Blood Cancer in the Elderly: European Expert Forum, Rome, 19—20 March 2011
Treatment of elderly multiple myeloma patients: Expert Roundtable
AP: Professor Antonio Palumbo (University of Turin, Italy)
JSM: Professor Jesús San Miguel (University Hospital of Salamanca, Spain)
ET: Dr Evangelos Terpos (University of Athens, Greece)
MB: Professor Meral Beksac (Ankara University School of Medicine, Turkey)
FC: Professor Fernando da Costa (UTM, Instituto Portugues De Oncologia, Lisbon, Portugal)
MD: Professor Michel Delforge (Catholic University, Leuven, Belgium)
AP: I will start with a question to Dr San Miguel on the salvage treatment: in a specific patient which is the sequence you would follow? Let’s say one patient is starting with MPT, the other one is starting with MPV, which could be the sequence of treatment you would adopt in that patient?
JSM: As I have mentioned, I think it’s important to make the right decision at the time of relapse to have the compass. This is critical because there are just four issues: one was what type of drug do you use. Sometimes doctors forget that alkylating agents are part of the myeloma treatment and they are treated with the fancy drugs but they forget the alkylator. The second is the efficacy of the drug – for how long you have been with disease control. The third point is the comorbidities and the toxicity induced by the drug. You need to have these four points in front of you in order to make the decision because what is easy is to say, “OK, now let’s move. I have started with MPT, move to Velcade,” but probably the patient has peripheral neuropathy already and you cannot move. If the patient had received MPT and for a short period of time, let’s say nine months, I enjoyed a prolonged period of time, this patient is clearly a candidate to be re-treated with an IMiD. Then I think my formal recommendation and the most important message is to keep in mind these four cardinal points will help a lot in order to make the right decision.
AP: Absolutely. Some comment from the panel?
ET: I totally agree with Jesús in that but I just want to mention that in the future we may need to change a little bit our way of managing our myeloma patients based in your and other studies with MPR-R; you can see that we may need this rather maintenance or consolidation phase after the first line therapy for patients with multiple myeloma. This is a real issue, mainly for the elderly populations, we may have patients who are frail also and we need to know what will be the maintenance result in this specific population. We know that Lenalidomide is a very good drug after MPR, we don’t know what’s happening if we have given MPV or MPT initially and then we have the Lenalidomide maintenance. So I think that as we have new results for elderly patients, we have new results for transplant patients with maintenance phase, I think that we have to keep in mind that maintenance may be needed in such patients and what is the best drug, we have to discover.
JSM: In one of my slides I suggested that in patients that, for instance, are on maintenance with a single agent, let’s say Lenalidomide, if they have biological progression you could add a corticosteroid that you can control again the disease. This comes from two data, which show that the biological progression under Lenalidomide maintenance has been clearly controlled with the addition of a corticosteroid. Also from our experience with Thalidomide/Cyclo/Dex and I think for the elderly this is another important message. In Spain we have used Thalidomide/Cyclo/Dex for a long period of time and our policy was as soon as the patient has disease control with a plateau phase for more than six months, we take out first the Cyclophosphamide then we took out the corticosteroid and we keep on a very low dose of Thalidomide. When the patient starts to progress you add the corticosteroid and eventually you add the Cyclophosphamide. This type of managing could also be something to think in mind for the elderly fragile operations.
AP: Absolutely. I agree, in this setting it’s very important, especially in the advanced stage of the disease to keep the disease under control instead of having a response. From this point of view the modulation of one drug is not enough; I add the corticosteroid, it’s not enough; I add an alkylating agent or on the other way around I can take some of them.
ET: Just to mention one other thing, I think that you have to take into consideration also the cytogenetic profile of the patients, including the elderly patients, because you know that the more aggressive disease we have then we may need more treatment to our patients, even if they are frail.
AP: May I ask the panel, I have two questions. One was we had a question during the beginning of the presentation which is, in your opinion, the toxicity rate that we should have in our regimen and therefore the discontinuation rate? Whether the 10% discontinuation rate is acceptable, 30% discontinuation rate is acceptable, 30% toxicities in a given regimen or we should have something less.
MB: Zero is the best. You already mentioned that 30% is something which is acceptable in trial designs but when it comes to reality, for instance in the VISTA trial, in the continuous part of the VISTA trial the discontinuation rate dropped. So we are really looking for something below 30%. In my opinion the first selection 10% was my selection but I think the panel will discuss this and I think it’s a matter of debate.
FC: I think we are stuck with the 30% now but if we can envisage something that will give us a lower discontinuation rate it’s better for the patients. I think that the discontinuation rate has to be related with the success rate so if we do accept that the less discontinuation the more success we have so we try and look for less discontinuation. If you had shown me the slides in the previous presentations that as a matter of fact giving lower doses because it came to less discontinuation at the end of the day the success was higher. So 30%, for now, is acceptable but definitely my choice was 10% too and that was because there was no 5% choice anyway.
MD: Can I just add one thing? In my point of view it’s also important to keep in mind which type of toxicity you are dealing with. For instance, if a patient is hospitalised because of pneumonia at the beginning of the treatment and so the pneumonia is treated and this was related to neutropenia or the Dexamethasone, it does not necessitate a switch for a treatment, you can go on with the treatment, give some GCSF, give eventually some antibiotic prophylaxis. It becomes quite different if your patient has a grade 3 neuropathy which necessitates treatment discontinuation and then the patient probably will suffer from that side effect for a longer period of time.
FC: You are quite right, more important than discontinuation is the reasons why we discontinue.
MD: And the first ability of tolerance…
FC: That’s right.
AP: If I can stay on the argument, high dose Dex is increasing the risk of infection versus low dose Dex so how would you discuss this issue?
MB: You can give the antibiotic prophylaxis and the other issues and try to keep with the maximum dose. I think we are learning how to deal with protocols. In the Turkish MPT trial we were lucky because we were very much influenced and we learnt a lot from your own experience, for instance, the use of routine antibiotics were what we implemented in our trial and the discontinuation rate dropped. So by time we learn how to deal with agents and we manipulate and we increase the things that combat the toxicities.
ET: I think that this is very important to know how to deal with the new drugs that we have. Everybody needs the best efficacy with the lowest toxicity and you have shown that lowering a little bit the dose of Bortezomib, meaning every week, then we may have the same efficacy with lower toxicity. It is probably the same with Lenalidomide because Velcade is one of the drugs like Thalidomide that you have a fixed dose for a patient who is 40kg or 100kg. So you have a fixed dose of the drug, maybe we need to change that and maybe with lowering the doses, as you have shown, we may have the same efficacy with lower toxicity. So I think that we continue to learn how we can handle the new drugs.
AP: You give me the opportunity to ask the next question for the panel. At this point, in your opinion, which is a) the definition of frail, very elderly patient and b) if I can, in your practice, once you define that that given person is a frail person, which is the regimen and the dose of agent that you use in that person?
ET: OK, if I can start. We have also shown that we have a benefit with the new agents in the age of 75, that was a study that was published by the Greek Myeloma Study Group in Leukaemia. So we continue to see an overall survival benefit until the age of 75 and after this age, then we have problems. The main problem, we haven’t seen any survival advantage.
AP: The cut off is 75?
ET: Yes, 75.
AP: I know that in the US some people may say 80, so you vote for 75?
ET: We’ve seen that even after the age of 75 we haven’t seen any survival advantage and this was mainly because of the toxicity and the discontinuation rate if we use the standard doses for this specific cohort of patients. Because this study includes patients outside of clinical trials so we’ve recommended with the licensed drug dosages. So we haven’t seen any survival advantage in this cohort of patients. So above the 75 and, of course, frail, we define it as a patient with comorbidities like, as you mentioned, renal problems, heart problems, diabetes, hypertension, that makes the toxicity of the drugs even higher than does have these side effects. So regarding what we give for such patients, to be honest outside of a clinical trial we give MPT in such a patient with a low dose of Thalidomide. We start for 100mg but we go down to 50mg very quickly. That’s our preferred regimen for this cohort of patients – above 75, frail patients. We also lower the dose of Melphalan very rapidly.
FC: I totally agree. 75 is the cut off for us at least, some people after 75 they may look fit but the problem is that we have realised that in people that apparently don’t have any comorbidity at all, all the standards of medical conditions seem to be OK, still once you start treating those patients very rapidly you realise that they are actually older than 75 so this might be a problem. My option would be that certainly for MPT not more than 100mg, reducing it whenever necessary and being very careful with the dose of Melphalan. Some people might even be treated with VMP but that’s definitely with not more than the weekly Bortezomib. But my choice for those people would be MPT normally.
MB: I think the frailty definition is based on the geriatric assessment but it’s not very widely applicable. So for that reason if a patient is independent and can perform his daily activities, in that case that patient deserves the best treatment. For that purpose most centres in our country, they try to push towards the maximum treatment of VMP starting with bi-weekly and then continuing once weekly as an approach. The traditional MPT is also another one, but these and the frailty can also be a cause of the disease itself so it’s kind of a balance. The benefit you achieve with the treatment will improve the performance status of the patient and then you eventually are happy with the treatment that you are choosing. In our Turkish MPT trial the median age was 72 but there are many centres in our country who try to push with the transplant even when they are 75 years old. So the age cut off that has been discussed a lot here is a matter of subjectivity and based on this factor even VMPT is another thing. So try to give the maximum as possible is our approach.
MD: In our centre we have indeed a team who make a geriatric assessment and if we ask for it. The question is, at the end of the day, how do you really…
AP: So you have a collaboration with the geriatrics?
MD: Yes, exactly. Not for every patient but especially for patients where we are not sure about which treatment to start. It’s helpful in some aspects, if it’s only maybe about logistical things, if you know the patient will he or she be able to tolerate Bortezomib every week or twice-weekly? So it’s helpful but we’re learning what to do with this data and in terms of which regimen we use, I think the studies you did have helped us enormously and in those patients above 75 years we go immediately for Bortezomib once-weekly and we follow the dose modification guidelines for MPT.
AP: I guess we have already some delay. So thank you, everybody, for the attention.