Uninvolved Immunoglobulins Predicting Hematological Response in Newly Diagnosed AL Amyloidosis

Introduction: Immunoparesis serves as a marker for progression in plasma cell proliferative disorders. However, the impact of immunoparesis in AL amyloidosis has not been addressed yet. Additionally, immunoparesis can vary from mild suppression to a major decrease in the uninvolved Immunoglobulins, but this has not been carefully studied.

Methods: Immunoparesis was defined qualitatively as any decrease below the low reference levels of the uninvolved immunoglobulins and quantitatively, as the relative difference between the uninvolved immunoglobulins and the lower reference levels’ values.

Results: Forty-one newly diagnosed AL amyloidosis patients were included. The median age was 67.2 years (range, 46-87). At the time of treatment initiation, 14 patients (34%) had preservation of the uninvolved Ig's while 27 patients (66%) had suppression of the uninvolved Ig's. Patients with any degree of immunoparesis had higher percentage of marrow plasma cells compared to patients with preserved levels of the uninvolved Ig's (median 25% vs. 15%, P=0.02). Regarding quantitative assessment of immunoparesis, the median relative difference of the uninvolved immunoglobulins was 18% above the lower reference levels [range (-71%)-210%]. Ninety percent of patients were treated with novel agents-based regimens, mostly bortezomib-containing regimens. Nineteen percent of patients did not attain response to first line treatment. There was no difference in the overall response rate between patients with preserved levels of the uninvolved Ig's compared to patients with immunoparesis [odds ratio (OR) for partial response and better vs. no response - 4.55 (95% CI 0.5-41.4), P=0.22]. However, patients with a relative difference of the uninvolved Ig's below -25% from the lower reference levels were less likely to respond to first line treatment compared to patients with a relative difference of -25% and above [OR for no response vs. PR and better 30 (95% CI 4.1-222.2), P=0.0004].  Patients who failed first line treatment were successfully salvaged with lenalidomide-based treatment. Median follow-up was 13 months (range, 1-86). Median Progression-free survival (PFS) and overall survival were 14 and 42.5 months, respectively. PFS differed between those with a relative difference of the uninvolved Ig's below -25% compared to those with a relative difference of -25% and above (6.7 vs. 26.8 months), without statistical significance (P=0.17). There was no significant difference in overall survival between the sub-groups. 

Conclusions: This study suggests a correlation between the depth of immunoparesis and hematological response to bortezomib-containing regimens in newly diagnosed AL amyloidosis patients. Furthermore, its results imply a favorable response to lenalidomide in AL amyloidosis patients with significant immunoparesis.