MULTIPLE MYELOMA AND PLASMACYTOMA DR KARANU JK

INTRODUCTION Most common primary malignancy of bone It is a plasma cell disorder- monoclonal neoplasms related to each other by virtue of their development from common progenitors in the B lymphocyte lineage

Plasmacytoma Thoughts that plamacytoma is simply an early, isolated form of multiple myeloma There are two important variants of myeloma, solitary bone plasmacytoma extramedullary plasmacytoma

Plasmacytoma Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis Extramedullary plasmacytomas usually involve the submuscosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis.

Etiology The cause of myeloma is not known Incresed frequency in those exposed to radiation Seen more frequently among farmers, wood workers, leather workers and those exposed to petroleum products

Etiology Chromosomal alterations identified: 13q14 deletions 17p13 deletions 11q abnormalities Common translocations t(11;14)(q13;q32) and t(4;14)(p16;q32)

Etiology Overexpression of myc or ras genes has been noted in some cases Mutations in p53 and Rb1 have also been described

No common molecular pathogenesis has yet emerged Etiology No common molecular pathogenesis has yet emerged

Incidence Represents more than 40% of primary bone cancers Peak incidence is in 5th to 7th decades 2:1 male predominance Blacks have nearly twice the incidence of whites. Yearly incidence is around 4 per 100000

Incidence Knh multiple myeloma 337 cases in 5 years, average of 67 per year Plasmacytoma 16 cases in 5 years, average of 3 per year

Pathogenesis and clinical manifestation Multiple myeloma cells bind via cell surface adhesion molecules to bone marrow stromal cells and extracellular matrix. This triggers multiple myeloma cell growth, survival, drug resistance and migration in the bone marrow milieu

Pathogenesis The cell effect is due to direct multiple myeloma and bone marrow stromal cell interaction , as well as induction of cytokines Cytokines involved include IL6, insulin like growth factor 1, vascular endothelial growth factor stromal cell derived growth factor

Pathogenesis Growth, drug resistance and migration are mediated via Ras/Raf/mitogen- activated protein kinase, PI3-K/Akt and protein kinase c signaling cascades

Symptoms The clinical manifestation of all the plasma cell disorders relate to expansion of the neoplastic cells secretion of cell products- immunoglobulins, lymphokines Host’s response to the tumour

Symptoms Bone pain most common complaint- precipitated my movement Weakness Weight loss Anaemia and thrombocytopenia Peripheral neuropathy Hypercalcaemia Renal failure

Symptoms Pathological fractures Symptoms are usually of short duration because of the aggressive nature of the disease The spine is the most common location followed by the ribs and pelvis.

Symptoms Hypercalcaemia, osteoporosis, pathological fracture, lytic bone lesions, bone pain Tumor expansion, osteoclast activating factor, osteoblast inhibitory factors Renal failure- Hypercalcaemia, light chain deposition, urate nephropathy, drugs

Symptoms Easy fatigue- anaemia Bone marrow infiltration, haemolysis, decreased erythropoietin levels Recurrent infections Hypogammaglobulinaemia, low cd4 count, decreased neutrophil migration

Symptoms Neurologic symptoms Hyper viscosity, croglobulinemia, Hypercalcaemia, nerve compression, POEMS syndrome Nausea and vomiting Renal failure, Hypercalcaemia

Diagnosing and staging The classic triad of myeloma is Marrow plasmacytosis (>10%)- CD138+, monoclonal Lytic bone lesions Serum and/ or urine M component

MGUS Monoclonal gammopathies of uncertain significance 1% go on to develop myeloma M protein in serum<30g/l Bone marrow clonal plasma cells<10% No evidence of other B cell proliferative disorder

Diagnosis Clinical evaluation of patients with myeloma includes a careful physical examination searching for tender bones and masses. Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia

Radiography Multiple ‘punched out’ sharply demarcated, purely lytic lesions without any surrounding reactive sclerosis

Bone scan The lack of reactive bone formation is shown by the fact that most lesions are negative on bone scan

MRI MRI offers a sensitive means to document extent of bone marrow infiltration and cord or root compression in patients with pain syndromes

Microscopy Histologically multiple myeloma appears as sheets of plasma cells These are small round blue cells clock face nuclei abundant cytoplasm perinuclear clearing or halo Amyloid production can be abundant and may be pathognomonic for the disease

Laboratory Serum immunoelectrophoresis shows monoclonal gammopathy A 24 hr urine specimen quantitate protein excretion concentrated aliquot is used for electrophoresis and immunologic typing of any M component

Laboratory The serum M component will be IgG in 53%, IgA in 25%, and IgD in 1%. 20% of patients will have only light chains in serum and urine.

Laboratory Fewer than 1% of patients will have no identifiable M component The heat test for detecting Bence Jones proteins is falsely negative in 50% of patients with light chain myeloma

Laboratory Complete blood count with differential may reveal anaemia ESR is elavated Serum chemistries calcium, urea, nitrogen, creatinine and uric acid levels may be elevated.

Differential diagnosis Solitary plasmacytoma pathological differentials may include chronic osteomyelitis with abundant plasma cells Plasmcytoma has monoclonal light chains whereas in COM they are polyclonal Myeloma cells stain positive for natural killer antigen CD56, whereas reactive cells do not

Differentials In poorly differentiated cases lymphoma could be a differential Lymphoma cells usually stain positive for CD45 (leukocyte common antigen) and CD20 ( a B cell marker),

Myeloma staging system- Durie-Salmon staging system Stage 1 Hb>10g/dl, serum calcium <3 mmol/l, normal bone xray or solitary lesion, low M component production

Myeloma staging system- Durie-Salmon staging system Stage 2- neither fitting stage 1 or 2 Stage 3- one or more of the following: Hb <8.5g/dl Serum calcium >3 mmol/l Advanced lytic bone lesion High M component production

Treatment 10% of patients will have an indolent course- slow progression These patients only require antitumor therapy when the disease becomes symptomatic anaemia, hypercalcaemia, progressive lytic bone lesions, progressive rise in serum myeloma protein levels or recurrent infections.

Treatment Primary treatment of multiple myeloma is chemotherapy Symptomatic bone lesions usually respond rapidly to radiation treatment 40 Gy Treatment of impending or actual pathological fractures of the spine, acetabulum, proximal femur or proximal humerus

Treatment Patients with symptomatic and/ or progressive myeloma require therapeutic intervention 2 sorts of such therapy Systemic therapy to control the progression of myeloma Symptomatic supportive care to prevent serious morbidity from the complications of the disease

Treatment Standard treatment for newly diagnosed cases depends on whether the patient is a candidate for high dose chemotherapy with autologous stem cell transplant Transplant candidates avoid alkylating agents such as melphalan Glucorticoids, vincristine, doxorubicin, thalidomide

Treatment Supportive care directed at the anticipated complications Hypercalcaemia-bisphosphonates, glucocorticoids,hydration, natriuresis Prophylactic IV gamma globulin in recurrent serious infections Anaemia- erythropoietin, along with haematinics

Treatment Short life expectancy in these patients operations aimed to earliest resumption of full activity Tumor debulking Internal fixation augmented with methacrylate Cemented total joint arthroplasty or hemiarthroplasty

Preop embolization

Treatment In most patients local radiation treatment should be instituted approximately 3 weeks after surgery or when the wound appears to be healed.

HIV and multiple myeloma No conclusive evidence on the corelation Aggressive course and worse prognosis in HIV Multiple myeloma can accelerate progression of HIV infection HIV plays a major role in the evolution of malignant plasma cell tumors

Prognosis Patients with solitary plasmacytoma without evidence of systemic involvement have a better prognosis More than half of patients who present with a solitary plasmacytoma eventually go on to develop multiple myeloma.

prognosis Patients in stage 1A have a median survival of more than 5 years and those in 3B about 15 months The median overall survival is 5-6 years with subsets of patients surviving over 10 years.

Prognosis The major causes of death are progressive myeloma,renal failure, sepsis or therapy related acute leukaemia or myelodysplasia. Nearly a quarter die of myocardial infarction, chronic lung disease, diabetes or stroke.

Knh -multiple myeloma ALIVE DEAD TOTAL CASES 2008 43 15 58 2009 41 20 61 2010 50 22 72 2011 31 74 2012 48 24

KNH-PLASMACYTOMA ALIVE DEAD TOTAL CASES 2008 2 1 3 2009 2010 2011 4 5 2012