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Multiple myeloma

Introduction: According to the recent International Kidney and Monoclonal Gammopathy Research Group Consensus report, the spectrum of monoclonal gammopathies of renal significance merges more than 12 conditions; and combinations of various patterns of monoclonal gammopathies of renal significance–associated kidney damage have already been described. We present a case of a previously unreported combination of C3 glomerulopathy and light-chain proximal tubulopathy. Case description: A 53-year-old Caucasian man presented with general weakness. Three years prior, a check-up revealed proteinuria and microhematuria, later accompanied by arterial hypertension, elevated serum creatinine, and a low serum C3 levels. On admission, his creatinine was 1.5 mg/dL; his protein excretion was 1900 mg/24 h with microhematuria at 150 hpf. His serum C3 was 79 mg/dL with a normal C4 level. Serum protein electrophoresis revealed an M-spike, immunochemistry confirmed monoclonal immunoglobulin G kappa secretion of 920 mg/dL, and traces of Bence–Jones protein kappa in his urine. A kidney biopsy showed mesangial hypercellularity with diffuse fine granular C3 mesangial expression and tubular atrophy with diffuse coarse granular kappa light-chain tubular epithelial cytoplasmic expression. Computed tomography did not reveal any destructive lesions. A bone marrow smear showed 5% plasma cells, and bone marrow cell flow cytometry demonstrated 87.4% of plasma cells with an aberrant phenotype. The patient was diagnosed with an monoclonal gammopathy of renal significance and administered bortezomib–cyclophosphamide–dexamethasone. After four courses, his monoclonal immunoglobulin G kappa secretion halved, but his serum creatinine and proteinuria remained almost unchanged. Chemotherapy was switched to lenalidomide–dexamethasone, and after five courses his immunoglobulin G kappa secretion decreased to traces, Bence–Jones protein was not observed and his urinalysis, serum creatinine, and C3 levels were detected as normal. Conclusion: The combination of kidney damage patterns, one of which was directly and the other indirectly associated with monoclonal gammopathy, complements the monoclonal gammopathies of renal significance spectrum. Chemotherapy led to a very good partial response and kidney function recovery.

Introduction: Myeloma cast nephropathy (MCN) is a main cause of acute kidney injury (AKI) at multiple myeloma (MM) onset. Wherein 5-9% of newly diagnosed MM patients are dialysis dependent. The introduction of novel agents has provided the achievement of rapid and deep hematologic response in most patients. However, the renal response in patients on dialysis is only 38-62.5%. The predictors of AKI reversibility in patients with MCN remain not enough studied. Aim: to determine clinical, morphological and immunohistochemical predictors of reversibility dialysis dependent AKI in patients with MCN. Materials and methods: 36 patients aged 38 to 74 years (median age=57 years) with newly diagnosed MM and dialysis dependent AKI stage 3 (AKIN, 2012) due to MCN were enrolled into the study from January 2006 till November 2019. The diagnosis of MM, hematologic and renal response were established according to the 2016 IMWG criteria. MCN was determined by renal biopsy performed prior to induction therapy. The assessment degree of acute tubular injury, tubular atrophy and interstitial fibrosis (IF/TA) were semi-quantitatively evaluated. The number of sclerotic glomerular were calculated manually. The median number of casts was defined by all casts in a section divided by number of fields observed (х100). Additionally, square of interstitial fibrosis, interstitial inflammation, expression of Immunohistochemical markers (E-cadherin, α-smooth muscle actin (α-SMA), vimentin) were measured by computerized quantitatively image analysis using the digital module Leica (Germany). The time from diagnosis of AKI to start of induction therapy did not exceed 3 months. Bortezomib based first line treatment regimen was used in 25 (69%) of patients; 9 (25%) patients received chemotherapeutic agents only, 2 (6%) dead before a start of induction therapy. Statistical software package SAS 9.4 was applied for calculations. Overall survival according to renal response was compared by using Kaplan-Meier curves. Also frequency, logistic, discriminant and ROC analysis were used. All estimates are shown with a 95%CI. Results: Hematologic partial response or better occurred in 19 (53%) of patients, median of 32 (13-129) days. Renal response - in 14 (39%). In 3 (8%) cases renal function improved after correction of dehydration before start of antimyeloma therapy, in the remaining 11 (30%) patients only when hematologic response was achieved (p = 0.001). The frequency of renal response was depending on start of antimyeloma therapy before and after 4 weeks from diagnosis of AKI and was 83% and 17%, respectively (p Patients with hematologic response were divided into two groups (Tab.). The main pathological findings associated with renal response were less frequent mild to severe IF/TA in patients with and without renal response (moderate 45% vs 75%, respectively, p=0.008), less area of interstitial fibrosis (24.9% vs 44.7%, respectively, p=0.001), percentage of proximal tubules with save epithelial phenotype and less area of expression E-cadherin at interstitium (15.9% vs 7.1%, respectively, p=0.006). The median number of casts per field was the same (6.4 and 6.3, p=0.64) as well as the percentage of tubule lumen obstruction by casts (13.6% and 15.1%, p=0.81). Statistically significant correlation between the expression area of E-cadherin and interstitial fibrosis was not found (Rs= -0.335, p= 0.065). Therefore, a combination of these factors can be used to predict renal response in the onset of AKI due to MCN (area under the ROC curve is 0.84). The prognostic model and logical rule allow to define groups of renal outcomes (Fig.). If expression area of E-cadherin is less than 10% and / or area of interstitial fibrosis is more than 40% of the interstitium, a renal response is unlikely (OR = 24.5) and will not be achieved in almost 90% of cases, despite hematological response. Discussion. Reversibility of dialysis dependent AKI due to MCN rely on the achievement of hematological response and the time from diagnosis of AKI to start of antimyeloma therapy. There are predictors of renal response of these patients determined by the severity of morphological changes: degree of IFTA, quantitative area of interstitial fibrosis and E-cadherin expression. Disclosures No relevant conflicts of interest to declare.

Cases of Immunotactoid Glomerulopathy (ITG) in patients with Multiple Myeloma (MM) are extremely rare. Consequently, data on efficacy and therapy results are limited. We report on a rare case of long-term follow up patient with MM and ITG. After chemotherapy the patient achieved complete remission with complete recovery of renal function. A repeat renal biopsy revealed complete resorption of the deposits. After four years, ITG was diagnosed again in another kidney biopsy during a relapse of MM. There was excessive glomerular infiltration by lymphoid cells and obstruction of capillary lumen was identified. Bundles of microtubules, similar to the deposits in kidneys, were revealed in some lymphoid cells.

A new oral anticoagulant, dabigatran etexilate (DE, a prodrug of direct thrombin inhibitor (DTI) dabigatran), has been used clinically to prevent thrombosis. The assessment of dabigatran efficiency is necessary in some clinical cases, such as renal insufficiency, risk of bleeding, and drug interactions. However, a specific thrombin generation test (TGT) that is one of the most informative and sensitive to anticoagulant therapy (calibrated automated thrombinography (САТ)) shows a paradoxical increase of test parameters, such as endogenous thrombin potential (ETP) and peak thrombin, in patients receiving DE. The paradoxical behaviour of ETP and peak thrombin in these patients in the presence of DTIs is mostly caused by a decrease in the activity of thrombin in the α2-macroglobulin-thrombin complex that is used as a calibrator in CAT. For a correct estimation of the TGT parameters in patient’s plasma containing DTIs we proposed to use our previously described alternative calibration method that is based on the measurement of the fluorescence signal of a well-known concentration of the reaction product (7-amino-4-methylcoumarin). In this study, the validity of such approach was demonstrated in an ex vivo study in patients with knee replacement and two special patients with multiple myeloma, who received DE for thrombosis prophylaxis.

Introduction. Multiple myeloma (MM) in its early onset is complicated by myeloma nephropathy in 20-30% of patients, 10% of whom require haemodialysis. Early studies have shown that renal dysfunction has no adverse effect on melphalan pharmacokinetics. Auto-HSCT in some patients allows to restore renal function and to stop hemodialysis. Aim of the study. To assess the safety and efficacy of auto- HSCT in MM patients with dialysis-dependent renal failure. Materials and methods. During a period from May 2010 to December 2016 thirteen (3 males, 10 females) MM patients with dialysis-dependent renal failure aged 48 to 65 years (median 58) underwent auto-HSCT. The diagnosis was made according to IMWG criteria. In the onset of the disease, the median creatinine level was 1091 μmol /L, and GFR (CKD-EPI) ranged 3 to 10 ml / min / 1.73 m2 (median 3). Induction therapy included bortezomib-containing regimens in all patients, bendamustine was used in 5 (38.5%) patients, immunomodulatory drugs were used in 2 (15%) patients. HSC mobilization was performed according to the scheme: G-CSF 10 μg/kg. The median number of harvested CD34+ cells was 3.46x106/kg. Subsequently, against the background of programmed hemodialysis and in the setting of high-dosed melphalan (100-200 mg/m2), 12 patients underwent a single and one patient underwent a tandem auto-HSCT. On Day 100 after auto-HSCT, an antitumor response and renal response were assessed. Survival curves were constructed using the Kaplan-Meier method. Statistical analysis was done using Statistica 10. Results. Before auto-HSCT CR was documented in 8 (61%) patients, VGPR was documented in 4 (31%) patients, PR was documented in 1 (8%) patient, with no renal response registered, GFR: 4-10 ml/min/1.73 m2 (median 5). The period of agranulocytosis after auto-HSCT was accompanied by infectious complications, cardiac and neurological dysfunctions (Table 1). The resulting complications were stopped; the mortality associated with transplantation (TRM) was 0%. At +100 days after auto-HSCT, the PR was confirmed in 9 (70%) patients and VGPR was confirmed in 4 (30%) patients. GFR: 5 - 17 ml/min/1.73 m2 (median 7). The minimal renal response was registered in 2 patients (15%), hemodialysis was stopped. After a median follow-up of 52 months 5-year progression-free survival (PFS) was 71%, and OS was 92%. Conclusion. Auto-HSCT in MM patients with dialysis-dependent renal failure is a feasible and effective treatment method, nevertheless, characterized by a high rate of early post-transplantation complications. Dialysis-dependent renal failure is not a contraindication for the use of high dosed melphalan followed by auto-HSCT. The probability of hemodialysis discontinuation after auto-HSCT was 15%. Survival rates are comparable to those in patients without renal impairment. Disclosures No relevant conflicts of interest to declare.