Muhamed Baljevic, MD

University of Nebraska

Interview Date: May 28, 2018

Many patients' myeloma can become resistant to an important class of drugs use for myeloma care - proteasome inhibitors. Most patients (70%) will respond to these drugs as single therapies but some patients can be resistant initially. Researchers at MD Anderson Cancer Center and the University of Nebraska found that expression of a gene called MUC20 could help predict how sensitive or resistant patients would be to proteasome inhibitors. They also found that the MUC20 protein could be potentially impacted by an already FDA-approved drug offered by Amgen called cabozantinib. 

Dr. Baljevic shares a clinical trial using cabozantinib with carfilzomib for patients who have become refractory (resistant) to carfilzomib. The study is open at the University of Nebraska and MD Anderson Cancer Center. Cabozantinib has shown the ability to reverse the resistance to proteasome inhibitors. 

Thanks to our episode sponsor, Celgene Corporation

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, Celgene Corporation, for their support of Myeloma Crowd Radio. Now before we begin our show, I'd like to remind everyone that we are launching a new product to help myeloma patients optimize their care, find the best treatment options, find and understand more about clinical trials, track their labs if they want to, see collective reporting about our myeloma experience while at the same time helping myeloma researchers advance a cure for us. That product is called HealthTree. We're launching that this summer. We have a 50+ city tour happening that you can go to www.myelomacrowd.org/healthtree and find the locations that we have so far. You can keep watching that page because we will continue to add locations that we'll be coming to over the summer. So watch for that on that page and in our newsletter. We are so excited about this project.

Now, today we have an important show to discuss. we are talking about proteasome inhibitors. In a lot of situations, myeloma patients become resistant to proteasome inhibitors. I had the pleasure of meeting Dr. Muhamed Baljevic at a meeting recently. We started talking about his research. It became clear that I really wanted to have him on the show.

Dr. Baljevic, I am so happy that you're joining us today. I would like to welcome you to the program.

Dr. Baljevic: Thank you very much. It's such a pleasure to be part of your show and to communicate with your listeners.

Jenny: Well, let me introduce you before we get started. Dr. Baljevic is an Assistant Professor of Medicine in the Division of Hematology and Oncology, the Department of Internal Medicine at the University of Nebraska. Dr. Baljevic moved to Doha, Qatar on an academic scholarship in 2001 where he completed secondary, undergraduate and medical education. He was the first student of the Qatar campus to take a year off of medical studies to perform medical research, having worked at the Ansary Center for Stem Cell Therapeutics at Weill Cornell Medical College in New York. In parallel to his fellowship, he pursued a Master's Degree in Clinical and Translational Research at the Graduate School of Biomedical Sciences at the University of Texas. He has been a recipient of many scholarships, honors and awards, most recently the 2014 Celgene Future Leaders in Hematology Award for Clinical Research and the 2015 ASCO/AACR Workshop on Methods in Clinical Cancer Research. He has contributed to publications in prestigious journals including Nature Medicine, Cancer Cell, the Journal of Clinical Investigation, Circulation Research, Hematology/Oncology Clinics of North America, and several chapters by invitation.

Dr. Baljevic, we're so happy that you're here. Let's get started.

Dr. Baljevic: Well, thank you very much again, Jenny. Please allow me the opportunity to thank you personally for such a wonderful work that you do. As you mentioned, we had the chance to meet and discuss several important topics when it comes to multiple myeloma and patient care. It became really clear to me the quality of work that you do and the platform that you are establishing for all of our myeloma patients. The access which they have through those platforms is really invaluable. So as a provider, as a physician who focuses on the care of these patients, I truly just want to thank you for such an important and wonderful work that you do.

Jenny: Wow, thank you for saying that. My goal is to just help as many patients as possible understand how to get the best care because it really would make hundreds of different or maybe even thousands of years of life with all of us collectively. Thank you.

Dr. Baljevic: Of course, certainly.

Jenny: So maybe we begin by you providing an overview of just in general about proteasome inhibitors because some patients may be really familiar with them and some may be not, and why there's such an important class of drugs in myeloma therapy.

Dr. Baljevic: Of course. Well, proteasome inhibitors are really considered the cornerstone medications and drugs that we use in the management of all phases of multiple myeloma virtually in all of our patients including those who are eventually eligible, for instance, for transplantation as well as those who are not eligible for a variety of reasons for stem cell transplantation. It’s been since the introduction of the proteasome inhibitors into clinical practice and particularly their combinations with other anti-myeloma agents, such as immunomodulatory agents such as thalidomide, for example, or lenalidomide that the outcomes for myeloma patients have changed drastically with survivals that previously were in only several years which have now increased to ten years or more.

We are at a particularly exciting time when it comes to multiple myeloma in the development of new therapeutic options. Even though that is not the topic of today's discussion, development of immune-based therapies is promising to change the landscape and outcome of multiple myeloma patients even more. When it comes to proteasome inhibitors, the first proteasome inhibitor that was approved for use in humans was bortezomib or Velcade with the mechanism of action that is reversible, and bortezomib in reversible manner inhibits chymotrypsin-like activity of the 26S proteasome subunit leading to activation of signaling cascades, cell cycle arrest and apoptosis. It was introduced and FDA approved first in 2003. It was subsequently approved for use in myeloma patients with newly diagnosed disease in 2008. In 2014, it was approved for use in those patients who have been in remission for six months or longer on bortezomib-based therapy.

Subsequent to that, we had the development of second generation proteasome inhibitor, carfilzomib or Kyprolis. The mechanism of action of this proteasome inhibitor is irreversible. Carfilzomib is a very potent selective irreversible inhibitor of chymotrypsin-like activity of the 20S proteasome subunit. The FDA approved Kyprolis or carfilzomib in 2012 for use in patients with myeloma who were treated with two lines of therapy including bortezomib and an IMiD such as lenalidomide.

Lastly, we have witnessed the arrival of the first oral proteasome inhibitor in the therapeutic arena for multiple myeloma. The name is ixazomib, or Ninlaro. The mechanism of action is reversible inhibition of the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome. As I mentioned, ixazomib is really the first oral proteasome inhibitor. This is particularly exciting because it allowed for tailoring of the oral regimens for myeloma patients.

Now, when it comes to some of the similarities or differences between these three proteasome inhibitors, ixazomib is an oral agent whereas bortezomib and carfilzomib are administered either subcutaneously in the case of bortezomib or intravenously in the case of carfilzomib.  Specifically, bortezomib and ixazomib are peptide boronates, and carfilzomib is epoxyketone. Peptide boronates work by reversibly inhibiting the beta subunit of the proteasome apparatus and epoxyketone is by conscious irreversibly inhibit the proteasome by covalently bonding to the beta subunits. Ixazomib also has more rapid on and rapid off pharmacology that makes it more specific than bortezomib to tumor cells, and as a result potentially having an improved therapeutic index. The big advantage here of carfilzomib, I might add, which as I mentioned is irreversible epoxyketone inhibitor over the boronates type inhibitor such as bortezomib and ixazomib appears to be really the potency of the drug. Of particular note, carfilzomib really only rarely produces neuropathy.

These are just in general some of the proteasome inhibitors that we have available to us. There's a number of other proteasome inhibitors such as oprozomib which is another oral agent that are being developed in early phase clinical trials. Marizomib is another one. It's a beta-lactone inhibitor. These, however, have not garnered FDA approval yet and are still in the investigational stages.

Jenny: In general, I've heard that proteasome inhibitor is described as like a garbage disposal for these proteins. They all in general kind of are doing the same thing, but what you're saying is there are three currently approved ones. They are different drugs. They're not the same drug.

Dr. Baljevic: Correct, absolutely. Our cells really rely on a particular order inside them. Proteasome inhibitors affect the settler machinery that essentially deals with degraded and misfolded proteins in our cells. This is a very complex process that happens on a continuous basis, and in particular this balance in the management unfolding and sort of cleanup of all of these proteins in the cell can really lead to, in cases of use of these inhibitors, it really leads to accumulation of variety of these cluttering proteins which receives the signals for apoptosis and cell death because of the disorganized disarray

Jenny: So it is an important process in the body and in myeloma it kind of gets tweaked a bit.

Dr. Baljevic: Absolutely. As I mentioned, the proteasome inhibition and the entire system of proteasome chaperones that manage all of these misfolded proteins is really one of the key targets of myeloma therapies. We use proteasome inhibitors in all patients at a variety of stages: newly diagnosed myeloma and particularly in the relapse refractory setting where we are testing a variety of new drugs. I don't really think that the outcomes of multiple myeloma patients that we're seeing these days would have been possible without the development of this class of medications.

Jenny: Right. I think it's really important that we have these different classes and medications. The immunotherapies, like you said earlier, are just additive to this. So we could be using kind of everything. Once we have new drugs in place, it's not necessarily like they'll take the place of somebody's drugs. You might be administering them in different orders and things, but it's great to have this type of arsenal against myeloma.

Dr. Baljevic: Absolutely. I might add that we are really privileged in a sense to have a lot of different therapeutic options available in multiple myeloma for the treatment and management of this disease for all of our patients. If we really take a look at the last 10 to 15 years in terms of regulatory approvals for the new agents, I would add that perhaps only lung cancer rivals the field of multiple myeloma in terms of not just the sheer number of agents that have been approved but also the classes and different classes of agents, different classes of drugs that are available that are targeting myeloma from a variety of angles.

Myeloma is not really like some other cancers. Myeloma really depends on concomitant targeting and drugging a variety of spots in the myeloma cells that are responsible for maintaining myeloma life and myeloma replication and the tumor burden. So targeting this disease at the same time variety of agents which hold a variety of different mechanisms of actions has really been developed as a very important paradigm in this disease. Newer immunotherapies in drugs such as daratumumab, for example, have somewhat shifted that paradigm with really groundbreaking results in the single agent setting. Of course, we're also witnessing very important responses in the CAR T cell area of the immune therapies. Nonetheless, at this point in time, really all of our management strategies are relying on combinatorial therapies rather than single agent therapies in multiple myeloma.

Jenny: Right. That's because so many myeloma patients have so many different types of clones. You're trying to just get it all at the get-go.

Dr. Baljevic: Absolutely.

Jenny: No part of that clone grows up and takes over.

Dr. Baljevic: Absolutely. This is sometimes confusing to patients because there's monoclonal term and  many sort of different aspects of this disease. While it certainly explains very well where variety of protein perhaps might be coming, a number of studies over the years have really demonstrated that even though a bulk of tumor burden in myeloma is responsible from a single clone, myeloma indeed is a top malignancy with a variety of different subclones which are present in subclinical amounts. It is really during the therapy and subsequent therapies and the months and years sometimes of management of this disease that this balance between these different subclones is shifted, and then the clinical behavior of the disease changes leading to a variety of problems that may encounter particularly in patients who stop responding to treatments and start developing resistances.

This led us to really start focusing on the area of proteasome inhibitor resistance namely because as we mentioned, proteasome inhibitor is such an important cornerstone of all myeloma therapies and any effort that we can apply in understanding a variety of different mechanisms of resistance and any strategies that we can develop in fighting all those problems can really lead to not only prolonged use of these agents but hopefully improve disease outcomes long term.

Jenny: Yes, totally. So you mentioned problems with proteasome inhibitor resistance. Is it common? I think it's pretty common for myeloma patients to become resistant at some point. Do you have any idea of percentages of how many patients over time become resistant? And then also is resistance consistent across the various proteasome inhibitors? Do you get more resistance on one or the other?

Dr. Baljevic: Well, it's difficult to say with certainty. However, some of the available studies have indicated that approximately 70% of myeloma patients are unable to achieve complete or partial remission with single agent bortezomib induction therapy. This suggests that in these cases, the bulk of the tumor comprises of inherently bortezomib resistant malignant plasma cells (for 30% of patients). Of course, we don't use bortezomib as a single agent in any induction therapy, but nonetheless the development of this drug over the years has yielded these very important insights.

In terms of resistance being consistent across the various PIs, I wouldn't say so. We have learned from clinical experience that generation proteasome inhibitor such as carfilzomib are more efficacious than all the generations PI such as bortezomib. In fact, during the clinical development and if we look at the regulatory approvals, really the carfilzomib is reserved for situations where patients progress on bortezomib-based therapies. In some sense, these problems can be considered sequential in nature. However, given the variety of different ways that proteasome inhibitor resistance can develop and variety of different points in the federal regulations where the proteasome inhibitor resistance can become really a major problem, it really depends what we're dealing with. It also depends what type of extrinsic influencers we have namely the type of therapy that the patients are receiving and the selective pressures the variety of therapies are exerting on some of those sub-populations of myeloma cells.

Jenny: Another follow-up question to that I guess is you mentioned being kind of intrinsically resistant if you're saying only 70% can with a single agent, if you're using a single agent, which, of course, you don't do typically. But it kind of gives you a clue that some people are just resistant from the get-go. How many patients are intrinsically resistant versus they acquire resistance over time?

Dr. Baljevic: Clinical course of multiple myeloma disease itself really teaches us that almost all patients invariably progress on standard regimens that we treat them with and bortezomib, for example, is really one of the basic proteasome inhibitors that we use in combination with other drugs in both stem cell eligible and stem cell transplant ineligible patients. This demonstrates to us that the acquired resistance, if it's not present at the beginning, will invariably develop in all patients. Development of this acquired resistance is variable as I mentioned and dependent on many factors. Some are intrinsic to myeloma cells and some are external factors such as type of therapy that we're applying, treatment delays, for example, treatment dosing of the drugs themselves.

The problem here is that there is no clinically validated tool to predict or screen those patients, as you mentioned, who are predicted to have this intrinsic meaning resistance at the beginning of the disease to these forms of drugs, and therefore predisposing these patients to particularly inferior outcomes from the very get-go. So this is a challenge at the moment. When we decide to start treatment, we treat everybody empirically with proteasome inhibitors. We have no assay that can tell us any particular patient may be predicted to have either inferior response to proteasome inhibitors or maybe predicted altogether to be completely resistant.

So our treatment strategies and our management strategies do not, unfortunately, rely at this point in time on any information up front the very diagnosis to tell us if we should perhaps adjust the way we treat a variety of these patients that are predicted to have intrinsic resistance.

Jenny: Wouldn't that be amazing if that happened?

Dr. Baljevic: Absolutely.

Jenny: I can just imagine how much it would just be so fabulous.

Dr. Baljevic: Absolutely. This is really not an effort that we're trying to do in multiple myeloma, but if you look across the spectrum of variety of different malignancies, this is really the effort of the 21st century where we are trying to generate tailored, patient-specific therapies for every patient based on their disease, based on their features, based on their performance status and such. All of these parameters are really essential in our efforts to try to cheat multiple myeloma in the best way possible from the very diagnosis.

Jenny: Yes, I agree. I think that's why we wanted to create this HealthTree product too is to help identify which treatments are working for which patients and then how do we see that. That's amazing.

Dr. Baljevic: Absolutely. That's why I mentioned it's so important really the effort that you're doing because it's very important, and we really live in a globalized times and society where information is really readily available. Sometimes it can be overwhelming and we see this all the time with patients who just sometimes have too much information to process. It becomes a challenge trying to extract what is valuable, what is useful, and what is applicable at any particular point in time. So again, really the efforts of your platform as well as efforts of other groups are really essential in trying to simplify things and point the patients in the right direction and point them to focus on the relevant questions with their providers.

Jenny: Right, absolutely. Well, let's talk a little bit about your research because you have found something that can indicate something that might be related to proteasome inhibitors. I read a little bit about this MUC20 expression. So maybe you want to explain what that is and why it might be a good biomarker and what its function is.

Dr. Baljevic: Absolutely. May I add first that this, in fact, is a project that has been started many years ago in the laboratory of Dr. Robert Orlowski at MD Anderson Cancer Center. I was really just privileged and fortunate to receive training and to receive many, many valuable lessons in the care of multiple myeloma patients under the mentorship of Dr. Orlowski during my time at MD Anderson Cancer Center, during my fellowship training. I had the privilege to be able to start working on this project while I was a trainee. In fact the, this project is, in some ways, still ongoing even in the basic science. There's a report that's being formulated that's going to become public hopefully very soon that shows the foundations and underpinnings of the clinical project and the clinical trial that we have actually already opened at University of Nebraska Medical Center.

So it's really going many years back, Dr. Orlowski and his team made an observation through gene expression profiling of carfilzomib-resistant cell lines as well as bortezomib-resistant cell lines that there was a suppressed expression of a member of the mucin gene family namely MUC20 as the most conserved and significant change compared to drug-naive cells. As I mentioned, the same observation was also made in bortezomib-resistant cell lines as well as  carfilzomib-resistant cell lines which were developed. Crucially, suppression of the MET pathway, c-MET pathway was observed. Suppression of the MET or ERK signaling restore the sensitivity to proteasome inhibitors. In this process, MUC20 expression level on the gene expression profiling correlated with greater likelihood of achieving and maintaining your response to bortezomib which ultimately translates into improved disease free and overall survival in bortezomib-treated patients.

So taken together, these data seem to support the use of high expression of MUC20 as a biomarker of proteasome inhibitor sensitivity and of low expression as an indicator of potential resistance. All of these could possibly be used to overcome this resistance in the clinic by using the combinations of medications with the proteasome inhibitors that could try to exploit this particular lesion in the myeloma cells.

Jenny: So MUC20 is a protein, right, sitting on the surface of myeloma cells?

Dr. Baljevic: Correct. MUC20, this is a gene that encodes a member of the mucin protein family. Mucins are high molecular weight glycoproteins that are secreted by many epithelial tissues to form insoluble mucus barrier. The C-terminus of this family of proteins associates with the multifunctional docking site of the MET proto-oncogene and suppresses activation of some downstream MET signaling cascades. We are reduced HCF activation and ERK 1/2 activation.  It maps of the human chromosome 3.

In our understanding in our experiments, really the MUC20 associates that the c-MET pathway receptor tyrosine kinase and the downstream map kinase STAT3 and pump access. It behaves in a way as a stabilizing factor of this c-MET pathway such that when present, the c-MET pathway is not active, presumably is not signaling, and therefore does not have the chance to participate in the creation of proteasome inhibitor resistance whereas when it's absent, it releases this signaling, this activation possibly explaining why proteasome inhibitor resistance develops in at least a subset of myeloma patients.

Jenny: So you're saying when you have these low MUC20 levels, then that effects the c-MET pathway and it just sends a signal like, hey, become resistant. So you're saying there is a connection between those two things, right?

Dr. Baljevic: Correct. MUC20 serves as a stabilizing factor for the entire pathway which downstream affects variety of proteins in the proteasome chaperone machinery. When MUC20 is present, it doesn't allow activity of this pathway and doesn't allow variety of this, shall we say, molecular players to be active in creation of the proteasome inhibitor resistance. When it's absent, then this pathway is active. It's signaling. It's allowing the variety of these mediators inside myeloma cells to express their function and express their role and then taken all together, the effect that this has on the proteasome chaperone pathway, this leads to resistance to the proteasome inhibitors.

Jenny: So this is an important point I think that I'd like to make. Sometimes myeloma is not just what's happening in on the myeloma cell. It's what it's affecting all around it. In this situation, there are all these different things happening in our body signals that are sending to do things correctly and not to do things correctly. When the wrong signal is sent, then things go bad.

Dr. Baljevic: Absolutely. That's a very important point that you make because we understand cancer and the entire process of oncogenesis has a very dynamic process and not really isolated process. Cancer interacts with its environment in a very intimate fashion even in all the studies that have been done so far over the decades actually in this entire field. In the field of proteasome inhibitor resistance, we have actually identified bone marrow microenvironment factors such as IGF-1 activity, Akt or proteins tyrosine kinase or map kinase pathways or NF-kappa pathway having really essential roles in the development of proteasome inhibitor resistance. But as I mentioned, not just in multiple myeloma, really in all malignancies.

So our best efforts in trying to treat and control cancer, in this case multiple myeloma, is really to understand this complex interplay between genetic factors, environmental factors, factors that we're responsible for such as initiation of therapy which then provides a selective pressure against clones that are sensitive to that therapy and then slowly allows for the growth of those clones that are actually resistant. Effectively, over time changing the bulk of the tumor from a  one that was initially responsive and showed a reduction in disease tumor burden to the one where a response then escapes because myeloma cells are now actually completely different than the ones that were at the beginning. We are then required to alter our truth and approaches to try to control the disease.

Jenny: Right. Myeloma is tricky. When you talked about the c-MET inhibitors, you found a drug that targeted those inhibitors. In adding that to carfilzomib, you're working to overcome resistance. Maybe you want to explain that drug that I don't know how to pronounce, cabozantinib, and then how you're using it with carfilzomib to try to overcome that resistance.

Dr. Baljevic: Absolutely. May I maybe just offer a couple of sentences on really what c-MET pathway is altogether? The c-MET receptor tyrosine kinase mediates the signal for a variety of physiologic processes that have implications in oncogenesis including migration, invasion, cell proliferation and angiogenesis. A wide variety of human cancers exhibit constitutively dysregulated c-MET activity either through the overexpression of the c-MET kinase itself through activating mutations in the c-MET or through increased, what we call, autocrine or paracrine secretions of the c-MET lag in HGF. These alterations have strongly been implicated in tumor progression and metastasis in a variety of cancers. In high constitutive activation of this c-MET pathway has been a quoted with poor clinical prognosis.

In myeloma studies, specifically correlating the HGF levels, so HGF is a substance that activates this pathway, the soluble substance, so studies correlating the HGF levels with clinical parameters showed that HGF was elevated at diagnosis in serum and marrows of patients and that HGF level or elevated in patients with more aggressive disease correlating with inferior prognosis. Conversely, declining HGF levels were seen in patients responding to anti-myeloma therapies. Patients with low HGF levels were more likely to achieve high-quality responses. For the more reduction of MET signaling using some of the scientific ways of downregulating the activation of this passing using small inhibitory RNAs or ribosome resulted in gross inhibition and apoptosis of myeloma cell lines.

So collectively, these findings provided the rationale for the study of c-MET inhibitors in myeloma altogether. Cabozantinib --

Jenny: Let me ask you a question before you move on to cabozantinib. I'll say it right by the end of the show. How do you test? You are saying through gene expression profiling, you were testing for this MUC20. So is this something that shows up if somebody goes and gets a SkylineDX test or the old MyPRS test? Is that something that shows up on that test, or is there some other way to test for that HGF that you were just talking about? If patients wanted to say, well, I want to see if I have higher or lower expression of that MUC20, because as a patient, I'm interested in that kind of stuff.

Dr. Baljevic: Absolutely. You are raising a very salient point here. When it comes specifically to what we we are studying right now namely MUC20 level, shall we say, and as we mentioned, MUC20 is really surface glycoprotein, there is no validated tool. There is no validated way of testing for the presence of this protein. However, during our research efforts over the last several years, we have developed a flow cytometry-based assay that we have used in the detection of MUC20 levels on myeloma samples from actual patients.

Now, as you alluded to, there are a variety of platforms, a variety of tools that are being used the next generation sequencing options. Some of those have really hundreds of genes that are tested at the same time, and embedded within that list of genes are some of these players that are associated with this c-MET pathway that we are involved in right now in terms of testing of this particular hypothesis. But as I mentioned, even that information is sometimes difficult to clinically utilize except perhaps in the setting where we have clinical trials that are just particularly created to take advantage of some of these molecular lesions with already approved molecular or small molecule inhibitors. In that context, sometimes patients can make use and take advantage of some of that information to become perhaps candidates for clinical trials of that nature. But in multiple myeloma, at this point in time, we are still not using any validated clinical tool or a biomarker for that matter that can help us understand who would be predicted to be resistant from the very get-go to have inferior outcome to the standard of care therapies that we offer to all of our patients and who would therefore benefit from the frontline adjustment and targeted tailoring of the therapy to allow us to actually try to aim for the same type of good outcomes that we can expect in patients who are very much sensitive to proteasome inhibitors.

Jenny: Yes, so interesting. I think dividing us all up as patients would be really helpful. So sorry, I didn't mean to interrupt you about cabozantinib.

Dr. Baljevic: No problem at all. So cabozantinib is an FDA-approved potent receptor tyrosine kinase inhibitor that has selectively against BRET, MET, VEGF receptor 1, 2, and 3 and a variety of other targets that are very much implicated in a variety of malignancies. So it's already FDA approved for the use in thyroid cancer medullary subtype metastatic with the cometric formulation. Recently, it also received FDA approval for renal cell carcinoma with the Cabometyx formulation. Nevertheless, activity has been noted in a variety of different malignancies such as differentiated thyroid cancer, carcinoma and tumors, pancreatic, neuroendocrine tumors non-small cell lung cancers, hepatocellular carcinomas. I mean there is variety of early phase clinical trials that have showed some of this activity and that's still ongoing in variety of malignancies.

As you can imagine, with variety of different targets that I just named earlier, cabozantinib represents an exciting tool for us to use. On the other hand, it can also represent a challenging drug for tolerance for patients given that it may have variety of target effects at the same time.

Jenny: Well, can you explain how you are thinking about using it with carfilzomib?

Dr. Baljevic: Absolutely. We are testing the use of cabozantinib. In this case, we are using cabozantinib specifically as a c-MET inhibitor. We chose to go with it because it's already established throughout because of its FDA approval and variety of malignancies and because of the abundance of clinical data in the early phase and later phase trials which have demonstrated safety and efficacy in some other cancers. Our efforts with the clinical trial that we have opened here at Nebraska and that will very soon also open at MD Anderson Cancer Center is to try and see if we can utilize this knowledge, if we can utilize cabozantinib as a specific c-MET inhibitor to try to see if we can reverse the development of potential resistance, if we can try to resensitize patients who have progressed on proteasome inhibitor carfilzomib. In this case, we're focusing on patients who are progressing on carfilzomib therapy. If we can demonstrate that, we can successfully prolong the use of carfilzomib-based therapies in myeloma patients.

We consider this to be very important for a variety of reasons, most of which we have mentioned earlier. PIs are essential cornerstone agents in all myeloma therapies, and prolonging their use would mean a lot to the control of the disease. Myeloma is, as we all understand, fortunately, for a lot of patients, a type of disease that is really chronic and is disease that we need very effective agents for control of disease long term. We consider this a very important effort in trying to suppress some of the resistance mechanisms whether they be intrinsic or extrinsic and trying to basically delay the use of some of these other agents which are reserved perhaps for situations where patients have progressed really on everything that we know works very well and where we are in a situation where we're having limited number of treatment options available for disease control.

So in this particular clinical trial, as I mentioned, we are really focusing on patients who have been exposed to at least two but not more than four prior lines of therapy in general. We're focusing on patients who are, as their last line of therapy, progressing on carfilzomib-based therapy. So whether that is carfilzomib in combination with dexamethasone, a doublet perhaps for patients who are not as functional and who are perhaps a little bit more frail and can't tolerate throughput combinations or whether they're on actual throughput combinations such as carfilzomib, Revlimid, dexamethasone or carfilzomib, pomalidomide, dexamethasone or carfilzomib, Cytoxan, dexamethasone, et cetera.

Any form of carfilzomib-based therapy would qualify patients for participation in this clinical trial. What we would do then is maintain carfilzomib at a dose of 27 mg/m2.  That would be a fixed dose. We would also maintain the use of steroids (namely dexamethasone) at a dose of 40 milligrams per week. For patients who are 75 or older, that would be reduced to 20 milligrams per week. On top of that base, we would then add cabozantinib at a particular drug level that we would determine to be safe during the Phase I portion of this trial. We would try to test whether adding cabozantinib to the carfilzomib and dexamethasone could really prolong the use of carfilzomib in patients with relapse and refractory myeloma.

Jenny: Great. This is a Phase I and II study. Can you explain how it's kind of both studies at the same time? It's great that you're using a pre-FDA-approved drug, in my opinion, because you just are able to test it in a faster way.

Dr. Baljevic: Yes. Sometimes these things are really of practical nature too. Truth be told, there isn't a great variety of available c-MET inhibitors out there. Sometimes investigators really have to rely on drugs that are completely investigational that have never been tested in humans before. We perhaps trust to go with a drug that was, as I mentioned, tested in other malignancies. But actually the one that has also been tested in myeloma as well, I might add, that there is actually a report of a previous Phase Ib study that was reported in 2016 in Blood journal where groups from Memorial Sloan Kettering Cancer Center and Harvard myeloma program investigators over there tested the use of cabozantinib as a single agent so as a single drug. In their eligibility criteria, they focused including multiple myeloma patients that relapsed or that were refractory after therapy with at least one IMiD and one prior proteasome inhibitor drugs. Overall, nine patients were treated in that trial. Median time in therapy was about 61  days or about two months. Best response for all patients was one patient with minimal response, eight with stable disease and two with progression of disease.

So cabozantinib in trial didn't have significant single-agent activity in patients with relapsed and refractory myeloma. Fortunately, HGF levels at the time of the study entry were not available  in these patients. Therefore, the study does not exclude the possibility that cabozantinib may have activity in myeloma patients with higher levels of HGF where disease is driven by HGF. Our group, Dr. Orlowski's group namely has reported the experience of tivantinib and other c-MET inhibitor in relapsed refractory myeloma. Over there we enrolled 16 patients. Overall, there was evidence of stable disease in four out of 11 patients which were available for disease response yielding disease control rate of about 36%. No patients exhibited partial response or better during that trial. Our analysis suggested the possibility that myeloma cells from our patients were not specifically dependant on HCF and c-MET signaling pathway, and that perhaps selected patients with high HGF levels could have benefited a little bit more.

The idea of c-MET inhibition is not completely novel in the field of multiple myeloma. However, this type of approach that we are utilizing with this study is, in fact, novel because through our pre-clinical studies in a variety of different cell lines and also in animal models, we have learned that, in fact, combining the c-MET inhibition in addition to proteasome inhibition actually leads to better results. It leads to more cellular deaths in terms of multiple myeloma activity which is why we specifically designed this study where we would keep the proteasome inhibitors going, we would keep the dexamethasone going, and we would add the cabozantinib on.

We sincerely hope that perhaps this may yield a different type of response if that has been observed by our colleagues with the previous Phase Ib reports and also from our own report would tivantinib in relapsed refractory myeloma. We believe that this is valuable and worthy of investigation. As you pointed out, by selecting the c-MET inhibitor, that we already have a sort of a safety profile on defined. We were able to design a study perhaps with a little bit more awareness of what we could potentially encounter in terms of toxicities with patients. We're able to take into account variety of these factors and specifically excluding patients which would be unsafe to be on a combination of therapy with cabozantinib and carfilzomib and dexamethasone.

Jenny: Right. Just an important point for patients. Sometimes Phase I studies are testing a drug that's never been used before, but sometimes Phase I studies are called Phase I because they're taking something that has been used in other cancer like the drug that we're talking about plus carfilzomib, and they've never really been combined together. So that's why it's considered a Phase I.

Dr. Baljevic: Exactly. Absolutely. You make a very, very good point. In fact, our application to the FDA for the IND was solely based on the fact that cabozantinib had not been previously combined with carfilzomib even though both carfilzomib and cabozantinib had been studied separately in multiple myeloma. To go back to your earlier question about Phase I and Phase II being combined in the same effort, this is not that uncommon and this is namely part of the effort to try to gain as much information as possible as a part of a single effort. Just for your listeners who may not be as familiar with the investigational protocols and the purposes of the different phases, Phase I of clinical study namely focuses on defining the safety of a drug and defining the safe level of the drug to use in human subjects, in patients such that after that safe level of drug is identified, then we can carry on with that knowledge to later phases of the study namely Phase II and Phase III. In the Phase II really we start asking that question and gaining information about any of the number of disease control parameters including progression-free survival, depth of response, duration of response, time to next therapy, overall survival, et cetera, et cetera. So really the Phase I portion is the one where we identify what is safe to do, and then in the Phase II portion we try to accrue a greater number of patients on that safe drug level so that we can ask the question, how efficacious is this really?

Jenny: Right. I think it's great to combine the two because you already have it FDA approved somewhere so you've already done the safety data for both of these drugs. I guess it is more efficient. I do want to point out that this is for people who have failed carfilzomib. So you can join if you have failed that. It's okay.

Dr. Baljevic: Yes, exactly. We decided to focus on the patients who are failing in carfilzomib because we want to avoid a situation where we are testing a clinical question in a bortezomib-resistant patients where this potentially could then be relevant for bortezomib-resistant patients, but then it becomes less relevant in patients who progress on carfilzomib. As you can imagine, a vast majority of myeloma patients, if not all, during the course of their disease and their life with the disease will be exposed to namely all the medications and all the variety of anti-myeloma drugs that are available to us clinicians and subspecialists who treat this disease. It was very important to try to use a clinical design which would test this important question in resistant myeloma situations where patients are progressing on a second generation proteasome inhibitor and not just the first generation proteasome inhibitor.

Jenny: Right, so that's important that hypothetically you might be able to add this to the others down the road, the other proteasome inhibitors down the road. Maybe it will have the same effect of helping overcome resistance.

Dr. Baljevic: Yes. That's an interesting point to think about and will be an important observation to perhaps make in the future with additional studies. Even though proteasome inhibitors really target sort of the same machinery, intercellular chaperone machinery, there's no guarantee that when you have resistance to one agent that you will necessarily have resistant to other. So these will be important efforts, I would say, at least starting efforts in trying to understand whether c-MET inhibitor pathway at least is partially responsible for a subset of patients and their resistance to PIs.

Jenny: Right. Wonderful. Well, I know I have other questions, but I do want to make sure that we have time for any caller questions. Let's do that first and then I will follow up with my other questions after this. You can call 347-637-2631 and press 1 on your keypad if you have a question. I know it's Memorial Day so a lot of people might be by the pool or might be listening to this later. But we have our first caller question. Go ahead with your question.

Caller: Hi there, Dr. Baljevic. Thank you for taking your time out in Memorial Day. I appreciate it.

Dr. Baljevic: Of course, my pleasure.

Caller: You mentioned for cabozantinib you said it had some side effects. I was wondering what those were.

Dr. Baljevic: Yes absolutely. Cabozantinib is this c-MET inhibitor in question that we are studying in this particular trial. Cabozantinib, as we mentioned earlier, is a tyrosine kinase inhibitor that targets variety of targets intercellularly in the myeloma cell but also in other cells in the body. Variety of adverse reactions have been observed over time in studying this drug in many different cancers. Adverse reactions that are noted greater than 10% of patients have been related to cardiovascular, so hypertension, fatigue, muscle pain, dermatologic side effects including palmar-plantar erythrodysesthesia, so skin conditions and rashes. Hematologic side effects including lower cell counts, neutropenias, thrombocytopenias, reduction in the platelet counts, some dysfunctions in the hepatic transaminases as well patients who have previously had fistulas will not be allowed to participate on this trial because of the dangers that this drug would pose in such patients in terms of complications and bleeding.

So these are just some of the issues that we are cognizant about when we were designing this study. We will certainly ensure that patients with any of these features who would potentially be predicted to not have the safest experience under struggle will not be part of this trial, but everybody else who reasonably can will certainly be allowed.

Caller: Thank you.

Jenny: Okay, great. Thank yo so much for your question. Our next question, please go ahead with your question.

Caller: Hello.

Caller:  I missed the first part about if it's a deletion 13 chromosome prevents the myeloma from reproducing so quickly, I believe? It has something to do with IL-2 and cytokines. I just wondered, couldn’t we give the patient those substances that would prevent the cells from reproducing?

Dr. Baljevic: Thank you very much for your question. We are certainly using variety of information available to us from the basic science laboratory bench including those that we gain in the clinical arena from our patients. In multiple myeloma armamentarium, we're trying to focus from a variety of directions and variety of agents that have effect against myeloma either through direct inhibition of, for example, in this case we're talking about proteasome inhibitors, but as you pointed out, sometimes we're trying to focus cytokines of chemo kinds, a variety of chemicals which have a role to play in cellular proliferation, multiplication of myeloma cells, the place where they home, place where they sit, the microenvironment of the places in the bone marrow and elsewhere with all the factors that are supporting the life and extending the life span of the myeloma cells. So you're certainly right in thinking that we can certainly try to utilize variety of efforts and mechanisms in trying to suppress myeloma growth overall.

Caller: Right. I think I was told by an oncologist that you can't get these substances into the cells to do what a chromosome could make the RNA -- DNA can make the RNA. Just giving those substances is not enough.

Dr. Baljevic: Cancer, in general, is as we mentioned a complicated process. Sometimes cancer specifically depends on one particular lesion or one particular axis that is overactivated. So for example, a poster child of this type of behavior is chronic myelogenous leukemia with the Philadelphia chromosome activation and the drug that specifically inhibits that exact activity and with dramatic responses in terms of cancer control and cancer killing and such. Unfortunately, a vast majority of cancers are not that simple, are not that dependent on only one pathway. Myeloma certainly we have a variety of mechanisms that over time lead to progression of disease from precancerous conditions that you have heard about, smoldering myeloma, for example, being a precursor condition to symptomatic myeloma which is a cancerous conditional therapy. We are, unfortunately, dealing with a variety of factors that we need to control. The better we do that and the safer ways we find of doing that, the better chance we have of ultimately better outcomes for our patients.

Caller: Well, God bless you for your persistence.

Dr. Baljevic: God bless you too, and hopefully give you health very soon.

Caller: Thank you.

Jenny: Thank you so much for your call, and thanks for your wonderful responses. Dr. Baljevic, I was going to ask you about your other myeloma research, but it looks like we are out of time. So we are going to just have to have you back on the show to talk about it.

Dr. Baljevic: My pleasure really. Thank you very much for the time today. It would be my pleasure to come back.

Jenny: Well, it's a privilege to have you. Thank you so much. We hope you do great things with this study and others. If you just want to finish up by telling us where it will be open. You mentioned the University of Nebraska is where it's open currently, and it will be open at MD Anderson. Do you have any other centers or re those two the primary?

Dr. Baljevic: Yes. Unfortunately, this is an investigating initiated effort with myself and Dr. Orlowski as co-principal investigators on this particular trial. So we have already opened and activated this protocol here at University of Nebraska Medical Center for our Midwest patients and broader. We expect that this study will be activated and opened shortly in Houston, Texas, at MD Anderson Cancer Center for all of our patients there. For the time being, these are our plans to have this study open at these two sites. But certainly, we hope that if we are able to observe safety signal in this trial and furthermore if we're able to validate some of our pre-clinical hypotheses and clinical hypotheses, then certainly our plan would be to try to open a later phase study with the same concept. Certainly, we would end to try to make this study available across the nation.

Jenny: Great. Well, we are interested to see what happens with this study. If you are on carfilzomib and you're interested in this study, we will have a link to the study when we post the show. So you'll be able to find it on SparkCures and follow up and go through the steps of participating.

Dr. Baljevic: I just wanted to mention that I would really welcome any questions from any of your listeners or any patients with multiple myeloma. I would be happy if you posted my email and would be really happy to respond to any questions or maybe clarify any trial candidacy points and maybe trying to offer some assistance in patients who would be interested in perhaps coming from other states and participating in this clinical trial.

Jenny: Okay, great. We will include your email in the full show when we have the transcript and everything. We're so thankful that you took time out on a holiday especially to join us. So thank you for all your great work.

Dr. Baljevic: My pleasure, absolutely. Thank you and all of your patients.

Jenny: Oh, thank you. We're happy to have people like you working in the field.

Dr. Baljevic: My pleasure.

Jenny: Thank you for listening to Myeloma Crowd Radio. Tune in next time to learn more about the latest in myeloma research and what it means for you.