Monoclonal Gammopathy of Renal Signficances
Nelson Leung, MD
Disclosures
Relevant Financial Relationships
Grant: Omeros Corportation
Advisor: Aduro, BTG, Prothena, and Takeda
Off-Label/Investigational Uses
Takeda and Janssen; Bortezomib and daratumumab
Light Chain Cast Nephropathy
Kyle et al. Blood 2008
Courtesy of Dr. Samih Nasr
Renal Pathologies in Myeloma Patients
Ivanyi. Arch Pathol Lab Med 1990
Nasr et al. AJKD 2012
Risk of Cast Nephrology by sFLC level
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
0-50 51-100 101-200 201-500 > 500
% P
ati
en
t
sFLC (mg/dL)
Leung et al. Kidney Int 2005
Yadav et al. BMC Nephrol 2018
Nasr et al. AJKD 2012
Kidney Disease and Multiple Myeloma
Leung et al. Nature Rev Med Nephrol 2019
N Engl J Med 1991; 324: 1845-51
casts
Tubular basement membrane deposits
Light chain crystals
Congo red positive deposits
Renal AL amyloidosis is 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
• Chemotherapy is the treatment of choice
• Indication – preserve organ function
Kyle & Gertz. Sem in Hematol. 1995
Said et al. C J Am Soc Nephrol 2013
Multiple myeloma negative affects overall survival in AL amyloidosis
Kyle & Braid. Medicine 1975
Kourelis et al. JCO 2013
IMWG Diagnostic Criteria of Plasma Cell Dyscrasias
MGUS SMM MM
M-spike < 3 g/dL 3 g/dL 3 g/dL
Bone Marrow PC < 10% 10% 10%
Hypercalcemia (C) absent absent +/-
Renal impairment (R) absent absent +/-
Anemia (A) absent absent +/-
Lytic lesions (B) absent absent +/-
Free light chain ratio <100 <100 ≥ 100
Bone marrow plasma cells < 60% < 60% ≥ 60%
Bone lesion on MRI ≤ 1 ≤ 1 > 1
Rajkumar et al. Lancet Oncol 2014
Observe Observe/Clin trial Treat
International Kidney and Monoclonal Gammopathy Research Group
Case #1
• 08/2003• 35 yo female presents with edema and hypertension
• Scr was 0.8 mg/dl (70 μmol/L)
• Proteinuria 10 g/d
• 09/2003• Renal biopsy was performed
• Membranoproliferative glomerulonephritis
Membranoproliferative glomerulonephritis with IgA lambda deposits with paracrystalline substructures
IgA2IgA1
λIgA
Soares et al. Am J Kidney Dis 2006
Hematologic evaluation
• SPEP – negative
• Serum/urine IFE – negative
• Bone marrow biopsy – no features of clonal proliferation
Disease course of a patient with MPGN with IgAλ
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Proteinuria…Scr (mg/dl)
CTDCyP
BM Bx (-)
MMF
Rituximab
CyPTacrolimus
dexamethasone
Acalculous
cholecystitis
Characteristics of MGRS related diseases
1. Kidney disease is progressive
2. Response to immunosuppression is poor (VGPR or better 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
AL amyloidosis
LCDD
Characteristics of MGRS related diseases
1. Kidney disease is progressive
2. Response to immunosuppression is poor (VGPR or better 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
Characteristics of MGRS related diseases
1. Kidney disease is progressive
2. Response to immunosuppression is poor (VGPR or better 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. Kidney disease is progressive
2. Response to immunosuppression is poor (VGPR or better is required)
3. High rate of recurrence after kidney transplantation
4. Like MGUS, some patients will progress to a malignant condition
• 8/2003 nephrotic syndrome
• 6/2008 ESRD
• 6/2011 Living donor kidney Tx Monoclonal IgA detected pretransplant
• 12/2011 Scr 1.4 mg/dl (123μmol/L)
• 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
MGRS
• Any B-cell or plasma cell clonal disorder that: 1. Causes one or more kidney lesions related to the monoclonal
immunoglobulin and
2. The underlying B-cell or plasma cell clone does not cause tumor complications or meet current hematological criteria for specific therapy.
3. Treatment is indicated to preserve kidney function
Leung et al. Nature Reviews Nephrol 2018
Vos et al. Br J Haematol 2016
Strati et al. Haematologica 2015
Clones associated with MGRS
Leung et al. Nature Rev Med Nephrol 2019
How is MGRS diagnosed?
• MGRS can only be diagnosed by a kidney biopsy
• Only exception is immunoglobulin amyloidosis which could be diagnosed by biopsy of other tissue
Rate of MGUS vs Glomerular Disease
Swaminathan et al. C J Am Soc Nephrol 2006
Therneau et al. Mayo Clin Proc 2012
Deposits with heavy chain and light chain restriction
C3 glomerulopathy with monoclonal gammopathy
• C3G with monoclonal gammopathy is much more common in patients older than 49 years of age
• 58 – 83% vs < ~2%
• Absence of mutations of complement regulatory proteins
• < 20% have C3nef
• <20% have factor H antibodies
Lloyd et al. Clin Kindey J 2016, Zand et al. 2013
Sethi et al. AJKD 2010, Bridoux et al. CJASN 2011
A direct causal effect has not be found in majority of cases
C3
Thrombotic microangiopathy
• POEMS syndrome• Polyneuropathy
• Organomegaly
• Endocrinopathy
• Monoclonal protein
• Skin changes
Leung et al. Nature Rev Med Nephrol 2019
Diagnostic evaluation of MGRS
1. Kidney biopsy
1. MGRS is defined by the presence of a monoclonal gammopathy related kidney lesion
2. A kidney biopsy is required in almost all situations
2. Monoclonal protein testing
3. Clonal detection
1. Bone marrow biopsy
2. Flow cytometry
3. Imaging studies
Leung et al. Nature Reviews Nephrol 2019
Clone directed therapy
Gumber et al. Kidney Int 2018
Chauvet et al. Blood 2017
Indications for Treatment of MGRS
Observation until
hematologic progression
Systemic AL
amyloidosis or MIDD
No
ESRD
Yes
TreatNo
Kidney Transplant
Candidate
Yes
No
Yes
Castro et al. Leukemia & Lymphoma 2012
Sayed et al. Blood 2015
Hematologic response based on front line treatment in MIDD
Sayed et al. Blood 2015
ASCT (any time) 16 13 0 2 0
Kourelis et al. Am J Hematol 2016
Treatment Duration and Durability of Response
• Treatment duration (cycles)
• Cohen (bortezomib based) - 4.5 (3 – 6)
• Ziogas (Vd/VCD) - 5 (4 – 6)
• Duration of response
• Cohen – after achieving a VGPR with bortezomib based treatment, median time to progression – 8.8 years
• Kourelis – time to hematologic progression was 55 m in patients with VGPR or better vs 23 months in those with < VGPR.
• Maintenance therapy is usually not required unless the patient has a history of relapse or high risk features
Cohen et al. Kidney Int 2015
Ziogas et al. Leukemia Lymphoma 2016
Kourelis et al. Am J Hematol 2016
Only 20-30% of patients with PGNMID have a detectable circulating monoclonal protein
Bhutani et al. Mayo Clinic Proc 2015
Clones involved in PGNMID
Clone detection 17%
• Plasma cell – 50%
• CD20+ - 30%
• CD20+CD38+ – 20%
Bhutani et al. Mayo Clinic Proc 2015
Gumber et al. Kidney Int 2018
Barnidge et al. J Proteome Res 2014
Single IgG kappa Patient over 7 years
Murray et al. The XIVth International Symposium on Amyloidosis 2014
Detecting very small monoclonal proteins negative on immunofixation
Detection of multiple monoclonal IgG lambda clones
Open label Daratumumab
Summary
• MGRS is a clonal proliferative disorder which produces a nephrotoxic monoclonal gammopathy that by itself do not meet criteria for treatment (malignancy)
• The diagnosis of MGRS requires a kidney biopsy
• Treatment of MGRS should target the pathologic clone
• Goal of therapy should be a hematologic response of VGPR or better
• Improvement in proteinuria and/or creatinine should accompany the VGPR
Team Approach to The Management of MGRS
Diagnosis of the Kidney
disease
Clonal identification
and treatment
Assessment of kidney
function and treatment
Renal Pathologist
HematologistNephrologist
Thank you for your attention
Questions