Towards a better understanding of monoclonal gammopathy of renal significance

In 1978 Dr. Robert Kyle, a leader in the field of haematology and multiple myeloma in particular, coined the term monoclonal gammopathy of undetermined significance, or MGUS, to describe a medical condition characterized by the presence of a monoclonal peak in the serum (Kyle, 1978). In this seminal paper, Dr. Kyle pointed out how some, but not all, MGUS patients would develop a plasmacytoid or lymphoproliferative disorder over time, suggesting that the nature of MGUS was undetermined, rather than benign. Over the past 40 years, research efforts led by Dr. Kyle and the Mayo Clinic group, as well as other groups, clearly demonstrated a rate of 1%/year progression to multiple myeloma (MM), AL amyloidosis or lymphoma for MGUS patients, and, critically, identified several factors predictive of transformation (Kyle et al, 2006, 2018). In 2012, the International Kidney and Monoclonal Gammopathy Research Group (IKMG) introduced the term monoclonal gammopathy of renal significance (MGRS) to recognize an entity of clear pathogenic significance from the renal perspective (Leung et al, 2012). The definition of MGRS was recently updated and defines haematological disorders that would not meet criteria for treatment, characterized by the production of a nephrotoxic monoclonal protein (Leung et al, 2019). Prior to this definition, most MGRS patients would have been diagnosed as having MGUS and therefore not deemed eligible for treatment. However, given the excess of morbidity related to advanced renal failure seen and the increased mortality, MGRS is not a benign disorder (Pozzi et al, 2003). MGRS encompasses a spectrum of disorders defined by a pattern of renal injury and discrete mechanisms of pathogenesis. To this end, a renal biopsy is necessary for definitive diagnosis (Bridoux et al, 2015). Given competitive aetiologies for chronic kidney disease (CKD), particularly diabetes mellitus and hypertension, as well as the lack of widespread use of renal biopsy, to rule out MGRS in patients with plasma cell disorders, the true incidence of MGRS is difficult to establish. In a recent retrospective study from the Medical University of Innsbruck, Austria, of over 2900 patients diagnosed with MGUS between 2000 and 2016, only 44 patients (1 5%) were diagnosed with MGRS. However, this cohort of patients included AL amyloidosis and renal biopsy was performed in only 60% of these patients (Steiner et al, 2018). There is current no therapy directed at the deposited paraprotein that could arrest deposition and/or elicit reabsorption. As such, the only feasible therapeutic option for patients with MGRS is clonally-directed therapy as a tool to block nephrotoxic paraprotein production and so improve renal outcome (Fermand et al, 2013). Definitive criteria to guide response in MGRS have not been established. When there is presence of an M spike and/or abnormal free light chains and ratio, a haematological response can be determined based on MM criteria; however, in approximately 30–40% of patients a malignant clone and/or abnormal laboratory values may not be identifiable (Hogan & Weiss, 2016). In addition, it is unclear if haematological remission impacts renal recovery and/or renal survival. There is a growing interest in the field of MGRS to use markers of renal function, such as creatinine and proteinuria, to determine organ response in a manner similar to AL amyloidosis (Palladini et al, 2014). Given the diversity of underlying plasmacytoid and lymphoproliferative disorders in conjunction with the pattern of renal injury across MGRS, it is difficult to generalize regarding the overall outcome in patients with MGRS. In the largest case series to date, progression to end stage renal disease (ESRD) was reported to be in approximately 40–50% at 5 years for light chain deposition disease (LCDD), 22% at 2 5 years for proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and 39% at 2 years for patients with monoclonal immunoglobulin deposition disease (MIDD) (Hogan & Weiss, 2016). Furthermore, given the overall perceived rarity of these disorders, large, multicentre, prospective studies are difficult to open and/or accrue. Consequently, an understanding of the best therapeutic strategy in MGRS is presently lacking. Correspondence: Dr Giada Bianchi, Dana Farber Cancer Institute, Medical Oncology, 440 Brookline Avenue, Boston, MA 02120, USA. E-mail: giada_bianchi@dfci.harvard. edu editorial comment