Addressing the treatment gap for patients with relapsed/refractory primary systemic AL amyloidosis: TOURMALINE-AL1 trial results

Prof Evangelos Terpos – University of Athens, Athens, Greece
Prof Efstathios Kastritis – University of Athens, Athens, Greece

ET: Hello, I am Evangelos Terpos, Professor of Haematology from the National and Kapodistrian University of Athens in Greece. I am here in Orlando with my colleague, Efstathios Kastritis, who is an Associate Professor of Medical Oncology in the same university, in order to discuss some important abstracts for the treatment of AL amyloidosis. So, Efstathios, thank you so much for being with me.

EK: Thank you Evangelos.

ET: One of the most important questions is what is amyloidosis, for the general population, and how the diagnosis is made.

EK: Yes, I think this is a very important first question because this is actually a disease that is not so common, it’s not like myeloma. Actually it may be 5-10 times less common than myeloma and it’s a very complicated disease. As you know, it’s a hematologic malignancy in which the plasma cells, which are also the same in myeloma, but in the case of amyloidosis these plasma cells produce the light chains, the immunoglobulin light chains, which form amyloid fibres. These fibres tend to go and deposit in the different tissues and organs like the heart, the kidneys, the liver, the nerves and the gut. They cause problems because of this deposition of the fibres. Also, we know that the light chains have a direct effect on the cells, especially the cardiac cells, so they can cause directly cardiac dysfunction. This disease is very challenging because of the symptoms that are associated with significant comorbidities – heart failure, renal failure, neuropathy – but also because it is very challenging to diagnose these patients. So you need a certain degree of suspicion in order to suspect the disease and then you will go through several investigations and finally a biopsy. It could be from the affected organ or from the fat to identify the amyloid deposits and then to type these deposits because there are many different types of amyloidosis. Of course in AL amyloidosis we are interested in this specific type of amyloid filaments derived from the light chains.

ET: I assume that when you have a renal dysfunction or when you have a heart failure then it is easier to suspect the disease. But if you have a patient, for example, who has an MGUS and in the biopsy of the bone marrow you have the report of the pathologist that you see Congo red positive. Do you say that this patient has amyloidosis or is it obligatory to treat such a patient?

EK: No, certainly not. The definition of systemic AL amyloidosis requires that you have some degree of organ dysfunction so that you have amyloid affecting a significant and vital organ. So if you only find amyloid in the bone marrow biopsy without any other symptoms in a patient with an MGUS in which you perform a biopsy then this does not justify starting therapy.

ET: Another important question is that although you may have renal impairment or even liver dysfunction or skin deposits, the staging system for amyloidosis is mainly based on two markers of cardiac failure. Why is it so?

EK: This is very important because it’s a hematologic malignancy, as we said. We have plasma cells producing the light chains but the prognosis of the patient is mainly affected by the degree of cardiac dysfunction. So patients with more advanced cardiac dysfunction, with heart failure, have a very poor outcome. So we use a staging system that was developed by Angela Dispenzieri in 2004 from the Mayo Clinic based on the NT-proBNP, a cardiac biomarker, and troponin either I or T, another cardiac biomarker. So two cardiac biomarkers define the prognosis of these patients and those patients with both cardiac biomarkers elevated, especially if they are elevated to high levels, they have a very, very poor outcome with a median survival for stage 3b patients being less than six months, one of the worst haematological malignancies.

ET: So what is the treatment of newly diagnosed patients with systemic AL amyloidosis?

EK: The treatment of AL amyloidosis is very challenging. It’s very challenging because you have to treat patients with regimens that are adapted from our experience in multiple myeloma. We have to kill the plasma cells in order to stop them producing the light chains, the toxic light chains. But on the other hand you have a patient that may have multi-organ dysfunction and this means that your therapy may be toxic. So we have to adapt regimens from our experience in myeloma and today, more or less standard although there is no approved regimen, is to give a proteasome inhibitor with dexamethasone and a third agent, usually cyclophosphamide. So we start treating these patients, trying to have as soon as possible a reduction in the free light chains in order to improve organ function, if this is possible, and we see usually an organ response in a minority of the patients and mostly in those that achieve a complete hematologic response, they eliminate the production of the light chains. This may improve their overall survival.

ET: So this proteasome inhibitor is mainly bortezomib or we use others also?

EK: Today we use bortezomib. Of course we have other proteasome inhibitors, two new proteasome inhibitors are ixazomib which is a proteasome inhibitor that is quite similar to bortezomib but is given orally and not subcutaneously. And we have carfilzomib, another proteasome inhibitor which is a different class of proteasome inhibitor that however is not used in AL amyloidosis because it has been associated with some cardiac toxicity. So it’s difficult to use a cardiotoxic drug, potentially cardiotoxic drug, in patients that already have severe cardiac dysfunction.

ET: So yesterday Angela Dispenzieri reported here in Orlando an important oral presentation from the second proteasome inhibitor that you mentioned, ixazomib, which is another oral proteasome inhibitor in combination with dexamethasone versus what the physician would choose from different regimens in patients with AL amyloidosis. Can you summarise us the results of this study?

EK: Yes. First of all I want to say that this is a very important study in the field of AL amyloidosis, one of the very few trials, randomised prospective trials, in the field of AL amyloidosis. So in this prospective and randomised clinical trial the treatments were tested in patients with relapsed AL amyloidosis, so in patients who had received primary therapy and at some point the light chains started going up and required again therapy. So in this study the experimental arm was the combination of ixazomib with dexamethasone and it was compared to what is considered physician’s choice, meaning other therapies but not including bortezomib because bortezomib and ixazomib are more or less very similar drugs. This could be either lenalidomide with dexamethasone or melphalan with dexamethasone or cyclophosphamide with dexamethasone. So the physicians could choose any of these regimens as standard of care and randomised against ixazomib. Now, most of the physicians elected to use lenalidomide with dexamethasone and this study had as a primary endpoint the overall hematologic response, meaning the reduction of the free light chains. So in this study there was no significant difference in the overall hematologic response between ixazomib and dexamethasone and physician’s choice. The hematologic response rates were very similar. However, there was a signal of higher rates of complete hematologic responses in the ixazomib dexamethasone arm.

ET: Is it of any significance? Because we know that if a study has failed in the primary endpoint it’s a negative study but you mentioned previously that it is a very important study.

EK: It is a very important study because, in my opinion, the target of superiority of hematologic response was very ambitious. The study had other outcomes that were also very, very important.

ET: How about the organ response because, from what I have understood, the organ response is of extreme importance for the patients?

EK: Exactly. So, as we said, it is important to remember that amyloidosis is not exactly myeloma which means that you have to treat the patient with effective therapies. But, on the other hand, it is very important that these therapies have minimal toxicity because you have a patient with renal dysfunction, cardiac dysfunction and more than a third of the patients had both cardiac and renal dysfunction. So we’re talking for frail patients. So in this patient population those who were treated with ixazomib and dexamethasone had higher rates of organ responses, meaning improvement with the criteria that we have, with the challenge that we have in evaluating these criteria, improvement in the organ function both in cardiac and in renal responses. Also another significant finding of this study was the fact that in the group of patients that were treated with ixazomib and dexamethasone there was a significant improvement to the time until there was a significant deterioration in the organ function of the cardiac or of the kidneys.

ET: So it seems that in this relapsed refractory population the combination of ixazomib and dexamethasone can give us a lot of solutions, mainly in patients with organ damage?

EK: This is very, very important. It is important to have an additional treatment choice for our patients with relapsed amyloidosis. Our primary choice at first line therapy is a regimen based on bortezomib and cyclophosphamide and dexamethasone, this is more or less considered the standard of care although it’s not officially approved. But in patients that relapse you have to have options and so far the options that we had was to use either an alkylator or lenalidomide with dexamethasone. Now, with this study we see that we have another option. So for patients who are not resistant to proteasome inhibitors we have an option to use ixazomib with dexamethasone according to this study which is a regimen with good response rates, in any case at least as good and perhaps a little better than the other regimens, and has lower toxicity which is also associated with what we see as improvement of organ function and prolongation of the time to the failure of the organs because of amyloidosis.

ET: So can we say that ixazomib in combination with dexamethasone cam be considered as a possible new standard of care for patients with refractory or relapsed amyloidosis?

EK: Yes, that would be nice to have in AL amyloidosis. The problem is that we don’t have any standard of care now so this is a problem. But we can say that it’s definitely one of the best treatment options that we have in the relapsed setting.

ET: Thank you so much for discussing this important study in this rare disease and thank you for attending.

EK: Thank you Evangelos.