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New Definitions and Treatments of MGUS and Smoldering Myeloma with Pioneer Robert Kyle, MD, Mayo Clinic
New Definitions and Treatments of MGUS and Smoldering Myeloma with Pioneer Robert Kyle, MD, Mayo Clinic image

Sep 27, 2016 / 11:00AM - 12:00PM MDT
HealthTree Podcast for Multiple Myeloma

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Episode Summary

Robert Kyle, MD Mayo Clinic Rochester Interview Date: September 16, 2016 

Dr. Kyle shares the story about his early discovery of multiple myeloma precursor conditions in the mid-1960s. He was able to make these discoveries because the Mayo Clinic had access to decade-long data on its patients. In fact, he has been saving myeloma data for over 55 years! Dr. Kyle describes the definition of smoldering myeloma and their ability to predict 80% if patients have high-risk smoldering myeloma (or disease that will likely progress to active myeloma). Treatment for high-risk smoldering myeloma is now becoming the norm, but he always encourages high-risk smoldering patients to receive treatment in clinical studies because it is the only way to validate the best treatment approaches. He sees promise in using immunotherapy for smoldering patients, but says that leveraging the immune system is not an easy task. Dr. Kyle tells us that the most important thing for smoldering myeloma patients is to be checked frequently for progression.

Thanks to our episode sponsor, Takeda Oncology


Full Transcript

Jenny: Thank you for joining us on today's episode on Myeloma Crowd Radio. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio. Now, it's Blood Cancer Awareness Month and it's time to learn what you can do to help advance a cure. One of the easiest and most important things you can do is to share information to help other patients get the best outcomes. On the Myeloma Crowd website, we feature latest news and information about myeloma. Another way to help is to help with research. The Myeloma Crowd Research Initiative is funding two immunotherapy research projects that are cutting edge studies to help all myeloma patients, but especially those with high risk. So take a look at this research initiative on the Myeloma Crowd site and share it with your friends and family during Blood Cancer awareness month. Now, we're thrilled today to have with us Dr. Robert Kyle. For over 50 years, Dr. Kyle has led the way in myeloma research and he was the pioneer that defined and determined both the term MGUS and smoldering myeloma. So Dr. Kyle, welcome to the program. Dr. Kyle: Thank you. Glad to be here. Jenny: Let me give a more full introduction for you before we get started. Dr. Kyle's groundbreaking work changed the way that myeloma was diagnosed and treated. He founded the Mayo Clinic's Myeloma, Amyloidosis and Dysproteinemia Clinic. He also founded a special protein laboratory and began collecting and recording data for patients with monoclonal plasma cell disorders. He has written over 1065 peer-reviewed articles and more than 1350 abstracts. He received the David A. Karnofsky Memorial Award from the American Society of Clinical Oncology and the Wallace H. Coulter Award from the American Society of Hematology. These are the highest honors awarded by these two groups and only two persons have received both. Dr. Kyle is Director and member of the Scientific Advisory Board for the International Myeloma Foundation. He has been chairman of the Myeloma Committee of Eastern Cooperative Oncology Group, Secretary General of the International Society of Hematology Inter-American Division and member of the Editorial Board of Leukemia. The International Myeloma Foundation has established the Robert A. Kyle Lifetime Achievement Award to honor the physician who most exemplified a singular dedication to and compassion for myeloma patients and treatment of their disease. And he continued his research at the Mayo Clinic today, even in recovering from knee surgery which is just incredible. So Dr. Kyle, we are so fortunate to have you with us and thank you again for joining us. Dr. Kyle: Thank you for inviting me. Jenny: I interviewed you about three years ago and you gave a history of myeloma advances but you have a specialty in these precursor disorders, so today I would love to focus on just Monoclonal Gammopathy of Undetermined Significance (MGUS) and smoldering multiple myeloma (SMM). So maybe you could start by giving us a little bit of history about how you discovered those in the '70s and early '80s. Dr. Kyle: Well, it actually begins a little before that in 1964. I saw a patient who was newly diagnosed with multiple myeloma with typical back pain, compression fractures, anemia, multiple lytic bone lesions, a bone marrow containing more than 20% myeloma cells and a large serum spike. The patient had an obvious multiple myeloma. I advised therapy with one of the two alkylating agents that was available at the time, cyclophosphamide, and the patient obtained some benefit but died from the disease nine months later. I looked at her Mayo Clinic history and here, we have the histories of every patient's prior visits.  I noted that this woman had been to the Mayo Clinic in 1945, almost 20 years before. At that time, she was complaining of fatigue but her hemoglobin and other laboratory tests were normal, but the erythrocyte sedimentation rate was very high. It was over 100. The clinician seeing her at that time ordered an albumin/globulin ratio which turned out to be abnormal. Now, why in the world didn't the physician order a serum protein electrophoresis? This is a test that's available all over the world today. Well, the simple reason was that this test was available only in a research laboratory and in fact, it took one technician one day to examine the serum (blood) from one patient at that time. So it's pretty obvious that it was not a practical test to order. Today, we do between 600 and 700 serum protein electrophoresis daily in our laboratory. In any event, the clinician also ordered x-rays of the bones and did a bone marrow examination which showed only 3% or 4% plasma cells which is normal. Very wisely, he did not recommend any specific treatment for the patient. She came back 13 years later and this time, she was asymptomatic and felt fine. Her laboratory tests were still satisfactory but, she had a serum protein electrophoresis and this showed a typical M spike or monoclonal protein in the serum of nearly three grams per deciliter, which is pretty substantial. She was still asymptomatic and had no other changes. Her bone marrow was unchanged. She had no bone lesions. So she was sent home without specific therapy. And then, a few months before I saw her in 1964, she developed bone pain and as I mentioned, had typical features of myeloma which led to her demise. And so we actually published that patient as a case report in 1966 and at that time, the M spike had been recognized particularly by Dr. Waldenström in Sweden. He, in the early 1950s, said these patients had “essential hypergammaglobulinemia” and advised no treatment for them. After a few years he used the the term Benign Monoclonal Gammopathy which was the term used at the time that I saw this patient. When we published the paper, we made the point that benign monoclonal gammopathy isn't always benign and that these patients should be followed. Over the next decade, I ended up finding 241 Mayo Clinic patients who had a monoclonal protein in the serum, a monoclonal gammopathy, but no features of multiple myeloma or a related disorder. When this paper was published about 15 years later, we found that 1% of the patients with a protein abnormality in the blood progressed to multiple myeloma, Waldenstrom's macroglobulinemia or to AL amyloidosis each year. At the end of ten years, 10% of the patients would have progressed and so on down the line. At that time, we had follow-up data for up to 25 years. When that first paper was published in 1978, I actually emphasized that 25% of patients who had (and then introduced the term monoclonal gammopathy of undetermined significance, MGUS) progressed at a rate of 1% per year. I emphasized this in the paper which alarmed many physicians and patients. I began seeing patients who were virtually scared to death that they had a 25% chance of developing a serious, incurable malignancy – multiple myeloma, macroglobulinemia, or amyloidosis. However, I didn't emphasize that you had to live for 25 years before you had this risk. And since the average age of a person with MGUS is about 70 years, if that individual is followed for 25 years then during that period of time, there are many other things that will happen to us such as heart disease, strokes, other cancers that are totally unrelated to myeloma and the plasma cells. Consequently, it becomes less of a scary diagnosis and the patient is much better served by simply following that M protein. That is an answer to your question and if there are any other questions about any of the details, I'd be happy to try to answer them. Jenny: Well, one thing that really stands out to me is that you were able to make this conclusion because you had data, you had records that have been tracked and kept so the value of having patient data that researches can go look at over a long period of time is incredibly valuable. Dr. Kyle: Yes. We're very fortunate here in that we have records of patients going back to 1907. For example, just a few months ago, I had an e-mail from a patient in Canada who asked me about his grandfather. With the date of birth of his grandfather and his address at that time, I was able to find his Mayo Clinic record and sure enough, this patient had been here. He had a cancer of the stomach and was operated on. And then at that time, 1919 as I recall, patients were in the hospital for ten days after abdominal surgery and unfortunately, on the 8th or 9th day, the patient started running a fever which turned out to be pneumonia which was a fatal complication. An autopsy had been done and it confirmed the diagnosis of pneumonia and it also showed that there was no evidence of cancer left in the abdomen after this surgery for his cancer of the stomach. And of course, in 1919 if they had had antibiotics for the pneumonia, that patient could well have been cured or would have had a significant duration of time until he had recurrence of his disease. So the records system is very important. The second is that I started collecting any serum, from blood that was left over after the tests had been done on that patient. Ordinarily that blood sample is thrown out after a week's time because one cannot possibly store all of the serum samples for every patient. In any patient with myeloma, Waldenstrom's macroglobulinemia, amyloidosis or monoclonal gammopathy, I saved the serum and this allowed us to go back to the patient’s record and the serum sample collected at that time. For example, my colleague Dr. Vincent Rajkumar about a decade ago, looked at our MGUS patients and used a new test that measures the free light chains in the serum. We were able to find serum samples on the majority of these 1,384 MGUS patients and this showed that the values for the free light chains turned out to be an important prognostic feature for monoclonal gammopathy of undetermined significance. I used to tease Dr. Rajkumar that we were able to do this study in about six weeks and if we did not have the serum bank, it would have taken 25 or 30 years. Serum banks are very important. Jenny: That is incredible. And before we talk about that, your look at this for over 40 years. I want to ask you about smoldering myeloma. So once you took a look at the MGUS and kind of identified that, how did you classify or define smoldering myeloma after you started making some of these discoveries. Dr. Kyle: I began abstracting the records of patients who had this particular disease and started saving the serum in 1960 which would be 55 plus years that this has been going on. Well, we defined the patients with MGUS as having a serum level of < 3 g/dL and a bone marrow, if done, containing 10% or fewer plasma cells. At that point, there was pretty much general agreement among people in the myeloma field to not treat the patients or to not make a diagnosis of multiple myeloma unless the M spike was greater than three grams and the bone marrow contained more than 10% plasma cells. It became obvious to me in seeing patients on a daily basis that some of these patients can have these high M spikes. In fact, I vividly remember the first patient that I saw with a large M spike. I was asked by one of my colleagues to see this patient in consultation. He had an M spike that was about 3 1/2 grams per deciliter and he had a bone marrow containing about 20% plasma cells. Both of those features fall into the diagnosis of multiple myeloma requiring treatment. However, this patient's protein abnormality had been recognized about a year before and so when I walked into the room, I expected to see a patient who was pale, anemic and who had back pain and so forth from multiple myeloma. Instead, I saw this 70-year-old business man who was completely healthy. I asked him the questions relating to symptoms of multiple myeloma. His answers were all negative. His laboratory tests except for the M spike and the bone marrow which contained 20% plasma cells were normal. The hemoglobin, calcium, creatinine, bone X-rays, etc., were all normal. And I said, “Well, gee, a patient with findings like yours are ordinarily treated for multiple myeloma; however, you look very good and your other laboratory tests are stable. If you promise to come back in six months, we'll delay the treatment.” And lo and behold, he came back in six months and nothing was changed. This went on for 20 years and then at his return visit, he was found to have large lytic lesions in his bones. At this time, he had congestive heart failure which was attributed to coronary artery disease and a myocardial infarction. There were no features of amyloidosis. And so this follow-up I actually decided not to treat him because he had no bone pain and no other symptoms other than his congestive heart failure. Any treatment for myeloma would contain steroids which would cause retention of fluids and make his congestive heart failure worse. So I didn't treat him and about a year later, he died of congestive heart failure but did not develop any bone pain or other features of multiple myeloma. With this experience of seeing a patient for 20 years, I reviewed our cases and found seven or eight patients who had an M spike that was greater than 3 g/dL and had a bone marrow with more than 10% plasma cells consequently fulfilling the criteria for myeloma but who had no symptoms over the succeeding five years. I labeled those patients as smoldering multiple myeloma. We have not treated them and some of those patients with SMM have gone for 25 years without requiring any therapy. Jenny: That's an important and critical finding. And in hearing you telling stories about these different patients and the conclusions you've made, it's not only scientific but it's personal. You're looking at these people coming into your office and I know you have seen probably thousands of patients. Dr. Kyle: That's why it's important to see the patient, ask and take a good history, examine the patient and take all of the laboratory features into consideration. I always tell the fellows and the residents to do this when they see a patient with one of these conditions. Jenny: So I wonder in your 55 plus years of research now that you had seen the field evolve, what are your major conclusions about these precursor conditions? I know the International Myeloma Working Group has changed some definitions over time but maybe you could give us a high level -- give us main key points about the changes that you've seen. Dr. Kyle: Well, first of all, you brought up the International Myeloma Working Group and we have altered what we have done with patients with smoldering multiple myeloma for a number of years. We have attempted to determine who is who, that is who is going to progress within the next two years and who may remain asymptomatic for a decade or more. That is not easy to do when you see the patient initially, so we've been on the alert for features that would identify patients who would be likely to progress to symptomatic multiple myeloma within two years. And our goal is to identify an 80% probability of progressing to myeloma and then the next step -- and I could stop and give you some of those features. First of all, if a patient who has smoldering multiple myeloma, which is completely asymptomatic, has a bone marrow that contains 60% or more plasma cells, that patients (in well over 80% of cases) will develop multiple myeloma in less than two years. Another feature is patients who have a very high free light chain level, a ratio of greater than 100:1 and an abnormal free light chain level of at least 100. And also, patients who have an MRI have two or more abnormal bone lesions. Those patients are destined to develop myeloma in about 60% to 70% of patients within the next two years. That increased risk of developing multiple myeloma coupled with therapy that is more easily given (i.e., the novel agents) and is less risky as far as the patient is concerned than conventional melphalan or other alkylating agents. The alkylating agents consist of melphalan, cyclophosphamide or BCNU. Those alkylating agents put a patient at risk for myelodysplasia or actually acute leukemia so we don't give alkylating agents for long periods of time. Now we have the novel agents of bortezomib, carfilzomib, lenalidomide, pomalidomide and Ixazomib. Those are much easily tolerated by the patient and much less risky than the alkylating agents. Patients who are designated as high risk myeloma, or high risk smoldering myeloma, need to enter prospective randomized studies to prove that those patients can actually be benefited as far as survival is concerned. Just lowering the M spike that is asymptomatic or reducing the plasma cells in the bone marrow may or may not stop the development of myeloma, macroglobulinemia or amyloidosis. We need to proceed slowly and carefully and make that designation between so-called benign and malignant disease as accurately as we can. Jenny: Let me ask you a couple of follow-up questions. When you talk about high risk, smoldering myeloma (I know some patients in typical or regular myeloma that might have high risk genetic features) but that's not necessarily what you're saying. Dr. Kyle: Well, high risk genetic features are also a factor but they are not associated with the 80% or more progression rate. It's lower. It's probably 50% or maybe 60% something like that. So it is a factor but just because a patient has only "adverse side of genetics" or unfavorable cytogenetics does not mean that one jumps in and treats because a patient can have these unfavorable cytogenetics and still not progress. One other point I will make is that we are saying that only 15% to 20% of patients fall into the "high risk cytogenetics" group. Jenny: Oh, okay. And you have those genetic features even when you have smoldering, correct? Dr. Kyle: Yes, you can. but if you don't have other features such as > 60% bone marrow plasma cells, free light chain > 100 and an MRI that has 2 or more lesions. In short, one should not treat a patient with high risk cytogenetics unless they have evidence of active disease. Jenny: And then what about circulating plasma cells that you're finding in the blood for smoldering? Is that considered a high risk smoldering feature? Dr. Kyle: Yes, but it depends upon the number of circulating plasma cells in the peripheral blood. When we first studied circulating plasma cells in the peripheral blood smears but that is a very limited way of recognizing circulating plasma cells. Now, with flow cytometry, one is picking up a lot more plasma cells in the peripheral blood. This may well be another important prognostic factor for patients with smoldering myeloma but more data is needed. Jenny: Now, before we get to how people are treating smoldering myeloma now or what you recommend, maybe we can talk about reasons for progression. So if somebody has MGUS or smoldering myeloma and there's a certain percentage who will progress and others who won't. Are there factors that trigger the progression? Or that could potentially be prevented? Of course, anybody with this precursor condition would love to shut it down early and get rid of it, but have you noticed in your research any specific factors? Dr. Kyle: Not really. There are no medications or supplements that are helpful in this regard. There was a study using curcumin for patients with MGUS but that was unsuccessful and did not prevent MGUS from progressing. Now, looking at smoldering myeloma would be a better group to study because, in contrast to MGUS, the risk of progression in smoldering myeloma is 10% per year for the first five years so that's a group of patients that should be looked for "preventive measures" in progression. Jenny: Yes that makes sense. I know that many groups have now started to say “How can we shut this down?” You mentioned lenalidomide and pomalidomide, agents that are not necessarily the harsh chemo alkylating agents that you talked about. So let's talk about that. What are people using now for smoldering myeloma especially for the high risk smoldering group and where is the field going for that? Dr. Kyle: Well, first of all, there are protocols and if a patient has smoldering myeloma, they should look into the possibility of getting into a smoldering myeloma trial. Just because the patient has high risk features is not an indication to treat because we don't know for sure whether reduction of the M spike and decreasing the number of plasma cells in the bone marrow will indeed significantly delay the development of symptomatic multiple myeloma. So this must be done, in my opinion, in a prospective randomized trial. There has been one study that has been reported from Spain in which the patients randomized to lenalidomide actually did better than those patients who were not randomized to treatment but there are shortcomings in that particular study and it needs to be confirmed. That is why the patient should get involved in a smoldering myeloma prospective randomized study if they possibly can. Jenny: Well, I want to echo your comment because the reason I started the Myeloma Crowd Radio Series is to encourage patients to join clinical trials because 3% to 5% of myeloma patients who joined clinical trials compared to some 80+% of childhood cancers, you see what they've been able to do by people participating and it's how we make these conclusions by getting this data and observing why people progress, why people don't. There are many smoldering myeloma clinical trials open now, and I know that Dr. Ghobrial has one that's just an observational study so they can collect some of this data like you have over the past almost 60 years. And I just want to echo that we completely encourage this so much so that we partnered with a company called SparkCures because they've come up with a very easy-to-use clinical trial finder for myeloma trials. And so the language is simplified and finding a trial site is simplified. It's not as hard as it used to be, trying to go on and finding a study that you could join. So there is help if you are interested in joining a study. It's something that we can help with because we believe that this is going to help find a cure for myeloma faster. Dr. Kyle: I'm 100% behind that. Jenny: Yes, we are too. It's something that patients can do. Sometimes patients think, “Well, I'm just going to hope and pray somebody comes up with this cure” and I don't think we have the luxury of time for that approach. So I think anything that we can do to make this go faster or make your research come to conclusions faster, is just in our self-interest. So a question about that. So Dr. Maria-Victoria Mateos of Spain I know has done some studies with lenalidomide. She started that a few years ago and like you mentioned, they were starting to use lenalidomide to treat. One of the questions/concerns that you touched on a little bit (and Lenalidomide has shown proof that it is effective to delay progression in smoldering myeloma) is that number one, am I going to have side effects that I need to deal with even on a non-chemo type drug or will it make my myeloma evolve in a different way? So should I be concerned about getting early treatment if that happens? Dr. Kyle: Well, again, we just don't know. One still has to keep in mind that there is no such thing as a safe drug. That was taught to us 170 years ago and if one looks at medical history, there are many, many drugs that have come and gone because they did not show efficacy when really tested. Secondly, some of these drugs have had unforeseen late side effects and that's particularly true with alkylating agents such as melphalan. The medical community had used melphalan for a decade when we noted in our practice that we had seen four patients who had developed myelodysplasia and acute leukemia. We raised the question as to whether the alkylating agent played a role and then everyone started to notice this problem and in fact the pendulum swung to the other side making many physicians reluctant to use melphalan. Melphalan is a very good drug for myeloma but there is risk. Fortunately, the risk factor is very, very low if you receive the melphalan in the high dose of 200 mg/Mover two days which is the dose and schedule for autologous stem cell transplantation. The risk of myelodysplasia or acute leukemia is low in those patients in contrast to the individual who was given melphalan and prednisone orally for several years. Jenny: Now, a question about lenalidomide. So doctors using lenalidomide in early smoldering myeloma studies, one of the questions I have is, is it effective because it has anti-myeloma effects or is it because it boosts the immune system because I heard that it's an immune system booster? Dr. Kyle: Well, actually the agents in this family – thalidomide, lenalidomide (Revlimid) and now pomalidomide (Pomalyst) are all members of the same family. Each one is a little better than the one before but these agents have multiple effects. Certainly the immunomodulatory effect and the anti-tumor effect are important and it's virtually impossible to say which is the most significant for that individual patient. Jenny: Okay. That makes sense. Let's talk a little bit about immunotherapies in smoldering myeloma because I think patients like the idea of using something that will boost their immune system to impact the myeloma without a lot of other side effects because it just seems that there are fewer side effects in some of the immunotherapy treatments than there are in some of the other drugs. So do you want to speak to that about immunotherapy use for smoldering? Dr. Kyle: Well, it's a laudable approach but one that is still in its infancy. We used dendritic cells 15 or 20 years ago and that provided a nickel’s worth of benefit but it was disappointing overall. Today, the CAR T-cell approach is a very interesting one but it has very significant side effects including fatalities. One is limited in myeloma because one-half the patients are above the age of 70 years when they're diagnosed. At present, one would not use the CAR T cell approach in those patients at that age level so it's something that is very exciting, very interesting but still the risk of side effects and the degree of efficacy must be determined. Jenny: Well, I think patients are excited about that and would like to see where this ends up going. Dr. Kyle: I was going to emphasize that patients do talk frequently about stimulating their immune system but that is much easier said than done. Certainly we know that patients with multiple myeloma have a reduced immune system but to give a specific immune stimulator is just not feasible. One should certainly be very cautious if they go to their health store and ask the proprietor for an agent that will stimulate their immune system. Oftentimes, they're given and sold products that are purported to do that but the scientific proof is pretty limited. Jenny: Oh, yes. And sometimes, it can just feed the fire right? With cancer cells? So you have to be really careful and make sure you're running everything by your doctor. Dr. Kyle: Well, even the doctor doesn't know. None of us know, really. Jenny: Yes. There was a story at my facility where they said that one patient came in and was being treated for myeloma and they were getting all the heavy duty transplant chemo and it just wasn’t touching the myeloma and they said, "Are you doing anything else?" And then he confessed he was taking this Noni juice every day or one of these power juices, and it was just making it spin out of control so they said, “Please stop taking that because it's making your cancer cells grow even faster.” I have a question for you. I went back and looked at our first show and on that show, you mentioned that heightened immunoglobulins in myeloma, one of those grows out of control but that across the board, they were caused by allergies, rheumatoid arthritis, or autoimmune disorders. So as we're talking about the immune system, do you think there's a link between myeloma and other inflammatory or autoimmune type of states outside of just the myeloma? Dr. Kyle: Well, are you asking does a patient with rheumatoid arthritis or a related connective tissue disorder (autoimmune disease) have a greater risk of multiple myeloma? Is that what you're asking? Jenny: Yes. That's my question. Dr. Kyle: In a nutshell, no. The evidence is extremely weak. We felt at one time that maybe rheumatoid arthritis is a risk factor for myeloma but we've not been able to really prove it. Jenny: Okay. Well, let me ask another question. I know that some of these immunotherapies are going after certain targets, the proteins found on the surface of myeloma cells and one of those targets is BCMA. So I interviewed one of the doctors who's working on a test to study BCMA levels because he found that it tracks, it correlates with the M spike so when the M spike goes up, the BCMA levels go up. The M spike goes down, BCMA levels go down. So I just wonder if you looked at the BCMA relationship and smoldering myeloma at all or the MGUS state. Dr. Kyle: We have not looked at BMCA in patients with MGUS so I just don't know. I am familiar with this person's interest and certainly I would encourage him to continue to study it and to publish his findings as time goes on. Jenny: And I think that's kind of related to the CAR T cell stuff because I know a lot of investigators are going after that particular protein. Let’s talk about minimal residual disease for a minute and some of the precursor conditions. In your opinion, what's the progress made I guess on minimal residual disease detection and for example, I heard that sometimes patients can go back to an MGUS state after they're treated. We are doing more testing on patients now I think post-treatment to see if they have achieved this minimal residual disease status. What would be your opinion on that? Dr. Kyle: Well, a patient who does achieve a minimal residual disease level has a stringent complete response. It is difficult to measure the amount of remaining tumor. We know that when you find monoclonal cells in the bone marrow, that tumor still exists even though the M spike in both the serum and the urine has disappeared and the immunoglobulins are normal, the calcium and creatinine is normal, no bone lesions and the PET/CT show no activity or lytic bone lesions, etc. So the better result that the patient achieves the better it is for that patient. One has to keep in mind that every patient who has a recurrence of his myeloma is of the same isotype that was present initially. If you have an IgG kappa myeloma when that tumor recurs, it is still an IgG kappa myeloma It doesn't recur as an IgA lambda or anything like that. That to me suggests  strongly that there are residual tumor cells and that if a patient has achieved a very minimal residual disease that it will take longer for that patient to relapse than it will for the patient who has a partial response (PR) or a very good partial response (VGPR) or a complete response (CR) or even a stringent complete response (sCR) so it's all a matter of degree but one does have to keep in mind that when the myeloma recurs after any treatment, you always see the same type of protein as before. One time a number of years ago, I had a patient who presented with an IgG kappa monoclonal protein (MGUS). This patient returned five or six years later with multiple myeloma of IgG lambda type. And so I said my gosh, has this patient developed another tumor? I went back to the original serum sample that we had in one of our freezers and looked more carefully at the serum. We found that he actually had a very small IgG lambda protein in addition to his large IgG kappa protein (biclonal monoclonal gammopathy). The smaller clone found initially grew and became the large IgG lambda protein. So when the patient had symptomatic multiple myeloma, we could find no evidence of the IgG kappa and it was now IgG lambda but that IgG lambda had been present in the original sample. One has to be very careful in these situations. One other thing that one needs to keep in mind is that we don't know the cause of multiple myeloma. We don’t know. Is there something in the bone marrow that could possibly enhance or cause the myeloma? And that if all of the myeloma cells are killed, will new plasma cells be infected or damaged and made to become malignant? We don't really know the cause of myeloma. Jenny: Yes, I think there’s a lot going on in that bone marrow environment. A lot of researchers are working to study someone like that patient. So myeloma is usually monoclonal or there's one protein that grows out of control. If that patient had the kappa and lambda, would that be called polyclonal? Dr. Kyle: Yes, unless they're monoclonal. You see, about 4% of patients with MGUS are actually biclonal; that is, they have for example an IgG Kappa and an IgA lambda or an IgM lambda and an IgA kappa monoclonal protein. We have followed a number of patients with a biclonal gammopathy and have found that they behave very much like the MGUS patient in that they can progress to myeloma or a related disorder over the years just as an MGUS can progress. Jenny: Interesting. Okay, my last question before I open it up for caller questions is, what is the most important thing for MGUS or for smoldering myeloma patients to know and to do? Dr. Kyle: Well, I think the most important thing is for the patient not to ignore it but to have the M protein measured on a regular basis. The physician will recommend the frequency that it should be done. I think if a patient has an MGUS that serum protein electrophoresis should be repeated in six months because there is no way to know whether this has just popped up in the previous few months or whether this has been present for ten years. And so one needs to check it in six months and if it's sill stable, then one can recheck it six months to a year later and the clinician makes a judgment depending upon the size of the protein and whether the uninvolved immunoglobulins are reduced or that sort of thing. But the critical thing is to be followed-up on a regular basis and not like some patients do. “I don't have any symptoms and ignore it.” However, the monoclonal gammopathy can increase and the patient may present with a broken bone or with kidney damage or a variety of other problems. Jenny: So I hear you saying regular checks, and I would add to that, by a specialist, a myeloma specialist because I think there are tests they run that are deeper -- that's just my opinion, maybe not yours. Dr. Kyle: Well, I think that the patient's local physician can certainly recheck the serum protein electrophoresis. This is readily available. And if it's the same or stable and the patient has no symptoms, I think that it's okay to continue to follow that patient. But if the patient has a smoldering myeloma or if the MGUS increases, then they should be seen by a hematologist or oncologist who has an interest in the plasma cell disorders. Jenny: In my experience going to a myeloma specialist versus a general hematologist or oncologist is just like a night and day difference, just in the testing that they require or the watch that they do. So I highly recommend that patients do that. They can always get treated by their local facility but I think it's great to get an evaluation from someone that's a specialist in myeloma. And there are so many great ones that it's a shame if people don’t. Well, Dr. Kyle, I would like to open it up to caller questions so if you have a question for Dr. Kyle and I have several write-in questions as well, you can call 347-637-2631 and then press 1 on your keypad.. Caller: Good afternoon, Dr. Kyle. I'm a smoldering myeloma patient. Thank you so much for taking the time out and providing this platform for patients to speak to someone like yourself who has been at this and trying to find ways to cure this disease for so many years. Thank you from my own standpoint as well as our communities, our smoldering and MGUS communities' standpoint. Appreciate it so very much. I do have a couple of questions and I think I want to make a comment and support what Jenny just said about seeking out a myeloma specialist. I am very active in Facebook groups and I always try to encourage patients if they're able to and if their insurance supports it to definitely seek out a consult at least once to make certain that everything is really being evaluated properly. I recently had a member share with me that their local hematologist-oncologist, -- and this individual has smoldering myeloma -- don’t even run an SPEP in that office because they explained to her that that is only a screening tool, that it's not needed to monitor further. These are the things that patients unfortunately run into. So I definitely support seeking out a myeloma specialist. That perhaps could set out the protocol for future monitoring if a patient wants to continue with the local oncologist. Is that correct? Is SPEP only a screening tool or should it be used to monitor going forward? Dr. Kyle: An SPEP should definitely be done to monitor the patient. If that patient has a small abnormality on the SPEP, initially the physician will do immunofixation to determine that it is still monoclonal, number one; and number two, to determine the type. Is it IgG, IgA, IgM and the light chain type (kappa or lambda)? And then if it is, then when the patient is rechecked, the SPEP is actually the first thing that the myeloma specialist does. Now, I want to make one other comment and that is that a general oncologist's practice consists of only one percent multiple myeloma patients. In short, some oncologists are very interested and knowledgeable about MGUS, SMM and multiple myeloma but others are not. So you can't really generalize about oncologists but keep in mind that only one percent of the tumors that a general oncologist in practice in this country encounters is one percent of their practice. Only 1 of 100 patients that walk through their door would have myeloma or a related disorder. Caller: So it would make sense to at the very least seek out a hematologist who may have more experience and/or practice related to these patients, yes? Dr. Kyle: Yes, it depends on the physician or practice. The old joke is that one practices hematology for fun and solid tumors (oncology) to put “bread on the table”. Caller: Oh, goodness. Dr. Kyle: Well, stop and think. Caller: Yeah, I'm hearing it. Dr. Kyle: Yes. One cannot make a living doing strictly hematology or especially myeloma unless one is at a large center. If you're practicing in your community and you don’t have a particular interest in myeloma and patients aren’t coming to you with a diagnosis of myeloma, only one in 100 of the patients that you see will have myeloma. Caller: It's very unfortunate though because this is how patients fall through the cracks  Unintentionally so, but nevertheless cracks. So we do try to encourage that in our Facebook groups and encourage folks, like I said, to even just if you can travel, do what you need to do, just even if it's one time and then be locally monitored going forward if you're not able to do the travel or if you have issues with your insurance company doing second opinions, because it just makes so much sense to really have somebody at least with a really keen sense of the disease to review your case and make certain that you truly are on the right pathway. Dr. Kyle, I have another question because I was interested in what you described as the biclonal disease and I know it's a very small proportion of myeloma. I think I'm a little bit confused because personally I have a report -- on my immunofixation, I always have something reported as an IgG kappa distinct band along with an IgG kappa faint band. So I never have two spikes. I only have one M spike. So I'm not quite sure if that IFE report designates me as a biclonal IgG kappa. Is that even possible? Dr. Kyle: Well, just a second. Let me go back and comment on the oncologist as a general oncologist in practice. A patient can always encourage their oncologist to contact someone at a center who is interested in myeloma. They can contact the myeloma specialist by email or whatever way that they can and even if they don’t have much experience with myeloma, they can delve into this a little bit more. And the other point I would make in this regard is that if a patient is able to get to a center and the program for myeloma is outlined or the patient is on a protocol, then the local oncologist is very capable of taking care of giving chemotherapy to a patient with myeloma. They are very experienced in managing low blood counts, low platelets and then altering the dose of chemotherapy and that sort of thing. They don’t need to know a lot about myeloma per se. Caller: Right, right, okay, good point. Thank you. Dr. Kyle: Getting back to you with your IgG kappa, presumably if you look at the electrophoretic pattern, do you see two spikes, do you know? Caller: No, I've only had one spike reported all of this time but the immunofixation will always state one distinct band and one faint band. Dr. Kyle: Okay, that faint band is very likely dimers of the monoclonal IgG kappa and of no clinical consequence. This would be particularly true with IgM monoclonal proteins. With IgM and with IgA, one can get monomers and dimers of the monoclonal protein. If the two bands are equal, then one can just add those two together and use that basic number. But just because you have reported on your immunofixation a second band, it is generally a small band and if so, it's probably of no real consequence. Just follow the major spike. Caller: Okay, excellent. Because I also have abnormal free light chains and it's interesting because my spike has been so relatively stable since discovery, and my free light chains is the one that always kind of bounces around quite a bit which I understand again is not uncommon to see either. So thank you for clarifying that for me. I always wondered what that meant. Dr. Kyle: I have two comments here. Number one is that about one-third of patients with MGUS have an abnormal free light chain ratio and at least 50%, maybe 60% of patients with smoldering myeloma will also have an abnormal free light chain result. Those two are risk factors, modest risk factors for progression of the MGUS or the smoldering myeloma. Caller: Alrighty. Well, very good. And again, Dr. Kyle, thank you so very much for taking my questions and so appreciate all that you continue to do for the myeloma community. Thanks, Jenny. Jenny: Okay. Thank you so much for your question. We have another caller, go ahead with your question. Caller: Yes, hello. Thank you for taking my call. I am a smoldering myeloma patient and I wanted to know if any research has been done in correlation to thyroid disorders and myeloma. Dr. Kyle: What kind of disorders? Caller: Thyroid disorders. Dr. Kyle: No, there is no relationship, to my knowledge, of smoldering multiple myeloma to thyroid function. Caller: I see. In particular, I was treated for a parathyroid tumor and it was successfully removed. Dr. Kyle: Benign or malignant thyroid tumor? Caller: Benign. Dr. Kyle: Benign tumor? That would very likely be an adenoma of the thyroid and that would have no effect, one way or the other, on your smoldering myeloma. The same is true of an associated parathyroid tumor. There is not an increased incidence of MGUS in patients with parathyroid tumors. Caller: Okay, some doctors I've had linked the parathyroid tumor to the formation of abnormal blood protein and the formation of MGUS. Dr. Kyle: No. If that were the case, they were saying that the adenoma of the parathyroid was producing the monoclonal protein? Caller: That there was a link between patients with a parathyroid tumor that they would develop MGUS. Dr. Kyle: Thyroid or parathyroid? Caller: Parathyroid. Dr. Kyle: Parathyroid, okay. No, there is no relationship. We published a paper many years ago and found no relationship between hyperparathyroidism and MGUS. Caller: Okay, that's good to know. Well, thank you so much for all your work in the field and for taking the call. Jenny: Thanks so much for your question. Appreciate it. Okay, Dr. Kyle, we had just Paul who wrote in a question that he really wanted me to ask you so I'm going to do that. He said, "Will you please explain the concept of secondary MGUS? And what are your thoughts on the impact the secondary MGUS may have on both progression free survival and overall survival and/or for PCL patients post-transplant?" Dr. Kyle: I presume that you mean the presence of a monoclonal protein after an autologous stem cell transplant. You can get clones of plasma cells and that is often called secondary MGUS. It generally signifies an active immune system in the patient. Those M proteins generally disappear within 6 to 12 months after the stem cell transplant. These are considered to be a favorable finding. Jenny: Okay, I will follow up. That's probably what he was talking about. Well, great. Dr. Kyle, we've kept you way over our time but I just really appreciate you joining us today and talking about what you've learned with smoldering and MGUS myeloma. I'm just thrilled at the research that you've done over so many years and the contributions that you've made. So thank you. We hope you keep going and continue to make more discoveries for myeloma patients. Dr. Kyle: Okay. Well, thank you very much. It's a fascinating area. I am glad to see and hear that patients and advocates like you are doing so much for the myeloma community. Jenny: Well, when we work together I think we can support what you're doing. So we're thrilled to do that. So thank you again. Dr. Kyle: Bye. Jenny: Thank you to all for listening to another episode of Myeloma Crowd Radio. Join us for future shows to learn more about the latest in myeloma research and what it means for you.

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