Multiple Myeloma

Interview OHIID02782



Interview Topics


multiple myeloma



Physician Demographics

TL # 10605

Specialty:  Hematology

Geography: Boston, MA

Interview Date =  01/22/2013



Interview Transcript


Let’s talk about myeloma.


We might need the whole day.



Coming out of ASH I would say that is possibly true.  That was a very data dense meeting.  You are the last thought leader who I am going to talk with in this series of post-ASH interviews.  I have gotten some areas of controversy.  Those are the things I want to start to talk about, to see where you fall out on some of them.  So they may not be in the natural order of what was presented at the meeting. 


That is absolutely fine.



I guess the consensus of the group is when looking at new mechanisms of action, so past our foundational drugs, past IMiDs, past proteasome inhibitors, the group of molecules that your colleagues have said to me they are most interested in are the CD38s. 





We have so many targets on the surface of these myeloma cells.  Why is there this consensus developing to go after CD38 either with daratumumab or with the Sanofi drug or with CARs targeting CD38 or antibody drug conjugates targeting CD38.  It seems like the hot area. 


It is.  I think multiple reasons.  The number one reason I would say came out because of the sexiness of daratumumab.  I think in the myeloma field.  Now, non-myeloma I would not know as much.  But in the myeloma area CD38 and CD138 are two very plasma cell specific targets.  I won’t say there is selectively only plasma cells, but we identify plasma cells forever using those two markers or one of the two markers.  So they have always been good targets.  Not pursued for various reasons for a long period of time.  Now there are CD138 antibodies in clinical trials too.  But CD38 was lagging behind a little.  But as the daratumumab results became a little better known it became two things.  One is that it does target myeloma and actually even in phase I/II studies we saw responses and even a complete response.  So even as a single agent it came out positive as an active molecule.  It also sort of relieved or satisfied the concerns that endothelial cells and other cells which do express CD38 are not being targeted and/or at least toxicity wise it is quite well managed.  I think confirmation that CD38 is a safe target and that it is an active target sort of has now become from only daratumumab which was around a couple of years ago to everybody else doing whatever they are doing.  I think that is the reason why I would think we all have.  And in this day and age when we have patients who get Revlimid, Velcade, carfilzomib, pomalidomide and a few other drugs we use, when they relapse from that we don’t see much single agent activity.  So if you take for example Revlimid.  Revlimid is always with dexamethasone.  Its approval is with dexamethasone.  And so many other drugs.  So to see a single agent activity, however small or otherwise, if it is a real single agent activity that is really exciting stuff.  So I would think my personal interpretation of why we are kind of excited about CD38 as a target.



So when I try to look at the on where these compounds are going it seems to me that for daratumumab this drug is heading into combination…and correct me if I am wrong about this, but I got the sense that they look like they are first going to try to do it in combination with bortezomib.  And then if I look at the Sanofi approach for SAR-650984 it looks like they are first trying to combine with lenalidomide.  And first, is that correct, and if so is Sanofi simply trying to find an area that daratumumab will not have already captured all of the thunder?


I agree, except I am sure the daratumumab guys also…so GenMab is now taken by BMS I think.



I thought they were Janssen.


Oh Janssen, sorry, my mistake.  I am almost sure they would also do Revlimid study because it will probably synergize and/or at least have additive effect with both agents.  And mainly because the Revlimid angle because it is very well known immunomodulator for antibody related cellular cytotoxicity.  It increases the ADCC and to some extent CDC too.  But the way it increases the activity of antibodies, Revlimid always is a great combination for any antibody agent.  I would be extremely surprised if Janssen would only restrict to Velcade and not use Revlimid.  Also, these stories are all going to be done in patients who are Revlimid/dexamethasone refractory at the end.  For approval purpose they will have to have those.  So whether you combine with Revlimid or Velcade you probably have to try both.  And Velcade is in my mind to be a little bit different.  There is some synergistic activity on in vitro studies too; from what I remember being told somewhere in some of the meetings at presentations.  So combining with Velcade was also meaningful from a preclinical study and then the same angle combining it with Revlimid, that Sanofi is doing, I think is I think almost a no brainer.



Are either of these drugs being formulated or coupled into these antibody drug conjugates yet?   


CD38 I don’t remember seeing data that is combined with the drug conjugate.  The one we just combined are CD138, and CD56.  We do not have CD30, which is a lymphoma drug now.  It used to be myeloma to start, but not anymore.  There are combinations.  The problem with combinations in general is, in all the combination drugs end up being combined with mainly mitotic inhibitors.  So if we look at the mode of action, they act like vincristine.  It’s not a very active drug in myeloma.  The problem with mitotic inhibitors is that you need dividing cells from mitotic inhibitors to work and myeloma is not a dividing cell in general.  Myeloma, if you look at labeling index, it is less than 1 percent most of the time; unless it shows high risk proliferative diseases.  So in general it is not a really great agent to be used.  So the reason the combinations are not of great excitement in myeloma and in other combinations, I mean the CD38, 138 is as good a target as you can find in myeloma.  But CD138 conjugate has not yet been a homerun.  There are some indications of something happening, but not a homerun mainly because I think the conjugated molecules are really not very active drugs in myeloma because of the differences in proliferative activity, etc.



Awesome.  We saw at the meeting some terrific results and there was a lot of press, it even made it to the New York Times where they were talking about the anti-CD19 CAR.  What do you think about a CD38 CAR?


Theoretically, I think a CD38 CAR would be interesting exactly because of the same reason.  It could be CD38, or CD138 CAR.  And CARs are right now en vogue because of the success in the NEJM from Carl June’s group about it.  I think CARs are going to be interesting.  How would it pan out because it is more of an adaptive immunotherapy, not active immunotherapy, it may have a little different angle.  But I think it may or may not end up being what one is hoping CD19 CAR is doing.



Okay.  Next topic.  I am going to sort of stay with the immunotherapy approach.  I guess historically immunotherapy has not been as effective in myeloma as, for example, renal cell or melanoma.  So a couple of years ago if I asked the panel about immunotherapy most of you guys would pooh-pooh it.  But I am hearing a lot of people make positive comments about either the PD1 approaches, like BMS has the PD1.  A lot of people focused me, coming out of this meeting about anything that is activating NK cells.  So talk to me about these kinds of immunotherapies.  Do you conceptually like any of them and have any of them shown you anything in terms of responses?


Yes, that is an area of my long-term interest.  My lab work focuses on immunotherapy and immune approaches and understanding immune system in myeloma, etc, etc.  So conceptually those are very all interesting things, especially PD1.  CTLA-4 is not as common but it is still a very good interesting target.  And whether it is PD1 or PD1L targeting or others, they have theoretical interest in that we can improve the immune dysfunction by blocking this and we can really improve either does it have a direct immune effect…how do I put it, by using this molecule we can activate the immune system enough or then we can do vaccine approaches to do that.  We have an ongoing study, for example, here where we do myeloma cell dendritic cell fusion and then combine it with PD1 blocking agent.  There are a number of them.  Some are more promising and some are not.



Quick question.  So the program that I think I know about that you guys have is using CTO11, which some people have questioned whether or not that is really a PD1 inhibitor in that?


You are very, very, up with the literature.  You are right.  We started with that thinking when we started it was known to be.  Now questions are raised by us and everybody else too.  I think we need the right targeting drug, whichever it ends up being, but it still is a good concept surely good things to do.



But BMS started a trial with their drug which that is one heck of a good PD1 inhibitor.  In melanoma it has had amazing results and I have seen the results in NSCLC. 


Correct.  Absolutely true.  But BMS has their focus.  And when the drug works in more frequent, prevalent diseases, then myeloma doesn’t get as much attraction with only a few thousand patients.  But I think combining it with really PD1 targeting drug, an active drug like they have, would be extremely interesting to do and I would think we will see some activity because PD1 is a pathway that has an effect on myeloma immune system.  And the same thing with the other thing you mentioned was anti-Kir antibodies, like one of them is Innate molecule.





So activating NK selectivity has indirectly been shown.  So PD1 is still untested, although very exciting.  But activating NK selectivity and having effect through this has been indirectly shown in myeloma.  So if we go back to the old days ten years ago where thalidomide activates NK cell function and has been shown as something that really activates NK cell function.  The same thing Revlimid does it.  There are a few other instances where NK cell mediated killing has been shown to be playing a role even in the regular treatment of myeloma.  And so then if you have agents that are activating NK cell function, whether it is anti-Kir or other approaches, I think are going to be theoretically quite important.  Now Innate’s molecule has been tested in smoldering myeloma and some results have been presented.  There is not anything yet that is super exciting.  But it is being tested in combination with Revlimid which even makes more sense because you can have NK cell activation and then have Revlimid mediated NK cell activation with two different mechanisms and then it would end up becoming quite exciting.  I think to me both approaches appear to be quite meaningful.  PD1 targeting or NK cell targeting approaches are quite important.  But by themselves may or may not be adequate.  So if you use in myeloma and other cancers just PD1 blocking may not be attractive enough in myeloma.  I would think we may need something more than that to achieve response.  Partly because the immune function in myeloma could be augmented and that then will lead to more activity of immune mediated mechanisms.



So other panelists have said they don’t really expect these immunotherapies to ever be a single agent.  But if you knock down the main wave of myeloma cells then bringing on immunotherapies like this where you have lower tumor burden seem to make much more sense.


Absolutely.  That is exactly true.  So I would never say never because we have seen so many funny things that happen in myeloma.  So vaccination alone in an advanced myeloma can still play a role.  And the reason I say this, is we are actually in our own center we have developed this peptide based vaccination and we are vaccinating smoldering myeloma patients with that.  So would it by alone or something else?  They can still do some activity, especially in early stage disease.  For example, the Innate molecule is being tried in smoldering myeloma that is a classic situation because it is not myeloma…goals are different, the patients are not treated with a lot of chemotherapy, etc, so we may see better eventual outcome.  But in general I think combination would end up becoming more attractive.



Good.  I want to touch on a couple of other mechanisms where people have shown some level of excitement to me and there were some presentations at the meeting, but I try to conceptualize where some of these kind of alternative mechanisms might fit in.  So the first one I want to ask about is the BAFF inhibitor from Lilly, tabalumab. 


Oh yeah.  So that is tabalumab?



Yes.  They have to change the name. 


I have no idea why all the antibody names have to be so complicated, but that has been the tradition and I think they will maintain the tradition.  So anti-BAFF is a great target from two angles.  Dr. Raje presented the work, she is from MGH next door to us, and she works with us.  And so anti-BAFF has shown significant activity but also in relationship to…so it has shown good activity and the data presented in combination with Velcade is very exciting.  And BAFF is a B-cell receptor, has effect on myeloma, anti-BAFF has an effect on myeloma and with Velcade it has very good synergism.  It also targets this dendritic cell plasmacytoid dendritic cells cell myeloma cell interaction, which biologically plays a very critical role.  We had actually a paper on the same issue in Cancer Cell, I think it is now a couple of years ago, plasmacytoid dendritic cells may be providing, important, great growth advantage to myeloma cell.  And anti-BAFF blocks that and that forms a good basis for doing it.  And the second aspect is a bone effect, that it does have some bone effect that provides a dual advantage in this system.  It may be also providing some immune effect that we still have not characterized very well, but BAFF may be playing the effect on the immunoglobulin related issues, suppressing immunoglobulin, etc, suppressing B-cell immunity and anti-BAFF may be able to overcome that too.  I think it has multiple activities and together becomes an interesting target with Velcade that is even more interesting.  I think that is a molecule I would be looking for to see where it goes.



And this is total conjecture, so you have a patient and let’s say you are getting them ready for transplant, so we are going to look at Velcade/Dexamethasone induction.  Do you envision that something like BAFF might be added into that to either get to a faster induction or a deeper response before transplant?


Absolutely.  Right the younger patient is standard and even a little more aggressive with the older patient also the combination is Revlimid/Velcade/dexamethasone.  And there would be some changes, maybe not, maybe yes.  We will wait and see whether the Velcade is changed by the other drug or not, etc., or Revlimid is changed by pomalidomide or not.  For now I think we can take as a standard back bone there will be one proteasome inhibitor, one immunomodulator drug and a steroid.  We do need to add something else that gives it a greater kick and more deeper responses and maybe even quicker responses.  And in that regard we and others have tried, for example Cytoxan, and it has not provided any greater benefit, it causes thrombocytopenia but not really a significant increase in responses.  The HDAC inhibitors have been tried and the Merck study was not really something to write home about.  And would other HDAC inhibitor, panobinostat, will go a little bit and see what the phase III looks like.  It is not a four drug regimen.  It is still a three drug combination, but still what does Velcade/panobinostat/dexamethasone versus Velcade dexamethasone does will determine what.  But the fourth drug space is still open.



And just clarify, is that PANORAMA 1.  What is the protocol for PANORAMA 1?


So PANORAMA 1 if I remember right, and I was really confused too, but the PANORAMA 1 trial is a randomization between bortezomib/dexamethasone plus panobinostat versus bortezomib/dexamethasone.





So it is a placebo controlled trial; panobinostat in combination with bortezomib/dexamethasone.



So the question there is you made the point that the standard right now for induction is Velcade/Revlimid/dexamethasone. 





Why are we going to consider Velcade/panobinostat/dexamethasone for induction?


No, panobinostat will not replace Revlimid.  The three drug regimen backbone would stay.





Revlimid/Velcade/dexamethasone will be the three drug regimen.  We want to add a fourth drug that will then make this three drug combination even better.



Yeah but PANO isn’t going to answer that question.  I have no idea why Novartis is running it?


The FDA would not accept that 4-drug trial design.  But, with PANORAMA 1, if with Velcade, panobinostat provides better benefit and it becomes a legitimate drug for myeloma that one can then think of adding to the three drug regimen.  If PANO trial fails that it is no longer becoming four drug in a three drug combination.  It is not going to automatically become a fourth drug for RVD but it will become potentially a drug that can be considered as a fourth drug.  So we are now looking for a fourth drug and if PANO is negative then it is not a fourth drug.  If PANO is positive then panobinostat could be considered, not necessarily automatically, but could be considered the drug.  The point that I was coming to was back to the antibody thing, that all these HDAC inhibitors have toxicities and that is why the first trial did not succeed as well.  So then we have a fourth drug which is less the amount of toxicity so one would end up with maybe less toxic HDAC inhibitor and there are a few floating around, or we could go to antibody, which otherwise by definition do not have overlapping toxicity and most of them are very well tolerated.  So then there will be space for a fourth drug.  Whether it is elotuzumab, it is daratumumab or any of the other antibodies, would be an open field once those are confirmed.  But those antibodies have to confirm their activity in a three drug combination before they look at a fourth drug.  But there are already talks about combining RVD with some antibody in phase I/II study or something like that.



Good.  I have people who say to me they actually like perifosine and then there are some people who say to me they are much more interested in the new AKT inhibitor from Glaxo. 


I think perifosine is a good drug except it hasn’t shown the activity it was supposed to show and we were hoping it would show.  Because of that, and then the study has been going on forever, that the enthusiasm for it is not yet as one would expect it to be.  That is what I would say.  Glaxo drug hasn’t yet been tested in the same where perifosine has been tested.  I think we will have to wait and see where perifosine goes.  There is a little bit of decreasing enthusiasm for it because of again all the technical and other problems that it has faced, but I wouldn’t yet give up on it because it is already in the phase III study.



Okay.  I had seen earlier in the fall it struck me as an interesting approach, this is something that Genentech is working on, and they called it TAHO, tumor antigens of hematopoietic origin polypeptides, these TAHO polypeptides.  And they were targeting a surface receptor called FCHR5.


Who is doing this?





What antibody is it?  I am trying to figure out if I don’t know it or if I don’t remember it.



I think it is the surface receptor that they were targeting that stood out to me.  It was called FCHR5.  I really appreciate you fitting me.  After ASCO we will have another follow up conversation. 


I will make sure I am on time.

Categories: CANCER, Multiple Myeloma
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