The Italian Medicines Agency Prospective Registry of Bortezomib-Based Treatment in AL Amyloidosis

Background: There is no licensed therapy for light chain (AL) amyloidosis; however, bortezomib (B) is considered standard upfront treatment. Existing data on safety and efficacy of B in AL amyloidosis derive from clinical trials and retrospective series from few referral centers and only partly reflect real-world practice. In 2011, the Italian Medicines Agency (AIFA) started a program to grant access to upfront B to patients with AL amyloidosis. Treated patients had to be enrolled in an online registry and prospectively followed during therapy. We report the treatment experience in this real-world setting.

Methods: AL amyloidosis diagnosis required tissue typing with mass spectrometry or immuno-electron microscopy. Patients samples could be sent to the Pavia specialized center for typing, but patients were not treated under the supervision of the referral center. Subjects with multiple myeloma were excluded. Variables were collected at baseline and hematologic and cardiac responses were assessed after 8 weeks (approximately 2 cycles) according to the International Society of Amyloidosis criteria. The cox proportional model has been adopted to assess the risk of treatment discontinuation according to the baseline characteristics.

Results: A total of 754 patients were treated between May 2011 and October 2019 and 605 were included in the analysis. Most common reasons for exclusion were retrospective data collection (45%), and incomplete data set (31%). Median age was 67 years (range 26-89 years). 82% of patients had heart involvement. Cardiac stage was I in 18% of subjects, II in 45%, IIIa in 21%, and IIIb, in 16%. Sixty-seven percent of patients had renal involvement, and 13% and 14% had severe (glomerular filtration rate [eGFR] between 30 and 15 mL/min) and end-stage (eGFR <15 mL/min) renal insufficiency, respectively. Differential free light chain level (dFLC) was >180 mg/L in 41% of cases. Bortezomib was administered with dexamethasone (D) alone in 41% of patients, with cyclophosphamide and D (CyBorD) in 44%, and with melphalan and D (BMDex) in 13% of subjects. Other combinations were used in 2% of patients. In the overall population, the initial dose of B was attenuated (<1.3 mg/m²) in 22% of patients. The proportion of patients receiving attenuated dosage was higher in stage III patients (38%). Fourteen percent of subjects required B dose reduction during therapy, while B dosage could be increased in 7% of patients who started at a reduced dose. A twice-weekly B schedule at treatment initiation was used in 22% of all subjects and in 16% of stage III patients. Fourteen percent of patients initially treated with the twice weekly schedule needed to be shifted to the once weekly schedule. After 8 weeks (approximately 2 cycles) the overall hematologic response rate was 58% (CR 3%, VGPR 20%) and cardiac response was attained in 14% of patients. The median number of cycles performed was 3 (range 1-9), median duration of monitored treatment was 4.3 months. Treatment was discontinued during monitoring due to achievement of satisfactory response or completion of maximum (9) allowed number of cycles in 3% of cases, progression in 14%, death in 8%, and toxicity in 1% of patients. The cause of discontinuation was defined as independent of drug and disease in the remaining 25.1% of subjects. Risk of treatment discontinuation was lower in patients who could tolerate a 1.3 mg/m² dose of B from cycle 1 (HR 0.70, 95%CI 0.54-0.91). Second-line therapy with immunomodulators (most commonly lenalidomide) was started in 14% of patients.

Conclusions: Patients with AL amyloidosis start treatment at an advanced stage and early deaths are common. The rate of severe/end-stage renal failure was higher (27%) than expected, possibly indicating that these patients are less likely to be referred to specialized centers. Remarkably, outside referral centers B is commonly administered with D alone. Dose reductions are frequently applied, but dosage can be escalated during therapy. Response rates at 8 weeks are comparable to those reported in other large studies and early cardiac responses are possible. To the best of our knowledge this is the only study prospectively evaluating treatment with B in a real-world setting. Treatment registries under the supervision of regulatory agencies are precious tools to assess common therapeutic practice in rare disease, to evaluate candidate comparators for future trials, and to assess unmet medical needs.