Efficacy and Safety of Bortezomib in Systemic AL Amyloidosis - A Preliminary Report.
Authors: Wechalekar Ashutosh , Gillmore Julian , Lachmann Helen , Offer Mark , Hawkins Philip 
Published: April 2020

Abstract
The prognosis for patients with AL amyloidosis (AL) who have relapsed following conventional treatment or stem cell transplantation has been little studied. Bortezomib (VelcadeTM) potently inhibits the 26S proteosome and has lately been shown to produce useful remissions in ~35–50% patients with relapsed myeloma. Multiple organ impairment in AL is associated with much greater treatment related toxicity than seen with similar regimes in myeloma. Concerns have been voiced regarding the use of bortezomib in AL since ubiquinitin-proteosome inhibition might conceivably influence the intracellular degradation of abnormal amyloidogenic proteins. No clinical studies of bortezomib in AL have yet been reported. We report 18 patients with AL amyloidosis who received bortezomib and were serially evaluated at the UK National Amyloidosis Centre. Median age was 59 yrs (42–73) and bortezomib was given as either 1 or 1.3 mg/m2/dose as a bolus intravenous injection twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period. Nine (50%) received dexamethasone in addition. All patients had evidence of progressive amyloidosis and had relapsed or become refractory to their previous line of treatment; all had previously received thalidomide, either with dexamethasone or cyclophosphamide and dexamethasone. The median number of previous lines of treatment was 3 (range 1–6), number of organs involved by amyloid was 2 (1–4) including the heart in 10 (55%) and end stage renal failure in 4 (22%). The median ECOG performance status was 2. The median follow-up since treatment was 10 months and since diagnosis was 31 months. The median number of bortezomib cycles given was 3 (1–6) with a median dose of 1.3 mg/m2/dose. Haematologic response was classified as the worst of conventional (paraprotein) response using EMBT criteria and serum free light chain response using the following criteria: complete response (CR) - sustained normalisation of clonal FLC isotype and ratio; partial response (PR) - sustained ≥50% reduction in pre-treatment clonal isotype. A haematologic response occurred in 14 (77%) patients, comprising CR in 3 (16%) and PR in 11 (61%). Improvement in amyloidotic organ function occurred in 5 (27%) patients, and regression of amyloid deposits was demonstrated by serial SAP scintigraphy in 2 (11%) cases. There was no evidence of progressive amyloidosis in any of the patients who achieved haematologic PR or CR. The median duration of haematologic response was 5.7 months (95% CI 2–9), and Kaplan Meier estimated median survival of the cohort from treatment was 22 months. Toxicity occurred in 11 (61%) patients, which was ≥grade 3 or necessitated cessation of treatment in 7 (36%). Adverse effects included: peripheral neuropathy (grade 1 or 2 only) in 4 (22%) cases; fluid retention in 3 (16%); thrombocytopenia in 2 (11%); myoclonus, herpes zoster, diarrhoea, hypotension, fatigue and chest infection in 1 (5%) case each. Peripheral neuropathy reversed completely in 3 patients, and there were no treatment related deaths. These preliminary results suggest that bortezomib may be efficacious in a substantial proportion patients with relapsed or refractory AL amyloidosis with an acceptable tolerability and safety profile. Haematologic response translated into improvement in amyloidotic organ function in 27% of the patients, but durability of the responses was relatively short. Bortezomib merits further study as treatment for AL amyloidosis, along with the hope that combination with other agents may improve the durability of response.