Multiple Myeloma – Flashcards
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Multiple Myeloma
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B-cell malignancy of neoplastic plasma cells that produce a monoclonal immunoglobulin. Clone of plasma cells proliferates in bone marrow.
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Clinical findings in multiple myeloma
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Skeletal destruction with osteolytic lesions, osteopenia or pathologic fractures, anemia, hypercalcemia, renal insufficiency, and recurrent bacterial infections.
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Multiple myeloma epidemiology
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2nd most common hematologic cancer in US (10%), 14,000 cases anually, 1% of cancers, 2% of cancer deaths. Mean age at diagnosis: 65-68, African-americans more than whites, men more common.
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Etiology
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Unknown cause, theories: chronic antigenic stimulation of plasma cell-->transformation, ionizing radiation, nickel, dioxin, benzene, aromatic hydrocarbons, silicon.
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Monoclonal Gammopathy of Undetermined Significance (MGUS)
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2% over 50, benign asymptomatic proliferation, plasma cell <10% of BM cells, premalignant condition, 25x greater risk of multiple myeloma- 1%/year.
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Pathogenesis of mutliple myeloma
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Fab fragment (Bence-Jones protein) found in urine. Malignant transformation is of only one plasma cell-monoclonal peak. Neoplastic cells form sheets replace normal NM, myeloma cells produce osteoclast-stimulating factors-cytokines destroy bone. Osteoblasts suppressed-->demineralization and bone destruction. Secondary hypercalcemia. IL-6 protects from apoptosis. Acquired cytogenic alterations in 80%, loss of Chr13 long arm, chr14 prognostic implication.
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Clinical picture of Multiple Myeloma
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Bone pain (back or chest, less extremity) 60%, pain in movement, not at night, height reduced by vertebral collapse. 80% of patients show abnormal radiograph. Focal osteolytic lesions (high osteoblasts, low osteoclasts) 60%, osteoporosis, pathologic fractures, compression fractures of the spine 20%, weakness and fatigue (32%), anemia, fever (<1%), bleeding uncommon, weight loss 24%, complications: hypercalcemia, renal insufficiency, amyloidosis.
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Physical findings of MM
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Pallor; palpable, hepatomegaly, splenomegaly, lymphadenopathy-rare. Extramedullary plasmacytoma: large, purplish, subcutaneous masses late.
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Neurologic disease
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Spinal cord compression from extramedullary plasmacytoma or bone fragment from vertebral body fracture 5%, severe back pain with weakness/paresthesias of lower extremities, bladder/bowel dyfunction/incontinence: medical emergency, test with MRI or CT myelography of entire spine. Followup with treatment. Peripheral neuropathy uncommon/amyloidosis.
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Infections with multiple myeloma
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Increased infection incidence, pneumococcus and gram negatives. From Ab response impairment, normal plasma function by hypogammaglobulinemia and chemo (neutropenia and corticosteroids).
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Renal disease
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Serum creatinine increased in 50% and over 2 in 20%. May be presenting manifestation of MM. Cast nephropathy (myeloma kidney) and hypercalcemia. Other types: AL-primary amyloidosis (amyloid fibrils-fragments of monoclonal light chains, acute renal failure after radiocontrast administration, proximal tubular dysfunction and Fanconi syndrome signs.
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Fanconi syndrome
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Proximal renal tubular acidosis, aminoaciduria, hypouricemia, and phosphate wasting. Releasting substances into proximal tubules that should be reabsorbed into blood.
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Myeloma cast nephropathy
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Large, waxy, laminated casts in distal and collecting tubules. Mainly composed of precipitated monoclonal light chains. Urine dipstick negative for protein usually.
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Lab findings
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Normocytic, normochromic anemia (Hb12) in 73-97%. Rouleaux formation (stacked erythrocytes) found in more than half of patients. ESR >20mm/h in 84% and >100 in 1/3. Leukopenia (20%) and thrombocytopenia (<100,000/uL-5%). Plasmacytosis in peripheral smear infrequent. Plasma cell leukemia in 1.5%.
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Monoclonal proteins
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Most important diagnostic finding. Demonstration of monoclonal (M) protein in serum/urine. 97% of patients.
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Which immunoglobulin is increased in MM?
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IgG (51.5%), IgA (21%), light chain (Bence Jones-16%), IgD (2%), IgM (0.5%-IgM melanoma). 7% have no monoclonal protein. Kappa mosre common than lambda (2/1) except IgD melanoma. Level of major uninvolved Igs (IgM and IgA) reduced in 91% patients overall, both in 73%.
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Nonsecretory melanoma
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Patients that have no M-protein in serum or urine on immunofixation at time of diagnosis. Renal failure uncommon. survival not different. Detection by concentrations of monoclonal serum FLC assay. More sensitive for detection of monoclonal FLC than urine, 19/28 reclassified as LCM.
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Light Chain Melanoma
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20% classified by light chain only in serum/urine, lack HC expression. Higher incidence of renal failures (serum creatinine 2mg/dL in 1/3).
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Laboratory artifacts
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Circulating monoclonal protein can interfere with other lab tests on liquid-based analyzers by precipitating or specific binding. Low HDL, high bilirubin, altered inorganic phosphate, psuedohyponatremia.
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Bone marrow examination in MM
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Confirm diagnosis: focal involvement. some pts require aspiration/biopsy at multiple sites to establish diagnosis.
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Beta-2 microglobulin
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Serum level is elevated (>2.7 mg/L) in 75%. Higher levels (>4mg/L) inferior survival compared to levels at 4 (28 vs 40mos).
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Diagnostic criteria of MM
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1. Plasma cells in bone marrow >=10% and/or presence of biopsy-proven plasmacytoma. 2. Monoclonal protein present in serum/urine, 3. Myeloma related organ dyfunction: CRAB.
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CRAB MM organ dysfunction
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1 or more for 3rd part of diagnosis: Calcium elevation, Renal insufficiency (creatinine), Anemia, and lytic bone leasions/osteoporosis
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Indolent (smoldering) myeloma diagnostic criteria
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1. Monoclonal protein present in serum/urine, 2. Monoclonal plasma cells present in BM/tissue biopsy, 3. No MGUS, MM or solitary plasmacytoma of bone or soft tissue.
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Diagnostic criteria for solitary plasmacytoma of bone
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All 3: 1. Biopsy-proven monoclonal plasmacytoma of bone in single site only. X-ray or MRI or PET imaging negative outside primary site. 2. Bone marrow >10% monclonal plasma cells, 3. No CRAB.
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Required testing for suspected MM
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History/physical exam, CBC/blood smear, Chem panel with Ca/Creatinine, SPEP, immunofixation, Ig quantification, routine urinalysis, 24h collection for electrophoresis and immunofixation, Quantification of both urine M-component (Bence-Jones protein), albuminuria, BM aspirate/biopsy with cytogenetics, bone survey including spine, pelvis, skull, humeri and femurs. B2 microglobulin, CRP, LDH, FLC optional if M-component negative or equivocal.
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Durie-Salmon Staging system
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Stage I: Hv>10, serum calcium normal, bone x-ray normal or solitary bone plasmacytoma only, low m-component: Ig low. Stage II: Not I nor III. Stage III: Hb12, advanced lytic bone lesions, high M-component, high Ig. Subclassification: renal function ab/normal. IA: normal renal function, Smoldering Myeloma.
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International Myeloma Working Group Staging System (ISS)
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Stage I: beta2M 3.5, Stage II: beta2M <5.5, Alb 5.5
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Poor prognostic factors
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Older age, poor performance status, higher beta2M, lower albumin, elevated Cr, LDH, CRP; low Hb, low platelets, plasmablastic morphology, deletion of chromosome 13, translocation 14 or 14/16.
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Treatment of MM
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Chemotherapy, radiotherapy, SC transplantation, supportive care. Not for MGUS/smoldering myeloma: observation alone. Solitary plasmacytoma treated by radiotherapy.
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Conventional MM treatment- Melphalan (MP)
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Alkylating agent together with prednisone effective in pts with MM refractory to melphalan alone. RR 60-70%, median OS 33-34mos, MP impaires stem cell harvesting and transplantation, MP good first treatment option for symptomatic elderly pats not candidates for ASCT
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MM conventional therapy: VAD
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Vincristine, Adriamycine, Dexamethasone, most common frontline therapy. RR 60-70%, not impair stem cell harvesting.
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Disadvantages of VAD
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Need central venous catheter and 4 day infusion, adds neurotoxicity without major benefit, adriamycin adds hair loss and cardiotoxicity with only 10-15% additional benefit. Pulse Dexamethasone alone acceptable primary induction for newly diagnosed MM.
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Diagnostic criteria for MGUS
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All 3 required: 1. serum/urine monoclonal protein low, 2. Monoclonal plasma cell <10%, 3. No CRAB
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High dose therapy with ASCT
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Standard approach for younger pts >65. After 2-3 courses of conventional chemo (VAD)--> stem cell harvesting. High dose MP alone or in combo with total body irradiation. Subsequent infusion of auto stem cells. Show to improve RR and survival. Not curative: 90% relapse. CR 24-75%, time to relapse 18-24mos, median OS 4-5yrs. Transplant related mortality 1%, Compared to standard chemo improved OS and QoL. Tandem transplantation is second planned transplantation months after first, benefits especially for residual disease after first.
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Allogenic transplantation
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Myeloma-free stem cells from donor effect and graft vs myeloma effect. Long term CR rare. Relapses continue at 7%/year, high transplant-related mortality (>30%). Conventional full-match AT rarely recommended as primary strategy because high risks of complications. AlloSCT considered in younger pts with HLA matched CMV negative sibling donor of same gender (lower risk). Reduction intensity "mini" alloSCT new approach.
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Novel therapies
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Thalidomide and thalidomide analogs (Revlimid), Bortezomib (VELCADE)
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Thalidomide
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Thal+Dex very active as frontline approach, (RR64%) sufficient to proceed with SC harvesting. Alone shown benefit as maintenance after ASCT. Low dose alone or with Dex improves OS in advanced MM pts. Thal+Dex as salvage therapy produced 52% RR with PFS 12 mos and OS 27 mos, better than conventional chemo. MPT potent and useful combo. Complications: neuropathy, somnolence, constipation, legs edema, DVT (esp with steroids).
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Revlimide
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Analog of thalidomide, more potent, no somnolence, constipation nor neuropathy. SE: neutropenia.
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Velcade
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Proteosome inhibitor (prevents protein degradation in cell), works with ubiquitin to create ubiquitin-proteasome pathway (UPP), playing essential role in regulating intracellular concentration of proteins, maintaining homeostasis. Inhibition of 26S proteasome prevents targeted proteolysis affecting multiple signalling cascades within cell-->cell death.
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Supportive care of MM
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Treatment of bone disease, management of anemia, management of renmal porblems, management of infections, management of hypercalcemia.
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Treatment of bone disease
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Chemo is important, biphosphonates for bone disease, inhibition of osteoclasts, reduction of bone resorption, bone pain, fractions hypercalcemia, osteolytic lesions, increase survival, direct and indirect antymyeloma.
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Biphosphonates
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Recommended in osteolytic bone lesion and osteoporotic bone in myeloma pts, not suggested in MGUS and and smoldering myeloma. Early stages to prevent bone disease and slow tumor development.
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Biphosphonates side effects
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Renal impairment, jaw osteonecrosis, hypocalcemia
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Management of infections in MM
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One of the most dangerous complication for MM pts, affects cell mediated and humoral immunity, increased by cytotoxic drugs and glucocorticoids. Susceptible to broad range of microbes. First 3 mos. highest risk. Prophylactic antibiotics (TMT-SMX), IVIG can be helpful.
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Hypercalcemia management in MM
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Less frequent because of early diagnosis and use biphosphonates. Hydration and steroids reverse. Biphosphonate therapy an option.
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Side effects of velcade
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Asthenic conditions (fatigue malaise, weakness-61%), GI symptoms, painful peripheral neuropathy (36%).
