The Multiple Myeloma Debates
Multiple Myeloma Debate 2014: Recent advances in multiple myeloma
PS: Dr Pieter Sonneveld – University Hospital Rotterdam, The Netherlands
MC: Prof Michele Cavo – Bologna University School of Medicine, Italy
JSM: Dr Jesus San Miguel – Universidad de Navarra, Pamplona, Spain
MD: Dr Meletios Dimopoulos – Alexandra Hospital, Athens, Greece
PS: Good afternoon. We’re here at the Multiple Myeloma Debate meeting in Copenhagen, Denmark where an international audience has gathered to hear about the latest developments and especially about presentations that are given at ASH that will change the practice of multiple myeloma. So I am here sitting with three friends and experts, Professor Michele Cavo from Bologna, the University of Bologna School of Medicine, in Italy; Professor Jesus San Miguel from the University of Pamplona in Spain and Professor Meletios Dimopoulos from the Alexandra Hospital and University in Athens, Greece. Welcome to this meeting. Today we have discussed about a number of different topics that are important for our daily clinical practice and we started with new data from ASH about transplant eligible patients. Dr Cavo presented some important novelties, maybe you can summarise them for us and explain how it will affect our clinical practice?
MC: Yes, at the last ASH meeting several previously reported trials including novel agents as part of the auto-transplant sequence were updated. In particular, two trials conducted by the HOVON German group and the Italian GEMIMA trial were updated confirming the value of the incorporation of bortezomib into the auto-transplant sequence as part of induction before transplant and consolidation or maintenance therapy after autologous stem cell transplantation. All these trials confirmed a progression free and overall survival benefit with bortezomib when incorporated into the auto-transplant sequence and, more importantly, there is a general agreement that the impact of bortezomib in patients with a high risk cytogenetic profile. So the first conclusion is that bortezomib may be of value when incorporated into transplant in patients with a high risk cytogenetic profile.
A second hot topic is related to the number of transplants to be given, single versus double, and a retrospective integrated analysis taking into consideration patient level data from three European phase III trials addressing the role of bortezomib versus a non-bortezomib based transplant provided demonstration that, in comparison with a single transplant, a double autologous stem cell transplantation was of value in significantly extended progression free survival and overall survival. And in this analysis we were able to identify three different adverse prognostic variables including a high risk cytogenetic profile in advanced high SS clinical stage and failure to achieve CR after induction therapy. Results have showed that, in comparison with a single transplant, the patients who have a high risk cytogenetic profile and fail to achieve CR after induction add progression free and overall survival benefit when receiving double autologous stem cell transplantation. Taken together, all this data can allow us to conclude that there are data supporting the incorporation of bortezomib and incorporation of bortezomib into a double auto-transplant procedure in patients with a high risk cytogenetic profile, particularly patients with 17p deletion and/or 1q.
PS: So for the panel, these findings, will this affect our daily clinical practice right now?
JSM: I think so, particularly for the high risk population bases with adverse cytogenetics the data on proteasome inhibitors induction plus double autologous transplant is really encouraging and I think this is going to support, in many centres outside of clinical trials, daily practice the use of this approach.
MD: Yes, I agree. For patients who are treated outside the clinical trial, after this data we discuss with them the potential benefits of tandem autologous transplant for patients who have 4:14 and/or 17p deletion. So already these analyses are applicable in our daily practice.
PS: So I regard this as a big step forward because now we can identify high risk patients and we can do something for them.
MD: No doubt.
PS: So the next question is about the non-transplant setting. The majority of the patients will not be transplant eligible; what’s new for those patients?
JSM: At the last ASH meeting it was presented one of the largest, probably the largest, trials so far conducted in non-transplant candidate patients. This was called the FIRST trial in which 1,600 patients were randomised to receive either one of the standards of care, MPT, versus lenalidomide plus low dose dexamethasone for eighteen cycles or until progression. The results from this study show that lenalidomide plus dexamethasone until progression is significantly superior to the two other arms in terms of PFS, with median PFS of approximately 25 versus 21, 20 months, and not only PFS but also overall survival upon comparing continuous treatment with len-dex versus MPT. In addition, this trial showed that the tolerability of the len-dex combination was pretty good, no haematological side effects, minor side effects. But I think probably we are going to have one new standard of care, alkylator-free, in the near future.
PS: So when do you think this will have some effect on our daily clinical practice?
JSM: I think as soon as it’s approved by the authorities, not yet.
PS: So then len-dex will be a kind of a new standard?
JSM: Another new standard. Then I think we can congratulate for the patients if eventually we have several new standards because each one may have different opportunities for the patient. I think this was the most important presentation; there is another interesting study also presented, this one, by the Spanish group in which they have used MPV, one of the standards – bortezomib, melphalan, prednisone, plus lenalidomide/dexamethasone for eighteen cycles either in a sequential platform or in an alternating form. The preliminary data is really encouraging with very high response rates and apparently a very prolonged PFS but the data is still immature. Just to conclude, I think we should also congratulate about other new drugs that are being tested already in the newly diagnosed patients and these include a second generation proteasome inhibitor, carfilzomib, in combination with lenalidomide/dexamethasone, highly effective. Other combinations also very effective, no peripheral neuropathy and also we have now in first line treatment of newly diagnosed patients the use of another proteasome inhibitor, ixazomib, that is like the twin brother for bortezomib: very low peripheral neuropathy and high activity in combination with lenalidomide/dexamethasone. And I think the panorama is very attractive.
MC: If I can briefly comment on the results of the FIRST trial which have been perfectly addressed by Professor San Miguel. I would like to emphasise that there was no signal of increased SPM for patients receiving continuous lenalidomide therapy. By the opposite, an increasing incidence of SPM was seen for patients in the MPT arm of the trial, suggesting the potential value of exposure to alkylating in predisposing patients to develop a second malignancy. I think that this is another important finding of this trial.
MD: Alkylating agents with IMiDs?
MC: Yes, alkylating agents with IMiDs.
PS: So we are moving, maybe, to a state where alkylators are no longer the first choice of treatment but for the time being with MPV, MPT it’s still an option that’s valuable for especially the non-transplant setting.
JSM: Yes, and has been already alluded by Professor Dimopoulos with MPV there was no sign of increased secondary primary malignancy. The good news is that lenalidomide in combination with dexamethasone has no signal of second primary malignancies.
MC: And these results further confirmed prior results coming from MLN9 and 10 trials showing that continuous exposure to len-dex for patients with resistant relapsed disease was not associated with an increased incidence of SPM. So I think that we have now robust data supporting that continuous exposure to len-dex for transplant ineligible patients not receiving alkylating agents is void of any risk of SPM.
PS: OK, so speaking about the relapsed refractory setting, Professor Dimopoulos, what can you tell us about the newest developments?
MD: I think the major presentations at ASH this meeting were an update of the pomalidomide low dose dexamethasone trials. The primary trial was published by Professor San Miguel a few months earlier. In this update at the ASH meeting a significant improvement in the overall survival was confirmed with longer follow-up despite a significant cross-over percentage of patients. Also, there was an update on the improvement of quality of life of patients treated with pomalidomide low dose dexamethasone. The benefit that this combination gives to patients with adverse cytogenetic features, especially 17p deletion, which is in contrast to its brother compound lenalidomide where we know that both in the relapsed and also in the front line setting lenalidomide does not appear to be very active in patients with adverse cytogenetic features with us. With pomalidomide and low dose dexamethasone things may be different. Also there was another interesting trial from the UK which, for the first time, evaluated the role of salvage autologous transplant in patients with myeloma. At the time of relapse patients received a bortezomib-doxorubicin-dexamethasone combination and they were randomised to receive either high dose melphalan with stem cell rescue or low dose cyclophosphamide maintenance and there was an advantage of high dose melphalan. So I believe this should impact our practice and we should keep in mind that when we have a younger patient, especially with stem cells stored, if the patient derived a significant benefit from the front-line therapy and high dose transplant up front then we should think of a salvage high dose therapy after the patient has been re-induced into remission.
PS: The relapsed refractory setting is typical, the setting where we test novel agents. At ASH there were several presentations about new drugs and new mechanisms of action that may be introduced in multiple myeloma. Would you like to elaborate a bit on that?
MD: Absolutely. I think the most promising class of agents are the monoclonal antibodies today and especially the anti-CD38 monoclonal antibodies. We have already three in development; of those daratumumab has been tested more so we have robust phase II data of single agent daratumumab and we know the appropriate dose and a response rate which is approximately 40%. This is very encouraging because we are talking about patients with relapsed refractory myeloma and it is clear that trials in evolution that combine anti-CD38 monoclonal antibodies with lenalidomide/dexamethasone or with proteasome inhibitors will provide new treatment options for patients with myeloma. One could envision that in a few years we will be able to give frontline therapy that will include a fourth category class of agents, monoclonal antibodies. So I think this is a pretty exciting period.
Also, new histone deacetylase inhibitors are being evaluated. We have encouraging data, apparently, with panobinostat in combination with bortezomib and dexamethasone with a four month improvement in PFS but also newer histone deacetylase inhibitors that are more specific, less toxic, better tolerated by the patient and this also will provide probably a fifth class of agents that could be combined with other agents for myeloma.
PS: Thank you. There are more classes of agents also being tested like PARP inhibitors, kinase inhibitors and so on that maybe we should move to other important topics that were discussed at this meeting dealing with management of multiple myeloma. Because in addition to our traditional diagnostic procedures, over the past few years we have learned that FISH analysis of the bone marrow, especially at diagnosis, has an important role and there are other ways to monitor disease once the patient has been treated. So let’s start with FISH, how should we use FISH in daily clinical practice and when should it be done?
MC: I usually do FISH in every patient at the time of diagnosis and my daily clinical practice is to perform a FISH at every subsequent relapse. FISH provide important prognostic information that now, although we have not a standard risk-adapted strategy, we can try to move to different treatment decisions based on the FISH profile of every single patient. So FISH is of crucial relevance and its routine application should be strongly encouraged for every patient included or outside the clinical trials.
JSM: I have a slightly different approach. We perform FISH in every patient at the time of diagnosis but at the time of relapse, outside the clinical trial, we only repeat FISH if a diagnosis was not high risk. If it was already high risk we don’t repeat.
PS: You do that with the purpose of seeing whether a more aggressive clone?
MD: Yes, 17p deletion.
JSM: Yes, in a standard risk they may become high risk.
MC: I agree. I omitted to say this, that the importance of repeating FISH is to capture new genetic lesions not those previously shown. So it is important.
PS: So have our procedures for imaging in patients, have they also changed?
MD: I think so, and I think they are going to change very much in the future. Yes, to have a lytic lesion you need to lose at least 30% of the bone substance otherwise it cannot be detected by conventional X-rays. This means that this is a low sensitivity technique and I think low dose CT is going to become more and more popular and probably one of the standards of care for the evaluation of bone disease together with MRI. I think these two techniques are going to have a critical role in the management of patients. On top of this, similar to what the lymphoma doctor does with a PET, just to measure the metabolic disease, the myeloma doctors we are going to use also PET in the near future just to evaluate the extramedullary disease, to evaluate response after intensive therapy.
PS: The last topic that I want to discuss is about how we should monitor the patients because we have now more effective treatments, more patients achieve a CR, CR rates have doubled or tripled in transplant eligible and doubled in younger patients compared to twenty years ago. So what is our criterion for a good response and how should we monitor those patients?
JSM: Do you want me to address this question?
PS: Yes, why don’t you start?
JSM: OK. The current definition of complete response is based on two techniques that are not very sensitive but they’re very valuable. One is M protein immunofixation and the other is the morphology. Nevertheless, I think we need more sensitive techniques; outside the bone marrow I think the PET scan is going to be the most valuable one and inside the bone marrow we need more sensitive techniques to assess the clonality, the mono-clonality and this comes from the high sensitivity Flow, the new Flow with 8-colour flow, and also the molecular technique mainly based on the approach that is the next generation sequencing.
PS: So, Dr Dimopoulos, is CR still the standard that we should try to achieve or…?
MD: I think so and I fully agree with Professor San Miguel. We have to keep in mind that immunofixation is pretty subjective. The evaluation whether this patient has a negative immunofixation or a positive immunofixation frequently depends on the interpretation of the person who reads it. So definitely we need more objective means of assessing response and I believe that with newer regimens increasing the complete response rate we need definitely to have better tools to assess objectively the response rate and then probably perform trials that will address the question should we treat patients who have minimal residual disease, for example detected by flow cytometry? Will this change their outcome? Like other diseases we know that in acute lymphoblastic leukaemia this has become the standard of care and I believe that it won’t be long before this will be the same for myeloma.
PS: Any other comments from the panel?
MC: I would like to echo what was already addressed by Professors San Miguel and Dimopoulos that the treatment paradigm is changing. We have introduced into the new treatment paradigm for myeloma patients new treatment phases including consolidation maintenance. All of us agree that our goal within the novel agent era is to achieve the deepest level of response as evaluated by laboratory and imaging techniques. Many treatment phases and the choice of many treatment phases may be based on the achievement or not of MRD negativity. So at this time there is the need to include MRD assessment in every controlled clinical trial because, based upon these results, we may provide useful information to be translated into the daily clinical practice in the next few years.
PS: With this I would like to end. I thank the panel for the discussion.
MD: Thank you for the opportunity.
JSM: A pleasure.