Multiple myeloma (MM) is a hematologic malignancy that causes multiple organ dysfunction through the clonal proliferation of plasma cells that produce monoclonal proteins. This disease is characterized by several manifestations related to bone marrow invasion of plasma cells, excessive production of monoclonal proteins (light or heavy chains), and immunodeficiency. Amyloidosis is a rare systemic disease where various low-molecular-weight protein subunits circulating in plasma form non-soluble fibrils in the form of β-pleated sheets and are deposited in the extracellular tissue. Immunoglobulin light chain (AL) amyloidosis is caused by the deposition of light chain of immunoglobulins or their fragments. The disease subtypes are primary amyloidosis, which is not caused by any underlying disease, and secondary amyloidosis in association with MM. The diagnosis and treatment of MM-associated AL amyloidosis can be delayed owing to its various non-specific manifestations, which significantly increases the mortality rate, especially in elderly patients.
An unusual association of mild MM and rapidly progressive AL amyloidosis with multi-organ involvement has been rarely reported. Herein, we describe the case of a 77-year-old woman who developed MM-associated AL amyloidosis involving the heart, kidneys, and peripheral nerves.
2 Case presentation
A 77-year-old female patient visited the renal clinic with complaints of generalized edema and dyspnea (New York Heart Association class III). The patient developed edema, ascites, and pleurisy while receiving antibiotics (ceftriaxone and meropenem) at another hospital for bacterial sepsis three weeks before the visit. Her clinical symptoms did not improve with intravenous administration of diuretics and albumin; therefore, the patient was transferred to our clinic. At the time of admission, her blood pressure (BP), pulse rate, respiration rate, and body temperature were 124/80 mm Hg, 116 beats/min, 20 breaths/min, and 36.5°C, respectively. The patient was conscious but chronically ill. A medical history assessment indicated that the patient had been treated for essential hypertension for 30 years. However, there was no history of specific disease, such as diabetes mellitus or chronic liver disease. Chest auscultation revealed regular heart beats and decreased breathing sounds in both lung fields. Abdominal examination revealed moderate distension and shifting dullness but no hepatosplenomegaly. She also had moderate bilateral pretibial pitting edema.
The results of the peripheral blood examination, serum biochemistry test, and urinalysis at the time of admission are presented in Table 1. The preliminary laboratory tests showed no specific abnormalities other than mild anemia, severe hypoalbuminemia, and nephrotic-range proteinuria. The estimated glomerular filtration rate calculated by the Chronic Kidney Disease-Epidemiology Collaboration equation was 54 mL/min/1.73 m2. The urinary protein excretion, creatinine (Cr) clearance, and selectivity index of proteinuria were 2,934 mg/day, 35.5 mL/min/1.73 m2, and 0.01, respectively. The serum immunological tests were negative for Venereal Disease Research Laboratory, hepatitis B surface antigen, anti-hepatitis C antibody, anti-human immunodeficiency virus antibody, and anti-nuclear antibody. Chest radiography revealed bilateral pleural effusions. The size and shape of both kidneys were normal on abdominal ultrasonography. The echogenicity of renal parenchyma increased, and massive ascites was observed in the abdominal cavity. A low-voltage QRS complex and prolongation of corrected QT interval (471 ms) were present on the limb leads of electrocardiography (ECG). Transthoracic echocardiography revealed concentric hypertrophy of the left ventricle (septal and free wall thicknesses of 16.7 mm and 17.1 mm, respectively), diastolic dysfunction, ejection fraction of 67.3%, and pericardial effusion. Sparkling and granular textures were observed on the thickened ventricular wall (Fig. 1A–C). Positron emission tomography (PET)-computerized tomography scan using 18F-fluorodeoxyglucose showed uneven fluorodeoxyglucose uptake with a maximum standardized uptake value of 4.95 in the left ventricular wall (Fig. 2). Serologic markers of myocardial injury including N-terminal pro-B type natriuretic peptide (NT-proBNP), creatine kinase-muscle brain fraction, and high-sensitivity troponin T, were all elevated (Table 1). These findings were highly suggestive of heart failure with a preserved ejection fraction associated with amyloid cardiomyopathy.
Table 1 -
Laboratory findings of the patient at the time of admission.
|Complete blood count
| White blood cells (/μL)
|| IgG (mg/dL)
| Hemoglobin (g/dL)
|| IgA (mg/dL)
| Platelet (×103/μL)
|| IgM (mg/dL)
| ESR (mm/h)
|| C3 (mg/dL)
|| C4 (mg/dL)
| Total protein (g/dL)
|| beta2-microglobulin (mg/L)
| Albumin (g/dL)
| BUN (mg/dL)
|| NT-proBNP (pg/mL)
| Cr (mg/dL)
|| CK-MB (ng/mL)
| Cystatin-C (mg/L)
|| hs-TnT (ng/mL)
| Ca (mg/dL)
||Free LC analysis
|| Serum κ (mg/L)
| Red blood cells (/HPF)
|| Serum λ (mg/L)
| White blood cells (/HPF)
|| Urine κ (mg/L)
| Protein/Cr (mg/g)
|| Urine λ (mg/L)
BUN = blood urea nitrogen, C = complement, Ca = calcium, CK-MB = creatine kinase-muscle brain fraction, Cr = creatinine, ESR = erythrocyte sedimentation rate, HPF = high-power field, hs-TnT = high sensitivity troponin T, Ig = immunoglobulin, κ = kappa, λ = lambda, LC = light chain, NT-proBNP = N-terminal pro-B type natriuretic peptide.
The patient underwent a continuous intravenous infusion of loop diuretics (furosemide, 10–20 mg/hour) combined with oral administration of angiotensin-converting enzyme inhibitor immediately upon hospitalization. Serum and urine protein immunofixation electrophoreses were performed owing to suspected dysproteinemia, and the results suggested monoclonal gammopathy of immunoglobulin G/light chain (LC) -lambda. In serum- and urine-free LC assays using immunochemical techniques, concentrations of both free LC-kappa and free LC-lambda increased (Table 1). The free LC-kappa to LC-lambda ratios of serum and urine specimens were 0.08 (reference range, 0.26–1.65) and 0.18 (reference range, 2.04–10.37), respectively. Subsequent bone marrow biopsy showed 30% plasmacytosis and scattered plasma cells with positivity for cluster of differentiation 138 (Fig. 3A–D).
On the fifth hospital day, a percutaneous kidney biopsy was performed. Light microscopy showed global or nodular sclerosis in nine of 29 glomeruli obtained, and increased amorphous deposits within the mesangial matrix were positive for Congo red stain (Fig. 4A–C). Staining observed by immunofluorescence microscopy suggested preferential deposition of LC-lambda in the glomerulus (Fig. 4D, E). Non-branching amyloid fibrils with an irregular arrangement were identified on electron microscopy (Fig. 4F). Supportive therapies were continued during the diagnostic processes, including administration of diuretics (furosemide, spironolactone, and thiazide), salt-poor albumin, and vasopressors (norepinephrine, vasopressin, and dobutamine). However, generalized edema and hypotension (mean BP <70 mm Hg) did not improve.
On the eighth hospital day, the patient complained of pain, numbness, and paresthesia in the lower extremities and motor weakness of the upper and lower extremities, leading to difficulties in independent mobility. Sensorimotor polyneuropathy of the axonal type was demonstrated based on the nerve conduction studies of both lower extremities. At this point, circulating NT-proBNP (6833 pg/mL), high-sensitivity troponin T (0.3 ng/mL), and serum Cr level (4.3 mg/dL) increased compared to those at the time of admission. Continuous renal replacement therapy (CRRT) was attempted as azotemia and hypervolemia worsened. However, severe hypotension (mean BP <65 mm Hg) and alteration of consciousness developed immediately after CRRT initiation; therefore, treatment was discontinued. From the 10th hospital day, melphalan (10 mg/m2) and dexamethasone (20 mg/day) were administered for four consecutive days as a combination chemotherapy for AL amyloidosis with oral dexamethasone planned every four weeks. On the 20th hospital day, the levels of plasma NT-proBNP and serum Cr were aggravated at 35,000 pg/mL and 7.5 mg/dL, respectively. The sequential organ failure assessment (SOFA) score was 12 points (range, 0–24). The patient did not show any further improvement and died of multiple organ failure on the 28th hospital day after refusing additional life-sustaining therapy.
MM is a plasma cell dyscrasia that causes excessive monoclonal immunoglobulin production, chronic anemia, skeletal lesions, renal failure, and recurrent infections. MM-associated kidney diseases include cast nephropathy, AL amyloidosis, monoclonal immunoglobulin deposition disease, cryoglobulinemic glomerulonephritis, and proliferative glomerulonephritis. AL amyloidosis occurs in 10% to 15% of MM cases. Amyloid nephropathy generally presents with asymptomatic proteinuria, nephrotic syndrome, and acute or chronic renal failure. The clinical presentations of renal amyloidosis are primarily determined by the physicochemical properties of protein precursors, the location of amyloid fragments deposited within the renal parenchyma (e.g., blood vessels, tubules, interstitium, and glomeruli), and the extent of the amyloid deposits.[7,8] In MM patients, the LC-lambda is detected more frequently than the LC-kappa at a 3:1 ratio, and patients with AL-lambda have a lower serum Cr concentration and increased urinary protein excretion compared to those with AL-kappa. In our case, the initial presentations suggested secondary nephrotic syndrome caused by the glomerular deposition of amyloid fibrils derived from the immunoglobulin G/LC-lambda. When the patient first visited our clinic, the serum Cr level (1.0 mg/dL) was within the normal range. However, estimated glomerular filtration rate as well as Cr clearance decreased, and the serum cystatin-C concentration (2.43 mg/L) increased, indicating renal insufficiency (Table 1). In this patient, the serum Cr level was lower than expected given the decrease in kidney function and might be associated with sex (female), age (elderly), and undernutrition.
Cardiac output decreases when AL amyloidosis involves the heart, leading to development of systemic symptoms, such as fatigue, general malaise, and congestive heart failure symptoms (for example, dyspnea on exertion and orthopnea). In some patients, signs of right heart failure, such as pitting edema in the lower extremities, hepatomegaly, and ascites, can manifest as the predominant symptoms. Low-voltage QRS complex and pseudo-infarcts are observed in the 12-lead ECG, and intracardiac conduction defects can occur. In the early stages of the disease, echocardiography shows diastolic dysfunction; however, amyloid infiltration eventually leads to prominent systolic dysfunction and restrictive cardiomyopathy. Additionally, cardiac echogenicity increases, and characteristic granular and sparkling textures are present in the myocardium. Increased concentrations of natriuretic peptides (for example, NT-proBNP) in the serum are considered sensitive indicators of cardiac amyloidosis regardless of clinical progression. Cardiac troponins are specific biomarkers that reflect small vascular ischemia or direct injury of the myocardium, and the levels are commonly elevated in patients with cardiac amyloidosis. Thus, these cardiac biomarkers are used as risk assessment indicators in the Mayo Clinic 2012 staging system, which predicts the overall survival of patients with AL amyloidosis. Recently, an imaging diagnostic modality to identify amyloid deposits in the heart using fluoride-labeled radioisotopes as PET tracers was reported.[11,12] In this patient, the standardized uptake value was increased along the left ventricular wall. These radionuclide techniques are expected to be rational alternatives to contrast-enhanced magnetic resonance imaging (MRI) for the diagnosis of cardiac amyloidosis in patients with renal insufficiency. In our case, an invasive endomyocardial biopsy was not performed; however, classic symptoms of heart failure, including ECG abnormalities and characteristic echocardiography, and PET- computerized tomography findings were consistent with a clinical diagnosis of amyloid cardiomyopathy.
At the time of admission, clinical signs of end-organ damage essential for a MM diagnosis, such as hypercalcemia, anemia, osteolytic lesions, and renal failure, were not prominent. However, dysproteinemia was suspected based on the immunologic test results, including serum and urine protein electrophoreses. The presence of monoclonal gammopathy, bone marrow biopsy results, and delayed manifestations of end-organ dysfunction satisfied all the diagnostic criteria of MM based on International Myeloma Foundation guidelines.
Treatment of plasma cell disorder, which is an underlying disease, where alkylating agents are administered to inhibit the production of monoclonal proteins and remove plasma cell clones is used to treat MM-associated AL amyloidosis.[1,7] The traditional treatment is combined chemotherapy consisting of melphalan and prednisone or dexamethasone. Autologous stem cell transplantation can follow high-dose melphalan in patients aged <70 years who do not show clinical evidence of cardiac involvement.[1,7] Additionally, supportive therapy is required to maintain the functions of clinically involved organs. When generalized edema develops in patients with AL amyloidosis that invaded the heart and kidneys, as in our case, the primary treatment involves limiting salt intake (≤2 g/day) and administering loop diuretics. If heart failure becomes evident, administration of calcium channel blockers must be avoided. Administering beta-receptor blockers has fewer therapeutic benefits, whereas it has a high risk for an excessive decrease in arterial BP. Gradual titration of angiotensin-converting enzyme inhibitors, starting with a low dose, is recommended as AL amyloidosis patients are less tolerant. Chronic anticoagulation therapy should be initiated to prevent ischemic stroke if atrial fibrillation is demonstrated.
In patients with MM, concurrent amyloidosis is a significant indicator of an unfavorable prognosis.[15,16] The median survival period of AL amyloidosis patients with nephrotic syndrome is 16 months. However, the association between the degree of urinary protein excretion and survival period has not been established. Patients with AL-lambda have a worse prognosis than those with an AL-kappa phenotype. Chronic renal failure, which develops in 50% of AL amyloidosis patients, is an independent prognostic factor for adverse outcomes. AL amyloidosis with cardiac involvement is a predictor of dismal prognosis, and in particular, congestive heart failure decreases the median survival time of patients to less than six months. Therefore, in this patient who demonstrated several high-risk prognostic signs, the probability of clinical improvement was very low. Our patient was afflicted with heart failure, nephrotic syndrome, and progressive azotemia, and her severe hypervolemia did not improve even with intensive diuretic therapy. The application of CRRT could not continue due to hemodynamic instability. Combination chemotherapy initiated after histologic demonstration of AL amyloidosis did not show additional therapeutic effects. These circumstances ultimately led to early mortality due to multiple organ failure.
In summary, we present the case of a 77-year-old female patient who was diagnosed with MM-associated AL amyloidosis involving the heart, kidneys, and peripheral nerves after systemic evaluations, including cardiac and hematologic workups, a kidney biopsy, and nerve conduction studies. Based on the clinical evolution of this patient, MM-associated AL amyloidosis has a high risk of rapidly progressing to life-threatening multiple organ failure. Therefore, if AL amyloidosis is suspected, prompt assessment of organ dysfunction and early initiation of intensive care including proper chemotherapy are required.
Conceptualization: In Hee Lee.
Data curation: Chang-Yeon Kim, Sungmin Kang, Min-Kyung Kim.
Formal analysis: Dong Jik Ahn, In Hee Lee.
Methodology: In Hee Lee.
Validation: Dong Jik Ahn, Min-Kyung Kim.
Writing – original draft: In Hee Lee.
Writing – review & editing: In Hee Lee.
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