Clinical Outcomes and Disease Progression after Daratumumab-Based Treatment in Primary Amyloidosis

INTRODUCTION Standard treatment for light chain (AL) amyloidosis includes triple therapy with Bortezomib, Cyclophosphamide and Dexamethasone (CyBorD); however, desired hematologic and organ response rates are yet to be achieved. Daratumumab, an anti-CD38 monoclonal antibody with a favorable profile and demonstrated efficacy in patients with multiple myeloma[1], has been evaluated as breakthrough therapy in the ANDROMEDA trial[2]. We conducted a retrospective cohort study of patients receiving CyBorD and Dara-CyBorD to evaluate clinical outcomes, all-cause mortality, and the extent of cardiac and renal damage in patients with AL amyloidosis. METHODS An observational, retrospective analysis was conducted using TriNetX, a repository of EHR data of over 100 million patients. Data was queried from de-identified patient encounter diagnoses, procedures, medications, and laboratory values, exempt from institutional review board review. Adult US patients with light chain amyloidosis were included. Patients with prior history of cancer diagnosis, HIV infection, liver disease, and dialysis were excluded. The control group consisted of patients prescribed CyBorD after diagnosis. The experimental group consisted of patients prescribed exclusively Dara-CyBorD. Using a 1:1 nearest neighbor greedy matching algorithm, we propensity matched for demographics, comorbidities (multiple myeloma, monoclonal gammopathy, heart failure, ischemic heart disease, hypotension, kidney disease, diabetes, hyperlipidemia, and hypothyroidism), glomerular filtration rate and serum creatinine, medications (antihypertensives and immunosuppressants), and adverse socioeconomic determinants of health. Clinical outcomes (rates of hospitalization, intensive care unit [ICU] admission, and all-cause mortality) and progression of cardiac and renal disease were assessed at 1, 3 and 5 years of beginning treatment. Cox proportional, with Hazard Ratios (HR) and 95% confidence intervals (95% CI), and Kaplan-Meier analyses were performed within the TriNetX Analytics Platform. RESULTS A total of 643 patients were included for each arm. In the control arm, patients were at greater risk of hospitalization (324/643, 50.39%), ICU admissions (116/643, 18.04%), and mechanical ventilation (65/643, 9.80%) compared to the daratumumab arm, which saw fewer hospitalizations (276/643, 42.92%; HR 0.74, 95%CI 0.64-0.88), admissions to the ICU (92/643, 14.31%; HR 0.75, 0.57-0.99), and mechanical ventilation (35/643, 5.44%; HR 0.53, 0.35-0.81). The CyBorD group also experienced greater rates of mortality at 1 year (181/643), 3 years (268/643), and 5 years (305/643) compared to Dara-CyBorD at 1 year (96/643; HR 0.50, 0.39-0.64), 3 years (159/643; HR 0.60, 0.49-0.73), and 5 years (169/643; HR 0.61, 0.51-0.74). The daratumumab-based treatment group demonstrated a significantly higher survival probability (57.35%) compared to the control group (42.88%) by the end of the study period (p<0.01). No significant difference was observed in instances of heart failure, arrythmia, conduction disorders, hypertensive disease, or pulmonary heart disease between the two groups. For renal outcomes, mean eGFR in the CyBorD group was 49.457 compared to 56.275 in the Dara-CyBorD group (p<0.01). Mean serum creatinine in the CyBorD group was 2.17 compared to 1.92 in Dara-CyBorD (p=0.03). The mean blood urea nitrogen in the control arm was 23.347 compared to 18.619 (p<0.01), and mean serum albumin in the CyBorD group was 3.28 compared to 3.471 in the Dara-CyBorD (p<0.01). Of the control patients, 76/669 went on to require dialysis compared to 48/669 (HR 0.63, 95% CI 0.45-0.89) in the experimental arm. CONCLUSION Our findings provide evidence of crucial benefits that stem from the addition of Daratumumab to standard therapy for AL amyloidosis. Further trials are warranted to determine the generalizability and potential side effects of this regimen.