Daratumumab in Patients With Bortezomib-Refractory Proliferative Glomerulonephritis With Monoclonal Immunoglobulin Deposits.
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ABSTRACT:
SUBMITTER: Almaani S
PROVIDER: S-EPMC8343787 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A 55-year-old man developed rapidly progressive glomerulonephritis and nephrotic syndrome. A kidney biopsy specimen showed diffuse proliferative and crescentic glomerulonephritis with monoclonal IgG1κ, humps, and nephritis-associated plasmin receptor, indicating infection-associated proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID). Despite dialysis-dependent renal failure, symptomatic therapy resulted in spontaneous recovery of the renal function, mimicking post-infectious glomerulonephritis (PIGN). A heterozygous complement factor H mutation was detected by comprehensive genetic testing of alternative pathway regulatory genes, which might lead to persistent infection-triggered alternative pathway activation and account for severe glomerulonephritis. Post-infectious PGNMID and PIGN might share common clinical presentations and pathogenesis related to the complement pathway.
| S-EPMC5457925 | biostudies-literature
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| S-EPMC7270977 | biostudies-literature
Project description:A 74-year-old man presented with nephrotic syndrome and kidney insufficiency. Laboratory tests revealed monoclonal gammopathy of immunoglobulin A-lambda. Renal biopsy revealed diffuse mesangial proliferation and double-contoured basement membranes. Immunofluorescent analyses showed granular deposition of immunoglobulin A and C3 at the capillary walls and mesangial regions. Immunohistochemistry suggested monoclonal deposition of immunoglobulin A1-lambda. Electron microscopic analyses showed finely granular electron-dense deposits at mesangial and subendothelial areas. These findings suggested immunoglobulin A-type proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Based on the results of bone marrow aspiration, multiple myeloma was diagnosed. Because the renal manifestation was considered to be affected by monoclonal gammopathy, chemotherapy was initiated rather than immunomodulatory therapy. Although bortezomib and dexamethasone proved ineffective, second chemotherapy with elotuzumab, lenalidomide, and dexamethasone was successful, and kidney function recovered. Effective treatments for proliferative glomerulonephritis with monoclonal immunoglobulin deposits have not been established. This represents the first description of a patient successfully treated for proliferative glomerulonephritis with monoclonal immunoglobulin deposits by chemotherapy using elotuzumab.
| S-EPMC7502091 | biostudies-literature
Project description:BackgroundGlomerulonephritis (GN) with non-Randall-type, non-cryoglobulinaemic monoclonal immunoglobulin G deposits encompasses rare diseases [proliferative GN with non-organized deposits (PGNMID) and immunotactoid GN] that cannot be distinguished without ultrastructural analysis by electron microscopy (EM).MethodsHere, we report and analyse the prognosis of 41 EM-proven (PGNMID for 39/41) and 22 non-EM-proven/DNAJB9-negative cases, diagnosed between 2001 and 2019 in 12 French nephrology centres.ResultsMedian (interquartile range) serum creatinine (SCr) at presentation was 150 (92-256) µmol/L. The predominant histological pattern was membranoproliferative GN (79%), with IgG3 (74%) kappa (78%) deposits the most frequently observed. Disease presentation and patient management were similar between EM-proven and non-EM-proven cases. A serum monoclonal spike was detected for 21 patients and 10 had an underlying haematological malignancy. First-line therapy was mixed between clone-targeted therapy (n = 33), corticosteroids (n = 9) and RAAS inhibitors (n = 19). After 6 months, nine patients achieved complete and 23 partial renal recovery. In univariate analysis, renal recovery was associated with baseline SCr (odds ratio 0.70, P = 0.07). After a median follow-up of 52 (35-74) months, 38% of patients had progressed to end-stage kidney disease independently associated with baseline SCr [hazard ratio (HR) 1.41, P = 0.003] and glomerular crescentic proliferation (HR 4.38, P = 0.004).ConclusionsOur results confirm that non-cryoglobulinaemic and non-Randall GN with monoclonal IgG deposits are rarely associated with haematological malignancy. The prognosis is uncertain but may be improved by early introduction of a specific therapy.
| S-EPMC9394706 | biostudies-literature
Project description:The diagnosis of membranoproliferative glomerulonephritis (MPGN) has recently undergone change from an electron microscopy-based classification scheme to one based largely on immunofluorescence findings. This change is due to the recognition that many of these cases are driven by abnormalities of the alternative complement cascade, resulting in the concept of C3 glomerulopathy. Here we reviewed our case files to identify those with an MPGN pattern that show false negative staining for monoclonal immunoglobulins by routine immunofluorescence. Monoclonal immunoglobulin deposits were unmasked by performing immunofluorescence on formalin-fixed paraffin embedded tissue after protease digestion. Clinico-pathological details of 16 such cases with a mean serum creatinine of 2.7 mg/dl and mean 24 h proteinuria of 7.1 g were then determined. Hypocomplementemia was present in two-thirds of patients. Fourteen patients had a paraprotein on serum immunofixation, all of which matched the biopsy immunofluorescence staining pattern. Bone marrow biopsy showed plasma cell dyscrasia or B-cell lymphoproliferative disorder in 13 patients. Ten of these patients had findings on biopsy most consistent with C3 glomerulonephritis prior to performing paraffin immunofluorescence. Thus a high index of suspicion is necessary to avoid misdiagnosis in these cases, as many would have been mistakenly diagnosed as C3 glomerulopathy or unclassified MPGN if paraffin immunofluorescence was not performed.
| S-EPMC4687465 | biostudies-literature
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| S-EPMC8343764 | biostudies-literature
Project description:Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0-27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P<0.0001) and improved the overall response rate (83.8% versus 63.2%; P<0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% con fidence interval, 0.12-0.29; P<0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.
| S-EPMC6269293 | biostudies-other
Project description:BACKGROUND AND OBJECTIVES: Glomerular deposition of monoclonal Ig has been exceptionally described as the cause of membranoproliferative glomerulonephritis, through activation of the complement alternative pathway (CAP). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We retrospectively studied six adults with monoclonal gammopathy and glomerulonephritis (GN) characterized by isolated C3 deposits. RESULTS: All patients presented with hematuria, associated with chronic renal failure and proteinuria in five patients, three of whom had nephrotic syndrome. Five patients had monoclonal gammopathy of undetermined significance and one had smoldering myeloma. The serum monoclonal IgG (κ four of six, λ two of six) was associated with light chain (LC) proteinuria in five patients. Four patients had low serum C3 and/or factor B levels. C4, factor H (CFH), and I protein levels were normal in five of five patients; none had detectable C3NeF. IgG anti-CFH activity was positive in one case. No mutations in CFH, CFI, and MCP genes were identified in four of four patients. Deposits were intramembranous, subepithelial, and mesangial by electron microscopy, and stained positive for C3 (six of six), properdin, and CFH (two of two) but negative for Ig LC and heavy chains, C4, and C1q (6/6) by immunofluorescence. Five patients progressed to end-stage renal disease over a median period of 47 months, despite chemotherapy in four patients. In one patient, monoclonal λLC deposits were observed on a follow-up kidney biopsy after 4 years. CONCLUSIONS: GN with isolated glomerular C3 deposits might represent an unusual complication of plasma cell dyscrasia, related to complement activation through an autoantibody activity of the monoclonal Ig against a CAP regulator protein.
| S-EPMC3358988 | biostudies-other
Project description: Not available
| S-EPMC10429394 | biostudies-literature
Project description:Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 blocking antibody durvalumab at the time of progression may reverse daratumumab-resistance. The efficacy and safety of daratumumab and durvalumab in daratumumab-refractory relapsed/refractory MM patients was evaluated in this prospective, single-arm phase 2 study (NCT03000452). None of the 18 enrolled patients achieved PR or better. The frequency of serious adverse events was 38.9%, with one patient experiencing an immune related adverse event (grade 2 hyperthyroidism). No infusion-related reactions were observed. Analysis of tumor- and immune cell characteristics was performed on bone marrow samples obtained at baseline and during treatment. Daratumumab combined with durvalumab reduced the frequency of regulatory T-cells and decreased the proportion of T-cells expressing LAG3 and CD8+ T-cells expressing TIM-3, without altering T- and NK-cell frequencies. Durvalumab did not affect tumor cell characteristics associated with daratumumab resistance. In conclusion, the addition of durvalumab to daratumumab following development of daratumumab-resistance was associated with an acceptable toxicity profile, but was not effective. This indicates that inhibition of the PD-1/PD-L1 signaling pathway at the time of daratumumab-resistance is insufficient to reverse daratumumab-resistance.
| S-EPMC8158123 | biostudies-literature