obesity influence the time to progression? 

Dr. Rajkumar: The time to progression of MGUS to myeloma and for smoldering myeloma to myeloma is dictated by a number of risk factors. For MGUS, the size of the monoclonal protein, the type of the monoclonal protein, the free light chain ratio are three factors that we use to determine whether a patient with MGUS will -- at what rate will they progress to myeloma. If a patient has a small monoclonal protein less than 1.5 grams that is IgG in type and associated with a normal light chain ratio, the risk of progression of MGUS to myeloma is very low. It's only 2% over a patient's lifetime. In such patients, maybe routine follow-up is not even needed. All you need to do is recheck in six months if they get symptoms. On the other hand, the other extreme is if patients have more than 1.5 gram M-spike with non-IgG subtype and high abnormal light chain ratio, the risk of progression is much higher. It's like 3% per year or more. And so, we can risk stratify using that. And other things that affect progression and MGUS might be the level of bone marrow plasmacytosis, less than 5% versus 5% to 10%, the suppression of uninvolved immunoglobulins whether they are there or not, and circulating plasma cells and so on. In smoldering myeloma, we do know that these kinds of factors are of value as well like the light chain ratio, the size of the monoclonal protein, the amount of plasma cells in the marrow. All the circulating plasma cells are all important. In addition, we know that the immunophenotype of the plasma cells -- and this is what the Spanish have done elegantly -- is to look at exactly what's on the surface of the plasma cells and using that to predict risk of progression. The actual immunophenotype is valuable in assessing risk. We also know that the underlying cytogenetic subtype of smoldering myeloma will affect the progression rate, so t(4;14) has a higher risk of progression to myeloma than t(11;14) and trisomies are in between. So we know that the underlying cytogenetic subtype does affect progression. If you see 17p in a patient with smoldering myeloma, that patient has a higher risk of progression than patients who don't have 17p, so we are certainly getting specific risk factors. 

Jenny: And you're saying those are probably more likely to determine the risk of progression than obesity. 

Dr. Rajkumar: Oh yes. I'm pretty sure that those are very powerful factors. I don't know that we actually have data that MGUS associated with obesity is more likely to progress than MGUS not associated with obesity. I don't think we have data for that. Race, the earlier studies actually suggested that there is no increased risk of transformation based on race. However, the most recent NHANES study suggests there might be a slight increase in African-Americans based on the type of MGUS they have, but we still need more data for that as well. 

Jenny: I had a patient ask, "Will myeloma doctors prescribe metformin for the obesity insulin hypersensitivity?" I don't know what metformin is. 

Dr. Rajkumar: Metformin is a drug that's used for patients with diabetes. No. As we've talked before with MGUS smoldering myeloma, we will intervene with therapies that are known to be effective. We cannot use therapies that we hope might help, so metformin is used if patients have diabetes. If there's a diabetes doctor recommending metformin therapy to treat diabetes, that's okay, but I will not give metformin trying to lower the risk of MGUS or change the risk of progression of MGUS to myeloma because that's completely unproven and I need actual data for that. 

Jenny: Can I ask how dexamethasone impacts the sugar levels in obesity? Because I know dex changes your sugar sensitivities and in some instances, it could give you temporary sugar issues and potentially diabetes. 

Dr. Rajkumar: Dexamethasone is basically a very potent version of the hormone in our body called cortisol. Cortisol is made by the adrenal glands and it's one of those that increase the level of glucose in the body and insulin decreases the level of glucose in the body, so they're hormones that act in opposite directions. When we give dexamethasone, we are giving supraphysiologic doses, very high doses of steroids. It's an analog of cortisol, so it will really increase the blood sugar. If you already are diabetic or if you already have obesity, then your ability to cope with that high blood sugar is going to be impaired. And so, you see either patients with diabetes having completely out of control blood sugars or patients who are not even known to be diabetics start to declare themselves in the diabetic range from the use of steroids simply because this is an analog of cortisol and it will increase the sugar level considerably. So we have to monitor and actually some patients need insulin that they never needed before. As we are starting to use lower and lower doses of steroids, hopefully this problem will be less, but you can make somebody diabetic just by giving them the dexamethasone that we use. 

Jenny: Well, I noticed a big change in my ability to cope with sugars when I was on dex. I have a question about inflammation in general. When you were talking about infection -- and I've read some things that say that obesity is a state of being in a state of inflammation -- are there other states of inflammation that you've seen like either allergies or environmental factors that could cause a state of inflammation that could be the secondary trigger event?

 Dr. Rajkumar: Well, we've always hypothesized that there is an increased risk of MGUS probably in states of chronic inflammation because in those states, the plasma cells are trying to respond and there's a greater chance for error. That's one of the reasons we looked at rheumatoid arthritis in the NHANES study because the NHANES study captured that data. There is an increased risk. It didn't reach statistical significance though, so we're kind of not sure, but in blacks particularly, the risk of MGUS in patients with rheumatoid arthritis was opposite of what we were expecting. In the overall population also, it didn't go the right direction. On the other hand, there are other studies that we have done where we have found this increased risk, so we're not sure whether it's because we don't have the right sample size or we're not studying the right population, but there's always been a hypothesis that chronic inflammatory states will have a higher risk of MGUS than patients without chronic inflammation. It's just been so difficult to prove because we just don't have good data sets to look at. 

Jenny: And what do you consider to be constant inflammatory states? Rheumatoid arthritis is an example. What would be some other examples? 

Dr. Rajkumar: Well, chronic infections. I mean, people have in the old days -- tuberculosis would be a good one, connective tissue disorders like lupus. All of these were looked at. Pardon me because sometimes I forget the study that we have published. We did a study and it's published in the Mayo Clinic Proceedings. It's looking at approximately 16,000 patients in Olmsted County, looking at the prevalence of each and every disease that has been in the ICD coding  -- there are over 16,000 diagnoses. And so, we looked at the prevalence of each one in patients with MGUS and patients without MGUS, and it was an unbiased study because all patients had the test done for screening. And so, it was not like, "Why did they get tested?" The test was done on every one and then we looked at what are the prevalence of rheumatoid arthritis and people with MGUS and people without MGUS. The whole spreadsheet for the whole 16,000 different diagnoses is available on the Mayo Clinic Proceedings website, and anyone interested can go and explore and see what's going on, but we found only -- of 150 different associations that have been reported in the literature, we could confirm only a handful to be truly related to MGUS. Again, partly maybe most of the others were coincidental. It could also mean that even with 16,000, we still didn't have the sample size, so one of those two reasons could still be at play. 

Jenny: I've read some things about diet and inflammation, that certain foods cause a constant state of inflammation like sometimes gluten or sugars or alcohol or foods with nitrates, things like that. Do you think that has an impact at all? 

Dr. Rajkumar: I don't know. Again, it's just so hard to study because it's hard to control for this. I think if you say, "Why do Japanese have a lower risk? Is that because of a genetic difference or it is because of dietary difference?" We don't know. It's hard to say. It's just very hard to do those studies. Short of randomization, there's no way to be sure whether it's cause and effect or not. 

Jenny: Yeah. I know when it comes to food, it's tough because it's hard to regulate and you would have to be very specific about different patient populations and what they were doing so you could get consistent results.

 Dr. Rajkumar: Right. 

Jenny: You mentioned also in the inflammation -- have you seen any pattern with either viral or bacterial infections being possibly the initial trigger for an MGUS state or a myeloma translocation? 

Dr. Rajkumar: That's our hypothesis and there are a lot of basic science studies that have shown how the response may be increased in this initial step where the clone is established, but nothing specific in terms of a particular infection that's driving it. The other problem we have is that when you diagnose MGUS, you already have had it for many, many years, so we don't know exactly when it started. So it could be an event that happened 10 years ago or 15 years ago and it's hard to know when the MGUS started because it's silent. And when you're detecting it, it may have already been there. In fact, we have done a study in which we found that it's been there -- when you diagnose an MGUS, it's likely already been there for ten years, so that makes it difficult. And then because the effect of the monoclonal gammopathy is immunosuppression in some patients, that will also increase the risk of infection, so then it's a chicken and egg. Which came first? Is the infection happening because of the immunosuppression or the infection caused the monoclonal gammopathy? Those are the real practical problems we are trying to solve when we're trying to do research. So we are doing a study trying to figure out if we can capture a population that did not have MGUS and now they do. That way, you know approximately when the MGUS happened and use that data. 

Jenny: What percentage of people do you think in the population have MGUS? 

Dr. Rajkumar: That's interesting. Again, as we talk, it depends on race. I think now for the United States, we have probably the best data from the NHANES study. We had initially thought that approximately 3% of the United States population over the age of 50 has an MGUS. Right now, the NHANES study would suggest it's more like 2.5%, and then that risk then varies according to race. With African-Americans, it probably goes up close to 5%. And as you age over the age of 70, then it also goes beyond 5% to 6% for the prevalence, so that's quite a bit actually. If you talk to 3% of the population over the age of 50, you're talking 1 in 30 people, so it's a fairly common condition. Again, we just diagnose only a very small proportion of patients with MGUS who have it in the population. We don't want to screen because we don't have anything to offer in terms of intervention. Other than stirring up anxiety, you don't really achieve anything. 

Jenny: Right. You'll just make everybody nervous.

 Dr. Rajkumar: Yes, and plus nothing really happens to 90% of the people, so there's no point in alarming people when most of them are going to be fine. 

Jenny: Well, we've talked for an hour and I know you have so much more to talk about, but I think we should have you on again to talk about a whole new topic of study. 

Dr. Rajkumar: Thank you. 

Jenny: Maybe you could just mention -- it sounds like there's a lot of study that needs to be done to follow up on some of these ideas or thoughts to drive them to become reality. Can you talk about the importance of patient participation in clinical trials for you? 

Dr. Rajkumar: Oh yes. Clinical trials are key and in myeloma, we've been blessed. It is because of patients' willingness to participate in clinical trials that we've had so many advances, thalidomide, lenalidomide, bortezomib, carfilzomib, pomalidomide, and liposomal doxorubicin. Six drugs, all of them through big clinical trials, phase I, phase II, phase III. Patient participation was key in getting these drugs out into the market, and there are many other drugs that we know now are active, ARRY-520, daratumumab, another CD38 antibody, SAR, there's cyclin-D1 inhibitors like dinaciclib. All of them have shown single agent activity. Others like elotuzumab, panobinostat are all showing promise, all because patients have been willing to participate. So first of all, I want to salute all the patients who have been willing to participate in large numbers to making these studies a reality and for making all these advances. There are many other trials that we are doing. One thing to point out is that we do lag behind in accrual in the US compared to Europe. And so, we should pick up the clinical trial accrual here. There are several trials. You name the stage of disease from smoldering myeloma to newly diagnosed myeloma to transplant to relapsed. For every stage of disease, most centers have a trial. So ask your doctors, "Is there a clinical trial that would be good for me?" I usually wear the doctor hat first. We will do what is best for the patient and not just because you're eligible for the trial doesn’t mean we'll do the trial for you. If that's in your best interest, then yes, but certainly ask physicians, "Is there a trial that I'm eligible for? Is that trial a good option for me?" And then if so, generally patients participating in clinical trials have better outcomes maybe because they're followed more closely. Some of it is because in myeloma particularly, most of our trials are with active drugs, not placebos, so you do stand a great chance for benefit. It's really important to inquire and participate. Most of these trials are designed very rigorously so that the risk to patients is minimized.

 Jenny: Well, thank you. I think it'd be remarkable if we could increase the participation rate from a 5% to 10% or 15% or 20% or 30%. 

Dr. Rajkumar: Absolutely, and trials are increasingly available at most centers, not just academic centers. Many community hospitals are participating in clinical trials. Many nationwide trials are available to the CTSU to most institutions in the US, these large cooperative group trials, so seek them out. 

Jenny: Yeas. Some of those trials have 300 locations where they're at. 

Dr. Rajkumar: Yes. 

Jenny: Well, Dr. Rajkumar, we're so grateful for you taking the time to share with us today about obesity and race in myeloma. We will certainly have you on again to talk about other topics that you're working on, but we're very grateful for your extensive and your very exceptional work to help find a cure and better treatments for this disease. We thank you.

 Dr. Rajkumar: Thank you, Jenny. Thanks for having me. It was a real pleasure talking to you. You're just so knowledgeable and you're doing an outstanding job for patients with both your websites, so all the very best. 

Jenny: Well, thank you so much. Thank you for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient Radio interview as we learn more about how we as patients can help drive cure for myeloma by joining clinic