Achieving a Difference in Involved and Uninvolved Light Chains (dFLC) of Less Than 10mg/L Is the New Goal of Therapy in Systemic AL Amyloidosis: Analysis of 916 Patients Treated Upfront with Bortezomib-Based Therapy
Authors: Manwani Richa , Sharpley Faye , Mahmood Shameem , Sachchithanantham Sajitha , Lachmann Helen , Gillmore Julian , Whelan Carol , Hawkins Philip , Wechalekar Ashutosh D. 
Published: October 2019

Abstract
Background
Based on international consensus criteria (ICC), the treatment goal in AL amyloidosis (AL) is at least a very good partial response (VGPR, defined by dFLC<40mg/L), associated with better organ responses and overall survival (OS). In patients presenting with low dFLC (<50mg/L), a low-dFLC partial response (PR, dFLC<10mg/L) predicts better renal and OS. Given emerging data on the impact of minimal residual disease in AL, we posited that a target of dFLC<10mg/L may be important in all AL patients, irrespective of baseline light chain levels. We therefore report outcomes in the largest cohort treated with upfront bortezomib-based therapy and explore the impact of dFLC<10mg/L as a potential therapy goal in AL.
Methods
All patients from a prospective observational study of newly diagnosed AL treated with upfront bortezomib regimes from 2010-2017 were included. All underwent serial organ function assessment and biomarkers. Organ responses were defined by ICC. Survival was calculated by Kaplan-Meier analysis. All outcomes are reported on an intention-to-treat (ITT) basis. Haematologic responses were assessed by ICC and absolute dFLC. Patients with presentation dFLC 20-50mg/L were regarded as achieving a low-dFLC PR if dFLC<10mg/L after treatment. Progression-free survival (PFS) was defined as time to death or progression to next therapy. Time-to-next-treatment (TNT) was defined as time from first-line therapy to second-line.
Results
916 patients were included. Median age was 66 years (29-89), M:F 59%:41%. The number of patients with cardiac, renal, liver, peripheral nerve and autonomic involvement was: 71%, 68%, 14%, 6% and 6%. The number of patients with Mayo Stage 1, 2 and 3 disease was 16%, 33% and 51%. The median NT-proBNP and dFLC were 2228ng/L (range 29-93776) and 180mg/L (0-15898), respectively. All received bortezomib-based therapy: CyBorD 95%, bortezomib-dexamethasone 3%, bortezomib-thalidomide-dexamethasone 1.3%, bortezomib-melphalan-prednisolone 0.3%, bortezomib-lenalidomide-dexamethasone 0.3% and bortezomib-melphalan-thalidomide-dexamethasone 0.1%. The median number of chemotherapy cycles was 5 (1-9).
ITT haematologic responses by ICC at 6 months were: complete haematologic response (CR) 15%, VGPR 30%, partial response (PR) 16%, low-dFLC PR 4%, non-response 35% (including deaths 25%). Evaluable haematologic responses were: CR 21%, VGPR 40%, PR 21%, low-dfLC PR 5% and non-response 13%. Absolute dFLC responses were: dFLC <10 mg/L 30%; dFLC 10-20mg/L 11%; dFLC 20-30mg/L 6%; dFLC 30-40mg/L 5%, dFLC 40-50mg/L 3%, dFLC>50mg/L 20% and deaths 25%.
Median OS, PFS and TNT were 72 months, 22 months and not reached (55% of evaluable patients not having progressed to next treatment at 7 years). Median OS was not reached in patients in a CR, VGPR or low-dFLC PR; median OS was 71 and 39 months in patients in a PR and non-response, respectively. Median OS in patients with 6 month dFLC<10mg/L, dFLC 10-40mg/L, and dFLC>40mg/L was not reached (86% alive at 6 years), not reached (61% alive at 6 years) and 53 months, respectively. Median PFS was not reached in patients in a CR or low-dFLC PR, and it was 48, 17 and 13 months in patients in a VGPR, PR and non-response, respectively. Median PFS in patients with 6 month dFLC<10mg/L, 10-40mg/L and dFLC> 40mg/L was not reached, 33 and 14 months, respectively. Median TNT in patients in a CR, VGPR and "low-dFLC" response was not reached; it was 16 and 13 months in those in a PR and non-response, respectively (Fig. 1A). Median TNT in patients with a 6 month dFLC<10mg/L, 10-40mg/L and dFLC>40mg/L was not reached, 38 months and 13 months (Fig. 1B).
Median OS, PFS and TNT at 3 and 5 years in patients achieving CR vs dFLC<10mg/L was: 76% vs 82%, and 67% vs 76%. 32% achieved cardiac responses in total, compared to 61% in those with 6 month dFLC<10mg/L (p<0.0001). 15.4% achieved renal responses overall, compared to 27.4% in the 6 month dFLC<10mg/L group (p=0.0003).
Conclusion
In this study, we report the largest cohort of AL patients treated with upfront bortezomib. On an evaluable basis, 66% of patients achieved CR/VGPR/low-dFLC response. The OS, PFS and TNT in patients in a CR are akin to those previously reported in ASCT. Strikingly, PFS, TNT and organ responses are markedly better in patients with dFLC<10mg/L after treatment, even compared to patients in a standard CR. We propose that dFLC<10mg/L should be evaluated in an international collaboration as the new therapy goal in AL.

Disclosures
Wechalekar: Janssen: Honoraria.