It may be time to meet with your radiologist to review your myeloma imaging tests. Imaging technologies have advanced greatly in the past few years and have become a new and important vehicle for diagnosis and prognosis. Dr. Jens Hillengass is a world renown expert on imaging techniques in multiple myeloma and shares his key learning about the technology in this show. He first shares that the traditional x-ray or skeletal survey does not provide as much information as the CT scan. Work is now being done by the International Myeloma Working Group to make CT the new gold standard over x-ray. He shares the importance of PET and MRI to see inside of the bone marrow and discusses the important use of MRI to identify unique patterns of lesions in the bone marrow: focal lesions, diffuse infiltration and a salt and pepper pattern. The number of lesions and the presence of the diffuse infiltration pattern are important for prognosis based on his research. He tells us that about a third of patients have focal lesions only and another third have diffuse only while the last third have both. If patients have more than 7 focal lesions, a dense diffuse pattern or both focal lesions and the diffuse infiltration, they have worse prognosis, but that prognosis needs to bear in mind a holistic view of each patient that also looks at LDH levels, cytogenetics and imaging results together. He gives recommendations about what imaging techniques newly diagnosed patients should receive and also shares his important recommendations for smoldering myeloma patients. This is a key show for patients who want to take charge of their care and know what questions to ask their doctor for their most accurate diagnosis and prognosis. The Myeloma Crowd Radio Show with Dr. Jens Hillengass, MD  

Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom and this is our 59^th show. We are looking forward to next month where on August 15 we will announce the selected projects to be funded for the Myeloma Crowd Research Initiative. This is an initiative we started back in January to find and fund research specifically for high-risk myeloma. We received 36 proposals and have narrowed it down to 10 and found that they are equally exciting for normal or low-risk patients. We started this research initiative knowing that if more patients were involved in supporting leading edge research, we could find a cure faster, which is what we all want and it’s the first time patients have been driving the project. The doctors are talented and brilliant but they need our help to make their research a reality. To show your support today, you can get started by creating your own fundraising page. In a web browser, type in https://mcri.myelomacrowd.org and click on Build a Team. You can upload your own photo and write your own text to customize your page. This is a way that you will be able to ask friends and family to support the discovery of a cure for you, so you can take that important step today and be ready for the final projects later next month. We are very privileged today to have with us Dr. Jens Hillengass of the University of Heidelberg. We welcome you doctor - please allow me to introduce you. Dr. Jens Hillengass is Head of the Hemato-oncological Imaging Work Group in the Department of Radiology, at the German Cancer Research Center in Heidelberg. He also serves as Deputy Chief of the Section Multiple Myeloma of the University of Heidelberg, and is Attending Physician in the autologous stem cell transplantation and multiple myeloma outpatient department. He also serves as head of the central blood withdrawal unit of the department of  internal medicine. Dr. Hillengass is a member of the American Society of Hematology, the International Myeloma Working Group, and the Black Swan Research Initiative of the International Myeloma Working Group. He regularly reviews research publications in Leukemia, Blood, Haematologica, the European Journal of Haematology and Annals of Hematology. Dr. Hillengass is the recipient of the Gerok-Scholarship from the German Cancer Research Center and the Young Masters Award. So, welcome Dr. Hillengass!

Dr. Hillengass: My name is Jens Hillengass. It’s an honor for me to be part of this program and the first question was on different imaging techniques and I think it’s quite interesting to discuss those because I think during the course of disease in a lot of patients get a lot of information about imaging and out of imaging. I think it’s important to understand what imaging techniques there are and what they are showing. First of all, it’s important to mention that the different imaging technique show or give different information. The most urgent question is mostly the status of the mineralized bone like the skeletal bone and for decades this information was mainly acquired from conventional X-ray, which is not so bad when it comes to the skull and the long bones and the extremities, but it has very limited sensitivity and specificity for stability of the spine and the pelvis and those are very important parts of the skeleton of course. And for this the problem in the pelvis and spine is that there are kind of struts in the sponge’s bone which makes the density higher. This is a limitation for the X-ray beam which goes just from one end to the other. The better technique for this is the computer tomography which has an X-ray beam going around the body with the detector on the other side. And so you get 3D information from the whole body and from the bones as well. So this technique, the CT Computer Tomography has a higher sensitivity and specificity. Within the International Myeloma Working Group, we are at the moment together with two very experienced radiologists are conducting a trial comparing X-ray and CT of patients who had those techniques within 4 weeks and we want to learn how those two techniques differ concerning the detection of a myeloma bone disease. In addition you can get information from the CT also on the infiltration of the long bones for example, not so good again in the spine and pelvis but in the long bones you can see if there’s an infiltration of soft tissue within the normally fatty bone marrow in the extremities - in the arms and the legs - but it’s not possible to see this in the spine where it is also very important. There are other techniques that show the bone marrow itself where the disease takes place with a better specificity and sensitivity like magnetic resonance imaging (MRI) and positron emission tomography (PET). Which we call MRI and PET, as I think you all know. They provide high sensitivity especially in early stages of disease and after therapy. When we started to investigate the results of MRI we found that the infiltration patterns are not as we expected for a hematological disease like myeloma to be diffused but we found out that there also focal accumulations of plasma cells or malignant cells all over the bone marrow and we found that those focal lesions and also the diffuse infiltration pattern were present in about third of the patient’s each and the combined pattern like a mixed pattern of diffused and focal infiltration in about third of the patients. We found out that those lesions can be of prognostic significance either before therapy and also in early stages of disease as well as after therapy. The problem for MRI is that after therapy you still have those lesions left. For example when there is osteolysis it will not go away after just six months or something when the treatment is finished. But there will be still residual lesions and we don’t know if they are really containing vital cells or if they are just scars or osteolysis left there without vital cells in them. So in this case, PET-CT comes into play because PET shows the metabolism of the cells investigated in this region, and it correlates quite well with the activity of the disease. So in summary, CT and X-ray are very good for diagnostics of the mineralized bone and CT is better than X-ray to our knowledge. And PET and MRI are more able to display bone marrow. So next question on the patterns of the lesions, as I mentioned we have some patients with diffusing infiltrations, some patients with focal infiltration, not really knowing what that means from a biological point of view but as I mentioned, regular distribution all over the patient group with some patients having focal lesions and some having diffused infiltration patterns, and some are having a mixed pattern or even a normal pattern like normal bone marrow in other non-malignant diseases for example. And there have been several studies on the prognostic significance of those patterns and it was shown that the diffused pattern, especially in the symptomatic patients have the most adverse prognostic significance and focal lesions are also not very good because the more focal lesions of course, the more tumor mass you have. And those are also of adverse prognostic significance and the normal pattern seems to be of a best prognosis for the patient who show that. As I mentioned also after therapy if residual lesions especially in PET CT remain, it’s also an adverse prognostic factor because it has been seen that those focal lesions might be the source of a relapse of the disease after treatment if they reside after completion of the therapy.

Jenny: The patterns of lesions are important I think. If you could continue explaining the different patters and how we can see those on the MRI and what those mean.

Dr. Hillengass: Actually, in the beginning it was kind of surprising because we know myeloma is a hematological disease, it’s a systemic disease. Maybe the cells have just flown all over the bone marrow and then we found those mentionted different patterns like the diffuse infiltration as we expected but also those focal lesions. Of course we knew that osteolysis are typical symptom of multiple myeloma showing also the circumscribe destruction of the bone but it was still surprising that there are those different infiltration patterns and some patients only have one pattern and some have different patterns. And so we investigated. Actually, at the moment we are investigating and comparing those different patterns and we are looking for the different genetic background of the focal lesions, so we are doing CT guided biopsies of focal lesions and we compare it to the random bone marrow sample as we do it in every patient at first diagnosis. And we want to learn if those cells are really different because some of them grow focal and some of them grow in a diffused pattern and to see how those differ and if this is really from a biological reason why they are all growing focal or diffused. And as well there are patients with both so there seems to be some difference in the phenotype like what we see and maybe there’s also difference in the genome type, but we don’t that yet.

Jenny: So when you describe it you describe it as focal lesions which I think we’re all pretty familiar with because those show up even on the X-rays, and then can you further describe because maybe I missed this when I was trying to get the technology to work. The diffuse infiltration or what you define that as how that shows up what it looks like and then the salt and pepper pattern that you were saying.

Dr. Hillengass: Yes. The diffuse infiltration is very difficult because it really takes some experienced radiologists because the diffuse infiltration just is a so-called “high point intensity” in one weighted imaging. There’s T1, T2 for the radiologist. In this audience (T1 and T2), they are weighted differently. They show rather a fatty content of the hyper intensity or a water content as the higher intensity in the images, like higher intensity meaning brighter color or brighter grey and the diffuse infiltration is it is shown has higher water content because there are more cells, it’s a higher cellularity. You can compare this grey scale you get out of the MRI image, usually you compare it to the intervertebral disk because the intervertebral disk usually looks as the same grey scale, a grey color. So you compare this and if it’s darker then on a high point intent compared to the intervertebral disk it’s a higher infiltration and if it’s lighter than the intervertebral disk, it’s a lower infiltration. And this as you mentioned the salt and pepper pattern which is also something we not totally have understood yet because it’s mainly found in older patients but not only. It seems to be we compare it with histology but it’s not easy because histology is very small, because the microscopic view and the MRI is like the whole body so we compare it and we think that it displays very small lesions, small focal lesions on a background of a fatty bone marrow. Fatty bone marrow is normal in older people because over the years the cellularity goes down and the fat content of the bone marrow goes up. This is very normal in a physiological process over the years. So we are interested in those different patterns with not knowing at the moment if there are really biological differences. We found out that from a prognostic point of view, the salt and pepper pattern is nearly the same as patients without visible infiltration in the MRI and we don’t know why some patients really look like a healthy control in the MRI but still have a myeloma. We are also looking into that but those patients with the normal kind of normal or minimal infiltration and the salt and pepper pattern have a quite good prognosis while the diffuse, really diffuse, high diffuse or severe diffuse infiltration plus the focal lesions, those patients have a little bit worse prognostic factor in this imaging point of view.

Jenny: So I don’t think I’m understanding the difference between the diffuse infiltration and then the salt and pepper pattern.

Dr. Hillengass: The diffuse is really homogenous. We usually use the spine we look at those vertebral bodies and we see there’s it’s a homogenous grayscale of the same pattern. If you look in the salt and pepper it’s rather a light background with some very small like salt and pepper you mix dark and white granula and they are like thrown into this background with quite high intensity light color. So the grayscale homogenous is the diffuse infiltration and the salt and pepper it’s just small islets of dark in this white or fatty background.

Jenny: That makes a lot of sense. And then, I guess next question is a little bit of what you covered I think at the beginning is, what the MRI provides that the other tests can’t. The X-rays - everybody does them but they are not terribly useful from what I understand.

Dr. Hillengass: So X-ray is really showing the bone, a mineralized bone because there’s really nothing to see concerning soft tissue involvement, concerning involvement of the fatty content in the long bones. Where you can see in CT for example, if the fat content in the long bones (where you can see really dark background with light infiltration in the CT images) - this is not visible in this X-ray at all, because the sensitivity is just too low. So, we have those long bones and you can see that in the CT, that infiltration of the long bones, but in the spine there is a sponge in bone with a lot of trabeculae, those small parts of bone. And so the density is quite high. The CT shows this like a sponge in the images but you’re not able to see the bone marrow within those small pores of the vertical bodies. And you can see this very well in the MRI as well and those different diffuse infiltration patterns which talked about are very well seen in MRIs. A lot of people ask why use MRI when we have PET-CT. So for the PET-CT we have the CT part which I mentioned is quite good for the mineralized bone and the PET part is quite good for the bone marrow where the actual disease takes place because there are the plasma cells, but MRI has a high sensitivity especially for this diffused infiltration as I mentioned. The diffuse infiltration is the most adverse prognostic factor from imaging point of view. PET is very good for focal lesions especially after therapy because you know if there is still an uptake of this nuclear tracer you can see that there’s still vital cells what you can’t see in MRI so the main benefit of MRI is early detection because of the high sensitivity for the bone marrow as well as the detection of this diffuse infiltration because in PET-CT it’s not very easy to really assess the diffuse infiltration, because sometimes it’s just a reactivation of the bone marrow - it could be inflammation whatever. So for focal lesions PET and MRI are good are good but for the diffuse infiltration MRI is a little bit better and especially in the early stage of disease like smoldering myeloma.

Jenny: I know, we have smoldering myeloma listeners that will probably ask some specific questions at the end that are always excellent. And I wonder if the doctors doing the initial diagnosis - now, I know this is a probably a question for later but when you are diagnosed typically you’re not going to see a myeloma specialist for that diagnosis, which is an issue because sometimes they’ll do the X-ray and then they’ll do a bone marrow biopsy but they sometimes in many cases won’t do an MRI or sometimes even a PET-CT scan. So do even myeloma specialists know about the value of the MRI as much as you would like?

Dr. Hillengass: It’s always interesting. When I give talks on imaging obviously, but also talks on other topics and especially the new guidelines which include MRI, it’s surprising how few doctors are really -- I don’t know if interested but really informed about the benefits of MRI. I think if you have osteolysis in the X-ray everything is clear because you have CRAB criteria and you have to be treated. If you don’t osteolysis in the X-ray, you don’t know if you still could have infiltration or osteolysis even in CT because CT shows all the very small osteolysis, which are not shown in the X-ray. So CT is even beneficial compare to X-ray. And we actually in our clinic we changed from X-ray totally to CT. We have the whole body low-dose CT, which has a little higher radiation dose than X-ray like 2-4 times. But still it’s quite low and doesn’t need any contrast agent so it’s very easy for the patient, like three to five minutes. They just lie down go into the machine, come out and we have the whole body CT with a very high sensitivity. And so this is quite easy and as I mentioned earlier we have at the moment we have a study going on within the international myeloma working group with a lot participants from all over the world, sending us CTs with Computer Tomography and X-ray of patients at first diagnosis without treatment and we want to compare them and see how much better is CT compared to X-ray. Because every radiologist you talk to they say, there’s no question that CT is better than X-ray. They say it’s obvious and everyone knows that but maybe not every hematologist. So the first thing I want to mention is that CT is quite superior to X-ray. But further more, if CT is negative the number of patient with this is getting smaller and smaller. So if we are X-ray positive it’s obviously osteolysis and you have to be treated. If CT is positive, okay also osteolysis we can discuss if they are very small if we you should already treat. And then the next step if CT is negative, we can do an MRI and if the MRI is positive and shows more than one focal lesion, according to the International Myeloma Working Group criteria now is called treatment eligible or treatment necessitating multiple myeloma. At the moment we are discussing a lot about this issue because if the radiologist is not really experienced, there might be some spots in MRI which are not really myeloma and those patients would not be treated because they are till smoldering. At the moment, it’s a little bit of an issue to train on the one hand to hematologist to really think about MRI and to think about early detection. And on the other hand the radiologists who don’t see very many myeloma patients for the study I just mentioned. We had the most experienced radiologist seeing 10 to 20 myeloma patients per day in their practice. But if you see one myeloma patient in one or two years it’s not easy to really differentiate. So also, the radiologists in our study are very interested to train their colleagues to learn what myeloma looks like in the MRI and what we can get out of this information. As I mentioned, if X-ray is positive, CT is positive it’s already CRAB criteria, no problem, but if the MRI is positive you really have to look carefully if this is really myeloma. You will not get the absolute answer because the absolute answer would be putting a needle and get some cells out (bone marrow biopsy). But on the other hand I think it’s important to know that there can be focal lesions in the MRI which don’t lead to osteolysis at that moment. So it could be MRI positive and CT negative.

Jenny: Interesting. Well it sounds like it’s scaled with X-ray being the least sensitive and MRI being the most sensitive. Maybe you like to tell us how the MRI technology has changed over the last few years to be able to do that because this wasn’t typically a key part of the diagnostics was it?

Dr. Hillengass: No it wasn’t. I think we started to do any MRI in myeloma in 2004 or so. Then we found those different patterns, they were already published because the first MRI papers or MRI in myeloma or monoclonal plasma cell diseases were published in the ‘90s even in the ‘80s, but the image quality was very low. So you saw something but you didn’t know what it was. The first publications on prognosis and on significance on MRI, which is if MRI is positive or doesn’t look normal - those were the first steps, but with the newer machines with the higher field strength like more Tesla, this is the unit you measure, with newer machines and newer scanners you get better quality and you get faster investigations, but I have to mention that MRI is still takes a long time. It’s the longest technique you can test for with multiple myeloma - it takes at least 30 to 60 minutes - but with these new scanners you get really good information on the bone marrow, again mentioning bone marrow. I have to admit MRI doesn’t show the mineralized bone at all. There’s just black where the mineralize bone is but you can see the bone marrow well and see those infiltration. For the assessment of bone and bone stability you still need an X-ray based technique and we use CT and I would also recommend the use of CT if available. MRI has really improved in quality and it came to a certain quality where it was really useful, and now it is useful for myeloma patients. As I mentioned earlier, especially in the early stages of disease because there you don’t have osteolysis and if X-ray is negative maybe CT is negative, but still MRI could be positive and you can see if those lesions are there, if the diffuse infiltration is there. We did a comparison of follow up MRIs, we did an MRI every 6 or 12 months in smoldering myeloma patients. And it was interesting that if there were focal lesions in the beginning and they didn’t change. It was not really an adverse prognostic factor but if they grew, if the size increased or if the number increased if they one and then three and then four whatever, they had a very early progression into symptomatic disease. So we think we can improve that, but we think that osteolysis is preceeded by those focal lesions in MRIs. So there are those accumulations of plasma cells leading to those focal osteolysis causing then fractures and pain and so on.

Jenny: Well that leads me to a follow up question. But how often should patients be having some of these because I know in some facilities they alternate. They’ll say okay at this six month check, we’ll do a CT and the next six months check we’ll do an MRI and some of it is based on what your insurance covers what they able to approve or not approve. But what do you believe is valuable for both smoldering or MGUS patients and fully active myeloma patients?

Dr. Hillengass: We’ve thought about that very, very much because it is an economic question of course. Each imaging costs for the patient or for the insurance or for whoever pays. So we really thought hard about, when are the most important time points? And we decided in our daily practice to do an MRI. We have the possibility to do a whole body MRI. I think if you have a whole body CT or a whole body PET-CT of course then you can maybe stick with the spinal and pelvic MRIs or an axial MRI, but we can do a whole body MRI. So we do a whole body MRI and a whole body CT at first diagnosis in every patient - mainly smoldering and symptomatic but sometimes also if is there are suspicious lab values, also in MGUS patients. We have one point where we do nearly everything, so CT and MRI. We have encountered the problem that PET-CT is not covered. In symptomatic patients, I also would recommend a PET- CT, and an MRI. The MRI mainly for the bone marrow and the diffuse infiltration we have the CT and the PET-CT for the focal lesions and for the osteolysis. And for follow up because we don’t have PET-CT after therapy, if a patient have achieved a good deep response then we do the MRI again. I would like to do a PET-CT but it’s not covered in Germany, so I do an MRI because it also gives me information mainly if the diffuse part of the infiltration has disappeared, which is mostly the case. And we also look to see if the number and the size of focal lesions has decreased. But as I mentioned the problem in MRI is that there’s still will be focal lesions if there were osteolysis. Because osteolysis does not heal within six months it takes much longer. We thought that osteolysis of myeloma patients never heal but when then we started to do CT – this is another topic. We started to do CT and did CT after therapy. We do that also after therapy and we found that at the mark of the osteolysis sometimes the sclerosis appears. And this seems to be a kind of a healing process and we only see this with another agent. We never saw this with melphalan and prednisone or VAD and high dose therapy, there was no change in osteolysis. But when we started to use bortezomib, lenalidomide and all the new agents (combined with bisphosphonates of course), there are in some patients the start of healing of osteolysis and this is very important information we get out of CT. In MRI there also seems to be a kind of a healing of those focal lesions, osteolysis and bone marrow infiltration. So, to summarize we do it at first diagnosis. We do it after therapy and this might be a lot, but we do it once a year in every smoldering patient. A whole body MRI, we do MRI and the CT in the first diagnosis to exclude osteolysis which would be myeloma and exclude more than one focal lesion which also would be treatment required in myeloma. But we do then in the follow-up just once a year an MRI. And we also do it oligo or asecretory (non-secretory) multiple myeloma which is not very often. But I just collected some patients, I think we have about 50 patients over the years with an oligosecretory or asecretory multiple myeloma. And there the whole body MRI is very useful because we can detect changes in lesions like growth in lesions or increase in number lesions before there is any serological or any bone marrow change if we do a biopsy. So we spare biopsies by doing more MRIs in those asecretory or oligosecretory multiple myeloma patients - but those patients are real.

Jenny: And these are patients that not secreting the M spike but they still have active multiple myeloma.

Dr. Hillengass: It’s very rare but there are some patients especially, after some lines of therapy in the further course of the disease and the later course of the disease that could be this asecretory or oligosecretory type of myeloma.

Jenny: Maybe we want to go back a little bit and explain what else MRI can provide that the other test cannot. So I was reading you recent paper in Haematologica. And it mention things like spinal cord or nerve compression or benign versus malignant fractures or bones plasmacytomas and things like that. Are there other things that the MRI can detect?

Dr. Hillengass: I think those that you have mentioned are very important especially this benign versus malignant fracture. It’s not an absolute yes or no but as I mentioned in an older patient, the bone marrow is replaced by fatty tissue over the years. This is normal and this takes place in everyone. But if there’s an infiltration of for example, myeloma this fatty bone marrow is replaced by the malignant cells. So you have again a higher cellularity. So if you have an older patient and you have osteoporosis, which is not uncommon in post-menopausal women. If they have an osteoporosis and a small M spike, you don’t know if it’s an MGUS plus the benign osteoporosis because of post-menopausal situation or if it’s really a multiple myeloma with a small M spike but infiltration. If there’s a fracture for example we can use the MRI to compare a fracture with a high cellularity, which would be expected in a malignant process like multiple myeloma or with a low cellularity which would rather point to a benign cost of the osteoporosis, like post-menopausal age. So, this is very useful to use this MRI. It’s not very often but of course an older MGUS patient will always have this question if he has osteoporosis. Is it caused by hormonal changes or by the infiltration of a malignant diseases like multiple myeloma. You mentioned something else I thought important. The spine and cell compression, this is very important, I know it’s the technique of choice for the neurologist and orthopedic surgeons. If there is a suspected cord or spinal compression of the fracture for example, or even a soft tissue tumor grows into the spinal canal then the MRI is the best technique to show this because you can see the nerves. You can see the spine and vertebral bodies and you can see if there’s a tumor or if there’s a fracture causing this injury of the spinal cord.

Jenny: Interesting. You’ve touch on it just a little in the beginning, but let’s go over your paper and how you are using imaging to score patients and project outcomes. So you mentioned the diffuse and if you could kind of review it for us or spell it out for us that would be great.

Dr. Hillengass: I mentioned now several times, the diffuse and focal lesions. It’s easy to count focal lesions. It’s kind of a lot of a work because when you have whole body imaging, you have a lot of images. Radiologists are not very happy to see that many images but they accept it. And so you can count those focal lesions. The more focal lesions the more, tumor mass the more urgent the treatment is. If you have symptomatic patients there was a very good paper from the Little Rock group from Arkansas and they compared patients with more than seven focal lesions - that was spinal MRI at that time - it quite an old paper already. So spinal MRI focal lesions more than 7, 3-7 and less than 3 and they found that if you have more than 7 focal lesion at first diagnosis of symptomatic disease even with the most aggressive treatment at that time called Total Therapy, they had an adverse prognostic significance to have those many focal lesions. The number (of focal lesions) is of prognosis significance in symptomatic myeloma. We looked into smoldering myeloma and found nearly the same but the cut off calculated by the statistician was more than one focal lesion which might be a little bit too few focal lesions as a prognostic factor, but still this was what we found and it was confirmed by another group. So, this number of focal lesions is of prognostic significance in all stages of disease actually. This diffuse infiltration was also found that if it’s present it’s an adverse prognostic factor. So we thought why always do this diffuse and stop and then do the focal counting and stop. We wanted to compare and again our very good statisticians looked into that and so we found a score combining the diffuse infiltration like severe diffuse infiltration, moderate diffuse infiltration, salt and pepper as we mentioned, and minimal infiltration compared or in combination with the number of focal lesions. We have this score that is mentioned in the paper and so we have that whole information from the MRI and put it into one score and you can score as like in other scores, you can score 1, 2, 3 in different groups. The more focal lesions, the more severe the diffused infiltration the worse the prognosis and if you have very few focal lesions or no focal lesions and a very few diffused infiltration regions or very low infiltration then you have a better prognosis concerning imaging. We haven’t compared it yet to the other very important prognostic sectors but we found (this is not published yet) but we found that there is a correlation of more focal lesions with for example, high LDH which is also a prognostic factor, and with high-risk cytogenetics. This correlation was very weak with the cytogenetics. A reason for this might be that cytogenetics rather show the biology and the genetics of the plasma cells, while the MRI more shows the tumor mass all over the skeleton. So there is a very weak correlation, but I think it’s also positive information, because we have additional information out of the imaging not only repeating what the cytogenetics already tell us.

Jenny: So you’re saying that high LDH levels are a known high risk factor. And then high risk cytogenetics like a deletion 17 or 14;16 or something like that. I’ve heard someone say and now I can’t remember who -- talking about how there could be more bone damage but kind of slower growing myeloma if that make sense. Even though it might be a worse prognostic factor, can you address at all what you seen from an imaging standpoint?

Dr. Hillengass: That’s true. We have some patients and I have no really certain explanation for this but if there is a slow growing myeloma, there can be a lot of osteolysis before there is any pain or before there is any fracture. The patient can the myeloma for a very long time without symptoms but then if you have the diagnosis maybe if the first fracture appears or occurs, then you have the diagnosis because the patient goes to the doctor and the whole world diagnostic machinery is going on. And so we know there is the myeloma but it could be that the myeloma has been there for a very long time earlier, but we didn’t see it because we haven’t looked for it. On Monday I just had a patient I’ve known for several years now. And he has a very, not benign, but very slow growing, long term myeloma, which responds very well at the moment to lenalidomide. I think it has been several years now on lenalidomide but he has very, very severe osteolytic destruction of the bone. I think it was not because the disease was very aggressive leading to very fast and bad destruction of the bone but it was a very slow growing myeloma which responds to the therapy now. But still he has those destructions from the time when we didn’t know that he had myeloma, and the myeloma already destroys his bones and then came the first fracture and he came to his doctor and then the diagnosis was made. So I think that could be an explanation and I also think it’s not always true that a high tumor mass must be an adverse prognostic factor. It also depends a lot on like biology, cytogenetics and so on. I think it’s always important to see the whole picture. Not only look at the imaging not only look at genetics, not only look at clinical parameters but see the whole picture. I think this is very important to really get an impression of what the real prognosis of the patient is. We still see patients with deletion 17P which usually should have a bad prognosis but still live for a very, very long time with the disease and we don’t why this is. But I think it’s more complex than just say this is a factor it always leads to this and that outcome.

Jenny: And so you’re saying now that we know more about what the MRI can provide and the number of lesions and the diffuse lesions in the pattern then now we can match it up potentially with the genetic features. And see if there are patterns that kind of crossover one another. And you’re just at the beginning stages of doing that?

Dr. Hillengass: Yes. We started and there is one publication from a Greek group and they compared MRI findings with genetics and there was -- actually I think no or very, very, very low correlation of genetics and MRI findings. We did it with functional MRI which measures functional processes like micro circulation, perfusion of the bone marrow which contrast agent, and we had quantitative parameters of this micro circulation and we found that there was a correlation of a high micro circulation meaning a lot of blood vessels in the bone marrow, and a lot of very destroyed blood vessels which are not very functional anymore. And those correlated better to deletion 17P and 1q 21 gain and so, there was a correlation of this case a rather functional and biological information but just the morphological information, just a lot of plasma cells and MRI does not mean that’s it’s also bad cytogenetics. So I think there is more to this than we know at the moment.

Jenny: Oh yes I think there is but there are people like you are working on, so we’re very hopeful.

Dr. Hillengass: Always.

Jenny: So a couple of more questions. Is the placement of your lesions predictive at all or important at all? Like in your spine, in your hip or wherever.

Dr. Hillengass: There’s two ways to look at this. If it’s located in spine, rib and in the pelvis in the extremities whatever, we found no correlation or no prognostic information out of the location within the body. What was interesting or what is interesting and what is quite well known if that location is inside or outside the bone itself like if it’s in the bone marrow or if it’s coming out of the bone going through the cortical bone into the soft tissue and the third being just in the soft tissue without connection to the bone is of course of prognostic significance, because we know that myeloma cells are very dependent on the micro environment which they find in the bone marrow. If they are quite advanced in their malignant development, they also are sometimes able to develop within organs or soft tissue. And so if you’re in MRI or PET-CT find focal lesions in the soft tissue alone, this is a very bad prognostic factor. We don’t see this very often at first diagnosis but sometimes, after several courses of disease there are also appearing of tissue tumors in myeloma patients or like in the skin sometimes and this is very bad sign actually for multiple myeloma patients. So the location concerning the bone is very important, inside the bone outside the bone with no connection to the bone but, if it’s in the skull or in the pelvis or in the spine to our knowledge and into our data is not important at all. It’s just important for of course stability like when the spine is infiltrated it’s worse than if there is a finger or whatever.

Jenny: Okay, well that makes a lot of sense and it means maybe the myeloma is just escaping and then you can’t lock it down to the bone, right?

Dr. Hillengass: Yes.

Jenny: Are there other factors that contribute to overall survival you mentioned the high LDH levels or in your paper you mentioned being stage three or later. Are there other factors beyond those things that are contributing as well?

Dr. Hillengass: In our study it was focusing on MRI obviously, but the correlation with LDH and as you mentioned a high ISS stage also correlate it with the imaging with the high infiltration, high tumor mass. This was well known but I think it’s interesting to get it confirmed by this imaging. So imaging really correlates to the tumor mass and ISS correlates to the tumor mass and both are prognostic factors. I think in our paper we found no other factors than the already known like the genetics and ISS but they were confirmed in this group of patients.

Jenny: Let’s talk about treatment a little bit. When you are doing MRIs after treatment, first you mentioned a little bit how long the bones being able to heal in some of the other therapies. So how long do bones take to heal in general?

Dr. Hillengass: This is extremely interesting and very often asked question, of course. My patients also want to know when can I do my sports again or exercise or what they like to do. This is very important but I cannot really answer it right now. We have seen after the first positive changes to better in CT was, I think six months after initiation of therapy but this is very, very early to really have significant changes and we want to look into that, we haven’t done it. We want to look at how long it takes. I think it takes years and years, because the bone is already damaged by a malignant disease. The first step is to eliminate the malignant disease like myeloma, get the deepest response possible but I think now, we can look into patients who has been on long-term complete remission but they were treated five or six or 10 years ago, so those are the long time survivors and we can look into them but they are not treated like the treatment today. So we cannot say now, what will be in 10 years, so this is kind of a complicated trial to do because we always have to see patients after a longer period of time We are aiming to do a study, doing imaging after a long remission but we don’t have very many patients right now because they were treated with the old drugs with only high dose. I think it’s very important and very interesting but we cannot answer this now because now the patients get those very new and very effective treatment and we will see in 5 and 10 years what the bone changes are over time.

Jenny: And then what more can the MRI tell you about the myeloma when you take it before and after -- what are looking for in the changes, the pattern changes or the quantity and what else?

Dr. Hillengass: It’s interesting that diffuse infiltration usually in every patient changes to a normal or minimal infiltration pattern so the degree of infiltration goes down if the patient responds to therapy. If not it stays the same, but if it goes down it correlates very well with the cellulogical parameters of remission. The number of focal lesions if there were no osteolysis also go down, but as I mentioned in MRI you cannot see if there are vital cells. So there is still a lesion but this lesion could be just dead cells or necrosis. This is a limitation obviously of MRI and if there is osteolysis you just see the focal lesions still while not seeing the bone in the MRI you still see the osteolysis, the focal lesions left there with some fluid in it or there’s just nothing, there is still a lesion. We look especially in the diffuse infiltration pattern but also in the focal lesions and if they really disappear, it’s a good sign. If they don’t disappear it doesn’t really tell you very much because you don’t know if those cells in those focal lesions are really relevant and vital anymore.

Jenny: You’ve make me intensely curious to ask my doctor about my diffused lesions, if I have any. Because I got a count of focal lesions but I think unless patients are asking questions like this, they never really review it. We had a show where pathologist said, you should pull pathologist aside and ask them to go over your records with you, because they’re happy to do it, is this something a pathologist would go over with you, is this something that you should really have your doctor review with your or while you’re in a clinic take a look at the screen and see the difference.

Dr. Hillengass: The hematologist or even the radiologist, because they are the experts for changes in MRI. So, in our clinic we have a tumor board where we demonstrate myeloma patients and as I mentioned because we have a lot of patients we have a very experienced radiologist and he discusses a lot. He says okay there is a change with that and this lesion is disappearing and sometimes even newer focal lesions appear because I said there is a med pattern PET sometimes. And sometimes the diffuse infiltration is so high that you don’t see the focal lesions under this diffuse infiltration. And if the diffuse infiltration goes away it could be possible that focal lesions appear which have been there earlier but you haven’t seen them because there was this high diffuse infiltration. This is very rare but even this can be told by experience and good radiologist and they should be trained to see myeloma or at least hematological diseases because it’s quite difficult. There’s another thing to mention especially in young patients. A young person as I mentioned already has a higher cellularity in bone marrow without myeloma and we did comparison with how he controls and the young patients looke like an older patient with the diffuse infiltration, but it was just a physiological hematolysis - the bone marrow producing the cells which is higher in younger patient and younger controls. It’s also tricky to really look into this diffuse infiltration. We are working on functional techniques which can really measure the cellularity but still you cannot differentiate if it’s just a lot of plasma cells or just a lot of healthy bone marrow cells. So this is still a topic to be addressed.

Jenny: It’s so fascinating and we’re going to keep you late if you don’t mind. I hope that the callers will hold on with us too. But you and your paper you were talking also about different therapies. The patients were on the variety of therapy. Is it giving you any indication about which therapy might be more effective?

Dr. Hillengass: Not beyond the point where we already know that some therapies are more effective than others where more effective in serological markers are also more effective in imaging. So it’s not really additional information we get out of the imaging concerning the depths of response. What is interesting is if we have residual lesions, it might be that if patient is in a serological CR, no M spike, no light chains in urine, no free light chains, maybe not even in plasma cells and bone marrow anymore but if there are still focal lesions outside the pelvis where you do the biopsy to confirm the complete response, it could be that those focal lesions are still relevant and could be the source of relapse later on. And this is also a important topic we are aiming to answer in this formally mentioned study on the CT guided biopsy. We will do it again, a CT guided biopsy, if we have residual lesions after therapy in our patients and see if there are still myeloma cells in there and maybe those patient would benefit from a maintenance therapy or a local therapy or whatever. And we cannot do this in one step but this would be topics to be addressed in the future and we do this CT guided study and we are really grateful that our patients are accepting this study and they are contributing by being available for the CT guided biopsies.

Jenny: A follow up question to that is would it be helpful because you’re specifically studying MRIs, would it be helpful at all if patients around the United States or other countries just sent you copies of their MRIs. Or do you really need to do it in a more -- in clinic in Germany or whatever?

Dr. Hillengass: That's true. The problem with that is that in Germany the ethical and the data security agencies are very strict, which I find quite good. And for us, it’s not just getting a CT from a patient but then doing an examination. And furthermore the techniques are different sometimes a little bit at least. The scanners are different maybe there’s another sequence of MRI when we do it. So at the moment we are doing mostly examining our own patients because we have a lot of patients - number is not a problem it’s rather time and the money to pay a radiologist to do the examination with thousands of MRI images. But not a lot of radiologists who are willing to sit there hours and hours and to the evaluation but we are working on this and we have really motivated colleagues. What we are aiming for and we already discussed this with colleagues from other countries and also from the U.S. to do an examination in our patients and then use this for example, the score as you mentioned earlier in the paper and put it on another group of patients in another clinic. For example in the US or in France, we discussed with colleagues from France from the US, from Greece so other colleagues having MRIs of myeloma patient at the same time with clinical information then we send them our results and they look to see if those results really are the same in their cohort. And this is very important but I think it’s more important to do this within big centers and if the patients are willing to get their imaging results reviewed they should go to a myeloma center. As you mentioned, I think it’s important that at least once in his or her career of myeloma bein a myeloma patient everyone should have been seen really and myeloma doctors specialized in myeloma treatment because it’s so complex. It’s so complex to have both imaging techniques those cytogenetic results. It’s really complex to do myeloma. I’m doing only myeloma, I will not treat any other tumor at the moment because I’m not specialized in this and I think myeloma is so complex that we really should aim to have specialists for myeloma.

Jenny: I’m such a huge advocate for that and so are all the patient advocates that I partner with. Because there is this too much, you just can’t know enough about that. I mean you think about the complexity that you’re trying to deal with even just do this genetic features match up with what we are seeing on the MRI with match up with like a high LDH level and maybe a low albumin level and something like that. And you just think, wow just too much for my one brain to figure out, it’s very complex and we strongly advocate all the time, that you need to see a myeloma specialist. You can always get treated, your weekly infusions or monthly infusion or somewhere else.

Dr. Hillengass: Most private practice doctors are very motivated to send the patient once and get some advice and then they do a very good job of course. This is not saying that the private practice doctors are not good enough for myeloma, but as you mentioned it’s so complex and we can help each other. I would never question what they decide, but I can give advice from experience with a lot of myeloma patients and I think this is very, very important to my knowledge and to my experience. A lot of private practice doctors are really happy to collaborate and to say okay, this is my patient what would you do. And then I say this is what I would do and then they decide and they come to a good decision overall and I think the collaboration is very very important and we cannot treat every myeloma patient it’s just too much. But we can support those people who are doing the work there.

Jenny: Well, I want to open in up for caller question just so we have time to do that. So let me say that if you have a question for Dr. Hillengass you can call 347-637-2631 and press 1 on your keypad. And we also have some emailed in questions. So we’ll start with our first caller .

Caller: Good morning Jenny. Good morning Dr. Hillengass. I’m so very happy to speak to you today. I’m a smoldering multiple myeloma patient. So I have a bunch of questions that I hope you’ll be able to answer for me. I guess my first one I want to start out with is related to MRI reports in general. Are we looking for the term “related to marrow signal” within the report that being within normal limits versus a diffuse signal or terms like focal lesion? What would signify to us that we have an abnormal MRI reading related to myeloma? What terms do the radiologists use?

Dr. Hillengass: Very good question. I think it’s important for patients to know what to look for. It’s still difficult and we just discussed how difficult it can be to treat myeloma and to diagnose myeloma but I absolutely recommend that you look for those as I say those specific words. And I would say “focal lesion” is one important word and of course this “diffuse infiltration”. I think “signal intensity” can be misleading because it can say everything and nothing but most important is focal lesion and diffuse infiltration. But even there you have to be cautious because sometimes a diffuse infiltration if it’s not a very experienced radiologist or if he or she does not have the proper information, it might seem like a diffuse infiltration but it’s just an increased cellularity because of an over activation of bone marrow. So sometimes we get patients referred to us with “multiple myeloma?” because of diffuse infiltration which is not true if you put a needle in it (e.g. bone marrow biopsy). It’s just a normal activated for example by inflammation, by infection, by whatever activated bone marrow. So focal lesions should be quite differentiating but also there could focal lesions which are just hemangiomas which are benign tumors without any significance. So look for focal lesions, look for diffuse infiltration, but do not be shocked if there is something written like this. Let your doctor look at it and see if it’s really a myeloma related focal lesion or if it’s, as I said, a hemangioma or whatever. I talk a lot to smoldering myeloma patients and MGUS patients who bring me their results and say “There is osteolysis in my MRI” which is not true because MRI does not show the bone. So there could not be an osteolysis in the MRI. So it’s quite difficult. Look for focal lesions, look for this infiltration but do not get shocked when there is written something like this. Just ask your doctor “Is it really a myeloma focal lesions or is it something else? Is it really diffuse infiltration by myeloma or is it something else?”

Caller: And would a direct biopsy of something that’s suspicious be the best way to seal the deal to more or less determine, if it is or not?

Dr. Hillengass: Yes it would be but a lot of regions in the body, you don’t want to reach by needle and sometimes it’s just better to do another MRI three months later.

Caller: That’s a good point. Which regions would you avoid? Which region would you not want to do that on?

Dr. Hillengass: Of course the upper spine. Of course the radiologist will not do it, because they know it’s too dangerous for the patient because the information you get out of it could be good but it also could be worthless. So you would not put your patient, as a radiologist or hematologist, in danger to get in information you maybe can acquire by something else. If it’s really suspicious, if something depends on it, if you would treat your patient because of this lesion alone, you should out a needle to confirm its myeloma and if not just repeat the MRI three or six months later because myeloma is not growing very fast in most cases. So you can just repeat the imaging and if the lesions stay the same, it’s not that malignant of course. So we do the MRI and follow-up and see if there is growth then we say okay it’s malignant there is growth, this is cancer but if not we just keep calm and try to tell the patient to be calm as well.

Caller: I know Dr. Landgren has stated that osteolytic lesions are a complication of the disease in the marrow. So it makes so much sense to look at the marrow for the myeloma activity. If the focal lesions or the diffuse infiltration, for a smoldering patient, is actually related to myeloma, will this always lead to osteolytic bone lesions?

Dr. Hillengass: This is an excellent question and I would love to answer it correctly - I don’t know. We are doing a prospective trial at the moment where we put as many smoldering patient as possible into the study and do an MRI every 6 months for years as long as it takes.  And then if there is some pain or something else going on then we do a CT and if there is an osteolysis we will see. In several patients over the years, I have seen some patients starting with the focal lesion in MRI then going on and then developing an osteolysis but this is just several patients, it’s not research, it’s not a study. Now we are doing a prospective study and I know that Ola Landgren also does these studies and we will see I think in a few months or years, if this is true. I think not every focal lesions will lead to an osteolysis because at a certain point when you have the first osteolysis you will treat the patient and those focal lesions will not hopefully will not go on to become osteolysis. But we are looking into that and this is a very, very important question.

Caller: Very good. Dr. Hillengass, are MRIs adequate for smoldering patients or do we need to also have PET-CT scans or skeletal surveys? Say for instance we had a skeletal survey and it was clean but we did get an MRI. Is that enough or do we need to go on to that next PET-CT scan to really rule out myeloma?

Dr. Hillengass: At the moment there is no scientific paper out saying that PET-CT is beneficial for smoldering patients. So the information to get out of the PET-CT, you could think if a PET lesion is positive and I know of some results, if there are PET avid or PET positive lesions in a smoldering patient there seems to be some kind of activity. And if the only chance to get a CT for you is to have a PET-CT, I would recommend it of course because the CT part for the mineralized bone is very, very sensitive. So if you have a good CT from the PET-CT you will still have an additional information to the MRI because as I mentioned in MRI you don’t see the bone itself, just the bone marrow. The first step for me would be an MRI and if it’s negative maybe you don’t need anything else, but on the other hand, some very small focal lesions are visible in CT and not in MRI and this is the reason why we do at the moment we do CT plus MRI at first diagnosis and then for follow up to spare radiation, we do MRIs once a year.

Caller: That sounds like a very good protocol and skeletal surveys really are not very sensitive from what I understand you need to have 30 to 50% percent or cortical bone already destroyed before it picks it up. So a low-dose whole body CT would make sense. And I think you did state that no contrast was needed for that and it’s two to three times more radiation than whole body x-rays?

Dr. Hillengass: Correct.

Caller: Okay. But much more sensitive.

Dr. Hillengass: Yes.

Caller: Wonderful.

Dr. Hillengass: You get more information on stability on the back part of the vertebral bodies which are very important for stability for neurological complications. We absolutely recommend low dose CT and at the moment we are working to change the guidelines in the International Myeloma Working Group, to change from skeletal survey to low-dose CT.

Caller: Oh yes, to make that the gold standard as opposed to the rusty standard of skeletal survey. Now, Dr. Hillengass do we need to have our MRIs with the gadolinium contrast or can we do this without gad?

Dr. Hillengass: We can. Usually we do it without. If there is a suspicious lesion maybe it could be helpful to use contrast but in really absolutely most patients, it’s not necessary to use gadolinium DGPA as contrast agent in myeloma.

Caller: Provided you have a good radiology group who is familiar with the myeloma process and is actually reading and interpreting. Okay, so that makes sense as well. As as smoldering patient do we actually need whole body MRI? They’re very difficult to find. I mean, I haven’t had one, I’ve only had MRIs of my full spine and pelvis. Do I need a whole body MRI? Am I missing out on something?

Dr. Hillengass: Yes, not very much. We have compared our whole body MRIs with spinal and pelvic MRI as you get and we found out that in 100 patients and in 10 of those 100 patients we found it was symptomatic and smoldering mixed and we found in 10 out of 100 patients that there were focal lesions outside the spine and pelvis. So 90% are inside in spine and pelvis and you also get this diffuse infiltration out of the information from the spine and pelvis. So, if you only have access to spine and pelvis it is okay. It’s not very much that you miss when you don’t do it as a whole body protocol.

Caller: Can you explain what diffusion weigted imaging is? Is that a technique that is superior to if there is such a thing as a regular MRI. I’m not quite sure of the different technologies? But I heard about the Diffusion Weighted Imaging?

Dr. Hillengass: Yes, very good. This is a very nice. It’s just another sequence another setting of the MRIs scanner to get this diffusion weighted imaging. You don’t need contrast agent, it’s just measuring the movement of water molecules in the tissue. And if you have a lot of cells like high cellularity, like in myeloma, you have small ways those molecules can go because there are a lot of cell membranes which are lipophilic, which contain fat, and the water cannot mix with fat. So the Diffusion Weighted Imaging is based on this fact that water molecules cannot move that far if there are a lot of cells and with fewer cells they can move further. There are some pitfalls with DWI with the Diffusion Weighted Imaging but we are working on this and I know that other colleagues are also working on it and I think it might at least an additional technique maybe even in the future the only technique because it is faster compared to conventional MRI and it gets a higher contrast because the focal lesions are very well visible. We do it in our whole body protocol as one part of the total protocol and we get a lot of good information out of it. The radiologists like it because it looks a little bit like a PET and our radiologists call it the poor man’s PET because you just do it in the MRI and you don’t need contrast agent, you don’t need PET tracer and so it might be the technique of the future, but it can just be implemented into the MRI protocol - it’s just part of the MRI protocol.

Caller: Great because my most recent one actually had that integrated into it and I never had one prior to it, so I was very happy to see that. What about the combined PET-MRI scanners that I’ve been hearing about. Is that the future?

Dr. Hillengass: I hope so. They’re very fancy toys of course. Radiologist love them and we as well because. The important thing is that you have this high sensitivity for the diffusing filtration I mentioned earlier from the MRI part but you also get the information on vital cells on disease activity on metabolism from the PET part. So PET-MRI is very rare, I know there were not very many scanners around the world at the moment. We have one and the images are amazing. The problem is that you don’t get information on the bone. So we are back to CT.

Caller: Oh that’s right.

Dr. Hillengass: So this is the problem we like the PET-MRI very much but we still need the CT.

Caller: We as patients are going to be stuck with CTs. Okay. Well that’s too bad. I’m looking to eradicate the radiation as much as I can. Dr. Hillengass can you detect age-related osteoporosis via MRI, X-rays or CT.

Dr. Hillengass: We cannot detect it but we can to a certain degree differentiate it. As I mentioned earlier if you have high cellularity you will have different display in the MRI and with high cellularity, meaning mostly malignant infiltration, and if very low cellularity and the high fat content which it normal in all patients - if you have high fat content then it’s rather a benign cause of the osteoporosis. To a certain degree you can differentiate between benign and malignant osteoporosis. It’s not absolute. You cannot it’s always, but it’s another piece of information you can get and then you do the bone marrow biopsy and get the information of the plasma cell content to see the M spike and so on. And if you have the whole picture, MRI adds additional information.

Caller: Yes, the whole picture is critical. I know sometimes we as patients focus on the numbers, our charts, and our trends and we really need to just remember that it’s whole picture that really will push us into the treatment zone. Dr. Hillengass, I can’t thank you enough for taking all of my questions it really truly has been a pleasure. My take away from this as a smoldering patient is that we deserve more advanced imaging and just skeletal surveys. And I encourage that within my own Facebook group to patients to push for that. Because it is not easy for smoldering patients to really get adequate testing especially within the community local settings. You know with the myeloma specialist, it’s a different story. They know, they know emerging data, they know the emerging info and they are willing to do that.

Dr. Hillengass: And maybe they have easier access of course to modern imaging. The big centers have more scanners, more scanning time, more radiologists. This is not the bad will of the doctors.

Caller: Exactly, it’s no fault of their own, it’s just the limitations. It’s just the limitation of their own practice. To not know and understand the nuances of this disease as certainly you do. I mean this is proof and to hear someone like yourself discuss the imaging and to take the time to respond all of my questions my personal questions as well as questions that I ask in behalf of the smoldering community. So I myself, I appreciate it very much and I could probably spend another hour asking you more. I certainly don’t want to use up all of Jenny’s time so with that I thank you both very, very much for taking my question and thank you Dr. Hillengass for doing this amazing work on behalf of all myeloma patients.

Dr. Hillengass: Thank you so much.

Jenny: Thank you for your questions and for your answers. And we have just five more minutes before the show closes. But I do have some several write in questions. So one patient says, I was diagnosed was no lesions. So my doctor said I was the luckiest unlucky myeloma patient because my disease has progressed. So could I have diffuse lesions and not know it?

Dr. Hillengass: I can’t answer this. You can have lesions without knowing it of course. But I think the most important thing is that you can have myeloma without seeing lesions in MRI. Because there’s always a limitation of the sensitivity of those techniques, so if you don’t see anything in bone marrow, in PET, in MRI in cytogenetics, wherever, it’s just a limitation of the technique. No technique is really absolute. Even in minimal residual disease measurement, there’s no zero, of course. There’s just a degree of depths of response and the same is true for imaging. If we don’t see lesions, it does not say they are not there. They might be too small, they might be too dim. So, it could be that you have lesions, but on the other hand we found in our patients where we just looked that the radiologist didn’t know if the patient had myeloma or smoldering or MGUS. They just looked at the image and said, “Okay, there is a focal lesion or there is no focal lesion or there’s a number of focal lesions” and we found that if you don’t see focal lesions it a good prognostic factor. Why? It’s not clear maybe because the tumor mass is slow and you have been caught early in the course of the disease and then an early treatment might be beneficial for this and there might be an answer to that.

Jenny: Well she is lucky then, that’s good.

Dr. Hillengass: Yes, maybe hopefully.

Jenny: The last question and you may have covered some of this but what is a minimum imaging requirements a newly diagnosed patients should requests or demand from their doctors? That’s our final question.

Dr. Hillengass: So from the guidelines, it’s at least an X-ray plus an MRI at least of the spine and pelvis for the first diagnosis better than the X-ray is CT. But this is not in the guidelines yet. It is now allowed to do a CT or PET-CT to diagnose osteolysis and you will find earlier, or smaller osteolysis of course because of the higher sensitivity. The guidelines at the moment say skeletal survey plus MRI of spine and pelvis at first diagnosis and I think this is good. CT plus MRI of spine and pelvis is even better CT plus whole body, MRI is even more better and a PET-CT is also very good. I think it depends very much where you will leave, what the access is, or what you can have. So the minimal requirement is skeletal survey plus MRI of pelvis and spine.

Jenny: Well perfect. Dr. Hillengass we are so grateful that you took time to talk to us today. I think I’m going go talk to my radiologist because of our conversation. I’ll give them some work to do. But I think it’s so helpful for patients, especially newly diagnosed patients to know what they should be asking for and why it matters and use to explain that in really excellent ways. So we’re just very, very grateful that you took the time and we’re very thankful that you have patience with our technology.

Dr. Hillengass: Thank you very much, it was my pleasure and my honor and I like your work very much. I found your homepage, your website, before we got in touch. I like it very much. It’s really, really important work you do because we researchers cannot do anything without the help of the patients because we have to examine patients to learn. And so you are also very, very helpful and very supportive and I could have done no study at all without the help of my patients and still are very grateful. I’m very grateful for the patients who are willing to support the research. They have benefit but we also have a benefit because we learn more about this this disease. Thank you also.

Jenny: We are just so happy that such smart people are working on this for us and we are thankful that you dedicated your life to multiple myeloma. We’re just so intensely grateful for it. Anyway we are just so thankful.

Dr. Hillengass: Thank you.

Jenny: Thank you for listening to Myeloma Crowd Radio. We believe that patients can help accelerate the discovery of a cure and we encourage you to become involved in part of the process.