ASCO 2010 Annual Meeting, 4—8 June 2010, Chicago

Interview with Dr Giampaulo Merlini (University of Pavia, Italy)

Early diagnosis of amyloidosis

You come from Pavia and you’re a big expert in amyloidosis and you’ve been talking at ASCO about this. Now I don’t suppose there are too many people at ASCO know too much about amyloidosis, what were you telling them?

I was supposed to discuss therapy and I elected to discuss the disease instead, putting the poster into the perspective of the disease, because I thought that it was so important to have the chance to pass on the message to the oncologists that it is very important to recognise these patients. It’s a rare disease but it’s not so rare as people think because the incidence now is considered to be around fifteen new patients per million per year. And it’s very important to recognise them very early in the disease before the light chains cause end-stage organ damage.

How do you do that? How do you recognise early amyloidosis?

Exactly. So, I gave some hints to them just that if any patient has some protein in the urine and they have cardiomyopathy  they can start showing some echo cardiography  abnormalities, but very early because later on is too late.

What are the early abnormalities? We do a lot of echoes for cardiotoxicity.

Yes, exactly. So you should look at what is called hypertrophy.

Left ventricular?

Yes, increased thickness of the ventricle associated with low voltage at ECG and some pericardial infusion. This is diagnostic, almost, in more than 90% of the cases.

And that’s still early? I would have thought that might be late.

That is rather late, so by ensuring recognising in the early phase; but if you look at protein because the kidney is the most affected organ. Some of these patients do have protein in the urine for some months or a year and it goes unnoticed. And then I just presented a slide with some prototypic presentations, such as periorbital purpura for instance, that is not common, it’s only in 12-15% of patients but doctors can not miss this type of patient. Unfortunately some of these patients are sent to the oculist or to the dermatologist so they lose time and really, here, time is life. So it’s very important to make the diagnosis very early because this is really the key to the success of the treatment. If we can have an early diagnosis then we can treat effectively nowadays.

How do you treat amyloidosis early?

These plasma cells do produce these mis-folded light chains and these mis-folded light chains are toxic to several organs but they are most likely toxic to the clone itself that is producing the light chains in the bone-marrow. So this is most likely the reason why the clone is always rather small in this type of patients. And now we have some drugs, some new drugs which are particularly effective in this type of patients. So with Bortezomib, for instance, there can be a response rate higher than 80% but was never seen, but very quickly – less than one month, medium time to response. That is exactly what we need to get rid of these light chains as soon as possible.

So that’s standard multiple myeloma therapy?

Exactly, but in this case it’s much more effective and in some of these patients we have reason to think that you can get rid of the clone or you can get rid of the clone for several years. And this is very important because research is going on all the time and in several years we would have many more tools to attack the clone and to attack the disease itself. The disease is a complex disease but the more we know, the more points of attack now we have. So people are just thinking about removing the amyloid deposits using monoclonal antibodies and so on. So at the end we will use several approaches just to get rid of these.

What sort of antibodies have you got in mind?

Well, we had this international symposium around amyloidosis in Rome, April 18th – 21st, that I organised as President of the International Society of Amyloidosis. The UK group presented their data on this monoclonal antibody against SAP. SAP is a common constituent of all types of amyloids and this antibody can induce the removal of the amyloid deposits. And another group in Tennessee has produced an antibody against the light chain amyloidosis that is being developed in collaboration with NCI. So things are progressing.

And can you label those antibodies with technetium and pick up?

Good point. Actually in Rome they presented data on imaging of the amyloid deposits; with these antibodies you can have very nice imaging. That was the prerequisite to use it as a therapy.

That’s hopeless as a screening tool, presumably.

Yes but for screening we have a very powerful, very simple technique such as abdominal fat aspiration which is innocuous, is very fast, rapid; you can do it in out-patients and you can have the answer in half an hour.

You aspirate fat and then?

And then you just squeeze it, you stain it with Congo red and then you look at the microscopic.

You can pick up the amyloid?

Yes. And the sensitivity is more than 80% and the specificity is more than 90%, so it’s very good.

Which cancers are linked to amyloidosis?

Well, amyloidosis is a general term because, as you know, it goes from Alzheimer’s to systemic amyloidosis. So systemic amyloidosis, one of the points that they made is very important – that is the diagnosis of the exact type of amyloid, otherwise you risk catastrophic mistakes. For instance, one amyloid is sustained by a mutated protein produced by the liver, transparatin, and this gives a type of amyloid that sometimes can mimic AL amyloidosis that is produced by light chains from the clone. So it is a disease of elderly people , it’s really an age-related disease. So in elderly people, as you know, MGUS is rather common, a small spike is commonly found in approximately 3.5% of people after the age of 50. So you could have a coincidence of these two effects and if you’re not careful you can just conclude that you have an AL amyloid, treat this patient with chemotherapy while actually this patient needs a liver transplant. So I pointed out that it is very important to make sure that you are treating the right disease and now in Rome we set out that the new gold standard is the proteomics technology to make the diagnosis, to make the exact diagnosis of amyloid.

On a tissue biopsy or can they do that on the light chains?

No, you can do it on this fat aspirate. So you just aspirate 20mg of fat and then you just use it for proteomics, electromicroscopy or the other type. So now, making the diagnosis and typing it is crucial for the right therapy.

So your combination is Bortezomib…?

Melphalan and Dexamethasone and this has been proved to be very effective and for this reason now we are starting a European trial for the first time that will be paralleled by a trial made by ECOG in the States using exactly the same protocol, comparing a standard treatment for patients who are not eligible for a stem cell transplant versus Bortezomib, Melphalan, Dexamethasone. We will see soon.

Most interesting, thank you so much. I really appreciate speaking to you.