Update Classification of MGRS Associated Disease

Nelson Leung, MD

Disclosures

Relevant Financial Relationships

Grant: Omeros Corporation

Advisor: Aduro, BTG, and Takeda

Off-Label/Investigational Uses

Takeda and Janssen; Bortezomib and daratumumab

International Kidney and Monoclonal Gammopathy Research Group

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.

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

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

Patient and Kidney Survival in MIDD

Heilman et al. Am J Kidney Dis 1992

Overall Survival Renal Survival

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

Chauvet et al. Blood 2017

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

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%

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

Steiner et al. Oncotarget 2018

Definition of

progression and

treatment data were

not provided

• 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

Location based classification

Sethi et al. Curr Opin Nephrol Hyperten 2016

Bridoux et al. Kidney Int 2015

Organized deposits

fibrils immunotactoidcrystals

/inclusions

Leung et al. Nature Rev Med Nephrol 2019

Leung et al. Nature Rev Med Nephrol 2019

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

Crystalglobulinemia

MacEwen et al . AJKD 2013

Leung et al. NDT PLUS 2010

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

Leung et al. Nature Rev Med Nephrol 2019

• 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

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

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

Rocha et al. Kidney Int Reports 2017

Rocha et al. Kidney Int Reports 2017

Clonal proliferative conditions of MGRS

Leung et al. Blood 2012

Clones associated with MGRS

Leung et al. Nature Rev Med Nephrol 2019

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

Thank you for your attention

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