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multiple myeloma; plasmacytoma/plasma cell myeloma

Lymphoid malignancy of plasma cells. Classification: stage 1: (5.2 years)* - serum beta-2 microglobulin < 3.5 mg/L - serum albumin 3.5 g/dL stage 2 (3.7 years)* - not stage 1 or 3 stage 3 (2.4 years)* - serum beta-2 microglobulin > 5.5 mg/L [4] * median survival Etiology: - most cases evolve from MGUS [12] Epidemiology: 1) 4.3 cases per 100,000 2) 1% of all cancers, 10% of hematologic malignancies 3) median age 70 years 4) black:white ratio = 2:1 [12] Pathology: 1) diagnosis based upon >= 10% plasma cells in bone marrow 2) malignant cells of myeloma resemble plasmablasts, rather than plasma cells (CD19-, CD56+, CD38+, syndecan-1+) - dysfunctional lymphocytes & plasma cells [4] 3) they produce very little immunoglobulin (a few picograms/day) - hypogammaglobulinemia [4] 4) myeloma cells are usually aneuploid, 13q-, 14q+. 5) hypodiploidy & the 13q-, 14q+ correlate with aggressive disease & resistance to treatment 6) hypercalcemia due to osteoclast activation [4] 7) accumulation of light chains in renal tubules (cast nephropathy) [4] - light chains crystallize in proximal tubule cells 8) see role of IL-6 in multiple myeloma Immunophenotype: - SIg-, CIg+ (G, A, rare D, or E; or light chain only) - most B cell antigens (CD19, CD20, CD22) - - CD79a +/-, CD45 -/+, HLA-DR -/+, CD38 +, EMA -/+, - CD43 +/-, CD56 +/- Genetics: 1) genetic abnormalities include translocations between chromosome 14q32 & chromosomes 6, 8, 9, 11, 16, 18 2) t11q13:14q32 involving CCND1 with the IgH locus 3) t(6;14)(p25;q32) involving IRF4 with the IgH locus 4) t(4;14)(p16.3;q32.3) {FGFR3} involving FGFR3 with the IgH locus 5) t(1;14)(q21;q32) forms a FCRL4-IGHA1 fusion protein 6) deregulation of c-myc is suggested 7) point mutations in N-ras & K-ras have been noted in 15% of new cases of myeloma & in relapses within the marrow 8) K-ras mutations are associated with a shorter survival 9) point mutations in p53 have been noted in extra-medullary relapses, but not in new cases of myeloma 10) Ig Heavy and Light genes rearranged or deleted 11) downregulation of DAZAP2 12) other implicated genes - CSAG2 Clinical manifestations: 1) most often presents as multiple myeloma, a multifocal plasma cell malignancy of the osseous system although some present as solitary bone or extramedullary tumor 2) often asymptomatic in early phase 3) manifestations result from: a) anemia b) infiltration of bone c) tumor mass d) abnormal immunoglobulin secreted by the tumor 4) skeletal pathology a) osteolytic lesions b) vertebral compression fractures c) osteoporosis d) osteopenia 5) renal insufficiency, acute kidney injury may progress to chronic kidney disease a) associated with urinary light chains b) correlates with poor survival c) proteinuria, nephrotic syndrome d) hematuria e) Fanconi syndrome 6) recurrent bacterial infections - patients may present with pneumonia [11] 7) AL amyloidosis 8) necrobiotic xanthogranuloma 9) hyperviscosity syndrome Diagnosis: 1) >= 10% plasma cells in bone marrow 2) active multiple myeloma results in end organ damage a) anemia b) renal insufficiency c) hypercalcemia d) osteolytic lesions Laboratory: 1) urinalysis, urine protein a) proteinuria (frequently presenting abnormality) - may reach nephrotic syndrome range proteinuria b) small amounts of protein on dipstick (dipstick measures albumin) c) large amounts of protein on 24 hour urine protein (immunoglobulin light chains) d) hematuria 3) serum chemistries a) chem7: 1] serum Na+, serum chloride, serum bicarbonate 2] serum creatinine may be increased due to renal insufficiency 3] low anion gap due to cationic charge of abnormal immunoglobulin b) serum calcium: hypercalcemia due to osteoclast activation [4] - ionized calcium; high serum protein increases serum Ca+2 - serum PTH normal or low (not useful) - PTH-related peptide in plasma not useful (normal) c) serum phosphate: hyperphosphatemia d) free light chains in serum* most sensitive test for paraproteinemia [4] - usually > 50 mg/dL [4] 4) complete blood count (CBC) - anemia out of proportion to degree of renal failure - peripheral smear may show rouleaux [4] - case presented with WBC count of 61,000/uL [11] 5) quantitative immunoglobulins 6) serum protein electrophoresis* (SPE) may show monoclonal gammopathy (M protein spike) 7) urine protein electrophoresis - 10% show urine light chains with normal SPE 8) immunofixation electrophoresis (IFE) a) in 55% of patients, the M component is IgG, in 25% IgA, & rarely IgD, IgE, or IgM b) free light chain (Bence Jones protein) in the urine may be observed in 70% of patients 9) serum beta-2 microglobulin generally > 0.3 mg/dL - useful for staging (see classification) 10) negative findings: a) serum complement levels are normal b) antinuclear antibody (ANA) is negative c) rheumatoid factor (RF) is negative 11) see ARUP consult [15] * combination has sensitivity of ~100% diagnosing multiple myeloma requiring therapy Special laboratory: 1) bone marrow biopsy: >= 10% plasma cells in bone marrow 2) renal biopsy for myeloma cast nephropathy if diagnosis of end organ damage in question a) end organ damage is indication for chemotherapy b) comordidities (i.e. diabetes mellitus) may also cause renal failure [4] Radiology: 1) radiographic survey, including long bones 2) radiologic lesions are generally purely lytic (no significant osteoblastic activity) - skull xray shows pattern of lytic or punched-out lesions that resemble raindrops hitting a surface & splashing [38] 3) magnetic resonance imaging (MRI) indicated if bone lesion is suspected & plain radiograph is negative [4] - back pain cited as example even in absence of motor or sensory deficits [4] 4) do not order bone scan - bone scan detects osteoblastic lesions - bone lesions of multiple myeloma are lytic * image (skull radiograph) [38] Complications: 1) infection due to hypogammaglobulinemia & humoral immune dysfunction 2) amyloidosis a) renal insufficiency of 50% of patients b) renal failure with large kidneys c) heart failure 3) increased suspecptibility to renal injury from nephrotoxic agents including radiographic contrast agents, loop diuretics & NSAIDs [4,19] 4) spinal cord compression (medical emergency) due to vertebral compression fracture with retropulsion of bone fragments [4] Differential diagnosis: - monoclonal gammopathy of uncertain significance (MGUS) - smoldering multiple myeloma Staging: - see ref [21] Management: 1) do not treat MGUS or smoldering myeloma 2) symptomatic multiple myeloma defined as evidence of myeloma-associated end organ damage a) hypercalcemia b) renal failure (myeloma cast nephropathy) c) anemia d) bone disease [4] 3) high-dose chemotherapy with autologous stem cell transplantation for most patients < 65 years of age [29] a) avoid melphalan induction therapy for stem-cell transplantations candidates [4] - high-dose melphalan after initial induction therapy for stem-cell transplantation patients [4] b) autologous bone marrow transplantation from peripherally harvested stem cells c) patients must have normal renal function d) hematopoietic cells from peripheral blood are preferred, because they restore hematopoiesis more rapidly, than do bone marrow cells e) relapse secondary to tumor cells in the graft is a problem f) transplantation of CD34+ progenitors may reduce contaminating tumor cells > 99.9% g) relapses treated with cyclophosphamide 500 mg weekly with prednisone 100 mg on alternate days [8] h) lenalidomide maintenance therapy, initiated at day 100 after stem-cell transplantation 1] increased toxicity 2] increased risk of 2nd cancer 3] increased survival [14] i) belantamab mafodotin + pomalidomide + dexamethasone may benefit patients refractory to lenalidomide [48] 4) allogeneic grafts from HLA-identical siblings show anti-tumor activity & possibly represent the only potential curative therapy for myeloma 5) chemotherapeutic agents: a) cyclophosphamide, melphalan, bortezomib & glucocorticoids are the most effective agents b) bortezomib for patients with renal failure [11] - useful in patients with renal insufficiency, including those with end-stage renal disease [11] - with or without dexamethasone [4,11,20] - high risk of peripheral neuropathy - melphalan, prednisone & bortezomib improves survival & time to disease progression [12,22] - panobinostat in combination with bortezomib & dexamethasone for relapsed &/or refractory multiple myeloma treated at least twice with bortezomib & an immunomodulator [NGC, NICE] - prophylactic valacyclovir to prevent reactivation of Herpes zoster regardless of Herpes zoster immunization status [4] c) daratumumab combined with bortezomib, melphalan, & prednisone reduces risk of disease progression or death in patients with stem cell ineligible multiple myeloma more than same regimen without daratumumab [35] - daratumumab-containing regimen associated with more grade 3 or 4 infections [35] d) bispecific antibodies that bind B-cell maturation antigen (BCMA) & CD3 to redirect T cells to multiple myeloma cells - FDA-approved for relapsed/refractory multiple myeloma - teclistamab - elranatamab-bcmm (Elrexfio) e) melphalan (alkylating agent) 1] high dose induction therapy: 200 mg/sq meter 2] 0.15 mg/kg & prednisone 20 mg TID is standard treatment for non-transplantation patients 3] objective response in 50-60% of patients 4] no maintenance therapy f) vincristine, doxorubicin, & dexamethasone (VAD)* g) vincristine, doxorubicin, & methylprednisolone (VAMP)* h) thalidomide (anticoagulation indicated) 1] thalidomide plus dexamethasone - thalidomide 200 mg plus 40 mg dexamethasone [9] days 1-4, 9-12, 17-20; repeat cycle every 28 days 2] thalidomide plus melphalan & prednisone [9] 3] thalidomide, dexamethasone & pegylated liposomal doxorubicin (ThaDD) [10] 4] thalidomide plus hematopoietic stem cell tranplantation 5] risk for peripheral neuropathy &/or venous thromboembolism 5] survival benefit in question [9] 6] use in patients with renal insufficiency has not been established [11] i) lenalidomide (thalidomide analog) in combination with 1] dexamethasone [23,24] improves 3-year overall survival 2] melphalan-prednisone [14] 3] risk for venous thromboembolism j) pomalidomide plus low-dose dexamethasone for refractory or relapsed & refractory multiple myeloma [31] - risk for venous thromboembolism 6) preferred combinations [37] - bortezomib, lenalidomide, & dexamethasone [4] - lenalidomide, low-dose dexamethasone - bortezomib, cyclophosphamide, & dexamethasone - satuximab, bortezomib, lenalidomide,& dexamethasone [49] 7) second line combinations [37] - bortezomib, doxorubicin & dexamethasone - carfilzomib, lenalidomide & dexamethasone - ixazomib, lenalidomide, & dexamethasone 8) combinations useful in certain circumstances [37] - bortezomib & dexamethasone - bortezomib, thalidomide, & dexamethasone - lenalidomide & dexamethasone - dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide, bortezomib (VTD-PACE) 9) interferon-alpha therapy is controversial 10) supportive therapy: a) adequate hydration (>= 2L/day) b) adequate analgesia [12] c) avoid potentially nephrotoxic agents (NSAIDs, contrast agents ...) d) bisphosphonates, inhibitors of bone resorption 1] for all patients with newly diagnosed multiple myeloma [4] 2] used primarily in treatment of hypercalcemia 3] reduce complications of osteolytic lesions 4] improve survival [4]; do not slow disease progression 5] pamidronate a] may reduce the incidence of pathologic fractures b] reduces hypercalcemia c] may alleviate bone pain d] may improve the quality of life e] dosage adjustment in renal failure (contraindicated in CKD4) [46] 6] denosumab (no dosage adjustment in renal failure) [41] 7] zoledronate contraindicated in renal failure (GFR < 35 mL/min) e) vaccination - pneumococcal vaccine - avoid varicella vaccine f) IV immunoglobulin monthly for recurrent bacterial infections or hypogammaglobulinemia [12] g) plasmapheresis for hyperviscosity syndrome h) corticosteroids & radiation therapy for spinal cord compression i) radiation therapy for painful lytic bone lesions j) surgery for pathologic fractures or symptomatic local disease [4] k) erythropoietin may be useful for treatment of the anemia of multiple myeloma 11) decreases in paraprotein level > 90% are associated with longest remissions 12) investigational: - oncolytic viral therapy shows promise [26] - CAR T-cell therapy targeting BCMA [36] 13) prognosis: median survival 2-3 years with standard treatment * give rapid induction of remission, but do not prolong survival

Interactions

disease interactions

Related

amyloidosis benign monoclonal gammopathy; monoclonal gammopathy of undetermined significance (MGUS) diagnostic criteria for multiple myeloma humoral immune dysfunction light-chain deposition disease; Light chain nephropathy renal amyloidosis; amyloid nephropathy role of IL-6 in multiple myeloma Waldenstrom's macroglobulinemia

Specific

smoldering myeloma solitary plasmacytoma

General

lymphoid leukemia paraproteinemia (monoclonal gammopathy) peripheral B-cell lymphoid neoplasm plasma cell dyscrasia

References

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