Plasma cell dyscrasia with renal impairment including MGRS

Transcription

1 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

2 Japanese Society of Myeloma COI Disclosure Shinichi Mizuno The author have no financial conflicts of interest to disclose concerning the presentation.

3 Looking from different Nephrologists angles Myeloma

4 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 : description of plasma cell 1900 : plasma cell Myeloma cell Blood 2008; 111:

5 Renal impairment(ri) is a common complication [ frequency of RI ] 1 newly diagnosed patients : % (10% of which may require dialysis) 2 during the course of disease : ~50 % Bone Marrow Transpl.2011;46: Expert Opin Pharmacother. 2013;11: Adv Chronic Kidney Dis ;21:36-47 Best Pract Res Clin Haematol. 2005;18(4): 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 B 22 StageⅡ A Fitting neither Stage I nor Stage III 58 StageⅢ A B 34 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 B 24 *subclassification:a. Cr < 2 mg/dl, B. Cr 2 mg/dl 62 45

6 Renal involvement is associated with poor prognosis normal renal function Renal failure Median survival time 8.6 vs 34.5 months Blade J, et al: Arch Intern Med 158(17): ,1998

7 Myeloma in CKD CKD:Chronic Kidney Disease Frequency of renal impairment at initial MM diagnosis (n=1773) egfr (stage) <15 7.7% 8.4% 6% 9.3% % 12.6% 11.2% 10.1% % 28.4% 29.5% 25.9% % 36.8% 34.8% 32.7% > % 13.8% 18.5% 22.1% egfr<60 : 40-50% (%) Early Mortality (<2 months from initiation of therapy) Mild or no RI moderate RI Severe RI Dimopoulos M.A, et al. Annals of Oncology. 2014; 25:

8 Myeloma kidney Cast nephropathy Monteseny 1998 Nasr 2011 Oshima 2001 Wirk 2011 Leung 2014 Cast Nephropathy 41 % 33 % 23.1 % % ~100 % Amyloidosis 30 % 21 % 13.5 % 7-30 % 5-15 % MIDD 19 % 22 % % % TIN/Fanconi synd. 10 % 0.5 % % Fibrillary GN 1% Immunotactoid-G 0.5 % 12.5 % tumor invasion 1 % 30.8 % Others 31% 40 % MIDD:Monoclonal Immunoglobulin deposition disease TIN:Tublo-Interstitial nephropathy AJKD. 2012; 59: Am J Hematol. 2001; 67, 1-5 Bone Marrow Transplantation. 2011; 46: NDT. 1998; 13: Advance in CKD. 2014; 21: 36-47

9 Comparison of novel agents for myeloma kidney Bor Thal Len Median renal response time (> renal PR ) Bor:1.3 months Tha:2.7 months Len:>6.0 months Leukemia.2013;27:423-29

10 Pathogenesis 1 Tubulo-Interstitial injury by Light Chain glomerulus Proximal tubule Cast Nephropathy obstruction & inflammation Distal tubule (thick ascending loop of Henle) CCP:Cyclized Competitor Peptide Prevention & treatment for cast nephropathy Leukemia. 2008;22: Nat Rev Nephrol.2011;8:168

11 Pathogenesis 2 Tubulo-Interstitial injury by Light Chain glomerulus Proximal tubule Cast-Nephropathy Distal tubule MCP-1 Br J Haematol (3): Serum free light chain analysis. 3rd ed; Nat Rev Nephrol.2011;8:168

12 Renal protective effect of chemotherapy in FLC induced Tubulo-interstitial injury Localization pathogenesis Plasma cell (Myeloma cell) Glomerulus Excessive FLC production ultrafiltration Excessive FLC endocytosis 1anti-neoplastic effect (indirect renal protective effect) Bortezomib Apheresis 3direct removal of FLC IMiDS Proximal tubular cell Redox pathway (H2O2) c-src, ASK-1 2direct renal protective effect? NFκB pathway, MAPK Bortezomib tubule Interstitium IL-6, IL-8, MCP-1(CCL2), TGFβ other inflammatory cytokines and chemokines ASK-1:Apoptosis Signal-regulating Kinase 1 Inflammation & Fibrosis & Apotosis unag, uβ2mg Blood. 2011; 117: AJP. 2012;180: JASN. 2010; 21: Leukemia. 2008; 22: NDT. 2012; 27: Cancer Reserch.2001; 61:

13 Early reduction of FLC associated with renal recovery in myeloma kidney Colin A Hutchison, JASN 22: , % Treatment strategy for FLC removal 1High Cut-off hemodialysis(hco-hd) 2Plasma exchange(pe) 60% Renal recovery correlates with overall survival. recovery group 42.7 months non-reversible group 7.8 months

14 PE+chemo for Cast Nephropathy N Engl J Med 2011; 364(24): egfr sflc achievement rate(>renal PR) : 86% FLC reduction rate: 74.6% 96.5% Median of 8 Plasma Exchanges(range, 3 to 14) were performed.

15 free light chain (mg/l) Creatinine (mg/dl) Case: 49 y.o, AKI(Cr 9), BJP-λ type cast-nephropathy clinical course : BD + Plasma Exchange (Evacure-4A ) free light chain Cr Bor plasma exchange on-line HDF Changing Hospital 29 day ASCT

16 Non-Cast nephropathy

17 Plasma cell dyscrasia Monteseny 1998 Nasr 2011 Oshima 2001 Wirk 2011 Leung 2014 Cast Nephropathy 41 % 33 % 23.1 % % ~100 % Amyloidosis 30 % 21 % 13.5 % 7-30 % 5-15 % MIDD 19 % 22 % % % TIN/Fanconi synd. 10 % 0.5 % % Fibrillary GN 1% Immunotactoid-G 0.5 % 12.5 % tumor invasion 1 % 30.8 % Others 31% 40 % related kidney disease MIDD:Monoclonal Immunoglobulin deposition disease TIN:Tublo-Interstitial nephropathy AJKD. 2012; 59: Am J Hematol. 2001; 67, 1-5 Bone Marrow Transplantation. 2011; 46: NDT. 1998; 13: Advance in CKD. 2014; 21: 36-47

18 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) Plasma cell MGUS + RI Myeloma therapy? conventional therapy (steroid,md)

19 Patchy Lesion both in bone marrow and kidney could lead to underdiagnosis Myeloma! Myeloma! Good! 20% Bad 5% MGUS?? Good! MIDD+Cast(+) Bad MIDD+Cast(-) MGUS?? renal biopsy Pathological lesion bone-marrow examination

20 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: Leuk Lymphoma 2012; 53:

21 Plasma cell dyscrasia associated renal lesion Interstitium Tubule 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 Plasma cell dyscrasia Myeloma MGRS MGUS Myeloma MGUS MGRS Novel agnets

22 [study design] a single-center retrospective case-series study All renal biopsy (Jan Dec. 2012) n = 1190 exclusion indication 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 diagnosis before biopsy diagnosis after biopsy Monoclonal gammopathy(+) n = 27 MGUS n = 21 MGRS group n = 10 Monoclonal gammopathy(-) n = 1163 Myeloma n = 4 Lymphoma n = 2 non-mgrs group n = 11 **All renal diseases in the study were limited to glomerular diseases

23 Clinical features MGRS (n=10) Non-MGRS (n=11) P value Age (y.o) 71.7± ± Sex (No) M : 7 F : 3 M:8 F: BMI 24.3± ± sbp (mmhg) 137.7± ± dbp (mmhg) 80.8± ± Cr (mg/dl) 1.44±0.37* 1.17±0.26* 0.17 egfr(ml/min/1.73m 2 ) 41.95± ± TP (g/dl) 6.20± ±0.48 <0.05 Alb (g/dl) 2.75± ±0.63 <0.05 U-protein (g/day) 2.80±1.39* 0.38±0.21* <0.01 Hematuria 3/7 1/ U-β2MG (μg/l) 1026±3941* 242.0±231.5* 0.13 U-NAG (U/l) 24.8± ±4.6 <0.05 Mean±SD (*Median±Q) unpaired t-test u-test, x2-test

24 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± ±0.74 <0.01 Amount of M-protein (mg/dl) 1194± ± 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 Limitation:We have not examined FLC. Mean±SD (*Median±Q) unpaired t-test u-test, x2-test

25 Proliferation of monoclonal plasma cell (After separated CD38 gating by FCM) [CD19 negative plasma cell(%)] P< (%) MGRS Non-MGRS

26 Renal pathological damage Global sclerosis(%) P< Tubulo-interstitial fibrosis(%) P< MGRS 1 2 Non-MGRS 0 MGRS 1 2 Non-MGRS Tubular atrophy(%) P< Mononuclear cell Infiltration (%) P< MGRS Non-MGRS 0 MGRS Non-MGRS

27 Result Renal 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

28 Hemato-renal features of MGRS Hematological feature Proliferation of CD19(-) monoclonal plasma cell Increase of s-β2mg 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?? Potential risks of progression to myeloma and renal failure

29 Working theory MGUS-MGRS-Myeloma-CKD Myeloma CKD stage5* MGUS MGRS CKD (Chronic kidney disease) *CKD stage 5 = End stage renal failure

30 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 : 3 BD 1cycle : Bor 1.3mg/m 2 d (standard) Dex 20mg/day d rflc hospitalization PS 3 0! sbp mmhg λ(mg/l) UP(g/day or g/gcr) Cr(mg/dl) off λ (mg/l) UP (g/day) Cr 3 2 (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 (day)

31 Proportion surviving Poor prognosis cancer chronic disease? (novel agents) Mayo Clinic MM: 2,981 cases Time(month) 140 S. K. Kumar et al.:blood, 111, , 2008.

32 Overall Survival in Multiple Myeloma(2000~2010) Mayo clinic All patient: 1038 Male:59% ISS: 1(30%),2(39%), 3(31%) S. K. Kumar et al.:leukemia, 28, , 2014.

33 Median age (y.o) % of total myeloma patients Increase in elderly patients Transplantation-ineligible patients Greek Myeloma Study Gloup 65y.o 65 >65y.o >75y.o Median age 68 69y.o 59% 59 % (%) % 50% 32% ~ N=306 N=414 N=403 N=650 Dimopoulos M.A, et al. Annals of Oncology. 2014; 25:

34 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)

35 Multi-department management from before and after the diagnosis and treatment Close collaboration between Hematologists, Nephrologist and several specialists Nephrologists HCO-HD, PE, renal biopsy CKD administration Orthopedists Cardiologists Hematologists Early diagnosis & intervention Gastroenterologists Neurologists Home doctors management in stable phase terminal care

36 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 地域連携 NEWS Vol. 56 1M-protein (+) or (s/o) or Dx. MGUS in other hospital 2UP>(+) or P/C > 0.5 g/gcr 3Renal dysfunction (egfr<60) 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)

37 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)

38 Thank you for your kind attention