Introduction:Light chain (AL) amyloidosis is a rare clonal plasma cell disorder characterized by the organ deposition of amyloid derived from misfolded immunoglobulin light chains. The involvement of vital organs, especially the heart, results in severe morbidity and high early mortality. Diagnostic delays of greater than 1 year from clinical evidence of AL have been reported in surveys and retrospective single-center studies. Earlier diagnosis prior to developing advanced organ dysfunction is a key unmet need in AL. To detect patients earlier, a better understanding of the patterns of AL-related signs/symptoms (AL-S/Sx) and healthcare utilization preceding AL amyloidosis diagnosis is necessary.
Methods: Using the Optum De-Identified Clinformatics® Data Mart healthcare claims database (Optum), we identified US commercially-insured patients who had one inpatient code or two outpatient codes of ICD-9-CM 277.30 or ICD-10-CM E85.81, E85.89, or E85.9 and treatment with one multiple myeloma drug within 90 days of diagnosis (01Jan06-31Dec18). Twenty-three AL-S/Sx were defined with sets of diagnosis codes, flagged in prior condition lists, and grouped by system affected (cardiac, nervous, renal/ureter, gastrointestinal, or other). The time between the first occurrence of each symptom and AL diagnosis was summarized and healthcare utilization patterns were described to better characterize the patient journey to diagnosis.
Results: Among 1313 AL patients, the median time from the first potential AL-S/Sx to AL diagnosis was 2.5 years. The most common AL-S/Sx were malaise/fatigue (53%), edema and swelling (57%), dyspnea (53%), and abdominal pain (52%), which occurred a median of 1-1.8 years prior to diagnosis. Arrhythmia (51%), cardiomegaly (27%), and cardiomyopathy (21%) were identifiable between a median of 1-1.5 years before diagnosis. Chronic kidney disease (45%) and edema (57%) were seen a median of 2.3 years prior to diagnosis. Patients with a first symptom of nephrotic syndrome presented less than 1 year before diagnosis. Peripheral nerve disease (46%), neuralgias (14%), and paresthesia/anesthesia (20%) appeared a median of 2.8 years prior to diagnosis. The cumulative incidence of each AL-S/Sx by organ system in the 5 years prior to diagnosis is shown in Figure 1. Sequencing of symptoms varied greatly among patients. The most common first symptoms in the sequences were abdominal pain, malaise/fatigue/weakness, peripheral nerve disease, and arrhythmia. Between initial AL-S/Sx and diagnosis, 20% of patients had 3 or more ER visits and 16% had 3 or more hospitalizations. More than 90% of patients visited 5 or more provider types between the first AL-S/Sx and AL diagnosis, with the most frequent specialties visited being cardiology (67%), hematology/oncology (43%), and gastroenterology (40%). About one quarter of patients had a monoclonal gammopathy detected at a median of 1 year prior to diagnosis; detailed analyses of this cohort will be presented at the meeting.
Conclusion: AL patients have a prolonged prodrome, including evidence of cardiac and renal dysfunction, with 50% of patients with a first AL-S/Sx observed more than 2.5 years before AL diagnosis. Only one-quarter of patients had a monoclonal protein detected before diagnosis, indicating a low level of suspicion for AL. Limitations of this study include underestimation of AL S/Sx if diagnosis codes are underutilized in claims. Future studies will use controls to understand background rates of symptoms. Overall, these findings suggest that novel approaches to early diagnosis have significant potential to improve outcomes in AL.
Figure 1.Cumulative incidence of the first occurrence of potential symptoms prior to the first light chain (AL) amyloidosis diagnosis
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