Multiple Myeloma Guidelines

Updated: Mar 06, 2020
  • Author: Dhaval Shah, MD; Chief Editor: Emmanuel C Besa, MD  more...
  • Print

Guidelines Summary


Similar recommendations for the standard investigational workup for suspected myeloma have been issued by the following organizations:

  • International Myeloma Working Group [128]
  • National Comprehensive Cancer Network (NCCN) [2]
  • European Society for Medical Oncology (ESMO) [129]

The International Myeloma Working Group guidelines recommend the following diagnostic studies [128] :

  • Serum and urine assessment for monoclonal protein (densitometer tracing and nephelometric quantitation; immunofixation for confirmation)
  • Serum free light chain (FLC) 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

The NCCN guidelines recommend the following diagnostic studies [2] :

  • Complete blood count (CBC), differential, platelet count
  • Serum blood urea nitrogen (BUN), creatinine, electrolytes, albumin, calcium, uric acid levels
  • Serum LDH and beta-2 microglobulin
  • Creatinine clearance (calculated or measured)
  • Serum quantitative immunoglobulins, serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE)
  • 24-h urine for total protein, urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE)
  • Serum FLC assay
  • Whole-body low-dose CT scan or FDG PET/CT
  • Unilateral bone marrow aspirate and biopsy, including bone marrow immunohistochemistry and/or multi-parameter flow cytometry
  • Metaphase cytogenetics on bone marrow
  • Plasma cell FISH on bone marrow: del 13, del 17p13, t(4;14), t(11;14), t(14;16), t(14;20), 1q21 amplification, 1p deletion

The ESMO guidelines recommend basing the diagnosis of multiple myeloma on the following [129]

  • Detection and evaluation of the monoclonal (M) component by electrophoresis of serum and/or urine protein (concentrate of 24h urine collection); nephelometric quantification of IgG, IgA, and IgM immunoglobulins; characterization of the heavy and light chains by immunofixation; and serum FLC measurement

  • Bone marrow aspiration and/or biopsy to evaluate the number and characteristics of plasma cells infiltrating the bone marrow; the bone marrow sample should also be used for cytogenetic/FISH studies on immunologically recognized or sorted plasma cells and also has the potential for immunophenotypic and molecular investigations

  • Evaluation of lytic bone lesions with whole-body low-dose computed tomography (WBLD-CT), or with conventional radiography if WBLD-CT is not available. Magnetic resonance imaging (MRI) provides greater details and is recommended whenever spinal cord compression is suspected. Either whole-body MRI or MRI of the spine and the pelvis may be used, according to their availability, to assess the BM plasma cell infiltration, in particular the presence of bone focal lesions. 18F-fluorodeoxyglucose positron emission tomography with CT (PET-CT) can be done to evaluate bone lesions, according to availability and resources.

  • CBC with differential serum creatinine, creatinine clearance and calcium level

Diagnostic criteria

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

  • Serum monoclonal protein ≥3 g/dL,  or
  •  Bence Jones protein ≥500 mg/24 h  and/or
  • Clonal bone marrow plasma cells 10%–59%  and
  • Absence of myeloma-defining events or amyloidosis

The NCCN also recommends that a patient whose bone survey is negative be assessed for bone disease with whole-body skeletal MRI, FDG PET/CT, of low-dose CT to differentiate active from smoldering MM. [2]

In the NCCN guidelines, active multiple myeloma is no longer diagnosed using the CRAB criteria (hyperCalcemia, Renal failure, Anemia, Bone lesions) for end-organ damage. The current diagnostic criteria for symptomatic multiple myeloma are as follows [2] :

  • Clonal bone marrow plasma cells ≥10% or bony or extramedullary plasmacytoma (confirmed by biopsy)
  • One or more myeloma-defining events.

Myeloma-defining events include the following  [2] :

  • Serum calcium level > 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 > 2 mg/dL [> 177 μmol/L] or creatinine clearance < 40 mL/min)
  • Anemia (hemoglobin < 10 g/dL or hemoglobin > 2 g/dL below the lower limit of normal)
  • One or more osteolytic bone lesions on skeletal radiography, CT, or FDG PET-CT
  • Clonal bone marrow plasma cells ≥60%
  • Abnormal serum free light chain (FLC) ratio ≥100 (involved kappa) or < 0.01 (involved lambda)
  • One or more focal ≥5 mm lesions on MRI scans

In November 2014, the International Myeloma Working Group added the following criteria to the CRAB criteria for multiple myeloma [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.” [128]  The presence of any of the CRAB criteria or any of these three additional criteria justifies therapy.


In 2015, the  International Myeloma Working Group published the Revised International Staging System for Multiple Myeloma. [130] The revised system was subsequently recommended by the NCCN. [2]  The Revised International Staging System (R-ISS) was created by combining the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase FISH (iFISH) after CD138 plasma cell purification, plus serum LDH assay results . [130]

Like the ISS, the R-ISS is based on three stages. Stage I criteria are as follows:

  • Beta-2 microglobulin ≤3.5 g/dL and albumin ≥3.5 g/dL
  • Standard risk for CA
  • Normal LDH

Stage II comprises patients who do not meet criteria for stage I or stage III

Stage III consists of the following:

  • Beta-2 microglobulin of 5.5 g/dL or more,   and either
  • High risk for CA  or high LDH

Median progression-free survival is as follows:

  • Stage I : 66 months
  • Stage II: 42 months
  • Stage III: 29 months


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 primary induction therapy in patients with MM who are candidates for transplantation, NCCN guidelines recommend the following combinations as preferred regimens [2] :

  • Bortezomib/lenalidomide/dexamethasone (category 1)
  • Bortezomib/cyclophosphamide/dexamethasone (preferred initial treatment in patients with acute renal insufficiency)

Other recommended regimens, according to the NCCN, are as follows:

  • Carfilzomib/lenalidomide/dexamethasone
  • Ixazomib/lenalidomide/dexamethasone (category 2B)

The NCCN considers the following regimens useful in certain circumstances (although triplet regimens should be used as the standard, patients not considered candidates for a 3-drug regimen can be started on a 2-drug regimen, with the third drug added once performance status improves):

  • Bortezomib/doxorubicin/dexamethasone
  • Carfilzomib/cyclophosphamide/dexamethasone
  • Ixazomib/cyclophosphide/dexamethasone
  • Bortezomib/thalidomide/dexamethasone (category 1)
  • Cyclophosphamide/lenalidomide/dexamethasone
  • Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide/bortezomib (VTD-PACE)

For primary induction therapy in patients who are not transplant candidates, the NCCN guidelines list the following as preferred regimens [2] :

  • Bortezomib/lenalidomide/dexamethasone (category 1)
  • Daratumumab/lenalidomide/dexamethasone (category 1)
  • Lenalidomide/low-dose dexamethasone (category 1)
  • Bortezomib/cyclophosphamide/dexamethasone

Other NCCN-recommended regimens for these cases include the following:

  • Carfilzomib/lenalidomide/dexamethasone
  • Ixazomib/lenalidomide/dexamethasone
  • Daratumumab/bortezomib/melphalan/prednisone (category 1)

For maintenance therapy, the NCCN recommends lenalidomide. Although lenalidomide is a category 1 recommendation, the NCCN notes that lenalidomide maintenance appears to be associated with increased risk of secondary cancers, especially after transplant; this should be discussed with patients. Other recommended agents are ixazomib (category 1) and bortezomib; bortezomib/lenalidomide is useful in certain circumstances.

For salvage therapy, the regimen used for primary induction can be repeated if relapse occurs after more than 6 months. Otherwise, category 1 preferred regimens include the following [2] :

  • Carfilzomib (twice weekly)/dexamethasone
  • Carfilzomib/lenalidomide/dexamethasone
  • Daratumumabm/bortezomib/dexamethasone
  • Daratumumabm/lenalidomide/dexamethasone
  • Elotuzumabw/lenalidomide/dexamethasone
  • Ixazomib/lenalidomide/dexamethasone

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. [46]  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. [45]

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. [45]


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. [131, 132, 133]

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 [131] :

  • 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 [125] :

  • 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 ESAs 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