Multiple Myeloma PDF

Multiple myeloma Dr Hisham Alrawi Assistant Prof/Hematopathologist MBChB FIBMS Medical college/ University of Sulaimani [email protected] Plasma cells Plasma cells arise from antigen-activated B cells in secondary lymphoid organs such as the spleen and lymph nodes. Remarkably, shortly aft...

Multiple myeloma Dr Hisham Alrawi Assistant Prof/Hematopathologist MBChB FIBMS Medical college/ University of Sulaimani [email protected] Plasma cells Plasma cells arise from antigen-activated B cells in secondary lymphoid organs such as the spleen and lymph nodes. Remarkably, shortly after their formation plasma cells tend to home primarily to the bone marrow where they may persist for months or even years. Plasma cells comprise up to 4% of all nucleated marrow cells. Multiple Myeloma Multiple myeloma (MM) is characterized by the proliferation of a single clone of plasma cells that produce a monoclonal protein. The plasma cell proliferation results in extensive skeletal involvement, with osteolytic lesions, hypercalcemia, anemia and/or soft tissue plasmacytomas. In addition, the excessive production of nephrotoxic monoclonal immunoglobulin can result in renal failure and an increased risk of developing potentially life-threatening infections due to the lack of functional immunoglobulins. Epidemiology The annual incidence of MM is 4 per 100,000. It represents approximately 1% of all malignant diseases and 15% of all hematological malignancies. The incidence of MM is lower in Asian populations and in blacks is twice that in whites; MM is slightly more frequent in men than in women. The median age at diagnosis is 65–70 years. 4 Pathogenesis: MM is a B-cell malignancy characterized by the accumulation of terminally differentiated clonal plasma cells in the bone marrow, the production of a monoclonal immunoglobulin detectable in serum and/or urine and the presence of lytic bone lesions. M protein: is an antibody or fraction of an antibody with the same negative charge & produced by clonal plasma cells. - is seen in 99% of cases in serum and/or urine - 1% of cases are non-secretory Clinical symptoms: Bone pain: Multiple myeloma cause pain in the back, ribs or hips. Bone fractures and spinal cord compression: Multiple myeloma can cause Lytic lesion, osteoporosis and fractures in different sites like the spine or long bones (arms and legs). Anemia: Tiredness, weakness and breathless. Hypercalcemia: May associated with the following, Thirst, fatigue, Abdominal pain, frequently urinate, constipation, some time confusion and drowsiness. Renal failure: Poor appetite, weight loss, swollen ankles, feet or hands, itchy skin. Infection: Infectious complications are the major cause of morbidity and mortality in patients with MM. The highest risk of infection is observed during the first 2months of starting therapy. Hyperviscosity: Classically presents with mucosal bleeding, visual and neurological abnormalities. Bleeding: Some people with multiple myeloma have bruising, epistaxis or heavy periods. Pathological fracture Pathological fracture Laboratory work-up for plasma dyscrasia. Complete blood count and blood film. Chemistry including calcium and creatinine. Serum protein electrophoresis and immunofixation. Quantification of immunoglobulins. urine for electrophoresis and immunofixation. Bone marrow aspirate & biopsy (morphology, cytogenetics, immunophenotyping by Flow Cytometry). Radiological skeletal bone survey: CT or MRI may be helpful. β2-Microglobulin, C-reactive protein and lactate dehydrogenase Diagnostic Criteria for Multiple Myeloma Monoclonal plasma cells present in the bone marrow ≥10%, and/or presence of a documented plasmacytoma. + Presence of M component in serum and/or urine. + One or more of the following (CRAB criteria): – Calcium elevation (serum calcium >11.5 mg/dL) – Renal insufficiency (serum creatinine >2 mg/dL) – Anemia (hemoglobin 2 g/dL, light chain >1 g/dL in 24-hour urine sample. 8 Common Sites for Bone Involvement Skull Spine – Thoracic – Lumbar – Vertebrae Pelvis Long bones Spinal cord – compression can occur 9 International Staging System for Symptomatic Multiple Myeloma STAGE VALUES Stage 1 ß2M 5.5 mg/dL β2M=serum β2 microglobulin in mg/dL; ALB=serum albumin in g/dL 10 Risk stratification — The aggressiveness of MM depends upon several variables that impact disease biology. Genetic abnormalities seen in the myeloma cells are one of the strongest predictors of tumor aggressiveness High risk disease — Approximately 15 percent of people with MM have high risk disease on cytogenetic testing. This includes patients with the following cytogenetic abnormalities: translocation t(14;16), translocation t (14;20) and deletion chromosome 17p. This type of MM is aggressive and may shorten survival. Intermediate risk disease — Approximately 10 percent of people with MM have intermediate risk disease on cytogenetic testing. This includes patients with translocation t(4;14). Standard risk disease — All patients with MM who lack high or intermediate risk genetic abnormalities are considered to have standard risk MM. With modern therapy, patients with standard risk MM have an estimated median survival of 8 to 10 years. MM Treatment Options Conventional chemotherapy: – Melphalan – Doxorubicin – Cyclophosphamide Steroid therapy: – Dexamethasone – Prednisone Novel therapeutics: – Thalidomide – Lenalidomide – Bortezomib Stem cell transplantation: – Autologous – Allogenic Radiation therapy Thalomid® Prescribing Information, Revlimid® Prescribing Information; Velcade® Prescribing Information 12 Disorder Associated with Monoclonal Protein Neoplastic cell proliferation – multiple myeloma – solitary plasmacytoma – Waldenstrom macroglobulinemia – heavy chain disease – primary amyloidosis Undetermined significance – monoclonal gammopathy of undetermined significance (MGUS) Transient M protein – viral infection – post-valve replacement Malignacy – bowel cancer, breast cancer Immune dysregulation – AIDS, old age Chronic inflammation CHRONIC MYELOPROLIFERATIVE DISORDERS 14 CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD) 1. Polycythemia vera 2. Chronic myeloid leukaemia 3. Essential thrombocythemia 4. Idiopathic myelofibrosis 15 CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD) MPD are clonal diseases originating in pluripotential haematopoietic stem cell. The clonal expansion results in increased and abnormal haematopoiesis and produces a group of interrelated syndromes, classified according to the predominant phenotypic expression of the myeloproliferative clone. 16 POLYCYTHEMIA VERA (PV) Pathogenesis: PV is a clonal disorder involving the hematopoietic stem cells; it leads to an autonomous proliferation of the erythroid, myeloid, and megakaryocytic cell lines. Increased erythroid proliferation is usually more prominent than that of the other cell lines and occurs independently of erythropoietin levels (which are usually very low in PV) very low in PV) 17 POLYCYTHEMIA VERA Clinical features 1. 2. 3. 4. 5. Facial plethora. Splenomegaly – is present in 70% of patients at the time of diagnosis. Hepatomegaly - is present in approximately 40% of patients at the time of diagnosis. Hypertension. On examination of the eye grounds, the vessels may be engorged, tortuous, and irregular in diameter; the veins may be dark purple. ( fundus policythaemicus) 18 POLYCYTHEMIA VERA Complication: 1. Erythrocytosis and hyperviscosity, leading to impaired oxygen delivery: Poor CNS circulation: headaches, dizziness, vertigo, tinnitus and visual disturbances Poor coronary circulation: angina pectoris Peripheral circulation intermittent claudication 2. Venous thrombosis or thromboembolism. 3. Hemorrhage: epistaxis, gingival bleeding, ecchymoses, gastrointestinal bleeding. 4. Peptic ulcer lead to the abdominal pain. 5. Pruritus is secondary to increased histamine release from the basophils and mast cells. 19 DIAGNOSTIC CRITERIA FOR POLYCYTHEMIA VERA Major Criteria Hb >16.5 g/dL in men, >16.0 g/dL in women, or Hct >49% in men, >48% in women, or increased red cell mass >25% above mean normal predicted value. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis), including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size). Presence of JAK2V617F or JAK2 exon 12 mutation Minor Criteria Subnormal serum erythropoietin level 20 Chronic Idiopathic Myelofibrosis Myelofibrosis is a chronic myeloproliferative disease with either clonal hematopoesis or secondary(non-clonal). Hyperproliferation of fibroblasts (stimulated by PDGF, EGF, TGF-β released from myeloid cells, mainly from neoplastic megakaryocytes) with increased collagen synthesis. It produces bone marrow fibrosis and to extramedullary hematopoesis in the spleen or in multiple organs. 21 Diagnostic Criteria of Myelofibrosis The following criteria have been proposed by the WHO for the diagnosis of primary myelofibrosis. Major criteria - requires meeting all 3 major criteria: Megakaryocyte proliferation and atypia accompanied by either reticulin and/or collagen fibrosis, or In the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased bone marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (i.e., prefibrotic PMF) Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm Demonstration of JAK2V617F or other clonal marker or no evidence of reactive bone marrow fibrosis Minor criteria - requires meeting 2 minor criteria: Leucoerythroblastic anemia Increased serum LDH Palpable splenomegaly 22 Prognosis of myelofibrosis - A median survival of 3,5 to 5,5 years - The principal causes of death are infections, thrombohemorrhagic events, heart failure, and leukemic transformation - Leukemic transformation occurs in approximately 20% of patients during first 10 years 23 laboratory findings Anemia - Hb