New data in the diagnosis and prognosis of multiple myeloma

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Published: 3 Apr 2013
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Prof Paul Richardson, Prof Phillippe Moreau, Prof Jesus San Miguel, Prof Gareth Morgan

Prof Paul Richardson, Prof Phillippe Moreau, Prof Jesus San Miguel and Prof Gareth Morgan join together for ecancertv for this expert panel discussion filmed at the 14th International Myeloma Workshop (IMW 2013), 3-7th April looking at understanding of new data in the diagnosis and prognosis of multiple myeloma.  

Pomalidomide and carfilzomib have recently been approved in the US for treatment of multiple myeloma (MM). Pomalidomide was approved on the basis of two Phase II trials. A robust response of approximately 30% was seen in both studies in double refractory patients, with durability of response and impressive progression free survival (PFS) and overall survival (OS).

In both trials, a predictable and manageable toxicity profile was observed. This drug represents a significant advance in the treatment of MM. Combination studies (with bortezomib and carfilzomib) and subgroup studies are underway. Carfilzomib received accelerated approval last year with low dose dexamethasone as a premedication and now in combination. It has shown clear activity in the context of double refractory relapse disease. Carfilzomib is associated with relatively low rates of neurotoxicity. There are other toxicities, although these are believed to be generally manageable.

The oral proteasome inhibitor, MLN9708, has shown favourable tolerability. Its activity in combination also appears to be encouraging. However, it does not seem to be as potent as IV or SC bortezomib.

Treatment of high risk smouldering myeloma is a key topic at this year's IMW. Smouldering myeloma is a very heterogeneous group of patients, as it also includes MGUS patients who have a very low rate of progression to MM. At the other end of the spectrum are the high risk patients for progression, sometime referred to as 'early myeloma', most of whom will progress to full-blown MM in 2-3 years. Recent Spanish data has shown that thalidomide and dexamethasone in combination can delay the progression to MM, and improve the OS in this group of patients.

Myeloma is not only a heterogeneous disease between individual patients, but also within an individual patient. There is more than one subtype of malignant cell, which has important implications for treatment. At any one time during the disease, a single subtype of clone can be dominant.

This has been termed the 'clonal tide' in MM. Because of the changing face of MM over the course of the disease, it is thought that a patient showing initial resistance to a therapy who then relapses can subsequently show sensitivity to this treatment again, as the clonal pattern of their disease changes. It is now possible to track the presence of clones over time and it may be possible to develop a myeloma tool based on next generation sequencing to use in biopsies to monitor the clonal content and intervene early before the clone has become too complex.

Several monoclonal antibodies have been investigated in MM in combination with lenalidomide and dexamethasone. Further studies are underway.

The assessment of minimal residual disease (MRD) should be assessed both inside the bone marrow and outside the bone marrow. Outside the bone marrow, imaging techniques such as PET scan should become the gold standard. In the bone marrow, there are two imaging techniques available. The first of these is molecular imaging and the second is multiparameter flow cytometry (MFC). The latter is more applicable for use in routine laboratories.

A combination of both extramedullary and intramedullary assessments would provide the best tool to help decide on therapy in the future. Currently, studies have shown that a positive MRD can help guide consolidation and maintenance therapy.

Bisphosphonates are used routinely in MM patients. A recent study on zoledronic acid has shown that the use of zoledronic acid not only reduced bone disease but improved survival in the patients treated. This is the first time a survival advantage has been seen with supportive care. As a result, guidelines now recommend the use of zoledronic acid until disease progression occurs.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

14th International Myeloma Workshop

New data in the diagnosis and prognosis of multiple myeloma

PR: Professor Paul Richardson – Dana Farber Institute, Boston, USA
PM:  Professor Philippe Moreau – Centre Hospitalier Universitaire de Nantes, France
JSM: Professor Jesus San Miguel – University Hospital of Salamanca, Spain
GM: Professor Gareth Morgan – The Royal Marsden Hospital, London

PM: Welcome everybody to live from Japan. We are in Kyoto, the location of the International Myeloma Workshop, and we are going to be doing four days, very hard, on all the novelties regarding the treatment and the biology of multiple myeloma. So first of all I would ask my colleagues, very famous experts in the field, some questions. Paul, maybe you would like to comment on the new data on the third in class, second in class, proteasome inhibitors and IMiDs and how do you think that it will change the therapeutic options? Maybe this is the US point of view with your comments but what do you think about these drugs?

PR: Well, thank you, Philippe, it’s a pleasure to be here with you today. Let’s start with pomalidomide first, as a third generation IMiD we’ve been very pleased with the accelerated approval in the United States of that drug in combination with dexamethasone based upon two studies, one from the IFM and the pivotal trial, the 002 study. And in both of these studies we saw a very robust response rate in double refractory patients, approximately 30%, with durability of response and impressive progression-free and overall survival for such a sick and vulnerable group of patients. What was also very exciting in both phase II trials was to see the very predictable and manageable toxicity profile. At this meeting we’re presenting data on the efficacy of this combination in high-risk cytogenetics as well, which is another plus to this platform, as part of the meeting and there are other presentations around pomalidomide focussing on its activity in various different settings with the clinical benefit that’s been seen. So pomalidomide has been a really important advance and combination strategies with pomalidomide are now going forward. They include with bortezomib, which we’re also presenting some data as a poster presentation on, and also actually with carfilzomib. That brings me to the second big piece of news which is obviously the accelerated approval last July of carfilzomib with low-dose dexamethasone as a pre-medication and now its more widespread use in combination, and that’s been exciting. Carfilzomib is clearly active in the context of double refractory and relapsed disease, in the context of bortezomib and IMiD failure. I think the biggest advance with carfilzomib is its relatively low rates of neurotoxicity, they’re much, much lower than we see with bortezomib. There are other toxicities with carfilzomib but they’re generally manageable although some require some caution, including the renal dysfunction and some cardiac signal, albeit at a very low level. I think for patients it’s all broadly good news; these two recent approvals signify the progress that’s being made.

MLN9708, ixazomib, is another important advance. That’s an oral proteasome inhibitor in the boronate peptide class, the tolerability appears to be very favourable, its activity also appears in combination to be encouraging. I think that, interestingly, it may not be as potent, I think it’s fair to say, as IV bortezomib or sub-cue bortezomib, for that matter, but I think that remains to be seen and we’re obviously very excited by it. So important advances, Philippe.

PM: Thank you very much, Paul. Jesus, we will have some discussion regarding the treatment of smouldering myeloma and especially in high risk patients. So do you think that it is prime time for treating these patients or do we have to wait for further results of on-going trials? What is your opinion regarding this very specific group of patients?

JSM: I think you have pointed out something that is important to mention, that when we talk about smouldering myeloma this is a very heterogeneous type of diagnosis because you include a population that are not really smouldering, that are MGUS patients that have a very low rate of progression. And in the opposite side you have what I like to call early myeloma because most of these patients will progress in 2 – 3 years. And probably the data that was presented by the Spanish group showing that now with lenalidomide-dexamethasone, you not only delay the time to progression but also you improve the overall survival of these patients. We are facing a situation similar to early detection of breast cancer, early detection of prostate cancer. In this type of tumour, in solid tumours, early detection and early intervention is associated with better survival; probably in myeloma we are facing the same situation. Then my position in this is that we are not talking about treating patients that have not myeloma, we are treating patients with active myeloma, we are detecting now with the new techniques and probably the time will come to treat this early myeloma.

PM: Thank you, Jesus. And Gareth we also heard important and interesting data regarding clonal evolution. What is your opinion regarding these specific changes to the biology of the tumour cells and do you think that we will have some implication for new therapies?

GM: So I think it talks to what Jesus was just talking about – early intervention. So it’s quite clear that myeloma is heterogeneous between people but also even within a patient there’s more than one sub-type of cell within the malignant cells themselves and this has important implications for treatment. If you delay the diagnosis and treat the disease late at the stage of extramedullary myeloma or plasma cell leukaemia, it’s clearly very difficult to treat because of the supreme genetic heterogeneity that’s present. Whereas if you intervene earlier in the disease course I think you can make a strong argument for treating high risk smouldering myeloma and expect to get better outcomes long term.

PM: And when the patient is at the time of the relapse, first relapse, second relapse and so on, now we do have many lines of therapy. Do you think that we need to look at the clonal evolution of the disease over time? Do we have to perform systematic biology tests to look at the modification of the clone?

GM: There’s this kind of curious concept that people have cloned the word: “clonal tide” which is difficult for people, certainly non-English speaking people, to understand. But it means that at different times during the disease one of the sub-clones is predominant and over time they can come and go. So you look at a kind of Darwinian approach to treatment where you reduce a lot of the clones and you can maintain them in a remission state but one of the things we’re learning is even if you’ve been exposed to a treatment and are resistant to it, it’s theoretically possible to relapse some years later and at that point in time be sensitive to the same treatment.

PM: Do we have the tools to look specifically at this very important issue? Can we retreat a patient that was supposed to be refractory to a drug?

GM: Well I think your colleague, Stefan, presented data here, Jon Keats presented data, we presented some data that you can now track the presence of clones over time and a firmly held view of mine is that you can design a tool, a sort of myeloma tool based on next gen sequencing, where you should be able to do biopsies, monitor the clonal content and intervene early, analogous to smouldering myeloma when the clone hasn’t got too complex. And I think this represents a very serious way forward with the management of myeloma.

PM: That’s very interesting. Paul, you mentioned the new proteasome inhibitors, new IMiDs, but you didn’t speak about another new class of agent which is the monoclonal antibody. So we’ve heard recent data on elotuzumab, daratumumab, do we think, do you think that we will have this R-CHOP treatment for multiple myeloma like we had in the past regarding non-Hodgkin’s lymphoma?

PR: I think arguably we already do and I think the best example of that has been the success of the combination of elotuzumab with lenalidomide and dexamethasone where we saw a progression-free survival estimate from our phase II optimal arm, which was 10mg/kg, three times what we saw in a similar disease setting from lenalidomide-dex alone. So in fact the time to median progression free survival is estimated at approximately three years compared to approximately a PFS of one year with lenalidomide and dex in the same population. Obviously that’s a phase II randomised trial, we have to be careful, but the phase IIIs that are on-going will hopefully answer this question definitively. And I think elotuzumab represents our first monoclonal antibody that will, I hope, prove its mettle in the relapsed setting and then move earlier. I think the next monoclonal on the block is daratumumab which targets CD38 and this, as a single agent, has shown very promising activity in the relapsed refractory setting, recognising that it remains a phase I/II experience so we have to be careful. But this is the first time we’ve seen a monoclonal antibody as a single agent with dexamethasone as a pre-medication perform this well. At this meeting, as a poster presentation, there is an update from Dr Plesner describing this and talking also about the safety. So next steps will be combinatorial studies and already right now the so-called 503 study is already underway in which daratumumab is combined with lenalidomide and dexamethasone and that phase I/II study is already accruing patients.

PM: So that’s very promising. And a question for you, Jesus: the quality of the treatment is improving and the depth of response, especially in young patients with high dose treatment in combination with novel agents. So we are assessing, we are trying to assess, minimal residual disease, that is really a hot topic, let’s say. What is your idea regarding minimal residual disease? What test, first, to evaluate this MRD and do you think that MRD evaluation should guide our treatment in the future? What is your opinion?

JSM: I think to evaluate MRD you should consider inside the bone marrow and outside the bone marrow. For outside the bone marrow, imaging techniques, PET scan probably is going to be, hopefully in the near future, a gold standard, particularly for detection of extramedullary disease. And this, in the context of the transplant, I think, is going to be very important just to use consolidation or maintenance therapy based on extramedullary disease. If we focus now in the bone marrow we have two techniques: one is the molecular technique that has been the gold standard but is really time-consuming and is not applicable to a substantial proportion of patients. The other is the multicolour flow that is getting better and better and now we are very close to having a very well standardised technique that can be spread to almost routine labs.  And this is the case, you also should consider something that is important, it’s that bone marrow infiltration in myeloma is not like in leukaemia, it’s a patch infiltration. Therefore, to have a minimal residual disease positive is clearly negative, this is something that demonstrates that you have still residual disease. But a negative minimal residual disease could be due to an error in the bone marrow sampling. Then a positive result for me can help just to go for a consolidation again and as a maintenance therapy and to guide the duration of this type of treatment. Then, if you combine both medullary assessment and extramedullary assessment, I think you will have better tools now to just develop it in the future.

PM: So are you aware of any clinical trials on-going with a treatment strategy according to the results of minimal residual disease evaluation?

JSM: We are going to open next month the Spanish clinical trial in which the duration of maintenance is based on minimal residual disease.

PM: That’s a very good point. So, last question for you, Gareth, regarding supportive care. We are using bisphosphonate routinely in our patients and you reported a very important study on the use of zoledronic acid. Can you comment on the results of this study and discuss the role of this drug, not only in young but also in elderly patients?

GM: It’s been a learning experience for me to have done a large clinical trial that actually you can see changing practice globally which I never would have expected at its onset. The basic result of the study was that the use of zoledronic acid not only reduced bone disease but it seemed to improve survival in the patients that were treated with it. So that was important because it’s the first time in a human setting that a survival advantage for a supportive care was seen. And you can imagine how it works by altering the microenvironment and positive feedbacks. So pretty soon after the study was published we changed the guidelines in the UK to say all patients at presentation should receive treatment with an IV Zometa until disease progression because that was the basis of the study. And Professor Terpos, Evangelos Terpos, has produced a set of guidelines internationally which translate the data from the study and the British guidelines into a global recommendation. So that’s a really proud moment, I guess, I’m very pleased that it’s been able to go through from idea, clinical trial, to widespread acceptance.

PM: Thank you very much, Gareth. And thank you all the experts. I would like to thank again all the experts on this very interesting session. Thank you very much.