Multiple Myeloma

Jasmine S. Beria, DO, MPH and Maria M. Plummer, MD Reviewed 06/2017

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Subject: Multiple Myeloma

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  • Multiple myeloma (MM) is a clonal proliferation of malignant plasma cells.

  • This clonal proliferation in the bone marrow can cause extensive skeletal destruction with osteolytic lesions and pathologic fractures.

  • The malignant plasma cells produce monoclonal protein in the blood and urine.

  • MM is also characterized by hypercalcemia, increased susceptibility to infections, renal impairment, and end-organ damage.

  • Monoclonal gammopathy of undetermined significance (MGUS) is a common disorder with limited monoclonal plasma cell proliferation that progresses to MM at rate of ∽1% per year.

  • MGUS progresses to smouldering or asymptomatic MM and eventually to symptomatic MM.

  • Synonym(s): plasma cell myeloma; plasma cell leukemia


  • Accounts for ∽1% of all cancers and slightly >10% of hematologic malignancies in the United States

  • Median age of diagnosis is 69 years.

  • Slight male predominance. Blacks about 2 to 3 times more commonly affected than whites; less common in Asians.


4 to 5 new cases/100,000 annually 


In 2012, there were 89, 658 cases in the United States. 


  • Clonal proliferation of plasma cells derived from postgerminal center B cells

  • Plasma cells undergo multiple chromosomal mutations to progress to MM.

  • Genetic damage in developing B lymphocytes at time of isotype switching, transforming normal plasma cells into malignant cells, arising from single clone

  • Earliest chromosomal translocations involve immunoglobulin heavy chains on chromosome 14q32, with the translocation at t(4;14), t(14;16), t(14;20), and deletion, del(17p) having a poorer prognosis.

  • Malignant cells multiply in bone marrow, suppressing normal bone marrow cells and producing large quantities of monoclonal immunoglobulin (M) protein.

  • Malignant cells stimulate osteoclasts that cause bone resorption and inhibit osteoblasts that form new bone, causing lytic bone lesions.


Rare family clusters; the hyperphosphorylated form of Paratarg-7, a protein of unknown significance, is inherited as an autosomal dominant trait in familial cases of MM and MGUS, suggesting a potential pathogenic role. 


  • Most cases have no known risks associated.

  • Older age; immunosuppression; and chemicals like dioxin, herbicides, insecticides, petroleum, heavy metals, plastics, and ionizing radiation increase the risk of MM.

  • MGUS stage consistently precedes MM.


Secondary amyloidosis commonly due to MM 



  • 34% of patients are asymptomatic at the time of presentation.

  • Hypercalcemia (28%): anorexia, nausea, somnolence, and polydipsia

  • Renal failure (20-50%)

  • Anemia (73%)

  • Bony lesions (80%): lytic lesions causing bone pain (58%) 1, osteoporosis, or pathologic fracture (26-34%)

  • Other symptoms: fatigue (32%), peripheral neuropathy, weight loss (24%), recurrent infections, hyperviscosity syndrome, and cord compression


  • Dehydration

  • Skin findings of amyloidosis: waxy papules, nodules, or plaques that may be evident in the eyelids, retroauricular region, neck, or inguinal and anogenital regions; petechiae and ecchymosis; “pinch purpura”

  • Extramedullary, plasmacytomas can present as large, purplish, subcutaneous masses.

  • Hyperviscosity syndrome in 7%: retinal hemorrhages, prolonged bleeding, neurologic changes

  • Tender bones and masses


  • MGUS

  • Smoldering MM

  • Metastatic carcinoma (kidney, breast, non-small cell lung cancer)

  • Waldenström macroglobulinemia

  • AL amyloidosis

  • Solitary plasmacytoma

  • Polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome


Criteria for diagnosis: The diagnosis of MM requires the following 2[A]: 
  • Bone marrow (BM) involvement with ≥10% of plasma cells (PC) or the presence of a plasmacytoma and any one or more of the following myeloma defining events:

  • Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

    • ▪ Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
    • ▪ Renal insufficiency: creatinine clearance ≪40 mL/min or serum creatinine >177 μmol/L (>2 mg/dL)
    • ▪ Anemia: hemoglobin value of >20 g/L below the lower limit of normal or a hemoglobin value ≪100 g/L
    • ▪ Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT
    • ▪ Any one or more of the following biomarkers of malignancy:
      • * Clonal bone marrow plasma cell percentage ≥60%
      • * Involved: uninvolved serum free light chain (FLC) ratio ≥100
      • * >1 focal lesions on MRI studies

Initial Tests (lab, imaging)

  • CBC with differential to evaluate anemia and other cytopenias with evaluation of peripheral blood smear

  • BUN, creatinine (elevated creatinine due to myeloma cast nephropathy)

  • Serum electrolytes, serum albumin, serum calcium

  • Serum lactate dehydrogenase (LDH), β2-microglobulin

  • Serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE): M protein level elevated

  • Quantitative serum immunoglobulin levels: immunoglobulin (Ig) G, IgA, and IgM

  • Quantitative serum FLC levels: κ and λ chains

  • Elevated ESR, C-reactive protein

  • Urine analysis: 24-hour urine for protein, urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE); 20% positive urine protein 3[A]:

    • ▪ Urinalysis dip is often negative for protein, as this test identifies albumin, and the protein in MM is Bence-Jones (BJ) monoclonal protein.
  • Bone marrow aspirate and biopsy for histology, immunohistochemistry, flow cytometry, cytogenetics, and fluorescence in situ hybridization (FISH)

  • Skeletal survey: for lytic bone lesions, osteopenia, osteoporosis, or compression fractures

  • MRI for any back pain or earliest signs/symptoms of spinal cord compression

  • Bone scan can be falsely negative in myeloma; use MR to confirm lesions from skeletal survey

Follow-Up Tests & Special Considerations
  • CT scan: if high suspicion for bone lesions despite normal skeletal survey; can differentiate malignant from benign vertebral compression fractures in patients who are not MRI candidates

  • PET scans: used if bone involvement is suspected despite a normal skeletal survey, MRI, and CT

  • Baseline bone densitometry may be indicated 3[A].

  • Bone marrow aspiration and biopsy to monitor response to treatment

  • SPEP with SIFE: M protein helps to track progression of myeloma and response to treatment.

  • Serum immunoglobulins and FLCs can be used to monitor response or relapse.

  • Plasma cell labeling index may be helpful to identify the fraction of the myeloma cell population that is proliferating 3[A].

Diagnostic Procedures/Other

  • Durie Salmon stage

    • ▪ Stage I: low cell mass: ≪0.6 × 1012 cells/m2 plus all of the following: hemoglobin >10 g/dL, M protein ≪5 g/dL if IgG or ≪3 g/dL if IgA, normal serum calcium, urine BJ protein ≪4 g/24 hr, no generalized lytic bone lesions
    • ▪ Stage II: neither stage I nor stage III
    • ▪ Stage III: high cell mass: >1.2 × 1012 cells/m2 plus one or more of the following: hemoglobin ≪8.5 g/L, serum calcium >12 mg/dL, bone lesions, M protein >7g/dL if IgG and >5 g/dL if IgA, urine BJ protein >12 g/24 hr, advanced lytic bone lesions
  • International staging system (ISS)

    • ▪ Stage I: albumin ≥3.5 g/dL and β2-microglobulin ≪3.5 μg/mL
    • ▪ Stage II: neither stage I nor stage III
    • ▪ Stage III: β2-microglobulin ≥5.5 μg/ml
  • Mayo Clinic risk stratification (mSMART)

    • ▪ Standard risk: t(11:14), t(6:14), and hyperdiploidy
    • ▪ Intermediate risk: t(4:14), del(13q) by cytogenetics, hypodiploidy
    • ▪ High risk: t(14:16), t(14:20), del(17 p), and plasma cell labeling index >3%

Test Interpretation

Bone marrow involvement with plasma cells ≥10%; Russell bodies 


  • Treatment varies depending on level of disease activity and stage of MM.

  • Key determinant factor in choosing chemotherapy regimen is to establish if the patient is an autologous stem cell transplant (ASCT) candidate or not.

  • Treatment protocols vary by institution and patient.

  • ASCT following induction chemotherapy is standard of care for patients with symptomatic disease.


Maintain adequate hydration to prevent renal insufficiency. All patients receiving primary melanoma therapy should be given bisphosphonates initially 3[A]. 


  • Induction chemotherapy for ASCT-eligible patients 1[C]:

  • Induction chemotherapy for ASCT-ineligible patients:

    • ▪ Same regimens as ASCT-eligible patients, however, the number of treatment cycles are increased 1[C].

First Line

  • Bortezomib

    • ▪ A proteasome inhibitor; it blocks the ubiquitin-proteasome catalytic pathway in cells by binding to the 20S proteasome complex.
    • ▪ Toxicity: peripheral neuropathy, cytopenia, nausea
    • ▪ Consider herpes simplex virus (HSV) prophylaxis.
  • Cyclophosphamide

    • ▪ Nitrogen mustard-derivative alkylating agent
    • ▪ Often used in combination with prednisone or thalidomide in cases of relapsed disease
    • ▪ Toxicity: cytopenia, anaphylaxis, interstitial pulmonary fibrosis, secondary malignancy, impaired fertility
  • Immunomodulators

    • Thalidomide and lenalidomide
      • * Works by antiangiogenesis inhibition, immunomodulation, and inhibition of tumor necrosis factor
      • * Toxicity: birth defects, deep vein thrombosis (DVT), neuropathy, rash, nausea, bradycardia
      • * DVT prophylaxis, usually with aspirin
  • Dexamethasone

    • ▪ Low doses (40 mg/week) superior to higher doses
    • ▪ Increases risk of DVT
  • Bisphosphonates 5[A]

    • ▪ No effect on mortality but decrease pain, pathologic vertebral fractures, and fractures of other bones
    • ▪ IV pamidronate or zoledronic acid can be used; evidence that zoledronic acid may be superior in preventing skeletal-related events.
    • ▪ Dose-adjust/monitor renal function.
    • ▪ Monitor for osteonecrosis of jaw.
  • Alternative options:

Second Line

  • May be treated with any of the agents not already used

  • The following agents can be used as salvage therapy to treat relapsed or refractory MM:

  • Emerging options: pomalidomide, thalidomide analog

  • Bortezomib is a highly effective option in previously treated/relapse patients and is well-tolerated.

  • Interferon-α may be appropriate in selected patients, but because of its toxicity and availability of better alternatives, it has a limited role in treating MM.


For spinal or other bone pathology, refer to orthopedics for support. 


  • Local radiation therapy for bone pain

  • Effective pain management: Avoid NSAIDs due to nephrotoxicity.

  • Kyphoplasty/vertebroplasty: consider for symptomatic vertebral compressions

  • Plasmapheresis: for hyperviscosity syndrome (a rare complication)

  • Erythropoietin: for selected patients with anemia

  • Patients should receive vaccines for pneumococcus and influenza.

  • Do not administer zoster vaccine and other live-virus vaccines.


Indications: pain, infections, cytopenia, renal failure, bone complications, spinal cord compression 
  • Avoid IV radiographic contrast materials due to risk for contrast-induced nephropathy.

  • Adequate hydration

  • Manage hypercalcemia and control hyperuricemia.






  • Median survival overall is 3 years. The 5-year survival rate is around 35%.

  • Median survival by ISS stage:

    • ▪ Stage I: 62 months
    • ▪ Stage II: 44 months
    • ▪ Stage III: 29 months
  • Median survival in patients with high-risk MM (see staging for definition) is ≪2 to 3 years, even after ASCT; standard risk has median overall survival of 6 to 7 years.


Many; including infection, pain, lytic bone lesions, hypercalcemia, hyperuricemia, spinal cord compression, anemia, hyperviscosity syndrome, amyloidosis, renal insufficiency 


Palumbo  A, Anderson  K. Multiple myeloma. N Engl J Med.  2011;364(11):1046–1060.  [View Abstract]
Rajkumar  SV, Dimopoulos  MA, Palumbo  A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol.  2014;15(12):e538–e548.  [View Abstract]
Mhaskar  R, Redzepovic  J, Wheatley  K, et al. Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev.  2012;(5):CD003188.  [View Abstract]
Palumbo  A, Hajek  R, Delforge  M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med.  2012;366(19):1759–1769.  [View Abstract]
Rajkumar  SV. Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol.  2013;88(3):226–235.  [View Abstract]
San Miguel  JF, Schlag  R, Khuageva  NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol.  2013;31(4):448–455.  [View Abstract]


  • Grass S, Preuss KD, Thome S, et al. Paraproteins of familial MGUS/multiple myeloma target familytypical antigens: hyperphosphorylation of autoantigens is a consistent finding in familial and sporadic MGUS/MM. Blood.  2011;118(3):635–637.

  • National Comprehensive Cancer Network. NCCN multiple myeloma clinical practice guidelines in oncology (Version 2.2014). Accessed September 23, 2016.



  • C90.00 Multiple myeloma not having achieved remission

  • C90.01 Multiple myeloma in remission

  • C90.02 Multiple myeloma in relapse


  • 203.00 Multiple myeloma, without mention of having achieved remission

  • 203.01 Multiple myeloma, in remission

  • 203.02 Multiple myeloma, in relapse


  • 109989006 multiple myeloma (disorder)

  • 94704006 Multiple myeloma in remission

  • 285420006 IgA myeloma (disorder)

  • 285421005 IgG myeloma (disorder)

  • 413587002 Smoldering myeloma (disorder)

  • 203436008 osteoporosis in multiple myelomatosis (disorder)

  • 230586003 Neuropathy due to multiple myeloma (disorder)

  • 440422002 Asymptomatic multiple myeloma (disorder)


  • MM is a plasma cell malignancy that causes endorgan damage.

  • Look for presence of “CRAB” (hypercalcemia, renal insufficiency, anemia, and bone lesions).

  • Suspect MM if high total protein-to-albumin ratio is present.

  • Maintain high index of suspicion for spinal cord compression.

  • Avoid nephrotoxins (radiographic contrast material, NSAIDs, dehydration).

  • Patients with MM are immunocompromised.