Applicazioni della misura delle Free Light Chain nella pratica clinica Maria Teresa Petrucci
Serum free light chain immunoassay Heavy chain Kappa Light chain Hidden surface Lambda Exposed surface
Serum free light chain immunoassay Heavy chain Kappa Light chain Hidden surface Lambda Exposed surface
Discrasie plasmacellulari Mieloma Multiplo Gammopatie monoclonali Plasmocitoma localizzato Macroglobulinemia di Waldenstrom Associate ad altre sindromi linfoproliferative Crioglobulinemie Amiloidosi Forme associate ad altre malattie
Screening for Monoclonal Gammopathies Serum electrophoresis Monoclonal intact immunoglobulins Urine electrophoresis Monoclonal free light chains
MM: laboratorio
MM micromolecolare: Bence Jones
Measurement of serum free light chains Diagnosis Prognosis Management
Light Chain Multiple Myeloma Normal sera Kappa LCMM Lambda LCMM Renal impairment (CKD2) Hutchison, unpublished data; Bradwell, Lancet 2003; 361: 489-491
Serum l FLC (mg/l) Intact Immunoglobulin MM No correlation between Ig and sflc 100000 10000 n = 120 IgGl MM patients 1000 100 10 1 0 20 40 60 80 100 Total IgG (g/l) Mead et al. Br J Haematol 2004;126 : 348 54
Light chain concentration (mg/l) Sensitivity of light chain analysis techniques 1000 100 SPE CZE sife 10 Normal range in serum UPE uife 1 sflc
Recommendations for the use of the serum FLC assay screening serum FLC assay in combination with serum PEL and serum IFE is sufficient to screen for pathological monoclonal plasmaproliferative AL requires all the serum tests as well as the 24-h urine IFE. If a diagnosis of a plasma cell disorder is made, a 24-h urine for PEL and IFE is essential for all patients.
Recommendations for the use of the serum FLC assay prognosis The serum FLC assay should be measured at diagnosis for all patients with MGUS smoldering active multiple myeloma solitary plasmacytoma AL amyloidosis
Risk of progression 1% per year MGUS? WM IgM lymphoma CLL MM AL amyloid LCDD Solitary plasmacytoma Follow up MGUS patients: How frequently?
Monoclonal Gammopathy of Undetermined Significance (MGUS) Risk Factors for progression: Serum M protein >15g/L Serum M protein NOT IgG Kyle R. NEJM 2002; 346: 564-569
Monoclonal Gammopathy of Undetermined Significance (MGUS) Risk Factors for progression: Serum M protein >15g/L Serum M protein NOT IgG sflc ratio Kyle R. NEJM 2002; 346: 564-569 Rajkumar Blood 2005; 106: 812-817
Cumulative probability of progression (%) 0 10 20 30 40 50 60 MGUS progression Abnormal FLC ratio ( / = <0.26 or >1.65) Normal FLC ratio ( / = 0.26 1.65) 0 5 10 15 20 25 30 Years Rajkumar Blood 2005; 106: 812-817
MGUS risk stratification model incorporating M-protein size, type and FLC ratio Risk of progression No. of abnormal risk factors No. patients Absolute risk of progression at 20 years* Low 0 449 2% Low-Intermediate 1 420 10% High-Intermediate 2 226 18% High 3 53 27% * Accounting for death as a competing risk Rajkumar Blood 2005; 106: 812-817
Risk of progression
Overall survival
Recommendations for the use of the serum FLC assay response assessment Serial FLC ascertainment should be routinely performed in patients with: AL amyloidosis multiple myeloma with oligosecretory disease It should also be done in all patients who have achieved a CR to determine whether they have attained a stringent CR.
Profondità di risposta Tempo alla Progressione Inizio del trattamento MR PR VGPR ncr CR scr Tempo La profondità delle risposte è correlata al TTP
International guidelines for sflc analysis in MM and related disorders Assessment of response All MM patients to define a stringent CR CR Negative S/U IFE BM plasma cells 5% Stringent CR Negative S/U IFE Normal sflc ratio Absence of clonal cells in BM Dispenzieri et al. Leukemia 2009: 23, 215 224 Durie et al., Leukemia, 2006. 20, 1467-73
Rapid evaluation of response to chemotherapy Dispenzieri et al. Retrospective analysis of ECOG trial E9486 FLC response after 2 months of VBMCP IFN or cyclophosphamide 399 patients Assessed sflc and M-protein responses to therapy therapy was superior to early M-protein measurement to predict overall response. Dispenzieri et al. Blood 2008; 111: 4908-4915
Light chain escape Rising monoclonal free light chain production at relapse without increased monoclonal intact immunoglobulin Drayson et al. Myeloma IX trial Estimate incidence: 5 % for IgG MM 15 % for IgA MM Drayson, M.T., et al., Clin Lymphoma Myeloma, 2009. February: 346a.
CONCLUSIONS Screening: serum FLC assay in combination with serum protein electrophoresis and immunofixation yields high sensitivity Prognosis: FLC assay is of major prognostic value in virtually every plasma cell disorder Monitoring: FLC assay allows for quantitative monitoring of patients with oligosecretory plasma cell disorders, including patients with AL Response evaluation: rflc a requirement for documenting stringent complete response according to the International Response Criteria