Maria Kraj, Barbara Kruk, Monika Prochorec-Sobieszek

Transkrypt

1 praca orygiala / origial research article 201 immuoglobuli heavy/light chai (HLC) ad free light chai (FLC) cocetratios at diagosis i multiple myeloma ad IgM maligat lymphoma patiets with survival exceedig 10 years Stężeia w surowicy wolych lekkich łańcuchów immuoglobuliowych (FLC) i łańcuchów lekkich związaych z łańcuchem ciężkim (HLC), w chwili rozpozaia choroby u chorych a szpiczaka plazmocytowego i chłoiaka złośliwego IgM z czasem przeżycia poad 10 lat Maria Kraj, Barbara Kruk, Moika Prochorec-Sobieszek Summary Immuoglobuli (Ig) heavy/light chai (HLC) is a ovel atibody based assay that separately measures i pairs the light chai types of each Ig class geeratig ratios of moocloal Ig/backgroud polycloal Ig cocetratios. Free light chai (FLC) assay measures uboud κ ad λ chais. The aim of the preset study was to assess the progostic impact of HLC ad FLC assays i multiple myeloma (MM) ad IgM maligat lymphoma (ML) patiets with real log term survival. Measuremets of serum HLC ad FLC cocetratios were performed i 23 MM ad 12 ML patiets with survival exceedig 10 years ad 43 (19 MM, 24 ML) patiets with survival ot exceedig 5 years. HLC ad FLC ratios at diagosis were less abormal i patiets with survival exceedig 10 years tha i patiets with survival up to 5 years (p=0.03). The differeces i media values were maifold. However, i patiets with survival over 10 years highly abormal HLC ratio (<0.022 or >45) was foud i 3 MM patiets ad 7 ML patiets ad highly abormal FLC ratio (<0.1 or >30) was foud i 5 MM patiets ad i 1 ML patiet. I coclusio, serum HLC ad FLC measuremets at MM diagosis provide progostic iformatio, despite that eve i MM patiets with survival exceedig 10 years i 15% of them at diagosis serum HLC ad FLC ratios may be highly abormal. Key words: Heavy/light chai assay, Free light chais, Multiple myeloma, Waldeström macroglobuliemia, Survival by Polskie Towarzystwo Hematologów i Trasfuzjologów i Istytut Hematologii i Trasfuzjologii Otrzymao: Zaakceptowao: Istytut Hematologii i Trasfuzjologii, Warszawa, Polad Dyrektor: Prof. dr hab.. med. Krzysztof Warzocha Autorzy ie zgłaszają kofliktu iteresu Adres do korespodecji: Prof. Maria Kraj Istytut Hematologii i Trasfuzjologii, Idiry Gadhi 14, Warszawa, Polad mkraj@ihit.waw.pl Acta Haematologica Poloica; 43 (2b): Streszczeie Opracoway ostatio immuoglobuliowy test Hevylite HLC (heavy/ light chai) pozwala a osobe mierzeie typów łańcuchów lekkich w parach każdej klasy immuoglobuliowej i ozaczaie stosuku stężeia mookloalej immuoglobuliy do stężeia polikloalej immuoglobuliy tej samej klasy. Test FLC (free light chai) ozacza wole lekkie łańcuchy κ i λ, iezwiązae z cząsteczką immuoglobuliową. Celem aktualych badań była ocea wartości progostyczej ozaczaia w chwili rozpozaia choroby HLC i FLC w surowicy chorych a szpiczaka plazmocytowego i chłoiaka złośliwego IgM z rzeczywiście długim czasem przeżycia. Wykoao ozaczeia stężeia w surowicy HLC i FLC u 23 chorych a szpiczaka i 12 a chłoiaka z czasem przeżycia poad 10 lat oraz u 43 chorych (19 a szpiczaka, 24 a chłoiaka) z czasem przeżycia ieprzekraczającym 5 lat. Wartości stosuku HLC i stosuku FLC w chwili rozpozaia choroby były w miejszym stopiu ieprawidłowe u chorych z czasem przeżycia poad 10 lat iż u chorych z czasem przeżycia poiżej 5 lat (p=0,03). Różica w wartościach średich była wielokrota. Jedakże u chorych z czasem przeżycia poad 10 lat wysoce ieprawidłowe wartości stosuku HLC (<0,022 lub >45) stwierdzoo u 3 chorych a szpiczaka plazmocytowego i 7 chorych a chłoiaka IgM, a wy-

2 202 praca orygiala / origial research article soce ieprawidłowe wartości stosuku FLC (<0,1 lub >30) stwierdzoo u 5 chorych a szpiczaka i 1 chorego a chłoiaka. Z badań wyika, że ozaczaie HLC i FLC w czasie rozpozaia szpiczaka dostarcza iformacji progostyczych, mimo że awet u 15% chorych z czasem przeżycia poad 10 lat w chwili rozpozaia wartości stosuku HLC i stosuku FLC w surowicy mogą być wysoce ieprawidłowe. Słowa kluczowe: Hevylite, wole łańcuchy lekkie, szpiczak plazmocytowy, makroglobuliemia Waldeströma, przeżycia Itroductio Recetly, a assay for serum immuoglobuli free light chais (FLCs) has become available for cliical use [1] ad is curretly applied to moitor patiets with plasma cell disorders [2 4]. The assay allows quatitatio of kappa ad lambda chais that are ot boud to itact immuoglobuli molecules, ad allows determiatio of cloality based o the kappa to lambda ratio. A abormal FLC ratio idicatig presece of moocloal free light chais has bee recetly show to be a idepedet risk factor for progressio i moocloal gammopathy of udetermied sigificace (MGUS) ad for progressio of smolderig (asymptomatic) multiple myeloma (MM) [5, 6] ad solitary plasmacytoma of boe [7]. Sozek et al. [8] ad Kyrtsois et al. [9, 10] suggest that the serum FLC ratio at iitial diagosis is a importat predictor of progosis i myeloma ad ca be icorporated ito the Iteratioal Stagig System [11] for improved risk stratificatio. I 2009 Bradwell et al. [12] developed immuoglobuli heavy/light chai immuoassays Hevylite (HLC). Availability of atibodies which bid to coformatioal epitopes spaig the juctioal regios betwee boud κ or λ light chais ad their respective heavy chai parters has allowed the specific measuremet of serum IgGκ,, IgAκ, IgAλ, IgMκ ad IgMλ cocetratios. I tur, this has eabled the calculatio of IgGκ/, IgAκ/IgAλ ad IgMκ/ IgMλ ratios (heavy/light chai or HLC ratios) for idividual patiets. Separate measuremets of the κ ad λ light chai types of IgG, IgA ad IgM allow evaluatio of idividual tumor cloes ad give quatitative iformatio about the immuosuppressio of each o-tumor immuoglobuli. Measuremet of molecule pairs, such as IgGκ/, IgAκ/IgAλ, IgMκ/ IgMλ, would idicate cloality i the same maer as serum free light chai (FLC) κ/λ ratios [1]. Util ow, apart from a key Bradwell s et al. [12] ad our [13] publicatios, ad case report [14], there appeared cogress reports o the results of the use of ephelometric measuremet of idividual immuoglobuli κ/λ ratios i assessmet of moocloal gammopathies icludig evaluatio of progostic value of Hevylite assays i these diseases [15 21]. The aim of the preset study was to assess the progostic impact of FLC ad HLC assays i MM ad IgM maligat lymphoma (ML) patiets with real log term 10 years or more survival. Material ad methods The study icluded 23 MM ad 12 ML patiets with survival exceedig 10 years ad 43 (19 MM, 24 ML) patiets with survival ot exceedig 5 years. All patiets were diagosed [22] ad follow-up for may years at the Istitute of Hematology ad Trasfusio Medicie i Warsaw. protei electrophoresis ad immuofixatio were performed o agarose media with desitometric scaig usig Hydrasys TM 2 apparatus (Sebia, Frace) ad atisera from the same compay ad also usig Beckma Parago Immuofixatio Electrophoresis Kit. Nephelometric immuoglobuli assays, performed usig a Siemes BN TM II ephelometer, were used to measure IgGκ/, IgAκ/IgAλ, IgMκ/IgMλ (HLC) ad also to quatify FLC i the archived froze ad fresh sera of assessed patiets. I this method there were applied atibodies (Hevylite TM Huma IgG Kappa Kit; IgG lambda Kit, Hevylite TM Huma IgA Kappa Kit; IgA Lambda Kit, Hevylite TM Huma IgM Kappa Kit; IgM Lambda Kit; The Bidig Site, Ltd, Birmigham, UK) specific for IgGκ,, IgAκ, IgAλ, IgMκ, IgMλ ad atibodies (Freelite ; The Bidig Site, Ltd, Birmigham, UK) specific for κ ad λ light chais i free form, ot boud to the heavy chai. Statistical aalysis was performed usig Fisher exact test. Results Cliical ad immuoglobuli study at diagosis i idividual MM ad ML patiets with survival exceedig 10 years are preseted i tables I III. Table IV presets serum FLC ad HLC IgG cocetratios i a patiet with POEMS sydrome ad survival exceedig 9 years. Table V summarizes results of tumor ad o-tumor HLC immuoglobulis cocetratios ad HLC

3 praca orygiala / origial research article 203 Fig. 1. Eormously high values of serum FLC ratios i a patiet with IgAκ multiple myeloma ad real failure, at diagosis (A) ad 17 years later at relapse (G) Ryc. 1. Niezwykle wysokie wartości stosuku wolych łańcuchów lekkich w surowicy chorego a szpiczaka plazmocytowego IgAκ i z iewydolością erek, w chwili rozpozaia choroby (A) i 17 lat późiej w czasie progresji choroby (G) IgGκ/, IgAκ/IgAλ, IgMκ/IgMλ ratios at diagosis i sera of patiets with IgG ad IgA MM ad IgM ML with survival exceedig 10 years ad table VI summarizes results of that study i patiets with survival ot exceedig 5 years. Table VII presets serum FLC cocetratios at diagosis i patiets with MM ad ML with survival exceedig 10 years ad table VIII presets results of that study i patiets with survival ot exceedig 5 years. Fig. 1 illustrates serum ad urie protei study results i a still livig patiet with MM ad acute real failure at diagosis ad durig 17 years period of observatio. Discussio I our previous study out of 600 assessed patiets with MM 45 (7.5%) survived over 10 years from the disease diagosis ad begiig of atitumor treatmet. Patiets with log survival were youger (media, age 55 years) at the time of diagosis tha the whole studied group ad had ormal serum creatiie, calcium ad β 2 M levels. Sixty eight percet of these patiets had stage I or II cliical progressio [23]. Also i preset study MM patiets with survival exceedig 10 years had followig characteristics at diagosis: media age 52 years ( 31 78), media serum β 2 M cocetratio 2.46 mg/l ( ), media serum moocloal compoet cocetratio 3.1 g/dl ( ); 70% of these patiets had stage I disease accordig to Iteratioal Stagig System criteria [11] (Tab. I III). Preset study add to these characteristics oly slightly to moderately, i compariso to the geeral MM populatio, abormal HLC ad FLC ratios (Tab. VII IX). Whe patiets were stratified accordig to their survival time over 10 years or ot exceedig 5 years serum HLC ad FLC ratios at diagosis were less abormal i patiets with survival exceedig 10 years (p=0.03). The differeces i media values were maifold (Tab. VII IX). However, i patiets with survival exceedig 10 years highly abormal HLC ratio (<0.022 or >45) was foud i 3 MM patiets (13.6%) ad 7 ML patiets (58%) ad highly abormal FLC ratio (<0.1 or >30) was foud i 5 MM patiets (23.8%) ad i 1 ML patiet (8%). Maier et al. [21] coducted the study i a series of 71 Waldeström Macroglobuliemia patiets at diagosis. The media serum IgM HLC ratio was 100 ( ) ad the media IgM ivolved HLC level was 21.9 ( ) g/l. It is worthy to otice that our still livig patiet with MM ad real failure had at diagosis ad have also presetly, 17 years later, eormously icreased serum FLC ratio (Fig. 1). Previously we reported [25] the case of a male patiet presetig with polyeuropathy, moocloal gammopathy, spleomegaly, icosiderable lymphadeopathy, dissemiated sclerotic ad sigle lytic boe lesios, papilledema, leg edemas, discrete hypothyroidism ad thrombocytosis. The POEMS sydrome was diagosed ad the patiet was iitially treated with the VAD regime. No improvemet of europathy was observed, but the other disease symptoms did ot progress. Oe year after diagosis the patiet uderwet myeloablative treatmet, followed by autologous peripheral blood stem cell trasplatatio. Subjective eurological amelioratio, ormalizatio of the platelet cout ad stabi-

4 204 praca orygiala / origial research article Table I. free light chai (FLC) ad heavy /light chai (HLC) IgG cocetratios at diagosis i idividual IgG multiple myeloma patiets ad survival exceedig 10 years. Tabela I. Stężeia wolych łańcuchów lekkich (FLC) i związaych z łańcuchem ciężkim (HLC) IgG w chwili rozpozaia choroby u chorych a szpiczaka plazmocytowego IgG z czasem przeżycia poad 10 lat Case Age (yr) Date of serum sample β 2 M ISS stage Isotype of M-protei M-protei (g/dl) HLC IgG g/l IgGκ HLC ratio IgGκ/ FLC ratio κ/λ Survival time (mo) Preset status IV I died X I 3.1 < < died XI I IgGκ died VII 1999 VIII 2008 XI I IgGκ > 192 CR V I IgGκ died VIII I IgGκ died I 1985 III I IgGκ > 312 SD XII II died I 1997 IV 2010 V I >180 SD VII II IgGκ died I 1995 II 2005 VI II IgGκ died VIII II > 108 PR Abbreviatios: CR complete respose, PR partial respose, SD stabilisatio of disease Table II. free light chai (FLC) ad heavy /light chai (HLC) IgA cocetratios at diagosis i idividual IgA multiple myeloma patiets with survival exceedig 10 years Tabela II. Stężeia wolych łańcuchów lekkich (FLC) i związaych z łańcuchem ciężkim (HLC ) IgA w chwili rozpozaia choroby u chorych a szpiczaka plazmocytowego IgA z czasem przeżycia poad 10 lat Case Age (yr) Date of serum sample β 2 M ISS stage Isotype of M-protei M-protei (g/dl) HLC IgA g/l IgAκ HLC ratio IgAκ/ IgAλ FLC ratio κ/λ Survival time (mo) I II IgAλ died VI 1992 VII I IgAκ IgAλ Preset status > 120 SD III I IgAκ died III 2001 VIII I IgAλ III I IgAκ > 190 SD VI 2001 I I IgAκ XII I IgAκ > 168 SD VIII 2002 II 2011 III 1995 I III IgAκ II IgAκ < > > 130 > 127 >113 CR CR PR > 202 PD I 1998 IgAκ > 156 PR Abbreviatios: SD stabilisatio of disease, CR complete respose, PR partial respose, PD progressio of disease, mo moth

5 praca orygiala / origial research article 205 Table III. free light chai (FLC) ad heavy /light chai (HLC) IgM cocetratios at the time of diagosis i idividual patiets with IgM maligat lymphoma ad survival exceedig 10 years Tabela III. Stężeia wolych łańcuchów lekkich (FLC) i związaych z łańcuchem ciężkim (HLC) IgM w chwili rozpozaia choroby u chorych z chłoiakiem złośliwym IgM z czasem przeżycia poad 10 lat Case Age (yr) M-protei (g/dl) HLC IgM g/l IgMκ IgMλ HLC ratio IgMκ/ IgMλ FLC ratio κ/λ Survival time (mo) IgMκ IgMκ IgMκ > IgMλ > IgMλ > IgMκ > IgMκ > IgMκ > IgMλ IgMκ > IgMκ > IgMκ >108 Table IV. free light chai (FLC) ad heavy /light chai (HLC) IgG cocetratios at diagosis ad i the period of follow-up i patiet with POEMS sydrome ad survival exceedig 9 years Tabela IV. Stężeia wolych łańcuchów lekkich (FLC) i związaych z łańcuchem ciężkim (HLC) IgG w chwili rozpozaia choroby i przebiegu obserwacji w surowicy chorego z zespołem POEMS i czasem przeżycia poad 9 lat Date of serum sample β 2 M ISS stage M-protei by IFE ad SPE (g/dl) HLC IgG g/l IgGκ HLC ratio IgGκ/ / FLC ratio κ/λ V 2003 (at diagosis) III 2005 (after ASCT) X 2011 (at follow-up) 2.17 I IgG λ Abbreviatios: ASCT autologous stem cell trasplatatio lizatio of other symptoms was observed. Sice that time for 8 years the patiet was followed without further treatmet. Stabilizatio of the disease was also reflected i stable serum immuoglobuli picture: slightly abormal IgGκ/ HLC ratio, ormal uivolved IgGκ HLC cocetratio ad ormal FLC ratio (Tab. IV). Some cogress publicatios provide data o progostic value of HLC aalysis i multiple myeloma ad MGUS [16 21]. Avet-Loiseau et al. [16, 17] reported that heavy/ light chai specific immuoglobuli ratios at presetatio were progostic for progressio free survival (PFS) i the IFM myeloma trial. I that study, Kapla Meier aalysis idicated that more abormal HLC ratios were associated with reduced PFS (> media for IgGκ ad IgAκ patiets, < media for ad IgAλ patiets; p=0.007). Whe usig more extreme ratios (>200 or <0.01), the sigificace level was higher icreased (p=0.002). Cox regressio aalysis cofirmed the associatio of the latter HLC ratios with reduced PFS (p<0.001) ad idicated that the associatio was idepedet of ad more sigificat tha that of β 2 M or albumi. The combied use of the extreme HLC ratios ad β 2 M >3.5 mg/l, i a risk stratificatio model, showed sigificat differeces i PFS for patiets with 0, 1, or 2 adverse risk factors (p= ). A more complex risk stratificatio model combiig HLC ratios with the Iteratioal Stagig System also showed sigificat differeces i PFS accordig to the umber of risk factors (p=0.0001). The use of HLC ratios provides a measure of both tumor immuoglobuli productio ad immuoparesis. Probably, the combiatio of these two factors has a progostic value. HLC measuremets may be a useful additio to the curret ISS assessmets. Also Ludwig et al. [19, 20] foud that the ratio of moocloal to polycloal immuoglobulis assessed

6 206 praca orygiala / origial research article Table V. Tumor ad o-tumor HLC cocetratios ad HLC IgGκ/, IgAκ/IgAλ, IgMκ/IgMλ ratios at diagosis i sera of patiets with IgG ad IgA multiple myeloma ad IgM maligat lymphoma with survival exceedig 10 years Tabela V. Stężeia owotworowej i ie owotworowej HLC i wartości stosuku IgGκ/, IgAκ/IgAλ, IgMκ/IgMλ HLC w chwili rozpozaia choroby w surowicach chorych a szpiczaka plazmocytowego IgG i IgA oraz chłoiaka złośliwego IgM z czasem przeżycia poad 10 lat HLC ratios IgMκ/ IgMλ HLC immuoglobuli g/l HLC immuoglobuli g/l HLC ratios IgAκ/IgAλ HLC immuoglobuli g/l HLC ratios IgGκ/ IgMλ IgMκ IgAλ IgAκ IgGκ Tumor sera with M-protei isotype acc. to IFE 24.0± ± ± MM IgGκ ± ± ± MM 30.95± ± ± MM IgAκ ; ; MM IgAλ 483.0± ± ± ML IgMκ 0.03± ± ± ML IgMλ Blood door sera (acc. to Bradwell et al. [12]. Abbreviatios: HLC heavy chai/ light chai; IFE immuofixatio electrophoresis; MM multiple myeloma; ML maligat lymphoma with the Hevylite test predicts progosis, is superior for moitorig the course of the disease ad allows detectio of moocloal immuoglobuli i multiple myeloma patiets with ormal or subormal ivolved immuoglobuli isotype. I a study of 103 multiple myeloma patiets media overall survival of the etire group was 37.9 moths. I multivariate aalysis, β 2 M, ad HLC ratio were foud as the oly parameters correlatig with survival. A three tiered risk stratificatio model utilizig β 2 M >3.5 mg/l, ad HLC > media value had a grater progostic value tha ISS (p=0.001 vs p=). Patiets with 0 risk factors (β 2 M <3.5 mg/l, HLC ratio < media) had a 50% survival time of 118 moths, patiets with 1 risk factor (either β 2 M >3.5 mg/l or HLC ratio > media) had a 50% survival of 53 moths ad those with both risk factors (β 2 M >3.5 mg/l ad HLC ratio > media) had a 50% survival of 29 moths (p=0.001) [19]. I recet aalysis whe patiets were stratified accordig to their presetatio HLC ratios beig moderately abormal ( ; =51) or highly abormal (<0.022 or >45; =52), survival was sigificatly shorter i those with highly abormal ratios (media 32,1 moths versus media ot reached, p=0.016). The survival rates at 5 years were 33.4% for the former ad 58.9% for the latter group (p=0.01). For patiets with a highly abormal FLC ratio (<0.1 or >30) a statistically o-sigificat tedecy for shorter survival was oted (40.8 moths versus media ot reached, p=0.08) compared to those with less abormal FLC ratios (0.1 30). A risk stratificatio progostic model with highly abormal HLC ad FLC ratios as risk factors at presetatio was developed. Overall survival was sigificatly differet betwee patiets with both, highly abormal HLC ad FLC ratios or oly oe, or oe of these risk factors (p=0.01). The media was ot reached i patiets with 0 or 1 risk factor ad was 29.2 moths i those with 2 risk factors. The respective five year survival rates were 67.4%, 50.0% ad 23.3% [20]. The serum FLC ratio at presetatio has bee show to be a idepedet progostic marker i multiple myeloma [8]. Also Hardig et al. [15] reported the use of serum FLC ad HLC ratios to predict survival i multiple myeloma patiets. Archived presetatio sera (=186) from British Medical Research Coucil multiple myeloma trials were aalyzed retrospectively usig sflc ad HLC assays. Kapla-Meier survival curves were costructed to compare patiets above or below the media value for FLC ad HLC ratio ad M-spike cocetratio. There was o sigificat differece i survival whe aalyzig itact M protei cocetratios, serum FLC cocetratios, FLC ratios or HLC ratios idividually. Addig FLC ad HLC ratios together there was a sigificatly shorter survival for those patiets with values greater the

7 praca orygiala / origial research article 207 the media (50% survival 949 days versus 1592 days; p=0.02). The serum FLC ratio is likely to be more predictive of outcome tha the cocetratio of the tumor sflc because it icludes a measure of immuoparesis (the deomiator) as well as tumor productio (the umerator). Use of the HLC ratio also icorporates a measure of immuoparesis but additioally, it will compesate for ay reductio i the cocetratio of moocloal immuoglobuli due to icreased catabolism (IgG) ad/or icreased plasma volume. It is probable that the use of the summated sflc ad HLC ratios was more predictive of outcome because there were some patiets with very low moocloal itact immuoglobuli productio for whom the FLC ratio was the most appropriate progostic marker ad vice versa for patiets with low FLC productio [15]. A carried out i our previous study [13] evaluatio of actual survival time of 21 IgM gammopathy patiets diagosed with multiple myeloma or Waldeström s macroglobuliemia ad mea follow-up time of six years showed o statistically sigificat differece i media survival depedig o the results of the HLC ratios tested at diagosis amoutig 7 years i patiets with HLC ratio values < the media ad 5.5 years for patiets with values of HLC ratio > the media (p=0.2738). I the preset study highly abormal HLC ratio (<0.022 or >45) was foud i 7 out of 12 (58%) IgM ML patiets with survival exceedig 10 years. However, Koulieris et al. [26] evaluated the progostic value of IgMκ/IgMλ HLC ratios at diagosis ad the role of HLC ratio i disease moitorig i 31 patiets with Waldeström s macroglobuliemia. Media IgM HLC ratio was sigificatly higher i patiets requirig treatmet at presetatio tha i those ot requirig treatmet. IgM HLC ratio correlated with boe marrow ifiltratio ad time to first treatmet. A simple risk stratificatio model utilizig IgM HLC ratio > media, β 2 M >5 mg/l ad abormal LDH idetified 3 progostic groups with respect to survival (p<0.001) i this series with a media follow up of 59 moths. Authors suggest that HLC IgM ad IgM HLC ratio seem to separate patiets with a more aggressive disease. Leleu et al. suggest that Hevylife test might replace the curret techique to measure IgM M-spike i the years to come [28]. IgG but ot IgA HLC ratios have bee show to predict maligat trasformatio i MGUS patiets [18]. Ackowledgemet The authors thak The Bidig Site Compay Ltd. Birmigham, UK, ad Dr B. Olszewska from Biokom compay for providig the reagets for Hevylite tests. Table VI. Tumor ad o-tumor HLC cocetratios ad HLC IgGκ/, IgAκ/IgAλ, IgMκ/IgMλ ratios at diagosis i sera of patiets with IgG ad IgA multiple myeloma ad IgM maligat lymphoma with survival ot exceedig 5 years Tabela VI. Stężeia owotworowej i ie owotworowej HLC i wartości stosuku IgGκ/, IgAκ/IgAλ, IgMκ/IgMλ HLC w chwili rozpozaia choroby w surowicach chorych a szpiczaka plazmocytowego IgG i IgA oraz chłoiaka złośliwego IgM z czasem przeżycia poiżej 5 lat HLC ratios IgMκ/IgMλ HLC immuoglobuli g/l HLC ratios IgAκ/ IgAλ HLC immuoglobuli g/l HLC ratios IgGκ/ HLC immuoglobuli g/l IgMλ IgMκ IgAλ IgAκ IgGκ Tumor sera with M-protei isotype acc. to IFE 37.31± ± ± MM IgGκ ± ± ± MM ± ± ± MM IgAκ 0.03± ± ± MM IgAλ ± ± ± ML IgMκ 0.01± ± ± ML IgMλ dla = ±0.17 mediaa 0.21

8 208 praca orygiala / origial research article Table VII. free light chai (FLC) cocetratios at diagosis i patiets with multiple myeloma (MM) ad IgM maligat lymphoma (ML) with survival exceedig 10 years Tabela VII. Stężeia w surowicy wolych łańcuchów lekkich (FLC) w chwili rozpozaia choroby u chorych a szpiczaka plazmocytowego i chłoiaka złośliwego IgM z czasem przeżycia poad 10 lat IgGκ MM Media; MM Media; IgAκ MM Media; IgAλ MM Media; IgMκ ML Media; IgMλ ML Media; Healthy persos Media; κ/λ ratio ; ; ; ; ; ; ; ; < ; ; ; ; ; ; ; ; ; ; Table VIII. free light chai (FLC) cocetratios at diagosis i patiets with multiple myeloma ad IgM maligat lymphoma with survival ot exceedig 5 years Tabela VIII. Stężeia w surowicy wolych łańcuchów lekkich (FLC) w chwili rozpozaia choroby u chorych a szpiczaka plazmocytowego i chłoiaka złośliwego IgM z czasem przeżycia poiżej 5 lat IgGκ MM Media; MM IgAλ MM 2 Κ FLC (mg/)l κ/λ ratio 6 877; ; ; ; ; ; udetectable IgMκ ML IgMλ ML 2 2.1; ; ; 0.06 Table IX. Compariso of serum immuoglobuli HLC ratios at diagosis i MM patiets with survival exceedig 10 years, ot exceedig 5 years ad patiets erolled to IFM 2005 trial. Tabela IX. Porówaie wartości stosuku IgGκ/, IgAκ/IgAλ HLC w surowicy w chwili rozpozaia choroby u chorych a szpiczaka plazmocytowego z czasem przeżycia poad 10 lat, poiżej 5 lat i chorych włączoych do próby kliiczej IFM 2005 MM patiets with M-protei isotype acc. to IFE IgGκ MM MM IgAκ MM Patiets with survival >10 years (=23) ivolved/u-ivolved HLC ratio media, IgAλ MM ; 0.16 Preset study Patiets with survival <5 years (=43) ivolved/u-ivolved HLC ratio media, IFM 2005 trial (=339) Avet-Loiseau et al. [16, 17] Bradwell et al. [24] ivolved/u-ivolved HLC ratio media, Refereces 1. Bradwell AR, Carr-Smith HD, Mead GP, Tag LX, Showell PJ, Drayso MT, et al. Highly sesitive, automated immuoassay for immuoglobuli free light chais i serum ad urie. Cli Chem, 2001; 47: Dispezieri A, Kyle R, Merlii G, Miguel JS, Ludwig H, Hajek R, et al. Iteratioal Myeloma Workig Group guide lies for serum-free light chai aalysis i multiple myeloma ad related disorders. Leukemia 2009; 23: Kraj M, Kruk B, Pogłód R. Cliical value of serum immuoglobuli free light chai quatificatio i multiple myeloma. Nowotwory Joural of Ocology 2011; 61(4): 52e 58e; Kraj M, Kruk B, Pogłód R, Szczepiński A. Correlatio of se-

9 praca orygiala / origial research article 209 rum immuoglobuli free light chai quatificatio with serum ad urie immuofixatio i moocloal gammopathies. Acta Haematol Pol, 2011; 42: Dispezieri A, Kyle RA, Katzma JA, et al. Immuoglobuli free light chai ratio is a idepedet risk factor for progressio of smolderig (asymptomatic) multiple myeloma. Blood, 2008; 111: Kyle RA, Durie BGM, Rajkumar SV, et al. Moocloal gammopathy of udetermied sigificace (MGUS) ad smolderig (asymptomatic) multiple myeloma: IMWG cosesus perspectives risk factors for progressio ad guidelies for moitorig ad maagemet. Leukemia, 2010; 24: Digli D, Kyle RA, Rajkumar SV, et al. Immuoglobuli free light chais ad solitary plasmacytoma of boe. Blood, 2006; 108: Sozek CLH, Katzma JA, Kyle RA, Dispezieri A, Larso DR, Thereau TM, et al. Progostic value of the serum free light chai ratio i ewly diagosed myeloma: proposed icorporatio ito the Iteratioal Stagig System. Leukemia, 2008; 22: Kyrtsois MC, Vassilakopoulos TP, Kafasi N, Sachaas S, Tzeou T, Papadogiais A, et al. Progostic value of serum free light chai ratio at diagosis i multiple myeloma. Br J Haematol, 2007; 137: Sobh M, Pharm M, Morisset S, Guilli T, Ducastelle-Lepretre S, Barraco F, Chelghoum Y, et al. kappa/ lambda ratio, a idepedet progostic factor at diagosis ad serum free-light chais level a early idicator of relapse/progressio i multiple myeloma. Blood, 2010; 116: (abstract # 2954). 11. Greipp PR, Sa Miguel J, Durie BGM, Crowley JJ, Barlogie B, Bladé, et al. Iteratioal Stagig System for multiple myeloma. J Cli Ocol, 2005; 23: Bradwell AR, Hardig SJ, Fourrier NJ, Gregg LF, Wallis GLF, Drayso MT, et al. Assessmet of moocloal gammopathies by ephelometric measuremet of idividual immuoglobuli κ/λ ratios. Cli Chem, 2009; 55: Kraj M, Kruk B, Pogłód R, Warzocha K. Evaluatio of IgG, IgA ad IgM moocloal ad bicloal gammopathies by ephelometric measuremet of idividual immuoglobuli κ/λ ratios Hevylite assay versus immuofixatio. Acta Haematol Pol, 2011; 42: Doato LJ, Zelderust SR, Murray DL, Katzma JA. A 71- year old woma with multiple myeloma status after stem cell trasplatatio. Cli Chem, 2011; 57: Hardig SJ, Drayso MT, Mead GP, Bradwell AR. Progostic value of free ad heavy/light chai aalysis. Cliical Lymphoma ad Myeloma, 2009; Suppl 1: (abstract B555). 16. Avet-Loiseau H, Harousseau J-L, Moreau P, Mathiot C, Faco T, Attal M, Bradwell A. Heavy /Light chai specific immuoglobuli ratios at presetatio are progostic for progressio free survival i the IFM myeloma trial. Blood 2009;114:722 (abstract #1818). 17. Avet-Loiseau H, Mirbahai L, Harousseau JL, Moreau P, Mathiot C, Faco T, et al. immuoglobuli heavy/ light chai ratios are idepedet risk factors for predictig progressio free survival i multiple myeloma. Haematologica, 2010; 95(suppl 2): 395 (abstract 0953). 18. Katzma J, Clark R, Dispezieri A, Kyle R, Ladgre O, Bradwell A, Rajkumar SV. Isotype specific heavy/light chai (HLC) suppressio as a predictor of myeloma developmet i moocloal gammopathy of udetermied sigificace (MGUS). Blood, 2009; 114: 711 (abstract 1788). 19. Ludwig H, Mirbahai L, Zojer N, Bradwell A, Hardig S. The ratio of moocloal to polycloal immuoglobulis assessed with the Hevylite test predicts progosis, is superior for moitorig the course of the disease ad allows detectio of moocloal immuoglobuli i patiets with ormal ad subormal ivolved immuoglobuli isotype. Blood, 2010; 116: 1646 (abstract # 4038). 20. Ludwig H, Fait J, Zojer N, Bradwell AR, Youg P, Milosavljevic D, et al. heavy/light chai ad free light chai measuremets provide progostic iformatio, allow creatio of a progostic model ad idetify cloal chages (cloal tidig) through the course of multiple myeloma Blood, 2011; 118: 1244 (abstract 2883). 21. Maier S, Lejeue J, Musset L, Boyle E, Dulery R, Debarri H, et al. Hevylite, a ovel M-compoet based biomarkers of respose to therapy ad survival i Waldeström macroglobuliemia. Blood 2011; 118: 1145 (abstract 2667). 22. Kyle RA, Rajkumar SV. Criteria for diagosis, stagig, risk stratificatio ad respose assessmet of multiple myeloma. Leukemia 2009; 23: Kraj M, Pogłód R, Sokołowska U, Kruk B, Maj S. Covetioal chemotherapy ad log-term survival i multiple myeloma patiets. Nowotwory Joural of Ocology 2010; 60: 69e-76e; Bradwell AR. free light chai aalysis (plus Hevylite) 6 th Editio. The Bidig Site Group Ltd, Birmigham, UK 2010 (Wikilite.com). 25. Pogłód R, Kraj M, Szczepiński A, Mariańska B, Warzocha K. Autologous peripheral blood stem cell trasplatatio i a patiet with POEMS sydrome. Nowotwory Joural of Ocology 2005; 55: Koulieris E, Kyrtsois MCh, Maltezas D, Tzeou T, Mirbahai L, Kafassi N, et al. Quatificatio of serum IgMκ ad IgMλ i patiets with Waldestrőm s Macroglobuliemia (WM) at diagosis ad durig disease course; cliical correlatios. Blood 2010; 116: 1238 (abstract #3004). 27. Katzma JA, Clark RJ, Abraham RS, et al. referece itervals ad diagostic s for free κ ad free λ immuoglobuli light chais: relative sesitivity for detectio of moocloal light chais. Cli Chem 2002; 48: Leleu X, Koulieris E, Maltezas D, Itzykso R, Xie W, Maier S et al. Novel M-Compoet Based Biomarkers i Waldeström s Macroglobuliemi, Cliical Lymphoma Myeloma ad Leukemia, 2011; 11(1):