International Journal of Laboratory Hematology

The Official journal of the International Society for Laboratory Hematology

REVIEW INTERNAT IONAL JOURNAL OF LABORATO RY HEMATO LOGY

Review of the NICE guidelines for multiple myeloma

G. PRATT*, T.C. MORRIS †

*Haematology, Centre for S U M M A RY

Clinical Haematology,
University Hospitals In February 2016, the National Institute for Health and Care Excel-
Birmingham NHS Foundation lence (NICE) published guidelines on multiple myeloma. NICE
Trust, Birmingham, UK
†
Haematology, Queen’s have published numerous guidelines relating to haematology, but
University Belfast Faculty of this was the first guideline focusing on a single haematological
Medicine Health and Life malignancy. The purpose of this review was to highlight the rec-
Sciences, Belfast, UK
ommendations made in the guideline and the implications for the
Correspondence: management of patients in the UK and also internationally. In
Guy Pratt, Centre for Clinical addition, we review the NICE process and highlight issues around
Haematology, University Hospi- current guideline development.
tals Birmingham NHS Founda-
tion Trust, Birmingham, UK.
Tel.: +44 1213714381;
Fax: +441214149913;
E-mail: guy.pratt@uhb.nhs.uk

doi:10.1111/ijlh.12581

Received 23 July 2016; accepted

for publication 18 August 2016

Keyword
Myeloma

and presentation of evidence, health economic anal-

THE GUIDELINE PROCESS
For the myeloma guideline, the guideline develop-
ment group consisted of 11 healthcare professionals
(six haematologists, two haematology clinical nurse
specialists, one palliative medicine specialist, one pal-
liative care clinical nurse specialist and one radiolo-
gist) and three patient/public representatives, and all
of these posts were advertised. There was strong pro-
fessional support from both the National Collaborat-
ing Centre for Cancer who were commissioned by
NICE for development of this guideline and who
provided a team for guideline development including
professional support for evidence searches, grading
ysis and leading the guideline group through the
NICE guideline process. For certain areas, co-opted
expert advisors including a spinal surgeon, an inter-
ventional radiologist and a clinical oncologist and
input from specialist experts from NICE joined the
guideline group. In total, the whole guideline group
spent 20 meeting days in 14 separate meetings in a
process spanning just over 2 years in addition to the
considerable work outside of these meetings in evi-
dence searches, health economic analysis and draft-
ing and revisions of the guideline. Declarations of
interest are central to the NICE process and were
divided into personal financial, personal nonfinancial

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2017, 39, 3–13 3
4 G. PRATT AND T.C. MORRIS | NICE GUIDELINES FOR MYELOMA
and nonpersonal financial. An individual with a per-
sonal financial interest that conflicted with a topic
would be excluded from any contribution including
verbal communication relating to that topic.
The initial step was defining the remit and then
the scope of the guideline. The remit defined the pop-
ulation of interest as being adult patients with sus-
pected myeloma or proven myeloma including
smouldering myeloma or plasma cell leukaemia at
any time point in the patient’s illness. Patients with
amyloid, solitary plasmacytomas and MGUS were not
included. NICE guidelines did not cover every aspect
of diagnosis and management (unlike current BSH
guidelines), and instead, there is an initial scoping
process which identifies a limited number of key
questions (or topics) that need to be the focus for the
guideline and the draft scope is sent out to stakehold-
ers for comments and revised following this. Stake-
holders are organization registered with NICE and
would include for example the Royal Colleges of
Physicians, Royal College of Pathologists, UK Mye-
loma Forum, Myeloma UK and other patient charities,
commercial companies from the pharmaceutical
industry, laboratory diagnostics and medical devices.
The eligibility criteria required to be a stakeholder is
listed on the NICE website. For each topic, NICE fol-
lows a set approach using PICOs which defines the
population of interest (P), the possible interventions
(I), what the comparators are (C) and the outcomes
(O) for each topic. Examples of this are given in Fig-
ure 1. Health economic analysis focused on two ques-
tions which were decided by the guideline
development group and based on the two areas felt to
have the most significant economic impact. For the
myeloma guideline, the two areas identified for health
economic analysis were the cost-effectiveness of alter-
nate imaging strategies for diagnosis in secondary care
of patients with suspected myeloma and the cost-
effectiveness of balloon kyphoplasty and vertebro-
plasty compared to non-surgical management for the
treatment of vertebral collapse in patients with mye-
loma. The evidence for each topic was presented to
the guideline group and was graded in terms of its
quality, by outcome, using the GRADE system based
on a number of factors including the nature of the
studies, risk of bias, consistency, reporting bias, con-
founding effects and the size of the effect and its pre-
cision. The guideline group would then formulate
recommendations based on this evidence. In many
areas, the evidence was weak, but if there was a con-
sensus amongst the group, then a recommendation
could be made. Importantly, the terminology used by
NICE reflects the strength of a recommendation. The
term ‘OFFER’ indicates a strong recommendation
based on confidence that the benefits do outweigh
harm and burden and are cost-effective. The recom-
mendation can be applied uniformly to most patients.
The term ‘CONSIDER’ is used when the magnitude of
benefit or not is less certain and requires judicious
application to individual patients. In addition to mak-
ing recommendations, the guideline development
group identified five key research recommendations.
The draft guideline was opened for consultation and
was available to view on the NICE website for several
weeks in the autumn of 2015. Comments were
invited from registered stakeholders, and subse-
quently, the guideline development group formulated
a reply to each stakeholder’s comment and adjusted
the guideline accordingly.
There are clear strengths to the NICE guideline
process in terms of the high quality of the process
and good governance, and they are recognized as
being of international standard. There is possibly an
increasing scrutiny on the credibility of guidelines
globally, and the NICE guideline process is seen by
many as a model for delivering guidelines. Unlike a
TA recommendation for use of a drug, there is some
lack of clarity as to the power of a NICE guideline
in changing UK practice, but it is expected that
commissioners and providers of health care would
look favourably on NICE recommendations. Con-
versely trusts who do not follow guideline recom-
mendations may potentially have to justify
themselves if challenged. There is recognition that
even well-supported guideline processes do not have
the capacity to look robustly at every single aspect
of a disease and in particular health economic anal-
ysis can only address a limited number of questions.
Evidence is weak in many areas and in such cir-
cumstances recommendations may depend on a con-
sensus, or alternatively no recommendation may be
made by the guideline development group. There is
always a concern in areas lacking evidence as these
are likely to be the most contentious and may not
reflect the consensus of healthcare professionals out-
side of the guideline group. It is critical therefore
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2017, 39, 3–13

Figure 1. Two examples of the
PICO approach to generating
recommendations for guidelines.
that stakeholders comment and that there is a pro-
ductive dialogue with guideline groups.
The guideline process is labour-intensive, under-
standably slow and, in terms of the NICE guideline,
relatively inflexible such that failure to define the
scope or PICO properly at the beginning cannot easily
be undone later in the process. Another issue is the
readability of guidelines as, for example, the full NICE
myeloma guideline is 287 pages with 89 pages for
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2017, 39, 3–13
G. PRATT AND T.C. MORRIS | NICE GUIDELINES FOR MYELOMA 5
appendices and may not be suitable for many readers
particularly as an educational resource.
The myeloma guideline group’s main concern with
the NICE myeloma guideline was the existence of
existing technology appraisals relating to all the com-
monly used drugs or anticipated new drugs to treat
patients with myeloma. The guideline group had no
remit to contradict or debate existing technology
appraisals or to discuss the effectiveness of drugs that
6 G. PRATT AND T.C. MORRIS | NICE GUIDELINES FOR MYELOMA
were likely to have an imminent technology appraisal.
This severely limited the NICE myeloma guideline as
we were unable to discuss antimyeloma therapy out-
side of selective situations such as renal failure,
plasma cell leukaemia and transplantation. For updat-
ing NICE guidelines, the current proposal is for there
to be a formal check for the need to update a guide-
line typically every 2–4 years and occasionally earlier
in exceptional circumstances. With an increasing
number of newer agents and changes in patient man-
agement, it will be a challenge for guidelines and TAs
to be updated in a timely way.
R E C O M M E N DAT I O N S F R O M T H E N I C E
MYELOMA GUIDELINE
Listed below are the main recommendations from the
NICE myeloma guideline
Communication and support
Provide information and support to people with mye-
loma or primary plasma cell leukaemia and their fam-
ily 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
individualized 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 complica-
tions of stem cell transplantation
• symptoms of myeloma and treatment-related side
effects (including steroid-related side effects, infection
and neuropathy)
• lifestyle measures to optimize bone health and renal
function
• how to identify and report new symptoms (espe-
cially 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 treat-
ment, 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 sup-
port services at diagnosis, at the beginning and end of
each treatment, at disease progression and at transi-
tion to end-of-life care.
Laboratory investigations for suspected myeloma
Use serum protein electrophoresis and serum-free
light-chain assay to confirm the presence of a para-
protein 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, serum-free light-chain assay or
urine electrophoresis (urine Bence–Jones protein
assessment) alone to exclude a diagnosis of
myeloma.
When performing a bone marrow aspirate and tre-
phine 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 tre-
phine biopsy to provide prognostic information:
• Perform fluorescence in situ hybridization (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.
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2017, 39, 3–13

• Consider performing FISH on CD138-selected bone
marrow plasma cells to identify the adverse risk
abnormality t(14;20), and the standard risk abnormal-
ities t(11;14) and hyperdiploidy.
• Consider performing immunophenotyping of bone
marrow to identify plasma cell phenotype, and to
inform subsequent monitoring.
• Consider performing immunohistochemistry (in-
cluding Ki-67 staining and p53 expression) on the tre-
phine biopsy to identify plasma cell phenotype and
give an indication of cell proliferation, to provide fur-
ther prognostic information.
Perform serum-free light-chain assay and use
serum-free light-chain ratio to assess prognosis.
Imaging for suspected myeloma
Offer imaging to all people with a plasma cell disorder
suspected to be myeloma.
Consider whole-body MRI as first-line imaging.
Consider whole-body low-dose CT as first-line
imaging if whole-body MRI is unsuitable or the per-
son declines it.
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.
Do not use isotope bone scans to identify mye-
loma-related 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 smoulder-
ing myeloma who have not had whole-body imaging
with one of the following, consider whole-body imaging
to assess for myeloma-related bone disease and extrame-
dullary plasmacytomas with one of the following:
•MRI
•CT
•fluorodeoxyglucose positron emission tomography
CT (FDG PET-CT).
For guidance on imaging for people with suspected
spinal cord compression, see the NICE guideline on
metastatic spinal cord compression.
Consider baseline whole-body imaging with MRI or
FDG PET-CT for people who have nonsecretory
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2017, 39, 3–13
G. PRATT AND T.C. MORRIS | NICE GUIDELINES FOR MYELOMA 7
myeloma or suspected or confirmed soft tissue plasma-
cytomas and have not already had either of these tests.
Service organization
For guidance on the facilities needed to provide inten-
sive inpatient chemotherapy and transplants for peo-
ple with myeloma, and the structure and function of
multidisciplinary teams (MDTs), see the NICE cancer
service guidance on improving outcomes in haemato-
logical cancers.
For guidance on service organization 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 specializing in myeloma
• supportive and palliative care, supported by: psycho-
logical support services, a 24-h acute oncology and/or
haematology helpline, physiotherapy, occupational
therapy, dietetics, medical social services, critical care
• clinical trials via the MDT specializing 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
• specialized pain management
• therapeutic apheresis
• radiotherapy
• restorative dentistry and oral surgery
• clinical trials, in particular early phase trials
First autologous stem cell transplantation
Consider using frailty and performance status mea-
sures that include comorbidities to assess the suitabil-
ity 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.
8 G. PRATT AND T.C. MORRIS | NICE GUIDELINES FOR MYELOMA
Allogeneic stem cell transplantation
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 leucocyte antigen (HLA)
matched donor is available
• how graft-vs.-host disease (GvHD) and other compli-
cations may get worse with age
• the risk of higher transplant-related mortality and
morbidity, vs. the potential for long-term disease-free
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.
Managing primary plasma cell leukaemia
• Consider bortezomib-based and/or lenalidomide-
based combination induction chemotherapy for people
with primary plasma cell leukaemia.
• Consider high-dose melphalan-based autologous
stem cell transplantation for people with primary
plasma cell leukaemia if they are suitable.
Managing acute renal disease
• Consider immediately starting a bortezomib- and
dexamethasone-based combination regimen for people
with untreated, newly diagnosed, myeloma-induced
acute renal disease.
• If a bortezomib-based combination regimen is
unsuitable for people with untreated, newly diag-
nosed, myeloma-induced acute renal disease, consider
immediately starting a thalidomide- and dexametha-
sone-based combination regimen.
• Do not perform plasma exchange for myeloma-
induced acute renal disease.
Preventing bone disease
To prevent bone disease, offer people with myeloma:
• zoledronic acid or
• disodium pamidronate, if zoledronic acid is con-
traindicated or not tolerated or
• sodium clodronate, if zoledronic acid and disodium
pamidronate are contraindicated, not tolerated or not
suitable.
Consider immediately referring people with mye-
loma for dental assessment and treatment before start-
ing 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 dis-
ease who have not already started bisphosphonates:
• zoledronic acid or
• disodium pamidronate, if zoledronic acid is con-
traindicated 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 stabilization followed by radio-
therapy 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 medi-
cation is not working.
Consider retreatment with radiotherapy if pain recurs
or if there is regrowth of a previously treated lesion.
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2017, 39, 3–13

Consider seeking advice from or referral to special-
ists in palliative care or pain medicine for people with
complex nonspinal bone disease.
Managing spinal bone disease
For guidance on treating metastatic spinal cord com-
pression, 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 con-
traindicated or not tolerated or
sodium clodronate, if zoledronic acid and dis-
odium pamidronate are contraindicated, not toler-
ated 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 treat-
ments for all people with myeloma and spinal bone
disease:
• interventional pain management
• bracing.
In people with radiological evidence of myeloma-
related spinal instability, consider immediate interven-
tion with:
• spinal surgery, with or without radiotherapy
• cement augmentation, with or without radiotherapy
• radiotherapy alone, if spinal intervention is unsuit-
able or not currently needed.
In people with radiological evidence of myeloma-
related spinal bone disease without instability, consider:
• cement augmentation, with or without radiotherapy
• radiotherapy alone.
Preventing infection
Offer people with myeloma the seasonal influenza
vaccination.
Consider extending the pneumococcal vaccination
to people with myeloma who are under 65.
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G. PRATT AND T.C. MORRIS | NICE GUIDELINES FOR MYELOMA 9
Consider intravenous immunoglobulin replacement
therapy for people who have hypogammaglobuli-
naemia and/or recurrent infections.
Consider continuing aciclovir or equivalent antivi-
ral prophylaxis after treatment with bortezomib or
other proteasome inhibitors ends.
Consider aciclovir or equivalent antiviral prophy-
laxis for people who are taking both immunomodula-
tory drugs and high-dose steroids.
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 neuro-
pathic pain in adults.
Explain the symptoms of neuropathy to people
with myeloma, and encourage them to tell their clini-
cal team about any new, different or worsening neu-
ropathic 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 neuropathy-inducing myeloma
treatments if people develop either of the following: grade
2 neuropathy with pain or 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
For people with myeloma who are starting
immunomodulatory drugs, offer thromboprophylaxis
with either:
• low molecular weight heparin (LMWH) at a pro-
phylactic dose, or
• vitamin K antagonists at a therapeutic dose, to
maintain an international normalized ratio (INR) of
2–3.
10 G. PRATT AND T.C. MORRIS | NICE GUIDELINES FOR MYELOMA
If LMWH or vitamin K antagonists are unsuitable,
consider low-dose aspirin[3].
When starting thromboprophylaxis, assess the risk
factors, contraindications and practicalities of each
prophylactic strategy.
Do not offer fixed low-dose vitamin K antagonists
for thromboprophylaxis to people with myeloma who
are starting immunomodulatory drugs.
Consider switching thromboprophylaxis to low-
dose aspirin for people who:
• are taking immunomodulatory drugs
• have achieved maximum response
• have no high-risk factors.
Managing fatigue
If other treatable causes of anaemia have been
excluded, consider erythropoietin analogues (adjusted
to maintain a steady state of haemoglobin at 110–
120 g/L) 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 long-
term 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:
• high-risk fluorescence in situ hybridization (FISH)
• impaired renal function
• disease presentation.
Monitoring for myeloma and smouldering mye-
loma 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 elec-
trophoresis
serum-free light-chain assay, if appropriate.
Do not offer people with myeloma or smouldering
myeloma routine skeletal surveys for disease monitoring.
Consider symptom-directed 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):
•whole-body MRI
•spinal MRI
•fluorodeoxyglucose positron emission tomography
CT (FDG PET-CT).
For people with smouldering myeloma and disease
progression, consider one of the following (taking into
consideration previous imaging tests):
•whole-body MRI
•whole-body low-dose CT
•whole-body CT
•spinal MRI
•fluorodeoxyglucose positron emission tomography
CT (FDG PET-CT).
Second autologous stem cell transplantation
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.
Consider a second autologous stem cell transplant
for people with relapsed myeloma who are suitable
and who have:
• completed re-induction 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
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2017, 39, 3–13
 G. PRATT AND T.C. MORRIS | NICE GUIDELINES FOR MYELOMA
• no adverse fluorescence in situ hybridization (FISH)
results.
RESEARCH QUESTIONS
The NICE guideline process encourages the identifica-
tion of a limited number of research questions. The
importance of this is highlighted by funding bodies
requesting research bids to investigate a research
question coming out of a NICE guideline process, and
it is hoped that these research questions can be incor-
porated into or form a basis for future studies.
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 serum-free light-chain assay and fluores-
cence in situ hybridization (FISH), in people with
newly diagnosed myeloma who are starting treatment?
Imaging investigations for newly diagnosed myeloma
What is the comparative effectiveness of whole-body
MRI, fluorodeoxyglucose positron emission tomogra-
phy CT (FDG PET-CT) and whole-body low-dose CT
in detecting lesions that may determine the start of
treatment for people with newly diagnosed myeloma?
Management of smouldering myeloma
Which combinations of FISH, molecular technologies,
bone marrow plasma cell percentage, whole-body
imaging, immunophenotype, serum-free light-chain
levels or ratio, Hevylite, paraprotein levels, immuno-
paresis 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 bone-directed
therapy), continuous treatment (with or without
bone-directed therapy) and no treatment (with or
without bone-directed therapy) for people with
smouldering myeloma?
Allogeneic stem cell transplantation
What is the effectiveness of combined autologous–al-
logeneic stem cell transplantation compared with
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2017, 39, 3–13
11
autologous stem cell transplantation, plus consolida-
tion and maintenance treatment in chemosensitive
patients at first response or first relapse?
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?
C O S T- E F F E C T I V E N E S S
The two recommendations below were considered to
have potentially the greatest financial impact and
were selected for health economic analysis.
The cost-effectiveness of alternate imaging strategies for
diagnosis in secondary care of patients with suspected
myeloma
The recommendation for whole-body cross-sectional
imaging (MRI or low-dose CT) instead of skeletal sur-
veys in patients with suspected myeloma would
clearly generate additional MRI or CT scan imaging
investigations but would reduce the number of skele-
tal surveys. The following is taken from the published
NICE guideline: ‘Even under the very conservative
assumption that there is no difference in diagnostic
accuracy between the different imaging modalities
there is a strong case that an approach of using cross-
sectional imaging at the time of diagnosis is a cost
effective strategy for diagnosis in patients with a
plasma cell disorder suspected to be myeloma. The
main driver of this result appears to be the avoidance
of the need for further cross-sectional imaging to
guide treatment decisions, following a positive result
on skeletal survey. Even under these conservative
assumptions this approach could be both cost saving
and health improving even with the use of WB-CT or
WB-MRI being the preferred option in greater than
50% of cases even when the health provider’s willing-
ness to pay per QALY is zero. The case becomes stron-
ger when the cross-sectional imaging starts to have a
higher diagnostic accuracy than skeletal survey with
the illustrative base case values again suggesting an
approach using either WB-CT or WB-MRI could be
cost saving and health improving. It is unclear which
is the most cost-effective between WB-CT and
12 G. PRATT AND T.C. MORRIS | NICE GUIDELINES FOR MYELOMA
WB-MRI given a paucity of good evidence around
diagnostic accuracy and the decision sensitivity to dif-
ferences in diagnostic accuracy between both. Whilst
it was the guideline group’s opinion that MRI was the
most sensitive of the considered imaging modalities it
was difficult to quantify by exactly how much, if at
all, without higher quality evidence. These conclu-
sions do not hold true for lower prevalences of mye-
loma where the number of subsequent cross-sectional
imaging following skeletal survey is likely to be much
lower. The WB-CT or WB-MRI imaging is therefore
very unlikely to be cost effective as a general screen-
ing tool for all paraproteinaemias and it is important
that the patient population is carefully defined. A
looser definition and therefore a lower prevalence
amongst the imaged population could lead to harm
through increased radiation burden and through inef-
ficiently allocated resources’.
The cost-effectiveness of balloon kyphoplasty and
vertebroplasty compared to nonsurgical management for
the treatment of vertebral collapse in patients with
myeloma
The recommendation to consider cement augmenta-
tion would be expected to increase the number of bal-
loon kyphoplasties or vertebroplasties performed. The
following is taken from the published NICE guideline:
‘The results of the base case analysis showed that bal-
loon kyphoplasty and vertebroplasty were not cost
effective over a 1 year time horizon and only verte-
broplasty was cost effective over a 5 year time hori-
zon. However, when considering the probabilistic
results, both cement techniques were shown to be
cost effective with a 5 year time horizon with verte-
broplasty also cost effective under a 1 year time hori-
zon. Furthermore, during probabilistic sensitivity
analysis and under a 5 year time horizon both cement
techniques were cost effective in the majority of itera-
tions with vertebroplasty being cost saving and health
improving in 40% of cases. The results were shown to
be particularly sensitive to the costs of non surgical
management. Threshold sensitivity analysis showed
that even if our economic analysis only modestly
underestimates the true cost of non surgical manage-
ment or the effectiveness of cement techniques then
both vertebroplasty and balloon kyphoplasty would
likely be cost effective’.
I M PAC T O F T H E N I C E G U I D E L I N E
Many of the recommendations in the NICE guideline
are already seen as standard of care, but it is hoped
that they will help support a more uniform delivery
of this across haematology units. One of the purposes
of NICE guidelines is to ensure improved compliance.
Withstanding the capacity and financial constraints,
there are a number of recommendations in the guide-
line that could drive changes in practice.
There is a strong recommendation in this guideline
for the availability of timely psychological and pallia-
tive care support and other support services such as
dental services, physiotherapy, occupational therapy,
dietary support, social services and access to clinical
trials. In terms of service organization, the guideline
distinguishes between which services should be pro-
vided locally or regionally.
Serum protein electrophoresis and serum-free
light-chain assay are used together for screening, so
there is no recommendation to perform urine analysis
for Bence–Jones protein for screening which may be a
change in practice for some units.
There is a recommendation to perform FISH testing
on bone marrows for suspected myeloma, and this has
implications for both future funding and capacity for
FISH testing. There is also a consideration to perform flow
cytometry which is not standard practice in many units
again with marked financial and capacity implications.
The guideline recommendations for imaging for a
patient with suspected myeloma will support a major
change in practice that is already underway in most
units. It needs to be emphasized that the recommenda-
tions are for patients who are suspected to have mye-
loma and not for patients with suspected MGUS. The
guideline group was unable to agree a definition of sus-
pected myeloma, so clinical judgement is required and
there is obviously a need to manage requesting for
cross-sectional imaging appropriately. Importantly, the
cost-effectiveness analysis in favour of cross-sectional
imaging for patients with suspected myeloma will not
hold true if skeletal surveys are requested in addition to
cross-sectional imaging or if the proportion of screened
patients subsequently confirmed to have MGUS
exceeds the limits used in the healthcare model. There
is recognition that currently the modality of cross-sec-
tional imaging will be determined by local capacity and
cost issues and MRI techniques such as diffusion-
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2017, 39, 3–13
 G. PRATT AND T.C. MORRIS | NICE GUIDELINES FOR MYELOMA
weighted MRI will require increasing adoption by radi-
ology units. Further research in this area is critical to
better define the use of cross-sectional imaging tech-
niques at diagnosis but also in the role of follow-up
evaluation or as markers of residual disease.
There is an increasing recognition that cement aug-
mentation should be considered for myeloma-related
spinal disease and the cost-effectiveness analysis sug-
gests this can be cost-effective for patients, and it is
hoped that this guideline can help drive improved
accessibility for this service.
The recommendation for preventing thrombosis for
patients starting immunomodulatory drugs may be a
change in practice for some units as there is a strong
recommendation for low molecular weight heparin
prophylaxis although acknowledging the need to
assess suitability and risk factors and may lead to an
increase in the proportion of patients having heparin
prophylaxis rather than aspirin.
The recommendations around transplantation,
management of patients with plasma cell leukaemia,
prevention of bone disease, management of nonspinal
bone disease and spinal bone disease, management of
acute renal disease, monitoring and supportive man-
agements should not be a change in practice, but it is
hoped that they will support a more uniform optimal
standard of care.
© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2017, 39, 3–13
13
It is hoped that the research recommendations will
help support future funding and adoption by the
NIHR for research bids. The impact of this guideline is
uncertain, but it is hoped that it will be a useful tool
to help healthcare professionals drive and support
changes of practice.
AU T H O R C O N T R I B U T I O N
GP and CM wrote and reviewed the manuscript.
AC K N OW L E D G E M E N T S
We would like to acknowledge the whole NICE Mye-
loma Guideline Group for supporting guideline devel-
opment (Curly Morris, Guy Pratt, Sam Ahmedzai,
Alan Chant, Andrea Guy, Matthew Jenner, Nicola
Montacute, Nicola Mullholland, Monica Morris, Les-
ley Roberts, Hamdi Sati, John Snowden, Matthew
Streetly, Jane Woodward) and the National Collabo-
rating Centre for Cancer supporting team (Angela
Bennett, James Hawkins, Angharad Morgan, Katrina
Blears and Elise Hasler). We would particularly like to
acknowledge support from our patient and public
involvement representatives and pay tribute to Jane
Woodward who sadly passed away before the comple-
tion of the guidelines.