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 angles

Myeloma

Nephrologists

Myeloma History

1844： mollities ossium fatigue, bone pain from fractures

（1845：abnormal urine protein）

1848： analysis of abnormal urine protein ‘hydrated deutoxide of albumen'

1873 : description of “multiple myeloma”

1875-95： description of plasma cell 1900 : plasma cell ⇒ Myeloma cell

Orthopaedic ?

Nephrology ?

1880：Bence Jones Protein(BJP)

Henry Bence Jones

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)

② during the course of disease : ～50 ％

The Durie and Salmon staging system

STAGE CRITERIA Surviving time(months)

StageⅠ A 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/24h

62

B 22

StageⅡ A Fitting neither Stage I nor Stage III 58

B 34

StageⅢ A 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

45

B 24

*subclassification：A. Cr < 2 mg/dl, B. Cr ≧2 mg/dl

Bone Marrow Transpl.2011;46:771-83 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

Renal involvement is associated with poor prognosis

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

Median survival time 8.6 vs 34.5 months

normal renal function

Renal failure

Myeloma in CKD

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

0

2

4

6

8

10

12

14

Mild or no RI

moderate RI Severe RI

Early Mortality (<2 months from initiation of therapy)

(%)

eGFR (stage)

1990-1994

1995-1999

2000-2004

2005-

<15 7.7% 8.4% 6% 9.3%

15-29 9.7% 12.6% 11.2% 10.1%

30-59 32.1% 28.4% 29.5% 25.9%

60-89 34.8% 36.8% 34.8% 32.7%

>90 15.7% 13.8% 18.5% 22.1%

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

CKD：Chronic Kidney Disease

eGFR<60 : 40-50％

Myeloma kidney ≒ Cast nephropathy

Monteseny 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 % 12.5 %

tumor invasion 1 % 30.8 %

Others

31% 40 %

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

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

Comparison of novel agents for myeloma kidney

Bor

Thal

Len

Leukemia.2013;27:423-29

Median renal response time (> renal PR ) Bor：1.3 months Tha：2.7 months Len：>6.0 months

(thick ascending loop of Henle)

Pathogenesis ① Tubulo-Interstitial injury by Light Chain

glomerulus Proximal tubule obstruction ＆ inflammation

Distal tubule

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

Cast Nephropathy

CCP：Cyclized Competitor Peptide

Prevention & treatment for cast nephropathy

Proximal tubule Cast-Nephropathy

Distal tubule

MCP-1

glomerulus

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

Pathogenesis ② Tubulo-Interstitial injury by Light Chain

Renal protective effect of chemotherapy in FLC induced Tubulo-interstitial injury

Excessive FLC production

Redox pathway ↑ (H2O2)

NFκB pathway↑, MAPK↑

Inflammation & Fibrosis & Apotosis ⇒ uNAG↑, uβ2MG↑

IL-6, IL-8, MCP-1(CCL2), TGFβ other inflammatory cytokines and chemokines

Blood. 2011; 117: 1301-6 AJP. 2012;180: 41-47 JASN. 2010; 21: 1165-73 Leukemia. 2008; 22: 1485-93 NDT. 2012; 27: 3713-18 Cancer Reserch.2001; 61: 3071-6

c-Src↑, ASK-1↑

ultrafiltration

Excessive FLC endocytosis

Plasma cell (Myeloma cell)

Glomerulus

Proximal tubular cell

tubule Interstitium

【Localization】 【pathogenesis】

Bortezomib

①anti-neoplastic effect (indirect renal protective effect)

IMiDS

Bortezomib

②direct renal protective effect ?

ASK-1：Apoptosis Signal-regulating Kinase 1

Apheresis

③direct removal of FLC

Early reduction of FLC associated with renal recovery in myeloma kidney

Colin A Hutchison, JASN 22: 1129-36, 2011

60％

80％

・Renal recovery correlates with overall survival. recovery group 42.7 months

non-reversible group 7.8 months

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

PE+chemo for Cast Nephropathy

achievement rate(＞Renal PR） : 86％

FLC reduction rate： 74.6％ 96.5％

N Engl J Med 2011; 364(24):2365-6

sFLC eGFR

Median of 8 Plasma Exchanges(range, 3 to 14) were performed.

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

0

2

4

6

8

10

12

0

5000

10000

15000

20000

25000

30000

1 8 15 22 29

Cre

atin

ine

(mg

/dl)

free

ligh

t ch

ain

(m

g/L

)

day

free light chain Cr Bor plasma exchange on-line HDF

Changing Hospital ⇒ ASCT

Non-Cast nephropathy

Monteseny 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 % 12.5 %

tumor invasion 1 % 30.8 %

Others

31% 40 %

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

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

Plasma cell dyscrasia related kidney disease

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 ?

Myeloma ⇒ Myeloma therapy (novel agents)

MGUS + RI ⇒ Myeloma therapy？

conventional therapy (steroid，MD)

Plasma cell

“Patchy Lesion” both in bone marrow and kidney could lead to underdiagnosis

Good！ 20％

Bad 5％

【 bone-marrow examination 】

Pathological lesion

【renal biopsy】

MIDD+Cast(-)

MIDD+Cast(+)

Good！

Bad

Myeloma !

Myeloma ! MGUS ??

MGUS ??

M G R S

• 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)

Monoclonal Gammopathy of Renal Significance

Blood 2012;120:4292-4295 Leuk Lymphoma 2012; 53:1656-1657

Plasma cell dyscrasia associated renal lesion

Eliot C.Heher, Nelson B.G, et al : blood 116 ; 1397-1404 ,2012

Glomerulus(UP↗) ①Amyloidosis ②MIDD：LCDD,LHCDD,HCDD ③Cryo-Nephritis ④Fibrillary-N / Immunotactoid-N ⑤PGNMID/PGNMILCD Tubulo-interstitium(Cr↗、eGFR↘) ①Cast Nephropathy ②Tumor invation ③dehydration, hypercalcemia NSAIDs ④Light 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

Interstitium

Myeloma

Myeloma

Novel agnets

Plasma cell dyscrasia

○

○

×

×

MGUS

MGUS MGRS ○

MGRS ○

Tubule

All renal biopsy

(Jan. 2010 - Dec. 2012)

n = 1190

Monoclonal

gammopathy(-)

n = 1163 Monoclonal

gammopathy(+)

n = 27

Myeloma n = 4

Lymphoma n = 2

MGRS group

n = 10

non-MGRS group

n = 11

diagnosis

after biopsy

diagnosis

before biopsy

exclusion

MGUS

n = 21

indication

[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

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

**All renal diseases in the study were limited to glomerular diseases

Clinical features MGRS (n=10) Non-MGRS (n=11) P value

Age (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±3.9 69.0±12.6 0.29

sBP (mmHg) 137.7±22.3 121.8±9.7 0.23

dBP (mmHg) 80.8±15.3 73.6±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

Hematuria 3/7 1/10 0.22

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

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

M-protein Heavy chain

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=3：4 κ：λ=5：3

IgA type κ：λ=1：1 κ：λ=2：0

Urine M-protein 6/10(60%) 1/11(9%) ＜0.05

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

Limitation：We have not examined FLC.

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

MGRS Non-MGRS

P＜0.05

(%)

0

20

40

60

80

100

[CD19 negative plasma cell(%)]

Renal pathological damage

0

20

40

60

1 2

Global sclerosis(%)

P<0.05

0

20

40

60

1 2

Tubulo-interstitial fibrosis(%)

P<0.05

0

20

40

60Tubular atrophy(%)

MGRS

MGRS

MGRS Non-MGRS

Non-MGRS

Non-MGRS

0

10

20

30

40

50

Non-MGRS MGRS

P<0.05 P<0.05

Mononuclear cell Infiltration (%)

• 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(%)

Result Renal biopsy is important to diagnose MGRS

MGRS will be underdiagnosed without renal biopsy in the existing myeloma criteria

Hemato-renal features of MGRS

• Proliferation of CD19(-) monoclonal plasma cell

• Increase of s-β2MG

• Massive proteinuria (2.8 g/day vs 0.3 g/day )

• Renal tubulo-interstitial damage

• Elevation of u-NAG (≒proximal tubular damage)

【Hematological feature】

【Renal feature】

? Reduced FLC absorption

Increase in urine M-protein (MGRS 60% vs non MGRS 9%) ?

Cast formation ??

?

Potential risks of progression to myeloma

and renal failure

MGUS

Working theory MGUS-MGRS-Myeloma-CKD

CKD (Chronic kidney disease)

Myeloma CKD stage5*

*CKD stage 5 = End stage renal failure

MGRS

MGRS Case: 67 y.o. : IgG-λ MGUS + systemic AL Amyloidosis

rFLC 0.05 1.17 0.80 0.89 0.99 0.97 0.83 0.88

245

7.6 14.6

4.79

0.95

3.1

0.9

0.6

0.91 0.92

0

50

100

150

200

250

300

0

1

2

3

4

5

6 λ(mg/l)

UP(g/day or g/gCr)

Cr(mg/dl)

1 50 100 150 200 250 300 350 400 (day)

BD 1cycle : Bor 1.3mg/m2 d1.8.15.22 (standard) Dex 20mg/day d1.2. 8.9. 15.16. 22.23

UP (g/day)

Cr (mg/dl)

λ (mg/l)

hospitalization

PS 3 → 0！ sBP 90→120 mmHg

⇒off

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

Nephrotic syndrome, persistent hypotension ECG: AVB , UCG : granular sparkling sign IgG 1300, Plasma 2.0%, Performance status : 3

Poor prognosis cancer ⇒ chronic disease?

0 0.0

20 40 60 80 120

1.0

0.8

0.4

Time（month）

0.6

0.2

140 100

Pro

po

rtio

n s

urv

ivin

g

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

S. K. Kumar et al.：Blood, 111, 2516-2520, 2008.

Mayo Clinic MM: 2,981 cases

2001-06(novel agents)

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

2006-10

2001-05

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

Increase in elderly patients

44%

50%

59% 59 %

12.5

18

24

32%

65y.o 65

68 69y.o

0

10

20

30

40

50

60

70

50

55

60

65

70

>65y.o

>75y.o

Median age(%)

Med

ian

age

(y.

o)

1990-94 1995-99 2000-04 2005~ N=306 N=414 N=403 N=650

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

Greek Myeloma Study Gloup

≒Transplantation-ineligible patients

% o

f to

tal m

yelo

ma

pat

ien

ts

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 management from before and after the diagnosis and treatment

Close collaboration between Hematologists, Nephrologist and several specialists

Early diagnosis & intervention

HCO-HD, PE, renal biopsy CKD administration

Nephrologists

Home doctors

Cardiologists

Neurologists

Orthopedists

Hematologists

Gastro-enterologists

management in stable phase terminal care

Nephrologists ⇔ Community physicians

“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 hospital ②UP>(+) or P/C > 0.5 g/gCr ③Renal dysfunction (eGFR<60)

地域連携NEWS Vol. 56

(Home doctors)

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

[Nephrologists ⇔ Hematologists] Sendai Myeloma seminar (2012, 2013, 2014, 2015)

[Nephrologist(Mizuno) ⇒ Hematologists & Nephrologists]

in Okinawa (2014), in Hokkaido(Sep 2015)

[Hematologist ⇒ Nephrologists] Myeloma kidney Seminar in Sendai (2012，2013，2014, 2015?)

Discussion

Lecture

Presentation (Lecture ?)

: break down a wall of misunderstanding

Thank you for your kind attention