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