Retrospective Study of the Efficacy of Bortezomib in Primary Systemic Amyloidosis.
Authors: Buadi Francis , Lacy Martha Q. , Dispenzieri Angela , Kumar Shaji , Hayman Suzanne , Short Kristen E Detweiler , Dingli David , Zeldenrust Steven R. , Greipp Philip R. , Lust John A. , Russell Stephen J. , Kyle Robert , Rajkumar Vincent , Gertz Morie A 
Published: October 2019

Abstract
Abstract 4953

Introduction
Primary systemic (AL) amyloidosis occurs as a result of the production a monoclonal protein by a clonal plasma cell or B-cell proliferative disorder. Reduction or complete eradication of the underlying clonal cell disorder is essential for an organ response. Melphalan/ dexamethasone or high dose chemotherapy with autologous hematopoietic stem transplant is currently considered the standard of care. Bortezomib a proteosome inhibitor is effective in reducing or eradication clonal plasma cells and has been shown to produce high complete hematologic response (CHR) rates in multiple myeloma. We therefore hypothesized that Bortezomib will produce a high CHR rate and hence a higher organ response in patients with AL.

Material and Methods
Our amyloidosis data base which is prospectively collected was searched for patients with primary amyloidosis (AL) who were treated with Bortezomib containing regimen during their disease course. We identified 20 patients. We then assessed clinical features, hematologic and organ response based on the amyloidosis consensus working group criteria. We also evaluated overall survival and time to next therapy.

Results
We identified 20 patients who received a Bortezomib containing regimen. The median age at diagnosis was 57 yr (range 43 - 79). There were 12 (60%) males. All patients had clonal plasma cell disorder except one patient with lymphoplasmacytic lymphoma. Median bone marrow plasma cell involvement was 10%. The amyloid protein was Lambda light chain in 12 patients and Kappa in 6 patients. Data was missing in 2 patients. The median serum m-spike was 0.5g/dL (range 0 to 3.5). The median number of organs involved was 1 (range 1 – 4). Nine patients had 2 or more organs involved. The specific organs involved were Kidney (13), Cardiac (12), Nerve (5) and liver (2). Median number of prior regimen was 1(range 0 to 3). Seven patients had received no prior therapy. The remaining 13 patients had received various treatments including oral Melphalan/dexamethasone (9), Lenalidomide/dexamethasone (3), Thalidomide/dexamethasone (1) and one patient who received R-CHOP for underlying lymphoplasmacytic lymphoma. Four patients had received a prior autologous stem cell transplant. The median time form diagnosis to Bortezomib treatment was 5 months. The Bortezomib regimen was mainly Bortezomib/dexamethasone (17patients), Bortezomib/Thalidomide/dexamethasone (1), Bortezomib/cyclophosphamide/dexamethasone (1). The Bortezomib was given mainly in the standard dosing 1.3mg/m2 days 1, 4, 8, and 11. Treatment was well tolerated. Hematologic response was seen in 17 patients including CHR (11), VGPR (3), PR (1), and MR (2). Thus resulting in a better than PR response of 75%. Three patients had no response. The median number of cycles to best hematologic response was 4 (range 1 – 9). The median total number of cycles administered was 4 (range 1 – 10). Organ response was seen in 10 patients (50%). These were mainly partial responses was seen primarily in patients with renal amyloidosis. Median time to next treatment was 7.5 months (95% CI: 4-9). Seven patients have received further therapy after their Bortezomib treatment. Three patients received consolidation treatment with Autologous PBSCT although they had all achieved VGPR or CHR. The other four received salvage chemotherapy for disease progression or lack or response, BMT (1), FCR (1), Pomalidomde/dexamethasone (1) and Melphalan/dexamethasone (1). Median follow up of all patients from diagnosis is 12 months (range 2 – 64). The median survival from diagnosis is estimated at 44.7 months (95% CI; 29.1 – 64.8). Median follow up from Bortezomib treatment is 5 months and median survival from Bortezomib treatment has not been reached.

Conclusion
Bortezomib produced high hematologic response in this population of patients. Organs response was seen in 50% of patients. The durability of these responses is not known, because of the short follow up time. This study suggests that Bortezomib containing regimen may be beneficial in amyloidosis patients. A larger prospective study, looking at single agent Bortezomib or in combination with alkylator agents compared to standard melphalan/dexamethasone or autologous stem cell transplant is needed to help define the role of Bortezomib in primary amyloidosis.

Disclosures
Lacy: celgene: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.