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Multiple Myeloma
Jasmine S. Beria, DO, MPH
Maria M. Plummer, MD
image BASICS
DESCRIPTION
  • 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
EPIDEMIOLOGY
  • 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.
Incidence
4 to 5 new cases/100,000 annually
Prevalence
In 2012, there were 89, 658 cases in the United States (1).
ETIOLOGY AND PATHOPHYSIOLOGY
  • Clonal proliferation of plasma cells derived from postgerminal center B cells (2)
  • 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.
Genetics
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.
RISK FACTORS
  • 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.
COMMONLY ASSOCIATED CONDITIONS
Secondary amyloidosis commonly due to MM
image DIAGNOSIS
PHYSICAL EXAM
  • 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
DIFFERENTIAL DIAGNOSIS
  • 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
DIAGNOSTIC TESTS & INTERPRETATION
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
  • Monoclonal protein (M-spike) in the blood and/or urine
  • Presence of one or more of the following: calcium elevation (>11 g/dL), renal insufficiency (creatinine >2 mg/dL), anemia (hemoglobin <10 g/dL or >2 g/dL below normal), bone disease
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), &bgr;2-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 free light chain (FLC) levels: &kgr; and &lgr; 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 (2)[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
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 (2)[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 free light chains 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 (2)[A].
Diagnostic Procedures/Other
Staging:
  • 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 &bgr;2-microglobulin <3.5 &mgr;g/mL
    • Stage II: neither stage I nor stage III
    • Stage III: &bgr;2-microglobulin ≥5.5 &mgr;g/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
P.689

image TREATMENT
  • Treatment varies depending on level of disease activity and stage of MM.
  • Treatment for smoldering MM is close monitoring at 3-month intervals. Early treatment with lenalidomide and dexamethasone delays progression and increases overall survival (3)[B].
  • 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.
GENERAL MEASURES
Maintain adequate hydration to prevent renal insufficiency. All patients receiving primary melanoma therapy should be given bisphosphonates initially (2)[A].
MEDICATION
  • Induction chemotherapy for ASCT-eligible patients (4)[C]:
    • Standard risk: (lenalidomide/low-dose dexamethasone)
    • Intermediate risk: (bortezomib/cyclophosphamide/dexamethasone)
    • High risk: (bortezomib/lenalidomide/dexamethasone)
    • After ASCT, maintenance can include a bortezomib compound for the high- or intermediate-risk group; lenalidomide can be considered for the standard group. Maintenance lenalidomide after ASCT has shown to improve progression-free survival (PFS) of 41 versus 23 months with placebo and has shown to be an effective treatment for MM (5,6)[A].
  • Induction chemotherapy for ASCT-ineligible patients:
    • Same regimens as ASCT-eligible patients, however, the number of treatment cycles are increased (4)[C].
First Line
  • Bortezomib
    • A proteasome inhibitor; it blocks the ubiquitinproteasome 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 (7)[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:
    • As first-line treatment for transplant-ineligible patients with newly diagnosed MM, bortezomib/melphalan/prednisone was associated with significantly increased PFS compared with melphalan/prednisone (8)[A].
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:
    • Bortezomib/lenalidomide
    • Liposomal doxorubicin
    • Carfilzomib: 2nd-generation selective proteasome inhibitor
  • Emerging options: pomalidomide, thalidomide analog
  • Bortezomib is a highly effective option in previously treated/relapse patients and is well-tolerated (9)[A].
  • Interferon-&agr; may be appropriate in selected patients, but because of its toxicity and availability of better alternatives, it has a limited role in treating MM.
ISSUES FOR REFERRAL
For spinal or other bone pathology, refer to orthopedics for support.
ADDITIONAL THERAPIES
  • 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.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
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.
image ONGOING CARE
PATIENT EDUCATION
  • http://myeloma.org/Main.action
  • http://www.nccn.org/patients/guidelines/myeloma/index.html
PROGNOSIS
  • 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 multiple myeloma (see staging for definition) is <2 to 3 years, even after ASCT; standard risk have median overall survival of 6 to 7 years.
REFERENCES
1. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2012. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2012/. Accessed 2015.
2. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev. 2012;(5):CD003188.
3. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438-447.
4. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046-1060.
5. 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.
6. Yang B, Yu RL, Chi XH, et al. Lenalidomide treatment for multiple myeloma: systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013;8(5):e64354.
7. Rajkumar SV. Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013;88(3):226-235.
8. San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalanprednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31(4):448-455.
9. Knopf KB, Duh MS, Lafeuille MH, et al. Metaanalysis of the efficacy and safety of bortezomib re-treatment in patients with multiple myeloma. Clin Lymphoma Myeloma Leuk. 2014;14(5):380-388.
Additional Reading
&NA;
  • Grass S, Preuss KD, Thome S, et al. Paraproteins of familial MGUS/multiple myeloma target family-typical 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). National Comprehensive Cancer Network Web site. Published 2014. http://www.nccn.org/. Accessed 2014.
Codes
&NA;
ICD10
  • C90.00 Multiple myeloma not having achieved remission
  • C90.01 Multiple myeloma in remission
  • C90.02 Multiple myeloma in relapse
Clinical Pearls
&NA;
  • 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.