Meet the expert
The clinical features of lichen amyloidosis can be many. They are often mistaken for other more common diagnosis, and the diagnosis of lichen amyloidosis is often delayed. The spectrum of clinical features depend on the type of and the severity of organs that are involved with the lichen amyloid. The most common organs that can be involved with the lichen amyloid include the heart, the liver, the kidneys, the gastrointestinal tract, the nervous system, skin and soft tissue. Patients can present with pedal edoema or difficulty with breathing, especially in patients who have significant cardiac involvement. Those with renal involvement often present with significant pedal edoema. The clinical presentation is very dependent on the type of the organs involved and the severity of the organ involvement. Patients with cardiac involvement often present with dyspnea on exertion as well as pedal edoema. Those with real involvement, which typically leads to development of nephrotic syndrome, can also present with significant pedal edoema and ascites. Liver involvement often presents with weight loss and anorexia, and as whereas gastrointestinal involvement can lead to significant alteration in the bowel habits, especially diarrhoea related to malabsorption. Patients can also have symptoms that involves difficulty in swallowing that might be related to the upper GI tract involvement. Nervous system involvement can be in the form of peripheral neuropathy that can present with numbness or tingling of the extremities, or can be autonomic nervous system involvement that often presents with postural hypertension and other autonomic symptoms. There is increased bruising that can be seen in these patients, related to the indifference of the fibrins with coagulation factors, as well as increased fragility of the blood vessels, both of which can again present with ecchymosis or other evidence of increased bruising. Enlargement of the tongue or macroglossia is a relatively unique finding, but it's not very common. Similarly, periorbital purpura, often referred to as raccoon eye signs, can also be Pathic Mnemonic of this disease, though again, not very common finding. Other symptoms can include, especially in those with cardiac involvement, the alterations in the cardiac rhythm, which sometimes can lead to fatal cardiac arrhythmias. Overall, the important thing to keep in mind is that when these constellation of symptoms are not explained by common illnesses, it is important to keep lichen amyloidosis on the top of the differential diagnosis so that it is not missed. When the diagnosis of lichen amyloidosis is suspected because of any one or more of the symptoms, that the patient's present with, it is important to do a systematic workup, in order to reach the right diagnosis. The first question that is often asked in patients who present with the symptom is whether there is an underlying monoclonal gammopathy. Now, in our particular patient that we are talking about today, the presence of monoclonal gammopathy was already known before. But the majority of the patients who present with these symptoms do not have a preexisting diagnosis of monoclonal gammopathy. The identification of monoclonal gammopathy depends on demonstrating presence of monoclonal protein in the serum or urine, and this is done using a serum protein electrophoresis or it can be through a urine protein electrophoresis. Now, a significant proportion of patients, the monoclonal protein consists only of Kappa or Lambda light chains. So a serum free light chain assay is important for the, not only for the diagnosis, but also for subsequent management. The FLC assay will demonstrate increased Kappa or lambda lichens in the majority of the patients with lichen amyloidosis. Once the presence of a monoclonal gammopathy from determine significance on monoclonal gammopathy is established, the next step is to demonstrate the presence of amyloid. Now, the easiest locations to demonstrate presence of amyloid is the bone marrow or the fat aspirate.
Initial tests that should be undertaken would be the fat aspirate, and the bone marrow aspirate and biopsy, which not only will provide us an opportunity to test the tissue for amyloid fibrils, which can be done using concurrent stain, where a characteristic apple birefringence under the polarised microscope is fairly pathic mnemonic of this disease. In addition to the demonstration of amyloid fibrils, the bone marrow aspirate biopsy will also provide an assessment of the degree of monoclonal plasma cell involvement of the bone marrow. That can have significant prognostic impact as well as an impact on the treatment decisions that are made. Now, if the bone marrow and the fat aspirate does not demonstrate presence of amyloid, then we will have to do an organ-directed biopsy in order to demonstrate the amyloid. So for example, if someone presents with cardiac involvement, a endo myocardial biopsy, or someone presents with nephrotic syndrome, then a renal biopsy will allow us to demonstrate presence of amyloid fibrils. Now obviously, the demonstration of amyloid fibrils with the concurrent stain is an important first step, but it does not necessarily tell us what type of amyloid that a patient might have. And it is important for us to ensure that we are dealing with light chain associated amyloidosis, because monoclonal gammopathy and amyloid due to other proteins can coexist. It is important to note that up to 40 different proteins have been identified that can give rise to amyloid fibrils. Now, once the biopsy demonstrates the amyloid fibrils, the next step is to utilise mass spectrometry based approach to identify the specific protein that is involved. Now, understanding that mass spectrometry may not be widely available, an alternate approach is to use immunohistochemistry, but the mass spectrometry remains the gold standard test for identifying the type of amyloid fibrils. Now, once a diagnosis of light chain amyloidosis is made, it is important to assess the extent of organ involvement, and this would involve testing, again, focused on the organs that we talked about before, an echocardiogram and cardiac biomarkers in the form of troponin and NT-pro-PNP will give us a good sense of the degree of cardiac involvement. It is important that the echocardiogram also includes a strain assessment. And another imaging modality that can be used from a diagnostic perspective is the MRI of the heart, where a delayed enhancement with gadolinium is often characteristic of amyloid. There are other imaging studies like technetium pyrophosphate that can also help differentiate between ATTR amyloid and light chain, or other types of amyloidosis. Renal involvement should be assessed using urine testing, which will again demonstrate the amount of protein that is being lost in the urine, and also the renal function through serum creatinine clearance. Hepatic enzymes and alkaline phosphatase should be measured as this will give an idea whether liver is involved. And the other organ involvement, particularly the neurological involvement can be more difficult to measure. However, EMG studies can provide a good baseline for subsequent assessment. So a combination of this testing as well as the functional status of the patient and this degree of symptoms can give us a sense of the functional impact of this disease and potentially provide prognostic information going forward.
Now, in terms of treatment of light chain amyloidosis, a lot has changed in the past few years. The majority of the treatments that we currently use for light chain amyloidosis have been developed in the context of multiple myeloma, and tends to be directed towards the plasma cells that are secreting the monoclonal protein. But it is also important to remember there are other important targets, which is again, trying to dissolve the amyloid fibrins that are already present, can provide an important therapeutic option. Most of the treatments that we currently use are directed towards plasma cell, while fibrin directed therapies are currently going through clinical trials. The specific treatments that have been used include the use of alkylating agents like melphalan in combination with dexamethasone, a regimen often known as melphalan and Dex that has been used extensively for a long period of time. More recently, the introduction of monoclonal antibodies targeted towards anti-CD38 on the plasma cells, like Daratumumab and Cetuximab, can also provide important control of the underlying plasma cell clone. In fact, the Phase-3 Trial ANDROMEDA STUDY, compared the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone in patients with the light chain amyloidosis and demonstrated a significant improvement over just bortezomib, cyclophosphamide and dexamethasone in a Phase-3 Trial. And this has led to its approval, and this combination remains the standard of care for a newly diagnosed patient with light chain amyloidosis. If daratumumab is not available, then the combination of bortezomib, cyclophosphamide and dexamethasone, is a reasonable approach, as is the combination of melphalan and dexamethasone. Now in the majority of the patients we know, approaches like autologous stem cell transplant, cannot be applied due to their functional status. However, this therapy remains a very effective approach in patients who can undergo an autologous stem cell transplant, and should certainly be considered as an option. Unfortunately, the majority of the patients will have the plasma cell clone reemerge after a period of time or may not be responsive to the initial therapy and may need additional treatments. And this have again, included most of the agents that we have used in myeloma, including the immunomodulatory agents, other protease inhibitors, alkylating agents, as well as some of the newer immunotherapies like the bispecific antibodies in CAR-T Trials, that are being explored in the context of clinical trials. In addition to the plasma cell directed therapy, other treatments that are currently undergoing evaluation include the Fibro Directed Therapy. There are several clinical trials that are ongoing that are looking at various approaches, either using monoclonal antibodies or antisense approaches to try and inhibited the fibrin formation in the different types of amyloidosis. Particularly in the setting of light chain amyloidosis, birtamimab is one of those agents that has previously been studied in Phase-3 Clinical Trial. It did not show a benefit in the overall patient population, but suggested that in those with advanced disease, it may have a role in Phase-3 Trials or are ongoing. Another agent of interest is KL-101. That is, again, going through Phase-3 Trials at this point in time. In addition to these therapies, supportive care management of these patients are extremely important. These patients often present with the symptoms related to the multiple organ involvement, and even though the modern therapies targeted towards plasma cells can lead to elimination of the plasma cells relatively rapidly, and decreasing the serum free light chain levels, the organ involvement and symptoms related to that do take a fair amount of time to disappear. In fact, the median time to organ involvement in the phase of effective hematologic therapies and response is nine to 12 months. So it's important that patients are managed through this phase, especially from a symptomatic standpoint.
The multidisciplinary team approach is very, very essential for patients with lichen amyloidosis. As was previously mentioned, cardiac involvement in lichen amyloidosis can lead to heart failure, but can also lead to life-threatening cardiac arrhythmias. So assessment by a amyloid cardiac specialist is an important part of the initial evaluation. They will assess the patients for any arrhythmias that may require either initiation of therapy with medications, or implantation of devices for management of these rhythms. They can also optimise the management of the heart failure symptoms with the use of diuretics and other cardiac medications. Involvement of the nephrologist is important, especially if the patient's present with advanced renal failure, which, thankfully, it's not very common in the setting of lichen amyloidosis. But these patients can have significant proteinuria that can lead to hypoalbuminemia and peripheral edoema, and a close management, especially with respect to diuretics and other agents, are important. And the role of nephrologist is vital in those patients with advanced renal involvement. Similarly, those patients with significant neurological involvement, especially those with autonomic neuropathy with postural symptoms, will require close management in terms of fluid, as well as use of agents such as midodrine in order to control their postural hypertension. Patients may also present with significant pain related to their peripheral neuropathy, though this is relatively less common in the setting of lichen amyloidosis. But that will require the use of medications in order to control some of the symptoms related to peripheral neuropathy.
Patients with lichen amyloidosis can have significant impact from a psychosocial perspective. This is often a life-changing event, especially considering that a significant proportion of these patients are younger, and this would have impact on their personal and work life. Many of these symptoms, especially those related to the cardiac symptoms, can significantly limit the functional status of these patients, and this also can have significant impact. So, in addition to controlling the symptoms, I think it's important to also explore the impact of this diagnosis on various aspects of their individual, the individual's life, and again, provide support, whether it be from a social worker or from a psychologist. But overall, I think it's important to make sure that a comprehensive approach is instituted for the management of the psychosocial impact.
Let's talk about the patient that we have in front of us, Jane, who is a 58-year-old female, who presented with symptoms of fatigue, dyspnea on exertion and pedal edoema. She was in good health until about six months ago when she started noticing increasing fatigue. Eventually, the symptoms worsened, and she also started noticing more shortness of breath doing activities that she could easily do before. The symptoms are progressively worsening, and she finds it difficult to even climb one flight of stairs without stopping. Over the past month, she has also noted significant edoema around her ankles, and this appears to be the worst towards the end of the day. Now it is important to note that she was noted to have a monoclonal protein about five years ago and was given a diagnosis of monoclonal gammopathy of undetermined significance. At that time, she had undergone extensive evaluation and a diagnosis like myeloma was ruled out at that time. Since that time, she has been under careful observation, and she has been undergoing testing on an annual basis, and the serial assessments have not really shown any significant change in her laboratory workup, with the exception of the serum free light chains, which have gradually increased over this period of time.
Once a diagnosis of light chain amyloidosis is made, it's very important to assess the prognosis. The outcomes of patients with light chain amyloidosis can be quite different, with early mortality in some of the studies reaching up to 40% during the first one year. The outcomes are dependent on the number of organs involved and the severity of organs involved, as well as the characteristics related to the underlying plasma cell clone. Amongst the organ involvement, the cardiac involvement is the one that mostly tries the outcomes, and as a result, the prognostic staging systems that have been developed have been heavily dependent on the cardiac biomarkers. What we use currently, the 2012 Mayo Clinic staging system utilises the cardiac biomarkers, serum troponin, and InterPro PNP using certain cutoff values and also serum free light chain levels. And using these three variables, we can group the patients with lain amyloidosis into four groups with very different outcomes. And it's also important to remember that the assessment of prognosis is not a static thing, but rather something that evolves over time. And it's important to reassess the prognosis at various points in time, especially as patients respond to therapy and their organs improve.
The treatments that we use for lichen amyloidosis, particularly the combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone, can be associated with certain side effects. The daratumumab is often associated with the fatigue. The injections can be associated with allergic reactions during the first one or two injections, but usually don't recur after that. The treatment with daratumumab often leads to significant drop in the IgG levels, which in turn can increase the risk of infections in patients. Bortezomib treatment can be associated with peripheral neuropathy, which in patients with pre-existing neuropathy can be a problem. So this needs to be carefully monitored. Patients should be instructed to let the providers know if they notice any of these symptoms. The cyclophosphamide can be associated with the drop in the blood counts. And again, the blood counts need to be carefully monitored while patients are on treatment. Long-term treatment with medications like cyclophosphamide can increase the risk of second cancers. So prolonged therapy is not typically advised. Dexamethasone or steroids, it's a common part of the combinations that we use for treating these class of disorders. They can be associated with increased blood sugars, particularly worsening of diabetes in patients with pre-existing diabetes. It can also cause significant mood disturbances as well as sleep disturbances and change in appetite. In patients with nephrotic syndrome, it can worsen the nephrotic syndrome symptoms because of increased fluid retention. So it's very important to monitor patients very closely as they go in these treatments, especially at the initial stages, until we know that we have a dose and schedule that the patients can tolerate well.
Dr Shaji Kumar, MD, is a consultant in the Division of Hematology, and Mark and Judy Mullins Professor of Hematological Malignancies at Mayo Clinic in Rochester, Minnesota, USA. He is Chair of the Myeloma, Amyloidosis and Dysproteinemia Disease Group at the Mayo Clinic, and Research Chair for the Division of Hematology. Dr Kumar’s research focuses on the development of novel drugs and drug combinations for myeloma. His laboratory focuses on the role of the bone marrow microenvironment in the development of myeloma. Dr Kumar is Chair of the National Comprehensive Cancer Network (NCCN) Multiple Myeloma Guidelines Panel.
