ASH 2014 Coverage: Myeloma Roundtable Discussion

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Topics include: Treatment

As part of our coverage of the 2014 American Society of Hematology (ASH) meeting, Dr. Robert Orlowski from MD Anderson Cancer Center led a Patient Power roundtable discussion featuring Dr. Ola Landgren from Memorial Sloan Kettering Cancer Center, Dr. Edward Libby from Seattle Cancer Care Alliance and Cynthia Chmielewski, a patient advocate and mentor. The panel of experts discussed the latest news in myeloma reported at the meeting, ranging from novel therapies to the role of stem cell transplantation. 

This program is sponsored by Patient Empowerment Network, which received educational grants from Onyx Pharmaceuticals, Novartis, and Millennium: The Takeda Oncology Company.

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Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

Dr. Orlowski:

Welcome.  My name is Bob Orlowski.  I'm the director of the myeloma program at MD Anderson Cancer Center, and we're coming to you today from the American Society of Hematology meeting here in San Francisco.  And it's my great privilege for this program to have a wonderful panel.  First, I'd like to introduce Dr. Ola Landgren from Sloan Kettering; Cynthia Chmielewski, who is a patient with myeloma; and Dr. Ed Libby from Seattle at the Fred Hutchinson Cancer Center.  So thanks all of you for coming.

There have been a lot of exciting developments in myeloma in general and particularly at this meeting at the American Society of Hematology, and I think we're going to try to digest some of this down and hit the highlights for patients. 

So, Ola, you've been very involved in high-risk smoldering myeloma.  Tell us your view of what a newly diagnosed patient with high-risk smoldering myeloma should do right now based on some of your research and also some of the things that were presented here at the meeting in San Francisco. 

Dr. Landgren:

Well, I think these are very important questions you're—you're touching on here, Bob.  There are a lot of things that are changing I think in the management of smoldering myeloma.  You said high-risk smoldering myeloma.  Just a couple of years ago, we didn't talk about high-risk or low-risk.  We just talked about smoldering myeloma, so we are now looking into differences in the phenotypes and the risk patterns in developing symptomatic disease. 

Still our guidelines, as both you and I know very well, say that patients should not be treated outside clinical trials.  What we are saying in these guidelines is that patients who do have higher risk of transforming into symptomatic disease should be considered for trials. And those trials—those trials started in the early 1990s, and they started with pretty low effective drugs because at that time we didn't really have those drugs that were effective available, and now what we are seeing is that the very potent drugs that you can use at symptomatic disease, at what we call multiple myeloma, are now being tested in clinical trials for high-risk smoldering, and the results, I think—I think they are very spectacular. 

There was this publication in the New England Journal [of Medicine] now half a year ago showing that lenalidomide (Revlimid) and dexamethasone (Decadron) significantly extends the time to progression, to symptomatic disease.  The progression-free survival was much longer, significantly longer.  And they also showed that if you do Revlimid and dexamethasone versus just follow-up for high-risk smoldering myeloma also overall survival was significantly better in that study. 

And I think adding to that then that's where our research has been going, and you asked me to briefly fill in on that, and we're presenting that here at the meeting.  We have done a pilot study using this backbone with lenalidomide and dexamethasone. We have added a third drug.  We have used Kyprolis, carfilzomib, in combination.  So the same debate that people have for newly diagnosed multiple myeloma, shall we have two drugs, shall we have three drugs, shall we have more drugs, same question comes into high-risk smoldering on clinical trials. 

We presented at the meeting here we have completed a first pilot study ever done with three drugs, and we show 100 percent complete response—100 percent of patients reached a complete response, and that's, of course, spectacular.  We also try to push the envelope, and we are using extremely sensitive assays to measure the response beyond the conventional criteria, and we look for minimal residual disease, and we have two approaches.  One is flow cytometry, the other one is next-generation sequencing, which has even higher sensitivity. 

And we show that in 11 out of the 12 the minimal residual disease, the MRD status by flow cytometry is negative, so it's not detectable disease.  And when we push it with this next generation sequencing 10 out of 12 patients are negative.  So I think these are major findings. 

So are we done?  Are we just starting?  I think we're just starting.  We are entering a new era for this disease space. And I think the next step will be to develop new studies that have longer follow-up and also where we can monitor the minimal residual disease status over time, because we have to make sure that we don't go into minimal residual disease, and then it comes back again.  That's a key question. 

So we need larger studies, and we need longer follow-up.  And we are working on this.  We are working on a new study with randomization using exactly this combination of therapy versus Revlimid and dexamethasone. And we hope to open that study in 2015, and I think that will be an important study to really address this question.  And there are other studies as well, but these are I think some of the highlights that I have picked up on, and it fits into our research. You asked me to comment on that. 

Dr. Orlowski:

So, Cynthia, from a patient perspective, what do you think someone with smoldering myeloma if they had a chance to, Ola, what would—kind of questions they would have? 

Cynthia Chmielewski:

A couple questions come to mind.  The first question is if I was diagnosed with smoldering myeloma, how would I know if I had high-risk smoldering myeloma?  Would there be special tests I would have to ask my doctor to perform?  Would my local doctor know about these tests? 

And, secondly, if I were a high?risk smoldering myeloma patient, how would I know which trials are available to me, where those trials are? Because you're saying that they—we can only be treated in a clinical trial, so how do I find them? 

Dr. Landgren:

These are extremely important questions.  Thank you for asking them.  I think the first question, how do you know if you're high-risk or low-risk? That I think takes an expert center to really do that thorough workup, because at this point the field is moving very fast forward, and there is a lot of fragmented information. 

So you probably have to go if you have smoldering myeloma to a center that has research agenda and has a particular focus on it and do a thorough workup.  And that can be inconvenient, of course, to travel and do that. But I do think I would strongly recommend patients with smoldering myeloma who are interested in considering a trial to go and do that, and then you can, of course, go back to a local doctor or another center and participate in a trial.  But I think the workup, it's a very important first step. 

There are very many approaches one can take.  You can do sophisticated flow cytometry approaches.  There are molecular tests that can be done, gene expression, you have FISH technologies, you have functional imaging, you know, a lot of details.  And it would probably take me an hour to go through all of these, so I don't think we can do that today. 

And also for individual patients I think no one is on average.  Everyone is unique, so therefore the patient needs to meet with a doctor with this particular focus, so he or she can deliver that information to that individual. 

And then when it comes to trials, the trials that are open are available on clinicaltrials.gov website.  It's a little bit difficult website, so you can go there, you can Google, you can look online. But I do think going to one of these centers, the doctors that work there know what trials are available.  And I think the doctors can guide and say these are the options in the region, and patients can get that information that way. 

Cynthia Chmielewski:

So I guess the word to get out is even though you have smoldering myeloma, which lot of times docs think that's okay, it's watch and wait, that you really should go see a myeloma expert just at the beginning of your diagnosis to guide which direction you should be going into.  

Dr. Landgren:

I do think that, yes.  I do think there are a lot of people that are being told they have smoldering myeloma, but they really have more the MGUS type. So to get that burden off the shoulder maybe it's not as bad as it sounds.  I think it's, of course, probably more important. And if you happen to have the higher risk, maybe you want to do something about it, but it's just taking that step knowing rather than not knowing. 

Cynthia Chmielewski:

Great.  Thank you so much.  

Dr. Orlowski:

And I think patients can also look at some of the advocacy groups.  The Leukemia and Lymphoma Society, the International Myeloma Foundation, the Multiple Myeloma Research Foundation, all of these have excellent websites which list trials.  Several of them have patient navigators as well, so that would be another resource that a patient could really take good advantage of. 

Cynthia Chmielewski:

Thanks so much. 

Dr. Orlowski:

Now, Ola, you mentioned a lot of testing that can be done.  You mentioned flow cytometry. You mentioned molecular studies as well.  One of the questions that patients may have is how often should I get this kind of testing?  We were discussing about this earlier before the program started.  What would be your guidance about that, because some of the tests require a bone marrow, which as we know is not exactly everybody's favorite test in the world either to have or to ask someone to have if you're a physician treating a patient? 

Dr. Landgren:

I think the guidelines, they say that these tests should be considered for workup at the initial diagnosis.  I think the need to repeat them over and over again is not there unless there are changes.  I think that's a good baseline rule.  And, of course, there could be deviations from that rule.  I think I see sometimes these tests are being repeated very, very often, and I don't really see the clinical need. 

I think any test that's been ordered for any reason has to be ordered, because there will be a potential clinical implication of it.  I mean that's obvious, but sometimes tests can be ordered maybe without thinking about why was it ordered.  And I think that's important.  It's a burden to the patients.  It's a burden to the financial system.  It's a burden to everybody.  Those tests should not be done. 

Dr. Orlowski:

So it sounds like, correct me if I'm wrong, but what you're suggesting is that these tests should be done at the time of the initial evaluation, and then let's say maybe later if there is evidence that the disease is relapsing, but not necessarily in between.  

Dr. Landgren:

I think that's a good rule to follow.  I'm sure you would agree that we should not do tests in an overexcessive way. 

Dr. Orlowski:

No, I would agree.  I think what I'm hoping is that some of the tests will be so sensitive that we will be able to do them just on peripheral blood, which will be a lot easier because patients are used to getting blood drawn for blood counts and chemistries, but I don't think we're quite there yet.  The sensitivity and the bone marrow are still much higher. 

Dr. Landgren:

Right.  Both your research and my research and other groups' research that we currently have ongoing, we can pick up disease in the blood.  We can look with genetic signatures.  But as you mentioned, the sensitivity, the reliability of these tests is not perfect.  So if those tests are negative, it could be due to the fact that the test failed.  So for that reason we cannot convert everything into the blood at this point. 

But I think in five years, many of the tests that we do in the bone marrow probably will be blood? or even urine-based. 

Dr. Orlowski:

Okay.  Excellent.  So let's go to Ed Libby.  You're from a center which is well known for stem cell transplantation, and one of the topics in the educational session for myeloma was a debate between Philippe Moreau and Paul Richardson about whether stem cell transplant should still be done as part of initial therapy for myeloma.  

We have now better chemotherapy.  For example, Ola and Andrzej Jakubowiak have shown that carfilzomib with lenalidomide and dexamethasone can give you very high response rates and very deep responses.  And at this meeting we have data about ixazomib with lenalidomide and dexamethasone, which is an all oral combination, which also has very high rates of overall and complete response. 

So what do you think?  Is there still a role today for stem cell transplant in the management of a patient who will walk into our office, say, not today but tomorrow when we get back to work?  

Dr. Libby:

It's a very big question for oncologists and patients alike, and we don't have an answer as yet, but I think the consensus internationally at this time is that stem cell transplant is still a critical backbone of therapy for patients with multiple myeloma who are candidates. 

We are anxiously awaiting the results of several trials, but in particular a study called the IFM/DFCI study where patients are randomized to getting a stem cell transplant early in the course of treatment versus later on when they first have a relapse.  And the results of that study weren't available for this meeting.  Perhaps a year from now we'll begin to hear the results, but that study should go a long way to establishing the benefits of up-front versus a transplant at relapse. 

I think the great majority of myeloma physicians feel that stem cell transplant still has a significant impact on the core outcome of multiple myeloma and would recommend to patients that they have a stem cell transplant depending on—perhaps depending on their response to induction therapy. 

One question in my mind is if a patient has an outstanding response to induction therapy, for instance, a stringent complete response, should that patient have an up-front transplant?  And I think that's an important thing that will be teased out.  We didn't get any answers as far as I know from this meeting, but those patients I may recommend that it's reasonable to postpone a transplant until the first time that they relapse. 

Dr. Orlowski:

Or especially with some of the testing that Ola mentioned where you do the flow immunophenotyping and also some of the sequencing studies, which are now available at least in the context of research. 

I think a very good question would be if you're flow MRD negative and sequencing MRD negative, would you still want to do a transplant in a patient like that if they're either standard risk or high risk?

Dr. Libby:

One—one hypothesis might be that we're going to attain an even deeper response then and perhaps even a cure, but we don't—we need data I think, given that transplant is not a benign procedure.  And with that kind of a decision in hand, I think I'd like to see the data then knowing whether or not—how much a transplant might add to somebody in the deepest complete remission that we could measure in 2014 or 2015. 

Dr. Orlowski:

So Cynthia, what kind of questions do you think a patient would have for Dr. Libby about stem cell transplant other than the should I do one or not question, which, of course, is the $64,000 one.  

Cynthia Chmielewski:

Okay.  I guess the first question we're talking about is we're talking about this MRD negativity.  Should everyone now be tested for—using a flow cytometry or the sequencing to see if they're MRD negative?  Is that part of a clinical practice now?  Is it something we should be asking our doctors to do, or is that something done just in trials?

Dr. Libby:

It's generally done I think in most centers.  One thing that I have found there to be some misunderstanding about is what is the value of MRD testing if you still have measurable disease.  If you have a measurable M spike or 7 percent cells that are visible by microscopy in the bone marrow, then there's really not a role in my mind for MRD testing, and that can confuse patients. 

It's when patients have a complete remission or better then we can look at flow cytometry and genetic techniques to see how—just how good is that remission.  And then it should be done.  I think it's valuable, at a minimum flow cytometry of a marrow specimen. 

Cynthia Chmielewski:

Okay.  Great.  And the other question is not about other transplants, but it's about the role of allogeneic transplants.  I have some friends who relapsed very quickly after an autotransplant whose disease doesn't seem to be getting under control with some of our conventional chemotherapies.  Should they be considering an allotransplant?  And I'm hearing some things with T cells going on these days.  Could you explain things like that? 

Dr. Libby:

Certainly.  Allotransplantation is still an investigational tool in multiple myeloma, and a number of studies have been done.  But the results have varied from study to study, so it hasn't found a home in terms of a routine approach in any type of multiple myeloma. 

I think at this point using allotransplant as part of a trial particularly in patients who are high-risk has a role, and we're desperate to find better treatments for patients who relapsed quickly or have very aggressive cytogenetically defined disease or aggressive disease defined by their ISS staging, etc.  So allotransplant is reasonable and appropriate I think for those types of patients. 

Cynthia Chmielewski:

Thank you. 

Dr. Orlowski:

And so, Ed, let's sort of have a take-home message.  If you have a newly diagnosed myeloma patient who needs therapy that comes to your office tomorrow, based on what you've seen here at ASH and all of the previous data that we have, what would be your recommendation, other than of course going on a clinical trial which we talked about, which is very important because that's the only way these questions will really get the best answers. 

But if people are too far away to be able to go to a clinical trial, they have other responsibilities, they just can't do it, what would you recommend as the best initial therapy for someone that has myeloma that needs treatment and is a transplant candidate?  And then the same question for someone who is not a transplant candidate. 

Dr. Libby:

For stem cell transplant candidates in general, I would use a bortezomib-based therapy and usually three drugs.  We often use bortezomib, or Velcade, plus cyclophosphamide (Cytoxan®) plus dexamethasone (Decadron).  Cyclophosphamide is an old drug, but it also has an amazing synergism with bortezomib, and it's inexpensive, so that's a very nice bonus.  And it gives deep responses.  That combination is amazingly well tolerated and gives deep responses in preparation for a transplant.  That would be my first choice, and—although it would not be unreasonable to use a very simple regimen like lenalidomide, or Revlimid, and dexamethasone, which is very convenient for patients and is still a reasonable way to get patients induced in preparation for a stem cell transplant. 

If you're not a—if you're not transplant eligible really both the regimens I just discussed are still very appropriate.  In older patients I—in all patients I like to think about quality of life, but especially in patients in whom it's hard to get to the clinic or they live a great distance, I like to offer them a chance of just being at home, taking pills and seeing the doctor once a month rather than coming in on a much more regular basis for injections.  So Revlimid and dexamethasone is a very nice treatment. 

I'd like to see I think other combinations that have shown to be efficacious that are used much more widely in Europe like Velcade, melphalan and prednisone or drug—or combinations like that are also things to think about, because it's shown impressive results.  Melphalan (Alkeran) orally is not used very much in the United States but that's a good regimen, and perhaps we'll have new regimens like that, perhaps carfilzomib (Kyprolis), Cytoxan and a steroid in the near future.  

Dr. Orlowski:

Okay.  Very good.  And I think other three drug regimens that people should probably hear about are bortezomib with lenalidomide and dexamethasone is frequently used for transplant eligible candidates.  

Dr. Libby:

Yes. 

Dr. Orlowski:

You could consider carfilzomib and lenalidomide and dexamethasone.  And the main thing to remember is that you don't want to be on lenalidomide for too long a period before you collect stem cells because if you're on it for a long time, it can be more difficult.  And you don't want to lose that option.  

Dr. Libby:

One thing I think is worth mentioning for patients is that the mortality, the risk of stem cell transplant, autologous stem cell transplant in 2014 is quite low.  Yesterday at a session I heard someone from a major study report zero percent mortality I believe in one of the transplant studies.  So it's below 2 percent in any major center I think, and therefore it's quite safe, and I think fear that may be engendered about the procedure isn't—isn't really necessary.  It was different 10, 20 years ago. 

Dr. Orlowski:

Sure.  So then let's cover relapsed and refractory myeloma, because unfortunately even with all the better therapies either earlier or better therapies for newly diagnosed myeloma the majority of people will still unfortunately relapse.  And you can have either relapsed disease, which means an increase in myeloma when you're off treatment, or you can have refractory myeloma, which usually means that the myeloma is growing on some kind of treatment. 

Fortunately, we've got many new drugs that are coming along.  So maybe I'll start with you, Ed.  Can you tell us some of the new drugs that are small molecules, and then, Ola, I'll have talk about antibodies.  So what are some of the new small molecule drugs in trials maybe or even some that could be available now that you've heard about that if a patient is in this situation you would recommend them thinking about getting either off of trial or on a trial?  

Dr. Libby:

Well, a couple of drugs that are interesting to me, one is a drug that has a name, LBH 447, a PIM inhibitor.  The results of that study are being presented at this meeting, and it's a unique mechanism of action for multiple myeloma.  It's oral drug I believe.  And so having completely new tools, if you will, to address this disease is a very exciting development for people who treat multiple myeloma and for patients.  That's a unique compound with a unique mechanism of action. 

Another drug that's been—being studied and a number of studies are being reported at this meeting is ibrutinib (Imbruvica), which has found a great success in another disease, in chronic lymphocytic leukemia, and has shown some efficacy in multiple myeloma that's been reported at this meeting. 

So those are two drugs available in research studies that I think patients might consider if they have relapsed or refractory disease. 

Dr. Orlowski:

And, Ola, in terms of antibodies, I think there's a lot of excitement about them.  I know it's tough to summarize in just a few minutes, because there are many answered bodies… 

Dr. Landgren:

Right.  

Dr. Orlowski:

…and many targets, but it's your job. 

Dr. Landgren:

Okay.  Thank you.  I got that easy question. 

So there are, as you pointed out, multiple new targets.  One target, for example, is the CS1 antigen on the surface.  We have elotuzumab.  There is an antibody that targets other cells, other myeloma cells, the KIR, anti-KIR monoclonal antibody that targets natural killer cells.  It protects them from being deactivated by the myeloma cells, and then they can do the job going after the myeloma. 

You have CD38 antibodies, and there are other antibodies.  You have PD1 antibodies, etc., etc.  There is a whole list, so in one minute I cannot go through the whole list. 

I do think at this meeting from where we are right now in my personal opinion I think the CD38 carries a lot of promise.  The others look interesting, but I think we need even more data.  I think we have quite a lot of data already for CD38.  There is daratumumab, and there is also a SOR compound, and there is another drug in Phase I also coming. 

So there are three drugs going after the same target, and from what we have seen in the early studies is that they seem to be very, very tolerable.  The toxicity profile I think is very low toxicity, almost no toxicity at all.  We have infusional reactions to begin with, and after that it seems to not be a problem for the most part. 

And in terms of responses, we are talking patients that have been treated with multiple prior lines of disease with recurrent disease have gone on these drugs as single agents, and we see responses I think in the range of 30 or 40 percent or something like that, which is I think spectacular.  If we compare to the best drugs we are currently using, we have talked about them already, when they were tested they were not even at that level, or they were at that level almost. 

So here we now have monoclonal antibodies either at the same or even a little bit better than some of the older drugs in patients who have been quite heavily pretreated, so, of course, this is very exciting.  We have a whole new class of drugs coming. 

I think it's very likely, I'm sure you agree with me, Bob, that these drugs probably could be bundled with most of the combinations we are currently using, so we are almost entering an era where we have some drugs plus an antibody or some other drugs plus an antibody, and that would be a paradigm shift for the treatment of myeloma.

Dr. Orlowski:

And I think some exciting things that are coming hopefully soon in 2015 is that we should get data from a couple of large studies.  One is with ixazomib, an oral proteasome inhibitor.  We talked a little bit about it earlier, but there should be data from a relapse study looking at ixazomib, lenalidomide and dex versus lenalidomide and dexamethasone. 

And then you mentioned elotuzumab.  We may have a data from an elotuzumab len-dex versus len-dex study in 2015 as well, as well as data about daratumumab from a Phase II study, and we're hopeful, of course, that all three will be positive so that they could lead to FDA approval of those drugs possibly before the end of 2015 as well. 

I think another small molecule to mention is filanesib, which is a kinase and spindle protein inhibitor that has

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