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Page 1: Clinical interpretation of Serum Free Light Chain assays

Clinical interpretation of Serum Free Light Chain assays

22 Feb 2013

Dr. Eric Chan

Consultant Immunologist

Queen Mary Hospital

Hong Kong

Page 2: Clinical interpretation of Serum Free Light Chain assays

Figure 3.6. Diagrammatic representation of plasma cells producing intact immunoglobulins with monomeric κ and dimeric λ FLC molecules.

(Serum Free Light Chain Analysis. AR Bradwell. 5th edition, 2008)

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Clinical uses of serum free light chain (SFLC) assays Screening of diseases with monoclonal gammopathy

SPE (serum protein electrophoresis) + SFLC provide a simple and effective screen

Can replace SPE+UPE (urine protein electrophoresis) UPE and serum IFE (immunofixation) can be ordered more selectively e.g.

for amyloidosis and for typing of myeloma respectively Monitoring

Light chain multiple myeloma – potentially can replace 24-hour urine light chain quantitation

Intact immunoglobulin multiple myeloma – for light chain escape Non-secretory or oligo-secretory multiple myeloma

Prognosis MGUS progression (monoclonal gammopathy with unknown significance) IMWG guidelines:

Smouldering MM progression plasmacytoma progression Myeloma outcome AL amyloidosis outcome B-CLL outcome Wald. Macro. outcome

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1. LYC (F/59)

Breast carcinoma Skull lesion ? Metastasis, biopsy: plasmacytoma Bone marrow: plasma cell myeloma, Kappa restriction SPE, UPE: no monoclonal detected (NMD) IgG, A, M: immunosuppression SFK ↑, SFL ↓

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Discussion Questions:

Mis-match between UPE and SFLC? Light-chain Myeloma or Non-secretory Myeloma?

High SFK levels may be due to polymerisation. This results in an over-estimation of the SFK level. Polymerisation would also cause a false negative result in UPE because the polymerised proteins are of different charges.

By definition this is non-secretory myeloma. There has been no modification of the definition which is based on SPE/UPE/IFX. But this patient is more likely to have LCMM.

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2. CKY (M/58) June 2005 – diagnosed Lambda light chain myeloma

BM - markedly hypercellular marrow for age. Sheets of abnormal plasma cells are seen. Jan 2006 – post BMT BM: residual myeloma

Collect Date : 29/06/05 02/07/05 03/07/06 30/07/06 14/08/06------------------------------------------------------------------------------------------------------------------------------IgG 633 L -- 767 L 776 L 1030 819 – 1725 mg/dlIgA 61 L -- 133 111 136 70 - 386 mg/dl IgM 29 L -- 68 86 156 55 - 307 mg/dl SPE Weak MD -- NMD weak MD weak MDSerum IFX free L -- -- weak GK Total protein 66 -- -- 51.0 61.0 g/l% Paraprotein 3 -- -- 4.2 5.2 %Paraprotein 2 -- -- 2.1 3.2 g/lS. Free Kappa -- -- -- -- 21.90 H 3.30-19.40 mg/l S. Free Lambda -- -- -- -- 61.90 H 5.71-26.30 mg/l S. K/L Ratio -- -- -- -- 0.35 0.26-1.65 UPE -- MD -- -- --Urine IFX -- FL -- -- --Urine protein -- 0.47 -- -- -- <0.15 g/DUrine % paraprotein -- 21% -- -- --

Jul 2006 – weak IgG/K band -> oligoclonal reconstitution

Discussion Weak monoclonal or oligoclonal responses are not uncommon when the bone marrow regenerates after

treatment by chemotherapy Raised SFK and SFL, SFLC ratio normal Renal function normal

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Nov 2006 – relapse with sheets of plasma cells in BM But SFLC mildly elevated and UPE weak

Trephine biopsy shows markedly hypercellular marrow diffusely infiltrated by abnormal plasma cells. Many show nuclear immaturity and prominent nucleoli. Little erythroid and myeloid activity are recognised. Megakaryocytes are not seen. Bony trabeculae are unremarkable. Reticulin fibres are moderately coarsened.

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Discussion

Discrepancy between bone marrow and serological findings (weak SPE or UPE bands, low SFLC levels, but marked immunosuppression)

In general paraprotein levels reflect tumour load. The tumour cells of this patient is oligo-secretory

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21/06/07 16/08/07 07/01/08 26/03/09 25/06/09 30/09/09 12/04/10 23/11/10

S Free Kappa 13,600 22.7 27.7 21.5 22.8 12.0 11.2 17.0

S Free Lambda 3.2 11.2 32.0 24.8 24.3 18.3 18.0 17.6

S K/L Ratio 421.53 2.03 0.87 0.87 0.94 0.66 0.62 0.97

urea 6.7 6.7 3.5 7.5 6.7 5.6 7.6 6

creatinine 219 118 113 125 145 104 110 115

Treatment VAD PBSCT

BM exam

pleomorphic plasma cells predominate

no p'cytosis

regenerating marrow

mild p'cytosis

Questions & Discussion:Reasons of ↑ SFK and SFL

•There is a mild degree of renal impairment. Hence both SFK and SFL are elevated.•Other causes: polyclonal activation

Normal ratio but still ↑SFK•Although the ratio is normal the elevated SFK levels indicate there is still residual disease•Continuously falling indicates complete remission

3. HWM (M/53)

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"Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure" BMC Nephrology 2008;9:11

doi: 10.1186/1471-2369-9-112

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07/03/2011

05/09/2011

24/10/2011

26/04/2012

28/05/2012

12/10/2012

12/11/2012

S Free Kappa 26.1 34.3 53.5 182.0 82.0 190.0 435.0

S Free Lambda

52.5 31.4 26.8 39.9 23.5 17.4 21.6

S K/L Ratio 0.5 1.1 2 4.6 3.5 10.9 20.1

urea 5.6 6.3 6.1 5.1 10.2 7 5.7

creatinine 109 111 110 111 106 117 102

Treatment thal Len/dx

BM examno plasma-cytosis

PET ++no plasma-cytosis

Discussion:↑ S Free Kappa and S Free Lambda with normal ratio initially

•Similar explanations as before•Continuously rising S Free Kappa indicates relapse

Discrepancy between serum levels and bone marrow•Bone marrow negative•PET – extensive lytic lesions throughout the skeleton

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4. Light chain escape (TWF)Collect Date : 26/10/07 26/10/07 06/12/07 26/12/07 15/01/08------------------------------------------------------------------------------------------------------------------------------IgG -- 4870 H 1580 853 880 819 - 1725 mg/dlIgA -- 40 L 22 L 27 L 27 L 70 - 386 mg/dlIgM -- 23 L 19 L 14 L 14 L 55 - 307 mg/dlB2M -- 2.56 H -- -- -- < 1.42 ug/mlSPE -- MD MD MD MDSerum IFX -- GL -- -- --Total protein -- 100.0 68.0 61.0 68.0 g/l% Paraprotein -- 27.5 18.8 9.9 8.3 %Paraprotein -- 27.5 12.8 6.0 5.6 g/l UPE MD -- -- -- --Urine IFX FL -- -- -- --%Parapro.(Ur) 14.5 -- -- -- -- %

2007 – present as IgG myeloma2008-2009 – partial remission

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Collect Date : 05/02/09 26/03/09 26/03/09 26/05/09 26/05/09---------------------------------------------------------------------------------------------------------------------------------------

-IgG -- -- 1190 -- 944 819 - 1725 mg/dlIgA -- -- 89 -- 54 L 70 - 386 mg/dlIgM -- -- 97 -- 59 55 - 307 mg/dl

SPE -- -- WMD -- NMD% Paraprotein -- -- WQ -- -- %

UPE NMD NMD -- MD --%Parapro.(Ur) -- -- -- 44.1 -- %

S. Free Kappa -- -- 0.64 -- 7.44 3.30-19.40 mg/LS. Free Lambda -- -- 127H -- 523H 5.71-26.30 mg/LS. Free K/L Ratio -- -- 0.005 -- 0.014

retrospective assay

5/2009: Clinical deterioration

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Collect Date : 12/08/09 20/08/09 28/08/09 28/09/09 27/10/09-------------------------------------------------------------------------------------------------------------------------IgG -- -- 646 L 521 L 394 L 819 - 1725 mg/dlIgA -- -- 24 L 18 L 10 L 70 - 386 mg/dlIgM -- -- 28 L 21 L 15 L 55 - 307 mg/dl

SPE -- -- MD MD MDTotal protein -- -- 79.0 68.0 64.0 g/l% Paraprotein -- -- 3.0 3.0 2.1 %Paraprotein -- -- 2.4 2.0 1.3 g/l

UPE MD -- -- -- --%Parapro.(Ur) 88.2 -- -- -- -- %

S. Free Kappa -- -- -- 6.86 -- 3.30-19.40 mg/LS. Free Lambda -- -- -- 5790 -- 5.71-26.30 mg/LS. K/L Ratio -- -- -- 0.0012 --

IgG paraprotein levels stableUPE & SFL increasing

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Collect Date : 05/07/10 05/07/10 05/07/10 19/07/10 23/07/10------------------------------------------------------------------------------------------------------------------------------IgG -- 267 L -- 445 L 448 L 819 - 1725 mg/dlIgA -- 14 L -- 35 L 37 L 70 - 386 mg/dlIgM -- 8 L -- 23 L 21 L 55 - 307 mg/dlS. Free Kappa -- -- <1.07 -- -- 3.30-19.40 mg/LS. Free Lambda -- -- >3000.00 H -- -- 5.71-26.30 mg/LS. K/L Ratio -- -- <0.0004 -- --

SPE -- WMD -- WMD WMDTotal protein -- 54.0 -- 67.0 61.0 g/l% Paraprotein -- 1.2 -- 2.4 2.7 %Paraprotein -- 0.6 -- 1.6 1.6 g/l

UPE MD -- -- -- -- %Parapro.(Ur) 69.0 -- -- -- -- %

SFL continuously ↑ → death (2010)

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