Impact of Light Chain Isotype on Clinical Features and Outcomes in Systemic AL Amyloidosis
Authors: Hopson Madeleine , Bhutani Divaya , Sarkaria Shawn M , Maurer Mathew , Griffin Jan , Lentzsch Suzanne , Chakraborty Rajshekhar 
Published: November 2021

Abstract
Purpose: In systemic AL amyloidosis, light chain (LC) isotype has been shown to predict outcome in patients undergoing upfront autologous transplantation. However, less than one-third of newly diagnosed AL patients are transplant-eligible. The objective of our study was to characterize the relationship between LC isotype, organ involvement, response, and survival in patients with newly diagnosed AL amyloidosis irrespective of transplant-eligibility.
Methods: We performed a retrospective cohort study on 112 patients with AL amyloidosis who had treatment records at Columbia University Irving Medical Center (CUIMC) between 2015-2019. Two-sided Fisher's exact test was used for categorical variables and two-sided Wilcoxon rank sum test was used for continuous variables. Survival analysis was done using Kaplan Meier method. Overall survival (OS) was the time from randomization to death due to any cause. Event-free survival (EFS) was the time to initiation of a subsequent line of therapy or death due to any cause, whichever was earlier. Two-sided log-rank test was used to test differences between survival curves.
Results: Kappa LC isotype was seen in 26% of patients. The proportion of patients with Mayo 2004 stage IIIA or IIIB disease in kappa and lambda isotype was 33% and 35% respectively (p=0.91). Bortezomib-based and daratumumab-based initial therapy was administered in 70% and 8% of patients respectively, with 36% having auto-transplant as part of first-line therapy. Patients with kappa LC isotype had a significantly higher baseline difference in free light chain (dFLC) and involved/uninvolved serum free light chain ratio (sFLCr) compared to lambda (median dFLC, 61.5 vs 21.6 mg/dl respectively, p=0.02; and median sFLCr, 63.5 vs 10.6 respectively; p&lt;0.01). Kappa LC isotype was also associated with a near-significant higher bone marrow plasma cell (BMPC) burden at baseline (median BMPCs, 20% vs 10% respectively; p=0.06). Patients with lambda LC isotype had a significantly higher incidence of kidney involvement compared to kappa (64% vs 38% respectively, p=0.02). There was no significant difference in the incidence of t(11;14) between the two groups. The incidence of hematologic very good partial response or better (≥VGPR), involved free light chain less than 20 mg/dl (iFLC&lt;20), and dFLC less than 10 mg/dl (dFLC&lt;10) at the end of first-line therapy was similar in the two groups (Table in Figure 1). There was no difference in cardiac or renal response rates between the two groups. The proportion of patients requiring a subsequent line of therapy in kappa and lambda isotype was 41.4% and 39.8% respectively (p=0.88). At a median follow-up of 43 months for surviving patients, there was no significant difference in event-free survival (hazard ratio (HR) [kappa/lambda]: 0.76 [0.43-1.38]; p=0.37). However, there was a non-significant trend toward superior OS (HR [kappa/lambda]: 0.47 [0.18-1.23], p=0.12; 4-year OS: 86% vs 67% respectively) in patients with kappa LC isotype. Achievement of hematologic ≥VGPR, iFLC&lt;20 mg/dl, and dFLC&lt;10 mg/dl at end of first-line therapy was associated with a superior OS in our cohort irrespective of light chain isotype.
Conclusion: Lambda AL amyloidosis is associated with significantly higher renal involvement compared to kappa. Despite a higher baseline disease burden (dFLC, sFLCr, and percent BMPC) in kappa compared to lambda, there was a trend toward superior OS in the former, which may imply decreased tissue toxicity of kappa FLCs. Further studies should investigate proteomic signatures and immunoglobulin gene usage according to light chain isotype and correlation with clinical phenotype.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.