Changing landscape of multiple myeloma care: Expert discussion

Prof Pieter Sonneveld – University Hospital Rotterdam, Rotterdam, Netherlands
Prof Meletios Dimopoulos – University of Athens, Athens, Greece
Prof Heinz Ludwig – Wilhelminenspital, Center for Oncology and Hematology, Vienna, Austria
Prof Michele Cavo – Seràgnoli Institute of Hematology, Bologna, Italy

PS: Hello, welcome to this filming meeting of ecancer. We are here with a couple of people, experts in multiple myeloma, at the meeting on current and future treatment practices in Amsterdam. I’m Pieter Sonneveld, an expert in myeloma from The Netherlands and I’m here with three colleagues from Europe, all of whom are very involved in the research and treatment of multiple myeloma. Next to me is Professor Dimopoulos from the University of Athens in Greece, Professor Heinz Ludwig from Wilhelmina Hospital in Vienna, Austria, and Professor Michele Cavo from Bologna, Italy. So welcome colleagues and friends. So we would like to discuss some issues that are now in the front line of myeloma clinical treatment research. One of those is, of course, the recent change in the diagnostic criteria for smouldering myeloma and multiple myeloma. So Professor Dimopoulos, you were one of the people involved in making these changes, can you explain what has changed over the past time?

MD: Over the years we have realised that we have better ways to image the bone disease in myeloma with CT scans, MRI and PET CTs. Also we have the change that we can evaluate also the activity of the disease and also we realised that by using creatinine clearance we can predict renal function in a much better way. Furthermore, we did not want to see a significant number of patients progressing to symptomatic disease with bone fractures or with renal failure. With all this data taken into consideration in 2014 the International Myeloma Working Group changed the diagnostic criteria to incorporate the new imaging techniques to require less decrease in the haemoglobin for a patient to start treatment and also to assess renal function with creatinine clearance. Furthermore, over the last few years we were able to identify a subset of patients with smouldering myeloma who had a very high probability to progress to symptomatic disease, 80% or more within the next two years. These ultra-high risk patients are now being called myeloma, they are eligible for trial treatment and also there is a recommendation that these patients should be treated rather than followed without treatment. Finally, we know that there is a high risk group of patients with smouldering myeloma which represents approximately 30% of the patients with smouldering disease and we believe that these patients may be candidates for trials which will investigate novel agents, novel combinations and also whether earlier treatment may alter the outcome of these patients.

PS: So, just to be sure, what’s your opinion, that those patients with smouldering myeloma should only be treated in the context of a clinical trial, or also in practice?

MD: In my opinion the ultra-high risk patients should be approached like symptomatic myeloma. The high risk smouldering myeloma in my opinion should be treated only in the context of a clinical trial.

PS: So thank you for this answer. So next I would like to ask Professor Ludwig about the risk assessment in myeloma. This is also a topic that gets a lot of attention, high risk versus standard risk patients. What is your take?

HL: Myeloma is a very heterogeneous disease and the risk of the individual patient depends very much on the biology of the tumour clones. So usually it is required to do a FISH cytogenetics, the result of which has an enormous impact also for treatment selection. You have, in addition, gene arrays which give you a close indication whether the patient is considered as high risk or standard risk. And, of course, we have the staging system, we have the ISS staging system which has been now revised and it’s not only including two parameters as it was in the original system with albumin and beta-2m. Now we have the combined system including FISH cytogenetics and the old traditional staging system. Of course you can build on that using other information in addition to that but I think for clinical practice the revised staging system is the most practical one and widely available and should be used.

PS: So to your opinion how does risk assessment influence our clinical practice?

HL: For a young patient I think the treatment is quite clear and everybody should be a candidate for high dose therapy and probably consolidation should be considered seriously in those patients and maintenance as well. In elderly patients risk assessment has an important role in my opinion because a patient with poor risk cytogenetics should probably be started on a proteasome inhibitor in addition to dex. So he’s not a very good candidate for an IMiD based therapy only. But in addition to these risk factors which depend on the biology of the disease the patient himself of course has to be assessed and, of course, we are all aware now that we have, particularly the elderly patients, that we have to categorise them in fit and frail patients and that depends, and the outcome depends, very much on what we would recommend for treatment in those patients as well.

PS: So if we really consider the high risk patients transplant eligible, what would be, let’s say, a good regimen to treat these patients with?

HL: In Europe we have now very good data favouring VTD which is Velcade, thalidomide, dexamethasone as induction therapy. This should be followed by high dose melphalan. High risk patients with high risk cytogenetics plus high LDH may be candidates for double transplant. And of course nowadays we have very good data showing the additional value of consolidation therapy meaning that you take the same regimen which you used for induction for consolidation and it depends whether you want to go with two or four consolidation cycles. The goal is, of course, to achieve the best possible depth of response, hopefully minimal residual disease negativity in your patients.
PS: So now you’re touching upon a new development in myeloma, like in other diseases like leukaemia, and this is MRD minimal residual disease assessment. So Professor Cavo, what is MRD in fact and what does it mean?

MC: Until ten years ago the primary study endpoint was to achieve a complete response, that means the disappearance of protein and of clonal plasma cells in the bone marrow. Over the past ten years the progressive availability of new novel agents including next generation proteasome inhibitors, immunomodulators and more recently monoclonal antibodies has allowed to increase not only the rate of complete response but also to deepen the quality of response. At this time it is possible to evaluate the minimal residual disease by using different techniques and those most commonly applied are multi-parameter flow cytometry and molecular techniques such as PCR in the past and more recently next generation sequencing. These techniques are able to detect one neoplastic cell in the background of up to one or ten million of normal cells so, based on the increased activity of new novel agents, it is now possible to evaluate MRD.

PS: So, if I may interrupt you, what is the extra value of MRD over the CR that we were used to?

MC: Yes, in the past the outcome of patients in conventional CR was very heterogeneous with some of them having an earlier relapse and others having a longer favourable outcome. This was related to the different number of residual myeloma cells. MRD is able to more carefully evaluate the depth of response and is also able to stratify patients in different groups according to the number of residual myeloma cells. The data so far available does suggest that MRD may be a surrogate marker for improved outcome in terms of prolonged progression free survival and overall survival. The question is which is the best method to be used in the daily clinical practice. Probably we are not… all these techniques are not yet ready for prime time. Molecular techniques such as NGS are almost standardised. Flow cytometry, there is a great effort in Europe and also in the US to standardise also flow cytometry. At this time it is likely that in the context of controlled clinical trials both the techniques can be applied in order to clearly establish which of them can be suggested.

PS: But are we already there that we can use it outside the context of a clinical trial? I would like to hear the opinion of all of you.

MC: In my opinion not yet and I would like to conclude saying that both these techniques evaluate the disease inside the bone marrow but we know that in myeloma that bone marrow plasma cells are typically spotty. So there is a clear limitation of these techniques and, based on this, many physicians are currently considering the use also of imaging techniques such as, for example, PET CT in order to capture eventual discrepancies between MRD inside the bone marrow with persistent disease outside the bone marrow. We are currently in a learning curve and we need to design prospective clinical trials not only in order to clearly identify the best method but also to use MRD as a driver for subsequent treatment decisions. At this time we are not in this position.

PS: So, anything that you would like to add?

MD: I think that MRD… we assess routinely MRD by using eight colour flow cytometry and we can provide this information to the patient and we feel secure that this has a prognostic significance and oftentimes patients are asking for this data. I agree with Professor Cavo that we cannot decide upon further treatment according to the MRD results but it can be used as prognostic information to the patient. We know that if a patient is MRD negative he has a high probability for his disease to remain under control than MRD positive patients.

HL: I would like to second what has been said. It’s a prognostic parameter, it’s excellent if we achieve that in our patients, it’s not a clinical necessity at this point of time. But if you have it available it’s fine to say that you are MRD negative and you will have a very good prognosis.

PS: Thank you. I would like to switch now from diagnosis and risk to treatment. Today we discussed with a lot of experts about the changing landscape of relapsed treatment because of the availability, or the availability that comes soon, of novel agents. In addition to bortezomib and lenalidomide and pomalidomide there are now other agents that may define the future landscape of myeloma treatment. So let’s start with the relapsed setting. Professor Dimopoulos, what in your opinion are the most significant changes that we are facing right now in the relapsed treatment landscape?

MD: Yes, two very important trials were presented recently at ASCO and EHA, the trial which compares bortezomib dexamethasone with bortezomib dexamethasone and daratumumab, another CD38 monoclonal antibody, and another trial which compares lenalidomide and dexamethasone to lenalidomide and dexamethasone with daratumumab. In both trials we saw a much higher response rate in the investigational arm than the control arm and a very long progression free survival. It is of particular interest that in both trials the hazard ratio was below 0.40 meaning a very significant improvement in progression free survival. I believe that these trials will change the way that we are treating patients with relapsed myeloma, one to three prior lines of therapy, and that the combination of daratumumab with either lenalidomide dexamethasone or with bortezomib and dexamethasone will be approved, reimbursed and used in the clinical practice very soon.

PS: So just to get an impression, we know that progression free survival in relapse with carfilzomib lenalidomide dex, the ASPIRE trial, was 26 months so what are we talking about with daratumumab in these two trials?

MD: Although the median has not been reached with daratumumab lenalidomide dexamethasone, which is a more fair comparison to KRD, I believe it will be at the range of 35-40 months so there may be an even greater improvement. Also we have minimal residual disease data which shows that one in four patients treated with daratumumab lenalidomide dexamethasone achieved an MRD negative status which is very impressive for relapsed setting myeloma.

PS: So Professor Ludwig, then the situation will occur that we have several choices for relapsed treatment. How are we going to decide which treatment we give to our patients?

HL: Yes, that’s becoming more and more complex but still I think we have four pillars on which we base the decision: on the biology of the disease, whether it is rapidly progressive, poor risk biology; on the treatment which was given prior to the relapsed situation, on the efficacy of the treatment, on the tolerance of the treatment and the time interval between the last treatment and relapse; and certainly on the patient’s situation – is he a fit patient or a frail patient and fourthly, and which is becoming more important now in Europe, on the availability of new alternatives. We recently have had the approval of four important drugs, Professor Dimopoulos has alluded on the important introduction of daratumumab. We have carfilzomib, which is a very highly active proteasome inhibitor. We have, of course, elotuzumab, an antibody against SLAMF7, and we have also panobinostat which improves the response rate and progression free survival in patients with very poor risk myeloma. We hope that we in the due future will have a fifth drug, ixazomib. So we have to use these drugs very wisely and it’s not easy because we don’t have randomised comparison between each drug. We can only base our decisions on what I have said before and looking for the best hazard ratio and the best hazard ratio was produced with dara based regimens.

PS: So Dr Cavo, now the situation will be that we have interesting and very active novel agents for the relapsed setting but what about the front line treatment?

MC: The front line treatment, again can be divided according to the age of the patients or their availability to receive high dose therapy. Regarding the role of transplant in the novel agent era, all the studies so far reported do support the continuous role of up front autologous stem cell transplantation. It can be concluded that up to now it has been clearly established that high dose melphalan is complementary with the novel agents, not only with the first generation proteasome inhibitors but also probably with the second generation proteasome inhibitors. Moving from transplant eligible to transplant ineligible patients, several phase III trials are currently running in order to evaluate all the standards of care such as, for example, bortezomib melphalan prednisone or lenalidomide dexamethasone in combination with the monoclonal antibodies. Daratumumab is currently combined with VMP and also with RD and is compared with all the standard regimens. I think that all the studies will be very important and one of the major relevant issues of monoclonal antibodies is the excellent toxicity profile. Due to the excellent toxicity profile and the very low rate of adverse events, it is likely that the triplet will be in the soon future also a four drug regimen, obviously not for all the patients. It may be that several regimens will be three drug but it is likely that for several subsets of patients the future will be a four drug regimen.

PS: So if we come to a conclusion about all these new developments, in three or four years from now what will be, let’s say, the preferred treatment for transplant eligible patients in front line? Dr Dimopolous, will it be all at once or, let’s say, triple or four drug regimens and saving some of the novel compounds for later stages of the disease? Can we achieve a cure?

MD: I am in favour of using all active drugs up front to try to increase the number of patients that achieve not only complete response but also MRD negative status because we are confident that by increasing this number of patients we will improve the progression free survival. Furthermore, as you pointed out, we will increase the fraction of patients that remain without evidence of disease for ten years or more. We want to think and we know that some of the patients are cured so I believe that myeloma is a chronic disease but in the future the survival will improve further and we will have a fraction of patients, an increasing fraction of patients, that will be free of disease and probably cured.

PS: So, Dr Ludwig, will this also be true for the older patients which is the majority of myeloma patients?

HL: I think so, that we should use the best possible regimen which is available and that will be a four drug regimen. In the far future it may be even a five drug regimen when we use checkpoint inhibitors in addition, if the preliminary data are confirmed that this will be a very active regimen. So the idea is to win the war in our patients and not a single battle. So to do this we need, as Professor Dimopoulos alluded to, to use the best regimen, give it to every patient who tolerates it. We have to be careful because we have to tailor the aggressiveness to the tolerance of the individual but if the patient is fit elderly he should have the best possible regimen in order to increase the response rate, the depth of the response, progression free survival and overall survival. If, when we have achieved that, we have a very high rate of complete remissions or MRD negative patients then we can try to find predictors which guide us to use which regimen in which patient population. But we are far away from this goal.

PS: And finally, Dr Cavo, people get older, there are more and more 80 year olds, 85, they get myeloma, so these frail people, will they benefit from the novel agents?

MC: Frail patients are a particular patient population and we think that at this time we need to adapt the therapy according to the frailty of the patients. So the whole concept then of one size fits all cannot yet apply, especially in this particular frail population. We need to still generate more data regarding the use of the new novel agents such as, for example, second generation proteasome inhibitors and the new monoclonal antibodies and we already know that some of them may have particular adverse events in several subsets of patients while these are lacking for other drugs. So the expanded armamentarium so far available will allow us to choose the best treatment for every subset of patients, including frail patients.

PS: So I would like to thank you all for your comments and thank everybody for your attention.