Prognostication in IgM and Lymphoplasmacytic Lymphoma Associated Systemic AL Amyloidosis
Authors: Khwaja Jahanzaib , Ravichandran Sriram , Foard Darren , Martinez-Naharro Ana , Venneri Lucia , Fontana Marianna , Whelan Carol , Hawkins Philip N , Gillmore Julian , Lachmann Helen J , Mahmood Shameem , D'Sa Shirley , Wechalekar Ashutosh D. 
Published: December 2024

Introduction:
IgM-associated systemic light-chain amyloidosis (IgM-AL) is a distinct clinical entity, accounting for up to 7% of systemic AL amyloidosis. Despite the expansion of novel therapies, deep clonal responses are rare. We previously reported a small series using bendamustine-rituximab (BR) in first-line IgM-AL but the largest series evaluating predictors of overall survival (OS) was in an era prior to widespread use of BR. We reviewed outcomes of modern treatment in IgM-AL.
Methods:
Patients enrolled in a prospective observational study at the United Kingdom National Amyloidosis Centre from 2012-2024 treated for systemic AL were reviewed. Patients with a serum IgM-AL or lymphoplasmacytic lymphoma (LPL) on histology were included. Diagnosis of AL amyloidosis was confirmed centrally by histology and typed with immunohistochemistry or mass spectrometry, or if not available, for patients with biopsy confirmed amyloidosis and cardiac involvement alone, if they also had a negative DPD-Tc99m bone scan. Overall survival (OS) estimates were generated using the Kaplan-Meier method. Statistical analyses were conducted using STATA v18 (STATAcorp, Texas). Ethical approval was obtained (REC:09/H0715/58).
Results:
Two-hundred-and-twenty-one patients (129 male, 92 female) were included. Median age at presentation was 70 years (range 37-89), with 97% White and 1% each Asian, Black, Other/mixed. A median of two organs (range 1-4) were involved: 95 (44%) had cardiac, 141 (66%) renal, 38 (18%) soft tissue and 28 (13%) each liver and peripheral nerve involvement. Sixty-seven percent had lambda AL-type and a median difference in involved and uninvolved free light chain (dFLC) 106mg/L (range 0-5718), monoclonal protein (M-protein) 9g/L (range 0-54) and bone marrow LPL infiltrate 10% (range 0-95). Median NT-proBNP was 1085ng/L (range 25-70000), troponin T 38ng/L (0-308), global longitudinal strain -16.7% (-27.8 - -5.4). Evaluable patients were classified as Mayo stages I, II, IIIa and IIIb in 34 (19%), 79 (39%), 57 (28%) and 35 (17%), respectively.
A median of 1 (range 0-4) line of therapy was delivered after the diagnosis of AL was made. Patients were treated with the following first-line therapies for AL: BR in 97 (44%); bortezomib-cyclophosphamide-dexamethasone + rituximab (VCD + R) in 77 (35%); dexamethasone-rituximab-cyclophosphamide in 19 (9%), RCHOP-like in 8 (4%), daratumumab-VCD in 4 (2%), zanubrutinib in 2 (1%) and others (14; 6%). None had an autologous stem cell transplant upfront.
At a median follow-up of 46 months (95% confidence interval [CI] 35-52), median OS was 58 months (95% CI 32-78). The estimated one, three and five-year OS was 71% (95% CI 65-77), 56% (95% CI 49-63) and 49% (95% CI 41-57). The median OS by was 72 months (95% CI 27-NR) and 42 months (95% CI 25-71) for BR and VCD + R.
Factors predicting OS in a multivariable model included: age, per year (HR 1.05 [95% CI 1.02-1.08], p=0.001), NT-proBNP, per 1000ng/L (HR 1.05 [95% CI 1.02-1.08], p=0.001), troponin, per 10ng/L (HR 1.04 [95% CI 1.02-1.08], p=0.05), M-protein, per g/L (HR 1.02 [95% CI 1.00-1.05], p=0.04), cardiac involvement (HR 2.44 [95% CI 1.50-3.96], p&lt;0.001), renal involvement (HR 1.65 [95% CI 1.02-2.54], p=0.04) and peripheral nerve involvement (HR 1.98 [95% CI 1.05-3.76], p=0.04). dFLC (p=0.10), free-light chain isotype (κ vs λ, p=0.14) and soft tissue involvement (p=0.26) were not independently prognostic.
Conclusion:
In the modern treatment era, the survival for IgM-AL appears to have improved (58 v 42 months in our previous report, n=250) and longer for BR v VCD + R. Survival is still dependant on cardiac involvement and intact IgM M-protein remain independent predictors, whilst dFLC is not independently prognostic.