Update on the Classification of MGRS€¦ · Case #1 •63 year old male with abnormal urinalysis...
Transcript of Update on the Classification of MGRS€¦ · Case #1 •63 year old male with abnormal urinalysis...
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Update Classification of MGRS Associated Disease
Nelson Leung, MD
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Disclosures
Relevant Financial Relationships
Grant: Omeros Corporation
Advisor: Aduro, BTG, and Takeda
Off-Label/Investigational Uses
Takeda and Janssen; Bortezomib and daratumumab
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International Kidney and Monoclonal Gammopathy Research Group
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MGRS
• Hematologic conditions that are associated with one or more kidney diseases where the hematologic condition does not meet criteria for treatment based on the clonal burden.
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Renal AL amyloidosis as a MGRS
• In AL, only 15% meet criteria for multiple myeloma• 40% - > 10% bone marrow plasma cells
• 7% - > 3 g/dL of M-protein
• 8.2% - lytic lesions
• 3% had SMM
• The use of cytotoxic therapy is justified to prevent further organ damage
Kyle & Gertz. Sem in Hematol. 1995
Gertz et al. NDT 2009
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Characteristics of MGRS related diseases
1. Patient survival is good in most patients but kidney survival is poor.
2. Response to immunosuppression is poor and often temporary. Clone directed therapy is required.
3. High rate of recurrence after kidney transplantation
4. Like MGUS, some patients will progress to a malignant condition
Heilman et al. Am J Kidney Dis1992
Gertz et al. NDT 2009
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Patient and Kidney Survival in MIDD
Heilman et al. Am J Kidney Dis 1992
Overall Survival Renal Survival
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Characteristics of MGRS related diseases
1. Patient survival is good in most patients but kidney survival is poor.
2. Response to immunosuppression is poor and often temporary. Clone directed therapy is required.
3. High rate of recurrence after kidney transplantation
4. Like MGUS, some patients will progress to a malignant condition Chauvet et al. Blood 2017
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Chauvet et al. Blood 2017
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Characteristics of MGRS related diseases
1. Patient survival is good in most patients but kidney survival is poor.
2. Response to immunosuppression is poor and often temporary. Clone directed therapy is required.
3. High rate of recurrence after kidney transplantation
4. Like MGUS, some patients will progress to a malignant condition
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Renal allograft survival of allografts with PGNMID
2 patients who lost their graft had a second kidney transplant
and PGNMID recurred within 4 months of the second transplant
Said et al. Kidney Int 2018
Recurrence rate = 89%
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Characteristics of MGRS related diseases
1. Patient survival is good in most patients but kidney survival is poor.
2. Response to immunosuppression is poor and often temporary. Clone directed therapy is needed.
3. High rate of recurrence after kidney transplantation
4. Like MGUS, some patients will progress to a malignant condition
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Steiner et al. Oncotarget 2018
Definition of
progression and
treatment data were
not provided
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• 8/2003 nephrotic syndrome
• 6/2008 ESRD
• 6/2011 Living donor kidney Tx Monoclonal IgA detected pretransplant
• 12/2011 Scr 1.4 mg/dl• Proteinuria 1.7 g/d
• SPEP and UPEP – IgA
• Serum FLC: = 12.3 mg/L, = 8.65 mg/L, ratio = 1.43
• Kidney biopsy – recurrent proliferative GN with IgA deposits
• Bone marrow biopsy – 30% light chain restricted PC
• 1/2012 Scr 3.3 mg/dl (290 μmol/L)
Herrmann et al. Clin Nephrol 2014
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Location based classification
Sethi et al. Curr Opin Nephrol Hyperten 2016
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Bridoux et al. Kidney Int 2015
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Organized deposits
fibrils immunotactoidcrystals
/inclusions
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Leung et al. Nature Rev Med Nephrol 2019
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Leung et al. Nature Rev Med Nephrol 2019
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Monoclonal Fibrillary Glomerulonephritis
• Majority of fibrillary Gn cases are polyclonal
• ~15% are composed of monoclonal immunoglobulin or have a circulating monoclonal immunoglobulin
Leung et al. Nature Rev Med Nephrol 2019
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Crystalglobulinemia
MacEwen et al . AJKD 2013
Leung et al. NDT PLUS 2010
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Thrombotic microangiopathy
Leung et al. Nature Rev Med Nephrol 2019
Monoclonal gammopathy-associated thrombotic microangiopathy
Jennifer C. Yui, MD1, Daniel Garceau, MD2, Kenar D. Jhaveri, MD3, Rimda Wanchoo,MD3,
Vanesa Bijol,MD4, Ilya Glezerman, MD5 Hani Hassoun6, MD, Angela Dispenzieri, MD7,
Stephen J Russell, MD PhD7, Nelson Leung, MD7,8
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Leung et al. Nature Rev Med Nephrol 2019
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• 57 yo male with recurrent pulmonary hemorrhage and renal failure
• 100% crescents
• Anti-GBM test was negative
• IgA deposits were noted on kidney biopsy
• Monoclonal IgA was found in the serum
• Bone marrow biopsy – 5% - 10% plasma cells
• Kidney transplant was performed for ESRD
• Disease recurred 1 year later
Am J Kidney Dis 2005; 45: 397–406
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Case #1
• 63 year old male with abnormal urinalysis 02/15
• PMH:
• (01/15) Gleason 3 + 4, clinical T2 adenocarcinoma of the prostate
• Hypertension
• Evaluation
• Creatinine – 0.9 mg/dl
• Proteinuria – 9.8 g/d
• Serum protein electrophoresis - negative
• Urine immunofixation – monoclonal kappa
• Kappa – 65.9, lambda - 1.76, ratio – 37.4
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Case #1 Kidney and Hematologic evaluation
• Light microscopy• Minimally thickened capillary basement membranes.
• Immunofluorescence• Granular capillary wall and mesangial staining for IgG (segmental trace) and kappa light chain
(2+). No glomerular staining for lambda light chain noted. Tubular reabsorption droplets stain for IgG and kappa and lambda light chain.
• Bone marrow• 10% kappa light chain restricted plasma cells
• 0.5% lambda light chain restricted CD5 population
• Bone survey• negative
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Rocha et al. Kidney Int Reports 2017
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Rocha et al. Kidney Int Reports 2017
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Clonal proliferative conditions of MGRS
Leung et al. Blood 2012
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Clones associated with MGRS
Leung et al. Nature Rev Med Nephrol 2019
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Pattern of expression of CD19 and CD20 antigens during B-cell development and associated
malignancies.
Veronique Blanc et al. Clin Cancer Res 2011;17:6448-6458
©2011 by American Association for Cancer Research
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Thank you for your attention
Questions