Advances in multiple myeloma from EHA 2012; bortezomib and beyond

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Published: 4 Jul 2012
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Prof Heinz Ludwig - Wilhelminenspital, Center for Oncology and Hematology, Vienna, Austria

Professor Heinz Ludwig talks to ecancer TV about the results of an interim analysis of a phase II study using bendamustine in relapsed/refractory multiple myeloma (MM).  Used in combination with bortezomib and dexamethasone, impressive response rates and good tolerability have been observed, and these data and their implications to clinical practice are discussed.


Professor Ludwig advises clinicians how to select between the available therapies, and how therapies might be combined.  Also, the possible synergistic effect of bendamustine with other agents.


Professor Ludwig gives an overview of the new heavy/light chain test which enables clinicians to distinguish the amount of monoclonal and polyclonal proteins, giving an indication of prognosis and tendency to progression. 


Finally, Professor Ludwig raises awareness of the important aspect of renal failure induced by light-chains, an emergency situation, and advises on what signs to look out for.


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

17th Congress of EHA, Amsterdam, 14-17 June 2012


Advances in multiple myeloma from EHA 2012; bortezomib and beyond


Professor Heinz Ludwig – Wilhelminenspital Centre for Oncology and Haematology, Vienna, Austria


This is and Heinz Ludwig, you are here all the way from Vienna; not too far to travel but you’ve got some important news because in multiple myeloma you’ve got a clinical study and you’ve got a few other insights to give us. Can I start first of all with your clinical study in relapsed refractory multiple myeloma? And you are using a drug, bendamustine, that’s quite an interesting agent, an old one but interesting.


It’s an interesting agent because it has been shown to be very active in low grade lymphoma, low grade lymphomas, and it’s an excellent drug for combination, for instance with a proteasome inhibitor. So we are combining it with bortezomib and dexamethasone, so we have a three-drug combination.


And it’s been sort of overlooked, because it was developed in the old East Germany and now it’s beginning to be ... proving to be quite effective in a number of clinical contexts.


Yes, that’s true, and also in myeloma and what is the advantage of this combination? It gives you excellent response rates in pre-treated patients and the response rates are in the range of 60-70% when you use this combination, and if you look at patients who have been pre-exposed to bortezomib or pre-exposed to lenalidomide you find the response rate in the range of 50-55%.


So it’s another option?


It’s an excellent option and the tolerance is fantastic, more or less.


Now can you give me the nuts and bolts of what you did, how many patients and what you found?


Yes. This is a phase II study, the goal is to enrol 80 patients and we are close to this score, so we will close the study very soon. We did an interim analysis which showed this high response rate in the range of 70% and in patients pre-exposed to normal agents it is still very active, and one of the beauties of this drug is that it seems to have an excellent tolerability profile. It certainly does not enhance the toxicity of other drugs, it seems really to really mitigate it. So patients come in and say, “I tolerate now this regimen much better than single agent bortezomib,” for instance, so it is something which we never expected to hear. But let’s not over-exaggerate that, but I think it is important that the tolerance is excellent. We use a dose of 70mg of bendamustine day 1 and 4, and we use the accepted dose of bortezomib in the schedule rate together with dexamethasone, and so patients are treated for up to eight cycles and progression free survival is excellent. Overall survival has not reached now the medians so we are quite optimistic.


And how would you decide between using an agent like bendamustine rather than targeting more of the immune system?


In myeloma when patients relapse you have only limited options so what you are looking for is a regimen or a drug which is well tolerated and gives you a high probability of good response. And so depending on what you have used before you have a few options but when you think about bendamustine and you can combine it with bortezomib, you can combine it with lenalidomide and so on, you have a certain, let’s say, probability that it is still active in patients who have been pre-exposed to both bortezomib and lenalidomide. So it seems to exert, let’s say, some sort of synergistic activity when it’s combined with other drugs. And what is important is it’s still working in patients who have been heavily pre-exposed also.


Right, now, looking at patients perhaps earlier in the disease that you want to choose the therapy you’ve been looking at something called the heavy light chain test and this actually looks at whether there’s a lot of cancer cells. Tell me about that and what you’ve been doing.


So this is actually a new test which has been developed by Binding Site and we have a very good co-operation with them, and what does this test tell you? For instance, if you have an IgA myeloma, if you have monoclonal IgA and you have polyclonal IgA, if you do a nephelometry you always capture both, you cannot distinguish. And if you do an electrophoresis you have certain situations where you cannot distinguish the amount of monoclonal from the polyclonal protein. So this test helps you to distinguish the amount of monoclonal and the amount of polyclonal protein, IgA for instance, so it gives you a feel about the relationship and if the relation is skewed towards the clonal population; the more it is skewed towards the clonal population, the poorer the prognosis of the patient.


How does it do this then, the test?


It’s a simple test which you just need serum of your patients and then it’s a lab test, and it’s an analyser and so ...


OK, so it’s a secret how it works?


So it’s not as difficult as, for instance, immunophenotyping so that’s another advantage. You can of course get information about the relationship between monoclonal cells and polyclonal cells when you do a bone marrow aspirate, but ...


This is less invasive?


This is very invasive, a bone marrow aspirate, but the test ...


The test is less invasive?


As you say, it is much less invasive.


Yes, yes.


So it gives you prognostic information but it also helps you to identify the amount of monoclonal protein.


The amount of cancer?


Yes, the amount of cancer.


Or tendency towards progression?


Yes, correct. So these are two really very significant advantages.


How might that affect treatment decision making?


I am not sure whether it really will affect treatment decision making but it will affect the precision with which you can identify the prognosis of an individual patient. It gives you prognostic information and it gives you information whether the patient is already in complete remission or whether there is still a monoclonal protein available, because what we have seen when you use all the tests which are available and you add the heavy light chain test on top you get additional information.


OK, now I know you’ve got your finger in a lot of pies here in Amsterdam at the EHA meeting but an emergency situation is something in multiple myeloma that you think is important, renal failure. Tell me what you have been doing there.


So renal failure can be due to several reasons but what we are focusing on, or looking at, is renal failure which is induced by the monoclonal paraproteins so by pathogenic light chains. And that can be really an emergency situation because the pathogenic light chains can induce different types of renal injury. Most frequency they induce what we call cast nephropathy and the patient is at risk that he enters complete renal failure and becomes dependent on haemodialysis for the rest of his life. So what is important is to recognise this problem, to have a very fast work-up of your patient to identify the problem, exclude other reasons for renal failure; but if it’s due to these pathogenic light chains then you have to install active treatment as fast as possible in order to increase the chance to reverse the renal failure which is induced by the light chains.


So you are urging doctors to be ready for this potential emergency?


Yes. I think that is really an important problem and myeloma doctors need to know about that. I am sure most of them have personal experience but I would alert them to the possibility of reversal of renal failure by highly active treatment which is installed as fast as possible.


How easy is it to look out for the signs?


Actually it depends on your health care system. If you have everything available on Saturdays and Sundays and so on you can do your diagnostic work-up within two or three days and you know then you have established the diagnosis, and as soon as you have established the diagnosis I think you are obliged to start treatment. And you have to be aware that renal failure impairment increases the risk for infections; you have to be aware that this is ...


But how does that suspicion begin; what do you look out for?


So some patients are admitted due to renal failure directly to the renal unit, so these people have also ... I mean that’s their business, they have to be aware of these problems, and they have to accomplish the diagnostic work-up as fast as possible, as mentioned before, and then they refer the patient to a myeloma unit.


So if doctors have more suspicion of the propensity towards renal failure how much difference might that make to the outcome?


I think it would increase the chance of reversal of this problem and it will increase the proportion of patients who will be taken off haemodialysis, so I think it has an important impact on the quality of life of these patients but also on the general outcome of survival. So I think that is something which we need to spread among the medical community and this gives me also the opportunity to say many myeloma patients have a long history of going with complaints, with symptoms, without being properly diagnosed. If you ask a patient, and this happens particularly in patients with light chain disease or low secretory or non-secretory disease, so community physicians have to keep in mind that lumbar pain can be due to other reasons than spondylosis.


You are one of the central experts here at the EHA Meeting. What messages would you like doctors to take home?


Very simple.


About multiple myeloma?


About myeloma, we have to be aware of these problems of establishing the diagnosis with too much delay, diagnosis of myeloma and particularly diagnosis of renal failure due to light chains too late so that we miss an opportunity to reverse the problem, to treat the patient properly, to prevent the need for chronic haemodialysis and to increase the survival expectancy of those patients. So we have a very important obligation here.


And do you think that there are exciting things coming along? I mean, would you give encouragement to doctors about the overall landscape of multiple myeloma?


Yes, things are greatly improving, let’s put it that way. They are improving, the outcome of myeloma patients is improving because of two main factors; one is novel drugs, but the other important factor which should not be underestimated is the increased professionalism of people caring for patients with myeloma. So the increased knowledge, the increase in experience with this, people are now treated by experts. In the old days they were treated in the general internal unit or so and that has a huge impact on the outcome; supportive care is much better than it was before and so the expertise of physicians treating myeloma is much better and that has an important outcome. It is not only the drugs which the drug companies would like us thinking.


It’s using more of them?


Yes, and the drugs are excellent, that’s clear and new drugs are coming, but there’s another interesting observation which has been made during the last year which has disillusioned us in some way because in the old days we were seeing cancer and myeloma as a relatively, let’s say, constant problem so we had one clone which was there all the time during the course of the disease. The contrary is true; cancer is much more complex than we ever thought about, that’s the problem, and so people stand up and say, “How do we envisage that a single drug will be able to cure a patient with so many chromosomal abnormalities?” So probably a single drug may be helpful and maybe curative at the very early stage but in the late stage, where we have several clones with different chromosomal abnormalities, we always will need a bunch of drugs in order to get the tumour in control and obviously to achieve what we are looking for, to achieve cure also in late stage myelomas.


Heinz, thank you very much for joining us on