14th International Myeloma Workshop

Myeloma bone disease: background and latest

Professor Evangelos Terpos – University of Athens, Greece
Professor Michel Delforge – Catholic University, Leuven, Belgium

Hello, my name is Michel Delforge from University Hospital, Leuven, Belgium and I’m here joined by Professor Evangelos Terpos from the University of Athens, Greece and we’re here together at the IMW meeting in the beautiful city of Kyoto. So we are going to talk about myeloma bone disease. Evangelos, why do you believe, or could you explain to the audience why myeloma bone disease is such an important topic?

First of all, this is the most common complication of multiple myeloma. When we have a newly diagnosed patient, approximately 70-80% of these patients have bone related pain; 60% of them present with lumbar spine pain and I think that the major complication of multiple myeloma may lead to orthological fractures, sometimes spinal cord compression, the need for radiation therapy. So it deteriorates a lot the quality of life of the patients, so I think that this is one of the most important issues in the management of patients with multiple myeloma because it has to do with the quality of life of the patient and pain, which is something very important.

I fully agree with that because, as you know, when we talk to patients their most important symptom is pain and it is mostly related to their myeloma bone disease. So yesterday there was an interesting symposium chaired by you on myeloma bone disease; in terms of diagnosis there is still the skeletal survey being the reference examination to diagnose myeloma bone disease but what is your feeling about the novel techniques – CT, MRI, PET scan, compared to conventional imaging.

Conventional imaging remains the cornerstone because it can detect the bone lesions in approximately 70% of patients at diagnosis, as I previously mentioned. However, in order to see a lytic lesion in the conventional radiography you have to use lose approximately 30-40% of your bone in this specific site so you can imagine that the bone destruction has started many, many months earlier than that. So for patients who have bone lesions in skeletal surveys, the conventional radiography, and we know that they fulfil the criteria of CRAB, the B criteria of CRAB, the bone disease criterion, and they have to be treated. For patients who have normal conventional radiography this does not mean that they don’t have bone destruction so we need a more concise imaging technique in order to find these lesions before losing this 30-40% of the bone locally. We have three of the modern techniques: we have whole body low-dose radiation computer tomography, we have the MRI and we have the PET-CT. So we don’t know which one of those is better compared to the others; we know that all of them can detect more bone lesions compared to the conventional radiography. We have to mention that the CT and the PET-CT detect lytic lesions while the MRI detects bone marrow involvement and pattern of involvement which may be focal and in the areas of focal lesions you may have a lytic lesion but this does not mean that you definitely have a lytic lesion; we have the diffuse pattern and we have the variegated pattern and also the normal pattern, of course.

So maybe, if you agree, let’s discuss treatment of myeloma bone disease and, of course, as you also clearly stated in the session yesterday, the bisphosphonates, more precisely the amino bisphosphonates, are still a cornerstone of treatment of myeloma bone disease. Of course this has been also clearly shown by the recently published data from the MRC9 trial where there was not only a benefit compared to the treatment arm with clodronate in terms of reduction in skeletal related events, but also an improvement, a significant improvement, in overall survival. What is your feeling about these data?

First of all, we have to say that despite the huge progress we have done in the biology of myeloma related bone disease, we have discovered many cytokines that interfere with the osteoclast osteoblast function, we have to say that only bisphosphonates have been licensed for treatment of myeloma related bone disease to date. Zoledronic acid is the most potent of the two bisphosphonates that we mainly use, Zoledronic acid and pamidronate, definitely we suggest that the intravenous bisphosphonates are better than the oral for use in multiple myeloma. The MRC9 study, I think, showed very clearly that zoledronic acid is better compared to oral clodronate regarding the reduction of skeletal related events but also regarding the development of new lytic lesions, and I think that this is very important because the development of new lytic lesions means progression of myeloma. So I think that this is important in this study.

The second important message, as you mentioned, is that patients who had bone disease at baseline and received zoledronic acid, together with their anti-myeloma therapy, managed to have a ten month survival advantage compared to patients who received oral clodronate with the same anti-myeloma therapy. I think that this is a very good signal of an anti-myeloma effect of zoledronic acid, either direct or indirect, I believe that indirect effect is more obvious because of the inhibition of osteoclasts and osteoclast is a cell that contributes to the growth of myeloma cells. So I believe that if we don’t have any reason not to give zoledronic acid, like renal impairment because the drug cannot be given in patients with creatinine clearance below 30ml/minute, then I think that zoledronic acid is the bisphosphonate of choice for the majority of the physicians. Of course, we don’t have a direct comparison with pamidronate in the era of novel agents because we have in the era of conventional chemotherapy where the two drugs were found to have similar efficacy regarding reduction of skeletal related events. However, a meta-analysis that was published by the Cochrane Group showed that the only bisphosphonate compared to placebo that had a survival advantage was zoledronic acid. And I think that this survival advantage has to be taken into consideration when we decide.

Something that at least I’m struggling with is the duration of the bisphosphonate treatment. We come from an area, years ago, where bisphosphonates were given for as long as the patient was living and then we had the occurrence of osteonecrosis of the jaw that we will discuss in a moment so therefore bisphosphonate use was limited to one or a maximum of two years and eventually on a case by case situation it could be given for a longer time if the physician thought that the risk benefit profile was positive. But now we are tending to move again to an area where some key opinion leaders are saying, no, just continue the bisphosphonates, more precisely zoledronic acid treatment, beyond two years. What is your feeling about that?

First of all we had the first recommendation to give it for life initially, then we had the recommendation for two years because of osteonecrosis of the jaw and other side effects. And this two years came out because of the big studies that have compared either zoledronic acid, pamidronate with placebo or another bisphosphonate and the duration of these studies was only two years. So this is why the two years came into it. Now with the MRC9 study that gave the bisphosphonate continuously until disease progression we can say that zoledronic acid can be given for more than two years because the advantages of zoledronic acid, even the skeletal advantages or the survival advantages from the Gareth Morgan publications, seem to continue after the two years of administration. However, in this study we have some missing data, let’s say, and the missing data is what’s happening with patients with complete response or very good partial response. Do these patients continue to have a survival advantage, or even skeletal related event advantages, with zoledronic acid over clodronate? I think that this is a crucial question. To my opinion I believe that patients who have active myeloma have to receive zoledronic acid, however, we have the recommendations of the International Myeloma Working Group that are going to be published in the Journal of Clinical Oncology, the paper has just been accepted for publication, and the panel of the experts believe that for patients who have achieved complete response or very good partial response, 12 – 24 month administration of zoledronic acid or pamidronate is enough. So for patients who have achieved partial response then zoledronic acid can be given until disease progression and for pamidronate we have not done such a recommendation for more than two years because we don’t have such data.

Now what at relapse, if the patient relapses a couple of years later and, of course, when he or she has developed new myeloma bone related disease it would make sense to restart treatment with zoledronic acid?

Yes, I think that this is totally logical to restart.

But for how long, then, would you continue? Until the best response or would you recommend something else?

I think that I would recommend what the International Myeloma Working Group experts suggest for patients at diagnosis, meaning that if the patient has achieved a complete response then probably after twelve months we may stop but for all the other cases, and as you know after the first relapse the duration of the response seems to be not so long unfortunately, but I believe that for patients with active myeloma, like PR or less than PR, all of them have to receive treatment with zoledronic acid or pamidronate.

So if you agree, let’s talk about the side effects of the bisphosphonates. We are aware that there can be some renal toxicity and it’s very important to monitor the creatinine clearance before the administration of the bisphosphonate and to make proper dose adjustments and to be very careful if the creatinine clearance is below 30ml/minute where the use of zoledronic acid cannot be recommended.

I totally agree with you. First of all, we have to be very careful with the creatinine clearance and you have to do creatinine clearance measurements each time that we have to give a bisphosphonate. Don’t forget that these patients are elderly patients, the majority of them, they have reduced renal function, only because of their age or concomitant problems like diabetes mellitus or hypertension, so you have to be very careful with the dose of zoledronic acid and also pamidronate. Both bisphosphonates are not recommended for patients with creatinine clearance of below thirty and also there are specific recommendations for pamidronate and zoledronic acid dose according to the creatinine clearance of the patients.

What were the major achievements in the prevention of ONJ during the last years?

First of all, during the last years we’ve had the results of two big prospective studies, the MRC9 that we discussed, and also the comparison of zoledronic acid with another antiresorptive agent, denosumab, which is an anti-RANK ligand antibody. We have seen that in these specific studies the incidence of ONJ is approximately 1% per year. So I believe that this is not a huge problem, however, we have to be very careful in the patient, before having the bisphosphonate they have to have a very proper dental examination to fix all the problems in the oral cavity and then to start the bisphosphonate therapy. I think that this is crucial because we have seen a lot of ONJs after dental extractions. So I believe that with the preventive measures and when the patient is under bisphosphonate to have a dental examination every six months, I think that we are going to face less and less osteonecrosis of the jaw.

So you already alluded to RANK ligand inhibitors in denosumab and maybe this brings us to our last topic, the newer agents, the new kids on the block. There are many molecules, many targets, DKK1 active in sclerostin, but you’re really one of the world leading experts in this field, what is your feeling? Which of these novel targets or novel agents will really result in a clinical benefit? In other words, which are the most important new players, from your point of view, in myeloma bone disease?

In multiple myeloma we have two major features in the biology of the disease. The first is that we have the osteoclast activation through to many molecules, RANK ligand is the most important of them, and we have also the inhibition of osteoblast function. So we have new drugs that manage to inhibit the osteoclast activity or to enhance the osteoblast function. Denosumab is an anti-RANK ligand which is in phase III studies now in multiple myeloma. In this study a big number of patients, I think 1,500 patients, are going to receive either zoledronic acid at the standard dose, 4mg every month, or denosumab at the standard dose of 120mg. I have to mention that denosumab is given subcutaneously and not intravenously. So from the results of this study we are going to see if the two drugs have comparable effects or the one is better than the other. The osteoblast enhancers, we have antibodies against DKK1 and sclerostin, these are Wnt antagonists and DKK1 and sclerostin are osteoblast inhibitors so when we inhibit their actions with monoclonal antibodies we expect that we have an osteoblast activity and bone formation and healing of the lesions. We have a new antibody against DKK1, which is named BHQ880. We have seen a first report in the last American Society of Haematology meeting about bone anabolic effects in the majority of the patients who receive the drug but, of course, the drug is in early development so now we are going to see if it’s going to be in phase II studies.

We need more time.

With anti-sclerostin antibodies we don’t have any study in multiple myeloma. We know that the company that produces this antibody wants to try it first in post-menopausal osteoporosis where the results are fantastic there. So I expect that after a while a study in myeloma probably will start.

We need more patients though.

And also we have activin A; activin A is the molecule that has a dual action, it enhances the osteoclast activity and inhibits at the same time the osteoblast function. We have now a monoclonal antibody, it has a name - sotatercept, targeting the activin A. So we expect with this sotatercept we are going to inhibit the osteoclast and enhance the osteoblast function.

OK, thanks very much. This was an excellent overview on myeloma bone disease and it’s really an area that is also moving fast forward with, first of all, a better understanding of the disease. We have a better knowledge on how to optimally use the different imaging techniques and then, last but not least, we know that the bisphosphonates are still the cornerstone of treatment but many new drugs are in different phases of clinical development. And that’s what it’s about, this will, as you mentioned, improve the quality of life of our patients and that makes also us, as physicians, very happy.