AL Amyloidosis with Nephrotic Syndrome: Clinical Response to Treatment Only after a Long-Term Maintenance Therapy with Daratumumab
Authors: Shawayli Hawra , Cherif Honar , Soliman Dina Sameh , Mudawi Deena , Abdalla Elmustafa , Al-Mashdali Abdulrahman , Abdulgayoom Mohammed , Mohamed Shehab 
Published: December 2024

Introduction

Free light chain amyloidosis (AL amyloidosis) is the most common and severe form of systemic amyloidosis. In these disorders, abnormal plasma cells in the bone marrow produce an excess of light chains, which misfold and aggregate into amyloid fibrils. These insoluble proteins deposit in various organs, with the heart and kidneys being most affected. AL amyloidosis should be suspected in cases of non-diabetic nephrotic syndrome and non-ischemic cardiomyopathy.

Despite the use of antimyeloma novel agents, particularly the proteasome inhibitor bortezomib, the response in AL amyloidosis remains suboptimal, with frequent drug toxicity reported compared to myeloma patients. Daratumumab (Dara) targets the CD38 protein expressed on clonal plasma cells in multiple myeloma (MM) and AL amyloidosis.

Methods and Results

A previously healthy 44-year-old woman presented with manifestations of nephrotic syndrome. A urine analysis detected +3 proteinuria, confirming the diagnosis. A kidney biopsy revealed renal AL amyloidosis, global glomerulosclerosis (0/15), segmental glomerulosclerosis (0/15), and no tubular atrophy, interstitial fibrosis, or interstitial inflammation.

Initial workup showed mild anemia with otherwise normal blood values and normal serum calcium. Beta-2 Microglobulin was high (3.59 mg/L) and serum protein electrophoresis showed low albumin with no clear monoclonal band. Urine protein electrophoresis revealed the presence of monoclonal lambda free light chains (FLC). Kappa FLC was 15.8 mg/L, lambda FLC was 186.3 mg/L, and the kappa/lambda ratio was 0.08. A bone marrow aspirate showed cellular marrow with adequate trilineage hematopoiesis and increased plasma cells (~9%). Flow cytometry revealed ~1% lambda monotypic plasma cells with aberrant expression of CD56, CD117, and partial CD20. Biopsy showed increased lambda-restricted monotypic plasma cells, as highlighted by CD138/MUM1/kappa/lambda immunostains and aberrant expression of CD56. The infiltration was estimated at 20-25%. It showed also small blood vessels with walls thickened by a pink, amorphous, waxy substance, positive for PAS stain, amyloid immunostaining, and Congo red with apple-green birefringence under polarized light, staining with lambda light chain consistent with light chain amyloid deposition.

An ultrasound of the kidneys detected increased parenchymal echogenicity.. PET CT confirmed renal involvement by amyloidosis.

The patient started on a daratumumab-based regimen (Dara-bortezomib-cyclophosphamide-dexamethasone) for four cycles. The plasma cell counts in the bone marrow aspirate decreased from 9% to 1%, and biopsy improved to 2-5%. However, kidney involvement showed very marginal improvement, with proteinuria remaining around 8 g/24 hours. The decision was made to continue Dara as a single-agent maintenance therapy based on studies showing the benefit of daratumumab in maintenance (given as SC injections in the standard dose of 1800 mg every 4 weeks). Follow-up after eight cycles and 12 cycles of Dara maintenance showed a dramatic response with the patient becoming euvolemic, a decrease in plasma cholesterol levels from 20 mmol/L to 4 mmol/L, and an improvement of proteinuria to 2 g/24 hours. The patient is continued on Dara as a single-agent maintenance and is being assessed for autologous stem cell transplantation.

Conclusion

The use of daratumumab in the management of AL amyloidosis has significantly improved treatment outcomes, resulting in substantial hematological and organ-specific responses. This patient case demonstrates the potential of daratumumab to provide disease control after long-term therapy even in the absence of early clinical response. Furthermore, it is safe and well-tolerated