Jonathan L. Kaufman, MD

AMYLOIDOSIS REMAINS a challenging and nuanced diagnosis. At the 2017 Debates and Didactics in Hematology and Oncology Conference, held in Sea Island, Georgia, Jonathan L. Kaufman, MD, discussed his approach to diagnosing amyloid light-chain amyloidosis. Dr. Kaufman is Associate Professor of Hematology and Medical Oncology at Emory University, which sponsored the conference, and Medical Director and Section Chief of the Winship Cancer Institute Ambulatory Infusion Centers, Atlanta. 

Amyloidosis is a protein conformation/deposition disorder. Amyloid light-chain amyloidosis is the most common form of this monoclonal plasma cell disorder, but there are many others, including hereditary amyloidosis (transthyretin-related amyloidosis and others), localized amyloidosis, and secondary amyloidosis, which is associated with chronic inflammatory states. 

In the cascade of molecular events leading to amyloidosis, an amyloid precursor interacts with the microenvironment of the target organs. The oligomers that arise and the persistence of amyloid fibrils in the organs can be toxic. “We are learning that both need to be addressed for better outcomes,” Dr. Kaufman said. 

Symptoms vary, and delay in diagnosis is common. Although symptoms can be informative, clinical manifestations are not reliable indicators as to the type of amyloid accumulation. 

“When the patient has more than 10% plasma cells, by definition, that is multiple myeloma. But the question is, when the patient has 20% to 30% plasma cells, do you treat it as myeloma or as amyloidosis? You make that decision by looking at the symptoms. When symptoms are consistent with myeloma, you manage it as myeloma, and when they are consistent with amyloidosis, you manage it that way,” he said. 

Patients who have myeloma and no organ dysfunction, but have amyloidosis according to their bone marrow biopsy, should be treated according to myeloma guidelines, not those for amyloidosis. On the other hand, the patient who has clear cardiomyopathy or nephrotic-range proteinuria, with 30% plasma cells in the bone marrow but no lytic bone disease or hypercalcemia, should be treated for amyloidosis and not myeloma, he pointed out. 

Common Manifestations 

DR. KAUFMAN further explained that, in terms of kidney dysfunction, amyloidosis is more likely to be associated with nephrotic-range proteinuria, whereas acute kidney injury and elevation of creatinine most likely indicate myeloma. 

The classic cardiac dysfunction associated with amyloidosis is a thickened myocardium, a “speckled” pattern on echocardiogram, and a low QRS complex on electrocardiogram. Liver involvement typically presents as elevated alkaline phosphatase. Gastrointestinal involvement can manifest as dysmotility or bleeding. 

Patients with amyloidosis also can demonstrate classic macroglossia, periorbital edema, and purpura, as well as bilateral carpal tunnel syndrome and peripheral neuropathy. These latter symptoms can be especially informative in cases that are not obvious, he said. 

“It’s especially important to note these symptoms, not when patients have clear-cut amyloidosis but when they have MGUS [monoclonal gammopathy of unknown significance]. That’s when we start thinking about amyloidosis,” he said. 

For amyloidosis vs myeloma, the underlying cause of symptoms is different. In myeloma, it is the overall burden of disease, with monoclonal protein “in and of itself ” rarely causing problems. In contrast, amyloidosis is associated with a much lower tumor burden from which few symptoms arise; the symptoms, instead, stem from M-protein aggregation or antibody activity. 

“These differences are important when we think about what we are targeting,” he said. 

Establishing the Diagnosis 

SERUM PROTEIN ELECTROPHORESIS with immunofixation, urine protein electrophoresis with immunofixation, and serum free light-chain assays are critical in the diagnosis of amyloidosis. If all three are within normal range, there is only a 1% chance the patient has amyloidosis, and further hematologic evaluation is not warranted, according to Dr. Kaufman. 

“In these patients, I will not do a bone marrow biopsy. In my entire career, I have had one patient with three negative tests who had amyloid light-chain amyloidosis,” he said. “Such a patient is more likely to have hereditary or senile cardiac amyloidosis.” 

When the patient has 20% to 30% plasma cells, do you treat it as myeloma or as amyloidosis? You make that decision by looking at the symptoms.

— Jonathan L. Kaufman, MD

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Dr. Kaufman also advised doing a fat pad aspirate and/or bone marrow biopsy, rather than a riskier organ biopsy, on a patient with monoclonal gammopathy suspected of having amyloidosis. In patients who have amyloid light-chain amyloidosis, these “noninvasive” tests will both be negative only 13% of the time. 

“You can make the diagnosis of amyloid light-chain amyloidosis almost 90% of the time without doing a biopsy of the organ,” he reiterated. 

Diagnostic Algorithm for Systemic Amyloidosis 

FOR SUSPECTED amyloid light-chain amyloidosis, the first step is immunofixation of serum and urine and serum free light-chain assay. If these tests are negative, amyloid light-chain amyloidosis is highly unlikely, and the patient should be screened for other types. If the serologic workup is positive, clinicians should obtain fat and bone marrow specimens for Congo red staining. If they are positive, this is proof of systemic amyloidosis. 

“You confirm that it’s light-chain amyloidosis and you start anti–plasma cell therapy,” he said. When there is less certainty, the patient should be referred for genetic and other specialized testing at a referral center. 

If the patient has monoclonal gammopathy—if both the fat pad and bone marrow biopsies are negative—and if there is evidence of organ involvement (such as a thickened myocardium or nephrotic-range proteinuria), the suspected organ should be biopsied. 

Diagnosing Amyloidosis in Patients With MGUS 

PATIENTS WITH MGUS, especially those with a lambda light-chain abnormality, should be screened annually for urine protein/ creatinine ratio and N-terminal pro b-type natriuretic peptide (NT-proBNP) level. When they are elevated (> 0.5 mg/mmol and > 330 pg/mL, respectively), amyloidosis is a possibility, he said. 

“I am not worried that I will miss their monoclonal gammopathy, but I may miss the elevation in their normal urine protein, where we would suspect the development of amyloidosis,” he said. “Also, once a year, I do an NT-proBNP to see if we can identify early evidence of cardiac amyloidosis.” 

Patients with MGUS also undergo serum protein and urine protein electrophoresis with immunofixation and serum free light-chain assays. The sequence of biopsy is bone marrow and fat pad aspirate first, then target organ biopsy. 

“Subtyping of amyloid is critical in any newly diagnosed amyloidosis patient, including patients with MGUS, to obtain the correct diagnosis,” Dr. Kaufman emphasized. “Typically, the only pathologist who can tell you this is a renal pathologist, who has experience with lambda and kappa immunuofluorescence.” 

Sending tissue for subtyping will reveal the difference between the various types of amyloidosis, whether it’s amyloid light-chain, hereditary, or other transthyretin-related amyloidosis. “I’ve stopped trying to figure it out without this test,” he commented. “I send for tissue typing so I can confirm what the underlying protein is.”

Prognostic Tests in Amyloidosis

THE PROGNOSTIC tests are the cardiac biomarkers—NT-proBNP, troponin T, and serum free light-chain assay. The size of the monoclonal protein is not prognostic, but the difference in the involved vs uninvolved free light chain is prognostic. Higher risk is conveyed by NT-proBNP ≥ 1,800 pg/mL, cardiac troponin T ≥ 0.025 ng/mL, and a difference between the involved and uninvolved free light chain ≥ 180 mg/L.

“Using this information, we can predict which patients will do poorly vs those who will do well for a long time,” he said.

Stage IV patients can be subdivided into two prognostic groups as well. Those with resting systolic blood pressure < 100 mm Hg and NT-proBNP ≥ 8,500 pg/mL have median survival times “that we measure in weeks, not months,” he indicated. 

There is also some prognostic value for cytogenetics, especially for the t(11;14) translocation. Patients with this abnormality may respond poorly to bortezomib (Velcade)-based therapy and should be considered for autologous stem cell transplant upfront. Transplant remains an important component of treatment, and eligibility for this procedure is highly individualized. Patients with NT-proBNP > 5,000 pg/mL and cardiac troponin T > 0.06 ng/mL are not candidates, based on a transplant-related mortality risk as high as 30%, compared to about 5% for other patients with noncardiac amyloidosis. 

Targeted Agent in Development

RECENT IMPROVEMENTS in plasma cell–directed therapies have not impacted amyloidosis to the same degree as myeloma. Amyloid light-chain amyloidosis is caused by an accumulation of misfolded proteins (ie, amyloid), resulting in the dysfunction of vital organs. Existing therapies reduce light-chain production, but they do not address the resident amyloid. Approximately 75% of patients do not achieve an organ response and have persistent organ dysfunction. 

To improve organ function, the investigational monoclonal antibody NEOD001 specifically targets the amyloid that accumulates in patients with amyloid light-chain amyloidosis. In a phase I/II trial of induction therapy plus NEOD001, a 53% response rate and “dramatic” and prompt decline in cardiac biomarkers were achieved among 36 previously treated patients with amyloid light-chain amyloidosis and persistent organ dysfunction.¹ Dr. Kaufman said that one of his own patients had a cardiac response and a complete hematologic response, which made her eligible for transplant. ■

DISCLOSURE: Dr. Kaufman reported no conflicts of interest.

REFERENCE

1. Gertz MA, Comenzo RL, Landau H, et al: NEOD001 demonstrates organ biomarker responses in patients with light chain amyloidosis and persistent organ dysfunction: Results from the expansion cohort of a phase 1/2 study. 2016 ASH Annual Meeting. Abstract 644. Presented December 5, 2016.