P0204PREVALENCE AND PREDICTIVE FACTORS OF BIOPSY-PROVEN NEPHROPATHY RELATED TO MONOCLONAL GAMMOPATHY

Background and Aims The prevalence of monoclonal gammopathy (MG) and kidney disease increases with age. When a patient present with both conditions, it is often necessary to perform a kidney biopsy in order to rule out a Monoclonal Immunoglobulin-Related Nephropathy (MIRN) that may require a specific therapy that targets either an overt hematological malignancy or a MG or Renal Significance (MGRS). The aim of our study was to identify factors that predict the presence of MIRN in this setting. Method This retrospective monocentric study included all patients who underwent a kidney biopsy between 2007 and 2018 with concurrent presence of GM, as defined by positive serum immuno-electrophoresis and/or Bence-Jones proteinuria. Results 328 patients were included, representing 11.8% of all kidney biopsies performed in our center during this period. Indication of biopsy was renal failure (eGFR <60ml/min/1.73m) in 77.4% of cases and/or proteinuria (urine protein-to-creatinine ratio >0.5g/g) in 75.9% of them. Median (IQR) serum creatinine was 155 μmol/L (111-233), eGFR 37.5 (22-56) ml/min/1.73m, serum albumin 29.5 (24-35) g/l. Median age was 67 (57/75), the M/F ratio was 198/130, diabetes mellitus was present in 21.3% of cases, hypertension in 53.1%. Kidney biopsy revealed that nephropathy was related to MG in 91/328 patients (27.7%). Myeloma cast nephropathy and AL amyloidosis were the most common histopathological subtypes (36 and 34% respectively), followed by monoclonal immunoglobulin deposition disease (15%) and cryoglobulinemic glomerulonephritis (8%). Patients with MIRN had more severe renal function impairment with median (IQR) serum creatinine of 176 (119-307) vs 149 (108-216) μmol/l (p=0.003) and heavier proteinuria, 3.9 (2.2-8.2) vs 2.0 (0.9-5.2) g/g (p< 0.001), when compared to non-MIRN patients. Hematological malignancy was diagnosed in 83 cases (25,3%) (Multiple Myeloma in 62, non-Hodgkin Lymphoma in 6, Waldenström Macroglobulinemia in 6, Chronic Lymphoid Leukemia in 6, Plasmocytoma in 3). Among them, MIRN was diagnosed in 51 (61%) cases but tumoral lympho-plasmocytic infiltration was observed in 9 (11%) cases. In this subgroup of patients, no laboratory test could predict the presence of a specific nephropathy. Among patients with no hematological malignancy (n=245), MIRN was diagnosed in 40 cases (16%) to confirm MGRS diagnosis. The markers that were most commonly associated with the presence of MGRS were positive Bence-Jones proteinuria (OR 4.7; 95%CI 2.2-10.3; p< 0.001), abnormal serum Free Light Chain (FLC) ratio (OR 4.2; 95%CI 1.7-10.7; p< 0.001), and serum electrophoresis spike >1.5 g/l (OR 5.9; 95%CI 2.6-13.5; p< 0.001). However, none of those markers had sufficient power to formally predict the result of the biopsy, as positive (PPV) or negative (NPV) predictive values were 36/41/45 % and 89/86/88 % respectively. Conclusion Almost one-third of patients with MG and kidney disease referred to our Department have biopsy-proven related nephropathy. Although negativity of Bence-Jones proteinuria and a normal serum FLC ratio are frequently associated with the absence of MGRS, kidney biopsy, beyond its diagnostic and prognostic interest, remains the most discriminating test.

Free Light Chain Escape in Multiple Myeloma : an Exceptional Phenomenon

Background : Free Light Chain (FLC) escape has been described for the first time in 1971 by Hobbs, who reported biochemical relapses of multiple myeloma (MM) with only Bence Jones proteinuria, in patients followed for an intact monoclonal immunoglobulin (Ig) MM. Indeed, FLC escape is defined as an increase of FLC without corresponding increase of the intact monoclonal Ig. In the era of novel-agent based therapy and autologous stem cell transplantation (ASCT), the patterns of disease progression may change, including a potential increased rate of FLC escape. Brioli and al (Blood 2014;123(22):3414-9) reported that 10% of the cases at relapse presented with FLC escape, and that FLC evaluation at relapse could represent an interesting marker of impact from intraclonal heterogeneity on myeloma outcome. We analysed the relapse patterns of patients treated according to the IFM 2009 clinical trial. Methods: Patients treated according to the IFM 2009 clinical trial (Lenalidomide bortezomib dexamethasone RVD + / - ASCT, Attal and al, ASH 2015) were analyzed. In patients presenting with an intact monoclonal Ig at diagnosis, serum and urine electrophoresis + FLC were compared in a central lab at the time of diagnosis and at the time of progression, in order to identify FLC escape. Results: 700 patients with symptomatic de novo MM were enrolled in the IFM DFCI 2009 clinical trial. Among them, 318 had a progressive disease, assessed with a centralized biochemistry analysis and 267 patients of them with an intact monoclonal Ig were included in this study. A vast majority (250 patients, 94%) showed an increase of the initial serum monoclonal component up to 5 g/L or up to 25% from the NADIR (IMWG criteria for progressive disease). 8 patients progressed with new bone lesions or plasmocytoma (3%) without any biological markers of progressive disease... Finally, 9 patients (3%) were identified as FLC escape as they did not exhibit an increased intact monoclonal Ig but they had an increased serum FLC and/or an increased Bence Jones proteinuria. Three of them had a serum and urinary measurable disease on diagnosis and they relapsed with both an increase of FLC and an increase of Bence Jones proteinuria. The six other patients presented at diagnosis only with an urinary measurable disease: 3 of them relapsed with an increase of FLC, without any Bence Jones proteinuria, the three others relapsed both on FLC and urines. Isotype of monoclonal component was IgG (6 patients), IgA (2) or IgD (1); light chain was Kappa for 6 patients and Lambda for the three others. Four patients were treated with RVD alone, and 5 patients with RVD + ASCT. The relapse occurred in a median of 2 years after diagnosis (5 months - 3.5 years). Conclusion: Based on a very large study of patients treated into a phase 3 clinical trial with centralized assessment of response and relapse, we are showing that FLC escape in a very rare phenomenom, observed in 3% of the cases. The low frequency of FLC escape does not lead to a systematic monitoring of intact Ig MM by FLC. Disclosures Attal: amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding; sanofi: Consultancy. Avet-Loiseau:sanofi: Consultancy; janssen: Consultancy; amgen: Consultancy; celgene: Consultancy. Moreau:Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria.

Multiple Myeloma in a Dog

Background: The multiple myeloma is a neoplasia characterized by the uncontrolled proliferation of plasma cells (plasmacytes) in the bone marrow and in other tissues. The infiltration of the neoplasia cells associated to the high level of anomalous immunoglobulin production (M protein) results in a variety of clinic-pathologic anomalies. It is a rare disease in dogs, corresponding to 0.3% of all malignant neoplasia and 2% of the hematopoietic, with few literature descriptions. So, the present paper aims at properly report a multiple myeloma in a dog of non-defined breed, emphasizing the clinic, laboratorial, radiographic and pathologic aspects.Case: In a Veterinary Teaching Hospital, an 11-year-old dog of non-defined breed was admitted, weighing 10.8 kg of body mass. The clinic history was claudication of the right thoracic member, hyporexia and lethargy in the past 20 days. The main abnormalities in the physical examination were holosystolic cardiac murmur III/VI on mitral focus, and high sensibility to touch in the right humerus. Laboratory tests showed pancytopenia, serum hypercalcemia and Bence-Jones proteinuria. Radiographic examination confirmed polyostotic punctate osteolysis on the right humerus; pelvic, femurs and vertebrae bones from L2 to L7, on generalized condition. Cytology by aspiration puncture from the left femur marrow bone did not confirm neoplasia cells. The clinic condition of the referred animal was progressively getting worse and euthanasia was performed. At the dog’s necropsy it was spotted tumor infiltrations on the femur, the humerus and the vertebrae canal. Histopathological exam of the bone marrow revealed diffuse occupation by distinguished plasmacytes, in some áreas reaching around 100% of cell population. Metastases on the primary tumor were found on the liver, kidney and spleen.Discussion: The diagnosis of multiple myeloma in this dog was confirmed by bone marrow histopathological exam. It is confirmed when there is more than 20% of plasmacytes in the examined structure. In this report, certain areas were spotted with 100% occupation of neoplasia cells. On the other hand, the first cytological assess did not reveal any abnormalities, suggesting that the place which received the puncture (aspiration) was not infiltrated by tumor cells. It is described that in the bone marrow may occur grouping of plasmacytes, as it was observed the animal’s necropsy of this report. This aspect point out that the diagnosis cannot be discarded only with a negative cytological exam from the bone marrow; especially if there are clinic, laboratorial and radiographic signs compatible to the illness. The spotted clinic signs by this patient are frequent in dogs with multiple myeloma, as well as the laboratory results, except to the monoclonal gammopathy. Due to a no realization of electrophoresis, this abnormality cannot be confirmed. At the initial assessment of the disease, the radiographic exam is considered golden standard as it was observed in this dog. The radiographic abnormalities were determinant, once they conducted the diagnosis towards the suspected neoplasia. According to current diagnosis criteria, on this present case, the pancytopenia, serum hypercalcemia and Bence-Jones proteinuria also helped towards the suspicion of multiple myeloma. However, the evaluation of the bone marrow was decisive to the final diagnosis; and a special attention was given to puncture more than one place in the bone marrow, which improved/enhanced the diagnosis possibility in this patient.Keywords: plasma cells, bone marrow, pancytopenia, osteolysis, radiography.