Newly diagnosed multiple myeloma: Laying a solid foundation for improved long-term outcomes

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Published: 14 May 2019
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Prof Xavier Leleu - Centre Hospitalier Universitaire de Lille, Lille, France

Prof Xavier Leleu speaks to ecancer at the 2019 MyKE Myeloma meeting in Barcelona about various topics that surround the clinical implications that surround newly-diagnosed multiple myeloma.

He gives a summary of what was discussed in the first session he chaired. This included presentations about the prognostic features of high-, standard- and ultra-risk multiple myeloma, bone disease and neuropathy in multiple myeloma.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

Newly diagnosed multiple myeloma: Laying a solid foundation for improved long-term outcomes

Prof Xavier Leleu - Centre Hospitalier Universitaire de Lille, Lille, France

Today’s first session at MyKE, an Amgen organised meeting in Barcelona, was dedicated to three main topics that are important issues, an important part of the way we take care of patients with multiple myeloma outside of the context of treatment that will be more covered tomorrow, on day two. So three essential parts of the way we diagnose myeloma and the issues we face. Number one is patients are treated and survival, the benefit the patients get from the patients, depends on risk features, high risk features is how we used to put it or standard risk features. Upon treatment some patients will massively decrease their tumour burdens while other patients will decrease their tumour burden but to a much lesser extent. So we call it minimal residual disease and so the first topic was about these two pieces of understanding the prognostication of the patient.

Bruno Paiva from Pamplona, Spain, participating on behalf of the PETHEMA group, the Spanish myeloma group, gave us a talk on definition of high risk features. He very nicely introduced the fact that today you must still use a scoring system called revised ISS which includes ISS, part of the genomic abnormalities from the tumour cells and a serum test called LDH, lactate dehydrogenase. These three groups of tests, LDH, genomic and a better tumour [?? 1:51] plus albumin ISS score makes the revised ISS and if you are revised ISS 3 you are in high risk feature myeloma. He also talked about the fact that on its own it’s not sufficient, there have been multiple other abnormalities that have been added to the revised ISS-3 system to improve the definition of high risk. Most of the tests are organised around the genomic abnormalities of the tumour cells. In the revised ISS-3 it’s mostly about translocation (4;14) and/or deletion 17p but other tests, other abnormalities, are now of importance and should be considered and looked into at the time you diagnose the patient and probably in the relapsed setting as well. That includes other abnormalities – he talked about (14;16), this is more discussion, but 1p 1q issues and certainly the fact that some of the patients with deletion 17p or some of the patients with revised ISS-3 have an ultra-high risk dismal prognostic with more complex abnormalities.

So that takes us to high risk definition versus standard risk and in the high risk definition a group of patients at ultra-high risk. The ultra-high risk most of the time, still today with all the drugs we have access to, die within two to three years in the median and for the high risk most of the patients will still die within 5-7 years at best with all the drugs we have access to these days. So really we have improved for these patients but we are really far away from what we get for the standard risk because, on the flipside of the coin, as you can say, there is a standard risk group which truly has incredibly improved in terms of survival but the high risk remains extremely complex. So Bruno touched upon other issues about other profiles, myeloma profiles, that could be associated to high risk – plasma cell leukaemia, plasma blastic features, extramedullary disease etc. – that at some point we’re going to have to add to the high risk group in a global scoring system if we can.

Then he switched gear to the other part of his expertise which is now that you have the risk features at initiation, before you start the treatment, let the patient get treated and upon treatment some of the patients will not or will poorly respond while some of the patients will incredibly massively debulk to the point of what we call minimal residual disease. So he discussed various issues regarding what best technique, is there a better technique. Two main techniques – next generation flow and next generation sequencing – and we all agreed that the two techniques are very important, very informative, probably very useful at a level of 10-5 or 10-6 for the study of MRD. Then you use a technique you probably can handle best in your country or in your centre.

We discussed the fact that probably you would start looking into MRD when you reach VGPR or CR and probably every six months, once a year, because as it has been pointed out by one of the attendees in the audience, Professor Heinz Ludwig, the question of reaching MRD at one time point, it’s not sufficient to consider that we already reached a level of very good prognostic in terms of PFS and overall survival, you have to have a maintained MRD over time, at least at repeated time points, if you really want MRD to be of great interest for the patients and really mimic the improved and significantly prolonged PFS and overall survival.

So Bruno Paiva discussed this then, because we were going through a case to put the speakers into a context, we then discussed in the case I was leading. We then discussed the bone myeloma disease, or myeloma bone disease, MBD. We have an incredibly increased number of patients which are diagnosed without any myeloma bone issues these days because they are diagnosed very early on, often because they were diagnosed as a pre-malignant stage, MGUS, or at the already malignant stage, smouldering myeloma but not yet symptomatic, so we were able to treat the patients slightly earlier to avoid the patients from developing myeloma bone disease. That’s more and more frequent in our practice, probably worldwide. However, we still have a lot of patients that are diagnosed with a lot of myeloma consequences on the bone skeleton. There are two types of issues – the cortical bone or the trabecular bone. The cortical bone is the outside part and the trabecular bone is the part inside the bone marrow that serves as a carpet, let’s put it this way, for the marrow to sit there. So you could develop myeloma bone disease, the bone is destroyed by hyperosteoclastic activity and a massive decrease in the osteoblastic activity. So not only do you have more resorption but on top you have a complete disappearance of the cells that try to reconstruct the bone, so you really have a massive instability in the bone structure. This was known for a very long time.

We have had in recent years more insight on the biology, how it works, but most importantly because we had access to drugs, especially for a long time we had the bisphosphonates, to limit the resorptive activity while we are trying to control the myeloma disease. But recently Amgen was able to develop a new generation of antiresorptive drugs from learning from the biology of the osteoclast which is the expression of the RANK ligand molecule and the so-called RANK ligand osteoprotegerin RANK pathway that sees the RANK ligand being massively expressed and the osteoclasts being massively activated. So they have developed denosumab, an anti-RANK ligand antibody that blocks the RANK ligand activity, limits the osteoclast activity. Dr Chantry from Sheffield, UK, beautifully explained to us the benefit of denosumab, the difference from denosumab to the bisphosphonate, why would denosumab really be progress compared to bisphosphonates and how should we be using these drugs for myeloma bone disease control.

Then finally going through the case we discussed a third and last issue that we tend to face probably much less now in myeloma which is the neurological issue that sometimes is related to the disease or to pre-existing other causes of neurological issues. But since the development of bortezomib, the first in class proteasome inhibitor, Velcade, we’ve had a lot of neurological issues associated to Velcade being a neurotoxic drug and also to other Velcade combination based drugs like thalidomide that also was a different mechanism of action but also was a neurotoxic drug.

So Professor Grisold from Vienna, Austria, is a neurologist. He touched upon the, first of all, different types of neurological disorders you would have before the diagnosis or could take you to the diagnosis of [?? 10:57] gammopathy, either malignant or not depending on the isotype of the M spike – IgM more anti-MAG, while if you are IgA or IgG a different type of neuropathy. So he discussed this, he discussed the importance of learning from the prior history of the patients because patients with some treatments, some diabetes and other issues, arthritis [?] from the spine etc., could actually have a neurological issue which has nothing to do with the gammopathy and sometimes could be misunderstood in who is responsible to what. So he discussed this.

He discussed the importance of running a test for velocity, electro-neurophysiological tests looking at the velocity of the nerve conduction, because this will lead you to understand a lot on whether you have an axonal issue or other types of issues. You still have to remember that you may have amyloidosis and that brings you to a specific test and potentially a biopsy. So Professor Grisold discussed in the end of his talk what would be the best painkiller for neurological pain which is very different from bone pain. Most of the bone painkillers actually have a very poor effect on neurological pain and often what we do is we increase the dose and the patient suffers more in the end from the side effects and from the real effect. So he discussed the importance of pregabalin and gabapentin [?] being the first neurological painkillers you should be using but always, and he very, very specifically repeated this, always be very informative to the patient that the effect from one patient to the other could vary a lot. Some patients benefit a lot, some patients benefit very mildly and sometimes some patients could benefit very rapidly but for some of the patients it could take months before they see a benefit to it. So we discussed this.

In the end we had a Q&A part of the talk, of the session, where there have been a lot of questions on MRD and how should MRD be performed and when should it be performed. Also the fact that when you look at MRD at one spot you think that the results you would get, let’s say in the sternum here, would be a clean representation of what you get for the whole body. In fact, we know in myeloma that this is possibly true for some patients but absolutely not true for other patients which is why we have developed, the Italians and my group in France, Intergroup Francophone du Myeloma, we’ve been quite pioneering this one. We have developed this PET-CT plus marrow MRD assessment, marrow really looking at the cell, at one spot, while the PET-CT looking at the hypermetabolism of the tumour cells but globally for the whole body. If you combine the two it seems to be a quite strong prognostic appreciation of what is MRD.

There has been a question also, which I think is very important, on should we run MRD tumour modelling in real life. The answer is no, not yet. There will be a lot of studies, clinical trials, starting globally, worldwide, and I can tell you that there are plenty in Europe that will look into MRD is prognostication – if you remain MRD positive you are not good risk anymore, if you turn MRD negative you significantly improve your risk factors. But should we change the treatment, should we tailor treatment on MRD? So because you’re MRD positive we would give you more treatment or potentially verse versa – if you are MRD negative we could de-escalate and give you less treatment. This is really not at all ready to provide any answer to this specific question.

So it was a very lively session when we learned a lot about, again, prognostication, bone disease and neurological issues that we tend to see with the patients.