MA: Sonja, I think that you had a very nice presentation yesterday here at EHA discussing with one of our colleagues from France the setting of multiple myeloma in our elderly patients. Can you just tell me about the multiple myeloma in the elderly, is that biologically different from the multiple myeloma in younger patients?
SZ: Well probably not. We’re not absolutely sure, of course, but when you look to the cytogenetic abnormalities in the ones over 65 or 75 and the patients under 75 the cytogenetic abnormalities are similar. Recently also in a French registry they’ve been looking into that and translocation (4,14), which is a prognostic factor, was even less pronounced in the over-75s.
MA: So multiple myeloma is a disease where, as in many other oncological illnesses, we have made quite a few progress from the past. I remember when I was trained by Brian Dury and Sid Sellman, a long time ago, it was melphalan/prednisone; since then we have quite a few new drugs. But what is the issue, then, about new drugs and elderly patients? If the biology is the same why don’t we have the same results in the older patients?
SZ: Even when you look into the randomised clinical trials the patients who are elderly have a worse outcome as compared to the ones who are younger. But they do benefit from the novel agents where the added value of thalidomide was shown recently also again in a meta-analysis and also in the ones over 75 there was an added value of thalidomide. Also at the last ASH it was shown that pomalidomide with low dose dex gave a better overall survival also in the ones over 75 years of age and the difference was even more pronounced as compared to the patients who were younger than 70 and that was because the high dose dexamethasone was very toxic in the elderly patient. Of course we know from the VISTA trial that bortezomib is also of added value in the elderly patients. But when you look in daily life we know that in the studies only the very fit patients are included and in daily life, in our general practice, we see a lot of patients who don’t qualify for participating in studies. A recent registry, also again from France, showed that progression free survival is similar but overall survival is less and probably the reason for that is that the toxicity during the first line of therapy is that high that it precludes patients from going on to second line of therapy. So it doesn’t affect progression free survival but that does affect overall survival. So that really highlights the need for specific care in the elderly.
MA: What you said is very important because many of our colleagues and it’s also the difficulty we have in the guidelines committees, have to extrapolate from studies and say, ‘Well, in the studies we have this population above the age of 70, 75. The data look as if things can be done,’ but, as you said, these patients are very well chosen in the studies. And you just told me about dexamethasone, how much of an issue is, for example, the use of dexamethasone in elderly patients who very often have diabetes?
SZ: It is an issue. When you look to an older study of Heinz Ludwig who compared melphalan/prednisone, and I worked in that timeframe too, only having melphalan/prednisone available. But when he compared melphalan/prednisone with thalidomide/dex there was no added value of thalidomide and that was because dexamethasone was very toxic and not because of diabetes but especially because of a high rate of infection. That’s quite a difference you observe when using high dose dexamethasone or lower doses of prednisone, that the incidence of infection is very high in dexamethasone. And also the ECOG trial has shown that high dose dex is more toxic, even in the ones who are younger than 75. So dex is a real problem for the elderly.
MA: What can we do when we see an elderly patient that comes to see us and needs some treatment in order to define whether this patient is really fit for treatment or needs some adaptation? What are the instruments that you would suggest that could be used?
SZ: Many haematologists use an eyeball test and I use also an eyeball test. So I get my patient out of the waiting room, which in Amsterdam is quite far away, so I know something about gait speed and a little bit about grip strength because I shake their hands, but for the rest many haematologists perform an eyeball test. And it’s known from studies in Belgium, in Leuven, that when you perform a G8, which is an abbreviated questionnaire geriatric assessment, and you follow up with a comprehensive geriatric assessment in those patients who might have a geriatric problem based on the G8 that 50% of patients are identified which I would not identify with my eyeball test. So geriatric assessments are important and there’s an increasing impact also now in haematology. That is because of the work of Antonio Palumbo; he started with performing geriatric assessments in the elderly and in approximately 900 patients he performed a limited geriatric assessment. So he looked at the activities of daily living, at the instrumental activities of daily living, and he scored according to the Charlson comorbidity index. Then he investigated what the impact was of these factors on overall survival in these elderly patients and he found that especially aged over 80 and a low ADL score were predictive for overall survival. Based on these hazard ratios he assigned a score and then he combined these scores and then he categorised these patients into frail, unfit and fit patients. It was found that frailty did have an enormous impact on overall survival but also on progression free survival. So these limited geriatric assessments might help to define patients who have an overall survival which is inferior and also, hopefully, will identify the patients who will experience toxicity and who are likely to discontinue the therapy.
MA: So what you said about Antonio Palumbo’s work is extremely interesting and important. The International Society of Geriatric Oncology has recently published in Annals of Oncology, or it’s going to be very soon on-line actually, a review of the available instruments to assess elderly patients. What we have realised is that these instruments are relatively general and are not directed specifically at the population that has various haematological malignancies. So we intend to put together a task force to look specifically at patients with CLL, multiple myeloma, DLBCL and so on. But these instruments, as you know, are predictive about the medium- or short-term outcome for the patients and not really designed to see whether the treatment is actually going to be tolerable or not and how we should modulate the treatment. So how do you see the future? Should we be potentially running a specific study trying to look at scores like there have been for solid tumours, scores proposed Doctor Martine Extermann which need some further validation, relatively complex, taking into account quite a few parameters but maybe a somewhat simplified score will be, nevertheless, easy? But maybe it has also to be tailored to the disease, maybe in CLL it’s different from multiple myeloma.
SZ: Yes, I think it’s extremely important and I think from the study from Antonio we have the first indication that this frailty score also predicts for toxicity and discontinuation because the discontinuation rate was almost doubled in the patients who were frail and also the toxicity was much higher in the frail patients. What we will be doing in the Netherlands, in the Dutch HOVON study, and are doing, actually, at this moment, is looking to the geriatric assessments and then try to predict the patients who will experience toxicity and who will therefore discontinue the therapy. We will not only be looking to the ADL and the IADL and the Charlson comorbidity index, by this actually we can also validate the score of Antonio Palumbo in a separate cohort of patients, which will be interesting. But we will also do some functional assessment like grip strength; I just heard that you are not that enthusiastic about that but also the gait speed. We will do some additional questionnaires on depression and also the mini-mental state examination. We will also try to find some novel biological markers for old age and that is performing a CT scan in order to see whether there’s sarcopenia and we will also perform skin biopsies to investigate the specific senescence markers. In this study we will hopefully get some more information about the factors that are predicting toxicity and discontinuation rate and then the important step, of course, is can we then make dose modifications based on the geriatric assessment because now we have a lot of expert opinions on how to modify the dose but we didn’t prospectively look into that. That will be the next step after performing geriatric assessments, define the patients who you will not treat or in whom you will adapt the dose.
MA: Absolutely. So, because it’s clear that even in an advanced disease setting if unfortunately the patient is already so precluded for survival because of other diseases, submitting the patient to the potential toxicity of a treatment which is not going to change a patient’s survival anyway doesn’t really make any sense. So we have also to be careful not to forget that some of these patients might benefit and that’s going to be a difficult balance there.
SZ: Yes, and also I do agree with you that in different diseases we might need different tools because, for example, in multiple myeloma there’s a lot of bone disease which is totally different from CLL and also different from other malignant diseases. So we certainly have a lot to do in the future.
MA: I think the supportive care side in the treatment of the elderly patients is clearly important to mention. The bone disease, we do have bisphosphonates, we do have denosumab which is still under investigation for multiple myeloma because the initial data were not fully perfect. But at least bisphosphonates we know, at least from recent studies, to be making an impact on patient survival. Of course if we have haematological malignancies which are treated and, as neutropenia, we know that GCSF appropriate usage is also important. There are many other things that we need to do and one thing you mentioned which is very important in the elderly is also to assess the fact that quite a few elderly patients tend to be depressed and that also can affect the compliance to treatment. [With some] treatments, they are oral treatments and if patients are not compliant it’s as though we are not treating them.
SZ: Yes, and that is also supported by data that also the cumulative dose of treatment is of impact on the outcome of these patients. So whenever you can start slowly and continue the therapy for a longer period of time, your outcome will be better. Of course the compliance is important then.
MA: Thank you very much Sonja. This was very informative and I hope that you’ll make lots of progress. Thanks also to the HOVON study.
