Myeloma: diagnosis and management

This guideline covers the diagnosing and managing of myeloma (including smouldering myeloma and primary plasma cell leukaemia) in people aged 16 and over. It aims to improve care for people with myeloma by promoting the most effective tests and treatments for myeloma and its complications.

# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.

# Communication and support
Provide information and support to people with myeloma or primary plasma cell leukaemia and their family members or carers (as appropriate), particularly at diagnosis, at the beginning and end of each treatment, at disease progression and at transition to end of life care.
Consider providing the following information in an individualised manner to people with myeloma and their family members or carers (as appropriate):
the disease process, relapse and remission cycle, and the person's overall prognosis
the treatment plan, including (if appropriate) the process and the potential benefits, risks and complications of stem cell transplantation
symptoms of myeloma and treatmentrelated side effects (including steroidrelated side effects, infection and neuropathy)
lifestyle measures to optimise bone health and renal function
how to identify and report new symptoms (especially pain and spinal cord compression)
the role of supportive and palliative care
how to access peer support and patient support groups.
Offer prompt psychological assessment and support to people with myeloma at diagnosis and (as appropriate) at the beginning and end of each treatment, at disease progression and at transition to end of life care.
Refer people who are assessed as needing further psychological support to psychological services.
Advise family members or carers (as appropriate) about the range of available local and national support services at diagnosis, at the beginning and end of each treatment, at disease progression and at transition to end of life care.
For guidance on communication and patientcentred care see the NICE guideline on patient experience in adult NHS services.

# Laboratory investigations

## Laboratory investigations for people with suspected myeloma
Use serum protein electrophoresis and serumfree lightchain assay to confirm the presence of a paraprotein indicating possible myeloma or monoclonal gammopathy of undetermined significance (MGUS).
If serum protein electrophoresis is abnormal, use serum immunofixation to confirm the presence of a paraprotein indicating possible myeloma or MGUS.
Do not use serum protein electrophoresis, serum immunofixation, serumfree lightchain assay or urine electrophoresis (urine BenceJones protein assessment) alone to exclude a diagnosis of myeloma.
When performing a bone marrow aspirate and trephine biopsy to confirm a diagnosis of myeloma, use morphology to determine plasma cell percentage and flow cytometry to determine plasma cell phenotype.
For guidance on the setup of laboratory diagnostic services see the NICE cancer service guidance on improving outcomes in haematological cancers.

## Laboratory investigations to provide prognostic information
Use the same sample for all diagnostic and prognostic tests on bone marrow, so people only have to have one bone marrow aspirate and trephine biopsy.
When performing a bone marrow aspirate and trephine biopsy to provide prognostic information:
Perform fluorescence insitu hybridisation (FISH) on CD138selected bone marrow plasma cells to identify the adverse risk abnormalities t(4;14), t(14;16), 1q gain, del(1p) and del(17p)(TP53 deletion). Use these abnormalities alongside International Staging System (ISS) scores to identify people with highrisk myeloma.
Consider performing FISH on CD138selected bone marrow plasma cells to identify the adverse risk abnormality t(14;20), and the standard risk abnormalities t(11;14) and hyperdiploidy.
Consider performing immunophenotyping of bone marrow to identify plasma cell phenotype, and to inform subsequent monitoring.
Consider performing immunohistochemistry (including Ki67 staining and p53 expression) on the trephine biopsy to identify plasma cell phenotype and give an indication of cell proliferation, to provide further prognostic information.
Perform serumfree lightchain assay and use serumfree lightchain ratio to assess prognosis.

# Imaging investigations

## Imaging for people with suspected myeloma
Offer imaging to all people with a plasma cell disorder suspected to be myeloma.
Consider wholebody MRI as firstline imaging.
Consider wholebody lowdose CT as firstline imaging if wholebody MRI is unsuitable or the person declines it.
Only consider skeletal survey as firstline imaging if wholebody MRI and wholebody lowdose CT are unsuitable or the person declines them.
Do not use isotope bone scans to identify myelomarelated bone disease in people with a plasma cell disorder suspected to be myeloma.

## Imaging for people with newly diagnosed myeloma
For people with newly diagnosed myeloma or smouldering myeloma who have not had wholebody imaging with 1 of the following, consider wholebody imaging to assess for myelomarelated bone disease and extramedullary plasmacytomas with one of:
MRI
CT
fluorodeoxyglucose positron emission tomography CT (FDG PETCT).
For guidance on imaging for people with suspected spinal cord compression, see the NICE guideline on metastatic spinal cord compression.
Consider baseline wholebody imaging with MRI or FDG PETCT for people who have nonsecretory myeloma or suspected or confirmed soft tissue plasmacytomas and have not already had either of these tests.

# Service organisation
For guidance on the facilities needed to provide intensive inpatient chemotherapy and transplants for people with myeloma, and the structure and function of multidisciplinary teams (MDTs), see the NICE cancer service guidance on improving outcomes in haematological cancers.
For guidance on service organisation for young people see the NICE cancer service guidance on improving outcomes in children and young people with cancer.
Each hospital treating people with myeloma who are not receiving intensive inpatient chemotherapy or a transplant should provide local access to:
an MDT specialising in myeloma
supportive and palliative care, supported by:
psychological support services
a 24hour acute oncology and/or haematology helpline
physiotherapy
-ccupational therapy
dietetics
medical social services
critical care
clinical trials via the MDT specialising in myeloma
dental services.
Each hospital treating people with myeloma should provide regional access through its network to:
facilities for intensive inpatient chemotherapy or transplantation
renal support
spinal disease management
specialised pain management
therapeutic apheresis
radiotherapy
restorative dentistry and oral surgery
clinical trials, in particular early phase trials.

# Managing newly diagnosed myeloma

## Firstline treatment
NICE has a suite of technology appraisal guidance on myeloma either published or in development. These published technology appraisals cover NICE's position in relation to primary disease treatment, salvage therapy for relapsed myeloma and consolidation/maintenance therapy after primary management. The recommendations in this guideline complement the existing technology appraisals, giving further guidance in addition to the technology appraisals where myelomarelated subgroups are not included.
Bortezomib is recommended as an option within its marketing authorisation, that is, in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adults with previously untreated multiple myeloma, who are eligible for highdose chemotherapy with haematopoietic stem cell transplantation. 
Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the firstline treatment of multiple myeloma in people for whom highdose chemotherapy with stem cell transplantation is considered inappropriate. 
Bortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the firstline treatment of multiple myeloma if:
highdose chemotherapy with stem cell transplantation is considered inappropriate and
the person is unable to tolerate or has contraindications to thalidomide. 
Consider using frailty and performance status measures that include comorbidities to assess the suitability of people with myeloma for first autologous stem cell transplant.
Do not use age or the level of renal impairment alone to assess the suitability of people with myeloma for first autologous stem cell transplant.
Take into account that only a small number of people with myeloma are suitable for allogeneic stem cell transplantation.
When assessing whether people with myeloma are suitable for an allogeneic stem cell transplant, take into account:
whether the person has chemosensitive disease
how many previous lines of treatment they have had
whether a fully human leukocyte antigen (HLA) matched donor is available
how graftversushost disease (GvHD) and other complications may get worse with age
the risk of higher transplantrelated mortality and morbidity, versus the potential for longterm diseasefree survival
improving outcomes with other newer treatments
the person's understanding of the procedure and its risks and benefits.
Consider allogeneic stem cell transplantation as part of a clinical trial if one is available.

## Primary plasma cell leukaemia
Consider bortezomibbased and/or lenalidomidebased combination induction chemotherapy for people with primary plasma cell leukaemia.
Consider highdose melphalanbased autologous stem cell transplantation for people with primary plasma cell leukaemia if they are suitable.

# Managing acute renal disease caused by myeloma
Consider immediately starting a bortezomib and dexamethasonebased combination regimen for people with untreated, newly diagnosed, myelomainduced acute renal disease.
If a bortezomibbased combination regimen is unsuitable for people with untreated, newly diagnosed, myelomainduced acute renal disease, consider immediately starting a thalidomide and dexamethasonebased combination regimen.In February 2016, this was an off-label use. See NICE's information on prescribing medicines.
Do not perform plasma exchange for myelomainduced acute renal disease.

# Preventing and managing bone disease

## Preventing bone disease
To prevent bone disease, offer people with myeloma:
zoledronic acid or
disodium pamidronate, if zoledronic acid is contraindicated or not tolerated or
sodium clodronate, if zoledronic acid and disodium pamidronate are contraindicated, not tolerated or not suitable.
Consider immediately referring people with myeloma for dental assessment and treatment before starting zoledronic acid or disodium pamidronate.
For people who need urgent myeloma treatment, consider referring for dental assessment and treatment as soon as possible after they start treatment.

## Managing nonspinal bone disease
Offer people with myeloma and nonspinal bone disease who have not already started bisphosphonates:
zoledronic acid or
disodium pamidronate, if zoledronic acid is contraindicated or not tolerated or
sodium clodronate, if zoledronic acid and disodium pamidronate are contraindicated, not tolerated or not suitable.
Assess the risk of fracture (in line with the NICE guideline on assessing the risk of fragility fractures in osteoporosis) in people with myeloma and nonspinal bone disease.
Consider surgical stabilisation followed by radiotherapy for nonspinal bones that have fractured or are at high risk of fractures.
Consider radiotherapy for nonspinal bones that have fractured or are at high risk of fracture if surgical intervention is unsuitable or not immediately needed.
Consider radiotherapy for people with myeloma and nonspinal bone disease who need additional pain relief if:
chemotherapy and initial pain management has not led to prompt improvement in pain control
chemotherapy is unsuitable and current pain medication is not working.
Consider retreatment with radiotherapy if pain recurs or if there is regrowth of a previously treated lesion.
Consider seeking advice from or referral to specialists in palliative care or pain medicine for people with complex nonspinal bone disease.

## Managing spinal bone disease
For guidance on treating metastatic spinal cord compression, see the NICE guideline on metastatic spinal cord compression.
Offer all people with myeloma and spinal bone disease:
bisphosphonates as follows, if not already started:
zoledronic acid or
disodium pamidronate, if zoledronic acid is contraindicated or not tolerated or
sodium clodronate, if zoledronic acid and disodium pamidronate are contraindicated, not tolerated or unsuitable
systemic pain control, when relevant using the NICE guidelines on neuropathic pain and opioids in palliative care.
Consider the following as adjuncts to other treatments for all people with myeloma and spinal bone disease:
interventional pain management
bracing.
In people with radiological evidence of myelomarelated spinal instability, consider immediate intervention with:
spinal surgery, with or without radiotherapy
cement augmentation, with or without radiotherapy
radiotherapy alone, if spinal intervention is unsuitable or not currently needed.
In people with radiological evidence of myelomarelated spinal bone disease without instability, consider:
cement augmentation, with or without radiotherapy
radiotherapy alone.

# Preventing and managing complications

## Preventing infection
Offer people with myeloma the seasonal influenza vaccination.
Consider extending the pneumococcal vaccination to people with myeloma who are under 65.
Consider intravenous immunoglobulin replacement therapy for people who have hypogammaglobulinaemia and recurrent infections.
Consider continuing aciclovir or equivalent antiviral prophylaxis after treatment with bortezomib or other proteasome inhibitors ends.In February 2016, this was an off-label use. See NICE's information on prescribing medicines.
Consider aciclovir or equivalent antiviral prophylaxis for people who are taking both immunomodulatory drugs and highdose steroids.In February 2016, this was an off-label use. See NICE's information on prescribing medicines.
Consider testing for hepatitis B, hepatitis C and HIV before starting myeloma treatment.

## Managing peripheral neuropathy
For guidance on the pharmacological management of neuropathic pain see the NICE guideline on neuropathic pain in adults.
Explain the symptoms of neuropathy to people with myeloma, and encourage them to tell their clinical team about any new, different or worsening neuropathic symptoms immediately.
If people who are receiving bortezomib develop neuropathic symptoms, consider immediately:
switching to subcutaneous injections and/or
reducing to weekly doses and/or
reducing the dose.
Consider reducing the dose if people are taking a drug other than bortezomib and develop neuropathic symptoms.
Temporarily stop neuropathyinducing myeloma treatments if people develop either of the following:
grade 2 neuropathy with pain
grade 3 or 4 neuropathy.
If neuropathy does not improve despite stopping myeloma treatment and further treatment is needed, consider switching to myeloma treatments less likely to induce neuropathy.

## Preventing thrombosis
This recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.
This recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.
This recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.
This recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.
This recommendation has been replaced by the NICE guideline on venous thromboembolism in over 16s.

## Managing fatigue
If other treatable causes of anaemia have been excluded, consider erythropoietin analogues (adjusted to maintain a steady state of haemoglobin at 110120 g/litre) to improve fatigue in people with myeloma who have symptomatic anaemia.

# Monitoring
Monitor people with smouldering myeloma every 3 months for the first 5 years, and then decide the frequency of further monitoring based on the longterm stability of the disease.
Monitor people who have completed myeloma treatment and recovered at least every 3 months. Take into account any risk factors for progression, such as:
highrisk fluorescence insitu hybridisation (FISH)
impaired renal function
disease presentation.
Monitoring for myeloma and smouldering myeloma should include:
assessment of symptoms related to myeloma and myeloma treatment and
the following laboratory tests:
full blood count
renal function
bone profile
serum immunoglobulins and serum protein electrophoresis
serumfree lightchain assay, if appropriate.
Do not offer people with myeloma or smouldering myeloma routine skeletal surveys for disease monitoring.
Consider symptomdirected imaging for people with myeloma or smouldering myeloma if any new bone symptoms develop.
For people with myeloma and serological relapse or disease progression, consider one of the following (taking into consideration previous imaging tests):
wholebody MRI
spinal MRI
fluorodeoxyglucose positron emission tomography CT (FDG PETCT).
For people with smouldering myeloma and disease progression, consider one of the following (taking into consideration previous imaging tests):
wholebody MRI
wholebody lowdose CT
wholebody CT
spinal MRI
fluorodeoxyglucose positron emission tomography CT (FDG PETCT).

# Managing relapsed myeloma

## First relapse
NICE has a suite of technology appraisal guidance on myeloma either published or in development. These published technology appraisals cover NICE's position in relation to primary disease treatment, salvage therapy for relapsed myeloma and consolidation/maintenance therapy after primary management. The recommendations in this guideline complement the existing technology appraisals, giving further guidance in addition to the technology appraisals where myelomarelated subgroups are not included.
Bortezomib monotherapy is recommended as an option for the treatment of progressive multiple myeloma in people who are at first relapse having received 1 prior therapy and who have undergone, or are unsuitable for, bone marrow transplantation, under the following circumstances:
the response to bortezomib is measured using serum M protein after a maximum of 4 cycles of treatment, and treatment is continued only in people who have a complete or partial response (that is, reduction in serum M protein of 50% or more or, where serum M protein is not measurable, an appropriate alternative biochemical measure of response), and
the manufacturer rebates the full cost of bortezomib for people who, after a maximum of 4 cycles of treatment, have less than a partial response (as defined above). 
People currently receiving bortezomib monotherapy who do not meet the criteria in recommendation 1.10.1 should have the option to continue therapy until they and their clinicians consider it appropriate to stop. 

## Second autologous stem cell transplantation
Offer a second autologous stem cell transplant to people with relapsed myeloma who are suitable and who have:
completed reinduction therapy without disease progression and
had a response duration of more than 24 months after their first autologous stem cell transplant.
Consider a second autologous stem cell transplant for people with relapsed myeloma who are suitable and who have:
completed reinduction therapy without disease progression and
had a response duration of between 12 and 24 months after their first autologous stem cell transplant.
Be aware that people with relapsed myeloma are more likely to be suitable for a second autologous stem cell transplant if they have:
had a good response to the first autologous stem cell transplant
a lower International Staging System (ISS) stage
not had many prior treatments
good overall fitness, based on resilience, frailty and performance status
no adverse fluorescence insitu hybridisation (FISH) results.

## Subsequent therapy
Lenalidomide in combination with dexamethasone is recommended, within its licensed indication, as an option for the treatment of multiple myeloma only in people who have received two or more prior therapies, with the following condition:
The drug cost of lenalidomide (excluding any related costs) for people who remain on treatment for more than 26 cycles (each of 28 days; normally a period of 2 years) will be met by the manufacturer. 
People currently receiving lenalidomide for the treatment of multiple myeloma, but who have not received 2 or more prior therapies, should have the option to continue therapy until they and their clinicians consider it appropriate to stop. 
Pomalidomide, in combination with dexamethasone, is not recommended within its marketing authorisation for treating relapsed and refractory multiple myeloma in adults who have had at least 2 previous treatments, including lenalidomide and bortezomib, and whose disease has progressed on the last therapy. 
People whose treatment with pomalidomide was started within the NHS before this guidance was published should be able to continue treatment until they and their NHS clinician consider it appropriate to stop. 

# Terms used in this guideline

## Smouldering myeloma
In this guideline, only recommendations that specifically refer to smouldering myeloma apply to this condition.
To find out what NICE has said on topics related to this guideline, see our web pages on blood and bone marrow cancers, complications of cancer, embolism and thrombosis and end of life care.# Context
Myeloma is a malignancy of the plasma cells that normally produce immunoglobulin. It affects multiple organs and systems, including the bones, kidneys, blood and immune systems.
Myeloma is the seventeenth most common cancer in the UK. In 2010, 4672 people in the UK were diagnosed with myeloma. It occurs more frequently in men and in people of AfricanCaribbean family origin. Diagnosis is often delayed because the symptoms are not specific to myeloma, and this leads to significant early morbidity and mortality.
Myeloma management is complex and challenging. Effective treatments have been developed over the past 15 years, and although myeloma is still incurable these treatments have led to improvements in overall survival and quality of life. However, myeloma treatment increasingly involves expensive drugs and frequent hospital visits. Complications of myeloma and myeloma treatment cause an increasing longterm strain on supportive and palliative care services, and on carers.
This guideline covers areas in which there is uncertainty or variation in practice. It contains recommendations on:
communication and support
laboratory investigations and imaging to diagnose myeloma and determine further treatment
managing bone disease and acute renal disease
autologous and allogeneic stem cell transplantation
preventing and managing myeloma and treatmentinduced complications
monitoring for people with smouldering myeloma and myeloma.
Because of the changes to the International Myeloma Working Group definition of smouldering myeloma, it was not possible to make any recommendations for clinical practice on managing this condition. The new definition has changed how smouldering myeloma and myeloma are differentiated, and there is currently no evidence available that is using the new definitions.
This guideline covers adults (aged 16 years and over):
who are referred to secondary care with suspected myeloma
with newly diagnosed or relapsed myeloma (including highrisk myeloma and primary plasma cell leukaemia).
This guideline does not cover people who have:
a solitary plasmacytoma without myeloma
amyloid lightchain amyloidosis in the absence of myeloma
paraproteins secondary to other conditions.# Recommendations for research
The Guideline Committee has made the following recommendations for research. The Committee's full set of research recommendations is detailed in the full guideline.

# Diagnostic investigations to predict treatment outcomes
What is the prognostic value of the Hevylite assay and ratio compared with other prognostic factors and tests, including the serumfree lightchain assay and fluorescence insitu hybridisation (FISH), in people with newly diagnosed myeloma who are starting treatment?

## Why this is important
Hevylite is a new assay that some studies have indicated is a useful prognostic tool. However, it is not clear how robustly it has been evaluated against other prognostic factors and tests, or whether it is an independent prognostic factor. The Hevylite assay should be evaluated in an accredited centralised laboratory independent of links with the manufacturer. Outcomes of interest are overall response, complete response, minimal residual disease, progressionfree survival, overall survival and resource use.

# Imaging investigations for newly diagnosed myeloma
What is the comparative effectiveness of wholebody MRI, fluorodeoxyglucose positron emission tomography CT (FDG PETCT) and wholebody lowdose CT in detecting lesions that may determine the start of treatment for people with newly diagnosed myeloma?

## Why this is important
Newer imaging techniques are replacing skeletal surveys for assessing myelomarelated bone disease in people with newly diagnosed myeloma. However, the most effective technique is not known. Outcomes of interest are lesion detection, sensitivity and specificity for myelomarelated bone disease, patient acceptability, incremental upstaging, radiation exposure, risk of second primary cancer, the impact of additional information on predicting progressionfree survival, overall survival and skeletalrelated events.

# Management of smouldering myeloma
Which combinations of FISH, molecular technologies, bone marrow plasma cell percentage, wholebody imaging, immunophenotype, serumfree lightchain levels or ratio, Hevylite, paraprotein levels, immunoparesis, and International Staging System (ISS) are most effective at risk stratification for people with smouldering myeloma?
What is the comparative effectiveness of fixed duration treatment (with or without bonedirected therapy), continuous treatment (with or without bonedirected therapy) and no treatment (with or without bonedirected therapy) for people with smouldering myeloma?

## Why this is important
Changes to the International Myeloma Working Group definitions of smouldering myeloma and myeloma have affected the risk stratification process for smouldering myeloma. It is unclear if the previous risk stratification approach remains valid. It is also unclear if earlier treatment will be of benefit to people with smouldering myeloma. This study should be a randomised multicentre prospective trial for patients with newly diagnosed smouldering myeloma (as defined by the International Myeloma Working Group 2014 classification). Outcomes of interest are time to biochemical and/or clinical progression, overall survival, adverse events, quality of life and resource use.

# Allogeneic stem cell transplantation
What is the effectiveness of combined autologousallogeneic stem cell transplantation compared with autologous stem cell transplantation, plus consolidation and maintenance treatment in chemosensitive patients at first response or first relapse?

## Why this is important
There are conflicting data from a small number of studies on longterm survival following auto/allo stem cell transplantation compared with autologous stem cell transplantation. These studies were performed before thalidomide, bortezomib and lenalidomide were used as myeloma treatments. These drugs produce better responses and also have the capacity to affect immunological responses after the transplant. Research is needed to see if there is a role for auto/allo stem cell transplant in the ongoing treatment of myeloma. Outcomes of interest are progressionfree survival, overall survival, transplantrelated mortality, quality of life, early and late toxicity including graftversushostdisease (GvHD) and resource use. This research should be included as an option in appropriate mainstream clinical trials for myeloma.

# Bisphosphonates for the prevention of bone disease
What is the effectiveness of monthly zoledronic acid given indefinitely compared with zoledronic acid given for a fixed duration in patients with myeloma?

## Why this is important
There is goodquality evidence to support the use of zoledronic acid to prevent bone disease in people with myeloma. However, the optimal frequency and duration of treatment is not clearly defined and needs further research, particularly given the qualityoflife implications for people needing regular, lifelong visits to hospital. This study should be a randomised controlled trial. Outcomes of interest are skeletalrelated events, progressionfree survival, overall survival, utility of bone biomarkers, incidence of osteonecrosis of the jaw, quality of life and resource use.