Multiply Myeloma DR. Ahmad Magableh Haematologist

Transcription

1 Multiply Myeloma DR. Ahmad Magableh Haematologist

2 Definition A malignant proliferation of plasma cells derived from a single clone involving more than 10 percent of the bone marrow The multiple myeloma cell produces monoclonal immunoglobulins that may be identified on serum or urine protein electrophoresis.

3 As a result! Tumor, its products, and the host response to it, result in a number of organ dysfunctions Fracture/bone pain Renal failure Susceptibility to infection Anemia Hypercalcemia Clotting abnormalities Neurologic symptoms Vascular manifestations of hyperviscosity

4 Etiology Cause not known! More commonly than expected among Low socioeconomic class Farmers (DDT exposure) Wood workers Leather workers Sheet metal workers Nuclear industry workers Those exposed to petroleum products (??benzene) Chromosomal alterations (50 % have an abnormal karyotype ) Single or combinations of hyperdiploidy of chromosomes 3, 5, 7, 9, 11, 15 and 19 Hypodiploidy of chromosomes 8, 13, 14 and sex chromosome X. 13q14 / 17p13 deletions 11q abnormalities Translocation t(11;14)(q13;q32) Overexpression of myc or ras genes Mutations in p53 and Rb-1

5 Incidence Increases with age The median age at diagnosis is 68 years Rare under age 40 In Middle east area diagnoses is at an earlier ages Males > Females (slightly) Accounts for about 1% of all malignancies in whites 13% of all hematologic cancers in whites

6 Cases/100, Incidence of Myeloma Age

7 Pathophysiology A precursor cell arises when one or more exogenous stimuli induce cytogenetic changes in the B-cell lineage at the lymph node Multiple myeloma cell establishes itself in the bone marrow by adhering to stromal cells and inhibiting osteoblastic activity and osteocalcin production Adhesion of the multiple myeloma cell stimulates production of interleukin-6 ( a paracrine and autocrine growth factor for the multiple myeloma cell & an osteoclast activating factor) Normal bone marrow contains less than 5% plasma cells Myeloma bone marrow contains over 10% plasma cells B cells, T cells and macrophages undergo immunologic alterations related to marrow invasion Osteoporosis Painful lytic lesions Hypercalcemia Increased susceptibility to infections

8 Pathophysiology Multiple myeloma cell clone produces an excess of Monoclonal immunoglobulins that are nonfunctional and are called paraproteins (M proteins) recognized as IgA, IgD, IgG, IgE or IgM, depending on their heavy chain class Responsible for the hyperviscosity syndrome which interferes with fibrin aggregation and platelet function. Incomplete immunoglobulins as free light chain proteins (kappa or lambda) in 75% of cases (Bence Jones proteins) May precipitate and deposit, producing organ damage (kidney) Secreted in the urine 1% of multiple myelomas are called nonsecretors because they do not produce any abnormal Ig

9 Classification of MM Classified according to identity of M protein heavy & light chain Distribution of Myeloma subtypes IgG IgA IgD IgM IgE k l k l k l k l k l Frequency (%) Bence Jones (BJ) myeloma occurs when immunoglobulin light chains are synthesised in the absence of heavy chains 1% of individuals over 25 years & > 3% over 70 years express monoclonal protein some are very early myelomas significant proportion completely stable & show no malignant progression monoclonal gammopathy of undetermined significance (MGUS)

10 Pathogenesis and Clinical Manifestations of Multiple Myeloma Clinical Finding Underlying Cause Pathogenic Mechanism Hypercalcemia Pathologic fractures Cord compression Lytic bone lesions Osteoporosis Bone pain Renal failure Skeletal destruction Light chain proteinuria Hypercalcemia Urate nephropathy Amyloid glomerulopathy Tumor expansion Production of osteoclast activating factors (OAF) by tumor cells Toxic effects of tumor products Light chains OAF DNA breakdown products infections Pyelonephritis Hypogammaglobulinemia

11 Findings Underlying Cause Pathogenic Mechanism Anemia Infection Neurologic symptoms Myelophthisis Decreased production Increased destruction Decreased neutrophil migration Hyperviscosity Cryoglobulins Amyloid deposits Tumor expansion Production of inhibitory factors and autoantibodies by tumor cells Decreased production due to tumor-induced suppression Increased IgG catabolism Products of tumor Properties of M component Light chains Bleeding Mass lesions Hypercalcemia Cord compression Interference with clotting factors Amyloid damage of endothelium Platelet dysfunction OAF Products of tumor Antibodies to clotting factors Light chains Antibody coating of platelets Tumor expansion

12 Clinical Manifestations of Multiple Myeloma Pain in the lower back, long bones or ribs Generalized malaise Infections Fever Bleeding Symptoms of hyperviscosity Headaches Bruising Ischemic neurologic symptoms Other neurologic symptoms Peripheral neuropathy Meningitis Symptoms of hypercalcemia Nausea Fatigue Thirst

13 Pathogenesis and Clinical Manifestations Bone Symptoms Bone pain (most common symptom affecting 70% of patients ) Involves back, ribs, long bones, skull and pelvis Precipitated by movement (unlike the pain of metastatic carcinoma, which often is worse at night) If persistent & localized usually signifies a pathologic fracture

14 Pathogenesis and Clinical Manifestations Bone Symptoms Bone lesions Caused by Proliferation of tumor cells Activation of osteoclasts that destroy the bone under the effect of osteoclast activating factors (OAF) made by the myeloma cells The bony lysis results in mobilization of calcium from bone and serious complications of hypercalcemia Better seen on plain radiography rather than radioisotopic bone scanning May expand to the point that mass lesions may be palpated (skull, clavicles, and sternum ) or local cavitation as "soft spots" or "holes" on the skull. Collapse of vertebrae may lead to spinal cord compression

15

16

17 Pathogenesis and Clinical Manifestations Susceptibility to bacterial infections Recurrent infections are the presenting features in 25% of patients Most common infections are Pneumonias (Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae) Pyelonephritis ( Escherichia coli and other gramnegative organisms )

18 Pathogenesis and Clinical Manifestations Susceptibility to bacterial infections Several contributing causes The M-proteins crowd out the functional Igs and other components of the immune system & also cause functional antibodies, which are produced by normal plasma cells, to rapidly break down. Diffuse hypogammaglobulinemia (if the M component excluded) related to Decreased production of normal antibodies. Increased destruction of normal antibodies Poor antibody responses to polysaccharide antigens on bacterial cell walls (large M component myeloma ) Decreased subset of CD4+ cells (most measures of T cell function are normal) Granulocytes Low lysozyme content Slow migration as a result of a tumor product.

19 Pathogenesis and Clinical Manifestations Renal failure / pathology Failure occurs in nearly 25% Some renal pathology is noted in > 50% Factors contributing to renal dysfunction Hypercalcemia ( most common cause of renal failure) Glomerular deposits of amyloid Hyperuricemia Recurrent infections Infiltration of the kidney by myeloma cells Tubular damage associated with the excretion of light chains ( almost always present )

20 Pathogenesis and Clinical Manifestations Anemia Occurs in 80% of myeloma patients Types Usually normocytic and normochromic Can be megaloblastic due to either folate or vitamin B12 deficiency Due to Replacement of normal marrow by expanding tumor cells Inhibition of hematopoiesis by factors made by the tumor Mild hemolysis

21 Pathogenesis and Clinical Manifestations Other Hematological Abnormalities Granulocytopenia and thrombocytopenia are very rare. Clotting abnormalities due to Failure of antibody-coated platelets to function properly Interaction of the M component with clotting factors I, II, V, VII, or VIII. Raynaud's phenomenon and impaired circulation (if M component forms cryoglobulins -protein in the blood forms particles in the cold, blocking blood vessels, leading to pain and numbness of the extremities-) Hyperviscosity syndromes (Thick, viscous blood, caused by the accumulation of large proteins, such as immunoglobulins, in the serum ) Develop depending on the physical properties of the M component (most common with IgM, IgG3, and IgA paraproteins)

22 Pathogenesis and Clinical Manifestations Neurological Symptoms Occur in a minority of patients Causes Hypercalcemia (lethargy, weakness, depression, and confusion) Hyperviscosity (headache, fatigue, visual disturbances, and retinopathy) Bony damage and collapse ( cord compression, radicular pain, and loss of bowel and bladder control) Infiltration of peripheral nerves by amyloid (Carpal tunnel syndrome and other sensorimotor mono- and polyneuropathies)

23 Amyloid deposition in the tongue of a myeloma patient

24 Diagnosis 30% of new cases are diagnosed incidentally during evaluation for seemingly unrelated problems In 30 % a pathologic fracture is the presenting feature In 25% of patients recurrent infections are the presenting features

25 Diagnosis The classic triad of myeloma Marrow plasmacytosis (>10%) Lytic bone lesions Serum and/or urine M component The diagnosis may be made in the absence of bone lesions if the plasmacytosis is associated with a progressive increase in the M component over time or if extramedullary mass lesions develop

26 STAGING OF MM: 1-stage Duire- salmon system: A HB > 10 GM /dl B -Ca normal or < 12MG/dl C -normal skeletal survey or solitary plasmacytoma D -low M protein with IgG < 5 GM /dl or IgA <3GM/dl E -Bence jones protein > 4G /24hours 2-Neither stage1 nor stage3

27 3-One of the following : A-HB < 8.5G/dl B-calcium > 12MG /dl multiple lytic lesions c-high M component: IgG > 7G / dlor IgA > 5G/dl D-Bence-jones protein >12g /24hours

28 ISS staging system : 1-beta 2 M <3.5 & albumin > 3.5G /dl 2-CRP<4 MG/dl 3-plasma cell labeling index <1% 4-absence of chr 13 deletion 5-low serum IL-6 receptor level 6-long duration of initial plateau phase 7-median survival of 62 months STAGE (b): 1-Beta 2M <3.5 G/dl, albumin <3.5 G/dl Median survival of 44 months

29 Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone

30 Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma

31 Clinical evaluation Careful physical examination Tender bones and masses Enlargement of the spleen and lymph nodes, the physiologic sites of antibody production (minority) Exudative macular detachment, retinal hemorrhage or "cotton-wool" spots Amyloid deposition on the tongue, causing macroglossia Cardiomegaly related to deposition of immunoglobulin. Positive Tinel sign, Phalen sign for carpal tunnel compression due to amyloid deposition. Imagings Chest and bone radiographs ( lytic lesions or diffuse osteopenia ) MRI To depict myeloma tumors To document cord or root compression in patients with pain syndromes. To assess efficacy of therapy (Radiographic improvement occurs in 30 % of treated patients)

32 Clinical evaluation Blood studies CBC (anemia, pancytopenia,) ESR (elevated) Ca, BUN, Cr and uric acid (elevated) Serum alkaline phosphatase is usually normal ( absence of osteoblastic activity) Hypoalbuminemia

33 Clinical evaluation Serum protein electrophoresis The use of an electrical field to separate proteins in a mixture (such as blood or urine), on the basis of the size and electrical charge of the Albumin Globulins Alpha1 = alpha1-antitrypsin + thyroidbinding globulin + transcortin Alpha2 = Ceruloplasmin + alpha2- macroglobulin + haptoglobin Beta = Transferrin + Beta-lipoprotein + sometimes IgA, IgM, and IgG, along with complement proteins Gamma = Immunoglobulins predominantly IgG + CRP globulins

34 Clinical evaluation Protein electrophoresis In Monoclonal gammopathies & Myeloma the single clone of plasma cells produce a homogeneous monoclonal immunoglobulin ( M protein) characterized by the presence of a sharp, well-defined band with a single heavy chain and a similar band with a kappa or lambda light chain The M protein is identified as a narrow peak or "spike" in the g, ß or a2 regions

35

36 Clinical evaluation Immunoelectrophoresis (sensitive for identifying low concentrations of M components not detectable by protein electrophoresis) A 24-h urine specimen To quantitate protein excretion (Bence Jones) For electrophoresis and immunologic typing of any M component. Quantitation of serum 2-microglobulin

37 Differential Diagnosis Other monoclonal gammopathies Heavy chain disease Waldenstrom macroglobulinemia MGUS monoclonal gammopathies of uncertain significance (most difficult) More common than myeloma (In 1% of > 50 yo and in10% of >75 yo). Usually have <10% bone marrow plasma cells; <30 g/l (3 g/dl) of M components No urinary Bence Jones protein No anemia, renal failure, lytic bone lesions, or hypercalcemia. About 1-2% per year develop myeloma. (need follow up) Typically require no therapy Survival is about 2 years shorter than age-matched controls without MGUS.

38 Differential Diagnosis Other monoclonal gammopathies Plasmacytoma Solitary bone plasmacytoma Single lytic bone lesion without marrow plasmacytosis May recur in other bony sites after Tx or evolve into myeloma (55% within 3-4 yrs) Extramedullary plasmacytoma Involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis Rarely recurs or progresses into myeloma Both are Associated with an M component in < 30% of the cases May affect younger individuals, Associated with median survivals of 10 or more years Highly responsive to local radiation therapy

39

40 Disease Phases Go! M Protein g/dl Asymptomatic MGUS or Smouldering Myeloma Symptomatic Active Myeloma Relapse Plateau remission Refractory relapse Therapy IIII IIII IIII

41 Prognosis Related to Serum beta 2-microglobulin level is related to survival and can substitute for staging CRP level Plasma cell morphology & histologic classification based on BM Bx (plasmocytic, mixed cellular or plasmoblastic ) Number of cytogenetic abnormalities (chromosome 13q deletion) % plasma cells in the marrow & circulating plasma cells Serum levels of many substances (IL-6, soluble IL-6 receptors, hepatocyte growth factor, C-terminal cross-linked telopeptide of collagen I, TGF-, and syndecan-1)

42 Indications for Therapy Indications for starting therapy Myeloma is not curable Is therapy required? MGUS & asymptomatic myeloma observed rather than treated 3 monthly physical examination Quantitation of serum & urine M protein Bone marrow & skeletal survey when new signs develop Chemotherapy is indicated for management of symptomatic myeloma Early intervention no benefit in randomised controlled trials Treatment is recommended when M protein is increasing Clinical problems or evidence of related organ or tissue impairment (CRAB) C - calcium elevation (> 10 mg/l) R - renal dysfunction (creatinine > 2 mg/dl) A - anaemia (haemoglobin < 10 g/dl) B - bone disease (lytic lesions or osteoporosis) Neutropenia Nerve damage

43 Goals of MM Therapy Goals of treatment Address pain relief & other disease symptoms Control disease activity prevent further organ damage Extend disease-free survival (DFS) Prolong overall survival (OS) Preserve normal performance and QOL for as long as possible

44 MM New & Emerging Therapies Thalidomide and analogues Revimid /Actimid VELCADE (proteasome inhibitor) Doxil (long-acting adriamycin) Trisenox (arsenic trioxide) Holmium skeletal targeted radiation Genasense (antisense-bcl2 drug) Farnesyl transferase inhibitors R115777, FTI-277, Zarnestra Mini-allo (non-myeloablative) transplant

45 Novel Therapies VELCADE Thalidomide and analogues Trisenox (Arsenic Trioxide) Genasense (bcl-2 antisense) Farnesyl Transferase Inhibitors

46 Supportive Therapy For bone: Bisphosphonates For anemia: Erythropoietin For renal complications For other symptoms such as pain

47 Treatment (Supportive care) Directed at the anticipated complications (may be as important as primary antitumor therapy) For Hypercalcemia ( bisphosphonates, glucocorticoid therapy, hydration, and natriuresis. For strengthening the skeleton( fluorides, calcium, and vitamin D, with or without androgens, have been suggested but are not of proven efficacy) For iatrogenic worsening of renal function (allopurinol during chemotherapy to avoid urate nephropathy and high fluid intake to prevent dehydration and help excrete light chains and calcium) For hyperviscosity syndromes (Plasmapheresis)

48 Treatment (Supportive care) To protect against infections Pneumococcal polysaccharide vaccines (may not elicit an antibody response) Urinary tract infections should be watched for and treated early. Prophylactic administration of intravenous globulin preparations ( in the setting of recurrent serious infections) Chronic oral antibiotic prophylaxis ( probably not warranted ) For neurologic symptoms in the lower extremities, severe localized back pain, or problems with bowel and bladder control may need emergency myelography and radiation therapy for palliation.

49 Treatment (Supportive care) For bone lesions ( analgesics and chemotherapy, but certain painful lesions may respond most promptly to localized radiation.) For chronic anemia may respond to hematinics (iron, folate, cobalamin), and some have responded to androgens & erythropoietin (in the setting of renal disease)

50 Velcade License and Indication VELCADE (bortezomib) for Injection is indicated for the treatment of patients with Multiple Myeloma (MM). 50

51 VELCADE Mechanism of Action Velcade, when discovered, was considered as the first advancement in Multiple Myeloma treatment in the last 30 years. The researchers who discovered the Ubiquitin-mediated protein degradation (Velcade mechanism of action) received the Nobel prize for chemistry research in

52 VELCADE Mechanism of Action One target Proteasome Inhibition multiple downstream pathways: The cell cycle and Gene transcription Apoptosis Angiogenesis Interaction of cell with microenvironment 52

53 Recommended Dose and method of Administration Recommended dosage The recommended starting dose of bortezomib is 1.3 mg/m 2 body surface area twice weekly for two weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). This 3-week period is considered a treatment cycle. It is recommended that patients with a confirmed complete response receive 2 additional cycles of VELCADE beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of VELCADE therapy. 53

54