Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis

Abstract

• Single-agent bortezomib produces durable hematologic responses and promising long-term overall survival in relapsed AL patients.• Once-weekly bortezomib is better tolerated and produces similar responses to twiceweekly bortezomib in relapsed AL patients.CAN2007 was a phase 1/2 study of once-and twice-weekly single-agent bortezomib in relapsed primary systemic amyloid light chain amyloidosis (AL) amyloidosis. Seventy patients were treated, including 18 and 34 patients at the maximum planned doses on the once-and twice-weekly schedules. This prespecified final analysis provides mature response and long-term outcomes data after 3-year additional follow-up since the last report. In the once-weekly 1.6 mg/m 2 and twice-weekly 1.3 mg/m 2 bortezomib groups, final hematologic response rates were 68.8% and 66.7%; 80% of patients in each group sustained their response for ‡1 year. One-year progression-free rates were 72.2% and 76.8%. Median overall survival (OS) was 62.1 months and not reached; 4-year OS rates were 75.0% and 63.0%. Low baseline difference in k/l free light-chain level was associated with higher hematologic complete response rates and longer OS. At data cutoff, 40 (57%) patients had received subsequent therapy, including 19 (27%) retreated with bortezomib, 11 (58%) of whom achieved complete or partial hematologic responses. Four patients received prolonged bortezomib for between 3.5 and 5.6 years, with no new safety concerns, highlighting the feasibility of long-term therapy. Single-agent bortezomib produced durable hematologic responses and promising long-term OS in relapsed AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00298766. (Blood. 2014;124(16):2498-2506 IntroductionPrimary systemic amyloid light chain amyloidosis (AL) is a protein misfolding disorder in which a clonal plasma cell dyscrasia results in excessive production of abnormal immunoglobulin light chains.1-4 Extracellular deposition and toxicity of these fibril-forming abnormal light chains can lead to end-organ damage, particularly in the kidneys and heart, 1-4 and death. Suppression of the plasma cell dyscrasia and reduction or elimination of the production of amyloidogenic immunoglobulin light chains is the aim of AL treatment.1 Amyloid deposits can be resorbed and organ function restored on elimination of plasma cells secreting the abnormal light chains.1 Achievement of a hematologic response to therapy, particularly complete response (CR), is associated with improved organ function and prolonged survival. 5-8The plasma cell dyscrasia in AL is similar to that in multiple myeloma (MM).3,9 Thus, therapies that are effective in MM are typically used to treat AL.1 High-dose melphalan followed by stem cell transplantation (HDM-SCT) is highly effective in AL; however, many patients may be transplantation ineligible 10,11 due to age, poor performance status, and multiple organ involvement. Despite improvements in the management of transplantation in AL patients in recent years, the observed transplantation-associa...

A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

“…[17][18][19] The proteasome inhibitor (PI) bortezomib is approved for the treatment of MM and has shown activity in both previously untreated and relapsed/refractory AL amyloidosis (RRAL) patients. 9,10,20 Demonstrating the feasibility and activity of PI therapy, single-agent or combination bortezomib treatment results in unprecedented high hematologic response rates and rapid and durable responses, 9,20,21 and it has been adopted as a front-line therapy for AL amyloidosis. 5,22 However, AL amyloidosis remains a severe condition with a poor prognosis and a median overall survival of approximately 12 months if untreated, 23,24 dropping to 6 months when the heart is affected 25 ; new treatment options are therefore needed.…”

“…4 Although there are no currently approved therapies for patients with relapsed or refractory disease, bortezomib, lenalidomide, and pomalidomide, all of which are approved for the treatment of MM, are effective. 5,[7][8][9][10][11][12] Achievement of a hematologic response is required and predictive of an organ response (which can take up to a year), 13 as well as prolonged survival. 14,15 Response criteria were established in 2005 16 and updated in 2012 based on the difference between levels of involved and uninvolved free light chains (dFLC) 17 ; these updated criteria were later validated.…”

A mouse model recapitulating human monoclonal heavy chain deposition disease evidences the relevance of proteasome inhibitor therapy

“…In a broader view, the intrinsic toxicity for plasma cells of immunoglobulin fragments prone to misfolding and aggregation deserves to be explored in other monoclonal immunoglobulin-related diseases including light chain (AL) amyloidosis and LCDD, in which preliminary studies suggest that bortezomib-based therapy has a strong impact on renal and patient outcomes. 44,[60][61][62] Transgenic mouse models could be of invaluable interest to explore this issue. 36 Altogether, the present transgenic mouse model of HCDD accurately recapitulates the early steps of the human pathology and represents a valuable tool to explore the mechanisms that govern toxicity of truncated HCs and the sequential events leading to glomerular injury in MIDD.…”

What is new in diagnosis and management of light chain amyloidosis?

“…65 Prospective trials and large retrospective series proved the efficacy and tolerability of bortezomib in AL amyloidosis. 66,67 More recently, 2 retrospective series showed unprecedented hematologic response rates (up to 90%, with 60%-65% CRs) in treatment-naive patients receiving CyBorD. 68,69 Subsequently, 2 retrospective matched case-control studies confirmed higher response rates with regimens combining bortezomib, dexamethasone, and alkylating agents (BMDex and CyBorD) compared with standard MDex or cyclophosphamide/ thalidomide/dexamethasone (CTD), but failed to demonstrate an overall survival advantage.…”