Dr. Jacob Laubach, MD, MPP
Dana Farber Cancer Institute
Interview Date: May 13, 2016

Proteasome inhibitors have been a staple of myeloma therapy since the late 1990s. Because they are so key to the death of myeloma cells, they have continued to be developed and now a variety of options are available. Dr. Jacob Laubach shares more about the history of the PIs in myeloma treatment and why they work so well. He addresses their use in combinations as well as the evolution of their development to hit different portions of the proteasome as well as the development of a new, oral option. Although myeloma patients wish there was a silver bullet cure with the upcoming immunotherapies Dr. Laubach says that this class of drugs is not likely to go away any time soon. He shares how they are now being tested in triple and quadruple combinations to help both newly diagnosed and relapsed/refractory patients extend their outcomes.

Thanks to our episode sponsor

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 today's episode sponsor Takeda Oncology for their support.

Now before we get started with today's show, I'd like to mention a new program from the Myeloma Crowd. You listen to this show because you want answers from Myeloma experts. We recently launched an additional way to get answers from experts and we call them Myeloma Crowd Round Tables. We recently held our first round table in Salt Lake City and invited three Myeloma experts to join us. The round tables cover new treatment options but also focus on relapsed and high risk disease because these are patients that need help the very most. Our next round table will be held on June 18th at Saint Louis and another that we'll post shortly on June 25th in Boston. We will have a link to that round table soon because we all need to plan ahead for our best myeloma care. These meetings are really for all of us.

Now on to today's show. Proteasome inhibitors, as you probably know, are a myeloma treatment staple. So today we are talking with Dr. Jacob Laubach of the Dana Farber Cancer Institute about how they are advancing and how they will be used in the clinic in this new era of new treatments and immunotherapies. So welcome, Dr. Laubach.

Dr. Laubach: Good morning and thanks very much for having me.

Jenny: Let me introduce you before we get started. Dr. Jacob Laubach is Clinical Director of the Dana Farber Cancer Institute's Multiple Myeloma Program as well as Senior Physician of Medicine at the Dana Farber Cancer Institute and Assistant Professor of Medicine of a Harvard Medical School. Additionally, he is Associate Physician in the Department of Medicine at Brigham and Women's Hospital. Dr. Laubach is a member of the American Society of Hematology Abstract Review Committee and reviews journal articles in publications such as Blood, the British Journal of Hematology, Cancer, Leukemia, the New England Journal of Medicine just to name a few.

Since joining the Dana Farber Cancer Institute Faculty in 2008, he has dedicated his efforts to the study of new therapeutic agents for multiple myeloma and was heavily involved in the study of HDAC inhibitors and the development of monoclonal antibodies, daratumumab and elotuzumab. Dr. Laubach teaches regularly on multiple myeloma for students and lectures regularly in other forms on the same topic.

Dr. Laubach, thank you so much for joining us. We really appreciate it. Maybe you can give us still a little background. When I attended ASH, I heard Dr. Richardson give a background from Dana Farber about Proteasome Inhibitors and maybe you want to do the same. What's the history of them? How they work and why do we use them in myeloma treatments?

Dr. Laubach: Sure. It's a great place to start and I will try to start in the most basic rudimentary way possible because I think that much of our discussion today will build on some of these concepts. So like other cancer types, multiple myeloma results from unregulated or disregulated growth of a certain cell type. And in the case of multiple myeloma as we all know that certain cell type is the plasma cell. Now proteins within the cell are critical for the various functions that a given cell needs to carry out - whether it's related to cell division or cell proliferation or other functions that allow a cell to live and proliferate.

Those proteins that carry out these vital functions, however, need to be processed appropriately once they have served their role and that is where the proteasome comes in. The proteasome is essentially like a trash compactor, or you could view it as a recycling bin. Proteins that have served their role within the cell are tagged with another protein called Ubiquitin which notifies the cell that this cell has to be processed. It has to be recycled, and the structure within the cell that does that recycling is the proteasome. It consists of various sub-compartments that contained what are referred to is enzymatic activity that lead to the reprocessing or processing metabolism of these cells -- of these proteins that have been used up and there are essentially three different types of proteolytic activity within the proteasome itself, and these are critical of course to the function of the proteasome.

As you can imagine, the discovery of the proteasome as the structure within the cell that carries out this critical function was a fundamental discovery not just for the field of myeloma, of course, but for the entire field of cellular biology and cell science, because it elucidated a critical mechanism within the overall function of cells. This discovery was really carried out over the course of many years and involved a large number of different scientists. One of them whose name was Alfred Goldberg who was really at the center of our understanding of the proteasome and in the early 1990's as the role of the proteasome within the cell became understood and the implications of that for various diseases was recognized. There was a shift in focus towards the clinical realm, and proteasome inhibitors were studied in the laboratory and then turned against human diseases.

As you can imagine this process took many, many years to find a compound that could be safely delivered to human beings and to find out which diseases might be best suited for treatment with proteasome inhibitors. Cancer was a natural and important focus of those efforts because as you can imagine, cancer cells are very, or tend to be, very metabolically active and a result, involve the activity of a variety of different proteins within in the cell. The thought was that if you can inhibit the cell's ability to process those proteins effectively, the cell, the cancer cell would accumulate excess protein and that this accumulation of excess protein would then become toxic to the cancer cell and ultimately lead to death of the cancer cell and potentially effective therapy.

By the late 1990's, there were efforts on their way, in the laboratory primarily, in cell models and then animal models to study proteasome inhibitors in cancer or cancer models. This endeavor proved to be successful and anti-cancer or anti-neoplatic activity was observed, and this of course then led to the first clinical trials of proteasome inhibitors and human cancer. One of the first of these was a clinical trial that involved patients with relapsed and relapsed and refractory hematologic or blood cancers. This wasn't a myeloma specific trial - it included individuals with multiple myeloma, but broadly it was individuals with blood cancers. Within that trial I believe there were 27 patients. There were eight or nine with multiple myeloma and it was that group of individuals who had the greatest degree of response to what is now known as bortezomib or Velcade. So that provides a bit of historical context in terms of the development of proteasome inhibitors at an early stage in the laboratory and then initial human studies.

Jenny: Are they used in other cancers today or have they been shown effective because it sounds like Ubiquitin is what tags the cell to say okay, I'm going to live or die. I'm ready to go and then the proteasome inhibitor takes care of it. So you would think it would have wider application to some of these other diseases and cancers. Does it?

Dr. Laubach: The clinical trials demonstrated the highest level of activity in multiple myeloma as I mentioned before. And it's clear why this may be the case. The plasma cell under normal physiological circumstances is charged primarily with the task of generating immunoglobulin molecules which are important in our immune defense and so these cells are loaded with proteins, and as a result, most susceptible to inhibition of that structure, the proteasome which is involved in intracellular processing of used proteins. As it turned out, as I mentioned before, myeloma turned out to be the disease which was most sensitive to the effects of proteasome inhibitor therapy. At present, the only other cancer for which a proteasome inhibitor is FDA approved is Mantle cell lymphoma where it's approved for initial therapy and also a therapy for relapsed disease.

Jenny: Well it's thrilling that we have other options. And so this happened in the early 1990's. When did we start using bortezomib in the clinic?

Dr. Laubach: Bortezomib was FDA approved in 2003. And this was based on a subsequent phase two clinical trial showing a high level activity or response to proteasome inhibitor therapy with bortezomib in patients with relapsed disease. So the FDA granted accelerated approval in 2003 and subsequently full approval to bortezomib for treatment of relapsed and refractory multiple myeloma in 2004.

Jenny: It's come a long way I think, right? There has been a lot of development in proteasome inhibitors and continuous to be. Do you want to give us an overview of the evolution of this very important drug?

Dr. Laubach: Absolutely. As I mentioned, the compound bortezomib was first approved in 2003 and there was great interest already at that time for utilizing bortezomib not only as a single agent but also in combination, so subsequent studies with combined bortezomib with Dexamethasone and later a phase three clinical trial was conducted comparing bortezomib and Dexamethasone to the previous standard of care for newly diagnosed multiple patients, a combination of Vincristine, Adriamycin and Dexamethasone. This was a positive study for progression free survival and led to the approval of bortezomib and Dexamethasone for newly diagnosed disease.

The drug was also combined with Melphalan and Prednisone. For individuals who were considered to be transplant ineligible, or generally speaking older or frailer patients, in a phase three clinical trial that compared a previous standard of care of Melphalan and Prednisone to bortezomib or Velcade plus Melphalan and Prednisone. And this likewise was a positive study and ultimately led to the approval of bortezomib in combination with Melphalan and Prednisone in newly diagnosed multiple myeloma. Rather quickly, over a period of four to five years, the drug moved from being applied in relapsed disease to newly diagnosed disease.

it's important to emphasize that there are various different types of a proteasome inhibitors. I think I mentioned at the onset that the proteasome structure itself has several different proteolytic compartments within it - three different protealytic compartments. And the different proteasome inhibitors are more or less selective for certain aspects of the proteasome inhibitor or the proteasome complex itself. So there was interest in developing additional proteasome inhibitors beyond bortezomib and this spawned a great deal of a drug discovery in the field and as a result of that, we now have several different proteasome inhibitors that have been approved in addition to bortezomib.

Carfilzomib has been approved as a single agent in combination with Dexamethasone and in combination with lenolidamide and Dexamethasone and most recently ixazomib, the first oral proteasome inhibitor was approved. There are several other proteasome inhibitors that are currently being studied in clinical trials including marizomib and oprozomib. There is a lot of ongoing activity in the field, and this is certainly not considered to be redundant. Because as I mentioned before, although these drugs are all within the same general class of proteasome inhibitors, they are distinct drugs with distinct pharmacokinetic and pharmacodynamic properties, distinct levels of anti-myeloma potency and distinct toxicity profiles. It's truly an advantage to the field to have had this ongoing interest in the development of not just one or two but several proteasome inhibitors and I think it's been very beneficial to patients.

Jenny: I could see that, because let's say you become resistant to one, you can move to another or use it in a different combination and then bring it back to working status again.

Dr. Laubach: That's a great point. With regard to the first points you raised about resistance to therapy, it is absolutely true that resistance to one proteasome inhibitor does not necessarily imply that a given patient will be resistant to all proteasome inhibitors and indeed in the initial clinical trials of carlfizomib, the vast majority of patients have received bortezomib and there was a significant response rate to carlfizomib, or Krypolis, even among patients who had become resistant to bortezomib. Similarly, with the development of ixazomib, patients who had previously been treated with bortezomib or previously treated with carlfizomib, showed response to ixazomib in a certain percentage of cases and likewise now with a development of marizomib. We're seeing a similar trend that some patients who have become resistant to a given proteasome inhibitor maintain sensitivity to a new proteasome inhibitor.

The second point that you allude to refers to combination therapy and there is no question that as in other hematologic malignancies as well as solid tumors, combination therapy combining agents from different classes holds a great deal of potential because of what we refer to as the synergistic activity of these various compounds. So a lot of the regimens that are currently employed for both newly diagnosed patients as well as patients with relapsed disease involve combinations of a proteasome inhibitor such as bortezomib or carfilzomib or now ixazomib, in combination with another drug or several drugs.

Jenny: Absolutely. As a myeloma expert, how do you choose? I know some of the questions might be around with the new announcement last November of ixazomib. Do you just go to your doctor as a patient and say “okay, I want to switch?” I know that's a big question for a lot of patients.

Dr. Laubach: Yes, several comments to make there, one is as I often remind patients, if you are currently responding to a given therapy and tolerating it well, it's generally advisable to stick with that particular agent or regimen of agents. The old saying that one in the hand is better than two in the bush definitely applies to a myeloma therapy. If you are responding to something well, tolerating it well, stick with it and wait until it is either no longer working or is producing side effects that are intolerable, to make a change in your therapy. In terms of making decisions about which drug or combination of drugs is most appropriate for a given patient, as you can imagine, a lot of factors are considered.

In individuals who have newly diagnosed myeloma, we look at the clinical characteristics of their cancer: how aggressively did it present, how many myeloma related complications like bone involvement or kidney involvement or anemia or others does the patient have, what other medical conditions are present in a given patient? These things all influence our thoughts; as do some of the biological characteristics of the diseases or relates to chromosomal findings. This certainly has an important impact on choice of therapy as well. For individuals who have previously been treated and relapsed, in that context too, a variety of different factors are considered. We look at how effectively eight prior line of treatment or several prior lines of therapy worked in terms of inducing a response to the therapy.

We look at how long an individual responded to a given regimen, we look at how well they tolerated a given regimen and we look at, as I mentioned with respect to newly diagnosed patients, we look at what other medical conditions they have. Based on these factors, we make a determination as to what might be appropriate next line of treatment. The data from clinical is of course of great importance in making these decisions and oftentimes, in the context of a clinic visit with a patient, we’ll discuss the results of recent clinical trials and determine whether a new regimen might be appropriate for a given patient.

Jenny: What you're saying is “it's complicated” and this is why I highly suggest that people see a myeloma specialist or have one on their care team because like you just said, I mean for newly diagnosed, you have a lot of things to be thinking about. Your health status, the genetics of your disease, how progressed it is, things like that. And then when you are relapsed, what worked and what didn't. I think the nuances of myeloma are so complex, that I highly suggest that myeloma patients have somebody that they can consult. Though you may get care at your local oncologist office, your care can be crafted by a myeloma specialist and then you can have that care implemented locally. So I want patients to know they can do that. They can consult with a myeloma specialist such as yourself. I think it's very, very important that they do that.

Dr. Laubach: There is no question. This is a very, very biologically complex disease and as was mentioned previously, the pace of drug discovery in multiple myeloma specifically let alone what's going on in the field of oncology in general over the course of the past 10 or 15 years and really beyond that. But the ten -- the past decade 15 years has been remarkable in terms of the pace of drug discovery.

We now have a great abundance of treatment options for patients, which is absolutely wonderful on the one hand. But it does create a situation where there can be uncertainty about which approach is best for a given patient. It is undoubtedly true that patients, I think, derive the most benefit when we really truly work together as a team. The patient is at the center of that team, their family members, loved ones, support group are critical within that team. The primary oncologist who may practice locally or close to where the patient lives is a critical member of that team and then a specialist, who is intimately involved in the care, is critical as well. I think with that type of team approach, patients are put in the best position to get the best most optimal long-term outcome in their treatment.

Jenny: Well let's talk a little bit about Velcade versus ixazomib because sometimes I wonder if you look at just convenience as well. How similar are they? Because you talked about the differences between the different drugs and we'll get to the other one that you mentioned marizomib in a minute. Just to share a little bit of like an example from my own experience, we were living in Mexico at the time and I was on maintenance therapy for a year and I had to fly from Mexico to Houston every 10 days for a year so that I could get my Velcade infusion like on day 1 and day 4. So having an oral option like that would have saved me about six months away from my family, and over $30,000 in travel. Do you look at convenience or distance from the clinic for this kind of thing when you're looking at which drug to choose and are they all that different?

Dr. Laubach: Yes. With respect to bortezomib and ixazomib, they are both borenate compounds. That type of proteasome inhibitor being distinct from the epoxy ketone carlfizomib as well as marizomib. They are both reversible as opposed to irreversible proteasome inhibitors like carfilzomib or morizomib. So in those respects, they are similar within the broad class of proteasome inhibitors. That being said, as a self-evident one is given either subcutaneously or intravenously, one is given orally. So as a result of differences in terms of mode of administration, there are also important what we call pharmacokinetic and pharmacodynamic effects of bortezomib or Velcade versus ixazomib or Ninlaro.

So they are distinct drugs, but rather similar and it's undoubtedly the case that the development of an effective oral proteasome inhibitor is a great advance for the field. Ffor patients it offers a variety of potential advantages with respect to convenience, and also is important to emphasize toxicity profile. So bortezomib has a long and storied history in the treatment of multiple myeloma and is by no means over. It's going to remain a fundamental part of myeloma management moving forward. But to have access to or the option of an oral effective proteasome inhibitor is of course wonderful for patients for the reason of both convenience as well as its toxicity profile.

Patients are well aware that an important side effect of bortezomib is nerve toxicity or a peripheral neuropathy which occurs in upwards of 50% of patients who receive bortezomib, and it can be quite challenging. Ixazomib or Ninlaro is not devoid of peripheral neuropathy as a potential side effect but the rate is markedly lower. In that sense there is a great advantage to patients in terms of other side effects. They're generally comparable. There is a higher incidence of rash related to ixazomib than to bortezomib but otherwise, overall the toxicity profiles are rather similar. They really are distinguished though with this issue of neuropathy.

Jenny: And that's a big issue for patients. I know that before ixazomib came out, people were trying to manage that with the sub-Q shots trying to do it that way, which seems to show lower neuropathy also, but that's good to hear.

Dr. Laubach: Yes. The subcutaneous formulation of bortezomib or administration of bortezomib I should say is definitely associated with less neuropathy than intravenous bortezomib, but the rates of neuropathy appear to be significantly lower still further with ixazomib as compared to subcutaneous bortezomib. Currently ixazomib is FDA approved as you know for relapsed multiple myeloma on the basis of the Tourmaline Clinical trial which was just published in the past few weeks in the New England Journal of Medicine. It's quite possible that in the coming years, its approval will also be applied in newly diagnosed disease.

Jenny: How long does it take typically to get something like that approved from the relapsed refractory settings? I know they always start with that right? Or usually start with that?

Dr. Laubach: That's typically where approval starts. Generally speaking, drug development begins with regard to human application or trials involving human beings and individuals with relapsed disease, who no longer have effective options available to them outside of clinical trials. This is often where new drugs are tested or evaluated in the context of clinical trials. Once success is observed in the setting of relapsed disease, consideration is then given to moving a particular agent into the setting of newly diagnosed disease.

Jenny: What's the difference between the reversible versus irreversible that you were talking about?

Dr. Laubach: The reversible versus irreversible has to do with the biochemical characteristics of a particular compound and how that compound interacts with elements of the proteasome. So carlfizomib or Krypolis for example, forms an irreversible bond with its target within the proteasome. Bortezomib in contrast forms a reversible bond. So there is latching on, latching off, latching on, latching off and both agents are quite potent in terms of their capacity to inhibit the function of the proteasome but undoubtedly that irreversible versus reversible plays into how potent a given drug may be and potentially into its toxicity profile.

Jenny: Do you see differences in the toxicity between the irreversible and the reversible? I mean I'm sure you do.

Dr. Laubach: It's hard to make the association between whether a compound is reversible versus irreversible and an agent’s toxicity profile, because there are other factors that play too, that contribute to drugs overall tolerance or toxicity profile. But certainly these are distinct compounds and they have distinct toxicity profiles. And as such, the data that is derived from the early phase clinical trials, the phase 1 clinical trials, the phase 2 clinical trials and then ultimately of course the phase 3 clinical trials, are critical for us in terms of understanding the safety of a given compound.

Jenny: Well that makes sense. Maybe we'll want to go back to the Tourmaline study that you referred to earlier. Can you share what the study was all about? This is to help ixazomib get their FDA approval and I just saw updated results just in the last week or so.

Dr. Laubach: Yes. This is in the trial that was referred to earlier that was just published in the New England Journal of Medicine. The development of ixazomib began many years ago. I don't know precisely when but I would venture to say it was 9 to 10 years ago and initially the drug was studied as a single agent, and performed well in that context. I think encouraging results came out of the initial clinical trials of ixazomib as a single agent, but based on laboratory preclinical science that had been conducted as part of the drugs development, it was evident that there was capacity for this synergy with other classes of drugs - notably the immunomodulatory drugs and notably lenalidomide.

So earlier phase, clinical trials of ixazomib in combination with lenalidomide and Dexamethasone were performed which showed impressive results. The drug led -- or the combination, the three drug combination lead to significant responses and overall was quite well tolerated. The combination of lenalidomide with ixazomib and dexamethasone was then evaluated in a randomized placebo control phase 3 clinical trial which provides for the scientific community and for the FDA really the highest level of scientific evidence for a given treatment intervention.

In this study, lenalidomide and dexamethasone were used, in combination with a placebo, was used as the controller. The primary end point of the study was progression free survival which is defined as that time between the point of randomization within the clinical trial to the time there is first evidence of either disease progression or death. The important secondary end point was overall survival, as well as further characterization of the safety of ixazomib in combination with lenalidomide and dexamethasone.

This was a large trial. It accrued over 700 patients in total I believe 722 patients. 26 different countries were represented at 147 different treatment centers. It was really a very, very large undertaking as many of these larger phase three clinical trials are. Because although myeloma is the second most common hematologic cancer, it is still in comparison to cancers like breast cancer or colorectal cancer or prostate cancer a relatively uncommon cancer that affects the US approximately 26 or 26,000 people per year, new diagnoses per year. In order conduct a trial like this, there needs to be involvement of many sites. And in this particular case, the design involved a one to one randomization. Flipping a coin, patients would be randomized to receive either Revlimid, dexamethasone with ixazomib or Revlimid, dexamethasone and placebo.

The patients didn't know whether they were getting placebo or ixazomib of course. The physicians didn't know and those people who were adjudicating, or overseeing the data, weren't aware either. So that’s a critical aspect of a phase three clinical trial is the efforts that are taken to eliminate potential bias that could impact the results of the study. So this was a very rigorously conducted phase three clinical trial and the primary end point was met. So the progression-free survival in the patients who received Revlimid, Dexamethasone and Placebo was 14.7 months whereas the progression-free survival for individuals who received Revlimid, dexamethasone and ixazomib was 20.6 months.

What we called the hazard ratio for disease progression or death was 0.74 and that met the level of statistical significance that was prescribed by the study. It's also important to emphasize that amongst this large group of patients, 720 patients or thereabouts, regardless of their disease characteristics as they related to cytogenetic abnormalities, their international staging system, their age, the number of prior therapies that they have received, regardless of what subgroup of patients was studied, the results held up. And it was particularly encouraging to see that individuals with higher risk cytogenetics including those that we do consider to be highest risk, including the 17P deletion and the translocation between chromosome 414, benefited from the three drug approach with ixazomib plus lenalidomide and dexamethasone.

Jenny: And that's really remarkable. I was going to ask you about that because it seems that especially the patients with deletion 17, I didn't know about the 4;14 as well, really respond to these proteasome inhibitors and they are good for both induction therapy and perhaps maintenance.

Dr. Laubach: There is no question. These individuals with chromosomal abnormalities like deletion 17P or translocation between 4 and 14 or between 14 and 16 or several others are at higher risk for progression at an earlier time point than individuals who don't carry these higher risk cytogenetic abnormalities, and the development of effective treatments for this population of patients specifically is of course of great interest. I think it's uniformly accepted within the field that these individuals need combinatorial therapy, meaning several drugs. Really at time diagnosis, a minimum of three. There was a very Important paper presented at the ASH meeting last December 2015 by Dr. Dory with the Southwest Oncology comparing Revlimid, Velcade, Dex to Revlimid and Dexamethasone that definitely showed the benefit of three-drug rather than two-drug therapy not only in terms of progression-free survival but in terms of overall survival.

So it is I think uniformly agreed upon at this point that unless a patient is too frail to receive three drugs, three drugs at a minimum should be given as initial therapy and there is also data from clinical trials that have looked at two versus three drugs in relapsed disease, after transplant, to suggest that three drugs is favorable to two. So that's I think uniformly accepted. Amongst patients who have high risk myeloma, there is no question. They should be receiving combinatorial therapy and a trial like this one or a trial like the spire trial which compared carfilzomib, lenalidomide and dexamethasone to lenalidomide and dexamethasone which likewise showed a significant benefit with three versus two drugs. These trials clearly show that this should be the standard approach.

Jenny: Well let me ask you a follow-up question to that. What about maintenance therapy? Because right now patients are hearing “almost all patients should be on maintenance therapy” and possibly indefinitely, and typically it's done with lenalidomide or an IMiD. But I've heard some doctors say like you were just saying you know you take these combinations and you might want to consider if it's tolerable that you might want to consider a combination maintenance therapy that includes a proteasome inhibitor. What do you think?

Dr. Laubach: These types of questions are most clearly addressed by randomized placebo controlled phase three clinical trials. But as you can imagine, randomized phase three clinical trials that involve a large enough number of patients to ensure that the statistical endpoints of the trial are met, are difficult to conduct. So we generally attempt to base our clinical practice on the basis of results from randomized phase three clinical trials, but it's not possible to do so in every circumstance.

In the case of maintenance therapy, fortunately, there has been a number of randomized phase three clinical trials, that has evaluated the impact of immunomodulatory therapy, lenalidomide specifically. Prior to that, there were randomized trials evaluating Thalidomide and very consistently in the case of these trials there has been a progression-free survival. In the case of post transplant maintenance, there have been two pivotal randomized phase three clinical trials that have been published, one performed by the IFM group in France, one performed by the CELGB or now Alliance group here in the US looking at lenalidomide maintenance post-transplant.

The American or CLGB trial has shown not only a progression-free survival benefit but also an overall survival benefit. The French trial showed a progression free survival benefit but not an overall survival benefit. In our practice, we generally consider immunomodulatory therapy with lenalidomide as maintenance therapy to be a standard of care. Is it absolutely uniformly applied in every patient's case? No. I think it's critical that this topic be discussed with patients who are considering maintenance therapy. What did the clinical trials show? What are the pros? What are the cons? What are the potential toxicities? And that's where the teamwork, the team structure comes into play. This decision is made in a patient's need to be informed about the rationale for maintenance therapy and the potential toxicities, and this decision is made together with their provider.

With regard to the potential role for bortezomib or ixazomib or carlfilzomib as maintenance therapy, there are clinical trials that have been performed, but none have been randomized phase three to date. When I say that I would point out that randomized trials that have incorporated bortezomib as a component of maintenance therapy have been conducted but the primary end point of the study, the primary question that was being addressed was not the impact of bortezomib maintenance. That wasn't the primary question study.

Several studies have incorporated bortezomib as maintenance therapy. The largest one was published by Sonneveld and colleagues in the Journal of Clinical Oncology in 2012 and involved a large number of patients who received bortezomib as maintenance every other week. And it was shown to be feasible, and it was shown that individuals who received bortezomib from start to finish, meaning at the time of diagnosis but before transplant, following transplant as maintenance, did quite well.

So we know that it's feasible, but there hasn't been a placebo control trial where bortezomib maintenance is compared to placebo. So it's harder to isolate the positive impact of a bortezomib in terms of maintenance. There have been several non-randomized trials that have looked at bortezomib in the context of consolidation therapy, post transplant and also as longer term maintenance, but they haven't been randomized. I think the day is coming, however. Our colleagues at MD Anderson, namely Dr. Shaw, have examined the combination of ixazomib in combination with lenalidomide as maintenance post-transplant in the phase two trial. And I suspect that eventually, this combination will be assessed in a randomized fashion, and we will know based on a highly rigorous randomized trial, whether the addition of a proteasome inhibitor to lenalidomide or Revlimid as maintenance therapy benefits patients.

Jenny: This is the challenge that you have, right? It's a great blessing to have all these new drugs available, but it's a challenge because you can't test everything you want to test. There are all these different iterations of combinations that you could potentially try, and then the challenge is, “how can we get enough patients to join these trials so that we can come to these conclusions in a meaningful way?”. So it's a challenge for you. We started this show with the objective of helping patients understand clinical trials so they would be willing to consider them because this is how myeloma care advances is through these trials.

So I want to talk to you about your open trials because you have a Panobinostat and then a Revlimid, Velcade, Dex trial and then you have the Revlimid, Velcade, Dex plus elotuzumab and then another one with Pomalidomide, Velcade, Dex and elotuzumab. So I guess my next question would be, if these proteasome inhibitors are are not going away anytime soon, (everyone thinks, oh, gosh, these new immunotherapies are coming out and that's going to be the “end all”) would it be more be so that you are using these combinations and adding, like you said at least three drugs together, and possibly even in fours.

Dr. Laubach: Yes. That has certainly been an interest of ours here at Dana Farber and at other sites as well. What we're seeking to do is really build on the existing foundation of clinical trial data to make things better and that's really the intent with a regimen for example like Panobinostat in combination with Revlimid, Velcade and Dexamethasone. We know based on a decade's worth of experience that the Revlimid, Velcade, Dexamethasone combination is quite effective. Can we enhance that with the addition of Panabinostat?

We have conducted this trial in relapsed disease of Panobinostat in combination with Revlimid, Velcade and Dexamethasone. We'll be presenting a poster at ASCO to describe the results of that study to date. It hasn't completed enrollment as yet but we have had enough enrollment to date that we are comfortable presenting the preliminary data for that particular combination and it looks quite positive and encouraging.

Dr. Shaw from MD Anderson has previously presented the experience at their site of that same combination, Panobinostat in combination with Revlimid, Velcade and Dexamethasone in patients with newly diagnosed disease. This was reported at the ASH meeting last December. So this combination I think holds a good bit of promise which is exciting. The Revlimid, Velcade and dexamethasone plus elotuzumab combination likewise is performed with the intent of adding more benefit to patients with the addition of elotuzumab which is you know was FDA approved in combination with lenalidomide and dexamethasone in late 2015. This is a trial that we have led through the Multiple Myeloma Research Foundation and collaborated on with multiple other sites around the country. We have completed enrollment to that one actually and patients are currently being actively treated on that and we are eager to see over time how well patients tolerate it, and whether they derive clinical benefit from this combination.

The Pomalidomide, Bortezomib Dex or Pomalidomide, Velcade Dex regimen has shown great promise to date, and these results have already been published and our colleague Andrew Yi at Mass General Hospital is leading this trial of elotuzumab and combination with Pomalidomide Velcade and Dex. Then we're conducting a straightforward trial of Lenalidomide in combination with subcutenous Velcade and Dexamethasone to gather more information about the safety and effectiveness of these three drug combination, and also gather more information about the use of subcutaneous bortezomib as maintenance therapy, because a component of patients or a portion of patients on this clinical trial who have higher risk disease characteristics are going to receive not only Revlimid but also subcutaneous Velcade as maintenance therapy in this study. These are just a few.

Jenny: That study is for newly diagnosed, right?

Dr. Laubach: That is for newly diagnosed.

Jenny: Okay. And the others were for relapsed refractory patients like the ones with the Elo and the Panobinostat, right?

Dr. Laubach: Actually the Revlimid, Velcade, Dex plus Elo was also newly diagnosed. The Panobinostat, Revlimid, Velcade, Dex and the Pomalidomide Dex plus Elo, those are both relapsed trials.

Jenny: So many different combinations, it's amazing. My last question before I open it up to caller questions then I have a few written questions I have received by email, but what do you believe is the future of these proteasome inhibitors in the era of more immunotherapies and are there combinations that are getting us closer to a cure in your opinion?

Dr. Laubach: I think that there is no doubt that the proteasome inhibitors will remain part of the foundation for myeloma therapy for newly diagnosed disease for relapse disease, and potentially especially with ixazomib now available with his favorable toxicity profile potentially even in smoldering myeloma but that remains to be seen. But certainly, a newly diagnosed disease and in relapsed disease, the proteasome inhibitors like the immunomodulatory agents lenalidomide and pomalidomide are going to remain foundational and we will see as new classes of drugs like the PD1 checkpoint inhibitors and other exciting new classes of drugs added into the mix. I think this practice is really based not only on our experience in myeloma therapeutics but on developments in cancer chemotherapeutics in general over the past not just due to the three decades.

But really the last 50 years where we have learned over time that drugs with distinct mechanisms of action can be given in a complementary way provided that their toxicity profiles allow for that and as a consequence of their complementary modes of anticancer activity, the potential for better, deeper and longer responses to treatments are there. Ultimately we certainly hope that this will lead to the possibility for a cure I think with a new era a treatment of monoclonal antibodies in multiple myeloma, the idea of achieving deeper responses with combination therapy is already being seen, and with new classes of drugs like the checkpoint inhibitors, that prospect improves even further.

Jenny: It's exciting to see what's happening in myeloma treatment and really wonderful for patients to have all these different and new options. I want to open it up for caller questions. So if you have a call, if you have a question for Dr. Laubach, please call 347-637-2631 and press 1 on your keypad and we'll start with our first question. Go ahead with your question.

Caller: Thank you very much Doctor for making yourself available. I at least have two quick questions. I have been on sub-Q Velcade for three years following a 7-year CR. And I have never gotten a CR from Velcade in the Dex which was what I'm also taking, but I have gotten pretty close. So for three years of partial remission, I'm at a point now where my numbers are starting to freeze up. So I have two questions. First one is would there be any benefit in adding and switching to Carfilzomib after all that exposure? And the second question is, you are familiar I guess with the abstract coming up about using carfilzomib with Vel Dex in relapsing patients in getting really good survival. Would you add that now or would you add that later? I'm completely asymptomatic.

Dr. Laubach: First of all congratulations on a really, really long standing response to your seven years of complete response and now three more years in a good response. That's absolutely wonderful. As far as next steps, I guess I would say two things. One is from your history, what little I know of it, you certainly demonstrate sensitivity to proteasome inhibitor therapy. Regardless of whether you turn next to carlfilzomib or potentially turn next to a regimen that incorporates ixazomib. I think you have once again a very, very good chance of recovering. You certainly seem to be in a situation, or an individual who has sensitivity to the proteasome inhibitors, which is wonderful. And I do quite well regardless of which next regimen you turn to.

The second point would be though however that you have now had three years on a proteasome inhibitor and oftentimes in our practice, because over the past decade, the proteasome inhibitors and the immunomodulatory drug have been really the cornerstones of our therapy. We will -- in a patient who is progressing on a regimen that's predicated primarily on a proteasome inhibitor, will convert to a regimen that incorporates an immunomodulatory drug. You might have the opportunity to be treated with carlfizomib plus len dex, outstanding regimen based on the Aspire trial. You would have the opportunity to be treated potentially with a combination that build on lenalidomide, which as you likewise know is an outstanding drug or even pomalidomide. With regard to lenalidomide, it's approved with carlfizomib as we alluded to with ixazomib and with elotuzumab, and there is emerging data on daratumumab in combination with both lenalidomide and pomalidomide.

Without knowing more about your history than we can really delve into and the context of a call like this, it's hard for me to necessarily make a suggestion one way or other but I do want to emphasize those two points. One you've had a great track record with proteasome inhibitor therapy and I suspect that you'll do well with whatever proteasome inhibitor you might receive in the future, whether that's part of your next line or the next line after that. But secondly, as your next line of therapy, I would presumably get an immunomodulatory drug with either lenalidomide or pomalidomide in there somewhere and your doctor can talk to you about the different options with respect to combing len with proteasome inhibitor or monoclonal antibody like elotuzumab or daratumumab.

Caller: Thank you very much.

Jenny: Thank you so much for your question. Okay, we have a written question from Jane who says: “how does myeloma become resistant and escape and then are there other combinations we can use to make it more sensitive. In another Myeloma Crowd, Dr. Siegel mentioned that an HDAC inhibitor made IMiDs work again. Is there anything similar that will make a proteasome inhibitor work again?

Dr. Laubach: That's a terrific question as well. And I think at the most fundamental level, what makes a given patient's cancer resistant to a therapy that have previously worked, is the presence of new mutations within the cell. These cells or clones of cells as they referred to are very dynamic cells. They're changing. They're evolving. And we seek with our therapy to suppress the growth of these clones and their capacity to evolve with our initial therapy or really whatever stage of treatment a patient may be in. But none the less, we face the reality that in spite of these formidable pressures exerted on the cancer by the chemotherapy, these clones continue to evolve.

And what does evolution mean? Well it means that things are happening at the level of both DNA and protein that impact the way that a given cell responds to chemotherapy. And ultimately over time, if those changes reach a certain level, a given treatment that had previously been effective is no longer effective. Then you have disease resistance and as a result disease progression. So it's been shown in both the preclinical context as well as in the clinical context that adding a new drug to a drug that was -- to which a patient that become resistant can in some instances allow for a renewed response, for a response to therapy to happen again.

Percentages, it's hard to say but probably safe to assume that 20 or 25% of patients may experience a situation like that. The alternative of course is just to turn to a different class of therapy. I think that some of the monoclonal antibodies that have been developed with elotuzumab and daratumumab as well as some of the monoclonal antibody therapies that are in development now, the so-called immunotherapies including the PD1 inhibitors or checkpoint inhibitors, do have that capacity to reverse resistance by affecting cellular process -- intracellular processes that are contributing to resistance.

Jenny: Okay. That's fascinating. Just to go along with that, my final question would be I just read recently about this new gene called this TJP1 gene that might be able to tell us who will and won't respond to proteasome inhibitors. Do you have any insight on that and I guess part of the gene expression profiling test, my PRS test to do that pretty interesting? I don't know if how far long that is but will that help us at all understand for whom these drugs are the best?

Dr. Laubach: I think that this is a very exciting new development in the field. This work comes out of Dr. Orlowski's Laboratory and Treatment and MD Anderson was just published in Cancer Cell. It appears on the basis of this work that this TJP1 molecule or its level within a given patient with myeloma may provide insights as to whether a given patient will respond to proteasome inhibitor therapy, and of course that is of great interest because we want to be treating patients with drugs that we have the most confidence are going to work. This is a scientific publication and I would imagine that Dr. Orlowski and his team will be evaluating this in a clinical setting in the months and years to come and we will learn more about its potential to help us predict which patients are going to most benefit from proteasome inhibitor therapy.

Jenny: Okay. Well we have kept you over Dr. Laubach but our conversation is so very interesting. We are just so grateful that you joined us today. It's clear that you are a true myeloma expert, and understand how best to apply these different tools that we now have which is so exciting that we have the tools and so wonderful that we have people like you that know how to use them. We're just so very grateful for your research and all your efforts for myeloma patients. You work hard every day on our behalf and we're just very thankful.

Dr. Laubach: Well I'd like to thank you once again Jenny for the opportunity to be part of the program today and really just to emphasize what a tremendous privilege it is to work with our patients and to work in this field and what a great, great source of excitement it is to see so much progress being made.

Jenny: Well we're excited to hear what you have for us next. So keep us posted and we'll have you on again. It was very nice talking to you. Thank you so much.

Dr. Laubach: Thanks again.

Jenny: Thank you so much for listening to another episode of Myeloma Crowd Radio. Join us for future shows to learn more about the latest in Myeloma Research and what it means for you.