Laboratory investigations for people with suspected myeloma

1.2.1.

Use serum protein electrophoresis and serum-free light-chain assay to confirm the presence of a paraprotein indicating possible myeloma or monoclonal gammopathy of undetermined significance (MGUS).

1.2.2.

If serum protein electrophoresis is abnormal, use serum immunofixation to confirm the presence of a paraprotein indicating possible myeloma or MGUS.

1.2.3.

Do not use serum protein electrophoresis, serum immunofixation, serum-free light-chain assay or urine electrophoresis (urine Bence-Jones protein assessment) alone to exclude a diagnosis of myeloma.

1.2.4.

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.

1.2.5.

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

1.2.6.

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.

1.2.7.

When performing a bone marrow aspirate and trephine biopsy to provide prognostic information:

• Perform fluorescence in-situ hybridisation (FISH) on CD138-selected 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 high-risk myeloma.
• Consider performing FISH on CD138-selected 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 Ki-67 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.

1.2.8.

Perform serum-free light-chain assay and use serum-free light-chain ratio to assess prognosis.

Imaging for people with suspected myeloma

1.3.1.

Offer imaging to all people with a plasma cell disorder suspected to be myeloma.

1.3.2.

Consider whole-body MRI as first-line imaging.

1.3.3.

Consider whole-body low-dose CT as first-line imaging if whole-body MRI is unsuitable or the person declines it.

1.3.4.

Only consider skeletal survey as first-line imaging if whole-body MRI and whole-body low-dose CT are unsuitable or the person declines them.

1.3.5.

Do not use isotope bone scans to identify myeloma-related bone disease in people with a plasma cell disorder suspected to be myeloma.

Imaging for people with newly diagnosed myeloma

1.3.6.

For people with newly diagnosed myeloma or smouldering myeloma who have not had whole-body imaging with 1 of the following, consider whole-body imaging to assess for myeloma-related bone disease and extra-medullary plasmacytomas with one of:

• MRI
• CT
• fluorodeoxyglucose positron emission tomography CT (FDG PET-CT).

1.3.7.

For guidance on imaging for people with suspected spinal cord compression, see the NICE guideline on metastatic spinal cord compression.

1.3.8.

Consider baseline whole-body imaging with MRI or FDG PET-CT for people who have non-secretory myeloma or suspected or confirmed soft tissue plasmacytomas and have not already had either of these tests.

First-line 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 myeloma-related subgroups are not included.

1.5.1.

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 high-dose chemotherapy with haematopoietic stem cell transplantation. [This recommendation is from Bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem cell transplantation (NICE technology appraisal guidance 311).]

1.5.2.

Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. [This recommendation is from Bortezomib and thalidomide for the first-line treatment of multiple myeloma (NICE technology appraisal guidance 228).]

1.5.3.

Bortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma if:

• high-dose chemotherapy with stem cell transplantation is considered inappropriate and
• the person is unable to tolerate or has contraindications to thalidomide. [This recommendation is from Bortezomib and thalidomide for the first-line treatment of multiple myeloma (NICE technology appraisal guidance 228).]

Primary plasma cell leukaemia

1.5.9.

Consider bortezomib-based and/or lenalidomide-based combination induction chemotherapy for people with primary plasma cell leukaemia.

1.5.10.

Consider high-dose melphalan-based autologous stem cell transplantation for people with primary plasma cell leukaemia if they are suitable.

Preventing bone disease

1.7.1.

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.

1.7.2.

Consider immediately referring people with myeloma for dental assessment and treatment before starting zoledronic acid or disodium pamidronate.

1.7.3.

For people who need urgent myeloma treatment, consider referring for dental assessment and treatment as soon as possible after they start treatment.

Managing non-spinal bone disease

1.7.4.

Offer people with myeloma and non-spinal 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.

1.7.5.

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 non-spinal bone disease.

1.7.6.

Consider surgical stabilisation followed by radiotherapy for non-spinal bones that have fractured or are at high risk of fractures.

1.7.7.

Consider radiotherapy for non-spinal bones that have fractured or are at high risk of fracture if surgical intervention is unsuitable or not immediately needed.

1.7.8.

Consider radiotherapy for people with myeloma and non-spinal 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.

1.7.9.

Consider re-treatment with radiotherapy if pain recurs or if there is regrowth of a previously treated lesion.

1.7.10.

Consider seeking advice from or referral to specialists in palliative care or pain medicine for people with complex non-spinal bone disease.

Managing spinal bone disease

1.7.11.

For guidance on treating metastatic spinal cord compression, see the NICE guideline on metastatic spinal cord compression.

1.7.12.

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.

1.7.13.

Consider the following as adjuncts to other treatments for all people with myeloma and spinal bone disease:

• interventional pain management
• bracing.

1.7.14.

In people with radiological evidence of myeloma-related 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.

1.7.15.

In people with radiological evidence of myeloma-related spinal bone disease without instability, consider:

• cement augmentation, with or without radiotherapy
• radiotherapy alone.

Preventing infection

1.8.1.

Offer people with myeloma the seasonal influenza vaccination.

1.8.2.

Consider extending the pneumococcal vaccination to people with myeloma who are under 65.

1.8.3.

Consider intravenous immunoglobulin replacement therapy for people who have hypogammaglobulinaemia and recurrent infections.

1.8.4.

Consider continuing aciclovir^[2] or equivalent antiviral prophylaxis after treatment with bortezomib or other proteasome inhibitors ends.

1.8.5.

Consider aciclovir^[2] or equivalent antiviral prophylaxis for people who are taking both immunomodulatory drugs and high-dose steroids.

1.8.6.

Consider testing for hepatitis B, hepatitis C and HIV before starting myeloma treatment.

Managing peripheral neuropathy

1.8.7.

For guidance on the pharmacological management of neuropathic pain see the NICE guideline on neuropathic pain in adults.

1.8.8.

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.

1.8.9.

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.

1.8.10.

Consider reducing the dose if people are taking a drug other than bortezomib and develop neuropathic symptoms.

1.8.11.

Temporarily stop neuropathy-inducing myeloma treatments if people develop either of the following:

• grade 2 neuropathy with pain
• grade 3 or 4 neuropathy.

1.8.12.

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

1.8.13.

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

1.8.14.

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

1.8.15.

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

1.8.16.

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

1.8.17.

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

Managing fatigue

1.8.18.

If other treatable causes of anaemia have been excluded, consider erythropoietin analogues (adjusted to maintain a steady state of haemoglobin at 110–120 g/litre) to improve fatigue in people with myeloma who have symptomatic anaemia.

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 myeloma-related subgroups are not included.

1.10.1.

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). [This recommendation is from Bortezomib monotherapy for relapsed multiple myeloma (NICE technology appraisal guidance 129).]

1.10.2.

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. [This recommendation is from Bortezomib monotherapy for relapsed multiple myeloma (NICE technology appraisal guidance 129).]

Second autologous stem cell transplantation

1.10.3.

Offer a second autologous stem cell transplant to people with relapsed myeloma who are suitable and who have:

• completed re-induction therapy without disease progression and
• had a response duration of more than 24 months after their first autologous stem cell transplant.

1.10.4.

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.

1.10.5.

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 in-situ hybridisation (FISH) results.

Subsequent therapy

1.10.6.

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. [This recommendation is from Lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy (NICE technology appraisal guidance 171).]

1.10.7.

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. [This recommendation is from Lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy (NICE technology appraisal guidance 171).]

1.10.8.

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. [This recommendation is from Pomalidomide for relapsed and refractory multiple myeloma previously treated with lenalidomide and bortezomib (NICE technology appraisal guidance 338).]

1.10.9.

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. [This recommendation is from Pomalidomide for relapsed and refractory multiple myeloma previously treated with lenalidomide and bortezomib (NICE technology appraisal guidance 338).]

Smouldering myeloma

In this guideline, only recommendations that specifically refer to smouldering myeloma apply to this condition.

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, progression-free survival, overall survival and resource use.

Why this is important

Newer imaging techniques are replacing skeletal surveys for assessing myeloma-related 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 myeloma-related bone disease, patient acceptability, incremental upstaging, radiation exposure, risk of second primary cancer, the impact of additional information on predicting progression-free survival, overall survival and skeletal-related events.

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 multi-centre 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.

Why this is important

There are conflicting data from a small number of studies on long-term 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 progression-free survival, overall survival, transplant-related mortality, quality of life, early and late toxicity including graft-versus-host-disease (GvHD) and resource use. This research should be included as an option in appropriate mainstream clinical trials for myeloma.

Why this is important

There is good-quality 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 quality-of-life implications for people needing regular, life-long visits to hospital. This study should be a randomised controlled trial. Outcomes of interest are skeletal-related events, progression-free survival, overall survival, utility of bone biomarkers, incidence of osteonecrosis of the jaw, quality of life and resource use.