multiple myeloma; plasmacytoma/plasma cell myeloma

Introduction

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

* median survival

Etiology

• most cases evolve from MGUS

Epidemiology

• 4.3 cases per 100,000
• 1% of all cancers, 10% of hematologic malignancies
• median age 70 years
• black:white ratio = 2:1

Pathology

• diagnosis based upon >= 10% plasma cells in bone marrow
• malignant cells of myeloma resemble plasmablasts, rather than plasma cells (CD19-, CD56+, CD38+, syndecan-1+)
  • dysfunctional lymphocytes & plasma cells
• they produce very little immunoglobulin (a few picograms/day)
  • hypogammaglobulinemia
• myeloma cells are usually aneuploid, 13q-, 14q+.
• hypodiploidy & the 13q-, 14q+ correlate with aggressive disease & resistance to treatment
• hypercalcemia due to osteoclast activation
• accumulation of light chains in renal tubules (cast nephropathy)
  • light chains crystallize in proximal tubule cells
• 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

• genetic abnormalities include translocations between chromosome 14q32 & chromosomes 6, 8, 9, 11, 16, 18
• t11q13:14q32 involving CCND1 with the IgH locus
• t(6;14)(p25;q32) involving IRF4 with the IgH locus
• t(4;14)(p16.3;q32.3) {FGFR3} involving FGFR3 with the IgH locus
• t(1;14)(q21;q32) forms a FCRL4-IGHA1 fusion protein
• deregulation of c-myc is suggested
• point mutations in N-ras & K-ras have been noted in 15% of new cases of myeloma & in relapses within the marrow
• K-ras mutations are associated with a shorter survival
• point mutations in p53 have been noted in extra-medullary relapses, but not in new cases of myeloma
• Ig Heavy and Light genes rearranged or deleted
• downregulation of DAZAP2
• other implicated genes
  • CSAG2

Clinical manifestations

• most often presents as multiple myeloma, a multifocal plasma cell malignancy of the osseous system although some present as solitary bone or extramedullary tumor
• often asymptomatic in early phase
• manifestations result from:
  • anemia
  • infiltration of bone
  • tumor mass
  • abnormal immunoglobulin secreted by the tumor
• skeletal pathology
  • osteolytic lesions
  • vertebral compression fractures
  • osteoporosis
  • osteopenia
• renal insufficiency, acute kidney injury may progress to chronic kidney disease
  • associated with urinary light chains
  • correlates with poor survival
  • proteinuria, nephrotic syndrome
  • hematuria
  • Fanconi syndrome
• recurrent bacterial infections
  • patients may present with pneumonia
• AL amyloidosis
• necrobiotic xanthogranuloma
• hyperviscosity syndrome

Diagnostic criteria

• >= 10% plasma cells in bone marrow
• active multiple myeloma results in end organ damage
  • anemia
  • renal insufficiency
  • hypercalcemia
  • osteolytic lesions

Laboratory

• urinalysis, urine protein
  • proteinuria (frequently presenting abnormality)
    • may reach nephrotic syndrome range proteinuria
  • small amounts of protein on dipstick (dipstick measures albumin)
  • large amounts of protein on 24 hour urine protein (immunoglobulin light chains)
  • hematuria
• serum chemistries
  • chem7:
    • serum Na+, serum chloride, serum bicarbonate
    • serum creatinine may be increased due to renal insufficiency
    • low anion gap due to cationic charge of abnormal immunoglobulin
  • serum calcium: hypercalcemia due to osteoclast activation
    • ionized calcium; high serum protein increases serum Ca+2
    • serum PTH normal or low (not useful)
    • PTH-related peptide in plasma not useful (normal)
  • serum phosphate: hyperphosphatemia
  • free light chains in serum* most sensitive test for paraproteinemia
    • usually > 50 mg/dL
• complete blood count (CBC)
  • anemia out of proportion to degree of renal failure
  • peripheral smear may show rouleaux
  • case presented with WBC count of 61,000/uL
• quantitative immunoglobulins
• serum protein electrophoresis* (SPE) may show monoclonal gammopathy (M protein spike)
• urine protein electrophoresis
  • 10% show urine light chains with normal SPE
• immunofixation electrophoresis (IFE)
  • in 55% of patients, the M component is IgG, in 25% IgA, & rarely IgD, IgE, or IgM
  • free light chain (Bence Jones protein) in the urine may be observed in 70% of patients
• serum beta-2 microglobulin generally > 0.3 mg/dL
  • useful for staging (see classification)
• negative findings:
  • serum complement levels are normal
  • antinuclear antibody (ANA) is negative
  • rheumatoid factor (RF) is negative
• see ARUP consult

* combination has sensitivity of ~100% diagnosing multiple myeloma requiring therapy

Diagnostic procedures

• bone marrow biopsy: >= 10% plasma cells in bone marrow
• renal biopsy for myeloma cast nephropathy if diagnosis of end organ damage in question
  • end organ damage is indication for chemotherapy
  • comordidities (i.e. diabetes mellitus) may also cause renal failure

Radiology

• radiographic survey, including long bones
• 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
• magnetic resonance imaging (MRI) indicated if bone lesion is suspected & plain radiograph is negative
  • back pain cited as example even in absence of motor or sensory deficits
• do not order bone scan
  • bone scan detects osteoblastic lesions
  • bone lesions of multiple myeloma are lytic

* image (skull radiograph)

Staging

• see ref

Complications

• infection due to hypogammaglobulinemia & humoral immune dysfunction
• amyloidosis
  • renal insufficiency of 50% of patients
  • renal failure with large kidneys
  • heart failure
• increased suspecptibility to renal injury from nephrotoxic agents including radiographic contrast agents, loop diuretics & NSAIDs
• spinal cord compression (medical emergency) due to vertebral compression fracture with retropulsion of bone fragments

Differential diagnosis

• monoclonal gammopathy of uncertain significance (MGUS)
• smoldering multiple myeloma

Management

• do not treat MGUS or smoldering myeloma
• symptomatic multiple myeloma defined as evidence of myeloma-associated end organ damage
  • hypercalcemia
  • renal failure (myeloma cast nephropathy)
  • anemia
  • bone disease
• high-dose chemotherapy with autologous stem cell transplantation for most patients < 65 years of age
  • avoid melphalan induction therapy for stem-cell transplantations candidates
    • high-dose melphalan after initial induction therapy for stem-cell transplantation patients
  • autologous bone marrow transplantation from peripherally harvested stem cells
  • patients must have normal renal function
  • hematopoietic cells from peripheral blood are preferred, because they restore hematopoiesis more rapidly, than do bone marrow cells
  • relapse secondary to tumor cells in the graft is a problem
  • transplantation of CD34+ progenitors may reduce contaminating tumor cells > 99.9%
  • relapses treated with cyclophosphamide 500 mg weekly with prednisone 100 mg on alternate days
  • lenalidomide maintenance therapy, initiated at day 100 after stem-cell transplantation
    • increased toxicity
    • increased risk of 2nd cancer
    • increased survival
• allogeneic grafts from HLA-identical siblings show anti-tumor activity & possibly represent the only potential curative therapy for myeloma
• chemotherapeutic agents:
  • cyclophosphamide, melphalan, bortezomib & glucocorticoids are the most effective agents
  • bortezomib for patients with renal failure
    • useful in patients with renal insufficiency, including those with end-stage renal disease
    • with or without dexamethasone
    • high risk of peripheral neuropathy
    • melphalan, prednisone & bortezomib improves survival & time to disease progression
    • 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
  • 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
    • daratumumab-containing regimen associated with more grade 3 or 4 infections
  • 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)
  • melphalan (alkylating agent)
    • high dose induction therapy: 200 mg/sq meter
    • 0.15 mg/kg & prednisone 20 mg TID is standard treatment for non-transplantation patients
    • objective response in 50-60% of patients
    • no maintenance therapy
  • vincristine, doxorubicin, & dexamethasone (VAD)*
  • vincristine, doxorubicin, & methylprednisolone (VAMP)*
  • thalidomide (anticoagulation indicated)
    • thalidomide plus dexamethasone
      • thalidomide 200 mg plus 40 mg dexamethasone days 1-4, 9-12, 17-20; repeat cycle every 28 days
    • thalidomide plus melphalan & prednisone
    • thalidomide, dexamethasone & pegylated liposomal doxorubicin (ThaDD)
    • thalidomide plus hematopoietic stem cell tranplantation
    • risk for peripheral neuropathy &/or venous thromboembolism
    • survival benefit in question
    • use in patients with renal insufficiency has not been established
  • lenalidomide (thalidomide analog) in combination with
    • dexamethasone improves 3-year overall survival
    • melphalan-prednisone
    • risk for venous thromboembolism
  • pomalidomide plus low-dose dexamethasone for refractory or relapsed & refractory multiple myeloma
    • risk for venous thromboembolism
• preferred combinations
  • bortezomib, lenalidomide, & dexamethasone
  • lenalidomide, low-dose dexamethasone
  • bortezomib, cyclophosphamide, & dexamethasone
• second line combinations
  • bortezomib, doxorubicin & dexamethasone
  • carfilzomib, lenalidomide & dexamethasone
  • ixazomib, lenalidomide, & dexamethasone
• combinations useful in certain circumstances
  • bortezomib & dexamethasone
  • bortezomib, thalidomide, & dexamethasone
  • lenalidomide & dexamethasone
  • dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide, bortezomib (VTD-PACE)
• interferon-alpha therapy is controversial
• supportive therapy:
  • adequate hydration (>= 2L/day)
  • adequate analgesia
  • avoid potentially nephrotoxic agents (NSAIDs, contrast agents ...)
  • bisphosphonates, inhibitors of bone resorption
    • for all patients with newly diagnosed multiple myeloma
    • used primarily in treatment of hypercalcemia
    • reduce complications of osteolytic lesions
    • improve survival; do not slow disease progression
    • pamidronate
      • may reduce the incidence of pathologic fractures
      • reduces hypercalcemia
      • may alleviate bone pain
      • may improve the quality of life
      • dosage adjustment in renal failure (contraindicated in CKD4)
    • denosumab (no dosage adjustment in renal failure)
    • zoledronate contraindicated in renal failure (GFR < 35 mL/min)
  • vaccination
    • pneumococcal vaccine
    • avoid varicella vaccine
  • IV immunoglobulin monthly for recurrent bacterial infections or hypogammaglobulinemia
  • plasmapheresis for hyperviscosity syndrome
  • corticosteroids & radiation therapy for spinal cord compression
  • radiation therapy for painful lytic bone lesions
  • surgery for pathologic fractures or symptomatic local disease
  • erythropoietin may be useful for treatment of the anemia of multiple myeloma
• decreases in paraprotein level > 90% are associated with longest remissions
• investigational:
  • oncolytic viral therapy shows promise
  • CAR T-cell therapy targeting BCMA
• prognosis: median survival 2-3 years with standard treatment

* give rapid induction of remission, but do not prolong survival

More general terms

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

More specific terms

• smoldering myeloma
• solitary plasmacytoma

Additional terms

• 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

Patient information

multiple myeloma patient information