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Why wait for end organ damage to treat myeloma? New IMWG guidelines allow earlier intervention with Dr. Vincent Rajkumar, MD Mayo Clinic
Why wait for end organ damage to treat myeloma? New IMWG guidelines allow earlier intervention with Dr. Vincent Rajkumar, MD Mayo Clinic image

Nov 20, 2014 / 11:00AM MST
HealthTree Podcast for Multiple Myeloma

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Episode Summary

Dr. Vincent Rajkumar, MD Mayo Clinic Interview Date: November 20

 Dr. Vincent Rajkumar, MD, of the Mayo Clinic shares the very large number of changes by the International Myeloma Working Group for the treatment of myeloma. This is a group created by the IMF with over 180 myeloma specialists who are weighing in to change the 2003 treatment guidelines that reflect the advancements made in myeloma care and better diagnostic tools. With deeper diagnostics and more knowledge about how and when myeloma will progress, myeloma specialists want to intervene early and prevent serious end-organ damage (bone and kidney) when they know the myeloma will ultimately progress. The new guidelines strike a delicate balance to allow earlier detection yet are careful that the new guidelines will not mean an increase in false-positive diagnoses.  Major changes were made in the lengthy paper he discusses. There are more definitions for separating MGUS patients into risk categories, new treatment standards for those with a solitary plasmacytoma (single lesion) and more clear definitions for smoldering myeloma patients. He notes an interesting fact, that smoldering myeloma patients' risk goes down the longer that they have had smoldering myeloma that does not progress. Dr. Rajkumar gives an excellent explanation of the detailed changes that is easy to understand. There is much to learn and share (with other patients and YOUR oncologist) about these new standards that change the treatment of myeloma.   The mPatient Myeloma Show with Dr. Vincent Rajkumar

Full Transcript

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. Because this is the last show of 2014 as we head into ASH on the holidays, we wanted to let you know that we will be continuing the show throughout 2015 with a new name, Myeloma Crowd Radio. So I will keep you updated online on the and Myeloma Crowd website about the change so you can watch for upcoming announcements and postings about that. If you'd like to receive a weekly email about past and upcoming interviews, you can subscribe to our newsletter on the homepage of either site or follow us there on Facebook or Twitter. Now, Dana Holmes' Mambo for Myeloma Awareness Campaign continues to gain support so feel free to watch the videos, make your own Mambo video and share myeloma awareness with your friends and family. One last announcement. Today is the final day to donate a song for our Songs for Life contest for myeloma research so if you know any musicians, you can help spread the word. We've had over 70 songs donated which is fantastic. If you want to help choose which songs end up on the final album, you can go to on the 2015 submission page, listen to the entries, and like your favorites. This is one of our initiatives to use music to help myeloma and cancer patients as they go through treatment while funding myeloma research at the same time. Now today we are pleased and honored to have with us as our last show of 2014, Dr. Vincent Rajkumar of the Mayo Clinic to explain new myeloma guidelines that make major changes to how myeloma is diagnosed and potentially treated. So Dr. Rajkumar, welcome.

Dr. Rajkumar: Thank you so much, Jenny, for having me on the show.

Jenny: Let me just give a short introduction for you, if you don't mind. Dr. Rajkumar is a Professor of Medicine and Chair of the Myeloma, Amyloidosis, and Dysproteinemia Group at the Mayo Clinic in Rochester, Minnesota. He chairs the Eastern Cooperative Oncology Group or ECOG Myeloma Committee. He's published more than 500 articles and 350 abstracts, and his career was profiled in the November 26, 2011 issue of The Lancet. He has an extensive research program in the field of plasma cell disorders and has led numerous phase I, II and III clinical trials investigating the role of new agents in myeloma including the very important randomized trials that led to the approval of thalidomide in the US. He also leads several large studies investigating the nature, prevalence, and progression of various monoclonal gammopathies, including myeloma. His lab research has been focused on investigating new agents in myeloma and studying the role of angiogenesis in various plasma cell disorders. He's been continuously funded as an independent investigator by the NCI through R01 grants, 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 the Blood Cancer Journal and received the “Relentless for a Cure” Award from the Leukemia & Lymphoma Society in 2010 and an award from the American Society of Clinical Oncology or ASCO in 2011. So Dr. Rajkumar, we are thrilled that you're here with us today.

Dr. Rajkumar: Thank you so much for that nice introduction. I'm really pleased to be here.

Jenny: Well, there have been a lot of changes made by the International Myeloma Working Group in general and this is highly relevant for how myeloma is treated and how it is diagnosed and then treated. So if you could give us an idea of the International Myeloma Working Group in general first as a preview -- who's involved, how it came about -- and then we can move forward to talking about the different guidelines.

Dr. Rajkumar: Sure. The International Myeloma Working Group is a group of, right now, about 180 researchers who are involved in the diagnosis, treatment of plasma cell disorders including multiple myeloma. The International Myeloma Working Group, also known as the IMWG, is the research arm of the International Myeloma Foundation, the IMF. It was set up initially to make sure that collaborative research happens across countries and across institutions to answer important questions in myeloma as well as to provide diagnosis and treatment guidelines that are applicable to the whole world. And some of the major publications of the IMWG were the 2003 diagnostic criteria for multiple myeloma and related disorders which has been used all the way till now, and the International Staging System which is how multiple myeloma is currently staged, and the International Myeloma Working Group Response Criteria which are used as a response in all myeloma clinical trials. There had been numerous other guidelines that the IMWG have issued including how to treat patients with newly-diagnosed multiple myeloma, the role of imaging modalities, vertebroplasty and so on. The most recent publication is the one that we are going to discuss today which is the International Myeloma Working Group Updated Criteria for the Diagnosis of Multiple Myeloma.

Jenny: And the whole point, it seems to me, is to establish consistent practice worldwide for multiple myeloma. Is that one of the major goals?

Dr. Rajkumar: The IMWG's major goals are to make sure patients receive the best possible care so that we provide the most accurate diagnostic, prognostic, and treatment guidelines that can be universally used. The IMWG is not only a body that issues guidelines but also conducts several original research projects, that is a second major goal and that played a very big role in many, many areas so far.

Jenny: Okay. Well, from reading that paper that I was able to see, the content is rich and there are many, many changes. So I will let you decide how you would like to launch into the changes and then we can talk about relevance and what it means for myeloma patients.

Dr. Rajkumar: Sure. I think the first question to ask ourselves when any time we want to change something is why are we going to change something. In this case, change was really needed based on numerous advances that have happened in the last decade or so in the treatment of multiple myeloma and related disorders. Number 1, we needed to change the diagnostic criteria for myeloma because current criteria required that patients be diagnosed only after end organ damage had already happened. Now that was fine when we did not have much in the way of treatment for the disease; it is not fine when we have several exciting options which have more than doubled the survival of multiple myeloma. So waiting for end organ damage to happen is not going to serve our patients well because it means you are telling the patient I will treat you after you get renal failure or after you get lytic bone lesions or pathologic fracture but not before. Number 2, we became aware that we don't need to wait because we can actually, using new laboratory testing and modern imaging modalities, diagnose end-organ damage fairly early so we don't need to wait for skeletal survey to show changes or creatinine to change. And finally, we have accurate biomarkers that tell us if you look at patients with high-risk smoldering multiple myeloma who are the patients who already have myeloma but have not just declared themselves and are almost guaranteed to declare themselves within two years so that waiting is only going to cause harm and not provide any long-term benefit. So the fact that we had accurate biomarkers now made it easier and important to change the criteria. Now, what did we change? We changed the diagnostic criteria for multiple myeloma to include three new biomarkers that allow us to make the diagnosis of myeloma and initiate the therapy before end organ damage occurs. The end organ damage we have to be liberated for is called CRAB, hypercalcemia renal failure, anemia and bone lesions that are felt to be related to the plasma cell process. In addition to the CRAB, now we have said that patients who have more the 60% or more involvement in the bone marrow or a free light chain ratio of 100 or more, or more than one focal lesions on MRI, are considered as having multiple myeloma even without symptoms and even without the presence of CRAB features. So that will allow the diagnosis of multiple myeloma to be made early. In deciding on these three factors, we wanted to make sure 1) that these markers were accurate and we have data from studies to support that. We did not want to use risk factors that would result in a large number of false positive diagnosis, errors in diagnosis. 2) We wanted to make sure was it was data-driven and there were at least two or more independent studies that validated these biomarkers. So each one of these three has more than three studies that show that patients with such features will progress with almost 80% certainty within the next two years and more than 90% within the next three years.

Jenny: So you have a lot of validation to change these.

Dr. Rajkumar: That would be the most important change that we made.

Jenny: And what testing has improved to be able to make these changes?

Dr. Rajkumar: Well, the serum free light chain ratio is very useful because when it's very high, like 100 or more, it indicates patients were at high risk for renal failure. And renal failure is one that we want to avoid because once patients get it, even if you manage to reverse it, the survival does not seem to improve back to baseline. Imaging has changed. We have computer tomography, CT scans, PET/CT which is Positron Emission Tomography which can identify lesions well before the skeletal survey can, and magnetic resonance imaging which is the MRI. These imaging modalities can be used to diagnose myeloma early -- in the case of MRI, even before lytic bone lesions happen. And so those enable us to make the diagnosis early. It means that a patient with smoldering myeloma diagnosed today will be called as myeloma if they meet one of the three criteria. But it also means that a patient with smoldering myeloma who's being followed does not need to wait for the full-blown CRAB to happen but if they're watched carefully, particularly high-risk patients, the diagnosis can be made early based on free light chains, bone marrow changes, or MRI changes.

Jenny: Okay. Well, that's going to be critical. I know you'll talk a little more about that. So I sort of interrupted you -- you were talking about the diagnostics and you have the three new markers and that's a big change. What else would you like to cover about the changes?

Dr. Rajkumar: Absolutely! The paper is so --

Jenny: It's so long!

Dr. Rajkumar: -- very dense. It's got a lot of data, a lot of information, and a lot of changes. Some of these other changes are also important and worthwhile going through. So for example, solitary plasmacytoma, this is a condition that is in between smoldering myeloma and multiple myeloma. In this condition, patients have one lesion so it's not multiple lesions. But it can be cured so we need to make the diagnosis correctly. So the new criteria classify solitary plasmacytoma into two categories: patients who have normal bone marrow because these patients have almost a 90% chance of being cured with radiation alone; and patients with solitary plasmacytoma who have less than 10% involvement of the bone marrow with clonal plasma cells where the risk of recurrences is high and therefore these patients are candidates for trials investigating adjuvant systemic therapy. And that's what changed. And we have also made an important change that when you make a diagnosis of solitary plasmacytoma or smoldering myeloma, that we recommend now that the patients have at least at minimum, a CT scan of the whole body or PET/CT of the whole body or an MRI of at least the spine and pelvis, if not the whole body. This will therefore make sure that the patients we classify as solitary plasmacytoma and smoldering myeloma are correctly classified and not under-staged. Additional changes that we have made are in regards to follow up of monoclonal gammopathy of undetermined significance. MGUS is the premalignant stage of plasma cell disorders and it can be divided into low-risk, immediate-risk, and high-risk groups. And the low-risk patients with MGUS are the ones who have only a 2%-5% lifetime chance of getting myeloma and do not need to be worried so much about myeloma because they're more than a 90%-95% chance that nothing will happen in that regard. And so we have recommended that if a patient appears to have low-risk MGUS that bone marrow biopsy can be deferred and that's a judgment call, as well as that if the first six months follow up are stable, that further follow up can be deferred as well until symptoms happen and this will then enable patients with this low-risk MGUS to have a better quality of life because their risk of getting myeloma is very, very low.

Jenny: Let me ask a follow up question, how do you classify MGUS patients? I haven't heard of that before.

Dr. Rajkumar: If you take just the diagnosis of MGUS which is less than three grams of monoclonal protein, less than 10% plasma cell from the marrow, and no evidence of end organ damage or any of the new myeloma defining events I mentioned, the general rule is that patients will progress at a rate of 1% per year. And 1% per year means in ten years, patients with MGUS have a 10% chance of getting myeloma or related disorder, it also conversely means that there's a 90% chance they won't get myeloma or related disorder. Now using the size of the M protein, whether or not the M protein is less than 1.5 grams per deciliter or more than 1.5 grams per deciliter, using the type of M protein, whether it's IGG or something else, and the serum free light chain ratio, whether it's normal or abnormal, you can classify MGUS patients into low-risk. These are patients who have none of the risk factors, patients who have one of the risk factors, two, or all three. So a patient with a M spike of less than 1.5 IGG and a normal free light chain ratio has only a 2% lifetime probability of getting myeloma or related disorder and that's much less than 1% per year and it's good for them to know that 98% of the time, they're going to go through life without getting one of these. And that means they can also focus on other things that are important -- cholesterol, cardiac disease -- and not just see the hematologist.

Jenny: I think that would be critical --

Dr. Rajkumar: This was published in Blood in 2005 and has been validated by others as well.

Jenny: Well, as part of this, we might want to include some of that in our transcripts for patients who are now diagnosed and want to know how they are classified.

Dr. Rajkumar: Absolutely. And Blood generally allows us to reproduce content by the author at no cost so I will be happy to provide you links for the actual tables which show you how to classify MGUS.

Jenny: Okay, that would be great. And is there anything else about MGUS you'd like to share?

Dr. Rajkumar: Well, there is a new type of MGUS that was described by Dr. Dispenzieri, called light chain MGUS that was published in the Lancet a few years ago. This is a condition that the new IMWG criteria has refined the diagnostic criteria for. The risk of progression in this group of patients is not well known. The diagnosis itself is made using the serum free light chain assay so that's one thing for people to know.

Jenny: Okay, terrific. Do you want to continue? I mean your list is very long. I want you to make sure you explain everything as much as you want to explain it.

Dr. Rajkumar: Sure. So let's go through it step by step. What else has changed with myeloma diagnostic criteria? Patients with multiple myeloma are at risk for renal failure. Patients of any monoclonal protein disorders including MGUS or smoldering myeloma are also at risk for getting renal problems. We clarify that only light chain CaSNA property will count as a myeloma defining event. There are other renal problems that patients can get as a result of monoclonal proteins but those are not considered as multiple myeloma or a malignancy and this includes light-chain deposition disease, light-chain amyloidosis, membranoproliferative glomerulonephritis. So that's been clarified so that it's very clear what kind of renal damage qualifies as myeloma and what doesn't. It's also clarified that not everybody with multiple myeloma will have a monoclonal protein and that patients without a monoclonal protein but clear-cut evidence of a clonal plasma cell disorder and the myeloma defining events are also considered as having myeloma. And so we have clarified that you do not need to have a monoclonal protein to make the diagnosis of myeloma. We've clarified that the type of bone changes that count as myeloma are osteolytic bone destructions seen on skeletal surveys, CT scan or PET/CT scan. Nearly having compression fractures which could be related to osteoporosis or changes on bone densitometry is not enough. These set of changes that I just discussed enable us to make sure that we are not over-diagnosing multiple myeloma. With the greater use of more modern imaging technologies, we run the risk of labeling patients with MGUS as myeloma and these patients will not be best served by being started on chemotherapies. So these changes are very important to make sure that we are making the diagnosis accurately and that we are neither under-diagnosing nor over-diagnosing multiple myeloma.

Jenny: It seems like a tricky balance to be able to treat it early so it doesn't progress but not to treat it when it's not necessary. That's difficult.

Dr. Rajkumar: Absolutely, absolutely. Because the more sensitive you get with your testing, the risk you run is that you will over diagnose and you will have a lot of false positives, patients who really don't have multiple myeloma and will do well for years who will then run the risk of getting chemotherapy and stem cell transplant and we just want to avoid that. I think the one good thing about this International Myeloma Working Group coming together for this is you have the collective wisdom of like 180 people. And particularly with this paper, I received comments from more than 80 of the world's best experts on developing this document and 34 authors from around the world. And so we manage to look at almost every paper that was done which pertains to these diagnostic criteria and to any changes we are planning to make so that any change has had a lot of thought gone into it. It's not just me. It's Dr. San Miguel and every one of the 34 authors and the 50-odd people who provided comments that we were not able to name as authors.

Jenny: Oh, it's amazing collaboration.

Dr. Rajkumar: Absolutely, absolutely. It was one of the best and it took a long time because we had to first generate data for any of the changes that we were going to make. Generating the data, publishing the data and then working on the change of the diagnostic criteria took a whole three to four years amount of effort into this. Then moving on to smoldering multiple myeloma, again, the criteria are necessarily updated because when you change the diagnosis of myeloma then the diagnostic criteria for smoldering myeloma automatically changed. So the updated definition is provided and there will be a paper that is authored by myself and Dr. Landgren and Dr. Mateos on smoldering multiple myeloma which takes into account the revised definition that will come out shortly. Then moving on, as I mentioned, we have made changes to the follow up recommendations for MGUS. We also made slight tweaks to the classification of MGUS, recognizing that not all types of MGUS progress to multiple myeloma. Most patients with IGM MGUS actually run the risk of progression to Waldenström's macroglobulinemia and amyloidosis. And so we have classified MGUS into non-IGM, IGM, and light chain types, each one with a slightly different risk of progression and a slightly different mode of progression. Fourth, we revised the classification of solitary plasmacytoma which we discussed earlier. We made changes to the follow up recommendations, also discussed earlier. I think the most important thing is we have set a threshold, a line in the sand so that the diagnostic criteria are living and evolve with time. So we made a final recommendation that future biomarkers which meet the threshold that we have now set which is able to identify patients with smoldering myeloma who have an 80% risk of progression within the next two years in two or more independent studies, those criteria, those biomarkers can then be incorporated into the myeloma diagnostic criteria in the future. So I think as time goes on, we will have new biomarkers added. Some of the most promising ones include immunophenotyping of plasma cells, rise or change in monoclonal protein levels over time, circulating plasma cells, as well as changes in bone marrow plasma cell proliferation. I think all of these are going to come in the future and that's another major recommendation in this paper, that the criteria evolve.

Jenny: And it seems like it would need to, because you're running new techniques. How do genetic features weigh in on that all?

Dr. Rajkumar: I think cytogenetic features will also play a role in the future and it will evolve. Right now, if you take patients with smoldering multiple myeloma, we generally say patients have a 10% per year risk of progression. But that is true if you take all patients. We do know that patients with 4;14 translocations, 17p deletion or 1q amplification have a higher risk of progression more than the order of 25% per year. Patients with hyperdiploid-myeloma have an intermediate risk of progression and all other abnormalities have a lower risk of progression. So this will play a role in the future as we update the criteria. None of them rise to the level by themselves of the 40%, 45% risk of progression in a year that we need to reclassify as myeloma but I think combining a cytogenetic change such as 4;14 translocation and 17p deletion with another biomarker, you may meet that threshold. And so that's something we'll be working on.

Jenny: And can you explain immunophenotyping of cells, what that is? I'm not familiar with what that means.

Dr. Rajkumar: Yes. You know you often hear about the word flow cytometry, multicolor flow cytometry and multiparametric flow cytometry. Basically what flow cytometry does is look for markers on plasma cells with immunofluorescent-tagged antibodies. And multicolor flow cytometry means you're able to add like seven or eight antibodies into a single tube to see what kind of antigens does the plasma cell have. And we are now looking for certain markers on the plasma cells. For example, CD56 is a marker of malignancy; this is seen in myeloma patients but not in plasma cells of normal patients. And so we can use the presence of CD56 to say okay, this cell is probably malignant. Same way CD19 is usually not present in myeloma cells but is present in more normal plasma cells and we can use that as a marker. So if you have a tube with 56 and 19, knowing whether the cells are 56-positive and 19-negative will tell you whether the plasma cells you're dealing with are malignant or not. And just expand this to eight markers, then you'll have multiparametric flow. So you look at all eight markers together and make a judgment call based on data and hopefully soon based on computerized analysis on whether what we are looking at is a marker of malignancy or not. And certain combinations of these antigens will tell you whether patients are at high risk for progression or not. So what the Spanish group has done is look at smoldering multiple myeloma patients with a multicolor flow. And what they find is if the plasma cells that you see in a patient with smoldering myeloma is more than 95% of those cells are aberrant, that means they have a phenotype that is more consistent with myeloma rather than normal plasma cells, that puts them at a high risk for progression, 25% per year, 50% over two years. That was the basis of the trial they did in high risk smoldering myeloma. They included such patients and found out that they do progress rapidly and that if you give lenalidomide dexamethasone therapy, that the rate of progression was slowed. So that's what we mean by immunophenotype. We're basically fingerprinting the plasma cell to see whether it's malignant or not.

Jenny: Well, thank you for that very good explanation. I wasn't making the connection between the word immunophenotyping and the flow cytometry. But a follow up question, when do you think a computerized flow cytometry will be available?

Dr. Rajkumar: Very soon. Again, the Spanish take the credit -- Dr. Orfao, Dr. Paiva, Dr. San Miguel -- they've been working hard on an automated method which is all part of the Black Swan Research Initiative of the IMF. The major problem with flow cytometry is that it varies lab-to-lab; what markers people use, how they interpret it, and more importantly, it requires an expert and experts vary. Experts have to make a judgment call and judgment can vary. So then what Mayo reads out may not be the same as what MD Anderson reads out or the Spanish read out and we wanted to eliminate such variation. And secondly, no expert can know -- I mean it's hard enough for me to know what to make all of two or three markers, let alone eight markers all expressed to various levels in terms of what does that mean. A computer on the other hand, can look at five million events, count every plasma cell and match each plasma cell to a normal profile that it already knows exists from a database and will tell you whether if you see 20 plasma cells in this patient are these normal cells or are they malignant. And it's able to do it much better than an expert because an expert's limited by only what they know and unfortunately, the variation is so much that it's not possible for the human brain to look at eight markers simultaneously at various levels of expression. I think it will be available soon. Hopefully, within one year, it will be a research test and I hope that within a couple of years it will become available in the US as a clinical test.

Jenny: Well that's perfect. We talked to Dr. San Miguel a little bit on this show about that but he didn't give a time frame and myeloma experts are few and far between, especially when it comes to community practice. So standardizing that is tough.

Dr. Rajkumar: Absolutely. The goal with this is to make it something that most reference labs can do and most send out tests that people send and the readout would be the same wherever you send the test because the method will be standardized. That's the goal.

Jenny: Great goal and we're very appreciative of IMF Black Swan Research Project for that so thank you. We're very appreciative for everyone's involvement in that.

Dr. Rajkumar: Thank you.

Jenny: I don't want to interrupt your growing list.

Dr. Rajkumar: I think we have gone through the list. I think if you want a summary,  there are changes in how myeloma's diagnosed and now we can diagnose myeloma before CRAB using accurate biomarkers; we have updated definitions for smoldering multiple myeloma and solitary plasmacytoma; we've updated the follow up recommendations for MGUS and smoldering myeloma particularly high-risk smoldering myeloma so that patients do not need to endlessly wait for the CRAB features, but can be diagnosed early. And we have laid down the metric, by which, new biomarkers will be evaluated and incorporated into the criteria.

Jenny: That's a great summary. Now, maybe you can talk for a moment about the significance and how this gets put into practice in a very practical way inside the clinic.

Dr. Rajkumar: Well, many of us have been doing this, in the sense that when I have been seeing patients with more than 60% plasma cells or free light chain ratio of more than 100 and they do not have CRAB, we have been saying that, based on all our research, this has really multiple myeloma, it is not smoldering myeloma and treating them as such. Many of us have been doing it; this just formalizes that and makes sure that the community recognizes that you do not need to wait for CRAB. Similarly, many of us have already been using MRI, PET/CTs and CT scans to diagnose multiple myeloma without waiting for skeletal survey changes to happen. This again formalizes that. Hopefully it eliminates any insurance problems for patients who undergo these procedures because it's necessary now for diagnosis. It's established by the world experts that this is not just a suggestion but a requirement for the diagnosis of smoldering myeloma or solitary plasmacytoma. So practically, I think the main thing would be that patients will be diagnosed early and we want patients to be diagnosed early and treated. We will know in trials which patients come in through this route and we can see how the impact of these criteria is on those patients in future trials. But I expect not just the practice to change but also new clinical trials will use the new criteria for trial entry.

Jenny: Well, let's talk about clinical trials. How does this create different clinical trials or newer approaches to clinical trials?

Dr. Rajkumar: Well, I think the myeloma portion would be easier because previously we would say that the first line in every myeloma trial would be patients should have multiple myeloma based on standard criteria and they will refer to the old 2003 criteria. Now they will refer to the 2014 Lancet oncology paper and that then would move forward. But the problem still remains for smoldering myeloma patients. I think we want to make clear that these new criteria do not change the fact that smoldering myeloma patients exist and high-risk smoldering myeloma patients exist. And the high-risk smoldering myeloma patients are still the same as the study that was done by the Spanish looking at Len/Dex, and we still need clinical trials for that group. Just because we have up-staged the high-risk group doesn't mean the high-risk smoldering myeloma goes away. These patients still post a dilemma as to whether they should be just watched, whether they should be treated on clinical trials or whether they should just be treated with therapy such as Len/Dex. And so that's a debate we still need to have, that's a group that we still need to conduct clinical trials for. Matter of fact, we have in the US these separate oncology group trial that Dr. Sagar Lonial is leading looking at lenalidomide for high-risk smoldering multiple myeloma. And so such trials will continue and I want to emphasize that the change in the criteria doesn't mean the high-risk smoldering myeloma went away. It stays and it's pretty much untouched. It's still the same as it was before the criteria

Jenny: So while there may be more opportunity for patients with, I guess, earlier stage features to now get into traditional multiple myeloma clinical trials, you're saying that the whole field with MGUS and smoldering myeloma really needs to be almost segmented and offering is provided to these patients that are unique to their situation.

Dr. Rajkumar: Absolutely.

Jenny: So let's talk about that a little bit because the Mayo Clinic has historically had really deep talent and work done in the MGUS-smoldering myeloma area. And in one of the past interview, we've talked with a researcher at Dana-Farber talking about how they wanted to really target this population as well. So do you want to share how you do that across an international community of smoldering myeloma patients?

Dr. Rajkumar: Sure. First of all, we have been collaborating with many centers on the prognosis of patients with monoclonal gammopathy of undetermined significance and smoldering myeloma and identifying biomarkers and identifying therapeutic strategies. We even had a long-standing collaboration with the Dana-Farber Cancer Institute, with Dr. Ken Anderson. We were part of the Myeloma SPORE that Dana-Farber and the Mayo had jointly for many years and now Dana-Farber continues to have. This SPORE had a project dedicated to early diagnosis and treatment, which I was fortunate to be a project leader for. So we've had long-standing experience. Many of the studies that I did and published were supported by the Dana-Farber SPORE led by Dr. Ken Anderson so I'm very appreciative of that. Secondly, we have also been working with the various institutions that are part of the IMWG in either collaboration by ideas or actual sharing of samples to do studies or sharing of data for example. Many of the biomarker studies that we use to validate the IMWG new myeloma diagnostic criteria were done in one institution and then each one of the three were replicated by the Greek Myeloma Study Group. Without that validation, we couldn't have changed the criteria so we work together. And now Dr. Helen Gogas is leading an effort bringing in imaging from many different centers -- the actual images, the imaging reports -- to see how we can better diagnose smoldering multiple myeloma, how we can better use the imaging information in prognosis and treatment decisions. And finally, there's always collaborative groups looking at treatment. So the Eastern Cooperative Oncology Group for example, and the NCT and National Clinical Trials Network offers opportunities to work together. In the US, multiple institutions can come together to do trials that it's not possible for one institution to do. And the example for that will be the ECOG smoldering myeloma trial, the SWOG trial that's going to come up for solitary plasmacytoma with minimal marrow involvement. And the Alliance is planning a smoldering myeloma trial as well with nontherapeutics. So, many of us work together in that area because it's just not possible to do it on one center.

Jenny: Well, it looks like it's following the model that children's cancers have followed and they've been really effective in that in running these cooperative trials and collaborating at a very deep level and it seems to be that myeloma is a very collaborative community.

Dr. Rajkumar: Oh, absolutely! I don't want to compare across these groups but if you just look at the myeloma field, most of us work really well with each other, collaborate with each other, are friends and it's just really, really nice. There's real desire to work together and it's very, very good. Here in the US, myself, Dr. Orlowski and Dr. Richardson lead the three cooperative groups, the ECOG cooperative group, the SWOG, an alliance and we plan our trials together so that if we do a trial in ECOG, it's supported by every one of the other groups, and vice versa, and we try not to overlap trials.

Jenny: Well, perfect. One of maybe two final questions for you because this is a lot of information to take in. How do you share these new diagnostic criteria with not only the network of the 180 people who are in this group but people who are treating myeloma throughout the world so that they're consistently treating.

Dr. Rajkumar: Absolutely, this is going to be a challenge and we have to… Because many physicians who treat myeloma are seeing only one or two patients with myeloma a year and they have very pressing issues in breast cancer and lung cancer and other more common malignancies to deal with, that it's very difficult to keep up with the literature. So we have to make aggressive education pitched to make sure that everybody hears that. So yeah, we're working with ASH, Hematology Education sessions, I'm sure Dr. San Miguel will highlight this in his role as Associate Editor of Blood. We will also work with the foundations and the pharmaceutical companies to make sure that the messaging gets across that changes happen. And you are well aware that some of it has been made easier with social media. People like you have been so helpful in spreading the word. What would have previously reached the hundred people who managed to read the Lancet Oncology article is now reaching thousands and thousands of people, because of social media and social media efforts by not just physicians, but patients and patient advocates. It's just incredible.

Jenny: Yeah. Well, we'll continue to spread the word and we can do several things to get the word out. So when you think about the smoldering myeloma patient group, we've talked for over a year-and-a-half now in this series about the importance of participating in clinical trials, and sometimes the smoldering patients are in this kind of watch-and-wait, I feel like they're stuck. How important is it that smoldering myeloma patients also participate in clinical trials as well as a higher percentage, hopefully, of myeloma patients?

Dr. Rajkumar: It's very important. And I think the risk stratification will help because not all smoldering myeloma patients need to participate in clinical trials testing early intervention because for some of them, the risk is low. So we can use several prognostic markers to look at smoldering myeloma patients and classify them into low-risk and high-risk. It's the high-risk patients that really need to be studied in clinical trials. If they're not on trials, then they need to be followed up closely every three months or so and they need to be, depending on the exact features, they may need imaging like MRI or PET/CTs to be done periodically to determine if they are progressing so that we can take advantage of new criteria and make the diagnosis early before skeletal survey changes or creatinine increases. Low-risk smoldering myeloma patients, on the other hand, can have some kind of reassurance that they are not going to get myeloma. And particularly, as time goes on, smoldering myeloma is a mix of patients who have MGUS and myeloma mixed in with each other -- it's not like a disease in itself. So as time goes on, myeloma patients will declare themselves and so if patients with smoldering myelomas had smoldering myeloma for more than five years, their risk actually goes down. It's not 10% per year but it's more like 3% per year and if they've had smoldering for ten years, then the risk goes down to MGUS level of only 1%,1.5% a year.

Jenny: Boy, I had no idea.

Dr. Rajkumar: That very knowledge can give quality of life improvement. I mean if they are constantly going to think they're going to get myeloma with 10% chance a year, that's going to affect quality of life. But if they know "I have gone through smoldering myeloma for ten years and now my risk is actually much lower", that changes everything.

Jenny: Yeah. That's the first time I've heard that. That's great.

Dr. Rajkumar: So I think we need to educate people.

Jenny: Yeah, very much so. I mean you don't want to be living with that hanging over your head if you don't have to. That's terrific.  I don't want to take up all your time, I want to allow some caller questions. So let's open it up for caller questions. If you have a question for Dr. Rajkumar, please call 347-637-2631 and press 1 on your keypad. And we will start with our first caller. Go ahead.

Caller: Hi Jenny! Hi, Dr. Rajkumar. It's really such a pleasure to speak to you? How are you?

Dr. Rajkumar: Hi! I'm doing well, thank you.

Caller: Wonderful, thank you for taking your time out this morning, it's really been just so educational and informative. I know you know that we have a smoldering myeloma group on Facebook and we have about 200 members and we try to share all of the information as best as we can so your interview has been extremely helpful and as have the guidelines, so thank you very much. I have a question and it's going to be pointed to your last comment about the risk of progression at 10% per year. Could you just elaborate a little bit more on that to help us understand; is that a cumulative risk? In other words, if it's 10% per year, at the five-year mark it's 50% and then what happens after that, it becomes 3%. So does it become 53%? Is that cumulative in that sense? Is that the way that we should look at that or do we discount the first 50% altogether and start from scratch at year five?

Dr. Rajkumar: That's a great question. If you are a patient, the way to look at it is this. You are diagnosed with smoldering myeloma today and you want to know "What are my probabilities that I will get smoldering myeloma in the next five years?" If you didn't know anything else and all you knew was that you had smoldering multiple myeloma, the risk is 50% at five years at an average of about 10% per year. And that also means that there's a 50% chance you will not get myeloma in five years. The way to interpret the next five years is once you reach that point, let's say you've declared yourself, five years have gone by and no progression has happened. Now you want to know what the next five years are going to be like. That's not going to be 10% per year, it's going to be 15% over the next five years -- it's 3% per year. And if you've gone through ten years, then it's a conditional probability. Provided you had smoldering myeloma since 2004 and now we are sitting in 2014 and you're still smoldering, now I can tell you that your risk of progression from now on is probably more likely to be only 1% or 1.5% per year or 5% chance in the next five years which will dramatically change your outlook on life.

Caller: Oh, absolutely without a doubt. Even hitting that five-year mark changes the attitude immensely. Dr. Rajkumar, do you see gene expression profiling playing a role as a future biomarker.

Dr. Rajkumar: Yes, absolutely! I think what gene expression profiling has the capability of doing is that we have many, many, many markers and many of them can collectively affect one gene. And so it's possible to come up with a signature that's highly accurate and tells patients what the odds are of just the same way as it's useful in multiple myeloma. The question though is not so much what gene expression profiling will do but what will it do in addition to the other ones that we already know which are easier to obtain? So my question always is like if I already knew the FISH cytogenetic classification and I already know about whether there are circulating plasma cells or not and the free light chain ratio, what's the incremental benefit of the gene expression profiling? Is it big enough to warrant the how many thousand dollars that it cost to get --

Caller: And to replace the others that are not…

Dr. Rajkumar: Yeah, if it can replace the others. And by doing the gene expression, you don't have to do any of the other ones then it's a different deal. But if the others are going to be done anyway, then you have to really ask yourself what is the incremental value and that's where we need more data to know what… but I think the SWOG group has published some data already. What we are looking for is incremental value and again, there are two things here. One is a signature that is predicting for such a high risk progression that it's actually identifying patients with myeloma who should be called as myeloma entreated; and the second is a signature in which it doesn't quite go that far but it identifies patients who are at high risk of progression so that they can be entered on trials.

Caller: Okay. Earlier in the week Dr. Morgan was interviewed and he stated that, he is likely going to be offering the high risk to progression smoldering group based upon his four gene expression risk score that being 1, 1-1/2, to 2 years at risk to progress to active myeloma. So it sounds like the ultrahigh-risk which is now redefined as newly-diagnosed myeloma. But he is thinking of offering CD38 monoclonal antibody therapy as it targets the myeloma cells directly to his cohort of patients. What are your thoughts about a trial such as that?

Dr. Rajkumar: It's exciting. So as I mentioned earlier on, what we have renamed as myeloma is really a tip of the iceberg. It's just the highest of the high-risk smoldering myelomas. Removing them or including them doesn't change the fact that smoldering myeloma still consists of two groups: patients with high-risk smoldering myeloma and patients with low-risk. The patients with high-risk smoldering myeloma will be defined as those with median time to progression of about two years. And those patients need clinical trials. There's one trial that's going on in the US that's with lenalidomide. We need more. We need more trials and so Alliance is planning one. People need to look at antibodies. People need to look at anything that we can do to delay progression of this course of high-risk smoldering myeloma patients.

Caller: Wonderful.

Dr. Rajkumar: So if the gene expression signature can identify those people accurately, then it should be used.

Caller: Okay. It's really just a matter of, as you said, having independent studies supporting the gene expression profiling as maybe one of the best biomarkers out in the open.

Dr. Rajkumar: It needs to meet those two thresholds. One is an 80% risk within two years which usually looks at a median time to progression of one year; and secondly, independent validation in two or more studies.

Caller: And what about plasma labeling index, does that have any role as a future biomarker? Because I know it's been used but it doesn't seem to be used much at all.

Dr. Rajkumar: Well, the plasma cell labeling index was a slide-based assay that was done in very few institutions and now it's no longer done even at Mayo Clinic. We are doing plasma cell proliferation estimation using S-phase on flow cytometry. What needs to be done and we are working on it is to identify the thresholds. So it won't be called plasma cell labeling index but it will be called S-phase or plasma cell proliferation index and it will come back into the mix surely.

Caller: Great! Dr. Rajkumar, thank you, thank you for your time. Thank you for everything that you're doing. This paper that you are referencing, do you have an ETA? Is it another few weeks, another month or so? When can we expect to see it?

Dr. Rajkumar: The smoldering multiple myeloma paper that I mentioned?

Caller: Yes.

Dr. Rajkumar: That paper which takes into account the changes to the myeloma diagnostic criteria will be published soon. I just don't know when, but it's already been planned.

Caller: Okay. So you can count on me to keep asking you when, very anxious to see that. Okay. Well, thank you again for your time. Thanks, Jenny, for taking the call. Have a great day.  

Jenny: Thank you so much for your questions, it's wonderful. Our next caller - go ahead with your question,

Caller: Hi! Thank you! I have two questions, hopefully we have time. First of all, thank you for the radio show this morning. It's fascinating and I really appreciate it. So my first question is, since it looks like we'll be able to start diagnosing myeloma patients much earlier, is the protocol for putting most transplant-eligible patients directly into having a transplant or is there may be some wisdom and seeing as those patients are receptive to initial therapy, and if they are, letting that play itself out before going in the transplant?

Dr. Rajkumar: It's a great question. I don't think the change to the diagnostic criteria really impact that question but that question's been there for a while and it's getting more and more important as we find out that we can achieve really deep responses with drugs alone. The strategy for this varies across institutions and between the US and Europe even. At Mayo for example, half our transplants are done delayed. So we do offer patients the choice of whether to do the transplant early or late. The trick though is that you need to be able to collect stem cells and cryopreserve for future use early in the disease course. So you have to give three or four cycles of initial therapy, get a good response, collect and freeze stem cells for future use and you have to have the facilities and the ability to do that. If you do that, we believe that in standard risk patients, that there is no data that early transplant is superior to delayed or vice versa. We, therefore, let patient philosophy and patient preference dictate that choice. The Dana-Farber Cancer Institute and the IFM -- the Intergroup Francophone du Myélome -- the French Myeloma Group, they've been doing a trial for many years now comparing a strategy of early versus delayed transplant, and results are expected soon. But the fact that the criteria changed I don't think affect that question. It's very relevant. We are already giving patients that option. I guess patients without CRAB, it probably makes it even more important for them to have the choice.

Caller: Okay. So why is it that stem cells need to be harvested early in treatment?

Dr. Rajkumar: Yes, a couple of reasons for that. One is that early in the disease course, whatever myeloma cells contaminate the graph that you collect are still early in their disease evolution. Whereas if you try to collect late, you're going to have some contamination but that contamination will be with cells that are far more clonally-evolved. But the second and more important reason is that we know that long duration of therapy will affect mobilization of stem cells per se and not just quantity but also the quality of the stem cells and may result in patients not able to engraft. And so we want to collect early to make sure that the normal stem cells are not damaged by a year or two of various drugs.

Caller: Okay, that makes sense. Do I have time for one more quick question? So the M-spike, those patients that don't have an M-spike, how are they going to be diagnosed?

Dr. Rajkumar: Great question. 97% of patients with myeloma have a monoclonal protein that is detected in the serum, in the urine, or by the free light chain assay. There's a small percentage, probably 1% to 2% of myeloma patients who do not have any evidence of a secreted product. The diagnosis typically in these patients is made on either a bone marrow biopsy or biopsy of one of the lesions and these patients typically present with a lytic lesion in one of the bones, you think it's myeloma and you do all the work up and then there's nothing for monoclonal protein. So then you put a needle to one of those lesions and it comes out as plasmacytoma and that's when you say well, it's probably a non-secretory myeloma. So that's how the diagnosis is made. We are going to come out with a paper, there's a Mayo Clinic paper that will come out soon in the European Journal of Hematology looking at the natural history of these patients, and how they have fared up with the treatment. It's a very rare subgroup, but it looks like they have benefited great deal from the new treatment advances as well. The main concern that I have is that many of our myeloma response criteria require patients to have a monoclonal protein, a measurable level, and so patients with non-secretory myeloma have been typically excluded from myeloma trials and we are trying to see if we can somehow include them using either the free light chain assay or bone marrow plasma cell percentage as markers of disease.

Caller: Thank you very much.

Jenny: Okay, Dr. Rajkumar, if you have time for one more question, would that be all right?

Dr. Rajkumar: Okay, sure.

Jenny: We have one more question - please go ahead.

Caller: Yes, hi. This is a basic question about how -- I was diagnosed as a high-risk patient as many other people out there have been also and was wondering if that diagnosis changes as your disease… I've now had it for six years. How has that changed? Am I still considered a high-risk patient? What things change would make that change?

Dr. Rajkumar: Well, good to hear you on this call. I think you answered your question which is that it does change. You are a great example of that. You were told you were high-risk and that means a median survival of approximately two, three years is what people talk about and then you're more than double that and doing great. The thing to recognize is that medians are just estimates of what happens to the average person and there are extremes on either end. Every time somebody tries to tell you that this is approximately what's going to happen, there's always a chance that you're in one or the other tail where very few patients are actually right average. So I try to tell people that any estimate of median time to progression or survival is applicable to both half the patients and half the patients are going to do differently -- much, much differently. So I think biology is more revealed by what actually happens. So a patient who does well for many years is already declaring that no matter what the initial markers showed, that they are really not high-risk, that they have done well and that the biology of the disease is dictated by more than that one factor that we checked at the beginning. So I think you want to make sure people are hopeful that the estimates and our decisions are based on what will happen to most patients but not every patient. There are exceptions to every rule -- there are patients who have p53 who live for many, many, many years even though they have p53 and myeloma. So our estimates are just for the average patient. There are exceptions to rules and biology will declare itself over time and that's probably more valuable then what you were told when you were first diagnosed.

Caller: Okay. All right. Thank you. It's been very informative and thank you for being on this program and thanks for those that provided it.

Jenny: Okay. Thank you so much for your question. Well, Dr. Rajkumar, we have learned a lot by talking to you today and we will certainly help spread the word about these different criteria. We are just very thankful for your leadership on this and the research that you and others are doing to move this field forward as quickly as possible and we look forward to your upcoming smoldering paper.

Dr. Rajkumar: Well, thank you so much, Jenny, for having me. I do want to, again, say that I owe a lot of thanks to the members of the International Myeloma Working Group, all 180 of them. it's a collective effort, it's not one person or ten people or even the thirty four authors -- it's much more than that than were involved in the criteria and many other papers; also thankful to the IMF which makes the IMWG possible. And thanks to you for having me on this show for the excellent questions and hope to see you again in this same show later on.

Jenny: Okay. We will have you on again at a future time. Thank you again.

Dr. Rajkumar: Thank you.

Jenny: Thanks for listening to another episode of Innovation in Myeloma. Join us for our next interview in 2015 as we learn more about how we, as patients, can help drive to a cure for myeloma by joining clinical trials.

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