Plenary Paper CLINICAL TRIALS AND OBSERVATIONS A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis

Immunoglobulin light-chain (AL) amyloidosis is caused by a usually small plasma cell clone synthesizing light chains undergoing conformational changes that lead to their aggregationanddeposition in tissues. This process leads toprogressivemultiple organdysfunction anddeath if left untreated.Advanced, irreversibleorgandamageatpresentation is the main limitation to improve theoutcomeofpatientswithALamyloidosis. Early diagnosis and recognition of reversible organ damage is crucial to improve patients’ survival and quality of life. Treatment should be risk adapted, based on accurate stratification of organ dysfunction. Light-chain amyloidosis is the commonest disease among the recently definedmonoclonal gammopathies of renal significance, and the kidney is involved in 70% of patients, manifesting with nephrotic syndrome and progressive renal failure. Renal involvement results in significant morbidity, and renal failure limits the therapeutic options. However, the current staging system of patients with AL amyloidosis that is used to guide the treatment strategy is based on the severity of heart involvement, which is the major determinant of survival, and does not take into account renal dysfunction. Although a recent consensus of the International Society for Amyloidosis (ISA) revised the criteria for hematologic and cardiac response to treatment based on patients’ survival, to date, there is no validated prognostic score for renal damage in this disease. Furthermore, the criteria for renal response to chemotherapyhave not beenupdated since 2005 andhave never been validated. Thus, there is a need for a simple and reliable means of stratifying the severity of renal involvement, as well as criteria for assessing the efficacy of treatment in preventing progression of renal damage, similarly to what has now become common practice for heart involvement after the introduction of cardiac biomarkers. However, because renal involvement has less relevant impact on patients’ survival compared with cardiac involvement, the criteria of renal response and progression should predict progression to dialysis and not necessarily death. Moreover, considering that the median time to a profound reduction in proteinuria is approximately 1 year, long after hematologic response is assessed, it is important to identify earliermarkers of renal response that can allow timely changes in the therapeutic regimen. Based on these considerations, we designed the present study in order to identify and validate criteria for assessing the risk of dialysis as well as criteria for early identification of renal response and progression in 732 consecutive, previously untreated patients with AL amyloidosis and renal involvement evaluated at 2 European referral centers: the Pavia Amyloidosis Research and Treatment Centre and the Heidelberg Amyloidosis Centre.