Sections

Guidelines

Guidelines Summary

Diagnosis

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

International Myeloma Working Group ^[139]
National Comprehensive Cancer Network (NCCN) ^[2]
European Hematology Association and European Society for Medical Oncology (EHA-ESMO) ^[140]

The International Myeloma Working Group guidelines recommend the following diagnostic studies^[139]:

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 EHA-ESMO guidelines consider the following tests obligatory for the diagnosis of multiple myeloma^[140]:

Blood count and smear
Serum electrophoresis and immunofixation
Serum FLC assay
Serum immunoglobulin levels
Kidney and liver function tests
Serum calcium
Serum LDH and beta-2 microglobulin
24-hr urine for assessment of proteinuria and light--chain proteinuria
Urine electrophoresis and immunofixation
Bone marrow cytology and biopsy to confirm plasmacytosis and monoclonality
Bone marrow next-generation flow cytometry or next-generation sequencing to detect clonal plasma cells
Bone marrow karyotype and FISH for detection of del17p, t(4;14), t(14;16), ampl 1q/gain 1q, t(11;14)
Whole-body low-dose CT; whole-body MRI if CT is negative

Diagnostic criteria

Multiple myeloma is defined as smoldering (asymptomatic) or active (symptomatic). The International Myeloma Working Group criteria for smoldering multiple myeloma are as follows^[139]:

Serum monoclonal protein ≥3 g/dL or urinary monoclonal protein (Bence Jones protein) ≥500 mg/24 h and/or clonal bone marrow plasma cells 10%–60%
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, or low-dose CT to differentiate active from smoldering MM.^[2]

The current diagnostic criteria for symptomatic multiple myeloma are as follows^[139]:

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 ^[139]:

Hypercalcemia: Serum calcium level > 1 mg/dL (> 0.25 mmol/L) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL)
Abnormal kidney function: Serum creatinine > 2 mg/dL (> 177 μmol/L) or creatinine clearance < 40 mL/min
Anemia: Hemoglobin < 10 g/dL, or > 2 g/dL below the lower limit of normal
Bone lesions: One or more osteolytic lesions on skeletal radiography, CT, or PET-CT
Biomarkers of malignancy: Clonal bone marrow plasma cells ≥60% and/or involved/uninvolved serum FLC ratio ≥100 (involved kappa) or < 0.01 (involved lambda) and/or one or more focal ≥5 mm lesions on MRI scans

Staging

In 2015, the International Myeloma Working Group published the Revised International Staging System for Multiple Myeloma.^[141]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 .^[141]

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

Treatment

National Comprehensive Cancer Network (NCCN) general treatment recommendations for symptomatic multiple myeloma (MM) 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

The NCCN guidelines recommend combining induction therapy for MM with bone-targeted treatment (bisphosphonates or denosumab) and supportive care as necessary. For primary induction therapy in patients with MM who are candidates for transplantation, NCCN guidelines recommend the following as the preferred regimens^[2]:

Bortezomib/lenalidomide/dexamethasone (category 1)

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

Carfilzomib/lenalidomide/dexamethasone
Daratumumab/lenalidomide/bortezomib/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/cyclophosphamide/dexamethasone (preferred primarily for patients with acute kidney insufficiency)
Bortezomib/doxorubicin/dexamethasone
Carfilzomib/cyclophosphamide/dexamethasone
Ixazomib/cyclophosphide/dexamethasone
Bortezomib/thalidomide/dexamethasone (category 1)
Cyclophosphamide/lenalidomide/dexamethasone
Daratumumab/cyclophosphamide/bortezomib/dexamethasone
Daratumumab/bortezomib/thalidomide/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)

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

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

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. The other recommended agent is bortezomib; bortezomib/lenalidomide is useful in certain circumstances.

For treatment of early relapses (1-3 prior therapies), the regimen used for primary induction can be repeated if relapse occurs after more than 6 months. Otherwise, category 1 preferred regimens for early relapse include the following^[2]:

Carfilzomib/lenalidomide/dexamethasone
Daratumumab/bortezomib/dexamethasone
Daratumumab/carfilzomib/dexamethasone
Daratumumab/lenalidomide/dexamethasone
Isatuximab-irfc/pomalidomide/dexamethasone
Ixazomib/pomalidomide/dexamethasone

Preferred regimens after two prior therapies that included an immunomodulatory drug and a proteasome inhibitor, and with disease progression on/within 60 days of completion of last therapy, are as follows:

Ixazomib/pomalidomide/dexamethasone
Pomalidomide/bortezomib/dexamethasone (category 1)

Preferred regimens after two prior therapies including lenalidomide and a proteasome inhibitor as as follows:

Isatuximab-irfc/pomalidomide/dexamethasone (category 1)
Daratumumab/pomalidomide/dexamethasone (category 1)

Preferred regimens after at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug are as follows:

Elranatamab-bcmm
Talquetamab-tgvs

European Hematology Association and European Society for Medical Oncology (EHA-ESMO)

EHA-ESMO guideline recommendations for front-line therapy of MM include the following^[140]:

For fit patients < 70 years without comorbidities, induction therapy (4-6 cycles) followed by conditioning with high-dose melphalan (200 mg/m ²) and autologous stem cell transplantation (ASCT) is the recommended approach.
For pre-ASCT induction therapy, daratumumab/bortezomib/thalidomide/dexamethasone (DaraVTD) is the new standard of care. If DaraVTD is not available, bortezomib/thalidomide/dexamethasone (which probably offers the best risk-benefit profile among bortezomib-based triplet regimens) or bortezomib/cyclophosphamide/dexamethasone may be used. Daratumumab/bortezomib/lenalidomide/dexamethasone and isatuximab/bortezomib/lenalidomide/dexamethasone are under clinical investigation and may be standards of care in the near future.
Consolidation therapy post-ASCT has not been established to date as standard therapy; 2 cycles of bortezomib/lenalidomide/dexamethasone consolidation has to be considered in patients who received bortezomib/cyclophosphamide/dexamethasone induction, while a tandem ASCT is recommended for patients with genetically defined high-risk disease or in all overall survival benefit, even in high-risk disease, compared with tandem ASCT.
Maintenance with lenalidomide is considered the standard of care for all MM patients post-ASCT; bortezomib may be considered for patients with high-risk disease. Ixazomib maintenance offers progression-free survival (PFS) benefit over placebo, but has not been approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).
For patients who are not eligible for ASCT, there are 3 new standards of care: bortezomib/lenalidomide/dexamethasone, daratumumab/bortezomib/melphalan/prednisone and daratumumab/lenalidomide/dexamethasone; if those are not available, bortezomib/lenalidomide/dexamethasone is the preferred option in fit patients; otherwise, lenalidomide/dexamethasone and bortezomib/melphalan/prednisone may be considered.

EHA-ESMO guideline recommendations for second-line therapy of MM include the following^[140]:

Second-line ASCT is an option for patients who received primary therapy that included an ASCT followed by lenalidomide maintenance and whose initial remission lasted for ≥36 months.
Patients who received bortezomib-based therapy upfront without lenalidomide or daratumumab should receive lenalidomide/dexamethasone plus carfilzomib, daratumumab, ixazomib, or elotuzumab. Daratumumab/lenalidomide/dexamethasone provides the best PFS for these patients, while only carfilzomib/lenalidomide/dexamethasone and elotuzumab/lenalidomide/dexamethasone have shown an OS benefit over lenalidomide/dexamethasone to date.
Patients with MM refractory to upfront lenalidomide could receive pomalidomide/bortezomib/dexamethasone, daratumumab/carfilzomib/dexamethasone, ixazomib/carfilzomib/dexamethasone, or daratumumab/bortezomib/dexamethasone. Of those regimens, only pomalidomide/bortezomib/dexamethasone has been approved yet by the EMA.
Venetoclax/bortezomib/dexamethasone is a suitable option for patients with t(11;14) MM that has failed to respond to lenalidomide and is sensitive to proteasome inhibitors, if available.

EHA-ESMO guideline recommendations for third-line and subsequent therapy of MM include the following^[140]:

For patients who have been exposed to, or whose MM is refractory to, both bortezomib and lenalidomide, recommended regimens are daratumumab/carfilzomib/dexamethasone, isatuximab/pomalidomide/dexamethasone, isatuximab/carfilzomib/dexamethasone, and elotuzumab/pomalidomide/dexamethasone.
Patients with t(11;14) MM that is refractory to lenalidomide and sensitive to proteasome inhibitors may be treated with venetoclax/bortezomib/dexamethasone, if available.
For triple-refractory patients, selinexor/dexamethasone or belantamab mafodotin monotherapy is recommended, if available.

Management of Multiple Myeloma–related Bone Disease

In 2021, the International Myeloma Working Group (IMWG) released updated practice guidelines for the management of multiple myeloma–related bone disease.^[47] The recommendations include the following:

Zoledronic acid is the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, whether or not they have multiple myeloma–related bone disease. Once patients achieve a very good partial response or better, after at least 12 months, consideration can be given to decreasing the frequency of zoledronic acid treatment or discontinuing it.
Denosumab can be considered for the treatment of multiple myeloma–related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem cell transplantation. Denosumab discontinuation is challenging due to the rebound effect.
Cement augmentation is effective for painful vertebral compression fractures.
Radiotherapy is recommended for uncontrolled pain, impending or symptomatic spinal cord compression, or pathologic fractures.
Surgery should be used for the prevention and restoration of long-bone pathologic fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.

In 2017, the American Society of Clinical Oncology (ASCO) issued an update to its clinical practice guideline on the role of bone-modifying agents in multiple myeloma.^[44]ASCO recommendations include the following:

For patients with multiple myeloma in whom imaging studies show lytic destruction of bone or compression fracture of the spine from osteopenia, intravenous (IV) pamidronate (90 mg delivered over at least 2 hours) or zoledronic acid (4 mg delivered over at least 15 minutes every 3 to 4 weeks) is recommended. Denosumab is an alternative.
In patients with solitary plasmacytoma or smoldering (asymptomatic) or indolent myeloma who have osteopenia but no lytic disease, starting bisphosphonates is not recommended.
In patients with monoclonal gammopathy of undetermined significance, starting bisphosphonate therapy is not recommended unless they have osteopenia or osteoporosis.
In patients receiving radiation therapy, analgesics, or surgical intervention for fractures or impending fractures, IV pamidronate or zoledronic acid is recommended as an adjunctive treatment. Denosumab is an additional option.
In patients with multiple myeloma who have osteopenia (osteoporosis) but no radiographic evidence of lytic bone disease, IV bisphosphonates may be started.

ASCO recommendations for patients with renal impairment include the following:

Patients with preexisting mild-to-moderate renal impairment (estimated creatinine clearance, 30 to 60 mL/min) should receive a reduced dosage of zoledronic acid. No changes in infusion time or interval are required.
Zoledronic acid is not recommended for use in patients with severe renal impairment. Denosumab may be preferred over zoledronic acid in patients with compromised renal function.
Pamidronate 90 mg administered over 4 to 6 hours, is recommended for patients with extensive bone disease and existing severe renal impairment (serum creatinine level > 3.0 mg/dL [265 µmol/L] or an estimated creatinine clearance < 30 mL/min). In patients with preexisting renal impairment, consider reducing the initial pamidronate dose. Infusion times less than 2 hours with pamidronate or less than 15 minutes with zoledronic acid should be avoided.

ASCO recommendations regarding duration of therapy include the following:

Continuing bone-targeted treatment for up to 2 years is suggested. Consider less frequent dosing \in patients with responsive or stable disease.
In patients who do not have active myeloma and are on maintenance therapy, consider a 3-month interval of bisphosphonate administration.
For patients in whom bisphosphonates were withdrawn after 2 years and relapse with new-onset skeletal-related events occurs, the drug should be resumed.
Denosumab should not be stopped abruptly, given its reversible mechanism of action.

Management of Complications

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.^{[142, 143, 144]}

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 2019. The specific recommendations for patients with multiple myeloma receiving concurrent chemotherapy include the following^[142]:

Depending on clinical circumstances, ESAs may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin (HgB) has declined to < 10 g/dL; red blood cell (RBC) transfusion is also an option, depending on the severity of the anemia or clinical circumstances.
ESAs should not be offered to patients with chemotherapy-associated anemia whose cancer treatment is curative in intent.
In patients with myeloma, clinicians should observe the hematologic response to cancer treatment before considering an ESA. Particular caution should be exercised in the use of ESAs concomitant with treatment strategies and diseases where risk of thromboembolic complications is increased. In all cases, blood transfusion is a treatment option that should be considered.
In patients who do not respond to ESA treatment within 6 to 8 weeks, the ESA should be discontinued and the patient should be reevaluated for underlying tumor progression, iron deficiency, or other etiologies for anemia.
Iron replacement may be used to improve HgB response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency.

Guidelines on the management of multiple myeloma complications by the European Myeloma Network include the following recommendations^[135]:

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.

A guideline from the European Myeloma Network includes the following recommendations for vaccination in multiple myeloma^[136]:

Influenza - All patients, nonimmune family members, close contacts and healthcare workers
Hepatitis A - Patients traveling to areas of high endemicity
Hepatitis B - Patients traveling to areas of high endemicity, behavioral/occupational exposure, hemodialysis
Pneumococci - PCV13, all patients; PPV23, > 2 months, or 6–12 months, after PCV13
Haemophilus influenzae – All patients
Meningococci - Patients with asplenia, complement deficiency, recurrent episodes of bacterial infections
Diptheria/tetanus/acellular pertussis (DTaP) - Patients who did not receive a primary vaccination for DTaP, or a booster dose of tetanus and diphtheria toxoid vaccine. May be limited to tetanus only, based on epidemiological prevalence
Herpes zoster – All patients

Medication

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Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.