The Importance of Establishing Baseline Disease Characteristics in Myeloma Diagnosis and Management

Transcription

1 I am Dr. Brian Durie at Cedars Sinai Medical Center, Los Angeles. I am also chairman of the International Myeloma Foundation, and I am very pleased today to be participating in this program with my friend and colleague, Dr. Kenneth Anderson from the Dana Farber in Boston. Dr. Anderson? Yes, I am Dr. Ken Anderson from Dana Farber Cancer Institute in Boston and Harvard Medical School, and both of us are really honored to be here today speaking for managing multiple myeloma, and the topic today is one of great interest, the importance of establishing baseline disease characteristics in myeloma diagnosis and management. There have been multiple advances in our area that is in myeloma and the diagnosis, understanding of the heterogeneity of the disease, understanding how we diagnose and how we have prognostic factors in our disease, and fortunately for all of us, many advances in therapy that have improved patient outcome. But unless we appreciate and utilize these scientific advances in diagnosis, prognosis, and treatment, our patients really will not benefit from the advances, hence the importance of today s session. 1

2 The objectives are shown on this particular slide. We are going to talk about both the NCCN and IMWG criteria and workup for multiple myeloma and how they have evolved and continued to evolve into the future. We want to really emphasize how important it is to adhere to these guidelines and how when we do not adhere and really do not utilize these criterion we really can compromise care, and we will talk about in the future strategies like this conference where we can assure that caregivers adhere to these guidelines and really in so doing ensure optimal patient here. 2

3 So, in the next slide is the iteration of the 2015 NCCN guidelines for multiple myeloma, and in fact, we have shown here certain tests that are useful for the diagnostic workup, some that would be useful only under some circumstances, and this is a very much evolving list of criterion, obviously measures of the monoclonal protein and bone marrow have been mandatory and required for a long time, but for example, in terms of the assays or tests that are useful under some circumstances, more sensitive bone imaging, as we will talk about in a little bit, such as MRI and PET CT scanning are now recommended and even have really modified the definition of who needs treatment in myeloma. This has resulted in evolution, 3

4 and in fact these NCCN guidelines are under change and revision as we speak. 4

5 Now, on the next slide, you can see that once you have made the diagnosis of myeloma or smoldering myeloma, and we will talk about those diagnostic criterion in a minute, there are also recommendations on how we should follow patients and at what intervals. This is very critical if we are going to assess 1) Whether they have responded and 2) whether that response continues or whether in fact the disease has recurred, and these again criterion for response and criterion for relapse of disease have also undergone evolution. There is a great effort in the NCCN to update these guidelines in real time to reflect the changes and diagnosis, prognosis, and treatment, 5

6 and as I say these guidelines are under revision as we speak due to the advances that we will be talking about in just a few minutes. 6

7 So, on the next slide, we have a depiction of the stages, if you will, of plasma cell dyscrasia development. There is in fact an entity described by Dr. Robert Kyle called monoclonal gammopathy of undetermined significance where one has a monoclonal protein to present in individuals, the frequency with which this occurs increases with age, but the protein is in a small amount. There are very few plasma cells, less than 10%, and in fact there is no other clinical sequelae, in particular, hypercalcemia, renal dysfunction anemia, or bone disease. Dr. Kyle has followed these patients with monoclonal gammopathy of undetermined significance, or MGUS, over many decades now and can show that about 1% of these individuals a year develop myeloma or a lymphoproliferative disorder. The vast majority grow old and die of something else. Within the monoclonal gammopathy of undetermined significance group, there are those who have a non IGG protein, those who have an abnormal kappa/lambda free light chain ratio, and those who have more than 1.5 grams of monoclonal protein who would be more likely to progress than those who do not have these risk factors. Still, the overwhelming majority of patients really do not get a related illness to myeloma and grow old and die of something else. Now, in the middle is smoldering multiple myeloma where one has higher amounts of protein often less than or equal to 3 g/dl of protein in association with 10% or more plasma cells, and these individuals still have no CRAB, or calcium/renal dysfunction/anemia/and bone disease, manifestation. Now, the definition of smoldering multiple myeloma has recently changed, and Dr. Durie and I will talk about that in a minute, but suffice it to say that we can now dissect out individuals with smoldering myeloma who have more than 60% plasma cells, who have in fact an abnormal kappa/lambda ratio greater than 100, or who have sites of bone disease detected on more sensitive imaging such as MRI or PET CT scanning. And these individuals have a high risk of progressing within the next 1 1/2 to 2 years, and they now are eligible for therapy with some of our novel treatments, so this paradigm is undergoing evolution and then on the right hand side, active myeloma are those patients who usually have more plasmacytosis, higher levels of protein, and they usually do have the manifestations of CRAB as well requiring treatment. 7

8 So, on the next slide, we can talk about, as I have mentioned, the prevalence of MGUS in different populations. It does increase with age as you can see in this slide, and is more common as is multiple myeloma in certain population such as in the black population where it is roughly, as is myeloma, more common in this subset of patients. Certain population such as Hispanics may have a slightly lower incidence of MGUS, but you can see in this slide that there is a slow but real rise in the incidence or prevalence of MGUS with age in all of these populations. 8

9 On the next slide, this is the risk of progression of MGUS to multiple myeloma in the various populations. You can see that even over approaching 15 or 20 years, it does approach roughly 20%, so it is on average 1% a year. There may be a slight increase in the risk of development of MGUS in the black population relative to the Caucasian affected individuals. 9

10 On the next slide, we do know that almost everyone who has multiple myeloma did at one time have a precursor condition or MGUS state. This is a paper by Dr. Ola Landgren that was published way back in 2009 and what it shows you is that this is the proportion of patients in myeloma and the number of years earlier when MGUS was documented. You can see there were patients that had MGUS documented in this retrospective sampling of blood samples that were available 2, 3, 4, up to 8 years earlier before their multiple myeloma was diagnosed, and we currently think that pretty much everybody does have this earlier MGUS precursor stage who eventually develops myeloma. As I have already said earlier however, the opposite is really not true. Most patients who have MGUS grow old and really do not develop myeloma and die of something else. 10

11 On text slide, here are some of the predictive factors for progression. I have already mentioned them, the M protein size, patients who have a non IGG protein are more likely to progress as are those who have an abnormal free light chain ratio. I have not mentioned the fact that the uninvolved immunoglobulins, that is the non monoclonal immunoglobulin class, so for example, if it is an IGG MGUS, then the IGA and IGM, but the polyclonal immunoglobulin being suppressed is also a risk factor, as are circulating cells, urinary light chain, as I have already mentioned, age, the risk does increase with age, and also bone marrow plasma cell percentage. 11

12 On the next slide, this is the revised IMWG criterion, and I might ask Brian to discuss this because I want to highlight right here the fundamental and central role of the International Myeloma Working Group in helping to define myeloma, define prognostic factors, define metrics for response, and now to help us in the era of novel therapies decide which therapies are most appropriate for which population, and I mention this because Brian really made seminal contributions in establishing the International Myeloma Working Group which is a wonderful collaboration of myeloma clinicians and investigators from all over the world who look at evidencebased medicine and establish these very, very fine evidence based metrics for diagnosis, prognosis, response, and treatment options, and really go a long way to making sure that the advances really count for patients. So Brian, would you like to discuss the new evolution here that has occurred because of the IMWG? Well, thank you Ken. The revised IMWG criteria which are displayed on this slide are the result of some major work by the IMWG members, led in this case by Vincent Rajkumar from the Mayo Clinic, looking at biomarkers which would indicate a high likelihood of developing myeloma in the immediate months to come, and so the criteria here which are listed as myeloma defining events, MDE, which are not present in MGUS and smoldering patients but present in myeloma patients, are indicators that myeloma is likely to emerge. And this is a very, very key step because one of the major problems with myeloma up to now is that we have started treatment at a point where there is advanced disease and already bone lesions or significant anemia or renal compromise and really too late to achieve the best outcomes, and so these revised criteria provide a huge opportunity to intervene with earlier therapy in a very precise and organized way, and so, this has been a major objective of the IMWG team working in this area. And so the items listed under myeloma in blue, the percentage of plasma cells, the FLC ratio, and the MRI focal lesion, those are the key MDE, myeloma defining events, that have been involved here, and so if I go to the next slide, 12

13 the publication with Vincent Rajkumar as the first author appeared in The Lancet Oncology in November of 2014, and this paper was written in such a way that the recommendations were felt to be in shape to be implemented in routine clinical practice, but as I think we can discuss as we go through these, there are significant implications in thinking about myeloma in this way where we are not just thinking about treating a disease which has immediate symptoms, we are thinking ahead and using biomarkers, and this is a significant shift. 13

14 So let me just first show the biomarkers and perhaps we can discuss the implications of looking at myeloma in this way. The first point to emphasize is that we are still using the CRAB criteria as a definition of myeloma, and so the traditional CRAB criteria, the calcium elevation, the renal impairment, the anemia, and the bone lesions based on x rays, these are still obviously acceptable as a diagnosis of active myeloma, but what is new is the introduction of the myeloma defining events in addition. 14

15 And so if we go to the next slide, this clearly lists these new myeloma defining events. Now, there was some precision introduced in terms of renal impairment where we introduced creatinine clearance less than 40 as a cutoff, so a little bit more precise versus the use of serum creatinine. The bone marrow plasma cells at greater than 60% is an important criterion, although truthfully most patients with greater than 60% plasma cells in the bone marrow will have active myeloma; however, those that that do not will likely develop myeloma as soon as we will see in a second. The same with the serum free light ratio of 100, again, this is typically seen in patients who do have active myeloma, but if they do not, then there is likely emergence in the immediate future. The imaging evidence of active disease is a key, key part of this new criteria approach. First of all, the introduction of the MRI criterion, greater than one, so two or more focal lesions on MRI are not indicative of a likely active myeloma within 9, 12, 15 months. This is a very important point, but in addition, there is another thing which was indicated in The Lancet Oncology article, which was that instead of just using x rays, using PET CT or whole body low dose CT can be used as a more precise indicator of active bone destruction, and so this is actually a finer discrimination of the CRAB criteria, and so these elements are very important in the way that we are now looking at myeloma. 15

16 If we look for second at the bone marrow plasma cells, this next slide shows you the likelihood of myeloma if the percentage is greater than 60%, and you can see a very, very high likelihood within a short time span. 16

17 The same is true to a slightly lesser extent with the 100 free light ratio cut off with a rapid increase in the likelihood of myeloma, and this can also be expressed in both directions. 17

18 Obviously, the light chain ratio can be high or low, and this just shows you the likelihood as you move towards an abnormal ratio.

19 Perhaps, an aspect that will become even more important in the coming months and years is the presence of circulating plasma cells, which again indicates a high likelihood of imminent myeloma. And so this really changes the way that we look at myeloma and the use of the different testing and so, Ken, maybe I can ask you what do you see as the biggest impact of these new criteria in your practice for myeloma? I think the biggest impact, Brian, will be that more patients are going to benefit from treatment. You know in myeloma we have had a literal explosion in terms of the novel agents that are available now for treatment. These drugs usually in combination have achieved unprecedented extent and frequency of response in patients who have active multiple myeloma. But if you think about it over the years, the fact that we have waited for CRAB features to develop, somebody to develop high calcium or renal dysfunction or anemia or bone disease, and then start treatment, really is no longer acceptable in the current environment. Since we have these effective agents, why don t we intervene if we have sensitive metrics earlier in the disease course when the benefit is likely to be even greater? What you have so nicely described from the IMWG is that with these features, even in the absence of CRAB, we have patients who we know are destined to develop CRAB or active myeloma if we do not intervene. So, the way I think about it is it has extended the benefit of novel therapies to a larger population of patients, and dare I say will prevent the development of CRAB in at least some cases by intervening very early. So, this is a major advance I think in our field and a most exciting one because more patients will enjoy the benefit and will not hopefully ever develop the CRAB features. 19

20 I completely agree, Ken, that this is the key point. It allows us to intervene in a precise way early and achieve better outcomes, so very, very important shift and so, in terms of the required testing which I show on this current slide, it has indicated that we can introduce in a careful way some of these additional tests. So obviously the SPEP and UPEP and immunofixation, standard things that we absolutely need, although I would just mention that as we are talking about this, we are also talking about where are we with the use of these testings in the general care of myeloma in the United States right now. And so as a member of team involved with myeloma registry, observing day to day care for myeloma centers across the US, both academic centers and community centers, I have become aware that the routine use of testing is not a 100%, that not all hematologists oncologists are getting the SPEP and the UPEP and the immunofixation as necessary to accurately measure response and also not routinely getting all of the different tests that we might need for diagnosis, prognosis, and monitoring, and so as we go through, I think that both Ken and I would like to emphasize how important it is to have these various testings to do a good job in providing the best care. So that on the bone marrow, we do need the results of the ifish testing to tell us if high risk features are present. We do not necessarily need GEP or other sequencing which are mostly within protocols, but now what you can see instead of just x rays, we are focusing on the best use of MRI, CT, and PET, and that is what we are going to talk about a little bit more. 20

21 There was an update publication that we would like to draw your attention to, the ISS staging system, a prognostic evaluation for myeloma at baseline. This ISS staging system was recently updated by the IMWG with Antonio Palumbo from Italy as the first author. The key point here is the systematic introduction of LDH measurement and the ifish testing into the ISS staging system to give you these three categories that you see identified here in the blue, yellow, and the gray curves. And basically, as you might expect, if one has an elevated LDH and abnormal FISH with the high risk 17p or 4;14 abnormalities then this would be putting a patient into the higher risk group, but I do not think that we can emphasize too strongly that the LDH measurements and the ifish measurements are really important to have this prognostic information at the beginning of therapy, and Ken I do not know if you have any comments about this particular new publication. I think it is a major advance, Brian, and again it came from the IMWG, again reflecting the world working together and gathering evidence based medicine in a manner in which we can evolve to a better practice. In this case, the use of the LDH and the FISH testing does add to the usual albumin and beta 2 microglobulin which were the initial metrics to formulate the ISS, and I think what I want to emphasize is the importance of obtaining these tests like practitioners worldwide. The ISS was generated because we wanted to use tests that were universally available and were able to be obtained internationally in order to form this staging system. So, we started with the albumin and beta 2 microglobulin and what we are excitingly able to share today is that if you add just FISH testing and LDH to that background you can even further refine and improve the prognostication in myeloma. 21

22 Absolutely, so I could not agree more, and so if we look at what I call the bottom line, it is helpful for practitioners to consider the testing that they are obtaining into three different categories. Obviously, there is testing that you need for the diagnosis and we are very pleased to have the new MDE features, but it is also incredibly important to have these testings for staging and prognostic evaluation. And then as we move forward, we need to have a baseline for imaging and staging and monitoring as you move forward, and so one part that I frequently emphasize is that we now need the imaging, not just as a precise tool for the initial diagnosis, but it is important for each practitioner to assess the availability of the imaging technologies at their center because whatever technology is being used at baseline has to be used for that subsequent monitoring and followup to assess response. And so if MRI is conveniently available at the center, some type of approach with spinal and pelvic MRI can be used as a baseline and for monitoring, and if PET CT is available, then whole body PET CT can be a baseline as a basis for further followup. 22

23 So, we need to have testing that will help us across the board and one thing that we tend to forget about is the checking for plasma cells in the blood, and I just want to draw attention to the fact that the IMWG also has a guideline for plasma cell leukemia, and a key point about this guideline I would say is this whole emphasis on early diagnosis. If we look for those plasma cells early, then we can be aware or more aware that this could be a higher risk situation where some alternate perhaps more aggressive therapy might be required. 23

24 And so, I would also like to draw attention to the fact that we do have very specific guidelines for the use of MRI and these were just published in the JCO this year, and I have highlighted one table there which shows the level of evidence for the use of MRI, and you can see immediately that MRI is listed as level A evidence for use in different settings for myeloma right now, and one of them certainly would be to identify the MDE, but also to characterize the myeloma in the best possible way as a basis for future monitoring. Ken, perhaps you can comment on your own use of MRI or PET CT scanning. What type of additional imaging would be typical in the practice at Dana Farber right now? Well, we do routinely utilize MRI and PET CT scanning now Brian. We already mentioned the early use of this, even in patients who have what would be considered smoldering multiple myeloma, in order to see whether they might have bone disease that would be detected only by these more sensitive techniques. Once we have a baseline MRI or PET CT as you have so nicely described, then we use those at repeated intervals as a metric of response; in particular, they are much more sensitive, so in fact as we measure with more sensitive techniques, the marrow disease with MRD measurements such as multicolor flow cytometry or sequencing, so it is true we need to make sure that patients do not have residual disease using these more sensitive bone imaging techniques as well. So, we will repeat the MRI scanning or repeat PET CT scans in individuals, even at a time of response, to assure the extent of their response. And I would like to point out that patients are doing so much better nowadays that sometimes we have extramedullary recurrence or extramedullary relapse of disease many years after patients have been responding, and these extramedullary relapses will only be detectable, for example, with PET CT scan and would be missed by all of the other assays. So, it is really incumbent to use these more sensitive techniques early at the time of diagnosis and then also in the followup as well. 24

25 Absolutely, and so I completely agree, and I do not want to skip over this without noting that we do understand that there sometimes can be difficultly to get reimbursement for this use of the technology. Some years ago I actually went to CMS Medicare and was able to ensure that there could coverage for PET CT for myeloma, but today, there is again some difficulty in getting full coverage, especially for the ongoing monitoring using this more sophisticated imaging, and we do have followup meetings scheduled with CMS Medicare to try to see if we can guarantee the more ongoing use of both MRI and PET CT for this monitoring that we now need. And so I know there is hesitation because of this reimbursement issue, but it is terribly, terribly important first to try to do this. And so this is just a note that obviously if it is possible the whole body PET CT is more useful than the MRI of the spine and pelvis just because the whole body PET CT can pick up disease wherever it might be located in a soft tissue area away from the spine and in a lung area or in a soft tissue area like close to the kidney as one spot noted here. This extramedullary disease is so important to be aware of because a patient may have disease at the beginning or following therapy and is actually not doing as well as you might think without the use of this imaging. 25

26 A key point that we have not finished working on as an IMWG team is to really standardize the use of PET CT, the question is when is a PET CT positive or negative? And the Italian team with Professor Cavo and Dr. Elena Zamagni, this is from a study that they published in Blood showing that if the SUV has 100% improvement after stem cell transplant, this is obviously significantly better than a persistent PET CT positivity, but we need to establish accurate cutoffs for SUV positive and negative, and they are just completing a collective analysis of this which will be very important to the myeloma community. 26

27 And so, with this baseline, I just want to, we are getting toward the end of our time here. just to finish up and show that these testings are so important as a basis for choices for initial therapy, and we will touch on in a second the importance of geriatric and risk assessment and we will not be able to get into the choice of two or three drugs or transplant or not or some of these other elements which can be the basis for future discussions. 27

28 But I would like to just touch on and get Dr. Anderson s feedback about what I think is a very important publication, again from Antonio Palumbo, looking at geriatric risk assessment which allows us to be proactive in the way we select and use drugs at the time of diagnosis in the elderly. So, do you want to comment on this aspect of assessment, Ken? 28

29 This is another wonderful study from the International Myeloma Working Group. Again, it is our dear friend and colleague Antonio Palumbo who is in Italy, but what he has appreciated is, especially in the elderly, that there are different categories of, if you will, well being. And he has classified patients into three categories: the fit, the unfit, and the frail, and he has in fact objectively made a scale to allow practitioners and patients alike to rank patients who are elderly into these different categories, and then can, if you will, predict therapies that will not only be effective in these populations, but will actually be very well tolerated. This is such a major advance. Honestly, it is the practice of medicine. We clearly have active treatments for patients who are elderly with myeloma. It stands to reason that they need to be able to take these medicines and tolerate them in order to appreciate the benefit, and so what Antonio has done is realize that not everybody is the same, that we have even though the same chronologic age we might have different physical characteristics or ability to tolerate stresses and treatment and he has categorized this and can make recommendations of how we might modify the dose or schedule of these very active drugs in myeloma to make sure that each and every patient appreciates the benefit of these novel twoand three drug combinations. So this is a major advance and it reflects a tremendous amount of work of trying to objectify or use evidence based medicine in order to predict for individual patients what is the best treatment for them, so it is really I think a major advance and will go a long way to improving outcome in the elderly patients with myeloma. Absolutely, I could not agree more on this point as well. I think that the proactive selection and dose adjustment is very, very important to have the best outcome, but particularly to have the least toxicities, and I also like the way that Antonio has summarized these categories as go go, moderate go, and slow go. I think that this does help for people to be aware of these different categories and actually we did not touch on it, but in the MDE category, Dr. Joe Mikhael who is a great advocate of the MDE, calls that category the SLiM CRAB which is an acronym for the MDEs which is kind of cute, but I think that these do help to draw attention to these very new and important categories. 29

30 Okay, so, we are toward the end of our time and also this presentation, but just to draw attention to the fact that IMWG does have some important treatment guidelines for transplant patients, for non transplant patients, and also global care guidelines and we are very much aware that people outside of the US are following along because they want to see what we are doing, what is recommended as a basis for a global care. And I think that we need to be aware of therapies that can be broadly available and aware that not every drug can be used for every patient, and so I think these guidelines are tremendously helpful, particularly the management of myeloma in Asia. 30

31 This was a project that we published in The Lancet Oncology also. It was very important because it was based on the resources available, both for diagnostic testing monitoring as well as the drug therapies, and quite helpful as a model to look at where ever one is trying to care for myeloma patients. 31

32 And just to finish up with all of this I think as you emphasized so nicely at the beginning, Ken, with these new approaches, we are so excited because they are leading to better survival and outcome for myeloma patients, and this is so nicely presented by Shaji Kumar over the years, the steady improvement resulting from a combination and initially autologous stem cell transplant, but more recently certainly from the introduction of the novel therapies. 32

33 So just to finish up on this note, we are so pleased that with the proper diagnosis and monitoring, we can take best advantage of these new agents that are introduced into myeloma therapy, and so we have moved from the old drugs to older drugs, the recently approved drugs, and maybe perhaps Ken, you can finish with your perspective on the future drugs. We are so fortunate to have such a collection of new drugs that are going to have a big impact in the very, very near future, so perhaps you can make that final area of comment, Ken. I think it is fair to say that Brian and I have been myeloma researchers and caregivers for many decades, and we have watched many advances come in terms of our ability to diagnose and to prognosticate and now to treat myeloma, and I think what Brian has just highlighted is that we have watched the first alkylating agents be used and then combined with prednisone, and we have watched stem cell transplantation come along, and in the last 10 to 15 years, we have watched the immunomodulatory drugs, the proteosome inhibitors. What is really exciting now are many classes of novel agents, too many to mention, but I will just highlight the immune treatments that are coming. The monoclonal antibodies, the potential for cellular therapy such as CAR T cells, the potential for checkpoint inhibitors, PD1 or PDL1 antibodies to allow the patient s own immune system to react against their own myeloma. Potential vaccines, combinations of immune treatments are really exciting. On the other hand, the whole field of precision medicine is defining genetic abnormalities that can be targeted, and I think even more importantly pointing to the Achilles heels in myeloma, those pathways that we can target that can either interrupt the growth or trigger the death of myeloma cells. This coupled with the fact this new development of effective therapies, coupled with the fact that we can treat earlier guarantees that more patients with plasma cell dyscrasias are going to benefit from treatment than ever before.

34 What I hope we have achieved for you during this presentation is to stress the importance of using this new knowledge at the time of diagnosis to prognosticate and to select treatments for your patients. It is very, very exciting what Brian and I have been able to see during our lifetimes. The natural history of myeloma has changed, but honestly, patients will only benefit if they have access to these advances in care, and we hope today that you have learned some of these advances and will keep apprised of these advances and use them in your practice so that the patients can count on us so that the new advances in science and understanding of the disease actually can translate into an improved outcome for patients and their families. So I would like to thank Managing Myeloma very much for this opportunity and hopefully it is the first of an ongoing series where we can share the excitement and progress in myeloma. 33