Multiple Myeloma

Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Osteoclastic activity results in bone resorption, bone pain, pathologic fractures, and metabolic disturbances. Excessive secretion of antibodies results in proteinuria and associated kidney damage as well as production and tissue deposition of amyloid fibrils. Metabolic disturbances combined with tissue amyloid deposition cause end-organ damage. Diagnosis is established by plasma electrophoresis and bone marrow biopsy. Treatments to slow down the disease progression are available; however, there is no cure for MM. The median survival is approximately 3 years.

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Multiple myeloma (MM) is a bone marrow malignancy arising from monoclonal plasma cells.


  • MM accounts for 10% of all hematologic malignancies
  • Incidence is 3–8 per 100,000 (race dependent).
  • The highest rate is in African Americans.
  • Men > women (2:1)
  • A disease of the elderly: Median age is 65–70 years old (race dependent).


  • Monoclonal proliferation of plasma cells that produce monoclonal antibodies
  • MGUS is considered a precursor.
  • The causative mechanism is unknown but proposed and/or contributing mechanisms include:
    • Chronic inflammation:
      • Chronic infection (hepatitis B, hepatitis C)
      • Autoimmune disease (rheumatoid arthritis, Sjögren’s syndrome)
    • Environmental/occupational exposure:
      • Herbicides and insecticides
      • Benzene and other organic solvents
      • Radiation
    • Genetic causes:
      • No strong evidence suggesting a hereditary pattern
      • 13q14 deletions, 17p13 deletions, and 11q abnormalities predominate
      • The most common translocation is t(11;14)(q13;q32).
      • C-myc, NRAS, and KRAS mutations have been inconsistently associated with the disease.



  • Commonly preceded by MGUS, progresses to smoldering MM, then progresses to full-blown MM
  • Approximately 1% of MGUS per year will progress to MM.
  • Exact mechanism of progression is unknown, but likely due to additional mutations.
  • Tumor cells show mixed morphology:
    • Some look like mature plasma cells
    • Some appear immature (large, multinucleated, bizarrely shaped)
    • Cells are positive for CD138 and CD56.
  • Monoclonal plasma cell proliferation is associated with antibody production:
    • IgG > IgA > IgD > IgM
    • Myeloma protein (M protein) is a monoclonal antibody and detected in > 95% of cases:
      • 1 heavy chain + 1 light chain
      • OR only light chains
  • Cytokines: 
    • Promote proliferation and survival of myeloma cells
    • Secreted by tumor cells themselves and bone marrow stromal cells:
      • Tumor necrosis factor (TNF)
      • Interleukin-1 (IL-1)
      • Interleukin-6 (IL-6)

Pathophysiologic effects

  • Bone lesions:
    • Myeloma cells upregulate the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) by bone marrow stromal cells.
    • RANKL stimulates osteoclast activity.
    • Tumor cells also release modulators of the Wnt pathway, resulting in osteoblast inhibition.
    • The result is lytic bone lesions and hypercalcemia.
  • Bone marrow infiltration:
    • Tumor cells infiltrate and replace normal bone marrow.
    • The result is cytopenia.
  • Monoclonal antibody production:
    • Bence Jones proteinuria:
      • Light chains are excreted by the kidneys.
      • Light chains are toxic to the renal tubular epithelium.
      • The result is renal dysfunction.
    • Amyloidosis: from deposition of excess light chains in kidneys and other tissues
  • Hyperviscosity:
    • Associated with excessive M proteins
    • Sludging in capillary beds
    • Mostly in MM subtypes associated with excessive IgA (approximately 7% of patients)
Bone resorption in MM

Bone resorption in MM:
Cytokine release by plasma cells results in osteoclastic activation

Image: “Myeloma bone disease” by Sanderson RD, Epstein J. License: CC BY 2.5

Clinical Presentation

  • Skeletal:
    • Bone pain/tenderness
    • Pathologic fractures
    • Possible spinal cord compression with vertebral involvement
  • Constitutional symptoms:
    • Weight loss
    • Malaise/fatigue
    • Fever
  • Hypercalcemia:
    • Renal stones
    • Confusion
    • Constipation
  • Hematologic abnormalities: 
    • Anemia
    • Thrombocytopenia
    • Neutropenia: increased susceptibility to infections (urinary tract infection (UTI), pneumonia)
    • Coagulopathy: M protein interacts directly with clotting factors and prevents aggregation.
  • Hyperviscosity:
    • Microvascular hemorrhage (purpura, retinal hemorrhage, etc.)
    • Coronary ischemia
    • Stroke
    • Somnolence, headache
  • Renal failure (multifactorial):
    • Amyloid deposition
    • Renal stones
    • Hypercalcemia
    • Direct tubular injury from filtration load (protein, calcium, etc.)
  • Amyloidosis: 
    • AL subtype: IgG lambda light chain
    • Clinical manifestations typical of amyloidosis:
      • Muscle deposition: shoulder pad sign
      • Tongue deposition: macroglossia
      • Bruising: eyelid purpura (raccoon eyes)
  • Neuropathy:
    • Compressive neuropathies: carpal tunnel syndrome in the setting of amyloidosis
    • Traditional “glove-and-stocking” peripheral neuropathy from small vessel disease (amyloid deposition in the nerves and vasoneurosum)
    • Dermatomal neurologic deficits from spinal cord compression


Features of MM: “CRAB

  • HyperCalcemia
  • Renal abnormality
  • Anemia and Amyloidosis
  • Bone fractures


Laboratory workup

  • CBC:
    • Anemia (normocytic)
    • Thrombocytopenia
    • Leukopenia
  • Chemistry:
    • ↑ Ca
    • ↑ LDH
    • ↑ Erythrocyte sedimentation rate (ESR)
    • ↑ Albumin
    • ↑ 𝛽2-microglobulin
    • ↑ Creatinine
  • Screening urinalysis: 
    • Elevated protein
    • Increased susceptibility to UTI
  • 24-hour urine collection: 
    • Bence Jones proteinuria (lambda free light chains in urine)
    • Creatinine clearance (indicates severity of renal impairment)
  • Electrophoresis (screening test):
    • M spike on SPEP
    • M spike on urine protein electrophoresis (UPEP)
  • Peripheral smear: rouleaux formation (aggregation of RBCs)
  • Bone marrow biopsy:
    • Confirmatory test
    • > 10% plasma cells


  • X-rays (skeletal survey) of the skull, long bones, and spine:
    • Lytic lesions
    • Pathologic fractures
    • Osteopenia
  • MRI of thoracic and lumbar spine to evaluate for:
    • Paraspinal involvement
    • Pathologic fractures
    • Spinal cord compression



  • Patients < 65 years old:
    • Cytoreduction (steroids/immunomodulators) followed by stem cell transplantation
    • Cytoreduction (aka primary induction therapy) regimens:
      • Bortezomib/lenalidomide/dexamethasone
      • Bortezomib/cyclophosphamide/dexamethasone (used in the setting of acute renal insufficiency)
  • Patients > 65 years old:
    • Stem cell transplantation is poorly tolerated and not routinely performed.
    • Chemotherapy:
      • Thalidomide, as a monotherapy, combined with steroids or melphalan
      • Lenalidomide combined with dexamethasone
      • Bortezomib combined with melphalan
      • Vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD)
      • Melphalan combined with prednisone
  • Supportive treatment:
    • Treatment of hypercalcemia:
      • Bisphosphonates
      • Calcitonin
      • Hydration
      • Natriuresis
    • Radiation to areas of pain or impending pathological fractures
    • Plasmapheresis
    • Erythropoietin for anemia
    • Vaccinations for prevention of pneumococcal infections
    • Pain management:
      • Analgesics
      • Spinal decompression: 
        • Kyphoplasty
        • Surgical decompression
      • Nerve root blocks/peripheral nerve blocks


  • Poor prognostic factors include the following:
    • Tumor burden
    • Hypercalcemia
    • Bence Jones proteinuria
    • Renal involvement
  • The median survival rate is 3 years.
  • 5-year survival rate < 50%
  • Infections are an important cause of early death in MM.

Differential Diagnosis

  • Waldenstrom macroglobulinemia: another plasma cell neoplasm that produces IgM specifically, resulting in hyperviscosity syndrome and splenomegaly. Waldenstrom macroglobulinemia (aka lymphoplasmacytic lymphoma) is more indolent than MM. The diagnosis is established with electrophoresis (IgM spike) and bone marrow biopsy. Asymptomatic cases do not always require treatment. Chemotherapy is the mainstay of management for symptomatic disease.
  • Monoclonal gammopathy of undetermined significance: moderate elevation of M protein without clinical symptoms. Serum M protein concentration is < 3 g/dL and plasma cell concentration is < 10%. The disease shows no evidence of end-organ damage. Diagnosis is established with plasmapheresis and bone marrow biopsy. The significance is the risk of progression to MM. No specific treatment is required.
  • Metastatic bone malignancy: distant spread of primary tumors to the bones. Metastatic bone malignancy is frequently observed in prostate, breast, and lung cancers, among others. Presentation may include bone pain, pathologic fractures, and constitutional symptoms. Diagnosis is usually established with imaging in the context of known malignancy. Treatment is mostly supportive.


  1. Azevedo, A. (2020). Multiple myeloma. Retrieved February 26, 2021, from
  2. Longo, D., et al. (2012). Harrisons Manual of Medicine, 18th Edition. US: McGraw-Hill Professional. Pages 2107–2114.
  3. Shah, D. (2021). Multiple Myeloma. Medscape. Retrieved February 26, 2021, from
  4. Robbins and Cotran Pathologic Basis of Disease. (2015). 9th Edition. Pages 599–601.
  5. Van de Donk N.W.C.J., Pawlyn C., Yong K.L. (2021). Multiple myeloma. Lancet. 397(10272),410–427. Retrieved February 26, 2021, from

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