2021 was “a landmark year” with the first FDA-approved treatment regimen for AL amyloidosis and 2022 is “a landmark moment” for Australians with amyloidosis, according to Dr Hasib Sidiqi.

At its May meeting, the Pharmaceutical Benefits Advisory Committee (PBAC) gave the green light to the Australia’s first-ever AL amyloidosis treatment regimen when daratumumab (Darzalex®) in combination with CyBorD (cyclophosphamide, bortezomib (Velcade®), and dexamethasone) was recommended for listing on the Pharmaceutical Benefits Scheme (PBS).

“Hopefully, this means this fantastic drug combination will be reimbursed on the PBS in the next six to 12 months for Australian patients with AL amyloidosis,” said Dr Sidiqi, a consultant haematologist at Perth’s Fiona Stanley Hospital, where he is the myeloma and amyloidosis lead.

“That would be the first time we have a medication specifically approved for AL amyloidosis.”

The U.S. Food and Drug Administration last year approved the first treatment regimen for newly diagnosed AL amyloidosis based on the results of the Phase III ANDROMEDA study which compared the combination of four medications – daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd), with the three-drug arm, VCd (bortezomib, cyclophosphamide, and dexamethasone).

“The overwhelming results were that people who got the four drugs did better in terms of response to therapy and depth of remission,” said Dr Sidiqi.

“It really was a landmark clinical trial and a landmark FDA decision for AL amyloidosis.” 

Several Australian sites participated in the large international multicentre randomised study that was published in the New England Journal of Medicine. Three  of the authors are members of the Australian Amyloidosis Network (AAN).

The AAN is a group of physicians, including Dr Sidiqi, with an interest in amyloidosis and in trying to improve the diagnosis, treatment, and patient experience with this rare disease.

Dr Sidiqi’s long journey to specialising in amyloidosis

Earlier diagnosis and better treatment are the greatest unmet needs in AL amyloidosis, says Dr Sidiqi, whose research interests are “to try and improve outcomes for patients with a focus on clinical research, particularly to expanding the clinical trials program [at Fiona Stanley Hospital], giving patients access to novel drugs that they may not have otherwise had”.

He completed his medical, general physician, and most of his haematology training in Western Australia. 

“As a haematology service registrar with the team at Royal Perth Hospital for three months, I really fell in love with the specialty,” he explained.

“I loved the people I worked with, the kind of pathology we saw, and the fact that you are so intertwined with the patient journey. 

“This was the impetus to apply for advanced training in haematology, and towards the end of my training, I started to think about sub-specialising in plasma cell disorders, which encompass myeloma, amyloidosis, and a few other conditions. 

“This was an area in haematology that was starting to expand, and a lot was happening in the space.”

Dr Sidiqi then spent two years at the Mayo Clinic in Rochester (U.S.) which he said, “has a fantastic plasma cell disorder group which is world-renowned when it comes to amyloidosis and myeloma”.

“I had the pleasure and the opportunity to work under Dr Morie Gertz. He’s one of the world’s leading experts in the field of amyloidosis,” said Dr Sidiqi. 

“My wife [a neurologist] and I had always planned on going to the U.S. for fellowships. Our hearts were set on the Mayo Clinic, and we were lucky enough to both have fellowships there at the same time.” 

That “wonderful experience” ended Dr Sidiqi’s training journey. He returned to Australia in 2019 and took up his current position at the Fiona Stanley Hospital where he also works with the CAR T-cell group. 

His pathway to that point was long, “with a lot of push from my parents”. 

“They migrated from Afghanistan when I was six years old. I come from a family of seven kids and my mum and dad knew that education was so important and that’s the reason they pushed us towards professional fields, through university,” said Dr Sidiqi.  

How Dr Sidiqi describes the AL amyloidosis subtype

Dr Sidiqi’s summarises amyloidosis as “an umbrella term that describes a group of disorders where, for one reason or another, a protein in the body misfolds. These misfolded proteins link up together to form amyloid fibrils that then deposit in tissues, causing organ damage and disfunction”.

“There are many different subtypes of amyloidosis, and the subtype is dependent on the protein that has gone wrong,” he said.

“The hallmark of immunoglobulin light chain amyloidosis (AL amyloidosis) is the amyloidogenic free light chain protein. These free light chains are secreted by abnormal plasma cells in the bone marrow. 

“That’s where the link with myeloma comes into play. Myeloma is a cancer of plasma cells, where you’ve got abnormal plasma cells that grow in the bone marrow.

“In amyloidosis, we have a similar problem, abnormal plasma cells in the bone marrow. They can grow in number but usually don’t overtake the bone marrow to the degree that we see in people with myeloma. 

“But these abnormal plasma cells secrete free light chains that misfold, are secreted into the blood circulation, and form amyloids fibrils that are then deposited in different organs, causing organ damage and tissue dysfunction,” said Dr Sidiqi.

How common is AL amyloidosis?

While demographic data is limited, some longitudinal studies have been done in the U.S. and Europe, and in Australia, Dr Sidiqi said, “Peter Mollee’s group has tried to look at some of these incidence rates”.

“Overall, compared to other blood disorders and malignancies in general, AL amyloidosis is a reasonably rare disease. It affects around nine to 12 people per million, per year.

“The median age at presentation is in the mid-60s, so it’s a disorder that is more common as we get older, and it tends to affect males and females equally.”

Common symptoms of AL amyloidosis

In terms of symptoms, Dr Sidiqi said, “it really comes down to which organs are affected by this condition”. 

“Remembering that the proteins form amyloid fibrils that then deposit in organs, the most common organs affected in AL amyloidosis are the heart (60-70% of people) and kidneys (50-60% of people),” he said.

“The other organs that can be affected, but to a lesser degree, are in the gastrointestinal tract; anywhere from the mouth all the way down to the small and large bowel, or the nerves, and that can be the peripheral nerves or the central nerves.”

With cardiac (heart) involvement, a common symptom “which people might notice” is shortness of breath on exertion.

“And they might notice a bit of swelling in the lower limb. This tends to be a progressive thing. It usually happens over many months and slowly gets worse,” said Dr Sidiqi.

“Because some of these symptoms are quite nonspecific, often there is a delay in people being diagnosed with amyloidosis and some of these symptoms don’t trigger investigations for amyloidosis. 

“Lots of things can make you a bit short of breath or cause oedema (swelling) in the leg, so it’s not uncommon for us to find that people have had symptoms for six, 12, or even up to 24 months before they’ve been diagnosed.”

Dr Sidiqi said the way amyloidosis affects the kidneys, is loss of the protein, albumin, from the serum.

“Once you lose a lot of albumin, you start to leak fluid from your blood vessels into the subcutaneous tissues, so again, you notice oedema in the lower limbs, or it can present elsewhere,” he said.

If amyloidosis affects the gastrointestinal tract, common symptoms people might notice are nausea (and when it’s more significant, it can cause vomiting), and indigestion. If amyloidosis affects the lower bowel, it can present as diarrhoea and abnormal bowel habits.

If the amyloidosis affects the nerves, the most common presentation is numbness and paraesthesia in the upper or lower limbs. As the disease progresses, patients can develop weakness and loss of function of the muscles those nerves supply. 

“So you can have difficulty in using your hands or difficulty in walking,” said Dr Sidiqi. 

Why amyloidosis is difficult to diagnose

Amyloidosis is “unfortunately, difficult to diagnose” because the symptoms are “quite nonspecific” and there needs to be “an index of suspicion”, Dr Sidiqi explained. 

“Because it’s a rare disease, you can understand why people don’t think of amyloidosis straight away.

“And you really need someone to have a potential diagnosis of amyloid at the forefront of their mind to put it all together.”

“There’s some good data on the time that patients have symptoms before being diagnosed,” he said.

“On average, people have symptoms for about 12 months and can see up to three or four physicians before a diagnosis is made.”

Dr Sidiqi gave the example of someone whose amyloidosis is affecting the nerves and who presents with some numbness, some paraesthesia – “a bit of what we call peripheral neuropathy”.

“Often, for the physicians that are seeing you, it doesn’t necessarily click that amyloidosis could be a possibility, and likewise for some of the other symptoms – whether it’s a bit of indigestion or nausea or abnormal bowel habits,” he said.

Testing to diagnose amyloidosis

“The gold standard” for a definitive diagnosis of amyloidosis requires a tissue biopsy that shows the amyloid deposits, and a specific stain called Congo red is used to highlight the amyloid on a tissue biopsy.

“We can detect that in any tissue that has amyloid. It could be a heart biopsy, a kidney biopsy, a nerve biopsy, or a biopsy of the stomach in someone that has had indigestion and has had an endoscopy,” said Dr Sidiqi.

“There are other tests that would be done before you even get to a biopsy, that may give clues as to someone having amyloidosis.

“The really important test is the free light chain assay. This test looks at the circulating light chains in the blood and there are two different types, kappa and lambda.” 

In people with amyloidosis, the levels of the light chains in the blood will be abnormal.

About 70% of people with AL amyloidosis will have lambda light chain amyloidosis, where the lambda light chain is elevated significantly compared to the kappa. And vice versa in the other 30% of people who have kappa light chain amyloidosis; their level of kappa light chain is elevated. 

The serum free light chain assay is a simple test that can detect abnormalities in light chain levels in the blood or urine that could then trigger a physician to ask the question, “could this be amyloidosis?”, and then go on to do more investigations.

“If we’re really thinking this is AL amyloidosis, we do a bone marrow biopsy to look for those abnormal plasma cells that are producing the abnormal light chains, and we can look for amyloid deposition in the bone marrow itself,” said Dr Sidiqi. 

“There is also a non-invasive test, called a fat aspirate or fat pad biopsy, where a little sample of fat is taken from the subcutaneous tissues in the abdomen, and we can do a Congo red stain on that to look for amyloid deposition in the fat.

“The combination of these two tests – a bone marrow biopsy and a fat aspirate – will show amyloid in 80-85% of people with AL amyloidosis and this is important, because we really need a tissue biopsy with amyloid to be 100% sure that’s what we’re dealing with,” he said.

Problems associated with a late diagnosis of amyloidosis

Dr Sidiqi said the problems associated with amyloidosis patients being “diagnosed so late” is one of the things that differentiates amyloidosis from myeloma.

“In myeloma, the primary problem is plasma cells in the bone marrow that are growing and taking over the bone marrow. They stop the bone marrow from working and can cause other problems,” he said.

“But in amyloidosis, plasma cells are producing bad proteins that form amyloid and these amyloid fibrils deposit in different organs, affecting the function of those organs.

“Imagine… you’ve got these proteins depositing in the heart for 12-18 months or in the kidneys for 12-18 months or in the nerves for 12-18 months.

“That means that for 12-18 months, these organs have been affected by this abnormal protein deposition, so by the time we diagnose a patient with amyloidosis, they are not doing well.”

“Some of that damage, unfortunately, is irreversible, so that’s really the problem,” said Dr Sidiqi.

“Organ dysfunction determines prognosis with AL amyloidosis and the main determinant is the degree of heart involvement – the degree of damage that the amyloid has done to the heart in the time that it’s taken to diagnose a patient.

“The way we assess that is a combination of things. The two most important tests are cardiac biomarkers that can indicate how much damage has been done to the heart.” 

These are blood tests for NT-proBNP and troponin which are released into the bloodstream when there’s heart tissue damage.

“They give us an indication of the severity of damage to the heart by amyloidosis, in patients that have been diagnosed, and that’s what determines prognosis,” said Dr Sidiqi.  

“A lot of work has been done by the Mayo group and we have this Mayo staging system based on abnormalities in these two blood tests.

“If they’re both completely normal that means you are at the lower stage and if they’re both significantly elevated, you’re at the higher stage, which means the heart has been damaged more.

“Prognosis is very different for people who have what we call advanced Mayo stage, where the heart has been damaged significantly. 

“Unfortunately, a good proportion of people in that category will succumb to amyloidosis within six to 12 months, which highlights the importance of organ damage in this disorder,” said Dr Sidiqi.

“There is a group of people that has kidney involvement, but very minimal heart involvement. If their heart is in good shape, they fall into the good category, or the lower Mayo stage, associated with a better prognosis.

Dr Sidiqi said a person’s baseline can affect how they react to their amyloidosis symptoms.

“Sometimes we have patients who are reasonably young, maybe in their 50s. They are very fit and active and because they have a lot of reserve, they may tend to ignore some mild symptoms for six months or so.

“Eventually they start seeing doctors to try and look into things. They may see physicians and it doesn’t click that this could be amyloidosis because the symptoms are nonspecific, and no one specifically looks for amyloidosis. 

“By the time they’re diagnosed, the organ damage has reached a very significant level. They’ve reached that threshold of their body’s reserve and all of a sudden, the heart, unfortunately, is significantly involved.

“For other patients who may not have as much reserve, their symptoms might be far more obvious and might trigger them to get seen and tested more quickly,” Dr Sidiqi explained. 

“It’s critical to try and get a diagnosis before the heart has been damaged extensively.”

“One of the problems with advanced stage disease, where the heart is significantly affected, is that makes tolerating treatment more difficult.

“I’m not saying that we can’t treat them, we certainly can, and we try to, and in some people we manage to really suppress production of those light chain proteins.

“I certainly have people who have come in with advanced cardiac stage and we’ve started them on treatment, they’ve responded to treatment beautifully, and six months later they’re doing much better. The heart is starting to improve.

“We definitely have success stories but that’s probably the minority of people in that category.” 

Amyloidosis treatment

Many of us would say that a diagnosis of light chain amyloidosis is a medical emergency, says Dr Sidiqi.

“It takes time to confirm the diagnosis and do all the staging tests, but the goal is to start treatment as soon as it’s practicable – within a week or two of diagnosis.

“This isn’t something you would leave for months.

“We don’t have any PBS-reimbursed medications specific for this condition and this has a lot to do with the rarity of the disease.

“The number of clinical trials and the data we have on treatments for this condition are far less than we have for myeloma, where we have a number of PBS-reimbursed medications. 

“In terms of treatment, that is improving. The goal of treatment has been to suppress production of the light chains that become amyloid, and our treatments have largely been borrowed from myeloma, to get rid of the plasma cells that are producing the light chain protein.

“Then you stop ongoing amyloid being deposited in the organ and you’re hoping that the body can then heal some of that damage that has occurred,” Dr Sidiqi explained.

“Some would argue there is no standard treatment because we have limited data on this condition.”

“Most of us would use a combination of drugs that we typically use for myeloma, which is bortezomib, cyclophosphamide, and dexamethasone. We have a lot of experience with these three drugs in myeloma, and quite a bit of data is now emerging in AL amyloidosis.

“This combination of drugs works very well in this condition, and we would usually give that treatment for a period of four to six months.

“The goal is to try and bring those light chains back down to normal levels, so the body then has an opportunity to try and heal some of the damage that has been done to the heart or the kidneys or the gut or the nerves.

“And that does happen in a proportion of people,” he said.

Clinical trials in amyloidosis

The holy grail of amyloidosis treatment is the answer to the question – how do you get the amyloid out of the organs that have already been damaged?

“Thus far, we haven’t had any treatments that have done this, but over the last five or six years, a number of new molecules have been studied. One in particular, CAEL-101, is now available on a clinical trial in Australia,” said Dr Sidiqi.

“It’s a monoclonal antibody, designed to bind on to the amyloidogenic light chain in the tissues and help solubilise it. By making it soluble again, you can remove it from the organs by flushing it out of the system.

“The early Phase I/Phase II studies showed some promising effects in helping get rid of the amyloid from the heart.

“Now we’ve got a Phase III clinical trial, which is open at five sites in Australia [Brisbane, Sydney, Melbourne, Adelaide, Perth] that is looking at using this agent (CAEL-101) in combination with VCd for patients with AL amyloidosis with severe heart involvement.

“This is a group of people that, unfortunately, is often excluded from clinical trials because the heart has been affected so much and they’re generally not in great shape.

“We want to see whether adding this drug, that helps clear amyloid from the organ, helps improve outcomes in this very high-risk population. 

“I think that’s a really exciting clinical trial. We don’t have any results or data yet. It’s a bit early, but I envisage that in the next 12-24 months, the data will start to read out from this clinical trial, and we’re all cautiously optimistic.

“If we can find a drug that helps clear amyloid from organs, I think that’s really going to be a game changer.”

“In terms of other clinical trials, the MM24 clinical trial is being run through the ALLG in collaboration with the French myeloma amyloidosis group, at four sites round the country.

“It is looking at a combination of isatuximab (a next generation daratumumab-like drug) with pomalidomide and dexamethasone in people with relapsed or refractory amyloidosis. These are people where the frontline treatment hasn’t worked.” 

Amyloidosis is treatable and Dr Sidiqi said the goal is to induce a remission “and hopefully that remission stays for as long as possible, but eventually the disease does come back”.

“So we have to look at what medications we can use at relapse to try and put it back into remission. The MM24 trial is really trying to answer that question,” he said.

“We need studies both in newly diagnosed patients, but also in patients that have had treatment in the past and unfortunately their disease has come back.”

George Yiannakis was the first patient recruited to the MM24 trial in Australia. Read his personal story. 

The importance of clinical trials

Clinical trials are vital in this disease, says Dr Sidiqi.

“They are the only way we are going to move forward in terms of better treatment for this condition,” he said. 

“The only reason we may [soon] have the four-drug regimen (daratumumab in combination with VCd) is because a clinical trial was performed that showed that it worked and is better than what we have been using thus far.

“Getting PBS reimbursement or government funding for these medications relies heavily on clinical trials showing that they’re effective.

“And with a rare disease, having access to clinical trial options is a fantastic way of potentially getting access to drugs that you may not have otherwise got for this condition.

“Let’s take the MM24 trial, for example. Isatuximab, pomalidomide, and dexamethasone is not a combination we can get for myeloma, let alone amyloidosis in Australia. 

“It’s a fantastic way of getting access to drugs that we know work well at getting rid of plasma cells and the only way for an amyloidosis patient to access that regimen is through the clinical trial. 

“I think it highlights the importance of these clinical trials for patients, particularly with rare diseases like amyloidosis.”

What Dr Sidiqi would do if he was diagnosed with AL amyloidosis

“The first thing would be to ensure that I try and see a physician or haematologist with a degree of expertise or knowledge in this disorder, and I’d have a very close working relationship with them,” said Dr Sidiqi. 

“There are a lot of online patient resources that can help you find your feet. The Leukaemia Foundation has a fantastic handbook on amyloidosis, which I give to all my patients, that I would use. And the Australian Amyloidosis Network has a website (www.aan.org.au) that has resources for patients, including contact information for the amyloidosis centres across the country, and I think that’s really important.

“Then, I would look to see if there are any clinical trial options available for me, because this is a fantastic way of accessing drugs that may be very effective for the condition, and that you may not otherwise be eligible for.

“The amyloidosis community in Australia is very close knit, and the AAN provides a monthly case forum where physicians from anywhere in the country can present and discuss difficult cases with us, and we have a round table discussion on what’s available and the best course of action.

“So there are plenty of resources now, and that are emerging, that can help manage your care,” Dr Sidiqi said. 

Key advice

Knowing there are other people who are on the same journey is important, particularly over the first three to six months after diagnosis, but it can be hard to find those people. 

“That’s one of the things I find people with amyloidosis struggle with a lot, because it’s such a rare disease.

“The online forums we have now help to some degree in terms of patient and support group meetings, and the AAN runs events that can help ground you in terms of where you are at in the journey and how things are likely to go, because it can be overwhelming when you are initially diagnosed with a very rare condition.”

The Australian Amyloidosis Network

Dr Sidiqi said that for a long time, there was a degree of underdiagnosis, late-diagnosed disease, and a lack of good diagnostic and treatment pathways for AL amyloidosis patients.

“The Australian Amyloidosis Network has been instrumental in educating healthcare professionals and physicians on amyloidosis and providing support for patients and families,” said Dr Sidiqi, who is on the AAN Board of Directors.

“The AAN laid the groundwork over the last decade or so in terms of trying to increase awareness of this extremely rare disease and it has been a fantastic group to be a part of since coming back from the Mayo Clinic.” 

There are four amyloidosis centres across the country: in Brisbane, headed by Associate Professor Peter Mollee; Sydney (Dr Fiona Kwok); Melbourne (Dr Simon Gibbs); and Perth (Dr Sidiqi).

Dr Sidiqi’s holy grail

“I would love to be involved in clinical trials that either ultimately cure AL amyloidosis or make it treatable as a chronic disease – something that you can live with, with a good quality of life,” said Dr Sidiqi.

“Cure is a word that you don’t want to throw around lightly, but I think the speed of progress in this area over the last five to 10 years gives you an indication of what might be possible.

“That really would be the holy grail of what we’d hope to achieve in this space over the next two to three decades.”