Dr A. Mousavi

 15 % of all malignant white cell diseases  1% of all cancer deaths  Group of lymphoid neoplasms of terminally differentiated B-cells that have in common the expansion of a single clone of immunoglobulin(Ig)-secreting plasma cells and a resultant increase in serum levels of a single homogeneous(monoclonal) Ig or it’s fragments.

 Caused by malignant changes to plasma cells or the B lymphocyte cell line.  Exhibit either:  Excessive amounts of normal immunoglobulin proteins (Igs)  Accumulation of Igs in an abnormal location  Structurally abnormal Igs

 Terminally differentiated B-cells  Not normally found in peripheral blood.  Account for less than 3.5% of nucleated cells in the bone marrow  Oval cells with low N:C ratio.  Cytoplasm is basophilic blue.  Nucleus (30-40% of the cell) is oval or round and typically placed eccentrically (to one side)of the cell.  A clear, colorless area adjacent to the nucleus contains Golgi apparatus  Russell bodies: Globules(2-3μm) of accumulated immunoglobulins in the cytoplasm of plasma cells. Usually round.  Russell bodies may be found in normal bone marrow.

 Develop from stem cells in bone marrow  Stem cells develop into B cells (B lymphocytes)  Antigens enter body then B cells develop into plasma cells  Produce antibodies

 Which of these are the heavy chains?  Name the 5 classes of heavy chain.  Gamma, mu, alpha, delta and epsilon  Which of these are the light chains?  Name the 2 classes of light chain.  Kappa and lambda NH3+ COO-

 Where is the constant region of the molecule?  Where is the variable region?  Which region defines the specificity of the antibody?  Variable  Which region is responsible for the physical properties of the antibody, such as ability to activate complement and binding to macrophages?  Constant NH3+ COO-

 Normally, plasma cells produce immunoglobulins to fight infection  However, in MM and MGUS a single cloned plasma cell proliferate and overproduce the same Ig ("M-protein" or “Paraprotein")  The M-protein is usually an IgG  MM cells can also just produce the light chain component (Instead of the entire Ig)

Consequence of producing lots of monoclonal Ig: o Hyperviscosity o Kidney Damage (from light chains only) o Bone pain, hypercalcemia and pathologic fractures from bone lesions. o Anemia/Pancytopenia from bone marrow invasion

Y B Cell Normal Plasma Cell Malignant Plasma Cell Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

 Accumulation of a single protein that arises from proliferation of a single plasma cell clone.  Since each B cell can respond to only one antigenic epitope, a plasma cell derived from that B cell produces antibody that is reactive against that unique epitope (monoclonal antibody).  Malignant changes to that plasma cell result in uncontrolled production of its specific antibody.  The specificity of the monoclonal antibody (M protein) varies between patients, but each affected patient has only one M protein specificity.

 Adhesion molecules  Stromal cells Interactions:  Cytokines (IL-6)  Growth factors that promote angiogenesis (IGF-1, VEGF, SDF-1α)  Inactivated immune system

 Gammopathy  Monoclonal gammopathy  Dysproteinemia  Paraproteinemia

 MGUS (62%)  Malignant Monoclonal gammopathies:  MM (18%) variants: smoldering myeloma (3%), non-secretory MM, light chain myeloma  Plasmacytoma  Plasma cell leukemia  IgD myeloma  POEMS syndromes (Osteosclerotic myeloma)  Waldenstrom’s Macroglobulinemia (Lymphoplasmacytic lymphoma)

 Malignant lymphoproliferative disorders  Heavy chain diseases (Gamma HCD, Mu HCD, Alpha HCD)  Immunoglobulin deposition diseases (Primary Amyloidosis, Systemic light chain and heavy chain deposition diseases)

 In any suspected Monoclonal Gammopathy should include to accurately classify the disorder:  Complete Blood Count (look for anemia)  Comprehensive Metabolic panel  Look for renal insufficiency, hypercalcemia and subtle clues like decreased anion gap

 Total protein and albumin level. Determine Globulin component.Too low globulin( 3.5gm%) is concerning:Determine if Polyclonal vs.Monoclonal. Evaluate further with:  Quantitative Immunoglobulins: Increase in all components usually, polyclonal. Increase in single component with reciprocal decrease of uninvolved globulin usually, may suggest monoclonal.

 Serum Protein Electrophoresis with immunofixation if monoclonal gammopathy is suspected.  24HR-Urine protein electrophoresis with urine immunofixation (Serum Free Light Chain assay(κ/λratio) may be used in place of UPEP}

 Bone marrow biopsy to evaluate% plasma cells if there is monoclonal protein or abnormal UPEP or Light chain assay or if strong clinical picture of myeloma.  Skeletal survey if monoclonal gammopathy has been established(Bone scans are usually negative in MM)  Beta-2 microglobulin and Albumin for staging and prognosis in MM (once diagnosis is made).

 Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder (i.e; Undetermined Significance)  M- protein < 3 gr/dl  < 10% plasma cell in bone marrow  No or small amounts of M- protein in urine  Absence of lytic bone lesions, anemia, hypercalcemia, renal insufficiency  No evidence of B- cell lymphoproliferative disorder  Stability of M- protein over time

 Incidence increases with age  Significance: can progress to monoclonal disease IgA or IgG MGUS IgM MGUS MM Primary Amyloidosis Related Plasma cell disorder NHL CLL Waldenstroms’ Macroglobulinemia

 Smoldering Myeloma:  Serum monoclonal protein ≥ 3 g/dl and/or bone marrow plasma cells ≥ 10%  No end organ damage related to plasma cell dyscrasia

 Rare variant: About 1% of Myelomas  May present with Bone lesions (most common presenting symptom bone pain)  No serum or urine monoclonal protein(diagnosis can be missed if one is not aware of this entity, NSMM).  Renal failure and hypercalcemia are generally lacking  Anemia may be present  Bone marrow biopsy must be performed in suspected cases: Immunostaining for a monoclonal protein on bone marrow sections may establish the diagnosis  Clonal plasma cell population in marrow.  Must rule out IgD and IgE myeloma

 Localized plasma cell tumor  Absence of a plasma cell infiltrate in random marrow biopsies  No evidence of other bone lesions by radiographic examination  Absence of renal failure, hypercalcemia or anemia  Younger median age at presentation (55 y)  Treatment: Radiation to site (5000 cGy)  50-60% will convert MM within 10 years  Possible bone marrow collection/ storage

 Arise outside the bone marrow with no features of MM  Most common: Head and Neck region  Less common: Lymph nodes, Salivary glands, spleen, liver,…  25% have small monoclonal spike  Rare dissemination, rare revolution to myeloma  Management:  If completely resected during biopsy,no further therapy  If incompletely resected,radiation therapy locally

 Three criteria: 1.Presence of a serum or urinary monoclonal protein 2.Presence of 10 percent or more clonal plasma cells in the bone marrow or a plasmacytoma 3.Presence of end organ damage felt related to the plasma cell dyscrasia, such as: M- CRAB: Monoclonal protein HyperCalcemia (calcium >11.5 gm/dl) Renal Insufficiency Anemia (Hb < 10gm/dl) Lytic Bone lesions

 Bone lesions:  Conventional Radiographs (Skeletal Survey) is abnormal in 80% of MM  Focal lytic bone: 57%  Osteopenia or Osteoporosis: 20%  Pathologic fractures: 20%  Vertebral body compression fractures: 20%

 Anemia:  Normochrome nomocyter in 75% of MM  Hb < 10 mg/dl  Renal insufficiency:  Serum creatinine increased in >50% at diagnosis  Creatinine >2g/dL in 20% of patients  Renal failure may be presenting manifestation

Cytogenetic:  14 q 32  1 q 5, 8, 12,….  Deletion 17 p and Abnormalities associated with chromosome13 carry a particularly unfavorable prognosis and respond poorly to therapy

Staging: International staging system:  Stage I— B2M <3.5mg/L and serum albumin ≥ 3.5g/dL  Stage II— neither stage I nor stage III  Stage III— B2M ≥ 5.5mg/L  Median overall survival dicreases with increasing stages

Indications: presence of any of CRAB, High risk patients Current frontline options:  Conventional chemotherapy  Survival ≤ 3 yrs  Stem Cell Transplantation  Prolongs survival 4- 5 yrs  Novel agents targeting stromal interactions and associated signaling pathways (Thalidomide, Lenalidomide, Bortezomib,…)  have shown promise and improved survival

 P olyneuropathy (Motor, 100%)  O rganomegaly (Hepatosplenomegaly, 50%)  E ndocrinopathy (Hypogonadism, Hypothyroidism, 66%)  M onoclonal gammopathy  S kin changes (Hyperpigmentation, Hypertrichosis)  S clerotic bone lesions (related to cytokines, VEGF, 97%)

 Diagnostic criteria:  Two major+ at least one minor  Major: Polyneuropathy, Monoclonal plasma cell disorder  Minor: Sclerotic bone lesions, Organomegaly, castleman’s dis, Volume overload, Endocrinopathy, Skin changes, Papilledema  Treatment: Radiation to bone lesion

 >2 X 10 9 /L plasma cells in blood(seen on peripheral smear)  Younger age  Higher incidence of organomegaly and lymphadenopathy  More extensive bone marrow infiltration  Renal failure more common  Less bone pain, fewer lytic lesions  Poor response to therapy

 Monoclonal gammopathy: IgM type  Plasmacytoid lymphoma  Median age at diagnosis: 60 yrs  Presentation:  Hyperviscosity syndrome(15%): visual impairment, neurologic manifestations  Bleeding(Acquired VWD)  Cryoglobulinaemia  Organomegaly, lymphadenopathy (20%- 40%)  Autoimmune hemolysis: common  Bone marrow involvement: 90%  Lytic bone lesions: 2%  Hypercalcemia: 4%

 Asymptomatic patients not treated until symptoms develop  If Hyperviscocity features: urgent Plasmapheresis  Symptomatic WM: Rituximab based therapy

 Amyloidosis caused by extracellular deposition of pathologic insoluble fibrillar proteins in organs and tissues  M-protein: 89%, Lambda: 70%  M-protein > 3 mg/dl: 7%  Hypogammaglobulinemia: 20%  Median bone marrow plasma cells: 7% (<10%)  Organ involvments: cardiac arrythmia, renal failure, skin changes, macroglossia

 Evaluate for amyloidosis in patients with a monoclonal protein in serum or with a monoclonal protein in serum or urine plus:  Nephrotic syndrome or renal insufficiency  Congestive heart failure  Peripheral neuropathy  Carpal tunnel syndrome  Hepatomegaly  Idiopathic malabsorption

Diagnostic Criteria:  Tissue biopsy showing typical morphology  Apple green birefringence under polarized light after Congo Red staining  Term amyloid first coined by Virchow in mid 19 th century (meaning starch or cellulose).  Typical fibrillar ultrastructure  Diagnostic methods and Sensitivity:  Bone marrow examination: 56%  Abdominal fat aspiration: 80%  Combined BM and fat aspirate: 89%

 Heavy chain of Ig  Alpha type:  Younger patients  Mediterranean lymphoma (Intestinal lymphoplasmacytoid Lymphoma)  Remission with antibiotics

 Gamma Heavy Chain Disease – seen in elderly  Symptoms –enlarged liver and spleen, recurrent infections, and anemia  Some patients experience no symptoms  Treatment with anti-lymphoma drugs and corticosteroids  Mu Heavy Chain Disease – rare  Symptoms include enlarged spleen, liver and abdominal lymph nodes  Survival and response to treatment varies

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