Multiple Myeloma Guidelines 

Updated: Jan 05, 2016
  • Author: Dhaval Shah, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Diagnosis

The 2014 International Myeloma Working Group guidelines for the standard investigative workup in patients with suspected multiple myeloma include the following studies [1] :

  • Serum and urine assessment for monoclonal protein (densitometer tracing and nephelometric quantitation; immunofixation for confirmation)
  • Serum free light chain assay (in all patients with newly diagnosed plasma cell dyscrasias)
  • Bone marrow aspiration and/or biopsy
  • Serum beta2-microglobulin, albumin, serum immunoglobulins, and lactate dehydrogenase (LDH) measurement
  • Standard metaphase cytogenetics
  • Fluorescence in situ hybridization (FISH)
  • Skeletal survey
  • Magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), or low-dose whole-body CT for better detection of bone and extramedullary disease

Current National Comprehensive Cancer Network (NCCN) clinical practice guidelines on multiple myeloma also recommend the use of FISH for 1q21 amplification as part of the initial diagnostic workup. [2]

Diagnostic Criteria

Multiple myeloma is defined as smoldering (asymptomatic) or active (symptomatic). Criteria for smoldering multiple myeloma are as follows [2] :

  • M-protein in serum: IgG ≥3 g/dL, IgA >1 g/dL or
  • Bence-Jones protein >1 g/24h and/or
  • Bone marrow clonal plasma cells ≥10%

Active multiple myeloma has been diagnosed using the CRAB criteria (hyperCalcemia, Renal failure, Anemia, Bone lesions) for end-organ damage, as follows [2] :

  • Calcium >11.5 mg/dL (>2.65 mmol/L)
  • Creatinine >2 mg/dL (177 μmol/L or more)
  • Hemoglobin <10 g/dL or 2 g/dL <normal (<12.5 mmol/L<normal)
  • Lytic or osteopenic bone disease

In November 2014, however, the International Myeloma Working Group added the following criteria for multiple myeloma that will require therapy [1] :

  • Bone marrow plasma cells (BMPCs) ≥60%
  • Involved/uninvolved serum free light chain ratio ≥100
  • Abnormal MRI with more than one focal lesion, with each lesion >5 mm

The International Working Group noted that these findings have been “associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma.” [1] The presence of any of the CRAB criteria or any of these three additional criteria justifies therapy.

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Treatment

National Comprehensive Cancer Network (NCCN) general treatment recommendations for multiple myeloma include the following [2] :

  • A single autologous stem cell transplant is the preferred approach in transplant-eligible patients
  • A second (tandem) autologous stem cell transplant is recommended for patients who relapse more than 12 mo after the first transplant

For transplant-eligible patients, the NCCN recommends the following regimens as category 1 for primary induction:

  • Bortezomib/dexamethasone
  • Bortezomib/doxorubicin/dexamethasone
  •  Bortezomib/thalidomide/dexamethasone
  • Lenalidomide/dexamethasone

For patients who are not eligible for transplant, NCCN category 1 regimens for primary induction therapy are as follows:

  • Lenalidomide/low-dose dexamethasone
  • Melphalan/prednisone/bortezomib (MPB)
  • Melphalan/prednisone/lenalidomide (MPL)
  • Melphalan/prednisone/thalidomide

For salvage therapy, the regimen used for primary induction can be repeated if relapse occurs after more than 6 months. Otherwise, category 1 salvage therapy options include the following:

  • Bortezomib
  • Bortezomib/liposomal doxorubicin
  • Carfilzomib/lenalidomide/dexamethasone
  • Lenalidomide/dexamethasone
  • Panobinostat/bortezomib/dexamethasone
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Management of Multiple Myeloma–related Bone Disease

In May 2013, the International Myeloma Working Group (IMWG) released practice guidelines for the management of multiple myeloma–related bone disease. [3] The recommendations, which were based on a review of the literature through August 2012 and a consensus of an interdisciplinary panel of experts, include the following:

  • Consideration of bisphosphonates in all patients receiving first-line antimyeloma therapy, regardless of the presence of osteolytic bone lesions on conventional radiography
  • Intravenous (IV) zoledronic acid or pamidronate for preventing skeletal-related events; because of its potential antimyeloma effects and survival benefits, zoledronic acid is preferred in patients with newly diagnosed multiple myeloma
  • Bisphosphonates should be administered IV every 3 to 4 weeks during initial therapy, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw
  • Zoledronic acid or pamidronate should be continued in patients with active disease and should be resumed after disease relapse
  • Kyphoplasty should be considered for symptomatic vertebral compression fractures
  • Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability
  • Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression

Bisphosphonate Therapy

In 2007, the American Society of Clinical Oncology (ASCO) issued an update to their clinical practice guideline governing bisphosphonate therapy for multiple myeloma patients who have lytic destruction of bone or compression fracture of the spine from osteopenia. ASCO recommends IV pamidronate, 90 mg delivered over at least 2 hours, or zoledronic acid, 4 mg delivered over at least 15 minutes every 3-4 weeks. Because the risk for osteonecrosis of the jaw is 9.5-fold greater with zoledronic acid than with pamidronate, patients may prefer pamidronate. [4]

Zoledronic acid doses should be reduced in patients with preexisting mild to moderate renal impairment (estimated creatinine clearance, 30-60 mL/min); the drug is not recommended for use in patients with severe renal impairment. All patients receiving pamidronate or zoledronic acid therapy should be screened every 3-6 months for albuminuria. If unexplained albuminuria (>500 mg/24 hours) is found, ASCO recommends discontinuation of the drug until the renal problems resolve. [4]

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Management of Complications

According to National Comprehensive Cancer Network (NCCN) guidelines, novel drugs such as bortezomib can be used with dexamethasone as primary treatment for multiple myeloma–associated amyloidosis. The combination of cyclophosphamide, thalidomide, and dexamethasone is also recommended for the primary treatment of amyloidosis. [2]

The NCCN, American Society of Clinical Oncology (ASCO), and International Myeloma Workshop clinical guidelines for prevention of venous thromboembolism agree that patients with multiple myeloma who are receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should receive prophylactic anticoagulation therapy with either aspirin or low molecular weight heparin (LMWH) for lower-risk patients and LMWH for higher-risk patients. [5, 6, 7]

A joint American Society of Hematology (ASH) and ASCO clinical practice guideline on the use of erythropoiesis-stimulating agents (ESAs) in cancer was updated in 2010. The specific recommendations for patients with multiple myeloma receiving concurrent chemotherapy include the following [8] :

  • If the hemoglobin concentration does not increase after chemotherapy, treatment with epoetin or darbepoetin may be considered in patients who are being treated with palliative intent and who are experiencing chemotherapy-associated anemia
  • Particular caution should be exercised in the use of epoetin or darbepoetin concomitant with chemotherapeutic agents where risk of thromboembolic complications is increased
  • Blood transfusion is also a therapeutic option
  • ESAs are not recommended in patients who are not receiving concurrent chemotherapy

Guidelines on the management of multiple myeloma complications by the European Myeloma Network include the following recommendations [9] :

  • Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus is recommended as the novel standard for the detection of lytic lesions in myeloma.
  • Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate.
  • Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid, but its advantage is not clear for patien ts with no bone involvement on computed tomography or magnetic resonance imaging.
  • In asymptomatic myeloma, bisphosphonates are not recommended.
  • Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use.
  • Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded.
  • Erythropoietic agents should be stopped after 6-8 wk if no adequate hemoglobin response is achieved.
  • For renal impairment, bortezomib-based regimens are the current standard of care.
  • For the management of treatment-induced peripheral neuropathy, drug modification is needed.
  • Vaccination against influenza is recommended; vaccination against Streptococcus pneumoniae and Haemophilus influenzae is appropriate, but efficacy is not guaranteed due to suboptimal immune response.
  • Prophylactic acyclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, or autologous or allogeneic transplantation
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