Amyloidosis: Overview of Diagnosis and Treatment Options

Educational Objectives

The goal of this program is to improve diagnosis and treatment of amyloidosis. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize amyloidosis based on disease presentation.
2. List signs and symptoms of amyloidosis.
3. Explain use of technetium-99m pyrophosphate scintigraphy in diagnosing transthyretin amyloidosis.
4. Cite the diagnostic tests for amyloidosis included in the Mayo 2012 model of staging system.
5. Distinguish among patients with amyloidosis who are eligible for stem-cell transplant therapy from those who are ineligible.

Summary

Introduction: ≈50% as many cases of amyloidosis as chronic myelogenous leukemia (CML); the goal is to develop diagnostic acumen

Diagnostic suspicion

Case study 1 the patient was diagnosed with monoclonal gammopathy of undetermined significance (MGUS), ie, there was no evidence of CRAB (elevated calcium, renal insufficiency, anemia, bone lesions) and no myeloma-defining event; this should raise suspicion

Case study 2: the patient was diagnosed with smoldering multiple myeloma; urinalysis is important in patients with MGUS or smoldering myeloma to identify potential markers for amyloidosis; in addition to multiple myeloma, patients with MGUS can develop Waldenstrom macroglobulinemia, lymphoma, chronic lymphoid leukemia (CLL) or amyloidosis; the patients may present with edema, dyspnea, or fatigue

Case study 3: a 79-yr-old patient presented with dyspnea for 1 yr and lower-extremity edema; a small spike of monoclonal protein on serum electrophoresis in a patient with history of dyspnea on exertion should raise suspicion of amyloidosis, as with this patient

Case study 4: for tonsillectomy a patient had her eyes taped shut for general anesthesia; she developed lesions; hematologic tests were normal; patient was diagnosed with periorbital purpura due to vascular fragility; patient had myeloma-associated amyloid; in patients with monoclonal gammopathy, MGUS is the most common diagnosis, but other possibilities including macroglobulinemia, lymphoproliferative disorders, myeloma, and amyloidosis must be considered; roughly, there is 1 amyloidosis case to 5 myeloma cases in the population

Disease presentation: not similar to myeloma; patients do not have bone pain; anemia occurs only if associated with renal insufficiency, and renal insufficiency occurs only if there is advanced nephrotic syndrome; ≈75% of patients have cardiac involvement, >50% have renal involvement, and ≈25% have nerve involvement; some referrals may be for MGUS with peripheral neuropathy, and while most of these patients have chronic inflammatory demyelinating polyneuropathy, a proportion have amyloid-associated neuropathy; if a patient presents with peripheral neuropathy and a monoclonal protein, particularly lambda, amyloid must be considered; two-thirds of patients have multiorgan involvement; MGUS neuropathy with carpal-tunnel syndrome is another clue as carpal tunnel is not seen in MGUS neuropathy

Diagnosis: symptoms of patients with amyloidosis are nonspecific, including fatigue, edema, weight loss, or dyspnea; macroglossia and periorbital purpura are very specific signs but lack sensitivity; 85% of patients do not present with these signs; in general, symptoms lack specificity and signs lack sensitivity; in a web-based survey, 40% of the patients had >1 yr between onset of symptoms and diagnosis; 1 yr of cardiac amyloid deposition can be fatal; only 19% of cases are diagnosed by cardiologists despite the fact that 70% of patients have cardiac amyloid; 23% are diagnosed by nephrologists even though 60% of patients have renal amyloid

Types of cases where amyloid must be considered: this includes atypical myeloma, smoldering myeloma, or MGUS; other conditions include heart failure with preserved ejection fraction, MGUS with proteinuria (amyloid must be checked for when there is proteinuria), MGUS neuropathy, autonomic failure and monoclonal protein, orthostatic hypotension, intractable diarrhea, urinary incontinence with a monoclonal spike or a light chain; signs include periorbital purpura, macroglossia, and bilateral carpal tunnel

Diagnostic process: once a tissue that is positive for amyloid is obtained, the type of amyloid must be identified, ideally by mass spectroscopy; microscopic evaluation of bone marrow shows amorphous eosinophilic hyalinized material that represents amyloid; the amyloid deposit is removed from the slide, put into a cuvette, digested, and the peptides are then sequenced using a mass spectrometer; 1) albumin that co-deposits along with amyloid is seen; 2) apolipoprotein E and 3) vitronectin are associated with amyloid; 4) key is kappa human light chain, which is not an intact immunoglobulin (Ig) light chain (molecular weight of 12 kD) and the constant region of the Ig light chain is missing; this is why commercial antisera and immunohistochemistry are not useful in identifying the type of amyloid; in mass spectroscopy, the computer has a library of peptide sequences, and when the specimen is compared with the existing sequences in the library, it identifies the Ig-kappa chain constant region; in every patient with amyloidosis, the type of amyloid has to be identified, as only amyloid light chain (AL) amyloidosis is treated by an oncologist; all other forms are not the responsibility of an oncologist

Evidence: in a literature review it was found that 59% of amyloid samples were AL amyloidosis, 28% were transthyretin (TTR) amyloidosis (previously called senile cardiac amyloidosis), which is responsible for amyloid cardiomyopathy; it is seen in elderly men and chemotherapy is contraindicated; 3% of cases were leukocyte chemotactic factor 2 amyloidosis (ALECT2), which presents with nephrotic syndrome and is seen in Mexican Americans and Punjabi Indians; chemotherapy is contraindicated

Immunohistochemistry vs mass spectroscopy: mass spectroscopy is found to be superior in identifying the type of amyloidosis; technetium-99m pyrophosphate scintigraphy (Tc-99m PYP) can be diagnostic for TTR cardiac amyloidosis; patients with TTR amyloidosis show exclusive uptake in the left ventricle; Tc-99m PYP is negative in AL amyloidosis; patient has to be referred back to the cardiologist as the patient is not a candidate for chemotherapy

Types of renal amyloid: light chain amyloidosis is the most common type; nephrotic syndrome can also be caused by ALECT2 amyloidosis, which is relatively rare in developed countries; there is a rare form of amyloidosis related to fibrinogen mutations (inherited form); fibrinogen deposits in the glomerulus lead to nephrotic syndrome; it is important to recognize that not all renal amyloidosis cases are AL type; in amyloidosis, monitoring the free light chain is important, not the free light chain ratio; key parameters are the involved light chain level or the difference between involved and uninvolved light chain; the light chain level determines the prognosis and response to therapy; if light chain levels are not elevated at diagnosis, it is probably not AL amyloidosis

Prognosis of the disease: there are many staging systems, but the speaker uses Mayo 2012 model; does not require echocardiography and bone marrow evaluation; requires only 3 blood tests, including the cardiac troponin test, N-terminal-pro hormone BNP (NT-proBNP) test, and the free light chain difference; the prognosis is driven by severity of cardiac involvement; the stages are highly predictive

Therapy for amyloidosis: historically, stem-cell transplantation was the most effective; patients show good response and prolonged progression-free survival (PFS), but currently only about 20% to 25% of patients are eligible for transplantation; if a patient is eligible for transplantation, then complete remission with 15-yr median survival, very good partial response (VGPR) with a 9-yr median survival may be seen; therapy-related mortality is ≈3%; eligibility criteria for transplantation include physiologic age ≤70 yr, reasonable performance status; adequate heart function with systolic blood pressure >90 mm Hg, troponin levels that are not elevated, and absence of significant renal impairment (creatinine clearance <30 mL/min); New York Heart Association Class I and II are eligible; 75% to 80% of patients are ineligible for transplant therapy and require systemic chemotherapy

Systemic chemotherapy for amyloidosis: years ago, melphalan with oral dexamethasone was the medical treatment for amyloidosis; bortezomib is currently the most important agent for treatment of light chain amyloidosis; in a randomized clinical trial, it was observed that the addition of bortezomib to the above therapeutic regimen increased the response depth, VGPR or better, and improves PFS; in the United States, oral melphalan is not used much, and the regimen is more likely to be bortezomib plus cyclophosphamide; dexamethasone doses in amyloidosis are not the same as in myeloma; patients with heart failure or nephrotic syndrome with low albumin should not receive 40 mg/wk of dexamethasone because of extreme fluid retention; 20 mg/wk is administered initially and likely reduced over time

Study: in a study published in Blood, the researchers found that stage of the disease determined outcome; stage was dependent on how early the diagnosis was made; it showed delayed diagnosis can result in progressive deposition of amyloid in the heart and growth of the clone leading to higher levels of light chain, resulting in a higher stage of disease; with earlier diagnosis in patients with less cardiac involvement there was 80% survival at 100 mo; if the diagnosis is later and there is elevated NT-proBNP median survival is 4 mo; the difference between involved and uninvolved serum free light chains (DFLC) of 20 mg/L is another criterion that has been described; a difference of <10 mg/L is associated with better prognosis; hence, early diagnosis before cardiac involvement, followed by therapy to reduce DFLC to the lowest levels are the aims of therapy

Chemotherapy regimens

CyBorD: CyBorD (cyclophosphamide 500 mg/wk, bortezomib 1.3 mg/wk subcutaneously, and dexamethasone 20 mg/wk) was the standard of care in the US until the introduction of daratumumab; stage is still important; in patients with end-stage organ failure, amyloidosis is irreversible

Ixazomib: this is another proteosome inhibitor used in the treatment of amyloidosis; in a small study, it was noted that the maximum tolerated dose was 4 mg/wk (dose given in myeloma); the overall response rate was 52%, VGPR or better was 43%, but the PFS was short and there was significant toxicity; this medication is still suitable for a nonambulatory patient

Carfilzomib: this has also been used for amyloidosis management but is cardiotoxic; it can cause hypertension, dyspnea, and fluid retention; 70% of patients with amyloidosis have cardiac involvement; speaker uses carfilzomib in patients with no cardiac involvement, such as those with amyloid neuropathy, in which bortezomib cannot be used because of its neurotoxicity

Ixazomib-dexamethasone vs physician’s choice: in a trial presented in 2019, combination of ixazomib and dexamethasone improved a composite endpoint of death and organ failure compared with physician’s choice of agent; ixazomib- dexamethasone improved the duration of survival and vital organ function, time to next therapy, complete response rate, and duration of response; in amyloidosis, deposition of light chains in tissue is more important than tumor mass, so the goal of therapy is to obtain a deep response

Genetics in amyloidosis: t(11;14) is a translocation found in 15% of patients with myeloma and 50% of patients with amyloidosis; response to bortezomib and survival is lower in a patient who has the t(11;14) gene translocation; response to transplantation is the same in patients irrespective of the presence of t(11;14); patients with the t(11;14) translocation are potential candidates for off-label use of venetoclax; venetoclax, active in patients with myeloma who have the t(11;14) translocation, has also been shown to be active in patients with amyloidosis who have the t(11;14) translocation

Daratumumab: the first approved drug for treatment of AL amyloidosis; early data was on relapsed/refractory amyloidosis cases; the drug is administered weekly for the first 8 wk then alternate weeks for another 8 doses and, after 24 wk, 1 dose every 4 wk, subcutaneously or intravenously; in the abovementioned case series, daratumumab showed high response; in a trial recently approved by the Food and Drug Administration, for biopsy-proven, mass spectroscopy-confirmed AL amyloidosis, previously untreated patients with cardiac stages I to IIIa (ie, patients with NT-proBNP >8500 ng/L were excluded) were given CyborD regimen or CyborD regimen plus daratumumab subcutaneously in standard myeloma therapy; in an additional maintenance phase, patients received daratumumab every 4 wk until 24 mo; the daratumumab-containing regimen had improved and more rapid responses

Other medications: pomalidomide 2 mg/day has been used as second-line therapy for patients with AL amyloidosis who do not respond to daratumumab-bortezomib-based regimens but it can cause cardiotoxicity; it causes increase in dyspnea, weight, and fluid retention; there are also hematologic and nonhematologic Grade 3 toxicities

Diagnostic workflow: if there is clinical suspicion of amyloid (eg, MGUS, smoldering myeloma, MGUS neuropathy, smoldering with fatigue or edema), a serum and urine immunofixation and free light chain assay must be obtained; if monoclonal protein is present, then bone marrow biopsy and fat aspiration should be obtained to stain for Congo red; if positive for amyloid, mass spectroscopy should be obtained to identify the type of amyloid; if it is TTR amyloid, then consider referral as some of these patients can have inherited or familial amyloid; gene sequencing is indicated; if the patient is negative for amyloid in the bone marrow or fat and clinical suspicion is low, the evaluation can be stopped; if clinical suspicion is high, then organ biopsy must be considered (eg, kidney, liver, nerve, heart); if the organ biopsy is positive for amyloid, then mass spectroscopy must be obtained to identify the type of amyloidosis; if there is no monoclonal protein, AL amyloidosis can be ruled out; the speaker suggests obtaining Tc-99m PYP to screen for senile cardiac amyloid because if positive, TTR amyloidosis is likely to be the cause of cardiac amyloid; gene sequencing can rule out inherited cardiomyopathy; 4% of Blacks in the US carry a gene for inherited cardiac amyloidosis; looking for mutations is relevant but if a negative result is obtained and the clinical suspicion is low, then rule out amyloid; if there is a patient with an incidental finding of amyloid in the skin, colon, or bladder, further assessment may be done but it could also be localized amyloid deposition

Treatment guidelines: if the patient is transplant eligible, the speaker recommends daratumumab, cyclophosphamide, and bortezomib and stem-cell collection and transplantation if the patient is eligible; if VGPR or better is achieved, the patient can be observed and no maintenance therapy needed; if VGPR is not achieved, second-line therapy is to be administered so that a VGPR is achieved; if patient is ineligible for transplantation, the speaker recommends daratumumab, cyclophosphamide, and bortezomib-dexamethasone; if a VGPR is achieved, no maintenance therapy is needed, but daratumumab is given monthly for 24 mo; if VGPR is not achieved, then a second-line therapy needs to be administered; if patients have not achieved VGPR with induction, assess if they were previously administered daratumumab or bortezomib; if they are not bortezomib-refractory after receiving daratumumab, then they need bortezomib-based regimen; and if they are not daratumumab-refractory, they need to be given daratumumab; salvage stem-cell transplantation can be used; carfilzomib can be used, venetoclax can be used in t(11;14) translocation-positive cases; bendamustine has also been shown to be effective in amyloidosis

Readings

Daratumumab for the Treatment of Patients With AL Amyloidosis - Full Text View - ClinicalTrials.gov. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02841033. Published 2021; Gertz MA, Lacy MQ, Dispenzieri A, et al. Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis. Bone Marrow Transplant. 2013; 48(4):557-561. doi:10.1038/bmt.2012.170; Giovanni Palladini, Paolo Milani, Giampaolo Merlini. Management of AL amyloidosis in 2020. Blood. 2020; 136 (23): 2620–2627. doi: https://doi.org/10.1182/blood.2020006913; Kelsey A, Smith DH, Meng J, et al. Amyloidosis: A story of how inframammary erosions eclipsed inconspicuous periorbital ecchymoses. Int J Womens Dermatol. 2016 Mar 2; 2(1):18-22. doi:10.1016/j.ijwd.2015.11.001; Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012; 30(9):989-995. doi:10.1200/JCO.2011.38.5724; Manwani R, Mahmood S, Sachchithanantham S, et al. Carfilzomib is an effective upfront treatment in AL amyloidosis patients with peripheral and autonomic neuropathy. Br J Haematol. 2019; 187(5):638-641. doi:10.1111/bjh.1612; Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol. 2011; 29(14):1924-1933. doi:10.1200/JCO.2010.32.2271; Poterucha TJ, Elias P, Bokhari S, et al. Diagnosing transthyretin cardiac amyloidosis by technetium Tc 99m pyrophosphate: A test in evolution. JACC Cardiovasc Imaging. 2021;14(6):1221-1231. doi:10.1016/j.jcmg.2020.08.027; Wisniowski B, Wechalekar A. Confirming the diagnosis of amyloidosis. Acta Haematol. 2020; 143(4):312-321. doi:10.1159/000508022; Xu L, Su, Y. Genetic pathogenesis of immunoglobulin light chain amyloidosis: basic characteristics and clinical applications. Exp Hematol Oncol 10, 43 (2021). https://doi.org/10.1186/s40164-021-00236-z.

Disclosures

Dr. Gertz reported nothing relevant to disclose. Members of the planning committee reported nothing relevant to disclose. In his lecture, Dr. Gertz presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Gertz was recorded virtually on January 23, 2021, at the 9th Annual Winter Hematology Conference, presented by Eastern Virginia Medical School. For information on future CME activities from this presenter, please visit evms.edu/education/cme. Audio Digest thanks Dr. Gertz and Eastern Virginia Medical School for their cooperation in the production of this program.

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