Highlights on multiple myeloma from ASH 2012

Professor Meletios Dimopoulos – University of Athens, Greece interviewed by Professor Michel Delforge – Catholic University, Leuven, Belgium

My name is Michel Delforge, I work as a haematologist in the University Hospital in Leuven, Belgium. My colleague here is Professor Meletios Dimopoulos from Athens and we’re here at the ASH meeting in Atlanta and we would like to discuss some of the highlights on multiple myeloma. There are about 700 abstracts on myeloma alone so there is so much information, in your opinion, Meletios, what are really the abstracts or the presentations that we should pay most attention to?

I have been impressed so far, there are several abstracts on pomalidomide, a long term follow-up of pomalidomide experience from major clinics with more than 300 patients which, again, indicates responses in 20-30% of the patients, even in patients with adverse feature cytogenetics. Also there will be the late breaking abstract of the randomised trial with pomalidomide low dose dexamethasone versus high dose dexamethasone in patients with relapsed refractory myeloma resistant to both bortezomib and lenalidomide. Also there are interesting data with combinations containing pomalidomide and carfilzomib, pomalidomide and clarithromycin and also with the oral proteasome inhibitors such as the MLN compound, the phase II trial with MLN ixazomib with lenalidomide and dexamethasone as front line therapy in newly diagnosed symptomatic patients with essentially a 100% response rate. The data with daratumumab look also very interesting so I think there are no pivotal trials that will be reported in this meeting but there are interesting phase II studies with new compounds that are focussing primarily in these patients that have the unmet need myeloma, those that are refractory to both IMiDs and proteasome inhibitors.

Well, as you mentioned, there’s really a lot of excitement because of the fairly good data with drugs like pomalidomide and also with second generation proteasome inhibitors like carfilzomib. From your point of view, where can we expect these drugs in the immediate future, outside of the context of a clinical trial?

We know that carfilzomib is approved in the US and hopefully the FOCUS trial which is being conducted in Europe will lead to the approval of carfilzomib in Europe as well because, as we know, we need a randomised trial to have approval by the EMEA. Also, pomalidomide the same, so carfilzomib and pomalidomide low dose dexamethasone will be first used in those patients that cannot tolerate a proteasome inhibitor, are refractory to proteasome inhibitor and to lenalidomide. What is your opinion?

I agree with it. Of course we see a lot of exciting data, as you mentioned, with several combinations but when it comes to real life outside of a clinical trial we will be happy if we have these drugs available in the near future, let’s hope pretty soon for pomalidomide but of course this is expected to be in refractory patients. Coming to that, you have a lot of experience with these drugs because you were the top recruiter in the MMO3 study. From a practical point of view, in your experience what are the benefits of pomalidomide compared to lenalidomide, not only in terms of response but also in terms of, let’s say, tolerability and side effects for patients?

The side effect profile of these two agents are pretty similar so they both cause myelosuppression, especially in neutropenia; they do not seem to exacerbate neurotoxicity and I know that you have a particular interest in this field. They can cause DVT, but this can be readily prevented in most cases with low dose aspirin, and they are relatively well tolerated as oral agents. Of course pomalidomide has been administered to patients with more advanced disease where we know that the side effect profile is higher. In my experience with the patients treated with pomalidomide low dose dexamethasone, of course a minority of patients achieve an objective response but I believe that even in some patients with minor response or even stable disease they may gain a meaningful clinical benefit by improving the symptoms, reducing the requirement for transfusion and being stabilised for a certain period of time.

You mentioned already, briefly, the new monoclonal antibodies like we know elotuzumab in combination with lenalidomide dexamethasone but you also alluded to daratumumab, the anti-CD39 monoclonal antibody, which is, as we know, for the time being the monoclonal antibody that has the most pronounced activity as a single agent. But looking to the near future, where do you think that we can most optimally use these monoclonal antibodies, for refractory patients or more in combination or more as a maintenance treatment? What’s your opinion?

Yes, that’s a very interesting question. For example, for elotuzumab we both participate in these trials that are evaluating elotuzumab in combination with lenalidomide and dexamethasone in both relapsed refractory patients and in the front line setting. So I think that if these trials are shown to be positive, maintenance administration on top of another agent would be an ideal study. For example, I could envision a trial that compares lenalidomide versus lenalidomide and elotuzumab as maintenance after high dose therapy or even in conventionally treated older patients with myeloma.

You mentioned the word maintenance and we all know this is still a very actual topic in myeloma and also a little bit controversial one. Of course there is continuous treatment with, for instance, lenalidomide and dexamethasone but there is also the issue of maintenance, maintenance after autologous transplant or maintenance for elderly patients, for instance, after a three or four combo induction. What’s your opinion about the current state of the art regarding maintenance?

I think that the data look quite promising; there is a very significant improvement in progression free survival. If one focusses in the high dose treated patients there may be a survival advantage which has been reported in the American trial, maybe emerging in the IFM trial. However, at this point I believe that, at least in Europe, because lenalidomide is not approved for this indication very few physicians would administer lenalidomide as maintenance. I am more in favour, at this moment, to administer some form of consolidation after high dose therapy based on the Italian data but what is your practice outside the protocol for a younger patient?

We follow the same approach, we give the induction autograft and then we go for consolidation in order to try to further improve the adaptive response.

What are you using as consolidation?

We give a bortezomib based regimen and our policy of induction is triplets with VDT or VCD and then repeat the same triplet as consolidation treatment for two or four cycles, depending on the depth of the response. But this faces us with the sometimes practical problem that we have now up to 50% of the patients that can achieve a CR with this type of approach then afterwards we need to try to implement the more sensitive techniques to further monitor the residual disease otherwise we give the treatment but we are basically not evaluating at that moment what is the impact on the disease. Alright, we know that there is still residual disease in the majority of patients with CR but don’t you think that it would help to more implement these more sensitive techniques like flow cytometry?

Absolutely, although I believe that an eight-colour flow cytometry cannot be readily used in many centres. But there is a need to be able to be more qualitative in the assessment of complete response in myeloma and I believe not only as far as the plasma cells are concerned but also maybe a different assessment of response to the bone because we know and we are seeing patients that are in complete response by the standard criteria that we use and they may progress with an isolated bone lesion or a soft tissue plasmacytoma arising from a bone.

Maybe we could just briefly touch this a little bit more controversial subject about the prolonged use of bisphosphonates. We are both from countries where we have been faced years ago with the problems of osteonecrosis of the jaw because at that time zoledronic acid was given monthly, frequently until the death of the patient, so for many years. We come from an area where, according to the guidelines, we restrict it to a maximum of two years and now with the data from MRC9 there seems to be more recommendation to continue. But given the prolonged survival of patients that can easily be seven or ten years or longer, what’s your feeling, how should we handle this?

We have an empirical approach that for patients who have been on bisphosphonates, on zoledronic acid for more than a year or two, then we start administering every three months. We don’t have any real data to support this approach however, as you know, zoledronic acid can stick to the bones for extended periods of time and maybe this is a reasonable way to give some bone protection to the patient and maybe reducing the incidence of osteonecrosis. The other issue is that it is our impression that osteonecrosis today is being diagnosed much earlier so we rarely see a patient with advanced, very invasive osteonecrosis. Most of the cases now are being diagnosed at early phases and can be adequately treated with conservative measures.

So we’re talking about quality of life of patients and, of course, can we think more about also elderly patients or frail, vulnerable patients, the very elderly patients? What’s your opinion about the most important recent progress made for this cohort of patients in terms of treatment?

I think even without having data, within the European Myeloma Network and because of our frequent interaction, most of us in Europe are not denying older patients the novel agents but we rather approach them in a more gentle way, we start at a lower dose and it is important to keep in mind that probably the most toxic drug for older patients is dexamethasone so we try to be more gentle and start at a lower dose and maybe increase the dose according to the patient’s tolerance. Do you have an age limit in your practice for using lenalidomide or bortezomib?

Basically we don’t. Of course in, let’s say, patients above 85 years of age it sometimes comes to, for bortezomib, to pure practical issues, that patients need to be able to get to the hospital and then we go for the once weekly regimen sub-cue, eventually 1mg/m2. We try to balance between efficacy, tolerability and then one of the primary aims is not to cause too much toxicity of the treatment. For lenalidomide, for the time being, there is no age limit but, as you mentioned, we start with a lower dose and then if the patient has a good tolerance we
eventually escalate the dose but to maximise the chance that the patient stays on treatment.

So Michel, if you want to give advice to our fellow haematologists who are having busy practices and are dealing also with myeloma patients, what would be the standard of care today for a 60 year old patient with myeloma and for a 70 year old patient with symptomatic myeloma?

Of course this is a very good question and it refers to our daily practice. For the 60 year old patient it’s important first of all to have a clear view on the prognostic factors, not only on ISS but also on FSH and cytogenetics. In terms of induction I believe that the majority of evidence points towards a bortezomib based induction regimen and we would prefer a triplet instead of a doublet combination. We would give three or four cycles and then go for the autologous stem cell transplantation and eventually followed by consolidation. So the issue on maintenance treatment is still a little bit more controversial and, from a practical point of view, maintenance with lenalidomide is not registered and reimbursed in Europe. For the elderly patients, their prognostic factors are important but maybe it’s more important to look at comorbidities, frailty, disabilities and see if this patient is a more fit elderly or more unfit elderly. According to whether it’s the fit elderly we would go for a triplet combination, for instance VNP, of course there are data from Dr Palumbo’s group showing the efficacy of a quadruplet, VNPT, but this is only for a limited age group, let’s say for the fit elderly. We would treat for about one year but we would not give maintenance treatment just also for issues of reimbursement of the drug. And can I ask you the same question?

I fully agree with you and we have the same approach. In younger patients, those that are between 55 and 60, we try to store stem cells and we always consider a salvage transplant, especially if the patient has a meaningful progression free survival that exceeds two years. And exactly the same approach for older patients; for some patients we may use CTD instead of MPV if there are patients that have issues coming to the hospital or if there are patients that have relatively indolent symptomatic myeloma with anaemia, not a lot of bone lesions, normal renal function. We have found that this is a convenient treatment as well. Also we should emphasise, because this is also our practice, that we always encourage patients to participate in clinical trials in the front line setting and also in the relapsed setting because now there are many, many trials available throughout Europe that could cover all kinds of patients with active myeloma.

I fully agree with that, we should not forget about trying to get more progress by just actively participating and including patients in clinical trials. I think you’re one of the big examples in trials.

We’re doing that, we’re both trying.