LYMPHOPROLIFERATIVE. ALL- Acute Lymphoblastic leukemia. Non Hodgkin Lymphomas. Hodgkin Lymphomas. CLL-Chronic Lymphocytic Leukemia

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1 של בדיקת Free Light Chains מקומה באבחון ומעקב של מיאלומה נפוצה ד"ר תמר תדמור מכון המטולוגי, בני ציון הקבוצה הישראלית למיאלומה נפוצה

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3 LYMPHOPROLIFERATIVE DISEASES ALL- Acute Lymphoblastic leukemia Non Hodgkin Lymphomas Hodgkin Lymphomas CLL-Chronic Lymphocytic Leukemia Plasma cell dyscrasia

4 PLASMA CELL DYSCRASIA MGUS- monoclonal gammopathy of unknown significant SMOLDERING MYELOMA MULTIPLE MYELOMA AL AMYLOIDOSIS SOLITARY PLASMACYTOMA

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6 לכיוון מיאלומה בירור תלונות קליניות: חולשה כאבים גרמיים זיהום בירור ראשוני: אנמיה היפרגלובולינמיה/ היפואלבומינמיה ה פואלבומ היפרקלצמיה גב כאבי אי ספיקה כלייתית ש"ד מוחשת

7 Differential Diagnosis of Polyclonal Gammopathy Infections Viral infections, especially hepatitis, human immunodeficiency virus infection, mononucleosis, and varicella Focal or systemic bacterial infections, including endocarditis, osteomyelitis, and bacteremia Tuberculosis Connective tissue diseases Systemic lupus erythematosus Mixed connective tissue Temporal arteritis Rheumatoid arthritis Sarcoid Liver diseases Cirrhosis Ethanol abuse Autoimmune hepatitis Viral-induced hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis Malignancies Solid tumors Ovarian tumors Lung cancer Hepatocellular cancer Renal tumors Gastric tumors Hematologic cancers (see below) Hematologic and lymphoproliferative disorders Lymphoma Leukemia Thalassemia Sickle cell anemia Other inflammatory conditions Gastrointestinal conditions, including ulcerative colitis and Crohn's disease Pulmonary disorders, including bronchiectasis, cystic fibrosis, chronic bronchitis, and pneumonitis Endocrine diseases, including Graves' disease and Hashimoto's thyroiditis

8 מדובר בחלבון חד שבטי? האם FLC האם יש להשתמש בבדיקת ה???..SCREENING לצורך

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12 IgG 50 % IgA 20% light chain only (Bence Jones) 16 % IgD 2 % Biclonal 2 percent IgM 1 % Non secretory 3% y Oligo-secretory myeloma 5-8 %

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14 Serum free-light chain ratio <0.26 or >1.65

15 FLC Normal lflci is 500 mg/day from bone marrow and lymph node cells. There is 40% excess immunoglobulin light-chain production over immunoglobulin heavy-chain synthesis. There are twice as many kappa-producing plasma cells as lambda plasma cells. Kappa free-light chains are normally monomeric, while lambda free-light chains tend to be dimeric, joined by disulphide bonds. Polymeric forms of both types of free light chain can also occur

16 In case of renal failure: Serum free-light chain ratio <0.37 or >3.1

17 Leukemia 23, International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders International Myeloma Working Group guidelines A Dispenzieri, R Kyle, G Merlini, J S Miguel, H Ludwig, R Hajek, A Palumbo, S Jagannath, J Blade, S Lonial, M Dimopoulos, R Comenzo, H Einsele, B Barlogie, K Anderson, M Gertz, J L Harousseau, M Attal, P Tosi, P Sonneveld, M Boccadoro, G Morgan, P Richardson, O Sezer, M V Mateos, M Cavo, D Joshua, I Turesson, W Chen, K Shimizu, R Powles, S V Rajkumar and B G M Durie SCREENING / DIAGNOSIS PROGNOSTIC VALUE MONITORING DISEASE RESPONSE ASSESSMENT

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19 Role of FLC assay -SCREENING For purpuse of SCREENING for monoclonal protein For all diagnosis EXCEPT AL- Amyloidosis The FLC- assay can replace The FLC- assay can replace 24/h urine IFE

20 DIAGNOSIS -ROLE OF FLC The serum-flc assay is recommended in all newly diagnosed patients with plasma cell dyscrasias Serum-free light chain estimation does not obviate the need for 24-hour urine studies Measurement of urine-free light chain levels or urine total κ and total λ levels els is not recommended. Serum FLC is important for: nonsecretory multiple myeloma (negative serum and urine IF) oligosecretory myeloma - secrete small amounts light chain myeloma solitary plasmacytoma smoldering myeloma

21 Prognostic value of serum FLC assay Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood May 28;113(22):

22 Risk of progression of MGUS Risk of progression to MM after 20 years of follow-up Monoclonal protein>1.5 g/dl Immunoglobulin A or M Serum free-light chain ratio <0.26 or >1.65

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24 Risk of progression of SMM Risk of progression to MM after 20 years of follow-up Monoclonal protein>3 g/dl BM plasma cell >10% Serum free-light chain ratio <0.125 or >8 Risk of progression to MM after 5years of follow-up 95% or higher abnormal plasma cell by flow-cytometry Reduction of uninvolved immunogloulins

25 Use of FLC in monitoring response The FLC assay allows quantititative monitoring of patients with : Oligosecretory plasma cell disorders AL amyloidosis i 2/3 of patients with non-secretory MM

26 Use of FLC assay in response assessment Normalization of rflc has been incorporated into the definition of stringent complete remission

27 Use of FLC to document CR (response to therap) rflc has been incorporated into the definition of stringent complete response

28 LIMITATION LOT TO LOT variation Monoclonal light chain( kappa++) do not dilute in a linear fashion Antigen excess- false positive low serum FLC Change in AA sequence- epitopes of FLC unrecognized

29 J Clin Oncol 29: Elevated Serum Free Light Chains Are Associated With Event-Free and Overall Survival in Two Independent Cohorts of Patients With Diffuse Large B-Cell Lymphoma Matthew J. Maurer, Ivana N.M. Micallef, James R. Cerhan, Jerry A. Katzmann, Brian K. Link,Joseph P. Colgan, Thomas M. Habermann,David J. Inwards, Svetomir N. Markovic, Stephen M. Ansell,Luis F. Porrata, Patrick B. Johnston, Grzegorz S. Nowakowski, Carrie A. Thompson, Mamta Gupta,Sergei I. Syrbu, Paul J. Kurtin, William R. Macon, Daniel A. Nikcevich, and Thomas E. Witzig J Clin Oncol Feb 10;28(5): Circulating serum free light chains as predictive markers of AIDS-related lymphoma. Landgren O, Goedert JJ, Rabkin CS, Wilson WH, Dunleavy K, Kyle RA, Katzmann JA, Rajkumar SV, Engels EA. National Cancer Institute, National Institutes of Health, Center for Cancer Research, Medical Oncology Branch, 9000 Rockville Pike, Bldg 10/Room 13N240, Bethesda, MD, 20892, USA. landgreo@mail.nih.gov

30 Transl Res Apr;149(4): Serum-free light chain-a new biomarker for patients with B-cell non-hodgkin lymphoma and chronic lymphocytic leukemia. Martin W, Abraham R, Shanafelt T, Clark RJ, Bone N, Geyer SM, Katzmann JA, Bradwell A, Kay NE, Witzig TE. Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.

31 Mayo Clin Proc Jun;87(6): Use of nonclonal serum immunoglobulin free light chains to predict overall survival in the general population. Dispenzieri A, Katzmann JA, Kyle RA, Larson DR, Therneau TM, Colby CL, Clark RJ, Mead GP, Kumar S, Melton LJ 3rd, Rajkumar SV.

32 Myeloma- a Chronic Relapsing Disease mass ease m Dise Treatment

33 Novel Agents 1962 Prednisone + melphalan 1990s Supportive care 1999 Thalidomide 2002 Lenalidomide 1980s Myeloablation + ASCT 1998 Velcade 2005 Velcade approved

34 Improved Survival Post Relapse Since Novel Agents

35 תודה רבה