Ravi Vij, MD
Washington University
Interview Date: February 6, 2019

A new CD38 targeted monoclonal antibody is coming soon to the myeloma clinic. A new drug called isatuximab is making its way through the FDA approval process. Learn how it will be used in combinations, how it could be used in smoldering myeloma, how it is administered and why quad therapies might be a great place to use this drug. Dr. Ravi Vij of Washington University was a Principal Investigator on several of the isatuximab trials and shares more about this new drug. He shares more about MRD testing in myeloma and past successes of drugs in this class. Having more options is always a good thing for multiple myeloma patients and we're happy to see more therapies represent greater progress in the field of myeloma.  

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Jenny: Welcome to today's episode of Myeloma Crowd Radio. I'm your host, Jenny Ahlstrom. We're excited you're joining us today for this important show and I want to give you an update on the new tool we created just for myeloma patients called HealthTree. If you haven't heard about it, or you're not already in using the tool, HealthTree was created specifically for myeloma patients and it can help you obtain better outcomes and have better conversations with your doctor.

With HealthTree you can find treatment options you can consider for every stage of disease for your personal situation and we encourage you to take the treatment ideas that you'll find in HealthTree to your doctor and talk about the different treatment options that are available to you. As we'll talk about in this show today, there is a growing list of treatment options. You'll also be able to find clinical trials that you are personally eligible to join so instead of a list of 450 trials on ClinicalTrials.gov that you might find for multiple myeloma, you'll be able to find a more personalized list.

You can also keep everything you need to know about your myeloma in a single place including the ability to track your labs automatically. It's been interesting people joining HealthTree are learning a lot about the type of myeloma they have or their myeloma genetics just by using this tool. You'll also be able to share your myeloma stories to other patients and researchers can learn from your experience and you can learn from others. You can print a summary page for second opinions and you can review reports based on shared anonymous data in HealthTree. We'll be adding a lot more value to patients in the coming months that will include some patient education, a way to find and communicate with patients in similar situations and a researcher portal. We're just thrilled. We've now been working with myeloma facilities to invite their patients to join and we have over 2,500 patients using HealthTree.

Just a note about that, we have a generous donor who is putting a matching grant in place for the first half of this year for HealthTree and they will match up to $500,000 or half a million dollars in donations so we're inviting your support to take advantage of this match and you can find that donation link on www.HealthTree.org at the top of the page.

Now onto our show, we are blessed to have Dr. Ravi Vij at Washington University join us today for this show. Welcome, Dr. Vij.

Dr. Vij: Well, my pleasure. Thank you very much for the invitation.

Jenny: Well, thanks for joining us. Before we get started, let me give introductions for you. Dr. Vij is a Medical Director of the Siteman Cancer Center at Washington University and Professor of Medicine, head of Bone Marrow Transplant and Leukemia Section. Dr. Vij received his medical degree in India and his post-doctoral training at Rush Presbyterian St. Luke's Medical Center in Chicago and Fellowships in Medical Oncology and Hematology at Washington University.

Dr. Vij is a member of several professional societies and serves on numerous national committees including the Clinical Trials in Oncology (or CALGB) Transplant, Myeloma, and Leukemia Committees and the Steering Committee of the Multiple Myeloma Research Consortium and the CTN Myeloma Committee. His honors include the MMRF Collaborator Award in 2017, the MMRF Innovator Award and the MMRC Center of Excellence Award. He was also listed in Best Doctors in America. He's the author of over a hundred peer-reviewed publications as well as a book called Contemporary Management of Multiple Myeloma. He reviews several journals including Blood, Clinical Oncology, Bone Marrow Transplantation, Experimental Hematology and Haematologica.

His academic interest include the treatment of myeloma and stem cell transplant and there's also some very unique work that's being done at his facility on nanotechnology. He leads numerous clinical trials and has established a large myeloma tissue bank at Wash U and has extensive active collaborations to study the genomics of a disease as well.

So Dr. Vij, thank you so much for joining us today.

Dr. Vij: It's my pleasure. Thank you very much once again for the invitation as I said.

Jenny: We are going to talk about kind of a specific class of drugs and then a specific drug within that class called monoclonal antibodies. It's a new drug that's coming to the clinic hopefully to be approved soon called isatuximab. So maybe you just want to give us a little bit of background first on how monoclonal antibodies work because we are already familiar with some of these in the Myeloma Clinic right now and you had several years of experience to work with these.

Dr. Vij: Correct. Monoclonal antibodies are a group of drugs that recognize certain molecules on specific cancer cells and thereby attached to these specific antigens and then by usually activating the immune system lead to the depth of the cancer cell. Monoclonal antibodies have been around for well over two decades in a variety of cancers, first in lymphoma but in myeloma two. Now you had monoclonal antibodies for over two years. Both daratumumab and Empliciti are drugs that we've been using in this span of time and belong to the class of monoclonal antibodies. So they work mainly by recognizing certain receptors on the cancer cell of interest and then usually through a mechanism of immune activation killing the cancer cell.

Jenny: What responses have you seen in the clinic by using these? Because this is really a new class of drugs that didn't exist before for myeloma?

Dr. Vij: Correct and I think there's a lot of excitement about this class of drugs. We, as I said, already have two drugs in this class that are commercially available. Both have been very important additions to our armamentarium of treatment for myeloma. The one drug that we will talk about a little later would probably be the third drug to be added to this.

Now, the ones that we already have as I mentioned are daratumumab, or Darzalex and Empliciti, or elotuzumab. The drugs were initially approved for use in patients who had progressed after initial treatment and then they have been studied in multiple other scenarios. Daratumumab also is now approved for us in the frontline treatment of patients who are not likely to undergo a stem cell transplant. I think there is an expanding indication. Empliciti too has a trial that is expected to read out which may lead to its role for frontline use as daratumumab got recently.

I think going forward, these drugs will become increasingly incorporated in frontline therapy in addition to the relapsed/refractory setting where they're already being used.

Jenny: Yes. It seems like they’ve had a good impact for relapsed refractory patients. They're moving a lot earlier for newly diagnosed patients so that's really exciting in my opinion. Now you mentioned daratumumab and Empliciti and daratumumab targets CD38 which is also the target for the drug we're going to talk about today. But Empliciti, Empliciti targets another target. Can you explain the targets and what does CD38 do and maybe for Empliciti, what does SLAMF7 do? What are the differences? Why go after these particular targets?

Dr. Vij: Sure. So the thing is you're trying to go after targets that are expressed on myeloma cell, either exclusively or to an extent or expressed on myeloma cells that are not targeted indiscriminately on other cells. The target, CD38, actually is surprisingly expressed not only in myeloma cells but on several additional kinds of cells in the blood compartment. Actually, for a long time there was some hesitation in going after this target for multiple myeloma because it was felt that one would have off-target effects and potential toxicity because they said this target is not totally unique to myeloma cells.

It came as a surprise when daratumumab was clinically studied that off-target effects were minimal and some of these is probably related to the fact that the highest expression of the CD38 antigen is on the myeloma cells and though other tissues express it, it is at low levels and so most of the drug targets the myeloma cells. The drug certainly works, as I said, through the immune system to kill the myeloma cell directly but there is increasing evidence based on laboratory data that it has a lot of other mechanisms by which it could also help kill myeloma cells not only by direct effects but also by stimulating immune cells directly to attack the myeloma cell and removing some protective effect that the immune environment provides to the myeloma and thereby removing that sheltering effect that myeloma cells have created around them. I think that we're still learning a lot about this drug.

In regards to Empliciti, as you mentioned, it targets a different antigen called SLAMF7. SLAMF7 actually is expressed much more exclusively on myeloma cells than CD38. It does also get expressed on a one kind of subset of immune cells which we call NK cells. The SLAMF7 antibody Empliciti does not have activity as a single agent. It requires combination with other drugs especially of the class of immunomodulatory drugs like lenalidomide and pomalidomide to exert its benefits. Daratumumab does have activity on its own as well, however even daratumumab works better when combined with other drugs.

I think that these drugs certainly are now being used in routine clinical care very commonly for relapsed refractory disease.

Jenny: They are typically used with other treatment combinations like a proteasome inhibitor, an immunomodulatory drug and then maybe a steroid. I heard one of the doctors say that four drug combination are becoming more prevalent. There were some studies done that I read about that used another chemotherapy like a Cytoxan or something. They added that as a quad but then they found out that it had too many toxic side effects but adding one of these monoclonal antibodies to an existing triplet combination might be just fine because you mentioned earlier that it didn't have a lot of extra side effects. That's why they are coming up earlier in the clinic and using them in quads.

Dr. Vij: Very true. So the thing is as you've just mentioned we very routinely use three drug combinations in treatment of multiple myeloma and there has always been the desire to add a fourth drug to make them the so-called “quad”. Previous efforts to do so relied on agents that were available which were mainly of the class of conventional chemotherapy drugs and those did not conclusively show much improvement in effectiveness and also did show some increased toxicity.

Quads did not get established in the treatment of myeloma, but now with the advent of monoclonal antibodies and very limited toxicity profile, there is great enthusiasm to actually incorporate them into the quad strategy. In that regard, the first quad is already approved by the FDA for treatment of patients who are not transplant eligible and that quad is a quad that combines daratumumab with Velcade, melphalan, and prednisone.

The regimen hasn't been utilized very much here in the United States because we try not to give a melphalan-containing regiment these days. The strategies are needed to get the drugs approved through the FDA but clinically this regiment is not a very attractive one to use. In that regard, there are other quads that are under study that will probably be adopted once insurance is able to pay for them and those include combining both daratumumab and Empliciti with a triple combination of either Velcade, Revlimid and Decadron or Kyprolis, Revlimid and Decadron.

The drug that we will talk about also later in the program is being looked at as a quad for future use in the frontline setting.

Jenny: Well, let's go ahead and talk about that drug. So it's called isatuximab. Do you want to describe what it is and how it works?

Dr. Vij: So isatuximab is another monoclonal antibody targeting CD38, the antigen that we discussed as the target for daratumumab already. The drug is made by a different pharmaceutical company. Sanofi is the manufacturer. This drug has been under study now for several years and we've worked extensively with the drug at our institution in a number of clinical trials and have published and presented at medical meeting.

The drug currently is being studied and reported mainly in the relapsed refractory setting. The drug both as a single agent and in combination seems to have very similar activity as demonstrated by daratumumab. The drug is likely to be approved. It is expected sometime later this year if all goes well in combination therapy with pomalidomide and dexamethasone. So pomalidomide is a drug that we know has already been on the market now for a few years and is already combined with both Empliciti and with daratumumab and earlier approved to do so. So now we would have a third agent of the monoclonal antibody class that we could combine with pomalidomide and dexamethasone.

The drug will ultimately move into earlier lines of treatment including frontline therapy, also as part of a quad possibly as we just discussed. The drug has activity certainly as I said comparable to daratumumab. What we do not know is whether it would work in patients whose disease has progressed through daratumumab. The drug does attach to a slightly different part of the CD38 antigen so it theoretically could have some activity potentially but that remains to be clinically proven in daratumumab failures.

Jenny: Okay. Now, can you talk about the level of CD38 that somebody might have because one of the things we're actually capturing in HealthTree is some of these CD markers. We don't know if they are important or not important but they could be important later, just kind of like the percentage of certain genetic features that you might have might be important?

I've heard sometimes patients lose the CD38 marker. You talked about different levels of CD38,. Is that important at all as a level of CD38 that you might have when you're thinking about using isatuximab?

Dr. Vij: So that certainly is an important question and the true answer to that is not known. At the moment, we do not look for certain level of CD38 expression before giving patients the drug. Literally, all patients have expression of CD38 on their myeloma cells especially when they've been not exposed to daratumumab in the past. The antigen is postulated once patients get treated with daratumumab. It does possibly disappear from some of the myeloma cells. There is some data that has been generated in the laboratory that suggest that exposure to the drug engenders this protective mechanism whereby the cells, cancer cells try to shed the antigen and thereby protect themselves from the effects of daratumumab. This however is something that still remains to be clinically proven as a mechanism of daratumumab-based resistance.

Yes, I think that at the moment the antigen is presumed to be present and we do not necessarily test for it before treating the patient with the drug. 

Jenny: I think that might be something interesting to look at, like what you start out with or how much you have. You talked about the loss of this CD38, a way that the myeloma tries to hide from this drug. I'm just wondering now that some work has been done for several years on this drug targeting this particular CD38 target, can you tell for whom or which patients this isatuximab might be most effective?

Dr. Vij: Well, I think that honestly it would be most effective for patients who have not seen CD38 targeting therapy before. I would say that ultimately its best chances of working would be in a patient who hasn't had perhaps any treatment and is being given as part of frontline therapy either as a triplet or a quad as we just mentioned. The drug approval however initially will be for relapsed refractory population and in that regard, once again, we will have to see as we develop experience what its potential is for patients who have had daratumumab like a lot of patients these days get in earlier lines of treatment.

If it has activity in patients who have progressed on daratumumab then certainly it would be much greater benefit to a lot of patients.

 Jenny: Has any work been done to determine which patients will become resistant to these anti CD38 treatments when you go back and you retrospectively look?

Dr. Vij: Sure. So we may have briefly alluded to this a few minutes ago that yes, there are a lot of research labs looking at the mechanisms of CD38 resistance and one of them has been at least in the laboratory, have been demonstrated to be the loss of CD38 expression on the plasma cells. There are also reports from laboratories that giving certain drugs like a vitamin A called ATRA which we use as actually a treatment for a rare leukemia called acute promyelocytic leukemia may actually increase the expression of CD38 on the cells so people are actually even interested in combining this class of drug with daratumumab to see if it can make it more effective. It remains to be seen whether this is going to be clinically a successful strategy or not.

Jenny: Interesting. I know that this isatuximab will probably like you said will be approved for relapsed refractory patients. Do you think the approval for newly diagnosed myeloma with daratumumab will help approval speed in general just because it's a similar target to something that is already approved, or does it just take the same amount of time to get moved up to the frontline?

Dr. Vij: I think unfortunately it does take its own time because you do need to complete the study that is currently enrolling, but that study will require either follow up because in any study wherein you're comparing it to an arm which already could potentially give three plus years of benefit and you're trying to improve upon that standard, you need to go at least that length of time or longer before you can actually say your study is successful. So I think that the frontline use of drug like isatuximab would probably be a few years down the road though daratumumab, as I've said, is already approved for frontline treatment in a slightly different cocktail of drugs. There was data presented with daratumumab in combination with Revlimid and Decadron at the ASH meeting in 2018 December called the MAIA study which is expected to also lead to approval for daratumumab with Revlimid and Decadron in frontline settings later this year. 

Jenny: So that's a combination that does not have a proteasome inhibitor with it, right? So, it's just a different triplet combination. That will be interesting to see what benefit you gain or lose by not including that drug class, right?

Dr. Vij: I think that again, we know that trials with daratumumab in combination with both proteasome inhibitors and independent trials with immunomodulatory drugs have shown that the daratumumab adds to the efficacy of the proteasome inhibitor and lenalidomide or Revlimid in independent studies.

 

Most folks have felt that the immunomodulatory drugs are a better fit for combination with daratumumab given that mechanistically these drugs like lenalidomide and pomalidomide give a boost to the immune system that the daratumumab relies on for exerting its anticancer effects to a large degree. It is also demonstrated that drugs like Velcade and carfilzomib could potentiate the effect of daratumumab on myeloma cells but it doesn't usually work through the immune system to do so. Those drugs independently directly attack the cancer cell. I think that there is potential for both those classes of drugs to work in combination with monoclonal antibodies of CD38.

Jenny: I like what you said earlier in this show too about how it might be managing the bone marrow microenvironment or what's happening around the cells, not just attacking the myeloma cells. I think that's a really interesting concept.

Well, maybe we should talk about the clinical trial results that they've seen so far. So I know we just really shared an article about the phase three results that just looks like they're out  for  isatuximab, pomalidomide and dex, which you mentioned. Do you want to talk about that study and then we'll talk about some other studies that it's being used in right now?

Dr. Vij: Sure. So the one that you're just referring to is a study that I think we will be seeing actual results presented at a scientific meeting perhaps sometime later this year but presently it was giving very topline data to say that the study was positive that isatuximab when combined with pomalidomide and dexamethasone was better than pomalidomide and dexamethasone alone. We did not in this press release I believe have any specific numbers to put to the results. The details will be presented at the meeting obviously. This is the trial that is expected to lead to the approval of isatuximab in patients with myeloma so it's exciting that we now do have the topline results saying this trial was a success. The drug obviously has been through a number of other studies and continuous to be looked at in both frontline setting as we said and in relapsed refractory disease in other trials.

Jenny: Do you want to talk about also some of the other studies like how it might be used in smoldering myeloma?

Dr. Vij: Correct. I think that the drug is being explored not only in multiple myeloma but there are studies afoot to look at the role of monoclonal antibodies in smoldering myeloma. Smoldering myeloma as you know is an entity which is associated with excess of plasma cells in the bone marrow and usually a cancer protein in the blood but usually not associated with much in the way of apparent organ dysfunction so about 15% or so of patients are picked up at the smoldering myeloma stage. It has been always the subject of great interest to see if treating patients in the smoldering myeloma stage would lead to better long-term outcomes in terms of improving long term survival.

This is something that still remains an unproven paradigm. There was a study that was done by a Spanish group and published in a prestigious medical journal, The New England Journal of Medicine several years ago that seem to suggest that lenalidomide with dexamethasone improved long term outcomes in patients with smoldering myeloma. However, there were some, without getting into too much detail, issues with the study that have prevented it from being adopted as a standard worldwide, though in Europe it is often resorted to.

But people who want to explore the smoldering myeloma space in trials, the use of monoclonal antibodies in smoldering myeloma actually is very attractive because once again as we said, these drugs at least as a single agent have little in the way of toxicity and so are pretty well tolerated and so to give a asymptomatic patient a drug, you want to make sure you're not creating a problem where none exist.

In that regard, daratumumab is currently under study, in a phase three study trying to get approvals for treatment of patients with smoldering myeloma. Isatuximab being a similar antibody too would be an attractive agent to use in this group of patients. How the development of the drug proceeds remains to be established.

Jenny:  I think they do have an open smoldering myeloma study for isatuximab.

Dr. Vij: Sure, yes.

Jenny: Yes, that's interesting. I saw also because I was looking at different clinical trials and different combinations and it looks like it's being combined with a drug called cemiplimab and I don't even know what that is. I'm just curious if that's another immunotherapy and maybe that opens up a whole new concept?

Dr. Vij: Sure. Cemiplimab is a drug that belongs to a class of drugs called checkpoint inhibitors. There are a number of checkpoint inhibitors that are marketed. This drug has been marketed for a skin cancer. Others, some of which your audience maybe familiar with, drugs like pembrolizumab, nivolumab, atezolizumab have been targeted for a variety of other cancers from lung cancer to melanoma to bladder cancer.

These class of drugs called checkpoint inhibitors also often referred to as PD-1, PDL-1 inhibitors have been looked at in myeloma . There was a lot of excitement toward these group of drugs a few years ago when it was seen that those again, as a single agent they lack much activity, when combined with drugs like lenalidomide and pomalidomide, the activity appeared to be fairly robust.

Unfortunately, the enthusiasm for these group of drugs were somewhat hampered when a large set of phase three studies with pembrolizumab both for untreated myeloma and for patients with disease that progressed on prior treatment showed that there was excess side effects that emerged when these drugs were combined. The fact is that the immune system is a very powerful system to attack cancer and when you start combining drugs that activate the immune system then the immune system often goes into overdrive and causes side effects by attacking normal tissues in the body as well. So that is the experience that we have with pembrolizumab.

Now, after that experience, the FDA put on hold any development on checkpoint inhibitors in combination with lenalidomide or pomalidomide but has allowed further trials to combine checkpoint inhibitors with other classes of drugs. So combining a CD38 antibody with a checkpoint inhibitor is one strategy that people want to pursue. There are trials that are currently ongoing with daratumumab in combination with atezolizumab and other checkpoint inhibitors in combination with daratumumab.

I think that along the same line it makes at least a clinical sense to explore the combination but again a lot caution is warranted given the experience that we have had with pembrolizumab when combined with lenalidomide and pomalidomide.

Jenny: Right, because the immune system is really complicated like you said. Okay, so I know they have a clinical trial open also using isatuximab with carfilzomib. Do you want to talk about that particular strategy?

Dr. Vij: I think that once again the concept of combining a proteasome inhibitor with an antibody to CD38 makes logical sense. Already as we said, daratumumab in combination with Velcade is an FDA approved option. Carfilzomib is in the same class of drugs as Velcade and isatuximab is in the same class of drug as daratumumab. So it makes logical sense to use this kind of combination. There is data with daratumumab in combination with Kyprolis that already exist. There is data with isatuximab in combination with Kyprolis.

That also looks similarly promising. These are often, once again, part of a quad strategy in the relapsed refractory setting. Kyprolis, Rev, dex with isatuximab is a combination that has been presented at trials and I think it is something that we'll have to see as time goes by whether it becomes clinically applicable standard.

Jenny: Right. That's why all these studies are being run, right? I know there is a study for newly diagnosed patients with isatuximab in this quad kind of approach using Velcade like you mentioned before and lenalidomide, Revlimid and dex, do you want to talk about that one?

Dr. Vij: Yes. So that study is again as I alluded to, trying to see if a quad can become a standard of care in the future so this study, the IMROZ study, the acronym stands for you know the title of the study but the study is something that is looking for patients who are not eligible for transplant. They are randomized to either bortezomib with lenalidomide and dexamethasone or the quad with isatuximab, bortezomib, lenalidomide and dexamethasone. Bortezomib with lenalidomide and dexamethasone is a clinical standard for patients and we know that it has produced data showing approximately a three-year period of disease control so combining isatuximab hopefully will lead to even longer periods of disease control. But as we just alluded to earlier in our discussion, this trial will take a while to read out and the adoption of this regiment will probably be a few years down the road. 

Jenny: I wish things could go faster.

Dr. Vij: True.

Jenny: It's a little bit painful to watch some of these studies go through and know that they have to take years to figure that out, so when you mentioned the MRD status or minimal residual disease status, maybe we'll get to the point where we can use that as a marker instead of waiting for some of these other numbers.

Dr. Vij: You're right. I am endorsing your suggestion. I think that the FDA is cognizant of the fact that drugs are taking a long time to reach patients and they are always looking for what we call the surrogate markers that you can actually often be able to read out earlier and then declare victory and not have to wait years to reach the other more harder endpoints. 

Jenny: Right. Now, I know with daratumumab, it's IV administration and there are some infusion reactions and things like that when you get your first dose potentially. How was isatuximab administered and what's the typical schedule that they used for the administration?

Dr. Vij: The schedule is fairly similar to that of daratumumab. Now, the infusion of isatuximab is a little shorter than the FDA licensed regiment for daratumumab. Daratumumab as you know, the first infusion can often go eight to nine hours, subsequent infusions are often four hours plus. But even with daratumumab there have been studies that have been done that after the initial few infusions, you can give it over 90 minutes without a problem and a lot of centers including ours do that clinically.

Isatuximab however is even probably in the FDA label when it gets approved, going to have a shorter infusion time than daratumumab does. The drug is probably going to take two to three hours less for the first infusion and probably take a total of two to three hours in all subsequent infusions but as I said, daratumumab already we can cut the infusion time down as well.

Daratumumab also is being developed for use in a different formulation to be administered under the skin and it remains to be seen if isatuximab development may go down that path or not.

Jenny: Another issue I think that patients and doctors have found is that you are looking for this monoclonal protein number to measure how much disease you have left before and after treatment. Sometimes I think with daratumumab you might have this really small monoclonal protein or M protein number but it's actually caused by the drug. Do you know if that's the case with isatuximab also?

Dr. Vij: Yes. I think that the same issue does exist with isatuximab for patients who have what we call an IgG kappa monoclonal protein which quite a few patients with myeloma do often at the end of several months of treatment, you have a very small protein that is detectable on a test and a conventional test do not tell us whether we are measuring the drug or are we measuring for actual disease.

There are however tests that can distinguish this but those are tests that are special tests that need to be ordered and classically in the past we've not pre-ordered such tests for patients but now as we move into this new era, I think those tests may need to be done. There are new technologies being developed to follow myeloma that may actually in the future displace our serum protein electrophoresis that if it happens will abrogate the problem completely anyway

Jenny: We did hear about that and tried to share that information but that's kind of like a nuanced thing, right? So, if you don't know a lot about myeloma, you may not know that. That's why we recommend people to see specialists like yourself because sometimes those little things like that that people don't know or their doctor might not even know if they're in in a community on oncology setting.

I think with what you've talked about with isatuximab and different treatment combinations, I think it's fascinating to think about that we have so many different drug classes now that are coming out for myeloma. I know you talked about it being used with immunomodulators and not being particularly effective. But are there any other treatment combinations that you could see isatuximab with these other CD38 targeting therapies or monoclonal antibodies be used with especially in this new world order? All these immunotherapies are of exploding. You mentioned the checkpoint inhibitors but are there others?

Dr. Vij: True. I think that there are certainly a number of things that people want to combine to CD38 antibodies with. We've talked about as we said proteasome inhibitor class, the immunomodulatory drug class, the checkpoint inhibitor class. People are also exploring these with some of the other classes of drug that are likely to come into the treatment paradigm for myeloma in the years to come including a drug called Selinexor which may also be a drug that may get approval later this year. Daratumumab combinations with Selinexor have been reported and that seemed very intriguing, the results, and it is possible that similar results in the future maybe produced with isatuximab.

Also combining these drugs with more conventional chemotherapy options and drugs that we used to use in the past and don't use very early in the course of treatment but we do resort to them in patients whose disease have progressed on more an FDA approved therapies and they still work and so in that train I would say, drugs like bendamustine, Cytoxan are very aggressive regiments that combined all chemotherapy drugs, some go by acronyms like DT-PACE, DCEP. They too would be agents to combine daratumumab with.

The other class of drugs that everybody is excited about is the drugs that are targeting the BCMA antigen, be it CAR T-cells, be it BiTEs or antibody drug conjugates thereto combining the CD38 antibodies would potentially make sense. Obviously we haven't seen any data in this regard. They are still in development as single agents right now to BCMA directed therapies but once they have finished their single agent development, combinations with monoclonal antibodies like isatuximab could also be postulated for the future. I think there's a lot of potential combination that these agents could move into in the future.

Jenny: Yes, that's amazing for myeloma patients. That's what really stood out to me at ASH this year was just the sheer number of drugs being developed and drug classes being developed for myeloma. So it's a blessing and then it's a challenge to figure out what to put it together with, right? For each individual patient, that's hard.

Dr. Vij: I agree but it's good to have a challenge of abundance rather than a challenge of scarcity.

Jenny: Right. Yeah, a good problem to have, I guess.

Dr. Vij: Correct.

Jenny: Well, you said they anticipate approval sometime this year, is there any timeline that you're aware of or do we just don't know?

Dr. Vij: I don't know. I think that obviously the trial that has just read out as positive is the very first step before the data can then be cleaned up and presented to the FDA so it takes at least several months I think so I can't give you a firm estimate but I anticipate somewhere in the second half of the year perhaps. 

Jenny: Okay. That sounds terrific. Well, we would welcome another drug being approved for myeloma. It's very exciting for patients. Well, we'd like to open it up for caller question. If you have a question for Dr. Vij, you can call 347-637-2631 and press 1 on your keypad. So we will start with our first caller. Go ahead with your question.

Caller: Hi, Jenny. It's Dana Holmes. Thanks so much for taking my call. Hi, Dr. Vij. I'm a smoldering myeloma patient and Jenny's platform of offering us the opportunity to speak to a specialist such as yourself, it's just so appreciated so thank you so much for taking your time today to chat with Jenny and allow us to call in with questions.

Dr. Vij: My pleasure.

Caller: I have a question concerning in general the anti CD38 monoclonal antibodies. Are any of the studies designed to look at the different myeloma subgroup types to see how they respond to these drugs, in other words someone with a primary 11;14 or 4;14 or deletion 17p, is there any data to suggest that it might, that these drugs might work better so to speak in a particular subtype? 

Dr. Vij: Sure, that's a very good question. I think that the problem is that when you start looking at subtypes, the number of patients starts dwindling and it is often very difficult to do prospective trials limited to specific subtypes. So what one is left with doing is enrolling a broad group of patients and then going back and seeing if they can see patterns that suggests better outcomes in one group versus the other.

In that regard, one thing that was somewhat surprising to a lot of people is that the trials that have been reported in the frontline setting with daratumumab both the study which is called the ALCYONE study which combined daratumumab with Velcade, melphalan and prednisone and the MAIA study that combined daratumumab with Revlimid and Decadron failed to show that daratumumab added to the benefit for the high-risk patients.

I think that is something that one needs to certainly delve into further. In the relapsed refractory setting, that paradigm is not felt to be in play. I think that it is somewhat unique to the frontline trials that this observation has been made. So I don't want people to take away that if you have a high risk disease then you shouldn't get daratumumab in the relapsed refractory setting. But in the frontline setting it seems like it doesn't add much to the benefit that the drugs that we use today already provide.

Caller: Okay, and are you seeing relapses on patients using daratumumab, I guess, because that's mostly the drug that's in the clinics now, not so much in the controlled study as the isatuximab is now. Are you seeing relapses that are more of a non-secretory or in other words, people are having normal lab results, myeloma lab results and yet if they have imaging, they're finding myeloma activity?

Dr. Vij: I think that is a natural paradigm of the disease progression itself. I don't know if it is unique to the class of antibodies that we are discussing today. So the fact is that at the outset, only about 5% or less of patients are what we call non-secretors if you add what we call oligosecretors which are those that make some protein but relatively small and where trends are difficult to establish. Those numbers probably dial up to into 15% but the fact is that we have known now for a while that after patients have been through a multiple lines of treatment that their disease often does acquire non-secretory phenotype or gene is characteristic of non-secretors and are on data which we published a few years ago suggested that by the time patients have been through three or four different treatments, even before the era of monoclonal antibodies, that about one-third of patients that had previously had protein in the blood that one could rely on to follow the disease was no longer able to be followed appropriately by blood test alone and in that case, management sometimes becomes somewhat more challenging that one has to rely often on imaging like PET scanning and sometimes bone marrow biopsies to follow the disease.

So the short answer to your question is yes, that's what you're seeing but I don't want you to take away that that is unique to patients getting treatment with monoclonal antibodies. It is a phenomenon that occurs in all drug classes. I'm not aware of any data that suggests that it occurs more in patients who have had monoclonal antibody.

Caller: Okay. So it's just really more of the disease pathway that it just becomes more aggressive as it becomes harder to treat, I guess, after each subsequent relapse.

Dr. Vij: Yes, it is that we call that the cells de-differentiate that is they start growing without making the protein. 

Caller: Oh, gosh. What a tricky disease we have. And Dr. Vij, what about MRD testing, just in general? Are there any limitations to it? In other words, I realized that, I mean, I've had four bone marrow biopsies myself and each time there is a different percentage being reported and you know, it's more like the game of chutes and ladders, one time I could be, you know, I have a great report and I could be deemed MGUS if this was my first bone marrow biopsy but we know in past bone marrow biopsies, I'm well into the smoldering percentage stage. So aren't there still limitations to this testing and sample bias behind it? And if there is, how is the myeloma community moving forward by potentially using these types of tests for these end goals in clinical trials? 

Dr. Vij: Sure. Again, a very loaded question so I think that as far as MRD goes, there is more than one way to ascertain MRD. There is what we call flow cytometry based MRD and there is what we call next-generation sequencing based MRD which is predominantly right now being done through one company called Adaptive.

I don't know what technology has been used in your case to follow MRD. Having said that, yes, there is variability in the MRD. It is a very sensitive test and also, the fact is that MRD is obviously at the moment primarily done on the bone marrow specimen that you alluded to. The issue is that often it all depends on the quality of the specimen to know how reliable the test is. When you initially ask for a bone marrow, you get certainly predominantly the marrow from the bone but after a few CCs of bone marrow has been aspirated, what you're drawing is blood to a large extent.

It also depends on when you send this sample for analysis, are you sending the very first few drops of bone marrow that come out or are you sending that for a different set of test and then the next five CCs that you get in the end you're dispatching for MRD analysis? So there can be a large variability if you use the first CCs versus the last CCs say of five or sometimes greater CC aspirate. So yes, there could be variability in that regard.

Now, as far as the issue of how to utilize this, this is a subject of I think research at this time. The ability of MRD is mainly right now in patients who have achieved a conventional complete remission. If one has disease detectable by other modalities of treatment then -- I mean, modalities of testing then MRD is going to be positive anyway and makes little sense to test for MRD when you're picking up disease based on other tests in the blood or the bone marrow.

What also we do not know is really how to utilize this test. What we know is that the patients who achieved MRD negativity have usually longer periods of disease control than those who are MRD positive. But we do not know is whether giving patients who are MRD positive more treatment after they have received a few months of treatment or generating their treatment to get them to MRD negative state would lead to better outcomes. It seems rational to assume so but we've had instances in the past where these kind of assumptions have not proven correct when studied respectively. Likewise, we do not know if patients are MRD negative and they start showing some measure of MRD positivity whether intervening earlier in those patients will improve their outcomes versus waiting for more conventional changes to occur in the blood.

I think that this is an area that there is a lot of controversy in at the time being. Some people who are conservative in their approach feel that we need to generate the data to be able to say which is the best way to proceed. Others feel that generating data may take several years and one should just proceed on what appears to be logical.

Caller: Okay. This sounds like there are still a lot of open questions and it just you know makes the landscape so difficult for patients to navigate and to decide which pathway to take but I appreciate all of the researches being done by your group and by all of the others. And thank you so much for taking my call and my questions. I appreciate it very much. 

Dr. Vij: Much welcomed. 

Jenny: Thank you for your questions and Dr. Vij, thank you for your excellent answers. I appreciate it.

Dr. Vij: My pleasure.

Jenny: So yes, it's been a fabulous show and I just want to say thank you for participating and for helping us learn more about this new drug that will be approved hopefully soon in multiple myeloma.

Dr. Vij: Thank you once again for the opportunity to speak to your audience and I think that yes, we are in exciting times and a lot more drugs beyond this drug that we talked about also should be coming down the pipeline in the next few years so things are going to get even better.

Jenny: Yeah. Dr. Vij, we have actually one more question. I just barely saw it so if you don't mind. And before we answer your question, do you have a question?

Caller: Okay, this is Bonnie. Can you hear me?

Dr. Vij: Yes, I can.

Jenny: Hi, Bonnie.

Caller: Hi. Hi, Dr. Vij, wonderful conversation, Jenny and Dr. Vij. I have a question, since daratumumab is being used now for maintenance therapy as well and patients are on it for a number of years. Anecdotally some patients are reporting that they are needing more use of the IVIG in the clinic. Is there some long term effect of using a CD38 monoclonal antibody on general immunoglobulin production?

Dr. Vij: I think that is again a very active area of research. As you've mentioned, there have been some reports, more anecdotal, word of mouth that people are seeing some infection with sometimes with organisms that we traditionally have not encountered that commonly in myeloma or perhaps a higher rate of infection and whether this is related to general immune suppression or other causes remains to be established. But it could also well be that because people are getting multiple lines of treatment and are living longer and longer that the natural history of the disease is just changing and these infections would materialize no matter what patients got.

So whether this is unique to CD38, slight different spectrum of infections that some investigators are reporting or not, I think only time will shed more light on this.

Caller: Okay. All right. Well, thank you so much for taking my question and we appreciate your research and Jenny, these interviews more than we can say. Thank you.

Jenny: Oh, thanks. Thanks, Bonnie, for your question. And Dr. Vij, thank you so much for helping us understand this and just everything you're doing in myeloma for patients and also for research. It's really wonderful what you're doing.

Dr. Vij: Thank you very much once again for your kind words and again, we strive for our patients and I think we're going to see even better treatment as I've said, emerge in the not-so-distant future.

Jenny: It's so exciting what's happening. Well, we thank our listeners also for listening to another episode of Myeloma Crowd Radio. We invite you to tune in next time to hear more about myeloma research and what it means for you.