Dr. Robert A. Kyle discusses the history of myeloma innovation and the key elements needed to drive towards a cure
Dr. Robert A. Kyle, MD, Mayo Clinic Interview date: August 9, 2013 Summary On this week's show, Dr. Robert Kyle, a myeloma pioneer, gives a history of "Innovation in Myeloma." With a perspective of the last 60 years of research, he shared how his research began in the 1950s, how common treatments originated, and how treatments have progressed faster in the last few decades. He pointed out experiences where studying the work of others, even in the past, led to innovative conclusions and described situations in which patients helped to drive new treatments in myeloma. He noted the potential future crisis we have in research with a lack of investment in federal funding and described the importance of patients joining clinical trials to move research forward at a faster pace. The live mPatient Radio podcast with Dr. Kyle
Thank you for joining us on today's interview for the Innovation in Myeloma Series on mPatient Radio. We are absolutely delighted for today's interview with Dr. Robert A. Kyle. For over sixty years, Dr. Kyle has led the way in myeloma research and was a pioneer that defined and determined both the term MGUS in 1978, and smoldering myeloma with one of his star students in 1980. His groundbreaking work changed the way that smoldering myeloma was diagnosed and treated. He founded the Mayo Clinic's Myeloma, Amyloidosis and Dysproteinemia clinic. He founded a special protein laboratory and began collecting a recording data for patients with monoclonal plasma cell disorders. He has written 890 peer-reviewed articles and over 1,200 abstracts. He has received the top two awards in Hematology, one from the American Society of Clinical Oncology and one from the American Society of Hematology. They are the highest honors bestowed by these two groups and he is the only person to have received both. Dr. Kyle is a director and member of the Scientific Advisory Board for the International Myeloma Foundation. He has been the chairman of the Myeloma Committee for the Eastern Cooperative Oncology Group, the Secretary General of the International Society of Hematology Inter-American Division, and a member of the editorial board of the Journal Leukemia. The International Myeloma Foundation has created a Robert A. Kyle Lifetime Achievement Award to honor the physician who most exemplifies a singular dedication to and compassion for myeloma patients and the treatment of their disease. His research continues at the Mayo Clinic today. A hearty welcome to you, Dr. Kyle. Thank you so much for joining us. Dr. Kyle, can you share with us your early work in myeloma therapy? Of anyone, you are by far the best person to give us context around Innovation in Myeloma. Dr. Kyle: All right. I am glad to, and if I get into too much detail, please ask me to move along. The history of treatment for multiple myeloma is relatively short. At the end of World War II in the mid-1940s, there was absolutely no treatment available for multiple myeloma except for radiation therapy, which was given for localized bone pain. As you can imagine, this was not very effective because multiple myeloma is a systemic disease. In 1947, Dr. Nels Olwall from Sweden introduced a drug called urethane and he reported that two patients given this drug had a decrease in their protein abnormality as well as a decrease in plasma cells. So for the next 15 years, urethane was the only drug that was available for this disease. There were occasional patients who responded, but then in the early '60s, a randomized prospective trial was reported. This was one in which 80 some patients with multiple myeloma were randomized to received urethane (the active drug) or a placebo. In this study, the placebo drug was cola syrup. When the data was analyzed, it was found that the survival of patients who received the urethane drug was no better than the placebo. In fact, it was just a shade worse. Furthermore, the patients who received the placebo, the cola syrup, did not report any nausea, vomiting, constipation or diarrhea nor did they develop any lowering of their blood counts, all of which were side effects seen with urethane. Then in the late '50s, in fact 1958 as I recall, Prof. Blokhin from Russia described a drug that he called sarcolysin, L-sarcolysin. This drug is known today to many of you as melphalan or Alkeran. It's an alkylating agent that has an effect against the proliferating plasma cells in multiple myeloma. This, I might add, was reported at the height of the Cold War in 1958, and it took a couple of years for the idea or the drug to permeate to the west. In 1960, plus or minus a year, Dr. David Galton at the Royal Marsden Hospital in London treated patients with melphalan and reported that it was active. Then a couple of years later, it appeared in the United States, the head of medicine at MD Anderson in Houston received the drug and was interested in testing it to see if it did indeed work. Jenny: And he had myeloma? He used it for myeloma? Dr. Kyle: Yes. We are coming to that. He used it or wanted to use in multiple myeloma. There was a young man, Danny Bergsagel, who was a relatively recent addition to the staff at MD Anderson and the chairman said, "Dr. Bergsagel, I'd like to have you study this drug." Dr. Bersagel was a Canadian and had gone to the University of Oxford to study and studied actually clotting and coagulation diseases of hematology. When he looked around for a job, apparently, there wasn't one in Canada that was to his liking, so he accepted the position at MD Anderson. And he told his chief that, "Look, I don't know anything about multiple myeloma, and furthermore I'm not really interested in it. I am actually interested in the coagulation of blood and in clotting and bleeding." In fact, that's kind of a subspecialty of hematology and those people are referred to as "clotters." Well, at that time, chairman of departments and division had I think considerably more power than they do today. And he said to Dr. Bergsagel, "I want you to study this drug." Dr. Bergsagel took a deep breath and did so and then reported that eight of the 24 patients that he treated had a good response. With that finding which was published in 1962 or '63 as I recall, Dr. Bersagel's life was changed. A few years later, he was recruited to the University of Toronto, and he kept working in the field of myeloma for the rest of his professional life, during which time he became the leader for myeloma for all of Canada. Again, I always joked with him that he forgot about clotting after he had recognized the value of urethane. Jenny: A more interesting topic. Dr. Kyle: Yes. Well, it's kind of strange the way things work out. The point I want to make with the urethane study, this randomized study, is that it had been used for more than a dozen years and people had seen occasional responses and continued to use it because there wasn't anything else except one other drug called stilbamidine. That was extremely toxic and nobody used it. In any event, melphalan became the favorite drug for the treatment of multiple myeloma. There was another that came along in the mid-'60s for myeloma and that was cyclophosphamide or Cytoxan. Following this, various combinations of alkylating agents were used along with prednisone for the treatment of myeloma. There were a great variety of combinations. There were occasional new alkylating agents and other drugs that were introduced for the treatment. But to make a long story short, there was a meta-analysis which is a fancy term for a situation in which an epidemiologist takes the results of a variety of studies reporting on a drug and then puts them all together and comes up with a conclusion. The conclusion was with over 5,000 patients that the survival of patients with multiple myeloma was no better with the combination of alkylating agents compared to that of melphalan and prednisone alone. As you can see, over this period of time, not much happened. There were two things however. The first was the use of autologous stem cell transplants. This was introduced in the early '80s by a fellow named Tim McElwain who was also at the Royal Marsden Hospital in London or the area of London. This, however, as you can imagine, was a toxic approach. Even though there were patients who responded and had good responses, there were considerable side effects and difficulty in managing this. In any event, as I recall, you asked me to say a little bit about how I became involved in the field of myeloma, correct? Jenny: Yes, I would love hear how you started your myeloma research. Dr. Kyle: Well, it was kind of by accident in a way. I was interested in hematology. I had taken my residency at the Mayo Clinic in Rochester, Minnesota. That would be a residency in internal medicine. During the time in internal medicine, the three-year training program one, I was expected to spend six months in a laboratory to do a project and to write a thesis actually and take a written examination for a master's degree in medicine and then to defend one's thesis in Minneapolis at the University of Minnesota. Well, the options at the Mayo Clinic for the resident at that time was pathology in which one would do autopsies basically for the six-month period and write up a project. The second was physiology, and at that time cardiovascular physiology was the major activity because this was just when open heart surgery was being started. The third option was hematology. I might add with the physiology, the major aspect of that was cardiac or heart catheterization. And during that six to nine-month period, the resident, the fellow was catheterized with a catheter going up from the femoral area up to the heart. That didn't seem like a very interesting sort of thing to me. The third option was hematology. I felt that I knew less about hematology than anything else in internal medicine. And what I would do is to take the six-month training in hematology. During that time -- and this was all laboratory based -- and during that time, one would learn how to read peripheral blood smears, bone marrow aspirates, and that sort of thing. What I would do is, when I finished, I'd go to California and open my practice and I would be able to read bone marrows, whereas the next internist would not be able to. It would give me a leg up. Well, I found that I really enjoyed hematology and I wrote a project on acquired hemolytic anemia and made two observations: one, that these patients by enlarge at a positive Coombs test; and the second point was that you could treat these patients with cortisone, that is the precursor of prednisone, and many of those patients benefited. At that time, I could read German and in my studies I found an article in German, and this had been published 50 years before in 1906. Jenny: That's amazing. Dr. Kyle: Yes, and the writer of that had made exactly the same observation I had, is that these patients with hemolytic anemia did better in general than patients with anemia due to a packed bone marrow. The only thing I had done is to say that they had a positive Coombs test, but the Coombs test hadn't been described until 1950 or so and cortisone had not been discovered and used until 1948. So it kind of took a little wind out of my sails that this fellow 50 years before me had the same idea. This I think is a very important thing for young physicians to realize and for everyone and that is the physicians and scientists of yesteryear were just as bright, just as able as any physician today. We sometimes, with our sophisticated knowledge, we just take a lot of the information that we are given for granted. If we had to start out like they did a couple hundred years ago, we wouldn't do nearly as well as many of them. So I spent my six months in the laboratory and then I realized that, "Gee, I didn't know anything about clinical hematology," and the field was becoming very interesting to me. So I took the clinical hematology hospital rotation for three months. During that time, two things happened that changed my life. The first was that I saw an electrophoretic pattern. And many of you with multiple myeloma know that that electrophoretic pattern shows a peak or a spike and that this represents the monoclonal protein or the abnormal protein in the blood and is very important because that's one of the features that we follow to see whether you are responding to therapy or whether you are not. In any event, I asked the physician who was running the service at the time what this funny-looking pattern was because I had never seen one before. And he said, "Well, we don't know much about it. It's a new test. Why don't you look into it? So it had been done at the Mayo Clinic for about three years before that time, so I reviewed all of the records. There were over 6,000 of them and came to the conclusion that if a patient had a peak in which the height of the peak was greater than the width of that peak or spike at midline, if it were greater than four to one, then this patient very likely had multiple myeloma or Waldenström's macroglobulinemia or amyloidosis. So that started me on the road in this area. And then on that on same hospital service came a woman, 48 or 49-year-old woman as I recall from Cincinnati who had developed back pain several months before and also fatigue. And she came to the Mayo Clinic because no diagnosis had been made at home. Her physician saw her and examined her and found that her skin was a little peculiar, a little thickened, and he thought that she might well have scleroderma which is an uncommon rheumatologic disease that involves thickening of the skin among other things. So he continued the evaluation, found that the patient was anemic and then with the anemia and the back pain ordered a serum protein electrophoretic pattern and that the patient had a spike and this of course led to a bone marrow examination which showed evidence of multiple myeloma, and so the patient was hospitalized. Believe it or not, all patients who received radiation therapy at that time were put in the hospital and given the treatment. I was the resident on duty that night. As I was going through her chart, I noted that she had seen dermatology. And what does a dermatologist do when he or she sees a patient with a peculiar skin lesion? Well, they'd take a biopsy. Just the day that she was admitted to the hospital, the biopsy report came back and the biopsy said that amyloid was present. Jenny: Amyloid is a buildup of protein or do you want to describe exactly what that is? Dr. Kyle: Yeah. What amyloid is -- well, I didn't know what it was except that I could remember back to pathology in medical school, and I remember we saw under the microscope a glassy-like material that showed no cellular detail or anything and it was considered to be an inert substance and it deposited in organs and could be very serious. In fact, at that time, tuberculosis was a major problem. While I was interning, I did see patients who had tuberculosis. I spent a period of time at the Chicago Municipal Tuberculosis Sanitarium in which there were hundreds of patients with the disease and there were a number of them who developed secondary amyloid, but that's all I knew about it. I had never seen or I suppose more correctly had never recognized a patient with primary amyloidosis; that is the type associated with myeloma during, four years of medical school, a year of internship, three years of residency or fellowship at the Mayo Clinic. I also, in the middle of my fellowship was drafted into the Air Force and spent two years in a 400-bed hospital seeing a lot of patients, and I had never recognized a case before. So I decided to go to the Mayo Clinic records and was able to find 80 or 81 patients with primary amyloidosis; that is amyloidosis that occurred without any particular cause. As I reviewed and studied these 81 patients, I found that a number of these patients actually did have multiple myeloma, and in fact all of these patients had abnormal plasma cells in the bone marrow and many of them had a spike in the serum protein electrophoretic pattern. So that fit together with the electrophoretic pattern. And with these two studies, you can look back now and you see the one with the electrophoresis in the four to one spike that looks pretty amateurish today, but at that time, the Journal or the American Medical Association (JAMA) saw fit to publish it and the paper that I wrote on amyloidosis was published in one of the leading internal medicine medical journals of the day. So these were, as I said, published and it was not until 1961 that Dr. Waldenström introduced the terms monoclonal proteins and polyclonal proteins. This was a very fundamental finding. Jenny: And your research was before that? Dr. Kyle: No, no, no. Today, it's just obvious. I mean, everybody knows that a monoclonal protein is one that is produced by plasma cells and can be malignant such as multiple myeloma or AL amyloidosis, that is primary amyloidosis, and is very serious or potentially serious, whereas patients who have a polyclonal increase in immunoglobulins have a broad based increase in gamma globulin instead of the spike. This broad-based process is an inflammatory or reactive response of plasma cells to the stimulus. The most common causes of a polyclonal increase in immunoglobulins -- IgG, IgA, IgM -- is chronic liver disease or rheumatic diseases like rheumatoid arthritis and related rheumatologic diseases. This was an absolutely fundamental observation that he made and is one that is extremely important today. Now he is the person obviously who described Waldenström's macroglobulinemia in 1944. Of course, Waldenström's macroglobulinemia was not a new disease that occurred at that time. Prior to that time, it was called a lymphoma or in some instances may have been mixed in with patients with multiple myeloma. Today, that just seems like, gee whiz, can't anyone tell the difference? But at that time, it was not really practically possible to do so. So in a nutshell, I have kept going in myeloma and amyloidosis and macroglobulinemia and obviously still haven't figured it out. I think that things are moving along pretty quickly here, and maybe I should just advance quickly to the novel agents. Jenny: Yes, go ahead please. Dr. Kyle: Okay, will do. And so in about 1998, a patient, in fact I had seen him seven or eight years before. He was a 35-year-old cardiologist from New York City, and I had put him on a combination of alkylating agents and he had had some response. And then as you can imagine, his disease came back and he made the rounds, saw many physicians, had a couple of autologous stem cell transplants. At this time, he was seeing Dr. Barlogie at the University of Arkansas. And his wife said to Dr. Barlogie, "What can we do?" And Dr. Barlogie threw up his hands and said, "We've done everything. He has had everything over these seven or eight years and there isn't anything else to do." She was a rather remarkable person and said, "There has got to be something." And she was reading and found a drug called endostatin, an antiangiogenesis drug that might be a benefit for malignancy. This drug was being studied by a scientist, Dr. Judah Folkman, at Harvard. Actually, he was the head of surgery, believe it or not, at Boston Children's Hospital. So she called up Dr. Folkman and said, "I really desperately want to have endostatin for my husband." And Dr. Folkman said, "Well, endostatin is only in its early phases of development and it'll be years before it becomes available. But if you are interested in an anti-angiogenesis drug, there is a drug called thalidomide and that's available at the National Cancer Institute. You have to ask Dr. Barlogie to obtain the drug by compassionate usage." So she talked to him and Dr. Barlogie then requested the drug from the NCI and then he treated the patient, the cardiologist. And what happened? Unfortunately, nothing and the cardiologist died a couple of months later of his myeloma. But Dr. Barlogie had another patient who also was refractory to myeloma and so he treated him with the thalidomide, and this patient had a remarkable response. To make a long story short, Dr. Barlogie then treated more patients. At a year or so later, Dr. Singal, who was one of Dr. Barlogie younger colleagues, reported 80-some cases of relapsed refractory myeloma and reported that 33% or 34% of these patients showed a significant response. That was remarkable and that was the beginning of the novel agents. This was followed in a couple of years by the introduction of Velcade or bortezomib. This is proteasome inhibitor and that's a drug that was engineered by a fellow, Dr. Julian Adams, a chemist and introduced everyone to the proteasome inhibitors. Then within a couple of years came lenalidomide or Revlimid which is a derivative or analog of thalidomide. Then now just this last year, pomalidomide, the third generation immunomodulatory agent following thalidomide and lenalidomide, was introduced and is available now for patients who have had two previous regimens and are now relapsed or refractory. Then also this last year, carfilzomib which is also a proteasome inhibitor, was introduced as well. So the effect, the prognosis, the outcome in multiple myeloma has improved markedly in the last dozen or 14 years. So we have all been privileged to see this and to live through this period of time and we're very, very optimistic about new drugs, new agents, new combinations thereof. Jenny: Well, it's been exceptional I think. And many contributions from patients and significant contributions from researchers. Dr. Kyle: Yes, and as the matter of fact, perhaps at another time we can talk about MGUS, smoldering multiple myeloma and how this kind of fits into the whole picture and talk a little bit more about research, the problems with funding, the challenges of clinical trials and that sort of thing. Jenny: Well, I have a question because there seemed to be a few themes with what you have talked about so far. First, I can see why you are such a great researcher because you have this natural curiosity and you discover something and then it leads you to many other questions. So whether that's going back in history to find out what's already been done and then relating it to what you are working on like the article that you found that was written in German 50 years earlier, to me that shows incredible natural curiosity. That seems to be one of the characteristics of someone who is going to come up with discoveries not necessarily by accident but by definitive purpose. Dr. Kyle: Well, a lot of things are discovered by chance and by accident, and sometimes something has been discovered. I always worry a little bit about the fact is could there be something out there that somebody has talked about, some approach, some novel sort of approach that appeared to be a dead end at that time, but now maybe 10, 20, 30 years later, with new techniques, new approaches and so forth, maybe that piece of information, that study, that observation could turn out to be very important today; that is putting two and two together and ending up with five or six or more. So I think that curiosity, interest in things is important and also persistence too. One has to stay I think in a field and keep working away. Jenny: I have a question about that. I am wondering as you look at the novel therapies and then what is to come, will more of the discoveries come from either serendipitous accidents or from targeted research? I know we are looking for a cure. And you have the longest view of this, so I'm just wondering if you have any wise words for the rest of us. Dr. Kyle: Well, I don't know of any wise words, but I think that it's probably a combination of "accident and persistent effort" and I think they go hand in hand. I think it's important when we see a patient that is a little different - the disease doesn't behave the way you would expect or something or other - to try to figure out if you can what might be going on in that situation. There are many instances in which observations are made years before. Thalidomide is a good example. Thalidomide was reported used in the mid-'50s, used for nausea and vomiting, of pregnancy and for anxiety. And then the congenital abnormalities were recognized, the horrific changes that could occur in the newborn and the drug was abandoned so to speak. But there are two studies in this country that were done in the early to mid-1960's in which a group of patients with malignancies were treated with thalidomide, and there were actually several patients with myeloma but no benefit was recognized, and so thalidomide was not considered for the disease until Mrs. W insisted on something like this treatment for her husband. Jenny: Well, hooray for her! Dr. Kyle: Yes. Jenny: I think it's wonderful. Now, in talking about discoveries because I have read a book on this that talked about serendipitous discoveries in science and how that can happen, but I know that I'm from a background in technology and I know that the right environment needs to exist for these new ideas to really thrive. I grew up in Silicon Valley where they have kind of a combination of a tolerance for risk, educated entrepreneurs, investment capacity and then very collaborative networks. So for science, what is the formula? What are the elements that need to exist for consistent discoveries? Dr. Kyle: Well, that's a very, very difficult and challenging question to answer, but I think a couple of things are very important and that is funding. I think it's terrible that research grants to the National Cancer Institute are funded at a level of about 7%. That means that 13 of 14 proposals submitted to the National Cancer Institute have to be rejected, not funded. What this I think is going to do in the long run is going to drive the researchers away. Researchers are PhDs or MD/PhDs. All of them have to eat. They have to provide for their family. The PhD, if they are not able to get extramural funding for their research are either going to have to go to teaching or to industry and in industry -- and I am not being critical of industry at all, but in industry the researcher works on a particular project or a particular idea or something like that whereas the academic or the PhD in academic research can kind of "follow his or her nose" so to speak. The problem with the MD/PhD is that this person too will be driven to practice clinical medicine in order to make a living and will have to leave the bench, leave the laboratory. So we lose those people. And then I'm afraid that in 15, 20 years, something like that, everybody will look around and say, "Oh, my gosh. Where is all of the medical research?" Jenny: That's why it isn't happening. Dr. Kyle: Well, it's disappeared simply because we have had a marked limitation of funding and the researchers have to go on and then it's very difficult to come back, in fact impossible to come back after a decade or more and pick up and go on. So we are losing a generation of researchers. Twenty years from now, we'll say, "Oh, there is a terrible shortage." The federal government will say, "Oh, weve got to put money into research." So they pump in many, many dollars into research and a lot of it could be wasted. Even at that, it takes a dozen years to train a person. I mean, you get your PhD four, five years sometimes, then you have to have a postdoc, many of them get two postdocs, and then start out in an academic career. The physician has had four years of college as has the PhD of course. And then after that is four years of medical school, three years of internal medicine, three or four years of a fellowship and then a PhD or you can get a MD/PhD. A number of medical schools have programs in which you obtain both the MD and the PhD, but that takes seven or eight years at least. So in a nutshell, it takes a long time to train a researcher. I mean, you can't grow them on a tree. Jenny: It's a very deep commitment. Dr. Kyle: Yeah. And the other big problem as I see it is clinical trials. We put probably no more than 3% or 4% of patients with multiple myeloma in the United States on clinical trials. In Europe, in France, for example, probably 75% to 80% of patients with multiple myeloma go on clinical trials. Consequently, over the last decade, the French have led the world in prospective randomized studies and have made some very, very important observations that are valuable to everybody, patient and researcher. Jenny: Why the big discrepancy? What is France doing that the US is not doing? Dr. Kyle: Well, the first thing is that there are no oncologists in private practice, number one. Number two, the drugs are not available to anyone, any physician or anything who is in any sort of practice. There, the patient with multiple myeloma - the diagnosis, for example, might be made by one's local physician but then that patient, once the diagnosis is made or even the diagnosis is suspected, is going to be seen by a specialist or a biohematologist who is in a regional hospital or a district hospital or whatever, and that hospital is linked to a university hospital and the university hospitals, there are just two cooperative groups in all of France. So the patient ends up there. Now, I'm not saying that that's what should be done because in this country we have many able practicing oncologists who are very, very busy and to put a patient on a study takes time and effort, and it's more and more difficult to get patients on study. There are many more regulations than there were three or four decades ago. All of this has "become necessary" and it ends up, it's protective for patients, it's helpful for patients, helpful all the way around, but it is a difficult, cumbersome system. The IRBs which protect patients, there is a lot of effort, a lot of frustration on the part of physicians and researchers and so forth, spending a lot of time writing the protocols, getting them approved by various committees and groups and IRB approval and all of that sort of thing. It's a difficult process in this country. And I'm not saying that that's necessarily bad, but there has to be regulation, but I'd like to see a little more common sense and less regulation. Jenny: I think our conversation is wonderful and I want to continue it. I also want to leave time for questions, so I think we might have to split this into two discussions because we have so much that I think that you can help us cover with MGUS and smoldering myeloma, but I think we should save that for another conversation. We have several caller questions, so let me go ahead and let people ask those questions. Caller: Hi, Dr. Kyle. Thank you, first of all, for taking your time and to explain in depth the history of myeloma. You are a true pioneer in this space and we just appreciate your commitment to this terrible disease. So a couple of things: One, I read a while back an interview that you did on the internet. In the interview, this doctor had found an innovative area that he thought was promising, but then he was ridiculed by his peers and then he dropped it -- and then later, six, seven, eight years later turned on to be kind of a very promising area. I don't have the name and the reference, but do you remember that experience? Dr. Kyle: No, but there are examples of such a thing and they go back for years. For example, back 150, 160 years ago, childbed fever was a terrible sort of thing and women who delivered babies in the hospitals had a very significant mortality rate. And there was a physician named Semmelweis at the University of Vienna, and he said that doctors should wash their hands before doing deliveries and so forth. And he was ridiculed and according to some was ostracized, ridiculed so much that he became mentally unbalanced and actually he did die in an insane asylum at that time. Obviously, he has been proven to be correct. Caller: The single biggest advancement in medical history, washing hands. Dr. Kyle: Well, it's one of them, yes. Caller: I had read up on that story also. I remember that he had two practices. He had one at a labor and delivery hospital and then one at a research hospital, and he was noticing the differences between the mortality rate between the mothers and the babies between the two areas. Dr. Kyle: You see, a lot of babies were born in the home and attended by midwives and not physicians. And the midwife delivered babies, actually the mortality rate among those women was much less than when they were seen by physicians who obviously saw patients who had infections and boils and carbuncles and abscesses and all of that sort of thing. Yes, you're absolutely right. Caller: And the mothers would sit outside this hospital and beg not to go inside and somebody deliver in their carriages on the outside so they wouldn't have to go the kill or the death hospital. So that's a great example. This knowledge had spread throughout the community about what was working, what wasn't working, but it wasn't yet accepted by the medical community. They were somewhat dragging their heels on this. Dr. Kyle: That is embarrassing for us. Caller: I apologize for not having the story at my fingertips, but you had mentioned something similar to this myeloma field years ago. And this still goes on, this fear of embarrassment to go and boldly do new things. What are those next promising areas that are going to come from of innovation, and who is going to do this? Who are the bold, Dr. Semmelweises of our time that will take those risks, those personal risks among their peers to take to identify these new research areas that will make a difference? Dr. Kyle: Well, I don't think it's possible to give a direct answer to that, but I think one of the things that's very important is to attract young people; that is the young physician, the young PhD and so forth to stay in the field, particularly we're talking about multiple myeloma now. In order to do that, those people have to be able to obtain grants and extramural support in that field in order to continue in the field. If there aren't grants and so forth, well then they will all go on to cardiology or some other field. That's one of the concerns I have about the funding in medicine and in research today. That's why, for example, I am sure that many of you are familiar with the International Myeloma Foundation or Myeloma Research Foundation, both of which raise monies for research. I think that one of the important things there is the grants that are given to younger people who are "entering the field" so to speak to get that initial grant, and then hopefully to get another and to continue in the field and not have to or not revert to strictly clinical practice or to another field or something like that. I think that we need to keep the young people, the young ideas, and so forth involved and around. There are so many things that we don't know and we don't understand that there is obviously a lot that can be done if we have the trained people to work in a field. Caller: So let's connect the dots for us patients and caregivers. What can we do to help identify these young doctors and researchers that you talk about that are going to be taking those, pushing that? What we can do to help support them? Specifically, who do we call? Where can we go? Where can we donate? Dr. Kyle: I think first that you need to make it clear to our legislative bodies that medical research is important. That's why various groups have advocacy activities in Washington. And this is one way to get more funds for the National Institutes of Health and specifically for the National Cancer Institute. We have to make it clear to our representatives in Washington, senators too, that the country needs to invest in research for the future. The second thing that we patients can do is to enter prospective randomized studies and to be willing and able to participate in these activities. And then, thirdly, financial contributions to foundations that are effectively working in the field. Caller: All right. Well, thank you very much. Dr. Kyle: But I think the big thing is to get through to Congress how important this is and that education is really the future of this country, I think. Jenny: Thank you. Our second caller has a question. Caller: Yes, doctor. With so little resources to go around, how can we collaborate and make sure we are not duplicating projects? Dr. Kyle: Well, "duplicating projects" is hard to define. One thing is that when a discovery or observation is made, maybe this is a fluke. It has to be confirmed. The same is true with randomized studies. Even though they are done carefully with adequate numbers of patients and appropriate statistical approach and so forth, they don't always come up with or always give the correct answer overall. So some things need to be duplicated and looking at it with a little different light. So I don't really think that when you come right down to it even though two individual or two individual groups are working on a particular agent or study or something like that, they oftentimes have a little different approach and there isn't that much "duplication" that an administrator can say, "Look, this problem has been solved and we don't want to do anymore research on it." That would be pretty rare. Caller: All right. Dr. Kyle: I dont know if I answered your question satisfactorily or not. Caller: I see what you are saying. I just wonder if even though that it's good to have independent analysis and separate looks, I wonder if sharing some of that in more real time would help people move forward together faster. I just feel like that could be facilitated. Dr. Kyle: Yeah. There are efforts currently to accumulate large bodies of data from tens of thousands of patients and that may well have merit. It certainly needs looking at and so forth because now we're getting larger and larger databases and we're able to integrate and to look at that data. There are many things I am sure that we kind of today take for granted that looking at very, very large numbers of patients may shed a different light on this. That is looking at, say, the databases that Medicare has and that sort of thing. Is this drug or regimen of drugs is it really effective for this disease? Caller: Thank you for your comment. Jenny: For our final question, we have someone email in a question that I'd like to ask on her behalf. Her name is Linda and she had a question, "With over 60 years of experience in the field of myeloma, how many patients have you seen?" Dr. Kyle: Oh, gosh! I can't really tell you personally how many I have seen. I was alone for many years because when I started this back in the '60s, hematologists did all types of hematologic diseases. In fact, when I said that I wanted to establish a laboratory for protein analysis and a clinic for patients with myeloma and so forth, I was criticized because it was too limiting and that one should not do that sort of thing. We have now become very sub-specialized. We have 15 people here in our group who see patients with multiple myeloma and related disorders. It's becoming more and more complex and more difficult to do so. Getting back to the numbers of patients, we have in our database since 1960, we have about 46,000 or 47,000 patients with monoclonal protein disorders. And of that group, about 8,200 something like, 8,200-8,300 have full-blown symptomatic multiple myeloma. By far, the larger number of patients are the patients with monoclonal gammopathy of undetermined significance, MGUS. Jenny: And we are going to have to dedicate a whole discussion to that because that's where the fundamental part of your research lies. Dr. Kyle: Well, and that's where myeloma begins. Virtually, every patient with multiple myeloma has a preceding MGUS. Jenny: I think it's worthy of an entire discussion. So we will have you again, hopefully soon. We thank you so much, Dr. Kyle, for joining us today. We are so grateful for your service. We are grateful for your contributions to the field of myeloma and are very fortunate to have benefited from your life's work and your truly stunning efforts. Dr. Kyle: Well, it all comes down to you, the patients. That's what's important. Jenny: We are very grateful. Dr. Kyle: Okay. Well, very good. I hope I didn't go into too much detail there historically. Jenny: No. It's perfect. Thank you so much. Thank you so much for joining us for another episode of Innovation in Myeloma. Join us next week for our next mPatient Radio interview with Dr. Don Benson to discuss his work in immunotherapy.