summary Multiple Myeloma is neoplastic proliferation of plasma cells that commonly results in multiple skeletal lesions, hypercalcemia, renal insufficiency, and anemia. Patients typically present at ages > 40 with localized bone pain or a pathologic fracture. Diagnosis is made with a bone marrow biopsy showing monoclonal plasma cells ≥10%. Treatment is usually chemotherapy and radiation. Surgical management is indicated for associated fractures. Epidemiology Incidence most common primary bone malignancy occurs in 3-4:100,000 accounts for 1% of all malignancies Demographics patients > 40 years of age (median age is 60) affects males > females 2x more common in African Americans Etiology Forms neoplastic plasma cells produces immunoglobulins heavy chains: IgG (52%), IgA (21%), IgM (12%) light chains: kappa, lambda aka Bence Jones proteins disease takes multiple forms that vary in treatment and prognosis and includes multiple myeloma (see below) solitary plasmacytoma osteosclerotic myeloma Pathophysiology results from osteoclastic stimulation by malignant cells malignant cells bind bone marrow stromal cells to stimulate the production of receptor activator of nuclear factor-κ B ligand (RANKL) and other pro-osteoclastic mediators (macrophage colony-stimulating factor (M-CSF, IL-6, IL-11, ) osteoprotegerin (OPG) synthesis is suppressed, resulting in further osteoclast activation OPG competes with RANK to bind to RANKL as a decoy receptor osteoblastic differentiation may also be inhibited TNF and Dickkopf-1 (DKK-1) have been shown to down regulate osteoblast function Classification Multiple myeloma most common form diagnostic criteria monoclonal plasma cells ≥10% on bone marrow biopsy or biopsy-proven bony/extramedullary plasmacytoma and ≥1 of the CRAB features and myeloma-defining events (MDEs) CRAB features of end-organ damage hyperCalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL) Renal insufficiency: creatinine clearance <40 mL/min or serum creatinine >177µmol/L (>2mg/dL) Anemia: hemoglobin >20g/L below the lowest limit of normal or hemoglobin <100g/L Bone lesions: ≥1 osteolytic lesion on radiographs, CT, or PET/CT if bone marrow has <10% clonal plasma cells, >1 bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement MDEs ≥ 60% clonal plasma cells on bone marrow biopsy serum involved:uninvolved free light chain ratio of ≥ 100 only applies if the absolute level of the involved light chain is at least 100mg/L “involved” free light chain is the one that is above the normal range “uninvolved” free light chain is the one that is typically at/below the normal range ≥ 1 focal lesion on MRI that is ≥ 5mm in size staging Internation Staging System (ISS) Criteria Prognosis Stage I Beta-2 microglobulin < 3.5 mg/L Serum albumin≥ 3.5 g/dL 62 months Stage II Beta-2 microglobulin 3.5-5.4 mg/L 44 months Stage III Beta-2 microglobulin≥ 5.5 mg/L 29 months Solitary plasmacytoma plasma cell tumor occurring in a single skeletal location and lacking appropriate criteria for diagnosis of multiple myeloma sensitive to radiation progresses to multiple myeloma in over 50% of patients diagnostic criteria solitary lesion on skeletal survey histologic biopsy confirmation of plasmacytoma negative bone marrow biopsy (i.e. no plasma cells in bone marrow) obtain MRI and FDG-PET additional lesions identified in 33% of patients Osteosclerotic myeloma rare syndrome characterized by POEMS Polyneuropathy often symmetric begins distally and migrates proximally usually does not improve Organomegaly Endocrinopathy sclerotic bone lesions occur in both the axial and appendicular skeleton M protein Skin changes characteristic occurs predominantly in the trunk up to 25-50% of skin lesions occur in the extremities Presentation Symptoms usually presents with localized bone pain (usually spine or ribs) pathologic fracture fatigue secondary to anemia, renal insufficiency, hypercalcemia Imaging Radiographs findings multiple "punched-out" lytic lesions only visible once >50% destruction has occurred lytic appearance caused by osteoclastic bone resorption via RANKL, IL-6 and MIP-1alpha punched-out appearance absence of slerotic border results from the lack of osteoblastic activity in myeloma obtain skeletal survey if there is a suspicion for multiple myeloma given that bone scans are cold in 30% MRI indications more sensitive than XR for pelvis, spine findings dark on T1 bright on T2 Bone scans cold in 30% so skeletal survey is recommended bone scans are "hot" due to radio-tracer integration into the inorganic phase of bone caused by osteoblastic activity multiple myeloma often lacks osteoblastic activity Fluorodeoxyglucose-positron emission tomography (FDG-PET) 93% sensitivity more sensitive than plain radiographs in diagnosing/screening for MM may uncover additional sites in "solitary" plasmacytoma uptake into cancer cells due to increased glucose metabolism in most types of tumors Labs Serum labs anemia elevated creatinine hypercalcemia present in 30% of patients due to excessive resorption of bone ESR often elevated SPEP (serum protein electrophoresis) M spike present (50% IgG, 25% IgA) beta-2 microglobulin marker of prognosis/disease severity Urine proteinuria UPEP (urine protein electrophoresis) may show Bence Jones proteins (secreted immunoglobulin kappa and lambda light chains) Histology Distinctive histology round plasma cells with an eccentric nucleus, prominent nucleolus, and clock face organization of chromatin characteristic clear area (Hoffa clear zone) next to the nucleus represents the prominent Golgi apparatus involved in immunoglobulin (protein) production Bone marrow aspirate percentage of plasma cells on bone marrow aspirate is one major criteria used to distinguish plasmacytoma (10-30% plasma cells) vs. multiple myeloma (>30% plasma cells) normal amount of plasma cells on bone marrow aspirate is < 2% Immunohistochemical stains CD138+ Differential Differential of Multiple Myeloma Bone lesion in older patient Multiple lesion in older patient Benefits from Bisphosphonate therapy Treatment is chemotherapy and radiotherapy Myeloma o o o Metastatic bone disease o o o Lymphoma o o o Chondrosarcoma o MFH o Secondary sarcoma o Paget's disease o o Fibrous dysplasia o Synovial sarcoma Hyperparathyroidism o Glomus tumor Treatment(by treatment type) Nonoperative annual surveillance indications monoclonal gammopathy of unknown significance, asymptomatic myeloma external beam irradiation alone indications solitary plasmacytoma multiagent chemotherapy +/- stem cell transplantation +/- bisphosphonates indications multiple myeloma techniques chemotherapy non-transplant candidates melphalan + prednisone + thalidomide or bortezomib lenalidomide + dexamethasone thalidomide + dexamethasone transplant candidates lenalidomide + dexamethasone bortezomib + dexamethasone bortezomib + lenalidomide + dexamethasone bortezomib + thalidomide + dexamethasone Operative surgical stabilization and external beam radiation therapy indications complete or impending fractures life expectancy >3 months kyphoplasty indications vertebral compression fractures with instability or neural compression resistant to radiation Treatment (by disease type) Monoglonal gammopathy of unknown significance, asymptomatic myeloma nonoperative annual surveillance Multiple myeloma nonoperative multiagent chemotherapy +/- autologous and allogeneic stem cell transplantation indications chemotherapy alone for non-transplant candidates multiple medical comorbidities advanced age >65 years old poor physical condition induction chemotherapy and stem cell transplantation for transplant candidates autologous and allogeneic stem cell transplantation isnot curative but increases disease free survival by 2-3 years agents non-transplant candidates melphalan + prednisone + thalidomide or bortezomib lenalidomide + dexamethasone thalidomide + dexamethasone transplant candidates lenalidomide + dexamethasone bortezomib + dexamethasone bortezomib + lenalidomide + dexamethasone bortezomib + thalidomide + dexamethasone bisphosphonates helps reduce the number of skeletal events in multiple myeloma patients operative surgical stabilization and external beam radiation therapy indications complete or impending fractures life expectancy >3 months vertebral compression fractures with instability or neural compression resistant to radiation techniques kyphoplasty/vertebroplasty painful vertebral compression fractures currettage, PMMA and modified Harrington pins periacetabular lesions with intact acetabular subchondral plate complex THA with acetabular cage periacetabular lesions where acetabular subchondral plate is violated Solitary plasmacytoma nonoperative external beam irradiation (45-50 Gy) indications mainstay of treatment operative surgical stabilization indications complete or impending fractures Osteosclerotic myeloma nonoperative chemotherapy, radiotherapy, and plasmapheresis indications mainstay of treatment outcomes neurologic changes usually do not improve with treatment Prognosis Prognosis is variable Data suggests 5-year survival rate of 30% and 10-year survival rate of 11% overall survival is related to stage of disease and secondary factors like renal failure or hypercalcemia median survival is 3 years from diagnosis shortest survival is seen in patients with renal failure Poor prognostic factors in multiple myeloma chromosome 13 deletion or translocation (t4;14), 4(14;16) circulating plasma cells increased beta 2 microgloblulin (indicates elevated tumor burden) decreased serum albumin increased marrow microvessels Solitary plasmacytoma has the best prognosis