Clinical Applications of Free Light Chain Analysis Online Training

Welcome to the Clinical Applications of Free Light Chain Analysis Online Training course. In healthy individuals and those with myeloma or related disorders more light chains than heavy chains are produced to form immunoglobulins.  The excess light chains entering and circulating the blood stream is referred to as free light chain.  The measurement of the amount of this free light chain in the blood stream is linked to the activity of myeloma.  Select Next to continue. This course was developed by: Farogh Nazari, PhD, MBA, MLS(ASCP)CM Senior Manager, Global Continuing Education Siemens Healthcare Diagnostics   Upon successful completion of this course you will be able to: Describe Free Light Chains (FLC) and the disease states associated with FLC   Define Multiple Myeloma   Define Monoclonal Gammopathy of undetermined significance (MGUS)   State the International consensus guidelines   Select Next to continue. International Myeloma Foundation. Understanding Serum Free Light Chain Assays. North Hollywood, CA. USA. 2011. Subtypes of Immunoglobulins IgG κ IgG λ IgA κ IgA λ IgM κ IgM λ IgD κ IgD λ IgE κ IgE λ Κ kappa λ lambda Plasma cells are the primary source of immunoglobulins Light and heavy chains are produced separately, and it is normal that about 40% more light chains are made than heavy chains There is a normal level of FLC in blood. ~ 2 times as more Kappa (κ) intact immunoglobulins are produced than Lambda (λ) intact immunoglobulins Hutchison CA et al. Nature Reviews Nephrology. 2009; 5: 621-637.   Mole Mass % cleared Serum ½ life Κ FLC 22.5 kDa 40% 2 to 4 hr λ FLC 45 kDa 20% 3 to 6 hr Hutchison CA et al. Nature Reviews Nephrology. 2009; 5: 621-637. Normal levels of serum FLC: Kappa: 6.7 – 22.4 mg/L Lambda: 8.3 – 27.0 mg/L Kappa/lambda ratio: 0.31 – 1.53 International Myeloma Foundation. Understanding Serum Free Light Chain Assays. North Hollywood, CA. USA. 2011. M-protein spike is a characteristic that confirms the diagnosis Serum immunofixation electrophoresis   Multiple Myeloma Disease Overview. 2011, Multiple Myeloma Research Foundation   Monoclonal Gammopathy of Undetermined Significance (MGUS) 3.5% of those > 50 years old have MGUS 1% of those with MGUS will progress to MM Smoldering Myeloma 10% of those w/ Smoldering Myeloma will progress to MM Multiple myeloma (MM)  estimates for 2013 ~ 22,350 new cases will be diagnosed (12,440 in men and 9,910 in women) ~ 10,710 deaths are expected to occur (6,070 in men and 4,640 in women) Multiple Myeloma, American Cancer Society. © 2013.  Kuehl  WM. , Bergsagel PL. Nature Reviews Cancer. 2002;2: 175-187. Rajkemar SV. Mayo Clin Proc. October 2010;85(10):945-948. CRAB = hypercalcemia, renal insufficiency, anemia and bone lesions PCPD = Plasma Cell Proliferation Disorder BM = Bone Marrow   Rajkemar SV. Mayo Clin Proc. October 2010;85(10):945-948.   Rajkemar SV. Mayo Clin Proc. October 2010;85(10):945-948. Myeloma is a cancer of the plasma cells in the bone marrow. Normal plasma cells produce antibodies, also known as immunoglobulins that fight infections. In multiple myeloma, one particular plasma cell is duplicated a very large number of times, causing excess production of monoclonal proteins. Multiple Myeloma Disease Overview. 2011, Multiple Myeloma Research Foundation Blood — As the number of myeloma cell increase, it interferes with the production of other blood cells.  When the WBC decrease, the risk of infection increases. Bones — masses may form that disrupts the normal structure and the myeloma cells release chemicals that interfere w/ bone growth & repair Kidneys — Excess M protein and calcium in the blood overwork the kidneys as they filter blood. Multiple Myeloma Disease Overview. 2011, Multiple Myeloma Research Foundation Common symptoms of multiple myeloma include: Bone pain Fractures Fatigue Weakness Infection & fever Loss of appetite & weight loss Multiple Myeloma Disease Overview. 2011, Multiple Myeloma Research Foundation   When the calcium level increases or kidneys function is compromised: Increased or decreased urination Increased thirst Restlessness, followed by extreme weakness & fatigue Nausea and vomiting Confusion Age. most diagnosed in their mid-60s Men are more likely to develop MM Race. Blacks are 2X  more likely to develop MM than are Caucasians History of a MGUS.  1 % of those w/ MGUS in the United States develop MM. Obesity. Your risk of MM is increased if you're overweight or obese Multiple Myeloma, American Cancer Society.  © 2013.    Multiple Myeloma Disease Overview. 2011, Multiple Myeloma Research Foundation Multiple Myeloma Disease Overview. 2011, Multiple Myeloma Research Foundation   Normal polyclonal population of plasma cells Normal electrophoreses scan: No M-spike Abnormal monoclonal population of plasma cells Abnormal scan: Very large M-spike O’Connell TX, et al. Am Fam Physician 2005;71:105-12.     Serum Immunofixation representing  IgG Kappa   Serum Immunofixation showing the suspicion of a FLC Kappa (to be confirmed by negative Anti IgD and IgE immunofixation) Multiple myeloma may be staged using the Durie-Salmon system. Newer diagnostic methods have made this system limited in its value.  Recently, a new staging system called the International Staging System for Multiple Myeloma has been developed. It relies mainly on levels of albumin and beta-2-microglobulin in the blood. Other factors that may be important are kidney function, platelet count and the patient's age.     Stage Criteria Median Survival (Month) I Serum β2 microglobulin <3.5 mg/L Serum albumin ≥ 3.5 g/dL 62 II Not Stage I or III 44 III Serum β2 microglobulin >5.5 mg/L 29 Griepp PR et al. J Clin Oncol. 2005;23:3412-3420. Durie-Salmon Staging is based on 4 factors: Abnormal monoclonal immunoglobulin in the blood or urine Calcium in the blood. Severity of bone damage from x-rays Hemoglobin in the blood   Stage I Small number of myeloma cells detected. All of the following features must be present: Hemoglobin level is low but still above 10 g/dL X-rays appear normal or show only 1 area of damage Calcium levels in the blood are normal (less than 12 mg/dL) Small amount of monoclonal immunoglobulin in blood/urine Stage II Moderate number of myeloma cells are present. Features are between stage I and stage III. Stage III Large number of myeloma cells are found. One or more of the following features must be present: Low hemoglobin level (< 8.5 g/dL) High blood calcium level (> 12 mg/dL) 3 or more areas of bone destroyed by the cancer Large amount of monoclonal immunoglobulin in blood/urine International Staging System has been shown to be more reproducible in clinical trials However, it is not useful for patients that have not progressed to Multiple Myeloma.  Therefore, those patients that have MGUS or SMM, staging must be done with the Durie-Salmon system. Recommendation:  Use both the International & Durie-Salmon Staging systems.   Solitary plasmacytomas — often treated with radiation therapy. If the plasma cell tumor is not in a bone, it may be removed with surgery. Chemotherapy is only used if multiple myeloma develops. Early myeloma — includes smoldering myeloma and stage I disease. Patients with early myeloma can do well for years without treatment. Starting treatment early does not seem to help them live longer. They may be started on a bisphosphonate if they have bone disease. Advanced myeloma — myeloma is stage II or higher are often given drug therapy. The drugs chosen depend on the patient's health (including their kidney function) and whether or not a transplant is planned.   The treatment  for multiple myeloma involves trying to stop the tumor growth and keeping the disease from spreading. Treatment options for multiple myeloma; Steroids and conventional chemotherapy High-dose chemotherapy and stem cell transplantation More targeted and less toxic treatments: Valcade or Revlimid   It is important to keep in mind that there is no one standard therapy for multiple myeloma.   KYPROLIS® (carfilzomib) for Injection is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including Valcade and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. FDA approved on July 20, 2012 Drug Class – Protease Inhibitor http://www.kyprolis.com/ POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including Revlimid and Valcade and have demonstrated disease progression on or within 60 days of completion of the last therapy. FDA approved on Feb 8, 2013 Drug Class - Immunomodulator http://www.pomalyst.com/ Elotuzumab from Bristol-Myer Squibb is a monoclonal antibody that has shown promising results in clinical trials.   ‘The problem in myeloma right now is many of the new drugs are in the same two classes (protease inhibitors & immunomodulators). If you want a sea change, you want a new class.’ Dr. Vincent Rajkumar Rockoff J. Wall Street Journal. New Drugs Slow a Fast-Spreading Cancer. March 5, 2013. Pretorius CJ. Et al.  Ann Clin Biochem 2012; 49: 450–455. “The N Latex FLC k and λ assays demonstrated good precision with a total % CV less than 5–7% across the measuring range. In contrast, the total %CV of the lowest pool on the FreeliteTM assay exceeded the 20% acceptable limit for both k and λ assays.” Pretorius CJ. Et al.  Ann Clin Biochem 2012; 49: 450–455.   Pretorius CJ. Et al.  Ann Clin Biochem 2012; 49: 450–455. Pretorius CJ. Et al.  Ann Clin Biochem 2012; 49: 450–455. In conclusion, we validated the N Latex FLC k and λ assays against the Freelite™, and although the results were not directly interchangeable, there was good agreement in the binary classification of samples. The N Latex FLC assay has the advantages of superior precision across the measuring range, and although not immune to nonlinearity, it did not exhibit gross antigen excess on the BNII analyzer. The N Latex FLC k and λ assays can be used in clinical practice based on their acceptable analytical performance characteristics. Pretorius CJ. Et al.  Ann Clin Biochem 2012; 49: 450–455. Excess involved FLC or an abnormal FLC ratio is common in virtually all plasma cell disorders Dispenzieri A. et al. Leukemia. 2009; 23:215–224. Excess involved FLC or an abnormal FLC ratio is common in virtually all plasma cell disorders Dispenzieri A. et al. Leukemia. 2009; 23:215–224. Database had 428 patients with plasma cell disorder had Serum electrophoresis, Immunofixation electrophoresis, and FLC analyses. Serum and Immunofixation missed 28 (6.5%)  MM=2, AL=19, PC=3, MGUS = 2, SM =1 FLC analysis alone missed 14% of all diagnosis Serum and Immunofixation and FLC analysis identified 99.5% of all diseases 2 missed were low-risk MGUS cases In screening, “the serum FLC assay in combination with serum protein electrophoresis and immunofixation yields high sensitivity, and negates the need for 24-h urine studies for diagnoses other than light chain amyloidosis (AL).” Katzmann JA. Et al. Mayo Clin Proc. 2006;81:1575-1578. Dispenzieri A. et al. Leukemia. 2009; 23:215–224. Dispenzieri A. et al. Leukemia. 2009; 23:215–224.   Complete Response is defined as: (1) negative serum & urine IFE; (2) Disappearance of soft tissue plasmacytomas: (3) ≤ 5% plasma cell in bone marrow Stringent Complete Response is defined as a Complete Response plus: (1)Normal FLC ratio; (2) Absence of clonal cells in bone marrow by IMH or IF   Dispenzieri A. et al. Leukemia. 2009; 23:215–224. Serum FLC – is prognostic value in MM, monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM) and solitary plasmacytoma of bone. It can be used in conjunction with serum protein electrophoresis and immunofixation when screening for the presence or absence of a monoclonal plasma cell disorder such as myeloma in place of a 24-h urine protein study. Serum FLC test is useful in monitoring disease course and response to therapy in patients who do not have measurable disease on serum and protein electrophoresis (including non-secretory myeloma) Dispenzieri A. et al. Leukemia. 2009; 23:215–224.