Content uploaded by Bronek Boszczyk
Author content
All content in this area was uploaded by Bronek Boszczyk on Mar 12, 2018
Content may be subject to copyright.
Optimizing the management of patients with spinal myeloma
disease
Sean Molloy,
1
Maggie Lai,
2
Guy Pratt,
3
Karthik Ramasamy,
4
David Wilson,
5
Nasir Quraishi,
6
Martin Auger,
7
David
Cumming,
8
Maqsood Punekar,
9
Michael
Quinn,
10
Debo Ademonkun,
8
Fenella
Willis,
11
Jane Tighe,
12
Gordon Cook,
13
Alistair Stirling,
14
Timothy Bishop,
15
Cathy Williams,
15
Bronek Boszczyk,
6
Jeremy Reynolds,
16
Mel Grainger,
14
Niall
Craig,
17
Alastair Hamilton,
18
Isobel
Chalmers,
8
Sam Ahmedzai,
19
Susanne
Selvadurai,
1
Eric Low,
2
Charalampia
Kyriakou
20
on behalf of the UK Spinal
Myeloma Working Group
1
Royal National Orthopaedic Hospital, London,
2
Myeloma UK, Edinburgh,
3
Department of Hae-
matology, Heart of England NHS Trust Founda-
tion, Birmingham,
4
Department of Haematology,
Oxford University Hospitals NHS Trusts,
5
St
Luke’s Radiology, St Luke’s Hospital, Oxford,
6
Centre for Spinal Studies and Surgery, Queen’s
Medical Centre, Nottingham,
7
Department of
Haematology, Norfolk and Norwich University
Hospital, Norwich,
8
Trauma and Orthopaedics
Department, Ipswich Hospital NHS Trust, Ips-
wich,
9
Department of Haematology, Lancashire
Teaching Hospitals NHS Foundations Trust,
Preston,
10
Department of Haematology, Belfast
City Hospital, Belfast,
11
Department of Haema-
tology, St Georges Hospital, London,
12
Depart-
ment of Haematology, Aberdeen Royal
Infirmary, Aberdeen,
13
St James’ Institute of
Oncology, Leeds Teaching Hospitals NHS Trust,
Leeds,
14
Royal Orthopaedic Hospital NHS
Foundations Trust, Birmingham,
15
Centre for
Clinical Haematology, Nottingham University
Hospitals NHS Trust, Nottingham,
16
Spinal
Unit, Oxford University Hospitals NHS Trust,
Oxford,
17
Orthopaedic Suite, Woodend Hospital,
Aberdeen,
18
Department of Orthopaedic Surgery,
Musgrove Park Hospital, Belfast,
19
Academic
Unit of Supportive Care, Department of Oncol-
ogy, University of Sheffield, Sheffield, and
20
Department of Haematology, Northwick Park
Hospital and Department of Haematology and
Summary
Myeloma is one of the most common malignancies that results in osteolytic
lesions of the spine. Complications, including pathological fractures of the
vertebrae and spinal cord compression, may cause severe pain, deformity
and neurological sequelae. They may also have significant consequences for
quality of life and prognosis for patients. For patients with known or newly
diagnosed myeloma presenting with persistent back or radicular pain/weak-
ness, early diagnosis of spinal myeloma disease is therefore essential to treat
and prevent further deterioration. Magnetic resonance imaging is the initial
imaging modality of choice for the evaluation of spinal disease. Treatment
of the underlying malignancy with systemic chemotherapy together with
supportive bisphosphonate treatment reduces further vertebral damage.
Additional interventions such as cement augmentation, radiotherapy, or
surgery are often necessary to prevent, treat and control spinal complica-
tions. However, optimal management is dependent on the individual nat-
ure of the spinal involvement and requires careful assessment and
appropriate intervention throughout. This article reviews the treatment and
management options for spinal myeloma disease and highlights the value
of defined pathways to enable the proper management of patients affected
by it.
Keywords: spinal myeloma disease, diagnosis, treatment, management,
pathway.
research paper
ª2015 John Wiley & Sons Ltd, British Journal of Haematology doi: 10.1111/bjh.13577
Stem Cell Transplantation, Royal Free Hospital,
London, UK
Correspondence: Charalampia Kyriakou MD,
PhD, Department of Haematology, Royal Free
and Northwick Park Hospitals, Pond Street,
London NW3 2QG, UK.
E-mail: c.kyriakou@nhs.net
Myeloma is the second most common haematological
malignancy with around 4 800 newly diagnosed patients
in the UK each year (http://www.cancerresearchuk.org/
cancer-info/cancerstats/types/myeloma/incidence/uk-multiple-
myeloma-incidence-statistics). It is the most common
malignancy involving bone (Roodman, 2009; Sezer, 2009;
Wood & Brown, 2012; Valesin Filho et al, 2013) and is
associated with skeletal complications such as bone pain,
hypercalcaemia, pathological fracture and spinal cord
compression.
Bone damage occurs as a result of the interaction between
myeloma cells and the bone marrow microenvironment.
Although the exact mechanisms are still unclear, uncoupling
of normal bone remodelling, whereby osteoclast activity is
increased and osteoblast function is inhibited, appears to
underlie the development of myeloma bone disease. Cru-
cially, the disruption in normal bone remodelling only fuels
myeloma cell growth and survival and the ensuing vicious
cycle serves to increase the destructive nature of myeloma
bone disease (Edwards et al, 2008).
Spinal myeloma disease
The spine is the most frequently affected skeletal site in mye-
loma (Kyle et al, 2004). Some degree of spinal involvement
(spinal myeloma disease) is present in up to 60% of patients
at diagnosis, (Lecouvet et al, 1997a; Body, 2003) which may
or may not be symptomatic. Another 15–30% of patients at
later stages of myeloma are affected by new spinal disease
every year (McCloskey et al, 2001).
Spinal myeloma disease is most commonly indicated by
the presence of lytic lesions or generalized osteopenia. Most
lesions occur in the vertebral bodies but they can also be
found in other parts of the vertebral column including the
facets, pedicles and transverse/spinous processes.
Affected vertebral bodies may become weakened with pro-
gressive bone destruction and eventually collapse, resulting in
a vertebral compression fracture (VCF). These can appear as
wedge deformities of the vertebral bodies caused by the col-
lapse of the anterior vertebral body wall, or as a symmetrical
collapse, which, if severe, can produce a vertebral plana. In
addition to affecting the vertebral body, a myelomatous
lesion may produce a defect in the posterior wall or in the
facets/pedicles, which means that a fracture may compromise
spinal stability and therefore neurological function.
Vertebral compression fractures are common conse-
quences of spinal myeloma disease and are associated with
significant morbidity and mortality. The overall incidence in
myeloma is estimated to be around 24% (Saad et al, 2007)
and in the UK, they are thought to affect around 2 500 mye-
loma patients per year. Initially, pain is the most pronounced
symptom and the approximate site of the fracture can be
diagnosed clinically by closed fist percussion over the spinal
processes (Langdon et al, 2010) although this is less specific
for lower lumbar disease. Depending on the type and num-
ber of fractures, they can also cause a significant spinal
deformity (kyphosis) and loss of total body height. Most
patients with pain and a significant deformity are affected by
impaired mobility, respiratory compromise with increased
risk of pulmonary infection, gastro-intestinal discomfort and
loss of appetite (Silverman, 1992).
Spinal cord or cauda equina compression is reported to
develop in 11–24% of myeloma patients with myeloma
spinal disease (Wallington et al, 1997; Loblaw et al, 2005;
Rades et al, 2007; Mak et al, 2011). Although not always
immediately obvious, clinical triggers include severe pain in
the cervical, thoracic or lumbar region; spinal pain aggra-
vated by straining (passing stool; coughing, sneezing); noc-
turnal spinal pain preventing sleep and neurological signs of
spinal cord or cauda equina compression including radicular
pain, limb numbness and/or paraesthesia, limb weakness, dif-
ficulty walking and loss of bladder/bowel control.
Spinal cord or cauda equina compression may be due to a
myelomatous mass arising from the vertebral body expand-
ing into the epidural space or, in approximately 5% of cases,
from a solitary plasmacytoma (Brenner et al, 1982; Dores
et al, 2009; Sobol & Stiff, 2014). Most commonly, the plas-
macytoma develops along the spinal column and the most
common symptom is pain at the tumour site. Regardless of
the cause, spinal cord or cauda equina compression is the
most serious complication of spinal disease myeloma and
requires immediate attention.
Whether spinal myeloma disease is acutely symptomatic
or not, its long-term sequelae have significant physical, func-
tional and psychological consequences that can be hugely
detrimental to patient quality of life and impact on their
S. Molloy et al
2ª2015 John Wiley & Sons Ltd, British Journal of Haematology
activities of daily living. Early detection of spinal myeloma
disease, together with timely and appropriate management, is
therefore of paramount importance.
Diagnosis of spinal myeloma disease
The diagnosis of spinal myeloma disease is dependent on the
use of one or more imaging techniques. In the UK, practice
varies considerably and is largely based on clinicians’ per-
sonal reference and availability of the imaging modalities.
X-ray
At the time of diagnosis, all patients undergo a radiological
skeletal survey, which currently remains the gold standard
for the initial workup for myeloma (Bird et al, 2011; Dimo-
poulos et al, 2011). Spinal myeloma disease can be confirmed
at this stage although a number of patients report back pain
despite a negative skeletal survey. The drawback to X-ray
imaging is its relative lack of sensitivity: it requires the loss
of 30–50% of trabecular bone mass before lytic lesions are
detected (Edelstyn et al, 1967). Furthermore, generalized os-
teopenia may be the only bone manifestation in up to 15%
of myeloma patients (Kyle et al, 2003) that is accurately
detected by X-rays but crucially, its presence increases the
risk of early vertebral collapse (Collins, 2010).
For patients with back pain, additional imaging is indi-
cated to rule out myeloma-related involvement or to confirm
and characterize the extent of spinal myeloma disease. Per-
formed early, this reduces the risk of potentially catastrophic
consequences from occurring.
Techniques such as computerized tomography (CT) scan
and magnetic resonance imaging (MRI) have become more
widely used over the years and are becoming more standard
practice for surveying the skeleton in myeloma patients. Both
techniques are more sensitive and have several advantages
over standard X-rays. They provide different information on
the nature and extent of existing myeloma spinal disease but
importantly, can detect it when X-rays have been unable to.
Computed tomography
Standard CT images can depict diffuse osteopenia, punched-
out lytic lesions, expansile lesions with soft tissue masses and
fractures (Mahnken et al, 2002). They can also accurately
identify unstable vertebrae at risk of fracture (Horger et al,
2005; Kropil et al, 2008; Touzeau & Moreau, 2013), aiding
the assessment of spinal stability, and are of use in identify-
ing bone destruction in cases where MRI is negative. From a
patient’s perspective, CT scans tend to be better tolerated
than X-rays because the acquisition time is relatively rapid
compared to X-rays and can be done without the need for
patients to be repositioned. For the detection of myeloma
spinal disease, reconstructed images in the sagittal and coro-
nal planes are generally sufficient.
Despite the various advantages over X-rays, CT scans have
not been used routinely to specifically detect myeloma bone/
spinal disease. This is largely due to the concern that patients
are exposed to significantly higher doses of radiation com-
pared to plain X-rays (Gleeson et al, 2009; Winterbottom &
Shaw, 2009). Instead, they are more likely to be used to
guide fine needle biopsies of lesions (Avva et al, 2001) and
plan for radiotherapy. However, growing evidence suggests
that low-dose whole body CT produces equally high resolu-
tion images capable of detecting lytic lesions, osteopenia and
soft tissue involvement (Gleeson et al, 2009; Chassang et al,
2010; Ippolito et al, 2013) and this is very likely to help pave
the way for wider use of CT scans in myeloma patients and,
potentially, as a replacement for X-rays in the near future.
Magnetic resonance imaging
Magnetic resonance imaging is increasingly being recognized
as an important method for evaluating spinal metastasis and
whole spine MRI is the recommended imaging modality of
choice when signs and symptoms suggest possible spinal cord
or cauda equina compression (Brooks et al, 2014).
For myeloma patients, MRI offers several advantages over
both standard X-rays and CT scanning, producing images of
the spinal skeleton that allow detection of acute and chronic
VCF and providing an accurate diagnosis where spinal cord or
nerve root compression is suspected, and enabling soft tissue
involvement to be identified (Joffe et al, 1988; Moulopoulos
et al, 1999; Dimopoulos et al, 2009). Moreover, MRI has the
ability to discriminate between normal and infiltrated bone
marrow (Moulopoulos & Dimopoulos, 1997; Terpos et al,
2011) and provide information on the actual tumour burden
(D’Anastasi et al, 2014). This is a useful feature, as it allows for
the early detection of initial lesions in either symptomatic
patients with negative skeletal surveys or asymptomatic
patients with myeloma spinal disease. It may also be capable of
differentiating a pathological fracture from one caused by gen-
eral osteoporosis. Finally, MRI can estimate prognosis based
on the number, size and pattern of lesions (Walker et al, 2007)
but its ability to predict the risk of VCF on the same basis is
less clear (Lecouvet et al, 1997a; Scherer et al, 2002).
The main methodological consideration with MRI is the
lack of specificity of findings. The false positive rate is
relatively high where acquired signals may reflect an alto-
gether different pathological process (D’Sa et al, 2007; Za-
magni & Cavo, 2012). For patients, the main limitations are
the lengthy acquisition time (45–60 min) and contra-indica-
tors such as patient intolerance (claustrophobia), cardiac
pacemakers or other metal implants. Sagittal T1 and short
T1 inversion recovery (STIR) sequence MRI of the whole
spine can be done in approximately 15 min and offers an
alternative to the standard more comprehensive magnetic
resonance studies (Langdon et al, 2010). STIR images can
also highlight oedema related to an acute fracture and the T1
weighted images may show the fracture line.
Optimising the management of patients with spinal myeloma disease
ª2015 John Wiley & Sons Ltd, British Journal of Haematology 3
Whether follow-on MRI or CT scans are carried out in
myeloma patients after a skeletal survey depends very much
on local availability and the clinical situation at hand. At
present, no clear guidance exists on what imaging techniques
should be used to complement (or replace) skeletal surveys
and confirm the presence or otherwise of myeloma spinal
disease. This is particularly pressing for patients presenting
with significant back or radicular pain and signs and symp-
toms of spinal cord or cauda equina compression. For the
reasons described earlier, there is an obvious need for this to
be done at the earliest opportunity.
Treatment and management of spinal myeloma
disease
Successful treatment and management of spinal myeloma
disease requires a multidisciplinary approach that addresses
the following: treatment of the myeloma with systemic che-
motherapy; adequate control of pain; relief of spinal cord or
cauda equina compression and maintenance of spinal stabil-
ity. To reduce the risk of further spinal bone destruction or
permanent deformity/neurological dysfunction and the
impact on patient quality of life, it is imperative these mea-
sures are addressed in a systematic manner.
For newly diagnosed or relapsed myeloma patients pre-
senting with persistent back or radicular pain, urgent investi-
gation is a priority to establish the exact nature of spinal
involvement. The most important aspect is to determine
whether patients have normal or abnormal neurology as this
will guide the best possible treatment for the individual.
This section provides a general overview of the different
pharmacological and non-pharmacological options currently
available for the treatment of spinal myeloma disease fol-
lowed by recommended pathways for the optimal manage-
ment of patients who have no abnormal neurology, those
who have abnormal neurology and, thirdly, those who have
been diagnosed with plasmacytoma.
Pain management
Pain is the most common symptom of spinal involvement
with myeloma and treatment is aimed at alleviating it as
much as possible to preserve quality of life. Patients with
VCF’s are postulated to get pain as a result of micromove-
ment at the fracture site. This pain is often very severe and
limits movement. Stability is assessed using the Spinal Insta-
bility Neoplastic Score (SINS) classification (Fourney et al,
2011). If there is overt spinal instability with translation of
one vertebral body on another then this can lead to neuro-
logical impairment and severe pain. Patients with cord/cauda
equina compression may manifest with impaired motor and
sensory function but they may also have pain because the
posterior wall of the vertebral body has been destroyed by
tumour and they have a degree of instability. Patients with
healed VCF’s often have a resultant kyphotic alignment and
as a result there is more stress on the facet joints (posterior
elements of the spine).
Various pain assessment tools are available and regular
assessment with even, for example, a simple 0–10 numerical
rating scale can greatly assist with treatment decisions
(Snowden et al, 2011). To manage pain, a multi-modal,
mechanism-based approach including evidence-based phar-
macological and non-pharmacological therapies is used
(Snowden et al, 2011). Opioids are the most commonly
used analgesics but they may cause significant adverse effects
that can reduce quality of life, especially in older patients
(Sloot et al, 2015). Patients with persistent severe pain
requiring high-dose opioid pain relief should be referred to
the palliative pain care specialist (Snowden et al, 2011).
Cement augmentation is considered for patients with VCF’s
to abolish the micromovement at the fracture site and
increase the strength and stiffness of the vertebral bodies
(Molloy et al, 2005; Mendoza et al, 2012). If the facet joints
are deemed to be the pain generators then targeted injec-
tions into these joints can improve the associated pain
(Wilson et al, 2011).
Bisphosphonates
As part of standard clinical practice, all newly diagnosed
symptomatic myeloma patients receive bisphosphonate treat-
ment whether or not they have evidence of myeloma bone
disease (Bird et al, 2011). The aim of bisphosphonate treat-
ment is to slow down or prevent the progression of bone
destruction and, in the process, can help alleviate bone pain
and reduce the risk of skeletal fractures. These improvements
are thought to result from the combined inhibition of osteo-
clast activity, reduction in osteoclast progenitor development
and recruitment, and promotion of osteoclast apoptosis
(Hughes et al, 1995).
Three bisphosphonates are licensed for myeloma bone dis-
ease but zoledronic acid is the preferred choice as it is also
associated with improved survival (Morgan et al, 2011). Cur-
rently, there is no consensus regarding the optimal duration
of bisphosphonate treatment and practice is varied. Most
patients are treated for a minimum of 2 years but, given the
risk of bisphosphonate-related osteonecrosis of the jaw, treat-
ment is usually stopped if patients have achieved a complete
or very good partial response to anti-myeloma treatment and
have no active bone disease. However, bisphosphonate re-
treatment is recommended at the time of relapse (Bird et al,
2011).
Anti-myeloma treatment
Current treatment for myeloma is based around various
anti-myeloma regimens combining chemotherapy agents with
steroids and either proteasome inhibitors or immunomodu-
latory drugs, with or without high-dose chemotherapy and
stem cell transplantation (Bird et al, 2011). By targeting the
S. Molloy et al
4ª2015 John Wiley & Sons Ltd, British Journal of Haematology
myeloma cells, anti-myeloma treatments can disrupt the
interaction with the bone microenvironment, thus inhibiting
the osteoclastogenic effect. In doing so, conventional treat-
ment of the myeloma is effective in reducing spinal pain and
the risk of further damage. Where a good response has been
achieved, it is often adequate in relieving pain that is due to
myeloma spinal disease. However, it is not effective in treat-
ing spinal fracture pain, which is probably due to the micro-
movement at the fracture site.
For patients who fail to achieve a good response, it is
important to consider a change in anti-myeloma treatment.
That said; it is possible that patients may respond with
reduction in their myeloma monoclonal protein but still have
persistent pain, in which case local approaches to manage
pain are more appropriate than switching systemic therapy.
Bortezomib has been linked to increased osteoblastic activity
and bone formation (De Matteo et al, 2010; Terpos, 2010),
with several studies reporting a positive effect on bone health
in patients on the drug, including an improvement in osteo-
lytic lesions (Delforge et al, 2011; Lee et al, 2011; Schulze
et al, 2014). Therefore, a switch to bortezomib may prove
more effective for targeting extensive bone disease.
Steroids
High-dose steroids can reduce swelling and inflammation
and provide rapid pain control and improvement, particu-
larly in cases involving spinal cord compression (Azad et al,
2013). Ideally, they should be commenced as soon as possible
but long-term use is not recommended because of the poten-
tial to cause further osteopenia and other steroid-related
adverse effects.
Radiotherapy
Myeloma lesions are extraordinarily radiosensitive and for
patients with levels of spinal pain that significantly affect
day-to-day function, radiotherapy can be useful for its con-
trol. Several studies have demonstrated its efficacy in alleviat-
ing pain and maintaining mobility in patients (Lecouvet
et al, 1997b; Balducci et al, 2011; Valesin Filho et al, 2013).
Radiotherapy is also indicated for the treatment of epidural
or extramedullary masses at risk of, or causing, spinal cord
or cauda equina compression. However, it should be used
judiciously as extensive radiotherapy could compromise the
bone marrow reserve for future treatment, namely high-dose
therapy and stem cell transplantation.
Spinal assessment
For many patients, treatment with pharmacological agents
(anti-myeloma treatments as well as analgesics) and/or radio-
therapy does not adequately relieve pain. This could partly be
explained by the fact that such treatments do not provide
mechanical support for fractured vertebrae. In these circum-
stances, it may be necessary to seek additional intervention
that could be used sequentially or simultaneously with anti-
myeloma treatment and/or radiotherapy. Options available
depend on a number of patient and disease-related factors
including patient performance status; whether there is neuro-
logical involvement; where the damage is along the spine;
where the lesions are located within the vertebra, and the
extent of spinal canal involvement. Where stability is a con-
cern, a SINS assessment is often useful in determining an
appropriate course of action (Schmidt et al, 2004; Fourney
et al, 2011).
Spinal Treatment
Bracing. For some patients, bracing may provide short-term
control of pain by stabilizing the spine and reducing the
mechanical load on the vertebral bodies. The optimal dura-
tion of bracing depends on each individual but to avoid
muscle weakening, skin irritation, increased segmental
motion at the upper/lower end of the brace and diminished
pulmonary capacity, it is generally not recommended for any
longer than 3 months. Supervised physiotherapy can be
advantageous to avoid muscle wasting.
Surgery. To date, surgical management of myeloma spinal
disease has been similar to the management of spinal metas-
tases in solid cancers. Patchell et al (2005) reported that
patients with metastatic cancer (excluding myeloma) who
presented with spinal cord compression and were treated
with surgical decompression followed by radiotherapy had
significantly improved outcomes compared to patients trea-
ted with radiotherapy alone. Outcome parameters were the
ability of patients to be able to walk and have urinary/faecal
continence.
However, this type of treatment is not always appropriate
or indeed possible for myeloma patients because of the often
extensive and diffuse nature of the lesions, which severely
impairs the strength of the vertebrae. As a consequence, insert-
ing rods and screws safely can be extremely challenging. More-
over, the majority of patients are poor candidates for invasive
surgery because of advanced age and comorbid factors, predis-
posing them to longer recovery times and increased risk of
morbidity and mortality. Patients are also significantly immu-
nocompromised, both as a result of the disease itself and its
treatments, thus risking infection of the inserted metalwork.
In most cases, epidural tumours are treated very effectively by
steroids/chemotherapy and radiotherapy, obviating the need
for surgical decompression. Therefore, surgical intervention is
reserved for those with significant spinal instability, for exam-
ple, where there has been significant destruction to all three
bony columns of the spine (determined by the SINS classifica-
tion and in concert with the spinal surgeon).
Vertebral augmentation with cement. Two minimally-invasive
vertebral augmentation techniques,percutaneousvertebroplasty
Optimising the management of patients with spinal myeloma disease
ª2015 John Wiley & Sons Ltd, British Journal of Haematology 5
(PV) and balloon kyphoplasty (BKP), have become increas-
ingly common treatments to decrease pain associated with
VCFs (Mathis et al, 2001; Berenson et al, 2011) and restore
strength and stiffness to the vertebral bodies (Molloy et al,
2003, 2005), thereby improving pain and quality of life
(Mendoza et al, 2012). In myeloma patients, vertebral aug-
mentation is indicated for those with significant pain affect-
ing day-to-day function as a result of VCF or bone
destruction with high risk of collapse.
Percutaneous vertebroplasty (PV) involves the percutane-
ous (small posterior stab incisions) placement of one or two
trocars into the vertebral bodies via the pedicles or the ex-
trapedicular approach for the injection of polymethylmethac-
rylate (bone cement) under fluoroscopic guidance. Reports
indicate that the procedure stabilizes the vertebra and pro-
vides rapid pain relief (Masala et al, 2008; Anselmetti et al,
2012). However, the procedure is not without risk. The
cement, when injected, may leak into the blood vessels or the
spinal canal, which has been reported to result in cement
embolus and neurological dysfunction respectively (Corcos
et al, 2014). These are rare phenomena but cement leakage
into the disc is a relatively common complication, which
may create mechanical stress that can result in the fracture of
an adjacent vertebral body (Lin et al, 2004). In addition, PV
does not correct spinal deformity.
Balloon kyphoplasty (BKP) is a modified version of PV
and is an alternative treatment for VCFs. During BKP, an
inflatable bone tamp is passed down the trocar in the same
way as during PV, inserted into the fractured vertebra and
inflated to create a cavity into which the cement can be
injected. BKP offers pain relief comparable to PV but is
reported to have a lower cement leakage rate than PV
(Deramond et al, 2006; Huber et al, 2009). One explana-
tion for this may be because the cancellous bone is pushed
to the periphery of the bone tamp, thereby creating a
pseudo-cortical wall of bone that prevents the cement from
leaking. BKP has also been reported to restore vertebral
body height (Wardlaw et al, 2012). In patients with a large
lytic lesion affecting a vertebral body the use of prophylac-
tic augmentation (BKP or PV) to prevent fracture and
subsequent collapse can be considered (Langdon et al,
2009).
Several reports have suggested the benefits of BKP and a
recent systematic review and meta-analysis of patients treated
with BKP for VCFs caused by myeloma and osteolytic metas-
tasis found a 41% and 30% reduction in reported pain and
improved functional outcomes, respectively (Bouza et al,
2009). In the first randomized study of 134 cancer patients
(including myeloma) comparing BKP with non-surgical
management (Berenson et al, 2011), those in the BKP group
reported a significantly greater reduction in pain after 1 week
that was sustained at 1 month compared to those who
underwent non-surgical management (P>0!0001). Further-
more, 63% of patients in the non-surgical management
group crossed over to the BKP group after 1 month (Beren-
son et al, 2011). However, the number of myeloma patients
in the trial who benefited from BKP is not clear and further
randomized trials with larger number of patients are needed
to confirm this.
The decision between PV and BKP is based on the clinical
features and the aims of the treatment. However, neither treat-
ment is recommended where there is evidence of spinal cord
compression with obstructing plasmacytoma (Hussein et al,
2008) but radiotherapy may be utilized to clear the spinal
canal of tumour prior to vertebral cement augmentation.
Pathways for the management of spinal
myeloma disease
Spinal disease is one of the most disabling consequences for
myeloma patients and effective treatment and management is
necessary to prevent further sequelae. Despite the various
treatments and procedures available, the management of
spinal myeloma disease remains hugely challenging and there
is currently no standard of practice. This is partly because
the evidence-base for treatment is weak and partly because
access to certain diagnostic and therapeutic modalities may
be limited.
In recognition of the need to optimize spinal care in par-
allel with systemic anti-myeloma treatment, the following
proposes defined pathways for the assessment, treatment and
management of myeloma patients with spinal disease. These
are based on the presence or absence of abnormal neurology
and are summarized in the corresponding algorithms.
Myeloma patients with spinal disease presenting with no
abnormal neurology
The proposed management of spinal disease in myeloma
patients with no abnormal neurology is summarized in
Fig 1.
For newly diagnosed or relapsed myeloma patients pre-
senting with persistent back or radicular pain, urgent investi-
gation to define the nature of spinal involvement/damage is
essential. In the absence of abnormal neurology, careful base-
line assessment is required to determine the severity of pain,
spinal instability or progressive deformity and risk of neuro-
logical dysfunction.
An urgent whole spine MRI scan will indicate whether there
is concern for spinal instability. Where there is a suggestion of
spinal instability, a CT scan with sagittal and coronal recon-
structions can assess for vertebral body fracture and any
involvement of the pars, facet joints and pedicles. The SINS
classification (Fourney et al, 2011) is useful for evaluating the
stability of the spine at the involved levels. This evidence-based
classification helps to determine stability/instability in a spine
affected by tumour by taking into account the location of the
spine, pain, lytic nature, alignment, percentage vertebral body
height loss and the presence of posterior bony elements: a
score between 0–6 denotes stability, a score of 7–12 denotes
S. Molloy et al
6ª2015 John Wiley & Sons Ltd, British Journal of Haematology
indeterminate (possibly impending) instability and a score of
13–18 signifies instability. CT results revealing bony destruc-
tion suggesting spinal instability would indicate bracing and
following a multidisciplinary approach, surgical intervention
may also be considered.
Where MRI reveals an epidural mass with risk for cauda
equina or cord compression, urgent initiation of steroids
and chemotherapy is indicated. Radiotherapy is also an
option for these patients. Repeat imaging will confirm that
the epidural mass has responded to treatment. For cases
where the residual mass has regressed, undertaking further
assessment will determine whether there is significant persist-
ing pain from the fractured level(s) or whether there is a
future risk of vertebral body collapse. If so, then cement
augmentation is appropriate. In cases where the epidural
mass has not regressed significantly on the repeat MRI, a
multidisciplinary approach can determine whether a change
in the anti-myeloma treatment is necessary, or if there is a
need for surgical intervention. Most cases of epidural
involvement however do respond well to steroids/chemotherapy
and radiotherapy.
The majority of myeloma patients with spinal involve-
ment, however, do not have epidural masses but present with
pain secondary to one or more VCFs that are confirmed on
MRI. With severe pain, as defined by a numerical rating scale
(NRS) >6 (on a 0–10 scale), and depending on the impact
of pain and mobility on daily activities, these patients should
be considered for cement augmentation and bracing.
For MRI-confirmed VCFs and mild to moderate pain
(NRS ≤6) that does not significantly affect daily activity,
bracing to help alleviate the pain and prevent further collapse
and deformity is a suitable option in the first instance. If the
pain worsens following 2–3 cycles of chemotherapy or is
affecting quality of life, then cement augmentation may be
considered for these patients.
Myeloma patients with spinal disease presenting with
abnormal neurology
The proposed management of spinal disease in myeloma
patients presenting with abnormal neurology is summarized
in Fig 2.
No abnormal neurology
Myeloma with spinal involvement: pain/instability/progressive deformity or risk of
neurological dysfunction
MRI SCAN WHOLE SPINE∞
CT SCAN (Saggital and coronal reconstructions)
Assess pars, facet joints, pedicles, posterior/anterior wall
involvement to determine if instability is a concern.
Conduct SINS** assessment
If concerned
about stability
MDT management review∞
(surgeon, haematologist, radiotherapist,
radiologist)
If bony destruction is present on CT (suggesting
spinal instability) consider brace or surgical
interventionΔ
Pain significantly affecting
day to day functioning (or
NRS pain score >6)
Pain not significantly affecting
day to day functioning (or
NRS pain score ≤6)
Epidural mass with risk
of cord or cauda equina
compression
Cement augmentation* or
radiotherapy, or combination of
both (according to MDT review)
•Balloon kyphoplasty - creation
of cavity, injection of cement
and partial restoration of VB
height
•Vertebroplasty - injection of
cement to stabilise fracture
Continue medical management
± brace***
After 2–3 cycles of
chemo if ongoing
pain affecting QoL
± brace*** (if high
risk of deformity)
Steroids, radiotherapy,
chemotherapy
Repeat MRI after 2–3
cycles of chemotherapy
(canal clear?)
Assess for cement augmentation
based on risk of VB collapse MDT management review
∞As per national cancer guideline (Bird et al 2011)
*Antibiotic prophylaxis recommended for all patients undergoing
cement augmentation (to avoid potential risk of severely
debilitating discitis)
**Spinal instability neoplastic score
***Thermoplastic/TLSO brace if available to prevent progressive
deformity ± further vertebral body collapse
Δ High-risk patient e.g. with bilateral facet joint destruction, posing
risk of spondylolisthesis
# Persistent severe pain (NRS > 6) or if analgesic side-effects are
significant
Yes No
Start opioids and other multimodal analgesics.
Refer to palliative care specialist where necessary#
Fig 1. Proposed algorithm for the management of patients with known history of myeloma presenting with persistent back or radicular pain/
weakness with no abnormal neurology. CT, computerized tomography; MRI, magnetic resonance imaging; MDT, multidisciplinary team; SINS,
spinal instability neoplastic score; NRS, numerical rating scale; VB, vertebral body; TLSO, thoracolumbosacral orthosis; QoL, quality of life.
Optimising the management of patients with spinal myeloma disease
ª2015 John Wiley & Sons Ltd, British Journal of Haematology 7
Myeloma patients can present with clinical symptoms and
signs of neurological dysfunction as a result of spinal cord or
cauda equina compression at diagnosis or at subsequent
relapse. All patients should be assessed according to the
American Spinal Injury Association (ASIA) classification
(Maynard et al, 1997). The ASIA scoring system utilizes
motor and sensory modality testing to elucidate the level of
spinal cord or cauda equina injury and its severity. Urgent
MRI and CT scans are important to define whether the
spinal cord/cauda equina compression is due to soft tissue or
bony involvement. A SINS classification to assess stability is
also recommended.
Where compression is secondary to soft tissue mass then,
depending on the severity of the clinical picture, manage-
ment with steroids, chemotherapy, bracing and radiotherapy,
is appropriate. However, if the neurological deficit is very
severe then spinal decompression may be indicated. For
patients showing clinical improvement in neurological func-
tion or stabilization of neurology at a low level of impair-
ment within 24 h of starting steroids, a non-surgical
approach may be continued but it is imperative that follow-
up MRI scanning is undertaken to ensure complete resolu-
tion of the spinal cord/cauda equina compression (usually
seen after the first cycle of chemotherapy/steroids or radio-
therapy). Cement augmentation is an option in these patients
if the epidural mass has resolved but there is persistent severe
pain (NRS >6) that affects daily activities or if the patient is
intolerant to analgesics. For those showing rapid clinical
response to conventional therapy as confirmed by MRI scan-
ning, but who have no significant pain [visual analogue scale
(VAS) ≤6], the recommendation is to continue with non-in-
terventional management.
Where abnormal neurology is secondary to bone involve-
ment or if neurological deficit is very significant, then a
spinal decompression procedure with metalwork stabilization
may be indicated. This should also be considered for patients
who do not improve neurologically after steroid/chemother-
apy/radiotherapy treatment. It is vital that any metalwork is
carefully considered in this patient group because of the high
risk of infection due to the immunosuppressive nature of the
disease. Nevertheless it may be necessary to halt further pro-
gression of neurological deficit.
Abnormal neurology
Cord compression; cauda equina; signs and symptoms of neurological dysfunction
MRI SCAN WHOLE SPINE∞
CT scan (SINS** assessment)
Bloods:FBC, total protein, calcium, ESR, renal function, clotting
Pain significantly affecting
day to day functioning (or
NRS pain score >6)
Pain not significantly
affecting day to day
functioning (or NRS pain
score ≤6)
Cement augmentation* or
radiotherapy, or combination of
both (according to MDT review)
•Balloon kyphoplasty - creation
of cavity, injection of cement
and partial restoration of VB
height
•Vertebroplasty - injection of
cement to stabilise fracture
Continue medical management ± brace***
Steroids, radiotherapy, chemotherapy, pain management
∞As per national cancer guideline (Bird et al 2011)
*Antibiotic prophylaxis recommended for all patients undergoing
cement augmentation (to avoid potential risk of severely
debilitating discitis)
** Spinal instability neoplastic score
*** Thermoplastic/TLSO brace if available to prevent progressive
deformity ± further vertebral body collapse
ΔHigh-risk patient e.g. with bilateral facet joint destruction, posing
risk of spondylolisthesis
Soft Tissue Involvement:
Urgent liaison with MDT
(surgeon, haematologist, radiotherapist,
radiologist)
Bone Involvement:
Cord compression due
to bone involvement
Immediate neurological
improvement
No improvement
(unusual)
Spinal Decompression
± stabilisation
(cement augmentation
± metal work)
2–3 cycles chemotherapy
Repeat MRI (canal clear?)
MDT
management
review
No
Yes
Fig 2. Proposed algorithm for the management of patients with known history of myeloma presenting with persistent back or radicular pain/
weakness with abnormal neurology. CT, computerized tomography; MRI, magnetic resonance imaging; MDT, multidisciplinary team; SINS,
spinal instability neoplastic score; NRS, numerical rating scale; VB, vertebral body; TLSO, thoracolumbosacral orthosis; FBC, full blood count;
ESR, erythrocyte sedimentation rate.
S. Molloy et al
8ª2015 John Wiley & Sons Ltd, British Journal of Haematology
Myeloma patients with spinal disease due to
plasmacytoma
The proposed management of myeloma patients with
plasmacytomas affecting the spine is summarized in Fig 3.
The management of patients with multiple spinal plasma-
cytomas is as according to the standard management of mye-
loma. Treatment of solitary bone spinal plasmacytoma
without associated neurological symptoms is with radical
radiotherapy (Molloy & Kyriakou, 2014) but when severe
pain is affecting quality of life (NRS >6) and there is no ex-
traosseous epidural extension of the plasmactyoma, then
cement augmentation should be considered.
For solitary spinal bone plasmacytomas that cause neuro-
logical symptoms, an urgent review for interventional opera-
tion for decompression and metalwork fixation may be
required.
Conclusion
Myeloma spinal disease is one of the most debilitating fea-
tures of myeloma and can result in significant morbidity
including disabling pain, spinal deformity and neurological
dysfunction from spinal cord or cauda equina compression.
Early diagnosis and treatment is critical in order to reduce
the risk of further complications. The establishment of more
clearly defined pathways encompassing a multidisciplinary
approach is required for the optimal evaluation, treatment
and management of patients with spinal myeloma disease.
Although they remain to be formally validated, the proposed
algorithms together with on-going and future studies should
hopefully provide best supportive spinal care for myeloma
patients.
Author contributions
Mr Molloy and Dr Kyriakou were involved in the design,
research and writing of the paper. Mr Eric Low was heavily
involved in the design and research. Ms Maggie Lai substan-
tially contributed by drafting the paper and critically review-
ing and approving the final version. All authors substantially
contributed to the design, interpretation of the paper and
critically reviewed and approved the final version.
References
Anselmetti, G.C., Marcia, S., Saba, L., Muto, M.,
Bonaldi, G., Carpeggiani, P., Marini, S., Manca,
A. & Masala, S. (2012) Percutaneous vertebropl-
asty; multi-centric results from EVEREST expe-
rience in large cohorts of patients. European
Journal of Radiology,81, 4083–4086.
Avva, R., Vanhemert, R.L., Barlogie, B., Munshi,
N. & Angtuaco, E.J. (2001) CT-guided biopsy of
focal lesions in patients with multiple myeloma
may reveal new and more aggressive cytogenetic
abnormalities. American Journal of Neuroradiol-
ogy,22, 781–785.
Azad, A., Tafreshi, A., Liew, M.S. & Yap, L.P. (2013)
“Vanishing” spinal cord compression in mye-
loma: dramatic and rapid response to dexametha-
sone monotherapy. Spine Journal,13, 588–589.
Balducci, M., Chiesa, S., Manfrida, S., Rossi, E.,
Za, T., Frascino, V., De Bari, B., Hohaus, S.,
Cellini, F., Mantini, G., D’Agostino, G.R., Gam-
bacorta, M.A., Leone, A., Valentini, V. & De
Stefano, V. (2011) Impact of radiotherapy on
pain relief and recalcification in plasma cell neo-
plasms: long-term experience. Strahlentherapie
und Onkologie,187, 114–119.
Berenson, J., Pflugmacher, R., Jarzem, O., Zonder,
J., Schechtman, K., Tillman, J.B., Bastian, L.,
Ashraf, T. & Vrionis, F; Cancer Patient Fracture
Evaluation (CAF
!
E) Investigators. (2011) Balloon
kyphoplasty versus non-surgical fracture man-
agement for treatment of painful vertebral body
compression fractures in patients with cancer: a
multicentre, randomised controlled trial. Lancet
Oncology,12, 225–235.
Bird, J.M., Owen, R.G., D’Sa, S., Snowden, J.A.,
Pratt, G., Ashcroft, J., Yong, K., Cook, G., Fey-
ler, S., Davies, F., Morgan, G., Cavenagh, J.,
Low, E. & Behrens, J; Haemato-oncology Task
Force of British Committee for Standards in
Haematology (BCSH) and UK Myeloma Forum.
(2011) Guidelines for the diagnosis and
Plasmacytoma
Solitary
plasmacytoma
Multiple
plasmacytomas
No abnormal
neurology Abnormal neurology
Radical radiotherapy
Consider cement augmentation
If risk of instability or if pain is
significantly affecting day to day
functioning (NRS pain score >6)
Urgent liaison with MDT
(surgeon, haematologist,
radiotherapist, radiologist)
Treat according to
MDT review decision
Treat as a patient with
multiple myeloma
according to standard
pathway
Fig 3. Proposed algorithm for the management
of patients with plasmacytoma affecting the
spine. MDT, multidisciplinary team; NRS,
numerical rating scale.
Optimising the management of patients with spinal myeloma disease
ª2015 John Wiley & Sons Ltd, British Journal of Haematology 9
management of multiple myeloma 2011. British
Journal of Haematology,154, 32–75.
Body, J.J. (2003) Effectiveness and cost of bis-
phosphonate therapy in tumour bone disease.
Cancer,97, 859–865.
Bouza, C., Lopez-Cuadrado, T., Cediel, P., Saz-
Parkinson, Z. & Amate, J.M. (2009) Balloon
kyphoplasty in malignant spinal fractures: a sys-
tematic review in meta-analysis. BMC Palliative
Care,8, 12–21.
Brenner, B., Carter, A., Tatatarsky, I., Gru-
szkiewicz, J. & Peyser, E. (1982) Incidence, prog-
nostic significance and therapeutic modalities of
central nervous system involvement in multiple
myeloma. Acta Haematologica,68, 77–83.
Brooks, F.M., Ghatahora, A., Brooks, M.C., War-
ren, H., Price, L., Brahmabhatt, P., De, V.S.,
John, C., Farnworth, E., Sulaiman, E. & Ahuja,
S. (2014) Management of metastatic spinal cord
compression: awareness of NICE guidance.
European Journal of Orthopaedic Surgery and
Traumatology,24, S255–S259.
Chassang, M., Grimaud, A., Cucchi, J.M., Novellas,
S., Amoretti, N., Chevallier, P. & Bruneton, J.P.
(2010) Can low-dose computed tomographic
scan of the spine replace coventional radiogra-
phy? An evaluation based on imaging myelomas,
bone metastases, and fractures from osteoporo-
sis. Clinical Imaging,31, 225–227.
Collins, C.D. (2010) Multiple myeloma. Cancer
Imaging,10, 20–31.
Corcos, G., Dbjay, J., Mastier, C., Leon, S., Auper-
in, A., De Baere, T. & Deschamps, F. (2014)
Cement leakage in percutaneous vertebroplasty
for spinal metastases: a retrospective evaluation
of incidence and risk factors. Spine,39, E332–
E338.
D’Anastasi, M., Notohamiprodjo, M., Schmidt,
G.P., Durr, H.R., Reiser, M.F. & Baur-Melnyk,
A. (2014) Tumour load in patients with multi-
ple myeloma: b2-microglobulin levels versus
whole-body MRI. AJR American Journal of
Roentgenology,203, 854–862.
De Matteo, M., Brunetti, A.E., Maiorano, E., Caf-
forio, P., Dammacco, F. & Silvestris, F. (2010)
Constitutive down-regulation of osterix in os-
teoblasts from myeloma patients: in vitro effect
of bortezomib and lenalidomide. Leukemia
Research,34, 243–249.
Delforge, M., Terpos, E., Richardson, P.G., Shpil-
berg, O., Khuageva, N.K., Schlag, R., Dimopou-
los, M.A., Kropff, M., Spicka, I., Petrucci, M.T.,
Samoilova, O.S., Mateos, M.V., Magen-Nativ,
H., Goldschmidt, H., Esseltine, D.L., Ricci, D.S.,
Liu, K., Deraedt, W., Cakana, A., van de Velde,
H. & San Miguel, J.F. (2011) Fewer bone disease
events, improvement in bone remodelling, and
evidence of bone healing with bortezomib plus
melphalan-prednisone vs. melphalan-prednisone
in the phase III VISTA trial in multiple mye-
loma. European Journal of Haematology,86,
372–384.
Deramond, H., Saliou, G., Aveillan, M., Lehmann,
P. & Vallee, J.N. (2006) Respective contributions
of vertebroplasty and kyphoplasty to the man-
agement of osteoporotic vertebral fractures. Joint
Bone Spine,73, 610–613.
Dimopoulos, T., Terpos, E., Comenzo, R.L., Tosi,
P., Beksac, M., Sezer, O., Siegel, D., Lokhorst,
H., Kumar, S., Rajkumar, S.V., Niesvizky, R.,
Moulopoulos, L.A. & Durie, B.G. for the Inter-
national Myeloma Working Group. (2009)
International myeloma working group consensus
statement and guidelines regarding the current
role of imaging techniques in the diagnosis and
monitoring of multiple myeloma. Leukemia,23,
1545–1556.
Dimopoulos, M., Kyle, R., Fermand, J.P., Rajku-
mar, S.V., San, M.J., Chanan-Khan, A., Ludwig,
H., Joshua, D., Mehta, J., Gertz, M., Avet-Loi-
seau, H., Beksac, M., Anderson, K.C., Moreau,
P., Singhal, S., Goldschmidt, H., Boccadoro, M.,
Kumar, S., Giralt, S., Munshi, N.C. & Jagannath,
S. (2011) Consensus recommendations for stan-
dard investigative workup: report of the Interna-
tional Myeloma Workshop Consensus Panel 3.
Blood,117, 4701–4705.
Dores, G.M., Landgren, O., NcGlynn, K.A., Curtis,
R.E., Linet, M.S. & Devesa, S.S. (2009) Plasma-
cytoma of bone, extramedullary plasmacytoma
and multiple myeloma: incidence and survival
in the United States, 1992-2004. British Journal
of Haematology,144, 86–94.
D’Sa, S., Abildgaard, N., Tighe, J., Shaw, P. &
Hall-Craggs, M. (2007) Guidelines for the use of
imaging in the management of myeloma. British
Journal of Haematology,137, 49–63.
Edelstyn, G.A., Gillespie, P.J. & Grebbell, F.S.
(1967) The radiological demonstration of osse-
ous metastases. Experimental observations. Clin-
ical Radiology,18, 158–162.
Edwards, C.M., Zhuang, J. & Mundy, G.R. (2008)
The pathogenesis of the bone disease of multiple
myeloma. Bone,42, 1007–1113.
Fourney, D.R., Frangou, E.M., Ryken, T.C., Dipa-
ola, C.P., Sgaffrey, C.I., Berven, S.H., Bilsky,
M.H., Harrop, J.S., Fehlings, M.G., Boriani, S.,
Chou, D., Schmidt, M.H., Polly, D.W., Biagni,
R., Burch, S., Dekutoski, M.B., Ganju, A., Gersz-
ten, P.C., Gokaslan, Z.L., Groff, M.W., Liebsch,
N.J., Mendel, E., Okuno, S.H., Patel, S., Rhines,
L.D., Rose, P.S., Sciubba, D.M., Sundaresan, N.,
Tomita, K., Varga, P.P., Vialle, L.R., Vrionis,
F.D., Yamada, Y. & Fischer, C.G. (2011) Spinal
instability neoplastic score: an analysis of reli-
ability and validity from the spine oncology
study group. Journal of Clinical Oncology,29,
3072–3077.
Gleeson, T.G., Moriarty, J., Shortt, C.P., Gleeson,
J.P., Fitzpatrick, P., Byrne, B., McHugh, J.,
O’Connell, M., O’Gorman, P. & Eustace, S.J.
(2009) Accuracy of whole-body low-does multi-
detector CT (WBLDCT) versus skeletal survey in
the detection of myelomatous lesions, and corre-
lation of disease distribution with whole-body
MRI (WBMRI). Skeletal Radiology,38, 225–236.
Horger, M., Claussen, C.D., Bross-Bach, U., Vo-
nthein, R., Trabold, T., Heuschmid, M. & Pfan-
nenberg, C. (2005) Whole-body low dose
multidetector row-CT in the diagnosis of multi-
ple myeloma: an alternative to conventional
radiography. European Journal of Radiology,54,
289–297.
Huber, F.X., McArthur, N., Tanner, M., Gritzbach,
B., Schoierer, O., Rothfischer, W., Krohmer, G.,
Lessl, E., Baier, M., Meeder, P.J. & Kasperk, C.
(2009) Kyphoplasty for patients with multiple
myeloma is a safe surgical procedure: results
from a large patient cohort. Clinical Lymphoma
& Myeloma,9, 375–380.
Hughes, D.E., Wirght, K.R., Uy, H.L., Sasaki, A.,
Yoneda, T., Roodman, G.D., Mundy, G.R. &
Boyce, B.F. (1995) Bisphosphonates promote
apoptosis in murine osteoclasts in vitro and
in vivo. Journal of Bone and Mineral Research,
10, 1478–1487.
Hussein, MA., Vrionis, F.D., Allison, R., Berenson,
J., Berven, S., Erdem, E., Giralt, S., Jagannath,
S., Kyle, R.A., LeGrand, S., Pflugmacher, R.,
Raje, N., Rajkumar, S.V., Randall, R.L., Rood-
man, D., Siegel, D., Vescio, R., Zonder, J. & Du-
rie, B.J; International Myeloma Working Group.
(2008) The role of vertebral augmentation in
multiple myeloma: International Myeloma
Working Group Consensus Statement. Leuke-
mia,22, 1479–1484.
Ippolito, D., Besostri, V., Bonaffinini, P.A., Ros-
sini, F., Di Lelio, A. & Sironi, S. (2013) Diag-
nostic value of whole-body low-dose computed
tomography (WBLDCT) in bone lesion detec-
tion in patients with multiple myeloma (MM).
European Journal of Radiology,82, 2322–2327.
Joffe, J., Williams, M.P., Cherryman, G.R., Gore,
M., McElwain, T.J. & Selby, P. (1988) Magnetic
resonance imaging in myeloma. Lancet,1, 1162–
1163.
Kropil, P., Fenk, R., Fritz, L.B., Blondin, D., Ko-
bbe, G., Modder, U. & Cohnen, M. (2008)
Comparison of whole-body 64-slice multidetec-
tor computed tomography and conventional
radiography in staging of multiple myeloma.
European Radiology,18, 51–58.
Kyle, R.A., Gertz, M.A., Witzig, T.E., Lust, J.A.,
Lacy, M.Q., Dispenzieri, A., Fonseca, R., Rajku-
mar, S.V., Offord, J.R., Larson, D.R., Plevak,
M.E., Therneau, T.M. & Greipp, P.R. (2003)
Review of 1027 patients with newly diagnosed
multiple myeloma. Mayo Clinic Proceedings,78,
21–23.
Kyle, R.A., Therneau, T.M., Rajkumar, S.V., Lar-
son, D.R., Plevak, M.F. & Melton, L.J. 3rd
(2004) Incidence of multiple myeloma in Olm-
sted County, Minnesota: trend over 6 decades.
Cancer,101, 2667–2674.
Langdon, J., Bernard, J. & Molloy, S. (2009) Pro-
phylactic stabilization of vertebral body metasta-
sis at risk of imminent fracture using balloon
kyphoplasty. Spine,34, E469–E472.
Langdon, J., Way, A., Heaton, S., Bernard, J. &
Molloy, S. (2010) Vertebral compression frac-
tures –new clinical signs to aid diagnosis.
Annals of the Royal College of Surgeons England,
92, 163–166.
Lecouvet, F.E., Vande Berg, B.C., Maldaque, B.E.,
Michaux, L., Laterre, E., Michaux, J.L., Ferrant,
S. Molloy et al
10 ª2015 John Wiley & Sons Ltd, British Journal of Haematology
A. & Malghem, J. (1997a) Vertebral compression
fracture in multiple myeloma. Part 1. Distribu-
tion and appearance at MR imaging. Radiology,
204, 195–199.
Lecouvet, F., Richard, F., Vande Berg, B., Malg-
hem, J., Maldaque, B., Jamart, J., Ferrant, A. &
Michaux, J.L. (1997b) Long-term effects of
localized spinal radiation therapy on vertebral
fractures and focal lesions appearance in patients
with multiple myeloma. British Journal of Hae-
matology,96, 743–745.
Lee, S.E., Min, C.K., Yahng, S.A., Cho, B.S., Eom,
K.S., Kim, Y.J., Kim, H.J., Lee, S., Cho, S.G.,
Kim, D.W., Lee, J.W., Min, W.S. & Park, C.W.
(2011) Bone scan images reveal increased osteo-
blastic function after bortezomib treatment in
patients with multiple myeloma. European Jour-
nal of Haematology,86, 83–86.
Lin, E.P., Ekholm, S., Hiwatashi, A. & Westesson,
P.L. (2004) Vertebroplasty: cement leakage into
the disc increases the risk of new fracture of
adjacent vertebral body. American Journal of
Neuroradiology,25, 175–180.
Loblaw, D.A., Perry, J., Chambers, A. & Laperriere,
N.J. (2005) Systematic review of the diagnosis
and management of malignant extradural spinal
cord compression: the Cancer Care Ontario
Practice Guidelines Initiative’s Neuro-Oncology
Disease Site Group. Journal of Clinical Oncology,
23, 2028–2037.
Mahnken, A.H., Wildberger, J.E., Gehbauer, G.,
Schmitz-Rode, T., Blaum, M., Fabry, U. & Gun-
ther, R.W. (2002) Multidetector CT of the spine
in multiple myeloma: comparison with MR
imaging and radiography. American Journal of
Roenterogenology,178, 1429–1436.
Mak, K.S., Lee, L.K., Mak, R.H., Wang, S., Pile-
Spellman, J., Abrahm, J.L., Prigerson, H.G. &
Balboni, T.A. (2011) Incidence and treatment
patterns in hospitalizations for malignant spinal
cord compression in the United States, 1998-
2006. International Journal of Radiation Oncology
Biology Physics,80, 824–831.
Masala, S., Anselmetti, G.C., Marcia, S., Massari,
F., Manca, A. & Simonetti, G. (2008) Percutane-
ous vertebroplasty in multiple myeloma verte-
bral involvement. Journal of Spinal Disorders and
Techniques,21, 344–348.
Mathis, J.M., Barr, J.D., Belkoff, S.M., Jensen, M.E.
& Deramond, H. (2001) Percutaneous verteb-
roplasty: a developing standard of care for verte-
bral compression fractures. American Journal of
Neuroradiology,22, 373–381.
Maynard, F., Bracken, M., Creasy, G., Ditunno, J.,
Donovan, W., Ducker, T., Garber, S., Marino,
R., Stover, S., Tator, C., Waters, R., Wilberger,
J. & Young, W. (1997) International Standards
for Neurological and Functional Classification
of Spinal Cord Injury. Spinal Cord,35, 266–
274.
McCloskey, E.V., Guest, J.F. & Kanis, J.A. (2001)
The clinical and cost considerations of bis-
phosphonates in preventing bone complications
in patients with metastatic breast cancer and
multiple myeloma. Drugs,61, 1253–1274.
Mendoza, T.R., Koyyalagunta, D., Burton, A.W.,
Thomas, S.K., Phan, M.H., Giralt, S.A., Shah,
J.J. & Cleeland, C.S. (2012) Changes in pain and
other symptoms in patients with painful multi-
ple myeloma-related vertebral fracture treated
with kyphoplasty or vertebroplasty. Journal of
Pain,13, 564–570.
Molloy, S. & Kyriakou, C. (2014) Expert’s com-
ment concerning Grand Rounds case entitled
“total spondylectomy for solitary bone plasma-
cytoma of the lumbar spine in a young woman.
A case report and review of the literature” (by
N. von der Hoeh, S.K. Tschoeke, J. Gulow, A.
Voelker, U. Siebolts and C.-E. Heyde). European
Spine Journal,23, 40–42.
Molloy, S., Mathis, S.M. & Belkoff, S.M. (2003)
The effect of vertebral body percentage fill in
mechanical behaviour during percutaneous ver-
tebroplasty. Spine,28, 1549–1554.
Molloy, S., Riley, L.H. 3rd & Belkoff, S.M. (2005)
Effect of cement volume and placement on
mechanical-property restoration resulting from
vertebroplasty. American Journal of Neuroradiol-
ogy,26, 401–404.
Morgan, G.J., Child, J.A., Gregory, W.M., Szubert,
A.J., Cocks, K., Bell, S.E., Navarro-Coy, N., Dray-
son, M.T., Owen, R.G., Feyler, S., Ashcroft, A.J.,
Ross, F.M., Byrne, J., Roddie, H., Rudin, C.,
Cook, G., Jackson, G.H., Wu, P. & Davies, F.E;
National Cancer research Institute Haematologi-
cal Oncology Clinical Studies Group. (2011)
Effects of zoledronic acid versus clodronic acid
on skeletal morbidity in patients with newly diag-
nosed multiple myeloma (MRC Myeloma IX):
secondary outcomes from a randomised con-
trolled trial. Lancet Oncology,12, 743–753.
Moulopoulos, L.A. & Dimopoulos, M.A. (1997)
Magnetic resonance imaging of the bone mar-
row in hematologic malignancies. Blood,90,
2127–2147.
Moulopoulos, L.A., Dimopoulos, M.A., Vourtsi,
A., Gouliamos, A. & Vlahos, L. (1999) Bone
lesions with soft tissue mass: magnetic resonance
imaging dianosis of lymphomatous involvement
of the bone marrow versus multiple myeloma
and bone metastases. Leukemia Lymphoma,34,
179–184.
Patchell, R.A., Tibbs, P.A., Regine, W.F., Payne, R.,
Saris, S., Kryscio, R.J., Mohiuddin, M. & Young,
B. (2005) Direct decompressive surgical resec-
tion treatment of spinal cord compression
caused by metastatic cancer: a randomised trial.
Lancet,366, 643–648.
Rades, D., Karstens, J.H., Hoskin, P.J., Rudat, V.,
Veninga, T., Schild, S.E. & Dunst, J. (2007)
Escalation of radiation dose beyong 30 Gy in 10
fractions for metastatic spinal cord compression.
International Journal of Radiation Oncology Biol-
ogy Physics,67, 525–531.
Roodman, G.D. (2009) Pathogenesis of myeloma
bone disease. Leukemia,23, 435–441.
Saad, F., Lipton, A., Cook, R., Chen, Y.M., Smith,
M. & Coleman, R. (2007) Pathological fractures
correlate with reduced survival in patients with
malignant bone disease. Cancer,110, 1860–1867.
Scherer, A., Wittsack, H.J., Strupp, C., Gatter-
mann, N., Haas, R. & Modder, U. (2002) Vert-
erbral fractures in multiple myeloma; first
results of assessment of fracture risk using
dynamic contrast-enhanced magnetic resonance
imaging. Annals of Hematology,81, 517–521.
Schmidt, M.H., Fourney, D.R. & Gokaslan, Z.L.
(2004) Metastatic spine disease. Neurosurgery
Clinic of North America,15, xv–xvi.
Schulze, M., Weisel, K., Grandjean, C., Oehrlein,
K., Zago, M., Spira, D. & Horger, M. (2014)
Increasing bone sclerosis during bortezomib
therapy in multiple myeloma patients: results of
a reduced-dose whole-body MDCT study. Amer-
ican Journal of Roenterogenology,202, 170–179.
Sezer, O. (2009) Myeloma bone disease: recent
advances in biology, diagnosis and treatment.
Oncologist,14, 276–283.
Silverman, S.L. (1992) The clinical consequences of
vertebral compression fracture. Bone,13(Suppl
2), S27–S31.
Sloot, S., Boland, J., Snowden, J.A., Ezaydi, Y.,
Foster, A., Gethin, A., Green, T., Chopra, L.,
Verhagen, S., Vissers, K., Engels, Y. & Ahmedzai,
S.H. (2015) Side-effects of analgesia may signifi-
cantly reduce quality of life in symptomatic
multiple myeloma: a cross-sectional prevelance
study. Supportive Care in Cancer,23, 671–678.
Snowden, J.A., Ahmedzai, S.M., Aschroft, J., D’Sa,
S., Littlewood, T., Low, E., Lucraft, H., Maclean,
R., Feyler, S., Pratt, G. & Bird, J.M; Haemato-
oncology Task Force of British Committee for
Standards in Haematology and UK Myeloma
Forum. (2011) Guidelines for supportive care in
multiple myeloma 2011. British Journal of Hae-
matology,154, 76–103.
Sobol, U. & Stiff, P. (2014) Neurological aspects of
plasma cell disorders. Handbook of Clinical Neu-
rology,120, 1083–1099.
Terpos, E. (2010) Bortezomib upregulates [cor-
rected] the osterix expression by osteoblasts in
the myeloma microenvironment: implications
into osteoblast function in myeloma bone dis-
ease. Leukemia Research,34, 700–701.
Terpos, E., Moulopoulos, L.A. & Dimopoulos,
M.A. (2011) Advances in imaging and the man-
agement of myeloma bone disease. Journal of
Clinical Oncology,29, 1907–1915.
Touzeau, C. & Moreau, P. (2013) Multiple mye-
loma imaging. Diagnostic and Interventional
Imaging,94, 190–192.
Valesin Filho, E.S., de Abreu, L.C., Lima, G.H., de
Cubero, D.I., Ueno, F.H., Figueiredo, G.S., Val-
enti, V.E., Monteiro, C.B., Wajnsztejn, R., Fujiki,
E.N., Neto, M.R. & Rodrigues, L.M. (2013) Pain
and quality of life in patients undergoing radio-
therapy for spinal metatstaic disease treatment.
International Archives of Medicine,18, 6.
Walker, R., Barlogie, B., Haessler, J., Tricot, G.,
Anaissie, E., Shagnessy, Jr, J.D.., Epstein, J., van
Hemert, R., Erdem, E., Hoering, A., Crowley, J.,
Ferris, E., Hollmig, K., van Rhee, F., Zangari,
M., Pineda-Roman, M., Mohiuddin, A., Yac-
coby, S., Sawyer, J & Angtuaco, E.J. (2007) Mag-
netic resonance imaging in multiple myeloma:
ª2015 John Wiley & Sons Ltd, British Journal of Haematology 11
Optimising the management of patients with spinal myeloma disease
diagnostic and clinical implications. Journal of
Clinical Oncology,25, 1121–1128.
Wallington, M., Mendis, S., Premawardhana, U.,
Sanders, P. & Shahsavar-Haghighi, K. (1997)
Local control and survival in spinal cord com-
pression from lymphoma and myeloma. Radio-
therapy & Oncology,42, 43–47.
Wardlaw, D., Van Meirhaeghe, J., Ranstam, J.,
Bastian, L. & Boonen, S. (2012) Balloon kyp-
hoplasty in patients with osteoporotic vertebral
compression fractures. Expert Review of Medical
Devices,9, 423–436.
Wilson, D., Owen, S. & Corkill, R. (2011) Facet
joint injections as a means of reducing the need
for vertebroplasty in insuffiency fractures of the
spine. European Radiology,8, 1772–1778.
Winterbottom, A.P. & Shaw, A.S. (2009) Imaging
patients with myeloma. Clinical Radiology,64,
1–11.
Wood, S.L. & Brown, J.E. (2012) Skeletal metasta-
sis in renal cell carcinoma: current and future
management options. Cancer Treatment Reviews,
38, 284–291.
Zamagni, E. & Cavo, M. (2012) The role of imag-
ing techniques in the management of multiple
myeloma. British Journal of Haematology,159,
499–513.
12 ª2015 John Wiley & Sons Ltd, British Journal of Haematology
S. Molloy et al
