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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.
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.
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.
34% of patients are asymptomatic at the time of presentation.
Hypercalcemia (28%): anorexia, nausea, somnolence, and polydipsia
Renal failure (20-50%)
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
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
Metastatic carcinoma (kidney, breast, non-small cell lung cancer)
Polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome
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:
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]:
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
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].
Durie Salmon stage
International staging system (ISS)
Mayo Clinic risk stratification (mSMART)
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.
Induction chemotherapy for ASCT-eligible patients 1[C]:
Induction chemotherapy for ASCT-ineligible patients:
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.
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.
Avoid IV radiographic contrast materials due to risk for contrast-induced nephropathy.
Manage hypercalcemia and control hyperuricemia.
Median survival overall is 3 years. The 5-year survival rate is around 35%.
Median survival by ISS stage:
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.
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). http://www.nccn.org/. 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.