LAUSR

In light-chain (AL) amyloidosis, the depth of hematologic response has been shown to be associated with improved survival and organ responses. Bortezomib has been shown to be efficacious in achieving hematologic responses in AL amyloidosis. We conducted a trial utilizing bortezomib with dexamethasone for induction, bortezomib with high-dose melphalan (B-HDM) for conditioning, followed by stem cell transplantation for AL amyloidosis (Clinicaltrials.gov Identifier NCT01083316). The results of this clinical trial with a median follow-up of 36 months have been reported previously (Sanchorawala et al., 2015). We, here in, report the long-term results of this clinical trial, conducted from Jan 2010 to Aug 2013 with a median follow-up of 77.3 months (range, 55.4 to 100.1). The objectives of this follow-up report were to describe long-term survival, hematologic response and relapse rates, progression free survival and median time to organ response for patients treated on this clinical trial. As reported in the prior publication, patients received 2 cycles of induction with bortezomib 1.3mg/m2 and dexamethasone 20mg on day 1, 4, 8, 11 every 21 days followed by conditioning regimen of bortezomib 1mg/m2on day -6, -3, +1, +4 and HDM at 140-200mg/m2 in two divided doses on days -2 and -1 with transplantation of >2.5 x 106 autologous CD34+ cells/kg on day 0. Thirty-five patients were enrolled. Hematologic complete responses (CR) and very good partial responses (VGPR) were noted in 27/27 (100%) of assessable patients at 6 months and in 26/26 (100%) at 1 year following SCT. By intention-to-treat analysis, hematologic CR and VGPR were achieved by 27/35 (77%) at 6 months and 26/35 (74%) at 1 year following SCT. Hematologic relapse was defined as recurrence of a monoclonal protein on serum or urine IFE and/or abnormality of serum free light chain assay corresponding to their original clone. In contrast, biochemical relapse was defined as hematologic relapse without the progression of organ parameters. Renal progression was defined as 50% increase of 24-hour urine protein to >1g/day or 25% worsening of serum creatinine or creatinine clearance and cardiac progression was defined as NT-proBNP progression (>30% and >300 ng/mL increase), cTn progression (>30%) or LVEF progression (≥ 10% decrease). Of the 27 patients who achieved a hematologic CR or VGPR at 6 months, 4 patients had hematologic relapse at a median of 42.3 months (range, 34.5-63.0), 1 patient had organ (renal) progression despite maintaining a hematologic VGPR at 37 months and 4 had biochemical relapse at a median of 53 months (range, 49-79). Immunomodulatory agents and proteasome inhibitors were used in 2 and 3 patients with relapse, respectively. None of the patients with biochemical relapse required additional anti-plasma cell directed treatment at the time of last follow-up (median follow-up of 12.5 months; range, 7-44). Of the four who had hematologic relapse, two patients had achieved a VGPR at 6 months, and two had achieved a CR at 6 months. The median overall survival and progression-free survival are not yet reached (Figure). Eight deaths occurred in the follow up period. Two of these occurred in patients who did not proceed to SCT. Three occurred within 100 days of SCT. Three occurred in the subsequent follow-up period at 10.4, 55.0, and 80.1 months following enrollment attributed to worsening cardiac and renal function due to relapse of AL amyloidosis. The median time to renal response, defined as a 30% reduction in 24-hour urine protein in those with a baseline level of proteinuria over 0.5 g/24 hr, and in the absence of a worsening of estimated glomerular filtration rate by 25%, was 12 months (range, 6-24). The median time to cardiac response, defined as a reduction of B-type natriuretic peptide level by 30% with a baseline level greater than 100 pg/mL, was 6 months (range, 6-24). There were two cases of biopsy proven autologous graft-vs-host disease during periSCT period, and both these patients are alive and maintain a hematologic CR. In conclusion, incorporating bortezomib into induction and conditioning yielded durable hematologic responses of AL amyloidosis with corresponding cardiac and renal responses, and prolonged survival. This clinical trial was partly supported by Takeda Oncology. Figure. Figure. Sloan: Stemline Therapeutics: Consultancy.