Dr. Nooka shares some surprising statistics about the number of people living with smoldering myeloma, that it could be as large as 400,000 whereas only 25,000 new myeloma cases are diagnosed per year. He notes that risk-stratifying smoldering myeloma patients is key to finding the best outcomes. He describes how he diagnoses and approaches treatment for a smoldering myeloma patient and shares that today's risk stratification in smoldering myeloma is based today on three key clinical features and not on genetic features. Dr. Nooka describes a new vaccine by OncoPep now being used in early clinical trials with lenalidomide for smoldering myeloma patients. The vaccine targets three proteins including CD138, CS1 and XBP1 and participants have to be tested as HLA2 positive. He explains the difference between preventative vaccines and treatment vaccines and suggests that the tumor burden has to be low in order for them to work. He notes that using lenalidomide in addition to the vaccine appears to boost the immune system and give the vaccine greater impact. The Myeloma Crowd Radio Show with Dr. Nooka

Jenny: Welcome to today's episode of Myeloma Crowd Radio, formerly mPatient Myeloma Radio, a show that connects patients with myeloma researchers. You can find all past and future shows on myelomacrowd.org and if you'd like to receive a weekly email about past and upcoming interviews, as well as weekly articles on the Myeloma Crowd, you can subscribe to our newsletter on the homepage, or you can follow us there on Facebook or Twitter. Now, we're excited to announce that we have officially launched our Myeloma Crowd Research Initiative for high-risk myeloma and investigators are submitting proposals throughout the month of February. We have an expert team of myeloma specialists on our scientific advisory board that will help validate and select the projects. For the first time, a group of myeloma patients will be involved in making the final selection of projects that we believe together are the most promising. We chose high-risk myeloma because today's options don't give extended life expectancy like they do for standard risk patients, and we think that if we can find solutions for the most aggressive types of myeloma, it will help even standard or low-risk myeloma patients. We think it's time for a new way of funding research. Now, on today's show, we are delighted to have Dr. Ajay Nooka of Emory Winship Cancer Institute with us today to talk about smoldering myeloma and newer approaches to stop myeloma before it gets started. Dr. Nooka, welcome to the program.

Dr. Nooka: Thank you very much, Jennifer. I'm really honored to be on your show and speak to the myeloma patients. I probably will start with my perspective on the magnitude of the problem with smoldering myeloma in United States.

Jenny: Okay. Well, before you do that, let me give a quick introduction for you just so people know who you are and what you work on. Dr. Ajay Nooka is Assistant Professor of Hematology and Medical Oncology at Emory University School of Medicine and is part of the Hematology Care Team at the Winship Cancer Institute of Emory University. Dr. Nooka attended medical school at the Andhra Medical College in India. He earned his masters degree in public health at the University of Texas, School of Public Health, and then he went on to complete his residency in Canton, Ohio. He did a fellowship at Emory. His research interests include integrating genomic and clinical data on a uniform platform to interpret in a meaningful way to risk-stratify myeloma patients and evaluate newer therapies aimed at prolonging survival. He serves on the editorial board for The American Journal of Clinical Oncology, Journal of Hematological Malignancies, Lymphoma and Chronic Lymphocytic Leukemias, and is an ad-hoc reviewer for the Annals of Oncology, Cancer, Oncology, Leukemia Research, Bone Marrow Transplantation, Biology of Blood and Marrow Transplantation, European Journal of Cancer, Current-Oncology, and Indian Journal of Medical Research. He's also the recipient of many awards including awards from the MMRF, the IMF, ASCO, the Fellowship of American College of Physicians, and the Frederick C. Whittier Excellence in Research Award in Canton and the Rochfort Scholarship, in addition to many more. Dr. Nooka, thank you so much for joining us today, and please go ahead with what you wanted to start out with in smoldering myeloma.

Dr. Nooka: Thanks very much, Jennifer. I'd like to take some time about what we're dealing with in terms of the magnitude of the problem in the United States. I'd like to start with simple numbers. If you take multiple myeloma, which is the second most common hematological malignancy, it accounts for probably 25,000 new cases per year in the United States. Now, let's take the prevalence of smoldering myeloma. I think we'll start with a small map. Take the US population today, which is approximately 300 million. If you see who are the patients who are more common to have smoldering multiple myeloma or any plasma cell dyscrasia, it's about the age of 65, so 15% of the population are about the age of 65, which makes it 15% of 300 million, which is 45 million people that are aged more than 65. Among these people, it's not uncommon to see the presence of a monoclonal protein in approximately 5%, so 5% of 45 million people are approximately 2.5 million people. If you take these 2.5 million people by the most conservative estimate, if 15% of these patients have smoldering multiple myeloma, it makes around 400,000 patients with smoldering multiple myeloma and only 25,000 new cases of myeloma are diagnosed every year.

Jenny: Wow! So people just don't know.

Dr. Nooka: Exactly. It's very essential to risk-stratify the smoldering myeloma patients and to identify those who are at a high risk for transformation and focus on this group, aiming at preventing the disease progression to symptomatic myeloma. That would be the best way to gain the best outcomes. The simple definitions of smoldering myeloma and symptomatic myeloma are essential to understand for better clarity. Basically, the defining criteria for symptomatic myeloma are an exhibition of end-organ damage as defined by the CRAB criteria. The mnemonic CRAB criteria stand for high calcium levels, renal failure, anemia, bone lesions. These, as a result of the clonal expansion, would be called a symptomatic myeloma. The absence of any of these CRAB criteria, patients presenting with the monoclonal protein due to clonal process are defined to have either an MGUS, which is monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. The differentiation is basically based on the disease burden. Smoldering multiple myeloma is defined as a serum M-spike of greater than or equal to 3g/dL, or greater than or equal to 10% monoclonal plasma cells in the bone marrow biopsy or both. So coming to the definition of MGUS, it is defined as having no CRAB criteria and less than 10% plasma cells in the marrow and less than 3g/dL of M protein. Historically and even today, both these precursor conditions are managed by the wait-and-watch approach. The good thing, which is really encouraging, is that in the recent days, there has been a push towards treating certain groups of the smoldering myeloma patients even without the presence of the CRAB criteria. These changes are reflected mostly in the recent changes by the definition from the International Myeloma Working Group. This is very welcoming for smoldering myeloma patients. The new definition of smoldering myeloma includes any patient with bone marrow plasma cells of 10% to 60% or M-spike of greater than or equal to 3g/dL or urine protein equal to or greater than half a gram of protein over a 24-hour period, which of course changes the definition of symptomatic myeloma. So now, the new definition of symptomatic myeloma in the absence of CRAB criteria include patients with bone marrow plasma cells of greater than 60% or equal to 60%, serum free light chain ratio of greater than or equal to 100, or presence of more than one focal lesion on the MRI. A few words on the biology, why does this happen? The transformation from a monoclonal gammopathy of undetermined significance to myeloma in my opinion is a disease-continuum process, so it starts with MGUS, proceeds to smoldering multiple myeloma, proceeds to symptomatic multiple myeloma. There are certain initiating genetic events that lead to transformation of a plasma cell to a malignant cell by acquiring certain chromosomal translocations involving the immunoglobulin heavy chain loci. These typically involve the IGH locus of chromosome 14. These are present on all the clones. Whenever there is this transformation, these are present in all -- these changes that I've seen are present on all the clones.

Jenny: I asked one doctor if you could kill it somehow in a set of clones. He said, "No. They're on every single cell."

Dr. Nooka: Yes, that's true, so these subsequent hits, the other transformations happen only in a certain set of clones that basically have -- they're more evolved. They have high proliferation rate. These are the ones where the secondary chromosomal changes happen, which typically have a proliferative advantage and have the potential to cause the progression of the disease. A few examples of such changes are point mutations of the NRAS or KRAS, or makeup revelations. All these things can call the second heads and that'll also correlate with the disease progression.

Jenny: Can I ask you a quick question about that? I know that you're testing with the FISH and sometimes the GEP, and you said you were doing RNA sequencing with finding some of these translocations. What test do you use to test for the NRAS and the KRAS?

Dr. Nooka: Right now, it's more from -- we don't do the GEP at this point, but it's more of looking at the RNA sequencing to look for any of these mutations.

Jenny: Okay. Sorry to interrupt you.

Dr. Nooka: Not a problem. I'll go with how I typically diagnose or typically what my overall strategy for a smoldering clinical trial -- a smoldering myeloma patient is. Initially, the first thing is to establish the diagnosis. In a smoldering myeloma patient, what I typically do is to proceed with a baseline bone marrow exam, get a skeletal survey, and I'll have a very less threshold to obtain an MRI of the spine and the pelvis because there can be occult lesions that can be seen that would change the whole diagnosis. I would have less threshold to obtain a PET/CT if that is needed, if I have high suspicion for any PET-avid lesions. There have been multiple trials before that had shown that any identification of any of these lesions by these imaging techniques can predict for a more rapid progression to multiple myeloma. Once the diagnosis is made, what's the next step? The next step is to go with the risk stratification as we just talked about, all these numbers of around 300,000 to 400,000 smoldering myeloma patients and among them, only a certain subset of them transformed to symptomatic myeloma very rapidly. How do you identify these patients? That's typically based on the available risk stratifications.

Jenny: And those are really clinical presentations, right? It's not like you're looking at do you have certain translocations or gene deletions. You're looking at what you're seeing on the lab results.

Dr. Nooka: Typically, these are based on the lab results. I'll speak in a bit about the role of any of these cytogenetic abnormalities like translocation (4;14) with smoldering, should they be treated or not. I strongly encourage my patients to go on to clinical trials when they're exhibiting any of these abnormalities, these new chromosomal abnormalities, including the translocations. In terms of the risk stratification based on the clinical parameters, there are only two more commonly accepted ones, one is the Spanish risk stratification, which is called PETHEMA Risk Stratification and the other one is the Mayo Clinic Risk Stratification. The more accepted one in the United States is the Mayo Clinic Risk Stratification, which typically takes three factors into consideration. All these three are based on the disease burden. The first one is the disease burden or the magnitude of the M-spike, so if it's greater than 3g/dL or less than 3g/dL. The second one is the plasma cell burden in the bone marrow biopsy, so whether it's greater than 10% plasma cells or not. The third one is the abnormal free light chain ratio, which also defines the magnitude of the clone. If the patient has one risk factor, it's classified as low risk smoldering myeloma. These patients typically have median time to progression to symptomatic myeloma of ten years. That means a 50% chance of converting it to ten years. There are two risk factors that are considered as moderate risk. The median time to progression is five years. If they have all three risk factors, the median time to progression is 1.9 years. So for those patients that are either more or greater high risk, I do recommend for this patient the clinical trials and treating early.

Jenny: Can I ask about that? So the M-spike, the plasma cell burden, and then what are you looking for in the free light chain ratio?

Dr. Nooka: Whether it is abnormal or not, so all the clinical trials that were done previously have shown that abnormality in this free light chain ratio defines the clone. So this free light chain assay is an assay that we've been using since 2007 or 2008. What it does is it measures the kappa and lambda light chains that circulate unbound to the heavy chain and in the serum. A normal ratio is defined between 0.26 to 1.65, and in the presence of a clonal disorder in myeloma, there is excess of production of one specific type like involved immunoglobulins.

Jenny: Like IgG or IgA or something.

Dr. Nooka: This is a free light chain, free kappa or free lambda.

Jenny: Oh, the kappa -- okay.

Dr. Nooka: Since it's defined as a kappa by lambda ratio, if it's a kappa involved immunoglobulin, the ratio is pushed to the right. If it's a lambda, it's pushed to the left, so it's more about the magnitude of a clone. What these current criteria do not take into consideration is exactly what you pointed out. It does not take the biology of the disease or the genetics into consideration, which is currently being proposed to be included in the high risk smoldering myeloma definitions. That's how I would go with the diagnosis. I'd go with the risk stratification and typically encourage patients who fall into moderate to high-risk smoldering myeloma to participate in the trials with good mechanisms of action. In regards to follow-up like how often do I follow these patients, initially I would obtain the restaging labs to be done every few months, around two to three months for the first year to confirm the stability of the protein, and then slowly extend the interval by every four to six months for the next year. If the paraprotein has remained stable, not budging, I eventually would do every 6 to 12-month follow-ups once clinical stability is established.

Jenny: It seems like there are a lot of new approaches in smoldering myeloma because I think you're all looking at it and saying, "Why are we waiting to treat this disease?" if someone is high risk and if someone has a very good indication that they will progress because like you said earlier, it's this continuum or progression.

Dr. Nooka: Sure. This is an area where I'm very much interested in and I strongly take pride in. One of the things that I've been working with is OncoPep. OncoPep is a therapeutic vaccine which is a -- it's actually to restrict tetrapeptide. It's a tetrapeptide of three known antigens, which are expressed in malignant plasma cells. The antigens are CD138, CS1, and XBP1. The trial basically was started with this vaccine, which is PVX-410 with the objective to determine the tolerability of a single agent. When you're talking about a phase one trial, your primary endpoint is always the safety and tolerability. What happened in this specific trial was adults with smoldering multiple myeloma who are considered moderate or high risk with more than two risk factors, as we spoke about from the Mayo Clinic Stratification, these patients, if they're HLA-A2 restricted, HLA-A2 positive, they were eligible to go under this trial.

Jenny: Can I ask a question about that first? So HLA testing is usually used when you're going to do an allotransplant and you have to see if someone's a match. Can you explain HLA just briefly and then explain why you need to be tested for that to participate in this clinical trial?

Dr. Nooka: Sure. HLA is also called the human leukocyte antigen. In simple words, just like how we have the blood groups, the white cells have this group called the HLA, the human leukocyte antigen system, so this peptide is specifically made for the HLA-A2 patients, which are probably around 60% of the Caucasians and 40% of the African-Americans.

Jenny: I didn't know that. Okay. And then this peptide is targeting these three proteins like the CS1, the CD38, and the XBP1. That's what it's targeting?

Dr. Nooka: That is correct. The XBP1, all these three are antigens that are very commonly expressed on the malignant plasma cells. So anytime you're talking about a cancer vaccine, basically -- I'll give you the idea of what a cancer vaccine is. It's based on the premise that the cancers have the ability to avoid the immune surveillance and the cancers develop as a result of the failure of mounting and effective immune response against the cancer cells.

Jenny: So they're not attacking it.

Dr. Nooka: Yes. By using a cancer vaccine at any time, you're retraining the immune system to recognize these cancer cells and trying to stop them from growing. A therapeutic vaccine like the PVX-410 that targets the tumor antigens of CD138, CS1, XBP1 has the potential to stimulate the immune system to tag the myeloma cells and at the same time, not interfering with the healthy cells.

Jenny: So that’s huge.

Dr. Nooka: So the goal is to elicit the tumor specific immune response and use a long-term, durable remission. About this specific vaccine, this was developed at Dana-Farber Cancer Institute by Nikhil Munshi's group. It was tested on the myeloma cells in vitro where this peptide cocktail elicited an immune response to target specific antigens on the myeloma cells. Moving forward in the phase one trial as we just spoke about where the goal of a phase one trial is to look at the safety and tolerability, the results for the recently presented American Society of Hematology Annual Meeting in December of 2014, a total of 12 patients were enrolled. The first three patients on this trial, the low dose of 0.4 mg was administered and once we'd feel the safety signal, the dose escalation was made to double the dose to 0.8 mg and then additional nine patients were enrolled. How do we look for the immune monitoring? There's an assay called the ELISPOT assay, whether all the patients were obtaining an immunological response is what's measured. These results were amazing in that all the 12 patients responded to at least one peptide at any time point.

Jenny: So when you say they responded to one peptide, are you checking all three, the CD138, CS1, and XBP1? So are you looking at all three to see a response or not?

Dr. Nooka: In each patient, these three immune responses were measured. The XBP1, as we talked about, two peptides of XBP1 on the first one, which was an unspliced version. It was seen on 9 of the 12 patients. In the spliced version, it was seen in 8 of the 12, and with the CD138, it was seen on 5 of 12. The last one, the CS1, it was seen in two of the nine patients, but I think at least three samples were not shared for logistic reasons. So every patient that was enrolled on the study had at least one peptide response, responded to at least one peptide at one time point.

Jenny: Wow.

Dr. Nooka: So currently, the trial has been expanded to a second arm. Again, this is a phase one where the patients are receiving the PVX-410 along with the adjuvant and lenalidomide, which is an immunomodulator, to augment the immune response.

Jenny: So now, this is still in phase one trials though or have you moved on to phase two?

Dr. Nooka: This is still in the phase one trial. The phase one trial was tested as a single agent first then we went down to test the phase one trial in combination with lenalidomide.

Jenny: Because lenalidomide was used -- I know by the Spanish group at first -- to try to prevent progression in smoldering patients, so now you're just combining the two?

Dr. Nooka: It's not only for that reason. It's more to augment the immune response. The trial that you talked about was one of the trials that we've talked about, and this was basically from the Spanish group that's called the PETHEMA Group where at one point, I think they randomized all the smoldering patients to lenalidomide and dexamethasone for some observation. The patients who were under the lenalidomide arm were given the same dose as we're giving it, 25 mg on days 1 to 21, every 28 days, along with dexamethasone 40 mg weekly. They gave it for nine cycles and then they stopped the dexamethasone and went on to lenalidomide at 10 mg as maintenance for another two years. Again, the primary endpoint for that trial, for the PETHEMA trial, was progression to symptomatic disease. The study met its endpoint and the three-year overall survival rate was much higher than the three-point group with 94% of the patients alive over the three-year mark for the lenalidomide and dexamethasone, and patients who are on observation, 80% were alive at the three-year mark. It was a good study with a positive endpoint. There were a lot of deficiencies in the studies. In that particular study, from what I believe, one of the things is there was no role for any MRI or a PET/CT that was done on this particular study, which means a patient could have symptomatic myeloma and still went down to the observation arm. It is just that they have not been looked carefully for enough consideration, so that is the main criticism for particular study. The second one is that also explains for the high mortality that is seen. At our institution, our five-year survival rate in a myeloma patient is greater than 80%. Here, for a smoldering multiple myeloma patient with three-year survival of 80% and the observation arm is very less, in my opinion. Besides, there were some adverse events that were seen in at least 40% of the patients that were enrolled on the trial, on the treatment arm. These were more related to the dexamethasone, so there's a new trial from the ECOG, which is the Eastern Cooperative Group, using only lenalidomide for observation and they're continuing it until the patient is progressing, so there is no early stopping. There is no fixed duration. It is given continuously.

Jenny: And I think the exciting part about using a vaccine is that you're able to use something that doesn't affect the healthy cells. Now, if you're using lenalidomide with it, you can boost everything. Maybe you can explain -- well, I guess in simple terms -- how it goes about leveraging the immune system and then maybe explain how it's given. What are the steps? How often do you give the shots and things like that?

Dr. Nooka: Sure. At the 0.8 mg dose -- I'll go with the dosing and schedule first, so what we're giving with the PVX, and I'll go with the comparison with the normal vaccine. So the patient currently receives 0.8 mg of PVX for a total of six shots for a ten-week duration. The lenalidomide was given for three cycles. Each cycle is 28 days long, days 1 to 21 on and one week off. Lenalidomide is orally administered and PVX is given as a shot. That is the schedule. In terms of how it leverages the immune system, the vaccine, the therapeutic vaccine serves very different than the preventive vaccines. I'll give you an example of any of these infectious vaccines that we talk about. The traditional preventive vaccines are administered to prevent the disease. They're not used to treat an existing disease unlike the therapeutic vaccine. That's the main way or the indication for a therapeutic vaccine or the main difference. There are certain challenges with the cancer vaccines over a long period and it's an ongoing challenge for many of the tumorologists that the immune system finds difficulty in distinguishing cancer cells from the normal cells because the cancer cells also carry the normal self antigens along with the tumor-associated antigens. What the tumor also does is it sends these signals to suppress immune responses and it evades the immune system. So all of these are consistent challenges with any of these therapeutic vaccines over a period of time and it was one of the main reasons why they have not made a huge progress until recently when we're seeing all these responses.

Jenny: Yes. It seems like there's a big boom in cancer vaccines. It's in myeloma, but it's elsewhere, too, so that's really, really exciting.

Dr. Nooka: Sure.

Jenny: So patients go in for six shots over ten weeks, you said?

Dr. Nooka: That is correct. Each vaccine is two weeks apart, so it's given over a period of ten weeks.

Jenny: Okay. That makes sense. I know in smoldering myeloma, sometimes it might be a challenge to find results because smoldering myeloma doesn't progress as fast. I know sometimes people have been hesitant to run smoldering myeloma trials because they think, "Oh gosh, the outcome could be years before we see if this works or doesn't work." But it seems that if you choose the high-risk smoldering myeloma patients that are close to progressing or would be progressing regardless, then you can get study results within a reasonable time frame. Is that how it's set up? What do you expect for your results? Because it seems like so far, you've got really promising results.

Dr. Nooka: Sure. As you've mentioned, it's always a challenge to run a clinical trial among patients who have to be followed over a prolonged period of time. What we're looking here is we're looking for the safety and the efficacy signal in the high-risk smoldering myeloma patients, which in the phase one trial, we're able to obtain that safety trial and the efficacy signaled by the immune correlatives were already seen. So in the future, it can be extended to other smoldering myeloma patients once it shows good efficacy results for the trials.

Jenny: Do patients ever need booster shots after that one set of shots?

Dr. Nooka: It's a great question. I think right now in this phase one trial, the trial is the -- we're testing the safety of the combination of the PVX and lenalidomide, which we had seen. In this current trial, there is no plan for the booster dosing, but eventually if the immune responses are failing over a period of time, it's worth considering booster shots.

Jenny: Well, one step at a time, right? You have to decide if it's safe first and then how much you give and then does it work, and it looks like it's working, so that's very exciting.

Dr. Nooka: Sure.

Jenny: I have a question for you. If it's working in smoldering myeloma patients, would a trial like this be considered for patients who are -- let's say they're MRD-positive, but their disease doesn't seem to be progressing at all. I know patients in that group sometimes, or who are in remission and don't want progressio, feel a little left out, that there aren't a lot of clinical trials open for them to do something that's preventative. Is this something that you think could be used for that in the future once it's been through all the testing or that's just not a reasonable study to put together?

Dr. Nooka: Absolutely true. If I have to use in a symptomatic patient a vaccine, that's probably the right place to start. I think at this point, the vaccine is being construed in an adjuvant setting, in a post-transplant setting with immune correlative cells of endpoints. I think you're absolutely right. That's a place where you had the lowest levels of disease burden and there's a potential for the vaccine to show efficacy and good responses.

Jenny: I've heard other people say the cancer vaccines that are therapeutic versus preventative should be used when there is a low tumor burden, like you just said, and not when there's a high tumor burden. Can you explain why that is? It just can't get it all or it's just not strong enough?

Dr. Nooka: I'll give you an example from an allogeneic transplant standpoint. For the body to mount an immune response, it takes time. In the meantime, you do not want the biology of the disease to take over and the disease being so aggressive. I think for the immune response to happen over a period of time, you need the disease to be controlled during the time and which can happen only in a setting where you have the lowest level of disease.

Jenny: Okay. Well, that makes sense.

Dr. Nooka: Does that make sense?

Jenny: Yes, that does. It does make sense. When you say it takes time to mount an immune response, how long does that take usually?

Dr. Nooka: It's over a period of weeks to months. Our assumption is we do not -- if the value of the disease is bad, we won't have that window for the immune response to take place.

Jenny: Right, because your disease is out of control anyway. You need something harder like a transplant or something like that to knock it down.

Dr. Nooka: That is correct. Some other form of therapy.

Jenny: Well, this sounds like a very exciting clinical trial. Is there anything that you would like to describe about the trial before I ask you about some of your other studies?

Dr. Nooka: Sure. In terms of the tolerability of this trial, the vaccine is very well tolerated with the adverse event that we had seen as a single agent or in combination with the lenalidomide. The results of the vaccine in combination with the lenalidomide are not out yet. But as a single agent what we had seen were all less than grade two and not significant. The more common adverse events are accumulated within the first two days after the dose and they had local reactions like chills, fatigue, and edema. They're the more common reactions I could expect from any vaccine.

Jenny: Yes. That's pretty typical of vaccines. Well, it sounds like it's promising and there's not a lot of downside to it, so I think it would be an exciting approach for smoldering patients.

Dr. Nooka: That's true.

Jenny: Now, I wanted to just spend a few minutes and we have several caller questions that I want to be able to get to, but you have other studies that you're working on, and some I was not familiar with and some I was. Is there anything in particular that you would like to share with us about other clinical trials that you're running?

Dr. Nooka: There's one phase one trial that we have, which is very interesting. In a sense, it's like a p97 inhibitor for symptomatic myeloma patients. P97 is considered a master control of the protein degradation pathways, so inhibiting this p97 would lead to inhibition of the protein degradation and polyubiquitinated accumulation and subsequently the myeloma cell death. This is a phase one study. There are currently two cohorts that are completed, cohort one with three patients with a lower dose, a second cohort with a much higher dose. All the six patients did very well and we got a great safety signal, so we're going on with the cohort three at a higher dose, so that is one trial, which is very promising.

Jenny: What's that one called? I have several numbers and I don't know which one that might be.

Dr. Nooka: It's CD5083, the CLC trial. There are others which I'm collaborating with the City of Hope in Washington University. One of them is Ixazomib with pom and dex. This is again in refractory multiple myeloma patients. Ixazomib is an oral proteasome inhibitor. It's evaluated in combination with pomalidomide and dexamethasone again in relapsed/refractory myeloma patients. Based on this oral regimen and based on the available data, this combination definitely has a potential for efficacy.

Jenny: Okay, and they just some good results recently about Ixazomib.

Dr. Nooka: That is correct. The presentations at ASH 2014 were pretty impressive. The main reason for this particular study is we know that there's a good synergy between an immunomodulator as well as a proteasome inhibitor. Having an all oral therapy would prevent doctor visits and would have a good efficacious agent as an oral combination treatment, so that's what all of us would be looking for.

Jenny: Well, that makes life much easier for myeloma patients, not to have to be in the clinic for all the infusions, if possible. And if not, we still go, but it's better to have oral. Well, Dr. Nooka, I would like to open it up for our caller questions, if that's okay with you. I know several people have questions. Well, my last question, you mentioned earlier that for smoldering patients, a lot of times, you recommend clinical trials. Can you describe the importance of clinical trials for you and how it helps you in your research?

Dr. Nooka: Sure. I think in my personal opinion, we cannot advance without clinical trials. What has ever been done in myeloma is because of the participation of patients in clinical trials. I always remember one great saying from Judah Folkman, who talked about it at one point that if humans were mice, we could have cured cancer. So what is happening outside the body is entirely different than what happens in vivo. What appears to be a promise in the cell lines in the xenograft models, that compound have no effect and it's vice versa. What shows at model to not work well may have an extremely effective. It's essential for all of us to recognize that without the clinical trial with human participation, we will never be able to make any progress that we'll need for myeloma so far. We have a strong respect for the patients and families that have participated in the clinical trials, and we strongly urge patients to participate in clinical trials that would eventually give the best outcomes.

Jenny: Well, I agree. You've extended life, but we still don't have a cure, so we need to move forward. I'm in agreement there. All right. Well, let me open it up for our first caller question. Caller, go ahead with your question.

Caller: My name is Linda and my question is this, a definition of what you consider to be smoldering. My doctor now tells me I returned to a smoldering state, but I am a post-transplant. I also did the evolution clinical trial. In 2008, I entered active treatment, but in 1991, the Mayo Clinic missed my diagnosis. Clearly all the components were there, which is clearly recognized by my doctor. And so, I was smoldering for at least 19 years and possibly way more than that because I've had blood count problems since 1976 following an injection, which I received way, way back when they thought I had a brain tumor of a mercury component, which I believe had a great demise for me. I really have trouble with this number of smoldering. Is there a place for a vaccine for somebody who now has reentered a smoldering state after treatment?

Dr. Nooka: Thanks for the question. I don't think we have any trials open for exactly suiting your clinical criteria for a smoldering state. I'll clarify for the other listeners what Linda means by smoldering state after she received the transplant. It's not uncommon for us to see a measure of small amount of protein after they finished their induction treatment, a consolidation treatment. Still you're seeing a small amount of paraprotein of around one gram or less than that. It shows stability over a period of time. For example, after two years, three years, it is not moving any longer. You're not on any treatment. It is not uncommon to call it that you had gone to your smoldering state where you are before all this diagnosis has happened. That is what Linda means by going to a smoldering state. In the absence of the stability over -- having seen the stability over 19 years, if it's not changing anything, I would not do anything different than what you're doing now with observation.

Caller: Well, the 19 years was -- 19 years ago -- well, it was 19 years that the Mayo Clinic did not catch the diagnosis even though it was all clearly there. All the factors were there clearly recognized by my oncologist, but in 2008, I entered active treatment, but I still have a question that if I return because my M-spike protein reaches 0.8, then why would it be that I could spend 19, 20 years at 1.62, which is double that amount and live a normal, healthy life other than some strange-looking blood counts? Why would you jump back into treatment?

Dr. Nooka: I'm sorry. I did not understand the question. If you have entered the state where it is smoldering, I would not recommend any treatment at this point unless you're showing --

Caller: I've been off treatment for about two or three years because I've been doing fine, but if I go back to a point that the statistics show that I'm supposed to go back into treatment, but my question was if following the misdiagnosis by the Mayo Clinic where I was at 1.62, which is double the amount of the 0.8 that would lead back into treatment, why do we look at numbers like that and say, "Go back into treatment," when I spent 19 years of having a good life?

Dr. Nooka: Your question basically points to the same thing that we talked about. It's not just the magnitude or the size of the paraprotein that should decide on the treatment options. It's the biology of the disease, how bad is the clone that we're dealing with. Is this a dormant clone that doesn't need to be monitored like it's staying stable compared to something else, which is extremely aggressive where I would recommend immediate treatment? At this point, I think staying off treatment and being on observation with the stability that you're saying is what I would recommend.

Caller: Yes. I've never had any bone involvement.

Dr. Nooka: That's good.

Caller: So do you see vaccines coming along for people like us who would like to stamp out this thing once and for all?

Dr. Nooka: Eventually, yes. If it's showing the same responses that we are seeing and if it is confirmed with the lenalidomide to augment the responses, it would be nice. I think talking about drug development, it's a tedious process. It takes a long time for it to be FDA approved. Probably on an average, each drug takes eight years from a phase one to its approval.

Caller: Eight years from now?

Jenny: It's a long process.

Dr. Nooka: Not this vaccine, but a typical drug. Who knows? We might see some great activity and it could go for an unexpected approval and probably would be available much sooner.

Caller: I second your idea of the clinical trials and just like to state that I did the evolution clinical trial and it knocked all those numbers down, so thank you for your work.

Dr. Nooka: Congratulations, Linda.

Jenny: Thank you very much for your question. Okay. We'll take another caller. Go ahead with your question.

Caller: Yes, doctor. Thank you for an excellent presentation. I had a question about your time to progression for the three criteria, especially the Mayo Clinic on smoldering. I'm a kappa light chain guy. I've been smoldering for a few years of free light chain issue that we watch, but you mentioned the three criteria, the magnitude of the M-spike, the plasma cell burden, and the free light chain. For those of us that are worried about our free light chain, once it goes over a hundred, which mine has recently and we're doing a bone marrow biopsy, let's say it goes to 200, is that indicative of a potentially imminent renal failure and the need to jump into treatment? If I followed your one-risk, two-risk, three-risk category, that would still say if you only have one of those three, you could potentially still smolder for quite a while, so how difficult is the renal environment so to speak for the high light chain people?

Dr. Nooka: This is a great question. Basically, in the previous trials, in the previous IMWG, International Myeloma Working Group's criteria, they did not include this 100 mg as a criteria. It was recently included. The way that I look at it is the stability of these free light chains. If your free light chain ratio is 150 and you had it for seven years, that is way different than somebody who had a ratio of 50 last month and 150 this month. That's where a clinical decision and following the history over a period of time makes a huge impact on the decision making. Why is the free light chain ratio -- why was it included? It was based on a lot of trials showing that the free light chain ratio of at least 100 is a predictor for progression in smoldering multiple myeloma, so that is one of the reasons it was shown by the Greek group. It was shown by multiple other groups basically that free light chain ratio of at least 100 had almost progressed in a year and a half. That's where all this comes from, but because you were not a smoldering myeloma in September, in October, the new guidelines came. Should we change everything and should you get started on treatment? I don't think so. You probably need to be followed for some more time and see where your protein is progressing. If it is not, if it remains stable, I would continue to watch.

Caller: I understand. Thank you.

Jenny: Okay. Thanks so much for your question. Caller, please go ahead with your question.

Caller: Hi, Jenny! This is Gary Peterson. How are you?

Jenny: Hi, Gary!

Caller: Yes, doctor, excellent presentation so far. I had recently interviewed Dr. Ghobrial from Dana-Farber and one of the things that she said was that it's not really watch-and-wait. It's watch-and-worry, and that's why she was working so hard to come up with a method, but yours sounds very interesting as well, which is to have a vaccine along with Revlimid, which is what the Spanish group used. My question to you is this. There are 400,000 people who are high risk -- or not high risk -- are smoldering according to your definition. One question, would 15% of those smoldering patients be considered high-risk? Is it the same percentage of patients who are smoldering high risk as a symptomatic high risk?

Dr. Nooka: To address your question, basically, the abnormal free light chain ratio is what was considered as one of the criteria for the smoldering myeloma. So if you look at the numbers, in the smoldering myeloma group, approximately 60% to 70% of them have abnormal free light chains, but the definition of an abnormal free light chain, which is in the Mayo Clinic, is considered anything about -- the ratio of about 0.8 or less than 0.125. So with that criteria, what percentage among the 400,000 patients would be in that -- it's difficult to estimate, but it would not be greater than 30%. That's my estimate. Does that answer your question, Gary?

Caller: Well, that would fit in to the high risk category, would be 30%. So 30% of 400,000, that would be 120,000, which is a lot of people. Now, my next question, which kind of follows that, would be at your facility -- and that's only your facility -- of all your patients, what percentage are smoldering?

Dr. Nooka: Around 15% are smoldering, which also explains for the referral bios for one reason that if not all mine is a specialist center so it typically -- if somebody is smoldering, there might come one time and they go back to their treating physician for a follow-up. What we do is give an opinion, so that probably might explain for why there could be a lesser number of smoldering patients that are seen, but when --

Caller: What I'm trying to understand to some degree -- and it's something that Jenny said earlier, which hit home for me, she said that of the smoldering patients that are out there, most of them have no clue that they're smoldering, given what you just said. Now, say you're wrong by 100% and it's really 30% of your patients, well, 25,000 patients a year you said are diagnosed, correct?

Dr. Nooka: Correct.

Caller: So 30% of that would be about 7500. So 7500 of -- what did we say it was -- 120,000, so we're not catching a whole heck of a lot of these folks that are going to turn into active myeloma patients in two years. How do we change that math?

Dr. Nooka: I think what you're asking is a question that I always encourage and always want more screening about. As I've mentioned, it's a continuing process. It has to go from MGUS to the smoldering state to myeloma. Every single portion goes through that. The rate at which they go differs, so it depends on the primary initiating events. It depends on the secondary hits and at what point it takes place. I would not differentiate how many patients were diagnosed at de novo myeloma versus diagnosed from a symptomatic myeloma. Every patient develops symptomatic myeloma and there's data to show that from the NIH. In the past, they had around 76,000 patients in NIH who gave monthly blood samples. I think it's three monthly blood samples over a period of time for ten years or so. When they started looking back at how many patients got myeloma, they found around 71 patients had myeloma among their group. They had the blood samples for the last ten years, so they went back to the blood samples of all these 70 patients and found that the majority of the patients had this diagnosed almost ten years ago. Eighty percent of them were able to show their protein lingering, so it is not something that happens over a month or over a year. It has been going on for a period of time. The point I'm bringing up from this discussion is every myeloma is preceded by a smoldering myeloma, is preceded by an MGUS. So how do we identify all these patients or all these 300,000 or 400,000 patients existing that have a potential for converting to symptomatic myeloma is the biggest question. It comes with some caveats. If you find a lot of MGUS patients, it is only giving them worry because all you're saying is a small protein and that statistically will not have a chance of converting to symptomatic myeloma in their lifetime, and they're living with this constant fear of when, so that is the biggest caveat that comes along when we're trying to aggressively screen for the smoldering myeloma patients.

Jenny: That's a catch 22 thing.

Caller: Yeah, but the same thing would hold true with breast cancer and/or colon cancer, lung cancer or anything else, is that yeah, you go in and you get a mammogram. You find out you have a tumor and breast cancer. For example, my wife had DCIS. Well, it's removed and there's 100% chance in five years she's going to be alive. Now, for some reason, you don't do that test. You don't get a mammogram and you find it when it's large, malignant, and one that has metastasized, you have a 22% chance of living five years. I think what you're saying is that if you attack it early, like all other cancers -- and why wouldn't it be that way -- that you have a high probability of success because the clones haven't developed and its resistance to drugs haven't developed. And all those things, those same reasons that they have such success with colon and breast cancer could happen with our cancer, but our issue is we've got to find it first. People will deal with the 1% chance if they got MGUS if in fact they get screened. So I guess my point is that we should be going for mass screening because the results of what you're doing are earth-shattering for the potential of success for smoldering patients who would progress. That would be my point.

Dr. Nooka: Sure. I completely agree with that. Going back to your question of why we screen for the colon cancer or the breast cancer, yes, we have a tool to address it. There is a surgical tool and probably everybody gets -- when somebody gets diagnosed with DCIS, you go and treat it with surgery. Now, at this point as of today, even if I'm diagnosed with all these patients who fall into the smoldering myeloma, we're not doing anything outside the context of a clinical trial, so that would be the biggest difference between what's happening with the breast cancer and what's happening with myeloma. Eventually, if there's a vaccine or if we find a tool that would address the plasma cell dysplasia from progressing to symptomatic myeloma, yes, I would strongly encourage everybody to go with the mass screening and diagnose all these patients and do the necessary to hold off on the transformation.

Caller: Thank you, doctor, so much. I think you are on your way, as is Dr. Ghobrial. You're at the tip of the spear as far as I'm concerned.

Dr. Nooka: Thank you.

Jenny: Thanks for your question, Gary. Dr. Nooka, do you have time for one more short question?

Dr. Nooka: Sure.

Jenny: Okay. Our next caller, go ahead with your question.

Caller: Hi! Good afternoon, Dr. Nooka. I'm a smoldering multiple myeloma patient. I'm actually sitting here and I'm astounded by the numbers that you're sharing about the potential smoldering multiple myeloma patients, 400,000. I'm sitting here dumbfounded because I have a Facebook group for smoldering multiple myeloma patients and we have a tiny little part of the 400,000. We're about 250 members strong, so I'm really just astounded by that. I just wanted to make an additional point, I guess carrying through what Gary had just said. I understand the caveats with mass screening, but I'm sitting here thinking that not providing screening would prevent many of these smoldering patients who don't know they're smoldering from actually engaging in some of these early clinical smoldering trials, so I just really wanted to make that point, and then I do have a few questions for you, please. You did explain that therapeutic vaccines are very different from preventative vaccines. And I believe in multiple myeloma patients and likely smoldering patients, we have impaired responses to vaccines, just in general, flu, pneumonia vaccine as we begin to lose our immune responses to childhood diseases in vaccines just due to the natural aging process, and I would imagine with myeloma, this is an added assault to this process. So would that in and of itself be the case with this peptide vaccine? I'm going back to your PVX vaccine. Would the response that we make be limited as a result of this?

Dr. Nooka: That's a great question. I don't think anybody knows the answer to this. We make a general statement that in myeloma patients, the responses are limited, but again, that's a general statement. It is not backed by a huge amount of data. So coming back to our data, we have seen immune responses in at least one peptide in every single patient that we have treated with a single agent. So by adding Revlimid, we probably would be augmenting the same immune response and we probably could find most of them, so that's the hope.

Caller: I see. Okay. So the Revlimid is to augment the immune response. Does it also knock the disease back a bit?

Dr. Nooka: That is correct.

Caller: So it has like a double duty factor to that?

Dr. Nooka: That is correct.

Caller: Great! I realized the inclusion criteria for the PVX trial is irrespective of cytogenetics and it does include the Mayo guidelines, the free light chain ratio outside of the normal range of 0.26 to 1.65. I find from my own monitoring that my free light chain ratio is prone to bounce around from test cycle to test cycle, so should the trend of the ratio be important to consider to participate in this trial or is any one given test result enough to meet the inclusion criteria?

Dr. Nooka: It should be the trend -- as with any clinical trial, it's more the screening criteria that make the difference. For example, if the free light chain involved -- if it's kappa, if the involved is 30 and the free lambda is 1, at one point, the ratio is 30, and the second time you do it with another machine, if it comes out with -- then the ratio is 3, it does not mean that you have an abnormal free light chain ratio. It is a problem with the testing. Unfortunately, with repeated testing, you probably will know where exactly you fall into. If you have an abnormal free light chain ratio and have a big amount of paraprotein and have plasma cells greater than 10%, if you fit in to two or three criteria, you will qualify for the trial.

Caller: Okay. Are patients' cytogenetics still tested for, for research purposes to determine if this can be effective for all disease subtypes? I know that it's probably not shared with the patient, but are you guys collecting that information?

Dr. Nooka: Yes. We collect the patient's cytogenetic information on every patient. We collect them for our research purpose. We do RNA sequencing on all the new patients and longitudinal testing on all the patients that relapsed.

Caller: Is the information shared with the patient from the trial, from this research?

Dr. Nooka: From this research, we have not done it on all the samples. The problem at this point is there are so many mutations that we're seeing. We didn't know which one is the causative mutation and which one is the passenger mutation, so it is very difficult with the data mining, with all these sequencing. But once we find some information that will be useful, we'd be happy to share it.

Caller: Are there any plans to modify the vaccine so those without that specific HLA typing can participate?

Dr. Nooka: Yes, Ma’am. That's what's currently being worked on.

Caller: Very good. Oh, that's very --

Jenny: That would be great.

Caller: How long will the patients be followed for and how? Is it just the ELISPOT testing for continued immune response or are there other diagnostics being used?

Dr. Nooka: Currently, it's the ELISPOT spot assay that's being used and typically they followed every three months. The assays are done while they're receiving the vaccine, but the immunological studies are done every three months.

Caller: So they'd be really long-term until they progress, if that's the case, right? So that's the plan?

Dr. Nooka: Yeah. The patients are following up with us, so we continue to get the data. We will have the data until the study is closed.

Caller: Wonderful! That's a wonderful approach. Would short-term Revlimid use exclude any of us from future trials, many of which have treatment naïve criteria? Is that something that we need to be concerned about?

Dr. Nooka: That's a great question. This came up in the discussion and we have made it very clear that this should not exclude anybody in the future for any clinical trials at the time of the progression.

Caller: Wonderful! Dr. Nooka, thank you so very much for your time. I appreciate you taking all of my questions and very best luck to you. We do share the trial information within our smoldering group and we are all keeping our fingers crossed for something like this to work for us, so thank you.

Dr. Nooka: Sure. You have a great afternoon.

Jenny: Dr. Nooka, thank you so much. Thank you so much, everyone, for your excellent questions. Dr. Nooka, thank you so much for joining us today. You gave an excellent description for us that was wonderful about the criteria for smoldering myeloma, probably the most thorough I've heard to date, and the vaccine sounds very, very exciting.

Dr. Nooka: Thanks, Jennifer. Thanks for having me on the show.

Jenny: Well, thank you so much for joining us today. We appreciate all you do for all myeloma patients. Thank you for listening to another episode of innovation in Myeloma. Join us for our next Myeloma Crowd Radio interview as we learn more about how we as patients can help drive to a cure by joining clinical trials.