15th Congress of the European Hematology Association (EHA), 10—13 June, 2010, Barcelona

Interview with Dr Evangelos Terpos (University of Athens, Greece)

Treating bone disease in multiple myeloma

What is the impact of multiple myeloma on bone structure?

First of all about the bone, we know very well that almost 80% of patients that are diagnosed have bone problems and some of them have some devastating problems like bone fractures or hypercalcaemia of malignancy, a lot of bone pain. The majority of patients with multiple myeloma are diagnosed because of the bone pain so it is very fascinating to see how you can improve the quality of life of these patients, how you can prevent the skeletal related events. And of course we also know that the skeletal related events, like pathological fracture or the need for radiation therapy or the need for surgery, also correlates with poor survival. So we have to try to understand the biology and to try to find targeted therapies for the bone disease.

How do multiple myeloma drugs affect bone?

Thalidomide and Lenalidomide, the two immunomodulatory drugs, seem not to have a dramatic effect on the bone, meaning that we know very well that in multiple myeloma we have increased bone resorption, meaning that the osteoclasts, the cells that resorb the bone, are more activated and, on the other hand, osteoblasts, the cells that produce the bone, are inactivated. So we have an imbalance between osteoclast and osteoblast function in multiple myeloma in favour of osteoclasts. We have increased bone resorption, increased bone destruction and lytic lesions. So every effective therapy seems to reduce the osteoclast function to reduce bone resorption. However, very rarely we see the healing of the lesions because the osteoblasts continue to be exhausted in terms of function. So the new agents, the three new agents, Thalidomide, Bortezamib and Lenalidomide, all of them have a beneficial effect in terms of bone resorption they reduce bone resorption. But on the other hand, it seems that only Bortezamib has an anabolic effect, meaning that it enhances the osteoblast function.

In this conference we present the data on Lenalidomide where we have shown exactly that thing, that in responding patients we have a reduction in bone resorption but unfortunately there is no bone formation effect of Lenalidomide for myeloma patients.

What does this mean for the clinician?

First of all that Lenalidomide and Thalidomide are very good drugs for myeloma, we know that. It seems not to have something more to offer in the bones in terms of bone anabolic effect. And I think that Bortezamib has a lot to offer because it has an anabolic effect and there are studies showing that also we have an increase in the bone mineral density and that is why the European drug organisation has given, in the SBC of the drug, that indeed it’s a beneficial drug for bone metabolism of myeloma patients.

But in this conference we wanted to check if Lenalidomide has also any effect on bone formation, it seems that it has not.

What work are you doing on markers?

We are going to present as the Greek Myeloma Study Group from our database of more than 1500 myeloma patients what happened in patients who started and received therapy after 2000 when Thalidomide was available in Greece, and of course Bortezamib and Lenalidomide appeared after a while. So we’ve seen that patients who are treated after 2000 had a better survival comparing with all other patients, something that, of course, is important and we confirm the results of the big clinical trials. And this is irrespective of the renal impairment of the patient, so even patients with renal impairment have a survival benefit with the novel agents, irrespective of the high LDH level because high LDH is a poor indicator for prognosis.

And the other interesting thing that we have seen is that patients above the age of seventy seem not to have such a survival benefit in our hands. However, I have to mention that the majority of the patients have not received these agents as first line therapy but at their indication which is in the relapsed, refractory setting and only during the last one or two years they had some first line therapy with Thalidomide and Bortezamib after their indication.

So we can see that in patients below the age of 65 we have all seen a double, twofold higher, overall survival from 35 months to almost 70 months,72 months, with the novel agents but we haven’t seen that result in the elderly patients. This is possibly one, due to the side effects; two, we have to know how to use these drugs better in the elderly patients and three, that possibly if we use these drugs as first line therapy then even the elderly patients may have an overall survival benefit as the studies have shown.

Are there indications that these markers will be useful in the clinic?

Again, about bone disease we try to understand, as I mentioned, in terms of the osteoclast activity we have a lot of drugs that reduce osteoclast activity, not only agents like immunomodulatory drugs or Bortezamib or chemotherapy. Or zoledronic acid, which is a very important agent and in this conference, as in NASCO also, there are exciting data by the Gareth Morgan group in the UK showing that zoledronic acid can even increase survival in multiple myeloma patients and not only reduce skeletal related events. But we have focussed on osteoblasts because we wanted to enhance the osteoblast function and we measured two molecules that are very important for the osteoblast function. One is the Dkk1, Dickkopf-1 protein; the second one is sclerostin. Both of them are wild-type signalling inhibitors, this means that they inhibit a crucial pathway for the osteoblasts and they inhibit the osteoblast function. In myeloma we have shown for the first time that sclerostin is elevated in patients with multiple myeloma. And we have also continued our study in Dkk1 and we have shown that patients at diagnosis and after relapse have increased levels of Dkk1 which is reduced at the plateau phase of their disease. So we believe that these two molecules are very important for bone biology and can be targets for the development of novel agents.

How might Wnt signalling become useful in myeloma treatment?

As I mentioned, the most important thing about Wnt signalling in myeloma and in the osteoblast function is that it is crucial for the proliferation and differentiation of osteoblast, it is something important for the osteoblast survival. You can say it so simply. The myeloma cell does not want the osteoblast to work so they produce Dkk1 protein and possibly this enhances the production of sclerostin and these two molecules reduce the osteoblast function. They make osteoblasts inactivated and exhausted.

So showing that, I believe that when we target these molecules we may liberate osteoblasts from this suppression of myeloma cells and we may have more treatment for the myeloma bone disease.

How can you help clinicians choose between novel agents?

This is very difficult as of course you understand that this has to be proven in clinical studies. Of course we know that some of these agents in combination with Melphalan and Prednisone, or the standard of care for multiple myeloma patients who are not eligible for a transplant, like a combination of Melphalan, Prednisone and Thalidomide or Melphalan, Prednisone and Bortezamib, and we expect that very soon we are going to have a novel agent licensed in Europe for first line therapy for patients who are eligible for transplant like Bortezamib or Thalidomide.

Are novel agents as strong in practice as the original studies?

Of course we participate in many clinical trials but we just, from the point of the Greek Myeloma Study Group, we wanted to have the experience from the patients who were treated all over Greece, many of these patients have not entered into clinical trials. And we have seen that, yes indeed, these three drugs have managed to increase the survival of our patients. We have to know how we have to use them sequentially or in what combinations in order to be more beneficial even for the elderly patients or how we have to use them in order to increase survival in our elderly population. And possibly if we use them at first line, at the trial stage, we may manage to increase the survival in the elderly also.

Do you have any guidance for treating refractory and relapsed multiple myeloma?

The thing is that you have here three agents. You have a lot of combinations, you have  a lot of clinical studies that are running in order to try to understand what is better – to give all the drugs immediately at the beginning, let’s say, in order to try to cure the patients or to give them sequentially in order to transform multiple myeloma into a chronic disease. I think that this question has a lot of different answers depending on the age of the patient, depending on the commodities that the patient has, the performance stats of the patients.

So I believe that the combination of Velcade with Dexamethasone or Lenalidomide and Dexamethasone that will be licensed for the relapsed refractory setting are the two combinations that can be given in patients. And of course you can choose according to renal function if you are going to give Velcade first and possibly Lenalidomide then or according to bone disease. If there is a lot of bone disease I would prefer Velcade based combinations and so on. But I think both drugs, Velcade and Lenalidomide are very effective in the relapsed refractory setting.

What advice do you have for clinicians?

These optimistic words come from the results of the clinical trials that are presented even in this meeting or in the last American Society of Clinical Oncology meeting where you see that the novel agents at baseline have managed to increase overall survival even though we have very exciting maintenance data from the IFM, the France group, showing that Lenalidomide maintenance also can increase the overall survival of our patients. So I believe that if we take advantage of all the agents that we have now and the newer ones like Pomalidomide, the new IMiD, Carfilzomib, a new proteasome inhibitor, and all the other drugs that seem to help, probably we can say that the multiple myeloma, which the median survival now is something between four and five years, is going to be expanded to seven or even ten years and be transformed to a chronic disease.