Learn about all myeloma happenings on the new Myeloma Crowd site: the first comprehensive site for myeloma patients and caregivers. Dr. Brendan Weiss, MD Abramson Cancer Center University of Pennsylvania Interview Date: June 6, 2014

 Dr. Brendan Weiss, MD of the Abramson Cancer Center specializes in MGUS treatment and precursor myeloma stages. He shares some interesting ASCO findings including panobinostat's success, how metformin (a diabetic drug) use was reviewed in 2,000 VA MGUS patients with diabetes who saw a 40% decrease in the development in myeloma. He also describes an ASCO discovery that low albumin levels seem to predict progression to myeloma. He shares that the percentage of patients with MGUS differ by age and ethnicity - roughly 1-2% in their 40s or 50s have a monoclonal protein while 4-5% over 50 have one, and 10-20% of those in their 70s or 80s have one. In the African American population, that number could be doubled. He discusses how he risk-stratifies MGUS and smoldering patients and how imaging and other tests like MRIs, PET scans, and bone marrow biopsies can or should be used for these patients. He shares common sense strategies to prevent progression. He describes his open study to observe MGUS and smoldering myeloma patients to track new biomarkers that could better identify progression (easy study to participate in!) and his study for high-risk smolderers that targets IL-6, a known growth factor for myeloma using a monoclonal antibody called siltuximab. He continues to search for general proteins part of other biological processes such as kidney injury or inflammation that could lead to future discoveries about why MGUS progresses to myeloma.    The live mPatient Myeloma Radio podcast with Dr. Brendan Weiss

Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. This is our 33rd show to help you hear about the very latest in research so you can make educated choices about your care. It’s also to help you understand why clinical trials are so important. As patients, we help determine the speed at which new discoveries can be found through our participation. If you'd like to receive a weekly email about past and upcoming interviews, you can subscribe to the mPatient Minute Newsletter on the home page or follow us there on Facebook or Twitter. We also have a new site called myelomacrowd.org that’s the first comprehensive site for myeloma. And just as one item that we have on the site for newly diagnosed patients, we have a link called "I Have Myeloma, Now What"? with some recommended first steps to help you navigate. This is just one of the features of this site. It has a wealth of myeloma information and links to the very best resources out there. Now, many patients have MGUS and smoldering myeloma and today’s show is dedicated to them, but at the same time to all myeloma patients and that will become more clear as we go through the show. We’re delighted to have with us today Dr. Brendan Weiss of the Abramson Cancer Center at University of Pennsylvania who is an expert in the study of MGUS and why and how it progresses to myeloma. So Dr. Weiss, thank you so much for joining us today.

Dr. Weiss: Thank you for having me, Jenny. I’m pleased to be here.

Jenny: Well, let me introduce you. Dr. Brendan Weiss is an Assistant Professor of Medicine in the Hematology-Oncology Division of the Abramson Cancer Center of the University of Pennsylvania. Before coming to UPenn in 2011, he spent 13 years as an active duty military physician in the US Army including seven years as an attending physician in the Hematology-Oncology Service at Walter Reed Army Medical Center in Washington, D.C. where he was the director of the Autologous Stem Cell Transplant Program. At the University of Pennsylvania, Dr. Weiss is solely focused on plasma cell disorders, multiple myeloma, amyloidosis and related conditions. Dr. Weiss is a clinical investigator whose primary research interest is in myeloma precursor conditions, MGUS and smoldering myeloma. Specifically, he’s interested in developing new biomarkers to identify patient’s risk of progression to active myeloma and perform intervention studies for patients with myeloma precursor conditions. His work in myeloma and its precursor conditions has been published in leading journals including Blood, Leukemia, Bone Marrow Transplantation, The American Journal of Hematology, Biology of Blood and Marrow Transplantation. So Dr. Weiss, thank you so much again for joining us today.

Dr. Weiss: Thanks for the kind introduction.

Jenny: ASCO has just wrapped up. So before we jump into MGUS and smoldering, would you like to give us your take on the most important things that came out of ASCO both for MGUS and smoldering and then anything else you like to mention in general for myeloma?

Dr. Weiss: Sure. So there were several interesting abstracts presented at ASCO. I think probably the one that was most anticipated because Novartis made a press release about the panobinostat study back in December where the results of the panobinostat in combination with bortezomib and dexamethasone compared to bortezomib and dexamethasone in relapsed myeloma patients. And so this was a Phase 3 study looking at panobinostat which is a drug from a class called histone deacetylase inhibitors or HDACs that had been known for some time to be a good combination with bortezomib. But the previous agent that had been tested, vorinostat, was not particularly effective. And panobinostat has some differences in its mechanism of action so it was felt that perhaps it would be better in combination with bortezomib and vorinostat. And in fact, there was I think encouraging finding of a nearly four-month survival benefit when panobinostat is combined with bortezomib and dexamethasone. And I think this will be coming forward to the FDA for approval this year.

Jenny: And how far away is that by the time they have great results like that?

Dr. Weiss: Well, it all depends on the speed of the FDA process but it could come within 6 to 12 months.

Jenny: I’ve heard a lot about panobinostat and that class of inhibitors as well. And because you study MGUS and smoldering, was there anything that was very key for you?

Dr. Weiss: Yeah. There were probably two studies that I think were interesting. One was one of our own studies that we presented looking at risk factors for progression in smoldering myeloma. We sought to look at our own population here at Penn to identify new biomarkers for progression but also to try and confirm biomarkers that had been identified by other groups as associated with a high risk of progression. One of the important things in medicine and science is to see if results can be confirmed in other studies to assess whether they’re truly valid. In some of the biomarkers that have been investigated in smoldering myeloma have not been validated in multiple studies. And so in particular we were most interested in looking at the group of patients who have an ultra high risk of progression as some people have described it. The threshold for ultra high risk would be about an 80% risk of progression within two years of the diagnosis of smoldering myeloma. And so smoldering myeloma patients by definition are asymptomatic but if they have such an ultra high risk, it may be useful to consider treating those patients. And so in our study we were able to confirm what had been previously reported by the Mayo Clinic and the Greek myeloma group that patients with smoldering myeloma who have greater than 60% bone marrow plasma cells do have a very high risk of getting myeloma within two years. In our study, 100% of patients develop myeloma.

Jenny: That seems pretty consistent and reliable.

Dr. Weiss: Yes. However, we did have some discrepancy with the Mayo and greek groups that were trying to look into in a little more detail. One of the other tests that patients with smoldering myeloma and myeloma get is the serum free light-chain assay. And that can be a very helpful assay for a lot of reasons in myeloma. And the Mayo group and the Greek group has previously identified that patients who have a very widely skewed serum free light-chain ratio of greater than a hundred have roughly a 75-ish percent risk of developing myeloma within 2 years. However, our study was a little bit lower than that and we only showed roughly a 50-ish percent risk in two years. So I think we need to go back and look at our own data in a little more detail to see why there's some difference before we can say with certainty that this biomarker is truly a strong biomarker to identify ultra high-risk smoldering myeloma patients.

Jenny: And what would be one of the factors why there would be a data difference? I’m just curious.

Dr. Weiss: I think that’s a really good question. I think one possibility and we’re in the process of going back and reanalyzing it is our initial analysis excluded patients with what is called light-chain only smoldering myeloma. And we did that intentionally because we wanted to include patients in our analysis that were most similar to the original Mayo Clinic studies. However, the Greek group and more recently the Mayo group did include a small group of patients with light-chain only smoldering myeloma. And so we’re going to go back and analyze the data including those patients. Another important factor that has been somewhat understudied and we’re not sure yet of the relevance of this is that in our population in Philadelphia we have a much more ethnically diverse population than at Mayo Clinic or in the Greek study group and about 20% of our patients are African American. Previous studies that I have done had shown a suggestion that in particular serum free light-chains might differ in patients who are of African American background and reasons for that are unclear. And so this is an area that definitely needs some more study if we’re going to use serum free light-chains as a biomarker for all patients.

Jenny: And I think we’re going to ask some questions about race because you’ve done specific studies on that. So we’ll come back to that I think.

Dr. Weiss: Okay.

Jenny: And is there anything else at ASCO you wanted to share?

Dr. Weiss: I’d like to share one other very interesting study because it also is an area of interest for us and it has to do with identifying the impact of metformin, which is a drug that is used for diabetes, and its impact on the transformation of MGUS to multiple myeloma. There have been many studies on the impact of metformin in diabetics and development of cancer and cancer outcomes, but these studies actually did not include patients with blood cancers. And so the reasons for this, there are probably many reasons that metformin may have anti-cancer effects. In those studies of diabetics I mentioned before, metformin can reduce the chance of getting cancer by about a third which is a pretty strong signal.

Jenny: Yes, definitely.

Dr. Weiss: And the reasons for that could be related to changes in insulin sensitivity because insulin is a known growth factor for cancer and in particular myeloma. But metformin may have other actions on specific cancer signaling pathways such as the mTOR pathway as an example. So this group from Washington University in Saint Louis in collaboration with investigators from the St. Louis VA medical center actually evaluated over 2,000 MGUS patients with diabetes in the VA system. And they did show that there was roughly a 40% reduction in development of myeloma in patients. So I think this is very interesting preliminary data.

Jenny: I have a question about that because with patients being on dexamethasone which does affect your blood sugar levels pretty significantly and can give you diabetes ultimately, in some patients it can. I am surprised I haven’t talked to anybody yet I guess about metformin and the impact it has in progressed myeloma. But you’re saying this has even been tested in MGUS. I didn’t know that.

Dr. Weiss: Yes. So we’re in the process of actually looking at all those questions through our own database here at Penn as well as through other pharmacoepidemiology databases available because as I said earlier, the effect of metformin has predominantly been studied in solid tumors but not in any blood cancers and not in myeloma specifically. But the reality is metformin is so commonly used and among the diabetics is common. And so it has been combined with chemotherapy one might say unwittingly in the sense that the patients continue on their anti-diabetic medications throughout their chemotherapy regimens. And in general, assuming they don’t develop a contraindication to continuing the metformin during their therapy which in myeloma the most common reasons for that would be development of kidney problems, many of these patients were continued on their metformin. So I think we have some possibility of answering this question regarding metformin and its impact on both patients who have myeloma precursor conditions as this group from WashU did but also in patients with active myeloma.

Jenny: And are you able to go back to the data that you already have from any retrospective studies to save time?

Dr. Weiss: Yes. So we are planning on looking at our own database here at Penn of patients who have both active myeloma and smoldering myeloma who were exposed to metformin or not.

Jenny: Okay. Well, that would be very interesting to see the results from that.

Dr. Weiss: Right. But I should say right now, when we have data like this from epidemiologic studies, it doesn’t mean that patients should be rushing out to start on metformin for the purpose of preventing myeloma.

Jenny: It sounds like you need more data before you can come to that conclusion.

Dr. Weiss: Correct.

Jenny: Well, let’s go back and first understand how you began to study MGUS primarily and smoldering myeloma. What intrigued you about focusing on that aspect of myeloma?

Dr. Weiss: So that’s a very interesting question and some things in life just sort of happen I think by serendipity. It was back in 2001, I had moved to Washington, D.C. to start my fellowship in hematology-oncology. At the time I knew I was interested in the hematology side of things but I wasn’t really sure if I wanted to go into malignant hematology and study blood cancers or actually do benign hematology and study thrombosis. So I was quite undifferentiated when I started my fellowship training. And as it happens, I met Michael Kuehl who you had on your program previously from the NCI and I met him playing squash actually, not in a more academic setting. So one thing led to another. As I progressed through my fellowship I became more and more clinically interested in myeloma and Michael Kuehl, as you know, is a scientist who has been studying myeloma for quite some time. And so he became a mentor of mine and we had many meetings, both on and off the squash court and he taught me a lot about the molecular pathogenesis of myeloma. One day we discussed the fact that this very fundamental question about the pathogenesis of myeloma, this question of whether myeloma is always preceded by a precancerous state, a premalignant state, had really never been answered, even though it seems simple but actually it’s quite difficult to answer because by definition patients with myeloma precursor conditions don’t have any symptoms. So patients aren’t being screened for this. However, I was able to take advantage of a resource that is present in the Department of Defense which is a serum repository that exists for now close to 25 years. Active duty service members have blood taken every other year for force testing for HIV and the serum, leftover serum, is stored. So now it’s obviously not collected in the context of a prospective clinical trial. So occasionally, a service member might miss a collection or, of course, when the repository began, it was being rolled out throughout the military. So over time, there are more and more samples. And so with that resource available to us, we designed a study to look at the patients with myeloma who were evaluated and treated with an autologous transplant at Walter Reed and to go back retrospectively from the time prior to their diagnosis and to pull their serum and test it for the presence of a monoclonal protein.

Jenny: Oh, that’s a fantastic resource, to be able to go backwards like that. I think that’s one of the downsides is that people aren’t tested right up front and then it’s hard to know if you have MGUS or not.

Dr. Weiss: True. And so in our study we were able to show that essentially all patients who have myeloma, who developed myeloma, have a pre-existing monoclonal protein that’s detectable many years before they actually developed myeloma.

Jenny: And in general, I’ve heard different percentages about what percent of people in the United States in general probably have an MGUS or do have an MGUS and then many probably don’t know that they do.

Dr. Weiss: Right. I mean the vast majority probably don’t know since we don’t have screening of the population.

Jenny: And I’ve heard percentages like one to two percent. Is that correct?

Dr. Weiss: So it really depends on age and ethnicity. The studies from the Mayo Clinic focused on Olmsted County and then more recently the NHANES study that was more geographically and ethnically diverse. But I would say as a rule of thumb roughly 4% to 5% of people over the age of 50 have a monoclonal protein. But the frequency of a monoclonal protein will change depending on age and ethnicity. So aging is a risk factor for developing a monoclonal protein so people in their 70s and 80s probably have a 10% to 20% prevalence of a monoclonal protein whereas patients in their 40s or 50s are down in the one to two percent. And for African Americans, those numbers could be about double what I quote. So it really depends on all those factors. So it is a reasonably common condition.

Jenny: And in talking to Dr. Kuehl, he was saying that there are a lot of people that don’t progress to myeloma. So maybe we want to talk about your general approach to evaluating somebody with MGUS and then how you are working to stratify patients into the various risk groups.

Dr. Weiss: Yeah. I think that’s a great question. And I think this is where seeing a hematologist who really thinks about monoclonal gammopathy is important. Most clinicians tend to focus heavily on is myeloma present or not. But the reality is the presence of a monoclonal gammopathy is really a biomarker for possibly other conditions that also need to be excluded. So generally, when I’m evaluating a monoclonal gammopathy and counseling patients on what their monoclonal gammopathy means, I usually tell them that there are two broad categories that we need to think about. One, is there evidence of myeloma or is there evidence of a protein mediated disease; that is, is that monoclonal protein in the blood actually causing a disease. And so those are things like light-chain amyloidosis or monoclonal gammopathy of renal significance or monoclonal gammopathies associated with a neuropathy. Those conditions are very uncommon but they are important to identify. And if those are not identified, if the patient doesn’t have any obvious evidence with myeloma with crab features and they have no evidence of a renal dysfunction as in a monoclonal gammopathy of renal significance or any evidence of light-chain amyloidosis such as heart failure or protein in the urine, unexplained weight loss, things like that, then the patient would be classified as having MGUS. And then the real question at that point is how much further of an evaluation is needed? Do the patients all need to have a bone marrow biopsy, X-rays? And now there’s much talk about doing other advanced imaging, and that’s really on a case-by-case basis; usually based on the patient’s individual risk factors.

Jenny: Well, that was one of the emailed in questions from one of the patients. It was Gerald and he said would you recommend that every MGUS patient have a bone marrow biopsy?

Dr. Weiss: So actually, that’s a great question. And the International Myeloma Working Group does have guidelines for the evaluation of monoclonal gammopathies. And their recommendation is that patients should have a bone marrow biopsy if they have any high-risk features. And those high risk features are the ones that have been laid out by the Mayo Clinic in their studies of MGUS progression and those include a monoclonal protein concentration greater than one and a half grams, a protein that is not an IGG type or an abnormal serum free light-chain ratio. So those patients, it is recommended that they have a bone marrow biopsy. Now, of course, I would say it’s appropriate for any patient to have a bone marrow biopsy who have a monoclonal gammopathy who want more information because one thing that’s missing if you don’t do a bone marrow biopsy is the ability to stratify between smoldering myeloma and MGUS because the key criteria there is having a bone marrow plasma cell infiltration of greater than 10%.

Jenny: And you only can identify that through the bone marrow biopsy. Well, I would think that’s critical then.

Dr. Weiss: Yeah. I mean, obviously, we can get additional information from the bone marrow biopsy and also if the patient is seen in the context of a research study, the bone marrow biopsy is critical to distinguish between MGUS and smoldering but also to obtain plasma cells for future study.

Jenny: And would it be valuable -- because we talked a lot on this series about genetic testing. Would it also be valuable to see if there are any translocations at that stage or only later on?

Dr. Weiss: Right. That is also a great question and this is one of the things that Dr. Kuehl has studied for a while and has been very influential and that is to say that the molecular genomic features that are seen in patients with active myeloma whether it is a translocation or a deletion of a specific chromosome. These can be found in patients with smoldering myeloma and with MGUS. And the frequencies can be somewhat different and it’s also not clear whether having certain translocations or deletions changes the risk of progression to active myeloma in MGUS and smoldering. In fact, the recent studies both from the Mayo Clinic and from the German group have shown that including various abnormalities found on FISH testing, so the FISH testing enables us to detect translocations, hasn’t allowed us to refine the risk of progression in smoldering myeloma. So I think right now it’s useful to have that information but it’s not going to change our management of the patients.

Jenny: Well, just in talking to others, and maybe this is just my personal preference, the more you know up front, the more choices you can make later on. And so I think that the deeper information that you have, just the more well prepared you are to make the choices that you need to about your treatment and your care.

Dr. Weiss: Yes. I mean I think it’s -- I kind of agree with you from the standpoint that it’s good to have as much information as you can. And it’s really hard I think from the physician's side to know what’s important for any individual patient to help them make decisions about their care. And so I think if in discussing with an individual patient they really feel that having as much information as possible will help them make decisions, I’m in favor of them having a bone marrow biopsy.

Jenny: Well, I would agree. And I think some of the concern is that if you start getting treatment at any smoldering stage, and if you don’t get that information, then some of the information can be lost to you.

Dr. Weiss: I would say treatment of smoldering myeloma does still remain an area of research and then in patients who do get treatment of smoldering myeloma, they should be in a clinical trial that obtains that information, I totally agree with you.

Jenny: And can you share what you are discussing about imaging tests to detect early MGUS or smoldering myeloma? How has that progressed?

Dr. Weiss: Well, I think imaging in myeloma both for active myeloma and the precursor conditions is really challenging because myeloma is a disease that affects the entire skeleton and so you have to image a large part of the body. The current standard is to use a skeletal survey which is simply a plain X-ray of all the bones in the body and the central skeleton basically and the appendicular skeleton, so the long bones. And that test is generally in patients with active myeloma is really only positive about 80% of the time to detect bone lesions. And so you can imagine in a patient with smoldering myeloma or MGUS, those types of test are going to be somewhat less sensitive even if there is bone disease. So there’s been a lot of investigation into using more sensitive techniques for detecting bone disease, so that’s osteolytic bone lesions with modalities such as low-dose CAT scan which can image the whole body very quickly and is more sensitive than a skeletal survey for detecting those bone lesions. And then MRI scanning has been investigated to look for focal bone marrow activity of myeloma and that also seems to be very, very sensitive even in smoldering myeloma. PET scanning has been looked at as well. That’s a technique where radioactive glucose is injected into the patient and the whole body is imaged along with a low-dose CAT scan. And that test, I would say, in smoldering myeloma has not been as helpful as MRI scanning.

Jenny: In the MRI scanning, I think it was the UK group talk about the whole body imaging. Is that progressing here in the states - it was a whole body MRI from what I thought.

Dr. Weiss: Yes, you’re correct. And so at our own center, we do not do MRIs routinely for patients with smoldering myeloma. It’s very challenging to get insurance approval for that and also most centers including ours are not routinely doing whole body. We’re doing spine and pelvis, which does cover a large area of possible myeloma activity in the bone marrow obviously, but it does miss part of the body. And so I think in the United States and others of my colleagues may disagree, but it’s quite difficult to use MRI, whole body MRI routinely.

Jenny: And maybe as the costs come down, I think they were trying to do it in a different way.

Dr. Weiss: Yes.

Jenny: Maybe if costs come down -- it's such a big issue.

Dr. Weiss: Exactly, exactly.

Jenny: There were some prognostic indicators that I read about in some of your work and I don’t know what they so you’ll have to explain them. So I saw you mentioned CMCCs, micro RNAs, MIR-16 and MIR-25 and I hope you can explain those in patient-friendly language.

Dr. Weiss: Sure. So I’ll focus first on the CMMCs. I think it will be the most easily understood. Currently, we’re doing a study here at Penn where patients with MGUS and smoldering myeloma can come and have an evaluation that includes collection of peripheral blood and for those who need a bone marrow biopsy as well and of the rest of the standard evaluation. The primary goal of the study is to evaluate the performance of a new test called circulating multiple myeloma cells. This is not a new idea per se, other groups have looked at the ability to detect and count the amount of myeloma cells that are circulating in the blood and they’ve used different techniques. However, those techniques either are very labor intensive or have not been developed for use at other centers. So they’re not widely available. The advantage of this technology is that it is an extension of a technology that was developed years ago that is called CELLSEARCH and it was originally developed for detection of very rare cells in the blood in patients with other kinds of cancers, so in breast cancer, colon cancer, prostate cancer as an example. In those diseases, there are very few circulating cells generally compared to blood cancers so they had to develop a technique to enrich the sample of the possible circulating tumor cell and then classify them. The other advantage of the technology, in addition to be able to find rare cells, is it is mostly an automated process. There's only a modest amount of actual human operator required for each individual sample so many samples can be done with less work and the turnaround time is much quicker for the results. So because of that, this could be easily used in the clinical lab. And one other advantage I should bring up is that when the blood is drawn from the patient, it’s stable for up to four days. And so the other ways of looking at circulating myeloma cells require that the sample be processed the same day. So it has a lot of possible advantages for both the ability to detect rare cells but also in pragmatic terms it can be used pretty easily in the clinic.

Jenny: And why is the number of cells important? Can you just give us perspective.

Dr. Weiss: Yes. When I speak to patients about myeloma, I always explain that the reason the disease is called multiple myeloma is that term means that it’s a cancer of many bone marrow tumors. If one were to look at a skeletal survey of a myeloma patient and see all those different lesions, those are different deposits of myeloma cells in the skeleton. And so there must be a way for the myeloma cells to go from one part of the skeleton to another and have these deposits. So it’s been known for many years that using different techniques, these cells can be found floating in the blood. And in patients with more advanced myeloma, there is generally more cells in the blood than in patients with less advanced myeloma. And also in some studies that have been done at the Mayo Clinic using their own technology in both MGUS and smoldering, the amount of circulating cells in the blood seems to result in a shorter time to development of myeloma. So detecting the circulating myeloma cells seems to capture another aspect of the biology of the myeloma precursor conditions namely the active spreading of the myeloma cells in the blood to other sites of the skeleton which is something that is not directly captured by our other tests.

Jenny: Okay, that makes sense. Are there any other indicators that you look at?

Dr. Weiss: In our ongoing study?

Jenny: Yes or in your clinical practice.

Dr. Weiss: Well, we use all the standard indicators that are recommended by the International Myeloma Working Group. One of the areas that's become somewhat of greater interest is in patients with MGUS we have to be worried about the concern of myeloma in the future, but we also have to be concerned about the possible development of light-chain amyloidosis which is a related disorder whereby the protein, the monoclonal protein itself is causing problems for the patient and not tumor growth of the myeloma cells. So for those patients, early detection of organ problems could be potentially useful. So some of us in the field have recommended checking blood test of heart problems, heart strain periodically in patients with monoclonal gammopathy to see if we can pick up this very rare patient who is developing light-chain amyloidosis. And so that’s something that I do consider in some patients. And then I think periodically patients should also have their urine evaluated for protein because in some patients urine protein is a more significant component of their myeloma precursor condition but also could be a sign of protein mediated diseases such as amyloidosis or monoclonal gammopathy of renal significance.

Jenny: Okay. Well, it seems like the testing is very critical, so you know which direction to head.

Dr. Weiss: Yes. And it’s always important to have a clinical history and to make patients aware of symptoms that they should report to their doctor. We recommend that MGUS patients and smoldering patients come back to see us about every year, every six months depending on the individual factors. But certainly, if there are things that patients are concerned about that could be worrisome for myeloma, we would like to hear about that.

Jenny: All right. Now that we’ve talked about diagnostics, I don’t want to take up all the time without talking about probably the most important question for MGUS patients which is, what can you do or what are you working on to prevent MGUS from progressing to active myeloma? And I know you’ve done some work studying the bone marrow angiogenic environment. So can you talk about that for a bit?

Dr. Weiss: I mean I think one of the great challenges in MGUS in contrast to smoldering myeloma is that the vast majority of patients with MGUS, so 90% or so, should be reassured that they are not going to develop myeloma or some related condition in their lifetime. And so that leaves a small group of patients who are at risk of developing myeloma. The real question is can we do anything for those patients to reduce their risk and could we even perform a study given the low risk of progression in those patients over a long period of time? So I think it’s really challenging to do a study in patients with MGUS of a specific intervention for, let’s just say, metformin as an example because the timeframe would be several decades and it would be very difficult. The question you are really asking is what would I tell the patient to do now if they have MGUS? And although we don’t really have clear studies that have looked at what personal interventions one could make to reduce the risk of myeloma, there are sensible recommendations for lifestyle and diet that can lead to healthier life including reduction in the cancer risk. Actually, at ASCO, Dr. Graham Colditz who is one of the investigators on the metformin project that I mentioned earlier, has a very detailed website talking about general things one can do for cancer prevention. I can send you that link later if you want to put it up on your website.

Jenny: That would be great.

Dr. Weiss: That I think makes sense for patients to follow. And they are the things that you hear about on the news periodically about exercise and following a plant-based diet, maintaining a healthy weight, avoidance of tobacco, and minimization of alcohol -- all these types of things make sense. And even if we don’t have a clinical trial that says it definitely will prevent myeloma, I think it will have great benefits for patients for their general health.

Jenny: I think we all are looking for a preventive strategy, even active myeloma patients that are now in remission. They want to extend that time frame as much as possible. And so the smoldering myeloma patients just we're all looking for those kinds of strategies.

Dr. Weiss: Yes. I think that’s true and that’s one of the most common questions I get in clinic.

Jenny: Can you talk a little bit about the bone marrow angiogenic environment? We’ve done other interviews, for example, with Dr. Raje who studies the bone marrow environment and how different signaling pathways can cause cell growth. And it sounded like from Dr. Kuehl there were several different steps that triggered myeloma. So can you share what you've found about the bone marrow environment and how it impacts myeloma growth?

Dr. Weiss: Well, I mean the only work that I did is that I participated in some imaging studies that while I was an adjunct investigator at the NCI that looked at the correlate of angiogenesis based on special MRI type test. And then I know that several groups over the years in Boston and at the Mayo have looked at angiogenesis. Dr. Rajkumar and Dr. Kumar have shown that there appears to be some type of so-called angiogenic switch that occurs during the development of myeloma at some point during the transition of MGUS to myeloma, if you will. I think the reasons for the angiogenic switch I think are still somewhat unclear, but it is something that has been seen in other cancers as cancers need to establish fertile ground for their growth. One of the things they need is nutrients and so forming new blood vessels can help with that process. But these new blood vessels are often not very healthy blood vessels and may not be as efficient as normal blood vessels in supplying the tumor with everything they need. In fact, it could be that that’s part of it is that these new blood vessels are allowing the tumor to have an environment that’s better for their growth by possibly by malfunctioning. One of the thoughts is that angiogenesis, in addition to other things that are in the microenvironment of the tumor, actually are protecting the tumor from the body’s defense mechanisms against the tumor growth. And that’s an area that’s obviously actively being investigated because if we can alter the environment of the tumor, we might be able to allow our body’s immune system, for instance, to more effectively target the tumor or by targeting the environment we might be able to increase the efficacy of our current drugs.

Jenny:  That makes a lot of sense. Now, I know we have caller questions and I want to get to those, but I want to also ask you about studies that you are working on right now and studies that you have planned. So is there a specific study that you’d like to talk about?

Dr. Weiss: Well, I would obviously like to reiterate that we do have an observational study for patients with MGUS and smoldering myeloma to develop these new biomarkers including circulating myeloma cells and others. We are also participating in a study that involves treatment of patients with high-risk smoldering myeloma. It’s a monoclonal antibody called siltuximab. And that’s an international study that is investigating this agent which targets Interleukin 6 which is a cytokine that is a known growth factor for myeloma. And so for patients with MGUS, smoldering and very high-risk smoldering, we do have studies for all those patients.

Jenny: How do you target Interleukin 6? I mean how do you test for it?

Dr. Weiss: Well, that’s a great question. Interleukin 6 can be difficult to assay in the blood and so it’s done by really some cytokine profiling methods but also as a surrogate we can use a common test called CRP, C-reactive protein, which can give us a rough estimate of Interleukin 6 levels in the blood.

Jenny: Well, I think the variety of the tests is really interesting. The patients need to be really on top of things to know what tests to ask for. So that’s why we always ask about tests. Well, I would like to open it up. I have so many other questions for you and I don’t know where the time goes. But I would like to open it up for caller questions so people have an opportunity to ask their questions while you’re online. So if you’d like to ask a question to Dr. Weiss, you can call 347-637-2631 and press 1 on your keypad and we have some emailed in questions as well.

Caller: Hi, Dr. Weiss. How are you? This is Dana Holmes. Thanks so much for doing the show today.

Dr. Weiss: Hi, Dana.

Caller: Hey. Thanks so much for doing this show and sharing all this great information. I have a couple of questions. First, concerning your ASCO poster which you presented the results from your retrospective study comparing the ultra high risk smoldering progression models, which support the Mayo and the Greek group models in relation to plasma cell burden, how does your perspective observational study differentiate an evolving versus a non-evolving state for those who are not ultra high risk? Which of the biomarkers that you are utilizing appear to have the most promise to actually differentiate this?

Dr. Weiss: You mean in my ongoing study?

Caller: Correct.

Dr. Weiss: Okay. Well, it’s nice to hear your voice. I’ve only met you via Twitter I guess.

Caller: Yes, yes.

Dr. Weiss: Anyway, so the answer to your question is we don’t know yet because we have not fully enrolled the study and we don’t have enough follow-up time yet. And so it’s really hard for us to know if any of the new tests that we are using are going to pan out. We just don’t know.

Caller: So you need in your study participants?

Dr. Weiss: We need participants, yes. I mean that’s the challenge of clinical research is that 97% of patients who have cancer in this country are not participating in clinical research. And so we would love to come up with strategies to increase interest and participation in clinical trials.

Caller: Do you need both MGUS and smolderers for your trial?

Dr. Weiss: Yes, yes.

Caller: You do, okay, because we do have those Facebook groups where everybody follows all of this and Jenny has been a tremendous support for us and provides us information. So it’s good to kind of get that word out by these interviews, maybe some of the smolderers and MGUS folks who live near UPenn might consider coming on up and participating.

Dr. Weiss: Yeah. I think that would be great. I didn’t know there was a Facebook group until one of my patients mentioned it. So we're always interested in evaluating patients for our studies.

Caller: Which tests would a participant undergo at the beginning of your study? Would all of us need a new or current bone marrow biopsy? Do you utilize the gene expression profiling? Which one do you use? You use the FISH probes? Which one?

Dr. Weiss: Right. So for our particular study, patients need a current bone marrow biopsy, and what that means is they have to have one that includes a FISH panel. We do not do gene expression profiling in the study. I shouldn’t say that. We may be doing that later on but we’re not doing that prospectively. And so patients, if they had a bone marrow biopsy with their local physician two months ago, they are not required to have another bone marrow biopsy. But they will be getting blood tests, peripheral blood tests for research. Caller: And that is what initially and then every six months?

Dr. Weiss: Correct.

Caller: Okay. And do you also run flow cytometry on the bone marrow?

Dr. Weiss: If they come to us to do it, yes.

Caller: And do you utilize the Pethema groups model, the flow?

Dr. Weiss: Yes.

Caller: And which results do you actually share with the participants?

Dr. Weiss: So we do not share any research test with the patients and that includes -- we have not been sharing the Pethema with the patients. Well, we haven’t really been asked by any of the patients about it. I have some concerns about the flow cytometry. I think it’s very interesting but again has really been only done in one center and another center is evaluating it right now. So I think it’s still investigational. So I would feel somewhat less comfortable letting patients know.

Caller: Okay. From past interviews, we’ve come to understand that the so-called first hit which causes an MGUS clone in the primary abnormalities of trisomies and the IgH rearrangements can perhaps be environmentally related or even a chronic stimulation of the immune system as a potential phenomenon, chronic infection, inflammatory autoimmune conditions. Yet the second hit which drives the proliferation is as random as a lottery. So as a patient, how do we put the predictive risk models into the right perspective?

Dr. Weiss: That’s a great question. My bias is that the majority of our current biomarkers in MGUS and smoldering focus on surrogates of the tumor itself, the tumor growth or tumor mass, if you will. So those are the things like the M protein, the bone marrow plasma cells, the serum free light-chain. But we also have to consider that myeloma is doing other things to patients, it’s destroying their bones, it’s injuring their kidneys, it’s having other effects on the immune system. And that’s why, for instance, in our study that we presented at ASCO, we were interested to find that a low albumin level seem to be a strong predictor of progression to myeloma. And albumin is very non-specific but it is also a biomarker for the staging system for myeloma. And so albumin might be telling us something beyond just the tumor, telling us about what’s going on with the patient more globally from the health perspective. And so this gets me the point that one of the other things we will be researching in our study is to do a broad proteomic profile, so looking at levels of over a thousand proteins in the blood to see if any of these other proteins which are participating in other biologic processes, so angiogenesis perhaps, kidney injury or kidney’s response to injury, inflammation as you mentioned before. There’s a lot of different proteins participating in inflammation. If whether detection of any of these abnormalities could tell us something more about tumor progression and perhaps put things into perspective of what’s happening with the first hit and then the random second hit perhaps. I don’t know.

Caller: So we’re still a long way off from having a real definitive kind of concrete answers?

Dr. Weiss: To what causes the second hit?

Caller: Just who would actually be evolving versus non-evolving.

Dr. Weiss: Well, I think we have some things that are helpful. I think the bone marrow plasma cells are 60% as you mentioned I think is helpful. I think that patients who have MRI lesions I think are probably at high risk. I think the serum free light-chain needs a little more work and may be a strong biomarker, but I still think we need to look more carefully there as a biomarker in isolation.

Caller: Great. Well, thank you for what you’re doing because we really do live in that gray zone and it’s very unsettling.

Dr. Weiss: Living with uncertainty is very difficult.

Caller: Oh, it is. It’s not an easy day-to-day kind of thing. Is your group considering -- because I know UPenn has been known to lead the way with immunotherapies and things of that nature. Is your group considering any strategies or trials to delay progression for smolderers who are not ultra high risk which includes immunotherapy coupled with novel anti-myeloma agents? Because on another interview, Dr. Richardson spoke to coupling the OncoPep vaccine, the PVX-410 with short-term Revlimid use, and Dr. Orlowski also spoke to similar Revlimid coupling with perhaps an anti-PD-1 antibody. Is your group looking at these types of strategies as well?

Dr. Weiss: So at present, we are not exploring those types of vaccine-based strategies. Now, we are open to exploring them. However, our efforts right now on an immunotherapy standpoint are devoted towards developing CAR T cells for active relapse myeloma. At present, that is not a technology that would be safe to give smoldering patients.

Caller: Okay. Well, great.

Dr. Weiss: But I mean in 15 or 20 years, I can’t tell you if that’s a technology that could be refined and be safe. It’s hard for me to know. But I do think the vaccine ideas are interesting.

Caller: Okay. Well, Dr. Weiss, thank you. Thank you for allowing me to ask you all these questions and thank you for all of your support for the smoldering and the MGUS communities. We really do appreciate it.

Dr. Weiss: Well, thank you. Thank you for your interest.

Caller: Great talking to you. Okay. Take care.

Jenny: Thank you so much for your question. And I have a couple more emailed questions that I’ll just ask very quickly because I know we’re overtime. First is by Gerald and he says, "Do you recommend that all MGUS patients be seen by a myeloma specialist?"

Dr. Weiss: Well, I’m obviously biased, but I would say at least once, and I think others of us in this field have said the same thing about a myeloma patient. I mean not everyone can easily get to a myeloma center. And so it’s obviously a big commitment in time and resources but I do think it’s very helpful. Our community oncologists do amazing work and most of them, I would say, are overwhelmed with patient care. But myeloma is 1% of cancers and so it’s hard for them to stay up-to-date on every little thing in MGUS and smoldering myeloma. So we’re really here as a resource for the community oncologists as well as the patients. If they are interested in learning more about their MGUS and smoldering myeloma, I would absolutely encourage them to seek out a center that has expertise. Jenny, as you told me before the interview began that you are developing a resource on your website to list all these centers I think is great.

Jenny: I think it’s crazy that people can’t go online right now and find a single place where they can find myeloma experts because as a patient, I really advocate going to see a specialist because they just look at it in a lot more detail. It’s different treating hundreds of patients versus five or ten MGUS or myeloma patients or smoldering myeloma patients in your clinic. So I’m a very strong advocate that no matter what, you have to go to see a specialist. The last question that I have is from David and he asks, "Can you explain monoclonal gammopathy of renal significance?"

Dr. Weiss: Yes. So this is a complicated term that is meant to capture the various forms of kidney problems that can occur in the setting of monoclonal proteins. There are many different subtypes to the MGRS but the common theme among them is that the patients have a plasma cell or B cell clone in their body that is producing a monoclonal protein that for reasons that are not fully understood have the propensity to injure the kidney. This was a term newly described by Dr. Leung and Dr. Kyle from the Mayo Clinic to try and make sense of this group of disorders and also to drive home the point that these disorders should be treated in a way that is similar to myeloma or amyloidosis in that chemotherapy should be given to eliminate the production of this bad acting protein, if you will. And so to that end, the International Kidney and Monoclonal Gammopathy Research Group has been meeting periodically to discuss these disorders and we published a paper in Blood about our opinion on how to treat them knowing full well that there have not been a lot of prospective studies of treatment.

Jenny: Well, I like the fact that everyone is getting divided into buckets that then helps them get the proper treatment for them personally. I think it’s very, very helpful and that’s why I was asking so many questions about the testing and where do I sit and what should I do with that information. And the last question I have is what does clinical trial participation mean to you or what could you do with your research if you had a larger number of patients participating?

Dr. Weiss: Well, that’s a big question obviously. And the short answer is that with more patients participating, we can complete these studies more quickly and we can accelerate advances in cancer care and understanding mechanisms of cancer, therapies for cancer. That’s how ultimately all patients benefit is through the work of investigators and the bravery of patients to participate in these studies. And you know, myeloma has been really fortunate to have such major advances over the last 15 years or so with so many new drugs and in fact new classes of drugs. And it proves that if we can get investigators and patients together, we can make advances.

Jenny: Well, we will follow up to help with you to find a way to write a post about your observational study easy to join.
Dr. Weiss: I wish it were true.

Jenny: Well, we’ll help spread the word. Well, we thank you for going overtime and we’re so thankful for what you are doing for myeloma patients. We hope you keep up the great work and we’re just very grateful for your dedication to the field and to the patients themselves.

Dr. Weiss: Thank you very much. It was a real pleasure. And thank you for what you are doing to spread the word to patients.

Jenny: All right. Well, thank you again. And thank you for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient Radio interview as we learn more about how we as patients can help drive a cure for myeloma by joining clinical trials.