Plasma cell dyscrasia with renal
impairment including MGRS
~ The importance of multi-departmental management ~Dept. Nephrology, Japan Community
Health Care Organization Sendai Hospital
Shinichi Mizuno

Japanese Society of Myeloma
COI Disclosure
Shinichi Mizuno

The author have no financial conflicts of interest to disclose
concerning the presentation.

Looking from different
anglesNephrologists

MyelomaMyeloma History
Orthopaedic ?

1844： mollities ossium
fatigue, bone pain from fractures（1845：abnormal urine protein）

1848： analysis of abnormal urine protein‘hydrated deutoxide of albumen'1880：Bence Jones Protein(BJP)
Nephrology ?

Henry Bence Jones

1873 : description of “multiple myeloma”
1875-95： description of plasma cell1900 : plasma cell ⇒ Myeloma cell
Blood 2008; 111: 2962-72

Renal impairment(RI) is a common complication[ frequency of RI ]① newly diagnosed patients ： 20-40 ％(10％ of which may require dialysis)
Bone Marrow Transpl.2011;46:771-83② during the course of disease : ～50 ％Expert Opin Pharmacother. 2013;11:1477-95
Adv Chronic Kidney Dis. 2014 ;21:36-47
Best Pract Res Clin Haematol. 2005;18(4):689-707

The Durie and Salmon staging system

STAGE
StageⅠ A
B
StageⅡ A

CRITERIA

Survivingtime(months)

All of the following:• Hemoglobin value >10g/dL • Serum calcium value normal or <10.5mg/dL• Bone x-ray, normal bone structure (scale0), or solitary bone plasmacytoma only
• Low M-component production rates IgG value <5g/dL; IgA value <3g/dL• Urine light chain M-component on electrophoresis <4g/24h62

Fitting neither Stage I nor Stage III

B

StageⅢ AB

225834

One or more of the following:• Hemoglobin value <8.5g/dL • Serum calcium value >12mg/dL• Advanced lytic bone lesions (scale 3)• Bence Jones protein >12g/24h• High M-component production rates IgG value >7g/dL IgA value >5g/dL*subclassification：A. Cr < 2 mg/dl, B. Cr ≧2 mg/dl

4524

Renal involvement is associated with poor prognosis

normal renal function

Median survival time
8.6 vs 34.5 months

Renal failure

Blade J, et al: Arch Intern Med 158(17):1889-1893,1998

Myeloma in CKDCKD：Chronic Kidney Disease

Frequency of renal impairment
at initial MM diagnosis (n=1773)

Early Mortality(<2 months from initiation of therapy)(%)
14eGFR(stage)19901994

19951999

20002004

2005-<157.7%

8.4%

6%

9.3%

15-29

9.7%

12.6%

11.2%

10.1%

8

30-59

32.1%

28.4%

29.5%

25.9%

6

60-89

34.8%

36.8%

34.8%

32.7%

12
1042>90

15.7%

13.8%

18.5%

eGFR<60 : 40-50％

22.1%

0
Mild orno RI

moderate RI

Severe RI

Dimopoulos M.A, et al. Annals of Oncology. 2014; 25: 195-200

Myeloma kidney ≒ Cast nephropathy
Monteseny1998

Nasr2011

Oshima2001

Wirk2011

Leung2014

Cast Nephropathy

41 %

33 %

23.1 %

40-63 %

~100 %

Amyloidosis

30 %

21 %

13.5 %

7-30 %

5-15 %

MIDD

19 %

22 %

19-26 %

59-65 %

TIN/Fanconi synd.

10 %

0.5 %

31-50 %

Fibrillary GN

1%Immunotactoid-G

0.5 %tumor invasion

1%

30.8 %

Others31%

40 %MIDD：Monoclonal Immunoglobulin deposition disease
TIN：Tublo-Interstitial nephropathy

12.5 %AJKD. 2012; 59: 786-94
Am J Hematol. 2001; 67, 1-5Bone Marrow Transplantation. 2011; 46: 771-83
NDT. 1998; 13: 1438-45
Advance in CKD. 2014; 21: 36-47

Comparison of novel agents for myeloma kidney

Bor
ThalLenMedian renal response time(> renal PR )Bor：1.3 months
Tha：2.7 months
Len：>6.0 months
Leukemia.2013;27:423-29

Pathogenesis ①
Tubulo-Interstitial injury by Light Chain
glomerulus

ProximaltubuleCast Nephropathy
obstruction ＆ inflammation

Distal tubule(thick ascending loop of Henle)

CCP：Cyclized Competitor Peptide
Prevention & treatment
for cast nephropathy

Leukemia. 2008;22:1485-93
Nat Rev Nephrol.2011;8:168

Pathogenesis ②
Tubulo-Interstitial injury by Light Chain
glomerulus

ProximaltubuleCast-Nephropathy
Distal tubule

MCP-1

Br J Haematol. 2004 126(3):348-54
Serum free light chain analysis. 3rd ed; 2005. 175–194
Nat Rev Nephrol.2011;8:168

Renal protective effect of chemotherapy
in FLC induced Tubulo-interstitial injury①anti-neoplastic effect【Localization】【pathogenesis】

Plasma cell

Excessive FLC production

Bortezomib

ultrafiltration

Apheresis(indirect renal protective effect)(Myeloma cell)

Glomerulus

IMiDS③direct removal of FLC

Excessive FLC endocytosis
Redox pathway ↑ (H2O2)
Proximal tubularcellc-Src↑, ASK-1↑②direct renal protective effect ?

NFκB pathway↑, MAPK↑
tubuleInterstitium

Bortezomib

IL-6, IL-8, MCP-1(CCL2), TGFβ
other inflammatory cytokines and chemokines
Inflammation & Fibrosis & Apotosis
Blood. 2011; 117: 1301-6⇒ uNAG↑, uβ2MG↑

ASK-1：Apoptosis Signal-regulating Kinase 1

JASN. 2010; 21: 1165-73
NDT. 2012; 27: 3713-18

AJP. 2012;180: 41-47
Leukemia. 2008; 22: 1485-93
Cancer Reserch.2001; 61: 3071-6

Early reduction of FLC associated withrenal recovery in myeloma kidney
Colin A Hutchison, JASN 22: 1129-36, 2011

80％

【Treatment strategy for FLC removal】①High Cut-off hemodialysis(HCO-HD)②Plasma exchange(PE)60％

・Renal recovery correlates with overall survival.
recovery groupnon-reversible group42.7 months
7.8 months

PE+chemo for Cast Nephropathy
N Engl J Med 2011; 364(24):2365-6

sFLC

eGFR

achievement rate(＞Renal PR） : 86％

FLC reduction rate： 74.6％
Median of 8 Plasma Exchanges(range, 3 to 14) were performed.

96.5％

Case: 49 y.o ♂, AKI(Cr 9) , BJP-λ type cast-nephropathy
clinical course : BD + Plasma Exchange (Evacure-4A®)
CrBor

plasma exchange

on-line HDF

30000

1225000

1020000

81500061000045000

201815day

Creatinine (mg/dl)

free light chain (mg/L)

free light chain

0Changing
Hospital2229⇒ ASCTNon-Cast nephropathy

Plasma cell dyscrasia
related kidney diseaseMonteseny
1998

Nasr
2011

Oshima
2001

Wirk
2011

Leung
2014

Cast Nephropathy

41 %

33 %

23.1 %

40-63 %

~100 %

Amyloidosis

30 %

21 %

13.5 %

7-30 %

5-15 %

MIDD

19 %

22 %

19-26 %

59-65 %

TIN/Fanconi synd.

10 %

0.5 %

31-50 %

Fibrillary GN

1%Immunotactoid-G

0.5 %tumor invasion

1%

30.8 %

Others31%

40 %MIDD：Monoclonal Immunoglobulin deposition disease
TIN：Tublo-Interstitial nephropathy

12.5 %AJKD. 2012; 59: 786-94
Am J Hematol. 2001; 67, 1-5Bone Marrow Transplantation. 2011; 46: 771-83
NDT. 1998; 13: 1438-45
Advance in CKD. 2014; 21: 36-47

MGUS with Renal impairment
Case ） MIDD (or AL amyloidosis)

M-protein:
IgG-λ M protein(+) , IgG 800 mg/dl
Renal impairment : Cr 1.0 mg/dl, UP 1.5 g/day
Symptomatic ?

Plasma cellMyeloma⇒ Myeloma therapy (novel agents)

MGUS + RI⇒ Myeloma therapy？
conventional therapy(steroid，MD)

“Patchy Lesion” both in bone marrow andkidney could lead to underdiagnosis
Myeloma !
Good！

Bad

MGUS ??

5％

20％

Myeloma !
Good！
MIDD+Cast(+)

Bad

Pathologicallesion

MIDD+Cast(-)

MGUS ??

【renal biopsy】【 bone-marrow examination 】

M G R S

Monoclonal Gammopathy of Renal Significance• a causal relationship between renal impairment and M-protein(MGUS)• Recommended treatment : MM regimen = novel agents(even though hematological status dose not meet the criteria of MM)
Blood 2012;120:4292-4295
Leuk Lymphoma 2012; 53:1656-1657

Plasma cell dyscrasia associated renal lesion
Glomerulus(UP↗)①Amyloidosis②MIDD：LCDD,LHCDD,HCDD③Cryo-Nephritis④Fibrillary-N / Immunotactoid-N⑤PGNMID/PGNMILCD

Plasma celldyscrasia

NovelagnetsMyeloma

○MGRS
MGUS

○×

Tubulo-interstitium(Cr↗、eGFR↘)
TubuleInterstitium①Cast Nephropathy②Tumor invation③dehydration, hypercalcemia
NSAIDs④Light chain proximal
tubulopathy (with Fanconi)⑤MIDD：LCDD,LHCDD, HCDD
⑥Amyloidosis

MGUS: Monoclonal gammopathy of undetermined significance
MIDD： non-Amyloid monoclonal immunoglobulin deposition disease
PGNMID：Proliferative glomerulonephritis with monoclonal immunoglobulin deposits
HSPN：Henoch- Schonlein purpura, MCNS: Minimal change nephrotic syndrome
MN: membranous nephropathy, TMA:Thrombotic microangiopathy

Myeloma

○MGUS
MGRS

○×

[study design]
a single-center retrospective
case-series study

MGRS group(n=10)
AL-amyloidosis: n = 3
Cryo-GN: n = 3
MIDD: n = 2
Immunotactoid-GN: n = 2

All renal biopsy(Jan. 2010 - Dec. 2012)n = 1190

Monoclonal
gammopathy(+)
n = 27indication

Monoclonalgammopathy(-)
n = 1163

diagnosis
before biopsy

MGUS
n = 21

non-MGRS group(n=11)

Membranous nephropathy: n =3
IgA nephropathy: n = 2
Obesity related nephropathy: n = 3
Nephrosclerosis: n = 2
Minor glomerular abnomality: n = 1

exclusion

Myeloman=4Lymphoma n = 2

diagnosis
after biopsy

MGRS groupn = 10**All renal diseases in the study were limited to glomerular diseases

non-MGRS groupn = 11

Clinical features
MGRS (n=10)

Non-MGRS (n=11)

P valueAge (y.o)71.7±11.7

58.3±18.4

0.06

Sex (No)

M：7
F：3

M：8
F：3

0.89

BMI

24.3±3.969.0±12.6

0.29

sBP (mmHg)

137.7±22.3

121.8±9.7

0.23

dBP (mmHg)

80.8±15.373.6±8.9

0.21

Cr (mg/dl)

1.44±0.37*

1.17±0.26*

0.17

eGFR(ml/min/1.73m2)

41.95±21.59

53.23±20.06

0.22

TP (g/dl)

6.20±0.93

7.30±0.48＜0.05

Alb (g/dl)

2.75±0.99

3.82±0.63＜0.05

U-protein (ｇ/day)

2.80±1.39*

0.38±0.21*＜0.01

3/71/100.22

U-β2MG (μg/l)

1026±3941*

242.0±231.5*

0.13

U-NAG (U/l)

24.8±16.7

6.5±4.6＜0.05

Hematuria

Mean±SD (*Median±Q)
unpaired t-test、u-test, x2-test

Hematological status
MGRS (n=10)

Non-MGRS (n=11)

P value

Plasma cell (％)

3.50 ± 1.49*

1.60±0.90*

0.06

S-β2MG (mg/dl)

4.39±1.31

2.23±0.74＜0.01

Amount of M-protein(mg/dl)1194±494

1322±552

0.59

IgG：A：M=7：2：0

IgG：A：M=9：2：0

Light chain

κ：λ=5：5

κ：λ=7：3

IgG type

κ：λ=3：4κ：λ=5：3

IgA type

κ：λ=1：1

κ：λ=2：06/10(60%)

1/11(9%)M-protein
Heavy chain

Urine M-protein

Limitation：We have not examined FLC.

＜0.05

Mean±SD (*Median±Q)
unpaired t-test、u-test, x2-test

Proliferation of monoclonal plasma cell
（After separated CD38 gating by FCM）

[CD19 negative plasma cell(%)]
P＜0.0510080(%)

60
40200MGRS

Non-MGRS

Renal pathological damage
60

Global sclerosis(%)
P<0.0560

P<0.0540402020012MGRS

60

Tubulo-interstitial fibrosis(%)

0Non-MGRS

Tubular atrophy(%)
P<0.05

150

Mononuclear cell Infiltration (%)
P<0.0540402

Non-MGRS

MGRS

302020100MGRS

Non-MGRS

0MGRS

Non-MGRS

ResultRenal biopsy is important to diagnose MGRS
• MGRS was rare : 0.8％ of total kidney biopsy in our hospital (10/1190)• Approximately half of MGUS with RI was MGRS : 47.7％(10/21)• No significant difference in : renal function
amount of M-protein
plasma cell in bone marrow(%)

MGRS will be underdiagnosed without renal biopsy
in the existing myeloma criteriaHemato-renal features of MGRS【Hematological feature】
Potentialrisks cellof• Proliferation of CD19(-) monoclonal
plasmaprogression to myeloma• Increase of s-β2MG
and renal failure【Renal feature】• Massive proteinuria (2.8 g/day vs 0.3 g/day )• Renal tubulo-interstitial damage• Elevation of u-NAG (≒proximal tubular damage)?

Reduced FLC absorption

Increase in urine M-protein?
?

(MGRS 60% vs non MGRS 9%)

Cast formation ??

Working theory
MGUS-MGRS-Myeloma-CKD

Myeloma
CKD stage5*

MGUSMGRSCKD(Chronic kidney disease)*CKD stage 5= End stage renal failure

MGRS Case: 67 y.o. : IgG-λ MGUS + systemic AL Amyloidosis
Nephrotic syndrome, persistent hypotension
ECG: AVB , UCG : granular sparkling sign
IgG 1300, Plasma 2.0%, Performance status : 3BD 1cycle : Bor 1.3mg/m2 d1.8.15.22(standard) Dex 20mg/day d1.2. 8.9. 15.16. 22.23

rFLC

0.05 1.17

0.80

0.89

0.99

0.97

0.83

0.88

λ

⇒off65UP300

λ(mg/l)hospitalization

UP(g/day or g/gCr)

PS 3 → 0！
sBP 90→120 mmHg

2454.794(g/day)250

Cr(mg/dl)

CR keep (After 16 months from the end of BD)
Cr 0.9, UP(-), P/C 0.2g/gCr
rFLC 1.16 dFLC -2.6(κ18.9、λ16.3)
ECG：sinus

3.1

3Cr(mg/l)

2
0.91

0.9

0.95

0.92

7.6

0150
100(mg/dl)

1200

1

14.6
50

100

150

200

250

300

350

50
0.6

0400 (day)Poor prognosis cancer ⇒ chronic disease?
1.0

1971-76
1977-82
1983-88
1989-94
1995-00
2001-06

Proportion surviving

0.8

0.6

2001-06(novel agents)

0.4

0.2

0.0
020

40

60

80

100120140Time（month）
Mayo Clinic
MM: 2,981 cases
S. K. Kumar et al.：Blood, 111, 2516-2520, 2008.

Overall Survival in Multiple Myeloma(2000～2010)
Mayo clinic
All patient: 1038
Male：59%
ISS: 1(30%),2(39%), 3(31%)

2006-10
2001-05

S. K. Kumar et al.：Leukemia, 28, 1122-28, 2014.

Increase in elderly patients≒Transplantation-ineligible patients>65y.o>75y.oMedian age

Median age (y.o)

70

6560

(%)

69y.o

68
65y.o

60

65
59%

59 %

50
4050%
44%

32%
24

55

30
20

18

1012.5

5070

1990-94
N=306

1995-99
N=414

Dimopoulos M.A, et al. Annals of Oncology. 2014; 25: 195-200

2000-04
N=403

2005~
N=650

0% of total myeloma patients

Greek Myeloma Study Gloupa variety of problems in elderly patients and chronicity■Comorbidities in multiple organs••••

Metabolic syndrome (HT, DM, Obesity, Dyslipidemia)
Cardiovascular events(AMI, angina, CHF, stroke , etc)
Dementia / ADL ↓Chronic Kidney Disease (CKD)■sequela after hematological response■drug: difficulty dose adjustment (cancer drug, antibiotic)■diet: salt restriction (sometimes adverse result??)■Background : personal and social• Increase in elderly single population• Increase in patients living in remote areas• Demand of Homecare medicine (national project)Multi-department managementfrom before and after the diagnosis and treatment

Close collaboration between Hematologists, Nephrologist and several specialists
Nephrologists
Orthopedists

HCO-HD, PE, renal biopsy
CKD administration

Hematologists
Cardiologists

Gastroenterologists

Early diagnosis & intervention

Neurologists

Homedoctors
management in stable phaseterminal careNephrologists ⇔ Community physicians(Home doctors)“MGRS Referral criteria” for early detection & intervention(original criteria in our hospital )① required, ② and ③ either or both

①M-protein (+) or (s/o) or Dx. MGUS in other hospital②UP>(+) or P/C > 0.5 g/gCr③Renal dysfunction (eGFR<60)
地域連携NEWS Vol. 56

renal biopsy

Non-MGRS･home doctor･visit once a year
in our hospital

MGRS･Novel agents(follow-up in our hospital)

Myeloma≧65 y.o ⇒ Novel agents(our hospital and/or hematologists)＜65y.o ⇒ ASCT + Novel agents(other hospital)

Approach to myeloma in our hospital
Contact regularly with Nephrologists and Hematologists
Discussion: break down a wall of misunderstanding[Nephrologists ⇔ Hematologists]
Sendai Myeloma seminar (2012, 2013, 2014, 2015)
Lecture[Hematologist ⇒ Nephrologists]
Myeloma kidney Seminar in Sendai (2012，2013，2014, 2015?)
Presentation (Lecture ?)[Nephrologist(Mizuno) ⇒ Hematologists & Nephrologists]
in Okinawa (2014), in Hokkaido(Sep 2015)

Thank you for your kind attention