Mutiple myeloma treatment in the non-transplant setting

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Published: 3 Apr 2013
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Dr Sonia Zweegman, Prof Marivi Mateos

Dr Sonia Zweegman and Prof Marivi Mateos talk to ecancertv at IMW 2013.

Defining an elderly multiple myeloma (MM) patient can be difficult. Currently we use chronological age, defined as those aged 65 years or older. A second age group is those aged 75 years and older, who tend to be more unfit or frail. However, the use of biological age through geriatric assessment should be considered in the future.

The objective of treatment in elderly MM patients has changed with the arrival of novel therapies. In the past, complete remission (CR) was not a viable objective. However, with the introduction of immunomodulatory drugs and proteasome inhibitors, CR rates have significantly increased. Studies indicate that elderly patients who achieve CR have a prolongation of progression free survival (PFS) and overall survival (OS).

Based on these results, the objective of treatment in elderly patients is now CR. It is possible to evaluate response to treatment through immunophenotypic assessment.

The depth of response is important but toxicity also needs to be taken into consideration when treating elderly patients. A balance is needed between a high CR and the degree of toxicity that the patient can tolerate in order to continue treatment. In Europe an alkylating-based regimen combined with a novel agent is frequently considered, in particular thalidomide and bortezomib.

These regimens have not been compared head to head, so it is difficult to ascertain which one is superior. However, the MPV (melphalan-prednisone-bortezomib) VISTA trial showed a significant improvement in OS of around 13 months. In contrast, the meta-analysis of the MPT (melphalan-prednisone-thalidomide) trials, showed an OS of less than 6 months. Based on these results, MPV is considered a good first line regimen and MPT is a good second option. In order to minimise toxicity in elderly patients, a weekly schedule for MPV with prolonged maintenance therapy was investigated.

This resulted in a significantly reduced peripheral neuropathy rate versus that observed in the VISTA trial. Gastrointestinal toxicity and discontinuation rate were also both significantly reduced. The efficacy was maintained and even improved with maintenance therapy. These results were reproduced in an Italian trial conducted by Dr Palumbo.

Another important consideration is the route of administration. The subcutaneous formulation has been found to be noninferior to the intravenous formulation. Interestingly, it has also been shown to result in significantly reduced peripheral neuropathy rates. Therefore, an optimal way to treat elderly patient with MM is to offer subcutaneous MPV on a weekly schedule as six induction cycles followed by maintenance therapy. However, maintenance therapy cannot be given outside of clinical trials. Therefore, in clinical practice the first cycle consists of bortezomib twice a week, followed by 8 additional cycles in which bortezomib is given just once a week.

Prolongation of therapy in elderly patients is important to ensure PFS is as long as possible as re-treatment may not be an option in these patients. With regard to MPT, this is more challenging. Peripheral neuropathy is more prevalent with a longer period of administration and patients frequently discontinue thalidomide maintenance therapy because it was not feasible for many of them. Cytogenic analysis prior to treatment with thalidomide is necessary to establish those at risk of harm. In patients with low levels of risk and in whom thalidomide is feasible, maintenance therapy can be continued. For lenalidomide, the MM015 trial demonstrated no PFS benefit without maintenance. In addition, the dose of lenalidomide was limited in patients over 75 years of age because of toxicity.

Therefore, a 'soft' start is recommended for this treatment. In terms of preference of an alkykating agent versus corticosteroid, data from the French MM020 trial, which is comparing MPT with a combination of lenalidomide and dexamethasone, is eagerly awaited and will provide an answer to this question.

Outside clinical trials, current clinical practice for the management of elderly MM patients in Europe is MPV as first line treatment, with MPT as a valuable alternative.

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

14th International Myeloma Workshop

Multiple myeloma treatment in the non-transplant setting

Dr Sonia Zweegman – VU University Medical Center, Amsterdam, The Netherlands
Professor Marivi Mateos – University Hospital of Salamanca, Spain

Hello, good afternoon. I am Dr Mateos and I work as a haematologist at the University Hospital of Salamanca in Spain. I am here in Kyoto joining the 13th International Myeloma Workshop and today it’s my pleasure to share this time with Dr Zweegman from the Netherlands to debate or to discuss about the options of therapy for elderly myeloma patients. I would like to ask Dr Zweegman about the definition of elderly myeloma patients - what do you consider a myeloma patient as elderly patients?

I think that’s rather a difficult question but I do think in the future we should apply geriatric assessments to define who is old and who is younger. But up to now we will use 65 years of age and I think a second number that is being used is 75 years of age because these are the real old patients and most of the time they are more unfit or frail. The question then is, and I might ask you, Dr Mateos, what do you think is the best treatment option in order to reach a goal and what is the goal to be reached in this type of patient?

It’s a good question and an interesting point because I think that the objective in elderly myeloma patients has changed with the arrival of the novel drugs. In the past there was not an important objective, complete remission was not an important objective as opposed with young patients because you know that melphalan plus prednisone was the standard of care and a complete remission rate was not superior to 5%. However, now with the introduction of novel agent based combinations, including immunomodulatory drugs and proteasome inhibitors, the complete remission rate significantly increased. So in studies it has been clearly demonstrated that even elderly patients who achieved complete remission had a prolongation of the progression free survival and also the overall survival. So I think that the objective of the treatment in elderly myeloma patients should be now to achieve complete remission and probably it is possible to evaluate in more depth the response and probably we can try to achieve immunophenotypic complete remission. Because in our experience we have observed also that elderly patients achieving immunophenotypic complete remission had also a significant prolongation of the progression free survival. So I think that this would be the objective of the treatment of elderly myeloma patients. Considering the different options of therapy for elderly patients, what is your preference?

I agree that the depth of response is very important in these patients. On the other hand, we know that the toxicity is far more pronounced in the elderly patients as compared to the younger patients so what we should look for is a balance between reaching a high complete remission without side effects that prevent patients continuing therapy. So what we normally do in Europe is using an alkylating based regimen combined with a novel agent and the two types of regimens that are currently registered and reimbursed are the combination with thalidomide and with bortezomib. These regimens are not compared head to head, so it’s difficult to say which regimen is superior but when you look, and you know everything because you did run the study, the MPV VISTA trial shows a considerable improvement in overall survival of about thirteen months. And when you look to the meta-analysis of the MPT trials that’s far less, that’s about six months. So I think that MPV is a very good regimen as a first line treatment and you have MPT as a second option, especially when you want to use an oral regimen. When it comes to the first effect I stated, that toxicity is an issue in the elderly patients, do you think that the MPV regimen can be adapted in order to decrease toxicity? What are your thoughts about that?

Yes, I think that the next step is clearly to optimise the treatment for elderly myeloma patients because with the novel agents we demonstrated that they are clearly superior to the standard MP, in fact MP should not be longer considered the standard of care. But we had to optimise the treatment, especially with the bortezomib based combination because it is one of the most commonly regimes used around the world and especially in Europe. So the first step to optimise the use of VMP in elderly myeloma patients was to move to the weekly schedule. You know that bortezomib was classically administered twice a week and in fact the Spanish Myeloma Group decided to conduct a trial giving bortezomib, basically, on a weekly schedule in order to reduce the toxicity but we wanted also to maintain the efficacy and for this purpose we decided to prolong the therapy with maintenance therapy. We clearly achieved the objective because the peripheral neuropathy rate decreased from 13% in VISTA to 7% in our trial. Also the gastrointestinal toxicity and also the discontinuation rate was significantly reduced. And when we evaluated the efficacy it was also maintained and even improved with the addition of maintenance therapy that we can discuss later on. But these results in addition were also reproduced by an Italian trial conducted by Dr Palumbo in which they decided also to use the weekly administration of bortezomib followed by a prolongation of the therapy with maintenance therapy and again the results were similar. So the weekly administration of bortezomib is an important way to optimise the treatment of elderly myeloma patients and I think another important way to optimise is the change in the route of administration of bortezomib because now the sub-cue formulation is approved in Europe to be used; results coming from the French group demonstrated that the sub-cue formulation is not inferior to the intravenous but the most interesting thing is that the peripheral neuropathy rate significantly decreased. So if we put together the weekly schedule plus the sub-cue formulation, I think it’s an optimal way to optimise the treatment of elderly myeloma patients. Concerning bortezomib we can also try to optimise other combinations, immunomodulatory drug based combinations although they have not yet been approved in Europe, but probably lenalidomide in combination with low dose steroids or to adapt the dose of lenalidomide according to the age or according to the bone marrow reserve can represent other important ways to optimise the treatment for myeloma patients.

May I ask one additional question because both you and Dr Palumbo showed that the weekly administration decreases the toxicity? Both of you have administered a cumulative dose which resembles the dose which is given in the VISTA trial, but recently you’ve also stated in Blood that outside of clinical trials you don’t use maintenance treatment of bortezomib. So in clinical practice what dose are you aiming for when you start MPV, or VMP like they say in Spain, for elderly patients?

In our trial we gave our patients six induction cycles followed by maintenance therapy but we can’t use maintenance therapy outside of clinical trials and so what we are doing is to administer the first cycle with bortezomib twice a week followed by eight additional cycles in which bortezomib is given just once a week in order to prolong a little bit the therapy as compared with our trial in which patients received only six cycles. I don’t know if it’s the most appropriate way to optimise the treatment because really I think that elderly patients can obtain a benefit more than a maintenance therapy until disease progression in the same terms than for young patients after autologous stem cell transplant. Elderly patients can benefit from a prolongation of the therapy with a soft therapy: low dose of thalidomide, low dose of bortezomib, one dose in sub-cue formulation every fifteen days or one conventional cycle every three months. So in order to try to optimise the treatment, to increase the quality of response and to prolong the progression free survival and probably the overall survival because in the Palumbo trial there is a clear benefit in terms of overall survival as compared with the group of patients where they didn’t receive maintenance. What is your opinion about maintenance therapy?

I do think, and I agree with you, that a prolonged administration of therapy, especially in the elderly patients is of importance because their first progression free survival should be as long as possible because many of these patients won’t get a second or third or fourth line treatment. So for bortezomib I think you would give very practical advice in elderly patients to give nine cycles instead of six cycles with maintenance in order to get a higher cumulative dose. For the melphalan-prednisone-thalidomide it’s rather difficult because we know that thalidomide gives rise to neuropathy with a longer period of administration and we also saw that in our own Leuven Nordic Myeloma Study Group trial that, especially during maintenance, 55% of patients had to discontinue thalidomide because it was not feasible. So I think for thalidomide there actually is a very limited role of maintenance therapy and also when you look to the MRC trials you see that even in the patients with high risk cytogenetics it did harm the patients. So whenever you give maintenance therapy with thalidomide I think you should do cytogenetic analysis in advance in order to see whether you won’t harm the patient. When you have a patient with good risk and when it’s feasible for that specific patient you can continue because then maintenance will be better than consolidation when you look to the date of the MRC and the meta-analysis they performed. For lenalidomide it certainly is necessary when you look to the MM015 trial of Antonio Palumbo you see that without administration of maintenance there was no progression free survival benefit but you also saw that in the patients above 75 years of age the dose of lenalidomide was limited because of toxicity. So for these patients we should look for an adapted dose, probably, of lenalidomide, maybe even lower than the dose we use now and also, like you said, with a soft start, so not a heartbeat in the beginning but just have a very easy going start of therapy and continue for a longer period of time.

Do you prefer to use lenalidomide in combination with alkylating agents in elderly patients or just with corticosteroids?

What I do think is we don’t know the best regimen because we did not do a head to head comparison. I think that actually our Leuven NMSG trial is important because this is the first trial that compares MP-thalidomide versus MP-lenalidomide so we know which combination is better, both incorporating a novel agent, because until now all the regimens were compared with MP, which is now not standard of care anymore. I think in Europe the use of an alkylating agent is used very much and I think there is an additive value of an alkylating agent; also in the younger patients you see when you use an alkylator that the response is deepening so I’m convinced that an alkylating agent is of additive value and so I would prefer to do so. On the other hand, we’ll have to await the MM020 trial of the French because they compare MPT with a combination of lenalidomide with dexamethasone. So within hopefully one or two years we know the answer to that.

What is your standard of treatment for elderly patients in the current clinical practice outside of clinical trials?

There was a Spanish-Dutch connection earlier and again we listen to you because we use MPV now in first line treatment because our study is closed now for inclusion so therefore we use now MPV with also MPT as a valuable alternative.

OK, thank you very much for this discussion and we finish here. Thank you.