Highlights from MyKE Myeloma 2019

Prof Heinz Ludwig - Wilhelmeninen Cancer Research Institute, Vienna, Austria

The day started with a presentation by Bruno Paiva who mentioned and showed the clear importance of MRD negativity and particularly of achieving MRD negativity which is associated with long-term survival. But what is important, if you reach MRD negativity it is irrelevant which treatment has been used to induce MRD negativity, number one, and, number two, if you have high risk disease, cytogenetically defined high risk disease, and if you achieve MRD negativity your prognosis is as good as the prognosis of standard risk patients who are MRD negative. So these are two important messages.

Then we went on to discuss imaging technologies and, of course, the standard of care is now the best imaging technology is MRI but it’s not widely available in Europe so low dose CT is agreed as the best clinically feasible imaging technology. The old technology like X-rays, conventional X-rays, is still a very good technique to detect skull lesions. Of course we have PET-CT which shows not only the distribution of myeloma sites but also the activity so you can distinguish between lesions which have been treated and which respond to therapy because then they lose the activity so that can be followed. If you are achieving PET negativity after four cycles it’s a very good prognostic feature, that was discussed.

We discussed also the impact of neuropathy for treatment decision and particularly what it means for an individual patient. But in order to assess neuropathy in patients the best approach is to use patient-reported assessments. So the patient needs to assess the intensity of the degree of symptoms because the clinical care team usually under-estimate the impact of certain side effects or symptoms. So it’s very well advised to ask the patient and to ask him to give his notion about the intensity of neuropathy. Neuropathy needs to be avoided but there are some treatments which are essential, particularly in certain countries or in certain treatment situations, like bortezomib or thalidomide. They are associated with a high risk of neuropathy and those patients have to be followed very carefully. There’s no good treatment for neuropathy, there is only symptomatic treatment available and so that was explained what should be used.

Then when we move forward to bone disease, how to manage bone disease, it’s clear that bisphosphonates are still standard therapy for patients with myeloma, even those without myeloma bone lesions. But there is a new treatment available which is denosumab. It is a monoclonal antibody against RANK ligand and this antibody is equally effective in terms of reducing the skeletal related events but when you look at the data in more detail you are surprised to find out that it has an impact on the progression of the disease. So it reduces the progression in about 18% of your patients, so it has an anti-myeloma effect. In the future we will probably use this antiresorptive treatment in addition with other drugs like anti-sclerostin drugs and so on in order to improve bone remodelling and bone production.

Some drugs like proteasome inhibitors can be cardiotoxic, carfilzomib is one of these drugs. So it’s important to manage patients who are scheduled for carfilzomib properly. They should not come in with uncontrolled blood pressure so blood pressure should be controlled. Then usually they tolerate carfilzomib quite well; if there are some symptoms of intolerance then one should be very careful and follow those patients. Usually you can continue treatment after a short interruption and it’s important to continue treatment because carfilzomib is a very effective drug and it would be a shame if you don’t use the benefits of carfilzomib. So it needs some experience to deal with the rare but still important side effects, cardiotoxicity side effects, of carfilzomib.

Then another important issue was renal disease. Renal disease is quite common in patients with myeloma so you find it when you look at newly diagnosed patients, you find renal impairment in about 40-50% of your patients. But you have to acknowledge that when you look at a similar population, a similar a group of individuals from the general population that you will find out that 15-20% also present with impaired renal function. So when you treat your patients with some sort of renal impairment then renal impairment improves in about 10-20% because some of the patients had dehydration or had toxic drugs, drugs which are toxic for the kidney, so that it will be corrected. So those will improve in the renal function with treatment but this is not myeloma specific.

The myeloma specific acute kidney injury is an emergency situation. So these are patients who develop kidney failure within a few days or a few weeks and if they come to the clinic and they present themselves it’s mandatory to accomplish the diagnostic work-up in a very short time because time is kidney saving and even life-saving. So you need to ensure that this is a myeloma induced kidney failure and then if that is clear you should start treatment immediately and, in my opinion, you need three drugs – proteasome inhibitors, IMiDs and dexamethasone – and, as mentioned, it should be started immediately after establishment of the diagnosis.

Then we had another discussion and presentation by a myeloma nurse specialist and she presented what she is doing and how much [?? 7:57] she can support patients and not only patients but also the medical caregivers, the physicians. Working together is certainly helpful to improve not only patients’ quality of life, patients’ communication with caregivers but in the end also, at least in a certain number of patients, survival. So that is important.

In the end we had the keynote lecture by Hermann Einsele on the prospects of immunotherapy in multiple myeloma. This was a fantastic lecture. He highlighted the importance of monoclonal antibodies, what we have achieved with using monoclonal antibodies, but there are new drugs now on the horizon and in early phase I, phase II and even phase III clinical studies. New antibodies, antibody-drug conjugates and they are smaller, antibody-like molecules called BiTEs which bring T-cells to the tumour cells enabling T-cells to really get in contact with the tumour cell and enhance the killing activity of T-cells which is a very promising approach. Then he talked about T-cell therapy and about CAR T-cells which really can probably be a game-changer in our treatment strategies of this difficult to treat disease. So with CAR T-cells you can induce a high rate of response in very heavily pre-treated patients, having five or more prior treatments, so the response rate which is achieved with CAR T-cells varies between 80-100%. The problem at this point of time is the responses are not lasting forever but we never have seen responses of this magnitude in late stage patients. So I think we will learn to improve our CAR T-cell technology, we will shift CAR T-cell treatment to the first line myeloma therapy in order to support conventional therapy using conventional drugs, monoclonal antibodies together with CAR T-cells.

Actually, during the last ASH meeting there was already an early report from China combining induction therapy, stem cell transplantation and CAR T-cell therapy. So that is the way to go but I think we should not ignore that there is still room for improvement. We have to acknowledge that CAR T-cell technology is in its infancy but I’m relatively optimistic that this technology will be advanced and will be improved and will probably be an important additional treatment modality for increasing the cure rate in our patients.