Monoclonal Gammopathy of Renal significance encompasses a spectrum of different renal pathologies that have a causal relationship with an underlying monoclonal protein produced by a, relatively indolent, plasma or other B-cell clone. These patients require anti-clonal treatment in order to salvage kidney function, however, there are few prognostic biomarkers that can help identify patients at higher risk for progression of renal disease. Increased plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and an elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR, in a large study (Hayek S et al, N Engl J Med 2015; 373:1916-1925). Increased Growth Differentiation Factor-15 (GDF-15) has been associated with the deterioration of renal function and progression to ESRD in diabetic patients but also in patients with AL amyloidosis. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is one of the earliest and most robust markers of acute kidney injury while serum Cystatin C (CysC) reflects renal function more accurately than creatinine and correlates with both tumor burden and renal function in MM. We measured serum levels of suPAR, NGAL, GDF-15 and CysC in the same frozen serum sample that was collected before any therapy was given. Measurements of the analytes were performed by means of immunoenzymatic techniques: suPAR (ViroGates A/S, Birkerod, Denmark), NGAL and GDF-15 (R&D Systems, Minneapolis, MN, USA), while CysC was measured with an immunoturbidimetric assay using the Roche Cobas 6000 Clinical Chemistry System. The study included 23 patients with MGRS (MIDD: 18, C3GN: 3, PGNMID: 2), 57% were men, median age was 66 years (range 47-85). Median baseline eGFR (by CKD-EPI) was 30.5 ml/min/1.73 m2 (range 3-102) and at the time of initiation of therapy one (4%) required dialysis. Median baseline proteinuria was 1.7 gr/d (range 0.6-10.2). Median dFLC was 57 mg/L (range 2-2,239) and median BM infiltration was 10% (range 0-50%). At initial presentation 92% had hypertension, requiring a median of 2 different drug classes (range 1-5). Median baseline levels of suPAR were 8.02 ng/ml (range 2.2-21), of CysC were 2.33 mg/L (0.94-7.03), of NGAL were 150.6 ng/ml (range 51.7-573) and of GDF-15 were 2,144 pg/ml (range 548-6,956). A correlation of suPAR levels was found with proteinuria (r=0.691, p=0.001), serum albumin levels (r=-0.706, p<0.001) and age (p=0.012) but not with baseline eGFR (p=0.49). GDF-15 correlated with eGFR (r=-0.662, p=0.001) but also with proteinuria (r=-0.535, p=0.018), while NGAL (r=-0.714, p<0.001), CysC (r=-0.727, p<0.001) correlated strongly with eGFR but not with proteinuria or serum albumin (p>0.2 for all). All these biomarkers showed significant correlations with each other (p<0.007 for all in between correlations). All patients received bortezomib-based therapy (with cyclophosphamide and dexamethasone); median follow up is 9 months and at 3 month landmark, 55% of evaluable patients had achieved a hematologic response while at 6 months 60% had a hematologic response. At the same time points a renal response (>50% reduction of proteinuria and <25% decline in eGFR) was 44% and 53% respectively. There was no significant correlation of baseline levels of suPAR, NGAL, GDF-15 or CysC with renal response; however, we found a trend towards an association of lower baseline suPAR with a higher probability of >50% reduction of proteinuria (p=0.096), which after adjustment for baseline proteinuria and eGFR became clearer (p=0.054). We conclude that suPAR, NGAL, GDF-15 and CysC are markers with significant associations with renal function in patients with MGRS, but, from a clinical standpoint suPAR is probably the most promising marker with potential prognostic significance for renal outcomes. Additional follow up of the cohort and inclusion of additional patients will allow us to further evaluate this biomarker in MGRS. Disclosures Kastritis: Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Amgen: Honoraria, Research Funding; Genesis: Honoraria. Gavriatopoulou:Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Papassotiriou:Roche: Employment. Terpos:Janssen: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.
Introduction: Severe renal impairment (RI) is a common complication of multiple myeloma (MM). Effective anti-MM therapy and supportive care can restore renal function in several patients, but we lack biomarkers that could predict renal outcomes. Neutrophil gelatinase-associated lipocalin (NGAL) is one of the earliest and most robust markers of acute kidney injury while serum Cystatin C (CysC) reflects renal function more accurately than creatinine and correlates with both tumor burden and renal function in MM. GDF-15 is secreted by bone marrow stromal cells and high serum levels indicate a poor treatment prognosis and a high risk of progression to dialysis in AL amyloidosis. Our aim was to evaluate serum NGAL, CysC, and GDF-15 in MM patients with severe RI defined as eGFR<30 ml/min/1.73m2, by CKD-EPI formula, including those on dialysis, as biomarkers for prediction of renal responses. Patients & Methods: MM patients who presented with myeloma-related severe RI in the Department of Clinical Therapeutics (Athens, Greece) were included in this study. NGAL, CysC and GDF-15 were measured in the same frozen serum sample collected before the administration of any therapy. Serum NGAL was measured using ELISA (BioPorto Diagnostics A/S, Gentofte, Denmark), while CysC was measured using a latex particle-enhanced nephelometric immunoassay (Dade Behring-Siemens Healthcare Diagnostics, Liederbach, Germany). GDF-15 was measured by a novel immunoassay, the Elecsys GDF-15 assay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), which is based on the sandwich immunoassay principle using biotin-streptavidin technology. Patients on dialysis received dialysis with regular membranes. IMWG renal response criteria were used. Results: In total, 101 newly diagnosed MM patients with severe RI were included in this analysis. Median creatinine was 4.6 mg/dl (range 2->10 mg/dl), median eGFR (ml/min/1.73 m2) was 11.3 (1.3-29.8) and dialysis was required in 35 (35%) patients. The median age was 71 years; median involved FLC was 4740 mg/L; hypercalcemia was found in 24%, LDH ≥ULN in 44% and high-risk cytogenetics in 25% of patients, while 98% of patients were classified as having ISS-3 and 49% as having R-ISS-3 disease stage. Treatment was bortezomib-based in all patients (in 21% VD and in 79% a triplet: VCD or VTD). Median NGAL levels were 182.3 ng/mL (range 20-550 ng/ml) and of CysC were 3.3 mg/L (0.9-8 mg/L); there was a strong correlation between NGAL and CysC levels (R2=0.653, p<0.001). There was also a strong correlation of both CysC and NGAL with eGFR (for CysC: R2=0.615, p<0.001 and for NGAL: R2=0.464, p<0.001). Both NGAL and CysC levels were higher in patients requiring dialysis vs those not in dialysis (median NGAL: 308 vs 166 ng/mL, p<0.002 and median CysC: 4.99 vs 2.83 mg/L, p=0.008). No significant correlations were observed with GDF-15 and the parameters tested. Renal response (Rrenal) was achieved in 63% of patients, including 45% with major Rrenal. Importantly, 40% of patients who required dialysis became dialysis independent. Median time to Rrenal was one month and median time to dialysis independence was two months. Lower levels of NGAL (p=0.0003) and CysC (p=0.03) were associated with higher probability of major Rrenal among patients with severe RI. Baseline eGFR, levels of sFLC and GDF-15 did not correlate with major Rrenal. None of these markers was associated with probability of dialysis independence among patients who required dialysis. Based on ROC analysis, in patients with severe RI (but not on dialysis), NGAL <138 ng/ml was strongly associated with major Rrenal (80% vs 20% at 3 months, p<0.001; Figure). Regarding CysC, levels <2.9 mg/L were associated with higher probability and shorter time to major Rrenal (p=0.012). In multivariate analysis performed in patients not on dialysis, that included age, NGAL, CysC and eGFR, only NGAL <138ng/ml remained a significant prognostic factor associated with major Rrenal (HR 5, 95% CI 2-18, p=0.002). Conclusions: Serum levels of NGAL were independent predictors of major renal response in MM patients with severe RI. Thus, serum NGAL could identify MM patients with severe RI who should be treated with more aggressive therapies and more effective and rapidly acting antimyeloma regimens. The absence of any predictive value of GDF-15 in MM-related severe RI in contrast to AL amyloidosis patients reflect the different biology of RI in these plasma cell dyscrasias. Figure Disclosures Dimopoulos: Sanofi Oncology: Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genesis: Honoraria; Prothena: Honoraria; Pfizer: Honoraria; Takeda: Honoraria. Papassotiriou:Roche: Employment. Gavriatopoulou:Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Terpos:Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria.
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