17th Congress of EHA, Amsterdam, 14-17 June 2012

Advances in multiple myeloma from EHA 2012

Professor Meletios Dimopoulos – University of Athens, Greece


Meletios, it’s good to see you again and to hear more news about multiple myeloma because you’ve got quite a lot to tell us about. There’s a recent New England Journal paper and you’ve got quite a lot of interest in young patients and also older patients who can’t have a transplant. First of all, what’s the most important news that you’re talking about here at the meeting in Amsterdam?

There are new data on how to manage patients, young patients, with myeloma who are eligible for high dose therapy. First of all it is becoming standard of care to use a bortezomib based combination with steroids and with a third agent. There is a Spanish trial which will be published in Blood which indicated that bortezomib thalidomide dexamethasone is a very active treatment for such patients. In some places instead of thalidomide cyclophosphamide is used or an anthracycline such as doxorubicin in the UK. So it is more or less a standard of care to use a triple combination which includes bortezomib steroids and a third agent. Then patients after four courses they proceed to stem cell collection and then high dose treatment with high dose melphalan and then there are important issues regarding the role of consolidation and maintenance. To that respect we have two large prospective randomised trials which were published a couple of weeks ago in The New England Journal of Medicine which addressed the role of lenalidomide as maintenance after high dose therapy in myeloma.

Now you’re an investigator of the lenalidomide study, what came out of it?

OK, in this these two particular trials there was a very significant improvement of the time to progression in favour of lenalidomide as compared to placebo. So there was an advantage of approximately eighteen months in the group of patients who received lenalidomide maintenance. So far we don’t have mature data to assess the effect on survival but these results are really impressive.

And in what category of patients would this work?

These are young patients who undergo high dose therapy and they receive lenalidomide maintenance. Also there was another trial which I participated in and in this particular trial the role of lenalidomide as maintenance in older patients with myeloma was assessed. This is the MMO15 trial which was conducted in Europe and patients were randomised to melphalan prednisone or melphalan prednisone with lenalidomide. One of the arms of the trial included lenalidomide as maintenance versus placebo. This trial showed a very significant improvement, again, in the time to progression, in the progression free survival in favour of lenalidomide maintenance.

And these were patients who didn’t have a transplant?

Right, yes. So it appears that lenalidomide is an effective agent for the maintenance of myeloma patients, for younger patients after high dose therapy and for older patients also without high dose therapy. In this meeting there will be a presentation by the Italian group who were again, in another trial in younger patients who underwent high dose therapy, there are positive results in favour of lenalidomide maintenance.

What about side effects of all of these agents? Has there been any news there?

Yes, lenalidomide, when given at low dose, it is usually well tolerated. It can cause some myelosuppression and the dose may need to be adjusted. Patients need to take some form of defence from prophylaxis, most often low dose aspirin, and there have been some issues with secondary primary malignancies occurring in some patients who receive lenalidomide maintenance. But I believe the benefit, as far as time to progression is concerned, outweighs the risks and we are very excited to see whether this significant improvement of time to progression will improve the survival of the patients.

And sub-cue bortezomib has been an issue as well, hasn’t it?

Great, yes, this has been a major advancement in the use of bortezomib because, as you know, the main limiting factor for the administration of bortezomib is the occurrence of peripheral neuropathy. Investigators have tried to administer bortezomib on a weekly basis instead of twice weekly, especially in older patients with myeloma and we have both Italian and Spanish trials that have been published recently with weekly bortezomib. More recently the subcutaneous formulation of bortezomib has been approved by the FDA and we expect approval in Europe as well in a month or so. With this route of administration, it is clear that the incidence and the severity of peripheral neuropathy is being reduced significantly.

What about individualising therapy, though, in multiple myeloma? Because it seems that there’s a big payoff from relatively aggressive approaches, but how do you choose your patients?

That’s a very good question. Unfortunately in myeloma we are not at the stage that we can select treatment according to patients’ genetic profile. There are studies on-going to assess gene expression profiling that may select one treatment over the other; for the time being there are certain situations that one would prefer one medication over the other. For example, if a patient with myeloma presents with renal failure, and this occurs in approximately 15-20% of the patients, we believe that the most appropriate treatment would be a bortezomib based combination. On the other hand, if you have a patient that has peripheral neuropathy, either from an unrelated cause or due to prior therapies, then we know that lenalidomide is the agent of choice. Other issues are patient convenience, distance from the hospital, oral formulation maybe preferable for patients who do not have an easy access to the hospital or who are really older. We will have to develop, though, more specific indications for specific therapies.

So in broad terms, how successful are these almost gold standard approaches now in treating, for instance, the younger patient who can go on to transplant, also the older patient?

Well we know that the survival of myeloma patients has significantly improved over the last decade and we know today that for a patient less than 65 years of age at the time of diagnosis of symptomatic disease, the likelihood of this patient to be alive for the next 7-10 years is pretty high. So we have made progress and we continue to make progress by extending the survival of the patients and by improving their quality of life.

And how much difference in efficacy is there between bortezomib and the lenalidomide option?

We think that these agents can be used in a complimentary fashion, in a sequential fashion, and we believe that by using all novel agents, including thalidomide and lenalidomide and bortezomib, and try to place them according to the patient’s needs, this will lead to the best outcome for a particular patient.

So the patient’s needs, you see how they’re doing but you also check for neurotoxicity and you balance your therapy?

Absolutely.

So what’s the simple clinical message for doctors?

I think that over the last ten years we have now three novel agents which are approved for the treatment for myeloma: thalidomide, lenalidomide and bortezomib and there are several studies which indicate that by using these agents, either together sometimes or more often in sequence, we can significantly prolong the quality of life and the survival of our patients with myeloma.

It seems you’ve done very well but what are the next steps in clinical research that you feel are needed?

That’s a very pertinent question because we know that despite the progress, very few patients with myeloma will be eventually cured and the majority of the patients will relapse. Thus we are facing patients, more and more patients, who have relapsed refractory myeloma which has acquired resistance to all novel agents and in this particular patient population the outcome is very dismal and we need novel therapies. We have two exciting novel agents which are being investigated in myeloma and we hope these will be approved for the treatment of myeloma. One is carfilzomib, a novel proteasome inhibitor, which appears to have some activity even in patients who are resistant to bortezomib. The other agent is a novel IMiD, pomalidomide, which again is being investigated actively in patients with disease resistant to lenalidomide and to bortezomib. Also we are very excited because for the first time we have a monoclonal antibody in myeloma, elotuzumab, which may not have significant single agent activity but when combined with lenalidomide and dexamethasone, you can see very high responses in the relapsed refractory setting and there are on-going trials to evaluate this combination in both patients with relapsing resistant disease and also in newly diagnosed symptomatic patients.

So just in a couple of words, how would you sum it all up?

I think that there is a real hope and reasons to be excited about the future treatment of myeloma with novel agents coming in that we are confident that will further improve the outcome of our patients.

Meletios, thank you very much for joining us.