#6325 A LONG TERM EXPERIENCE OF MANAGEMENT OF BIOPSY-PROVEN RENAL AL AMYLOIDOSIS WITH DARATUMUMAB MONOTHERAPY
Authors: Rabajoli Gianluca , Careddu Andrea , Marchisio Martina , Lalloni Stefania , Morrone Marco , Fenoglio Roberta , Sciascia Savino , Roccatello Dario 
Published: June 2023

Abstract

Background and Aims
Daratumumab is an anti-CD38 monoclonal antibody recently approved as a first-line therapy on top of standard therapy for the treatment of multiple myeloma and AL amyloidosis. The mechanism of action of Daratumumab is based on its ability to bind CD38, a transmembrane receptor expressed in particular by pathogenic plasma cells, inducing their death through multiple intra and extracellular signaling mechanisms and thus interrupting the production of monoclonal light chains and consequently the deposition of new amyloid substance. The following data describe the good results reported by our group and the long-term experience achieved in recent years on the efficacy of daratumumab used in monotherapy.

Methods
This paper describes 17 patients affected by AL amyloidosis who were treated with Daratumumab alone, 24 iv administration at a dose of 16 mg/kg. All of them had an histological confirmation and staging of renal involvement before treatment was started and were ineligible for ASCT A bone marrow biopsy excluded overt multiple myeloma and the patient could either be naïve or refractory. Haematological and organ response was evaluated every 4 infusions by checking NTproBNP, dFLC and FLC ratio, serum creatinine, Upt (24h), serum and urine IF; responses were defined by using the International Society of Amyloidosis extended criteria. When feasable, the patient who underwent the whole cycle of therapy underwent a second kidney biopsy at the end of the treatment.

Results |
mean age at diagnosis was 73 years. 16 out of 17 patients had proteinuria (in the nephrotic range in 11) that was associated with renal function impairment in 11. Two patients were on dialysis at the time of therapy initiation. 9 patient completed the treatment; 13 over 17 underwent at least 12 infusions. At this time, At the 12 th administrations 11 out of 13 pts (84,6%) had an overall hematological response. 6 pts (46,5%) achieved a complete hematological response, 5 pts had a very good partial response (38%), and 2 were non responders (15,5%). As regard to renal response 5/13 had already achieved an organ response; 6 didn't meet renal response criteria yet; the 2 patients who were in dialysis at the time of therapy initiation, remained on dialysis. 1 of them had a complete hematological and cardiac responses, the remaining pt didn't have any response. 7/9 achieved a renal response; the 2 remaining patients who were in dialysis at the time of therapy initiation, remained on dialysis. A significant decrease in 24-hour proteinuria from 6,02 g/24 hours (range 0,8 – 16,8) to 1,28 g/die (range 0,9 – 3,6 gr/die, p &lt; 0.005) with stabilization or improvement of sCr (from 1,66 mg/dl to 1,1 mg/dl, p = 0.17) were observed. 8/9 patients with cardiac involvement obtained at least amelioration. At the end of follow-up (mean 30 months, range 19-46) 5 patients have persistent hematological and renal response. One patient with initial partial response had a relapse and initiated a treatment with Bortezomib plus cyclophosphamide and dexamethasone. Two patients died to COVID infection and cardiovascular disease respectively. The last patient is still alive and is currently being treated with a second line of therapy, because no hematologic or organ response was achieved with Daratumumab. 7 patients underwent a second kidney biopsy at the end of the treatment. Histological findings showed stable deposits in 6 over 7 cases, while the last one showed a reduction in the extention and amount of amyliod deposits.

Conclusion
The optimal management of patients with AL amyloidosis remains to be defined. In particular patients who are ineligible for transplant continue to have a poor outcome. In recent years daratumumab has emerged as an appealing therapeutic alternative as shown by several reports. However, in clinical trials daratumumab was always added to bortezomib, cyclophosphamide and dexamethasone. Our data, based on the real life experience of our center, suggest that daratumumab monotherapy may represent an effective therapeutic option, capable not only of inducing a substantial improvement in the renal status in pretreated or naïve patients, but also of limiting progression of amyloid deposition.