Leukemia (2009), 1­15
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REVIEW
International Myeloma Working Group guidelines for the management of multiple
myeloma patients ineligible for standard high-dose chemotherapy with autologous stem
cell transplantation
A Palumbo1, O Sezer2, R Kyle3, JS Miguel4, RZ Orlowski5, P Moreau6, R Niesvizky7, G Morgan8, R Comenzo9, P Sonneveld10,
S Kumar3, R Hajek11, S Giralt5, S Bringhen1, KC Anderson12, PG Richardson12, M Cavo13, F Davies8, J Blade´14, H Einsele15,
MA Dimopoulos16, A Spencer17, A Dispenzieri3, T Reiman18, K Shimizu19, JH Lee20, M Attal21,22, M Boccadoro1, M Mateos4,
W Chen23,24, H Ludwig25, D Joshua26, J Chim27, V Hungria28, I Turesson29, BGM Durie30 and S Lonial31 on behalf of
the IMWGn
1Divisione di Ematologia dell'Universita` di Torino, Azienda Ospedaliera S. Giovanni Battista, Ospedale Molinette, Torino, Italy;
2Department of Hematology/Oncology, Charite´­Universitaetsmedizin Berlin, Germany; 3Division of Hematology, Mayo Clinic,
Rochester, Minnesota, USA; 4Servicio de Hematologi´a, Hospital Universitario de Salamanca. CIC, IBMCC (USAL-CSIC),
Salamanca, Spain; 5Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas,
USA; 6Department of Clinical Hematology, University Hospital, Nantes, France; 7Center for Lymphoma and Myeloma, Weill
Medical College of Cornell University, New York, New York, USA; 8Institute of Cancer Research, Royal Marsden Hospital,
London, UK; 9Blood Bank and Stem Cell Processing Laboratory, Tufts Medical Center, Boston, Massachusetts, USA;
10Erasmus MC, Department of Hematology, Rotterdam, the Netherlands; 11Department of Internal Medicine, University Hospital
Brno, Brno, Czech Republic; 12Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts,
USA; 13Institute of Hematology and Medical Oncology, Seragnoli, Bologna, Italy; 14Department of Hematology, Hospital Clinic,
Barcelona, Spain; 15Universita¨tsklinik Wu¨rzburg, Medizinische Klinik und Poliklinik II, Wurzburg, Germany; 16Department of
Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; 17Department of Haematology, The Alfred
Hospital, Melbourne, Australia; 18Department of Medicine, Cross Cancer Institute, Alberta, Canada; 19Department of Internal
Medicine, Nagoya City Midori General Hospital, Nagoya, Japan; 20Division of Hematology-Oncology, Gachon University Gil
Hospital, Incheon, Republic of Korea; 21Department of Hematology, Service d'He´matologie, Ho^pital Purpan, Toulouse,
France; 22Department of Biostatistics, Service d'He´matologie, Ho^pital Purpan, Toulouse, France; 23Department of
Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; 24Department of Oncology, Beijing
Chaoyang Hospital, Capital Medical University, Beijing, China; 25First Medical Department and Medical Oncology,
Wilhelminenspital, Vienna, Austria; 26Institute of Hematology, Royal Prince Alfred Hospital, Bosch University of Sydney,
Camperdown, New South Wales, Australia; 27Department of Medicine, Queen Mary Hospital, Hong Kong, China; 28Department
of Hematology, Clinica Sa~o Germano, Sa~o Paolo, Brazil; 29Department of Hematology/Medicine, Malmo¨ University Hospital,
Malmo¨, Sweden; 30Aptium Oncology Inc., Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive
Cancer Institute, Los Angeles, California, USA and 31Department of Hematology, Emory University, Atlanta, Georgia, USA
In 2005, the first guidelines were published on the management
Working Group of the UK Myeloma Forum (UKMF) on behalf of
of patients with multiple myeloma (MM). An expert panel
the British Committee for Standards in Haematology (BCSH) and
reviewed the currently available literature as the basis for a
by the Nordic Myeloma Study Group (NMSG).1 Here an expert
set of revised and updated consensus guidelines for the
diagnosis and management of patients with MM who are not
panel presents the revised and updated guidelines based upon a
eligible for autologous stem cell transplantation. Here we
review of current available literature. These guidelines include
present recommendations on the diagnosis, treatment of newly
new developments in disease classification and staging, as well
diagnosed non-transplant-eligible patients and the manage-
as incorporating new therapeutic agents such as thalidomide,
ment of complications occurring during induction therapy
bortezomib and lenalidomide. The following are sections of the
among these patients. These guidelines will aid the physician
guidelines: (1) methodology, (2) epidemiology, (3) facilities, (4)
in daily clinical practice and will ensure optimal care for
patients with MM.
diagnosis, (5) monitoring and start of therapy, (6) staging and
Leukemia advance online publication, 4 June 2009;
prognostic factors, (7) response criteria, (8) treatment strategy
doi:10.1038/leu.2009.122
(dose and age), (9) front-line therapy, phase II grade A
Keywords: myeloma; guidelines; treatment; chemotherapy
recommendation level Ia evidence, (10) front-line therapy,
phase II, grade B recommendations, level IIa evidence, (11)
reduced-intensity transplant, (12) maintenance, (13) relapse III,
phase III, grade A recommendation, level Ia evidence, (14)
Introduction
relapse II, phase II, grade B recommendations, level IIa
evidence, (15) treatment strategy, (16) palliative care and (17)
In 2005, the first guidelines for the diagnosis and management of
complications.
multiple myeloma (MM) were published by the Guidelines
Correspondence: Dr A Palumbo, Divisione di Ematologia dell'Uni-
Methodology
versita` di Torino, Azienda Ospedaliera S. Giovanni Battista, Ospedale
Molinette, Via Genova 3, Torino 10126, Italy.
Expert panel
E-mail: appalumbo@yahoo.com
nSee Appendix.
The 2008 Update Committee of the International Myeloma
Received 8 April 2009; accepted 14 April 2009
Working Group (IMWG) consisted of a panel of experts in
International Myeloma Working Group guidelines
A Palumbo et al
2
clinical medicine, clinical research, health services and related
11 190 cases in men and 8730 cases in women, and 10 690
disciplines (biostatistics, medical decision-making, patient­
deaths.2 The median age of myeloma patients at diagnosis is 69
physician communication), and a patient representative. The
years for men and 72 years for women.3
committee members are listed in Appendix A1. The panel
reviewed the evidence relating to each clinical question and
Facilities
made writing assignments for each of the respective sections.
Additional work on the guideline was completed through
A consultant haematologist or oncologist should lead the care of
teleconferences and electronic mail. Each panel member
patients with MM. However, owing to the existence of a range
participated in the preparation of the draft guideline, which
of complications that are likely to occur during the course of
was then disseminated for review by the entire panel.
the disease (for example, bone disease, renal failure, haemato-
logical toxicity, deep vein thrombosis (DVT), infections and
peripheral neuropathy), input from other professionals who
Literature and analysis
specialize in these areas is required to provide effective and
The electronic databases, MEDLINE, preMEDLINE and the
high-quality care to the patient (Table 2). It is important to
Cochrane Collaboration Library, were searched from December
maintain good communication between the general practi-
2004 to December 2008. Congress abstracts from the American
tioner, the haematology team and other teams involved in caring
Society of Hematology (ASH) annual meetings were also
for the patient throughout the course of the disease. In addition,
searched from 2006 to 2008. Articles/abstracts were included
the ability to give appropriate clinical care is related to the
in this systematic review if they met the following criteria: (1)
number of patients seen by a physician on a monthly basis.
evidence-based practice guidelines addressing diagnosis and
management of myeloma, or (2) randomized controlled trials
(RCTs) or meta-analyses that (a) compared standard chemo-
Recommendation
therapy versus experimental new drugs in newly diagnosed and
It is recommended to develop a specific clinical unit devoted to
relapsed-refractory patients with MM, (b) reported overall
treatment of MM, and establish clear policies and protocols for
survival (OS) or disease-free survival as a main outcome, and
access to specific therapies and supportive services. A minimum
(c) were published in peer-reviewed journals or reported in a
conference abstract. Articles published in a language other than
English were excluded. Detailed chemotherapy protocols and
Table 2
Required expertise and services for management of
dosages were not included as they are beyond the scope of this
patients with MM
document.
Diagnostic
Diagnostic haematology and haematopathology
services
Clinical biochemistry and immunology
Recommendations
Diagnostic radiology
Specialist
Renal services, including rapid access to haemodialysis
Questions regarding diagnosis, staging, front-line therapy and
services
Clinical oncology/radiotherapy
salvage therapy will be addressed by summarizing the available
Orthopaedic surgery
data followed by the recommendations of the panel. The levels
Neurosurgery
of evidence and grades of recommendation are summarized in
Accredited bone marrow/stem cell transplant centre
Table 1.
Support
Haematology/oncology nurse specialists
services
Palliative care physicians/nurses
Pharmacy with expertise and facilities for dispensing
cytotoxic drugs
Epidemiology
Physiotherapy/rehabilitation
Administration support for case registration, audit and
Multiple myeloma is a malignant neoplasm of plasma cells that
clinical trials
accumulate in bone marrow, leading to bone destruction and
Patient information including information available
marrow failure. It was estimated that MM would account for
social services and financial advise
Patient support group
19 920 new cancer cases in the United States in 2008, including
Table 1
Levels of evidence and grades of recommendation
Evidence
Source of evidence
Recommendation
Basis for recommendation
level
grade
Ia
Meta-analysis of randomized controlled trials
A
At least one randomized controlled trial of good
quality and consistency in addressing specific
recommendation
Ib
At least one randomized controlled trial
IIa
At least one well-designed, non-randomized study,
B
Well-conducted studies but no randomized
including phase II trials and case­control studies
controlled trials on the topic of the recommendation
IIb
At least one other type of well-designed, quasi-
experimental study, that is, studies without planned
intervention, including observational studies
III
Well-designed, non-experimental description studies.
Meta-analyses of randomized controlled trials or phase II
studies which are published only in abstract form
IV
Expert committee reports or opinions and/or clinical
C
Expert committee reports and/or clinical experience
experience of respected authorities
of respected authorities
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International Myeloma Working Group guidelines
A Palumbo et al
3
of two newly diagnosed patients per month should receive
Complete blood count with differential and peripheral blood
induction therapy to ensure appropriate skill and experience of
smear review
the health personnel.
Chemistry panel including calcium and creatinine
Serum protein electrophoresis, immunofixation
Nephelometric quantitation of immunoglobulins
Routine urinalysis, 24 h urine collection for proteinuria,
Diagnosis
electrophoresis and immunofixation
Quantification of both urine M-component level and
There is no change from the original guidelines, as no relevant
albuminuria
additional data have been published. The aim is to identify
patients with active or symptomatic MM who require systemic
3. Bone Marrow Testing: Obtain an aspirate plus trephine biopsy
therapy, and to exclude patients with monoclonal gammopathy
with testing for cytogenetics, fluorescent in situ hybridization
of undetermined significance (MGUS), smouldering or indolent
(FISH) and immunophenotyping.
myeloma, and solitary plasmacytoma (Table 3).4 It remains
important to demonstrate the presence of `myeloma-related
4. Imaging
organ dysfunction' or CRAB features (C ¼ calcium (elevated),
Bone survey including spine, pelvis, skull, humeri and femurs.
R ¼ renal failure, A ¼ anaemia, B ¼ bone lesions), which may
Magnetic resonance imaging of the axial skeleton is very
require biopsy and/or other specialized testing.
informative if available/feasible, but is not mandatory.
Whole-body fluorodeoxyglucose/positron emission tomo-
graphy imaging is also not mandatory, but can be used to
Recommendation
confirm MGUS (positron emission tomography negative)
The recommended tests for the diagnosis of myeloma and
or exclude unsuspected and/or extramedullary myeloma
related organ dysfunctions are listed below. Most of these tests
(positron emission tomography positive), infection and/or an
are well established and widely accepted.
associated second malignancy. Positron emission tomo-
1. History and Physical Examination
graphy imaging was recently approved by CMS/Medicare
2. Routine Testing
(United States) for use in myeloma.
Table 3
Diagnostic criteria
Diagnosis
Diagnostic criteria: all three required
Symptomatic multiple myelomaa
Monoclonal plasma cells in the bone marrow X10% and/or presence of a biopsy-proven plasmacytoma
Monoclonal protein present in the serum and/or urineb
Myeloma-related organ dysfunction (X1)c
[C] Calcium elevation in the blood (serum calcium 410.5 mg/l or upper limit of normal
[R] Renal insufficiency (serum creatinine 42 mg per 100 ml)
[A] Anaemia (haemoglobin o10 g per 100 ml or 2 gonormal)
[B] Lytic bone lesions or osteoporosisd
Monoclonal gammopathy of
Serum monoclonal protein lowe
undetermined significance (MGUS)
Monoclonal bone marrow plasma cells o10%
No evidence of end-organ damage attributable to the clonal plasma cell disorder:
Normal serum calcium, haemoglobin level and serum creatinine
No bone lesions on full skeletal X-ray survey and/or other imaging if performed
No clinical or laboratory features of amyloidosis or light chain deposition disease
Smouldering or indolent myelomaf
Monoclonal protein present in the serum 3 g per 100 ml or higher or
Monoclonal plasma cells 10% or greater present in the bone marrow and/or a tissue biopsy
No evidence of end-organ damage attributable to the clonal plasma cell disorder:
Normal serum calcium, haemoglobin level and serum creatinine
No bone lesions on full skeletal X-ray survey and/or other imaging if performed
No clinical or laboratory features of amyloidosis or light chain deposition disease
Solitary plasmacytoma of bone
Biopsy-proven plasmacytoma of bone in a single site only. X-rays and magnetic resonance imaging and/or
FDG PET imaging (if performed) must be negative outside the primary site. The primary lesion may be
associated with a low serum and/or urine M-component
The bone marrow contains no monoclonal plasma cells
No other myeloma-related organ dysfunction
Adapted with permission from Kyle and Rajkumar.73
aThese criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA becomes smouldering or indolent myeloma.
bIf no monoclonal protein is detected (non-secretory disease), then X30% monoclonal bone marrow plasma cells and/or a biopsy-proven
plasmacytoma required.
cA variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support
classifications myeloma if proven to be myeloma related.
dIf a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) is the sole defining criteria, then X30% plasma cells are
required in the bone marrow.
eLow is defined as serum M protein o3.0 g per 100 ml.
fThese criteria identify Stage IA myeloma by Durie/Salmon stage.
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International Myeloma Working Group guidelines
A Palumbo et al
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The recent IMWG imaging guidelines provide a full summary
Recommendation
of current overall recommendations.5
Cytogenetics and/or FISH should be performed in all newly
diagnosed MM patients as well as subsequently at the time of
5. Ancillary Testing
relapse, as patients may develop new chromosomal abnormal-
ities at the time of progression. Although treatment regimens,
b2-Microglobulin, C-reactive protein and lactate dehydro-
which include bortezomib and/or lenalidomide, may overcome
genase
poor prognosis, no specific alternate therapy is routinely
Measurement of free light chains in serum is very important if
recommended for patients with abnormal chromosomes. Risk
conventional M-component quantitation is negative or
stratification on the basis of cytogenetics or FISH warrants
equivocal, that is, in patients with non-secretory or oligose-
confirmation from further studies with large numbers of patients.
cretory myeloma, as well as in light chain myeloma. The
recommendations for use of free light chain testing have
recently been published.6
Response criteria
The response to therapy is a key determinant of myeloma
Monitoring and start of therapy
treatment. Table 4 lists two different sets of response criteria,
one developed by the European Group for Bone and Marrow
There is no change from earlier guidelines.1 Systemic anti-
Transplant (EBMT)14 and the other developed by the IMWG.15
myeloma therapy is indicated for initial treatment of sympto-
The IMWG criteria were developed in 2006 and have been
matic myeloma with myeloma-related organ dysfunction.
commonly used by a larger number of physicians and have
However, no benefit from the early intervention has been
substituted for the EBMT criteria. Serum free light chain assays
shown for the treatment of asymptomatic myeloma,7,8 although
are useful for monitoring patients with non-secretory myelo-
it should be noted that there are several ongoing studies
ma,16,17 and have recently been introduced in the definition of
evaluating new agents in the context of asymptomatic MM, and
stringent complete response in the IMWG criteria.
participation in these trials is encouraged.
Recommendation
The IMWG criteria have been validated and we recommend
Recommendation
assessing response according to these criteria.
Monitoring of MM during treatment should be according to the
clinical conditions; for patients in remission, follow-up should
be every 2 months. The criteria for retreatment are the same as
Overall treatment strategy related to age
those used at diagnosis with the exception that retreatment
should be administered in patients without organ damage if the
Patients over 65 years of age are generally not considered to be
M-protein has doubled within less than 2 months.
candidates for transplantation outside the United States. How-
ever, as biological age may differ from chronological age in
elderly patients, it is important to take biological age into
account when determining if a patient is a candidate for
Staging and prognostic factors
transplantation. In addition to the age limit, patients with serious
heart, lung, renal or liver dysfunction should not be considered
On the basis of the results of the clinical and laboratory
for transplantation. With these limitations, it is generally
evaluation discussed earlier, patients are initially classified as
accepted to use 65 years as the age limit for melphalan
either having asymptomatic (smouldering) disease or sympto-
200 mg/m2 followed by autologous stem cell transplantation
matic (active) disease. Those with symptomatic myeloma are
(ASCT). For patients 65­75 years of age, full-dose conventional
then further categorized according to disease stage, based on the
therapy is suggested. For patients over 75 years of age (or
International Staging System (ISS). The ISS developed by the
younger with significant co-morbidities), the dosages of any
IMWG uses serum b2-microglobulin and serum albumin to
therapy should be reduced and a more gentle approach
provide a reproducible three-stage classification system that
considered.
defines three risk groups with median survival of 62 months
(serum b2-microglobulin o3.5 mg/l and serum albumin 43.5 g/l),
44 months (serum b2-microglobulin 43.5 mg/l and serum
Recommendation
albumin o3.5 g/l or serum b2-microglobulin 3.5­5.5 mg/l) and
Patients younger than 65 years should be considered candidates
29 months (serum b2-microglobulin 45.5 mg/l).9 Further
for induction therapy followed by ASCT. Patients aged 65­70 or
factors, such as serum free light chain ratio or the bone resorption
younger with significant co-morbidities may be considered for
marker ICTP, incorporated into the ISS may improve the risk
reduced-dose intensity autologous transplantation. In patients
stratification.10,11
65­75 years of age full-dose conventional therapy should be
Cytogenetics and FISH can be used to detect chromosomal
considered. In patients older than 75 years or younger with
abnormalities. In MM patients, any chromosomal abnormality is
co-morbidities, the dosages of therapy should be reduced
associated with poorer outcomes compared with normal
accordingly.18
karyotype. Among FISH-based abnormalities, patients with
isolated del 13 do not have a less favourable outcome, although
del 13 associated with 17p deletion or t(4:14) are associated
Front-line therapy, phase III, grade A recommendation, level
with poorer outcomes. By FISH, t(4;14) or t(14:16) is associated
Ia evidence
with poorer outcome; t(11:14) does not have negative
outcome; hypderdiploidy is associated with more favourable
Phase III studies in newly diagnosed patients are summarized in
outcome.12,13
Table 5. Thalidomide in combination with dexamethasone (TD)
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Table 4
Response criteria
Response
EBMT criteria
IMWG criteria
sCR
NA
CR as defined below plus normal FLC ratio and absence
of clonal cells in bone marrowa by immunohistochemistry
or immunofluorescenceb
CR
No M-protein detected in serum or urine by
Negative immunofixation on the serum and urine and
immunofixation for a minimum of 6 weeks and
disappearance of any soft tissue plasmacytomas and
fewer than 5% plasma cells in the bone marrow;
o5% plasma cells in bone marrowa
No increase in size or number of lytic bone lesions;
Disappearance of soft tissue plasmacytomas
VGPR
NA
Serum and urine M-protein detectable by immuno-
fixation but not on electrophoresis or X90% reduction
in serum M-protein plus urine M-protein level
o100 mg/24 h
PR
450% reduction in serum M-protein level and/or X90%
X50% reduction of serum M-protein and reduction in 24 h
reduction in urine free light chain excretion or reduction
urinary M-protein by X90% or to o200 mg/24 h
to o200 mg/24 h for 6 weeksc
If the serum and urine M-protein are unmeasurable,d
a X50% decrease in the difference between involved
and uninvolved FLC levels is required in place of the
M-protein criteria
If serum and urine M-protein are not measurable, and
serum free light assay is also not measureable, X50%
reduction in plasma cells is required in place of M-protein,
provided baseline bone marrow plasma cell percentage
was X30%
In addition to the above listed criteria, if present at
baseline, a X50% reduction in the size of soft tissue
plasmacytomas is also required
MR
25­49% reduction in serum M-protein level and/or
NA
50­89% reduction in urine for light chain excretion,
which still exceeds 200 mg/24 h for X6 weeksc
No change/stable
Not meeting the criteria of either minimal response
Not meeting criteria for CR, VGPR, PR or progressive
disease
or progressive disease
disease
Plateau
No evidence of continuing myeloma-related organ
NA
or tissue damage o25% change M-protein levels
and light chain excretion for 3 months
Progressive diseased
Myeloma-related organ or tissue damage continuing
Increase of X25% from lowest response value in any one
despite therapy or its reappearance in plateau phase
or more of the following:
425% increase in serum M-protein level (45 g/l) and/or
Serum M-component and/or (the absolute increase
425% increase in urine M-protein level (4200 mg/24 h)
must be X0.5 g per 100 ml)f
and/or 425% increase in bone marrow plasma cells
Urine M-component and/or (the absolute increase must
(at least 10% in absolute terms)e
be X200 mg/24 h)
Only in patients without measurable serum and urine
M-protein levels; the difference between involved and
uninvolved FLC levels. The absolute increase must be
410 mg per 100 ml
Bone marrow plasma cell percentage; the absolute
percentage must be X10%g
Definite development of new bone lesions or soft tissue
plasmacytomas or definite increase in the size of
existing bone lesions or soft tissue plasmacytomas
Development of hypercalcaemia (corrected serum
calcium 411.5 mg per 100 ml or 2.65 mmol/l) that can
be attributed solely to the plasma cell proliferative
disorder
Relapse
Reappearance of disease in patients previously in
Clinical relapse requires one or more of:
CR, including detection of paraprotein by
Direct indicators of increasing disease and/or end organ
immunofixation
dysfunction (CRAB features).f It is not used in
calculation of time to progression or progression-free
survival but is listed here as something that can be
reported optionally or for use in clinical practice
1. Development of new soft tissue plasmacytomas or bone
lesions
2. Definite increase in the size of existing plasmacytomas
or bone lesions. A definite increase is defined as a 50%
(and at least 1 cm) increase as measured serially by the
sum of the products of the cross-diameters of the
measurable lesion
3. Hypercalcemia (411.5 mg per 100 ml) (2.65 mmol/l)
4. Decrease in haemoglobin of X2 g per 100 ml
(1.25 mmol/l)
5. Rise in serum creatinine by 2 mg per 100 ml or more
(177 mmol/l or more)
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Table 4 (Continued )
Response
EBMT criteria
IMWG criteria
Relapse from CRd
Any one or more of the following:
Any one or more of the following:
(To be used only if
Reappearance of serum or urine M-protein by
Reappearance of serum or urine M-protein by
the end point studied
immunofixation or electrophoresis
immunofixation or electrophoresis
is DFS)h
Development of X5% plasma cells in the bone
Development of X5% plasma cells in the bone marrowg
marrowg
Appearance of any other sign of progression (that is,
Appearance of any other sign of progression
new plasmacytoma, lytic bone lesion or
(that is, new plasmacytoma, lytic bone lesion
hypercalcaemia)
or hypercalcaemia)
Adapted from Durie et al.15 and Kyle and Rajkumar.73
Note: A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by serum FLC levels: CR in such
patients is defined as a normal FLC ratio of 0.26­1.65 in addition to CR criteria listed above. VGPR in such patients is defined as a 490% decrease
in the difference between involved and uninvolved free light chain (FLC) levels.
aConfirmation with repeat bone marrow biopsy not needed.
bPresence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by immunohistochemistry and/or immunofluorescence
requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting the presence of an abnormal clone is k/l of 44:1 or o1:2.
cFor patients with non-secretory myeloma only, reduction of plasma cells in the bone marrow by 450% of initial number (partial response) or
25­49% of initial number (minimal response) is required.
dAll relapse categories require two consecutive assessments made at anytime before classification as relapse or disease progression and/or the
institution of any new therapy. In the IMWG criteria, CR patients must also meet the criteria for progressive disease shown here to be classified as
progressive disease for the purposes of calculating time to progression and progression-free survival. The definitions of relapse, clinical relapse and
relapse from CR are not to be used in calculation of time to progression or progression-free survival.
eIn non-secretory myeloma, bone marrow plasma cells should increase by 425% and at least 10% in absolute terms; MRI examination may be
helpful in selected patients.
fFor progressive disease, serum M-component increases of X1 g per 100 ml are sufficient to define relapse if starting M-component is X5 g per
100 ml.
gRelapse from CR has the 5% cutoff versus 10% for other categories of relapse.
hFor purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated using criteria listed above for
progressive disease.
Table 5
Phase III studies in newly diagnosed MM
Regimen
N
ORR (CR), %
Median PFS, months
Median TTP, months
Median survival, months
TD vs D (Rajkumar et al.20
470
63 (7.7) vs 46 (2.6)
14.9 vs 6.5
22.6 vs 6.5
TD vs MP (Ludwig et al.18)
289
68 (2) vs 50 (2)
16.7 vs 20.7
21.2 vs 29.1
41.5 vs 49.4
RD vs D (Zonder et al.21)
198
79.4 (22) vs 26.2 (4)a
77 vs 55% @ 1 year
93 vs 91% @ 1 year
RD vs Rd (Rajkumar et al.20)
445
82 (52) vs 70 (42)b
87 vs 75% @ 2 years
MPT vs MP (Palumbo et al.24,25)
255
76 (15.5) vs 47.6 (2.4)
21.8 vs 14.5
45.0 vs 47.6
MPT vs MP (Facon et al.26)
321
76 (13) vs 35 (2)
27.5 vs 17.8
51.6 vs 33.2
MPT vs MP (Hulin et al.27)
232
62 (7) vs 31 (1)
24.1 vs 19
45.3 vs 27.6
MPT vs MP (Gulbrandsen et al.23)
357
42 (6) vs 28 (3)
16 vs 14
20 vs 18
29 vs 33
VMP vs MP (San Miguel et al.29)
682
71(30) vs 35(4)
24 vs 17
83 vs 78% @ 16 months
VMP vs VPT (Mateos et al.30)
246
78 (18) vs 78 (23)
VMPT vs VMP (Palumbo et al.31)
393
55 (31) vs 42 (16)c
83.9 vs 75.7% @ 2 years
89.5 vs 88.7% @ 3 years
MPT vs MP (Wijermans et al.28)
344
66 (2) vs 47% (2)
14 vs 10
37 vs 30
Abbreviations: CR, complete remission; MM, multiple myeloma; MP, melphalan and prednisone; MPT, MP plus thalidomide; ORR, overall response
rate (at least partial remission); PFS, progression-free survival; RD, lenalidomide and high-dose dexamethasone; Rd, lenalidomide and low-dose
dexamethasone; TD, thalidomide and high-dose dexamethasone; TTP, time to progression; VGPR, very good partial response; VMP, MP plus
bortezomib; VMPT, VMP plus thalidomide; VPT, bortezomib, prednisone, thalidomide.
aPercentages reported for ORR include minor response.
bPercentages reported for CR include VGPR.
cPercentages reported for ORR are at least VGPR.
showed clear benefit in overall response rate (ORR) compared
(Rd) showed further benefit in terms of OS compared with
with high-dose dexamethasone alone or melphalan­prednisone
RD.20­22 In addition, the reduction of the dexamethasone dose
(MP).18,19 In addition, TD resulted in a benefit in time to
in the Rd regimen also resulted in a reduction of adverse events
progression compared with high-dose dexamethasone, whereas
compared with RD.20
compared with MP there was no significant difference.18 The
Five randomized studies have compared the combination of
incidence of grade 3 or 4 adverse events was higher with TD,
thalidomide and MP (MPT) to MP in elderly patients with newly
and OS was inferior compared with MP.
diagnosed MM. These studies consistently reported that MPT
Lenalidomide plus dexamethasone (RD) resulted in a higher
resulted in higher ORR (42­76 vs 28­48%), higher at least very
complete response (CR) rate and 1-year progression-free survival
good partial response (VGPR)/near-CR (nCR) (15­47 vs 6­8%),23
(PFS) compared with high-dose dexamethasone alone, and the
and longer PFS (13­27.5 vs 10­19 months).23­28 However, only
combination of lenalidomide plus low-dose dexamethasone
two studies demonstrated improved OS with MPT (45.3­51.6 vs
Leukemia
International Myeloma Working Group guidelines
A Palumbo et al
7
27.7­32.2 months)26­27 and two studies reported similar OS with
Front-line therapy, phase II, grade B recommendation, level
MPT (33­47.6 months) and MP (29­45 months).23,25 The data
IIa evidence
strongly support the use of MPT as the standard of care for elderly
myeloma patients. In all studies the MPT regimen was associated
The combination of melphalan, prednisone and lenalidomide
with a significantly higher incidence of grade 3 or 4 non-
(MPR) at the maximum tolerated dose (0.18 mg/kg melphalan,
haematological adverse events, including neurological adverse
2 mg/kg prednisone and 10 mg lenalidomide) achieved an ORR
events, infections, cardiac toxicity and thromboembolism. There-
of 81%, at least VGPR of 47.6%, median time to progression
fore, antithrombotic prophylaxis is recommended when using
and PFS of 28.5 months, and 2-year OS of 90.5%.32 Myelo-
MPT. The dosage of thalidomide needs to be modified based
suppression, including grade 3 or 4 neutropenia in 52.4% of
on the tolerance in the elderly to minimize toxicity. In patients
patients, was the main adverse event. Grade 3 or 4 non-
475 years of age, the recommended dose is 100 mg per day.
haematological adverse effects were less frequent and included
The bortezomib plus MP (VMP) regimen resulted in significant
febrile neutropenia (9.5%), skin rash (9.5%) and thromboembo-
improvement in ORR, time to progression and OS compared
lism (4.8%). Similar results were obtained from another phase
with MP.29 The incidence of peripheral neuropathy, gastro-
I/II study, which reported an ORR of 69%, at least VGPR rate of
intestinal complications and herpes zoster infection was
31%, median PFS of 16.7 months and median OS of 23 months
higher with VMP. When comparing the VMP regimen with the
following MPR treatment.33 This combination is currently being
bortezomib, thalidomide and prednisone (VTP) regimen, there
validated in a randomized phase III trial comparing MPR with
were no significant differences in ORR, but VMP had less non-
and accepted standard MPT.
haematologic adverse events than VTP.30 The thalidomide plus
VMP (VMPT) regimen did result in higher VGPR and CR rates
than the VMP regimen, although longer follow-up is needed to
Recommendation
assess their effects on PFS and OS.31 The incidence of the most
Although showing interesting results, the MPR regimen needs
common adverse events (neutropenia, thrombocytopenia, per-
validation in a randomized study, before it can be recom-
ipheral neuropathy and infections was similar between the
mended in clinical practice for the induction of elderly patients
thalidomide plus VMP and VMP regimens. When weekly
with newly diagnosed MM.
infusions of bortezomib were used in the thalidomide plus
VMP schema, the incidence of grade 3­4 peripheral neuropathy
was reduced in comparison with the standard biweekly infusion
without influencing outcome.30,31
Reduced intensity autologous transplant
Results of reduced intensity transplantation studies are summar-
Recommendation
ized in Table 6. Patients over 65 years of age are not generally
In five randomized studies, MPT has shown consistent
considered to be eligible for melphalan 200 mg/m2 followed
improvement in PFS (and/or time to progression) but incon-
by ASCT. Two randomized studies compared intermediate
sistent OS advantage. MPT is considered a standard of care
dose melphalan (100 mg/m2) and reduced intensity ASCT with
for patients 465 years. In one randomized trial, VMP showed
MP. In patients aged 65­70 years, ASCT was superior to
both PFS and OS improvement. VMP is another standard of
MP.34 However, in patients aged 65­75 years, response rates
care for elderly patients. In the VMP regimen, weekly infusion
were superior with ASCT, but there was no difference in PFS or
of bortezomib significantly reduces the incidence of PN and
OS compared with MP.26
should be considered in patients with pre-existing PN.
The efficacy of bortezomib, pegylated liposomal doxorubicin
Although TD was superior to dexamethasone in the older
and dexamethasone (PAD) induction therapy before reduced
patient population, as defined by improved PFS, it is associated
intensity ASCT, followed by consolidation with lenalidomide
with inferior OS compared with MP, and is not recommended as
and prednisone, and maintenance with lenalidomide alone, was
standard therapy in the elderly patient population ineligible for
evaluated in patients aged 65­75 years. Preliminary data from
high-dose therapy and ASCT. Higher doses of thalidomide are
this study reported that the ORR was 94% following PAD and
especially difficult in elderly and frail patients.18 The combina-
100% following consolidation with lenalidomide and pre-
tion of RD demonstrated improvement on PFS compared with
dnisone; at least VGPR rate was 59% (13% CR) following
dexamethasone alone, but Rd was superior to RD, and was
PAD and 88% following consolidation with lenalidomide and
better tolerated. Thus, Rd can be considered a standard of care,
prednisone.35 These data indicate that this is a highly effective
especially in patients who wish to postpone ASCT.
regimen in elderly patients.
Table 6
Reduced intensity transplant studies in newly diagnosed MM
Regimen
N
ORR (CR), %
Median PFS,
Median TTP,
Median survival,
months
months
months
MEL 100+ASCT vs MP (Palumbo et al.34)
194
67 (25) vs 49 (8)a
28 vs 16.4b
58 vs 37.2
MEL 100+ASCT vs MP (Facon et al.26)
322
65 (18) vs 35 (2)
19.4 vs 17.8
38.3 vs 33.2
PAD+tandem MEL 100 ASCT+RP
102
100 (53)
92% at 1 year
97% at 1 year
92% at 1 year
(Palumbo et al.35)
Abbreviations: ASCT, autologous stem cell transplantation; CR, complete remission; MEL, melphalan; MM, multiple myeloma; MP, melphalan and
prednisone; nCR, near-CR; ORR, overall response rate (at least partial remission); PAD, bortezomib, pegylated liposomal doxorubicin and
dexamethasone; PFS, progression-free survival; RP, lenalidomide and prednisone; TTP, time to progression.
aPercentages reported for CR include nCR.
bEvent-free survival.
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8
Recommendation
Thalidomide­dexamethasone combination
Intermediate-dose melphalan followed by ASCT can be used in
Several phase II studies have reported that thalidomide­
patients aged 65­70 years or younger with pre-existing co-
dexamethasone (TD) is effective in patients with relapsed or
morbidities, where full-dose ASCT appears too toxic. The use of
refractory MM.19,34,43 Retrospective studies have reported
bortezomib-based approaches for induction before ASCT is
significant improvement in OS with TD salvage therapy
suggested. Consolidation with lenalidomide, although quite
compared with chemotherapy (patients with 1 earlier therapy)
appealing, needs further validation in randomized trials.
and second ASCT.34 TD is associated with less neurotoxicity,
somnolence and constipation than thalidomide alone, but the
risk of DVT is higher.
Maintenance
Maintenance therapy has the potential to provide new treatment
Bortezomib­dexamethasone combination
options for patients with MM. However, although maintenance
The ORR was 51%, including 11% CR. Dexamethasone was
therapy with thalidomide following ASCT was shown to be
added in 208 patients (33%), of whom 70 (34%) showed
superior to tandem ASCT in terms of PFS and OS at 3 years
improved response.44
in patients younger than 60 years,36 there is currently no
evidence regarding the efficacy of maintenance therapy in
Thalidomide combinations with chemotherapy
elderly patients. Future studies are needed to assess the role
Thalidomide­dexamethasone has been incorporated in several
maintenance therapy with novel agents, such as bortezomib,
chemotherapy regimens, with responses of 75­76% in combi-
thalidomide and lenalidomide.37
nation with doxorubicin45,46 and 57­79% in combination with
cyclophosphamide.47­50 Of note, the combination of thalido-
Recommendation
mide with dexamethasone and doxorubicin can increase the risk
There is insufficient evidence regarding the use of maintenance
of DVT to 25%.46 The use of an intermittent schedule for
therapy in elderly patients.
thalidomide administration resulted in a low cumulative
incidence of DVT and peripheral neuropathy.48
Therapy at relapse, phase III data, grade A recommendation,
Lenalidomide combinations with chemotherapy
level Ia evidence
Lenalidomide has also been evaluated in combination with
conventional chemotherapy. Lenalidomide (maximum tolerated
Phase III studies in relapsed or refractory MM are summarized
dose of 10 mg) in combination with doxorubicin, vincristine and
in Table 7. For patients with relapsed and/or refractory MM,
dexamethasone achieved an ORR of 75% (29% CR/nCR) and a
bortezomib monotherapy is superior to high-dose dexametha-
median PFS of 12 months.51 Lenalidomide (maximum tolerated
sone,38,39 bortezomib in combination with pegylated liposomal
dose of 25 mg) in combination with doxorubicin and dexa-
doxorubicin is superior to bortezomib monotherapy40 and
methasone (RAD) achieved an at least VGPR rate of 74% (21%
lenalidomide plus dexamethasone is superior to high-dose
CR) in the appropriate dose level (5 þ G).52 Lenalidomide in
dexamethasone.41,42
combination with cyclophosphamide and dexamethasone
(RCD) achieved an ORR of 65% (5% CR) in 21 heavily
Recommendation
pretreated patients.53
Bortezomib with or without dexamethasone or in combina-
tion with liposomal doxorubicin is recommended in relapsed/
Bortezomib combinations with chemotherapy
refractory patients
Bortezomib in combination with cyclophosphamide has been
Lenalidomide in combination with dexamethasone is recom-
tested in several phase I/II trials, with ORR of 75­89%.54­56
mended in relapsed/refractory patients
Bortezomib in combination with doxorubicin and low-dose
dexamethasone has been reported; 67% of patients achieved at
least PR 25% with at least VGPR.57
Therapy at relapse, phase II data, grade B recommendation,
level IIa evidence
Combinations of novel agents
Phase II studies in relapsed or refractory MM are summarized in
Bortezomib,
thalidomide
and
dexamethasone
(VTD)
in
Table 8.
heavily pretreated refractory patients (92% had earlier ASCT;
Table 7
Phase III clinical studies in relapsed and/or refractory patients
Regimen
N
ORR (CR), %
Median response
Median TTP,
Median survival, months
duration, months
months
V vs D (Richardson et al.38)
669
38 (6)a vs 18 (0.6)
8.0a vs 5.6
6.2a vs 3.5
80a vs 66% at 1 year
V vs V+PLD (Orlowski et al.40)
646
41 (2) vs 44 (4)
7.0 vs 10.2
6.5 vs 9.3
65 vs 76% at 15 months
RD vs D (Dimopoulos et al.41)
351
60 (16) vs 24 (3)
11.3 vs 4.7
Not reached vs 20.6
RD vs D (Weber et al.42)
353
61 (14) vs 20 (0.6)
11.1 vs 4.7
29.6 vs 20.2
Abbreviations: CR, complete remission; D, dexamethasone; ORR, overall response rate (at least partial remission); RD, lenalidomide and
dexamethasone; TTP, time to progression; V+PLD, bortezomib plus pegylated liposomal doxorubicin; V, bortezomib; VD, bortezomib and
dexamethasone.
aExtended median follow-up of 22 months of the bortezomib arm reported an ORR of 43%, CR of 9%, median response duration of 7.8 months,
median TTP of 6.2 months and median survival of 29.8 months (Richardson et al.39).
Leukemia
International Myeloma Working Group guidelines
A Palumbo et al
9
Table 8
Phase II studies in relapsed or refractory MM
Regimen
N
ORR (CR), %
Median PFS, months
Median TTP, months
Median survival, months
TD (Dimopoulos et al.19)
44
55 (0)
10a
4.2
12.6
TD (Palumbo et al.43)77
41b (3)
12
Not reached
TD vs chemotherapy (Palumbo et al.34)
120
46 vs 42
17 vs 9
19 vs 19
TD+doxorubicin (Offidani et al.45)
50
76 (26)
22
17c
79% at 1 year
DVd-T (Hussein et al.46)
49
75 (20)
15.5
39.9
CTD (Kyriakou et al.47)
52
79 (17)
34% at 2 yearsc
Not reached
73% at 2 years
CTD (Dimopoulos et al.48)
53
60 (5)
8.2
17.5
CTD (Garcia-Sanz et al.49)
71
57 (2)
57% at 2 years
66% at 2 years
CTD (Kropff et al.50)
60
72 (4)
11c
19
DVd-R (Baz et al.51)
62
75 (15)
12
Not reached
CVD vs VD (Davies et al.54)
36
75 (31) vs 47 (5)
7 vs 5
CVD (Kropff et al.55)
54
82 (16)
12c
22
CVP (Reece et al.56)
37
89 (53)d
15
24.3
VTD (Pineda-Roman et al.58)
85
63 (22)e
6% at 4 yearsc
23% at 4 years
VMPT (Palumbo et al.74)
30
67 (17)
61% @at 1 year
84% at 1 year
VMDT (Terpos et al.61)
62
66 (13)
9.3
VTD vs MyVTD (Ciolli et al.62)
70
81 vs 59
15 vs 8
19 vs 11
RVD (Richardson et al.60)
64
67 (24)e
21f
Not reached
Not reached
RCD (Morgan et al.53)
21
65 (5)
5.7
Abbreviations: CR, complete remission; CTD, TD plus cyclophosphamide; CVD, VD plus cyclophosphamide; CVP, cyclophosphamide, bortezomib,
and prednisone; DVd-R, DVd and lenalidomide; DVd-T, pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone and
thalidomide; MM, multiple myeloma; MyVTD, VTD plus myocet; nCR, near-CR; ORR, overall response rate (at least partial remission); PFS,
progression-free survival; RCD, lenalidomide, cyclophosphamide and dexamethasone; RVD, VD plus lenalidomide; TD, thalidomide and
dexamethasone; TTP, time to progression; VD, bortezomib and dexamethasone; VMDT, bortezomib, melphalan, dexamethasone and thalidomide;
VMPT, bortezomib, melphalan, prednisone and thalidomide; VTD, TD plus bortezomib.
aMedian TTP for responders not reached, expected to exceed 10 months.
b450% decline in myeloma protein.
cEvent-free survival
dPatients treated at dose levels 5 and 6 (bortezomib: 1.3 mg/m2 days 1, 4, 8, 11 (level 5) and 1.5 mg/m2 days 1, 8, 15 (level 6); cyclophosphamide:
300 mg/m2 per week; prednisone: 100 mg every 2 days).
ePercentage for CR includes nCR.
fDuration of response.
74% had earlier thalidomide) resulted in an ORR of 63%
(1) For patients who relapse following a durable response (that
(22% nCR).58
is, longer than the median PFS for the previous therapy), the
In a phase I study, the combination of lenalidomide and
same treatment should be repeated.
bortezomib achieved an ORR of 39% (6% CR/nCR). There was no
(2) For patients who relapse following a short response (that is,
significant peripheral neuropathy and only one DVT episode.59 In
shorter than the median PFS for the previous therapy), the
a phase II study that evaluated lenalidomide, bortezomib and
patient should be sequentially introduced to new regimens.
dexamethasone in patients with relapsed/refractory MM and 1­3
(3) Drugs that were used before the rechallenge remain
earlier lines of therapy, the ORR was 67% (24% CR/nCR).60
secondary options if there was no clinical evidence of
Four drug combinations, of bortezomib, melphalan, predni-
progression under that drug.
sone/dexamethasone and thalidomide either daily (thalidomide
(4) The choice of drug depends on pre-existing co-morbidities.
plus VMP)61 or intermittently (VMDT), resulted in an ORR of
66­67%, including at least VGPR in 40­43%. Addition of other
Primary salvage therapy includes bortezomib and dexametha-
agents, such as doxorubicin or liposomal doxorubicin, to the
sone, bortezomib and doxorubicin, or lenalidomide and
backbone of bortezomib/thalidomide also resulted in significant
dexamethasone and is currently recommended for patients with
responses.62
relapsed or refractory MM. Combinations with chemotherapy,
such as doxorubicin or cyclophosphamide, or melphalan, or
immunomodulatory drugs, are alternative, less tested options for
Recommendation
these patients. The choice of combination depends on earlier
Both TD and VD remain convenient regimens for relapsing or
exposure to a particular drug and concomitant co-morbidities,
refractory patients. Other approaches, including combinations
which might contraindicate the delivery of a specific
with chemotherapy or novel agents, should be considered when
compound.
established salvage regimens have been already used. The
Lenalidomide- or bortezomib-based regimens are also re-
alternative combinations should be used to increase the
commended for patients who relapse after thalidomide-based
therapeutic options when standard salvage regimens have
treatment.63,64 Patients with residual neuropathy following
been used.
thalidomide- or bortezomib-based therapy may not tolerate
either agent. For these patients, lenalidomide-based therapy is
recommended.
Overall treatment strategies for relapsing patients
In patients with renal impairment close follow-up of the
renal function is needed. Bortezomib-based combinations are
In managing the patients with relapsed or refractory MM several
preferred as they are associated with improvement in renal
key points should guide the choice of treatment:
function. Lenalidomide is also an option with dose adjustment.
Leukemia
International Myeloma Working Group guidelines
A Palumbo et al
10
Combinations including doxorubicin or cyclophosphamide may
includes systemic analgesia, local measures and chemotherapy.
increase haematological toxicity and be contraindicate in
The use of analgesics in myeloma is summarized in Table 9.
patients with pre-existing cytopenia.
Local radiotherapy is effective for pain relief of bone disease.
Cytogenetic abnormalities, such as del 13 or t(4;14) or del 17,
Studies have reported pain relief in 91­97% of patients,
are considered negative prognostic factors. Preliminary data
including complete relief in 21­26%, with fractionated radio-
indicate that bortezomib may cancel the negative impact of
therapy.66,67
these cytogenetic abnormalities,30 lenalidomide the negative
Vertebroplasty involves percutaneous injection of polymetha-
effect of del13 and t(4;14),32 and thalidomide the negative
crylate or equivalent material into the vertebral body.68 The
impact of del 13.26
procedure provides local pain relief and bone strengthening, but
does not restore vertebral height. However, a recent randomized
Phase III trial of balloon kyphoplasty (a procedure in which
Palliative care
balloon expansion of the area of vertebral damage is used before
the polymethacrylate injection) showed marked reduction in
The aim of palliative care is to relieve disabling symptoms rather
back disability and pain at 1-month after procedure.69 Balloon
than obtain control of disease activity. This will require good
kyphoplasty also improves vertebral height.68
communication with the patient to ensure that the wishes of the
Bone pain, hypercalcaemia and pathological fractures are
patient are addressed. Palliative care may include planning for
important causes of morbidity and mortality in patients with
terminal care (for example, hospice, home care and so on),
myeloma. Long-term bisphosphonate treatment is increasingly
management of bone pain, psychological support and manage-
being used to try to prevent these problems. Available options
ment of other complications (for example, hypercalcaemia,
include intravenous pamidronate, intravenous zoledronic acid
renal failure, infections and so on).
as well as oral clodronate in some countries (for example the
United Kingdom). Osteonecrosis of the jaw is an uncommon
but potentially serious complication of intravenous bisphos-
Recommendation
phonates.
The primary aim at this stage is to alleviate symptoms. Good
supportive care and continuity of care are important. Good
communication between the patient, palliative care team and
Recommendation. The use of prescribed analgesics should
the doctor are essential to ensure that the desires and concerns
follow established principles of the World Health Organiza-
of the patient are addressed.
tion.70 Consider use of balloon kyphoplasty, if appropriate,68,69
as an alternate for pain relief. Use of non-steroidal anti-
inflammatory drugs (NSAIDs) should be avoided due to the
Complications
potential for gastric irritation and adverse effects on renal
function. For difficult problems, the support and expertise
Bone disease
from in-hospital pain clinics should be requested. The use of
Skeletal complications,1,65 such as vertebral compression or
`alternative' medical procedures may be beneficial to some
collapse from osteoporosis, and pain arising from these compli-
patients (for example, relaxation techniques, aromatherapy and
cations are common. The pain requires an active approach that
hypnosis).
Table 9
Analgesia in multiple myeloma;
Class
Examples
Comments
Simple non-opioid
Paracetamol: 1 g 4­6 hourly
Oral as tablets or liquid; suppositories
analgesics
Useful in mild-to-moderate pain
available
Non-steroidal
Should be avoided or used only with caution
anti-inflammatory
drugs
Weak opioids
Provide effective analgesia for moderate pain, for example, Codeine
Confusion, drowsiness may be associated
8 mg/paracetamol 500 mg as co-codamol tablets; usual dosage is
with initial usage in some Weak (and strong)
two tablets 6 hourly
opioids
Codeine 30­60 mg or dihydrocodeine 30­60 mg up to 4 hourly
Cause constipation which usually requires
simple laxatives
Caution required in renal impairment
Strong (natural)
Provide effective analgesia for moderate to severe pain
Confusion, drowsiness, constipationFsame
opioids
Morphine; as liquid or tablets commencing at 5­10 mg orally and
principles as for weaker opioids
given 4 hourly is the treatment of choice in severe pain
Patients can be `converted' to slow release preparations when daily
requirements are established, breakthrough pain can be treated with
additional doses of 5­10 mg morphine in short acting formulation as
required
Diamorphine is preferred for parenteral usage, it is highly soluble and
is most suitable for use in a syringe driver for continuous administration
or as a 4 hourly injection
Synthetic opioids
Provide effective analgesia for moderate to severe pain Oxycodone,
which may be given orally
Fentanyl given as slow release transdermal patches may be a valuable
alternative to slow release morphine for moderate-to-severe chronic pain
Leukemia
International Myeloma Working Group guidelines
A Palumbo et al
11
The use of radiotherapy should be limited whenever possible
drugs. Thalidomide and lenalidomide in combination with ESAs
as the long-term use of radiation can ultimately affect
appears to increase the risk of thrombosis.71
haematopoietic reserve and bone healing. When using local
radiotherapy, the recommended dose for control of bone pain in
Recommendation. Erythropoiesis-stimulating agent treat-
myeloma is an 8-Gy single fraction.
ment is generally recommended when the haemoglobin level
The bisphosphonates are recommended. All patients should
is below 9 g per 100 ml; however, treatment may begin earlier
receive a comprehensive dental examination and appropriate
(haemoglobin 10­12 g per 100 ml) for patients with heart
preventive dentistry before bisphosphonate therapy. It is
disease or those who have difficulties performing regular daily
generally recommended to continue bisphosphonate therapy
activities. The ESA dose should be adjusted to maintain a high
for 2 years; however, 1 year is sufficient for patients in CR/nCR.
enough haemoglobin level to avoid blood transfusion, but
Bisphosphonates should be resumed if the patient experiences
below 12 g per 100 ml.
a relapse with new onset of skeletal-related events.
DVT. The choice of thromboprophylaxis depends on the risk
Renal failure
of venous thromboembolism associated with a given regimen.71
Renal impairment is common in myeloma. Factors involved in
The following risk factors should be taken into account when
the pathogenesis of renal failure in MM include, the capacity of
determining the form of thromboprophylaxis: individual risk
the light chain component of the immunoglobulin to cause
factors (age, obesity, history of venous thromboembolism,
proximal tubular damage, dehydration, hypercalcaemia, hyper-
central venous catheter, co-morbidities, surgical procedures
uricaemia, infection and use of nephrotoxic drugs. Use of
and inherited thrombophilia), myeloma-related risk factors
NSAIDs, including over-the-counter drugs, is a frequent
(diagnosis
and
hyperviscosity)
and
therapy-related
risks
precipitating factor.
(high-dose
dexamethasone,
doxorubicin
or
multiagent
chemotherapies).
Recommendation. Maintain a high fluid intake (at least 3 l/
day), avoid potentially nephrotoxic drugs (for example, amino-
Recommendation. Aspirin is only recommended for
glycosides and NSAIDs), correction of hypercalcaemia and
patients with no risk factors or one individual/myeloma-related
treatment of infection. Clear communication is needed between
risk factor. Low-molecular-weight heparin or full-dose warfarin
the nephrologist and the myeloma team to optimize the
is recommended for patients with at least two individual/
outcome. Agents such as thalidomide and bortezomib require
myeloma-related risk factors.
no dose modification in the context of renal dysfunction.
Lenalidomide can be used, but should be dose modified and
haematological function watched closed in the early cycles.
Infections. Infections1 are common in MM and the risk
increases during the course of the disease. Strategies to prevent
and manage infection depend on the clinical situation.
Haematological toxicity
A common symptom of myeloma is myelosuppression. Suppor-
tive care and dose modifications might be needed to manage the
Recommendation. For all MM patients, fever should be
myelosuppression.
treated promptly with broad-spectrum antibiotics. Intravenous
antibiotics are required for severe systemic infection. For
patients starting on chemotherapy, prophylactic trimethoprim-
Neutropenia. The greatest concern with neutropenia is
sulphamethoxazole is recommended for the first 2 months or
the occurrence of infections. The use of granulocyte-colony
during steroid administration periods. Acyclovir prophylaxis is
stimulating factor is effective and well-tolerated method to
recommended for all patients receiving bortezomib-based
decrease or prevent the occurrence or lower the severity of
therapy, and may be useful during the induction period in
neutropenia.
order to reduce the risk of VZV reactivation.
Recommendation. Treatment should be withheld for grade
4 neutropenia lasting at least 7 days despite granulocyte-colony
Peripheral neuropathy. Peripheral neuropathy72 is an
stimulating factor administration. When the adverse event
adverse event that is frequently reported with bortezomib and
resolves to grade 2, treatment can be reintroduced with dose
thalidomide therapy. As there are currently no pharmacological
reduction at the start of the next cycle. Prophylaxis with
medications known to relieve neuropathic symptoms, dose and
granulocyte-colony stimulating factor is also recommended for
treatment schedule modifications are the mainstays for treating
the prevention of febrile neutropenia in patients at high risk
peripheral neuropathy.
based on age, medical history, disease characteristics and
myelotoxicity of the chemotherapy regimen.
Recommendation. For bortezomib, a dose reduction to
1.0 mg/m2 is recommended for grade 1 with pain or grade 2
Anaemia. Erythropoiesis-stimulating agents (ESAs; epoetin
peripheral neuropathy; dose interruption until peripheral neuro-
and darbepoetin) can be used to treat chemotherapy-associated
pathy resolves with re-initiation at 0.7 mg/m2 per week is
anaemia, and iron supplements may improve the effectiveness
recommended for grade 2 with pain or grade 3 peripheral
of ESAs. However, using ESAs to maintain haemoglobin above
neuropathy, and treatment discontinuation is recommended for
12 g per 100 ml in cancer patients may create serious health
grade 4 peripheral neuropathy. As alternative, the biweekly
risks. For patients at high risk for developing blood clots (earlier
bortezomib infusion can be reduced to weekly infusion when
blood clot, recent major surgery, long periods of bed rest or
grade 1 with pain peripheral neuropathy occurs. If grade 2
limited activity and certain types of chemotherapy and hormone
or higher are present, interruption is suggested until grade 1 is
therapy), it is important to weigh the risks and benefits of these
reached followed by restart on a weekly basis.
Leukemia
International Myeloma Working Group guidelines
A Palumbo et al
12
Conflict of interest
19 Dimopoulos MA, Zervas K, Kouvatseas G, Galani E, Grigoraki V,
Kiamouris Ch et al. Thalidomide and dexamethasone combination
The authors declare no conflict of interest.
for refractory multiple myeloma. Ann Oncol 2001; 12: 991­995.
20 Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D,
Williams MV et al. Randomized trial of lenalidomide plus high-
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Appendix A-1
Gosta Gahrton, Karolinska Institute for Medicine, Huddinge,
Sweden
International Myeloma Working Group:
Morie Gertz, Mayo Clinic, Rochester, Minnesota, USA
John Gibson, Royal Prince Alfred Hospital, Sydney, Australia
Rafat Abonour, Indiana University School of Medicine,
Sergio Giralt, MD Anderson Cancer Center, Houston, Texas,
Indianapolis, Indiana, USA
USA
Ray Alexanian, MD Anderson, Houston, Texas, USA
Hartmut
Goldschmidt,
University
Hospital
Heidelberg,
Kenneth Anderson, Dana-Farber Cancer Institute, Boston,
Heidelberg, Germany
Massachusetts, USA
Philip Greipp, Mayo Clinic, Rochester, Minnesota, USA
Michael Attal, Purpan Hospital, Toulouse, France
Roman Hajek, Brno University, Brno, Czech Republic
Herve Avet-Loiseau, Institute de Biologie, Nantes, France
Izhar Hardan, Tel Aviv University, Tel Aviv, Israel
Ashraf Badros, University of Maryland, Baltimore, Maryland,
Jean-Luc Harousseau, Institute de Biologie, Nantes, France
USA
Hiroyuki Hata, Kumamoto University Hospital, Kumamoto,
Leif Bergsagel, Mayo Clinic Scottsdale, Scottsdale, Arizona,
Japan
USA
Yutaka Hattori, Keio University School of Medicine, Tokyo,
Joan Blade´, Hospital Clinica, Barcelona, Spain
Japan
Bart Barlogie, M.I.R.T. UAMS Little Rock, Arkanas, USA
Joy Ho, Royal Prince Alfred Hospital, Sydney, Australia
Regis Batille, Institute de Biologie, Nantes, France
Vania Hungria, Clinica San Germano, Sao Paolo, Brazil
Meral Beksac, Ankara University, Ankara, Turkey
Shinsuke Ida, Nagoya City University Medical School, Nagoya,
Andrew Belch, Cross Cancer Institute, Alberta, Canada
Japan
Bill Bensinger, Fred Hutchinson Cancer Center, Seattle,
Peter Jacobs, Constantiaberg Medi-Clinic, Plumstead, South
Washington, USA
Africa
Mario Boccadoro, University of Torino, Torino, Italy
Sundar Jagannath, St Vincent's Comprehensive Cancer Center,
Michele Cavo, Universita di Bologna, Bologna, Italy
New York, New York, USA
Wen Ming Chen, MM Research Center of Beijing, Beijing, China
Hou Jian, Shanghai Chang Zheng Hospital, Shanghai, China
Tony Child, Leeds General Hospital, Leeds, United Kingdom
Douglas Joshua, Royal Prince Alfred Hospital, Sydney, Australia
James Chim, Department of Medicine, Queen Mary Hospital,
Michio Kawano, Yamaguchi University, Ube, Japan
Hong Kong
Nicolaus Kro¨ger, University Hospital Hamburg, Hamburg,
Ray Comenzo, Tufts Medical Center, Boston, Massachusetts,
Germany
USA
Shaji Kumar, Department of Hematology, Mayo Clinic,
John Crowley, Cancer Research and Biostatistics, Seattle,
Minnesota, USA
Washington, USA
Robert Kyle, Department of Laboratory Med. and Pathology,
William Dalton, H Lee Moffitt, Tampa, Florida, USA
Mayo Clinic, Minnesota, USA
Faith Davies, Royal Marsden Hospital, London, England
Juan Lahuerta, Grupo Espanol di Mieloma, Hospital Universitario,
Ca´rmino de Souza, Univeridade de Campinas, Caminas, Brazil
Madrid, Spain
Michel Delforge, University Hospital Gasthuisberg, Leuven,
Ola Landgren, National Cancer Institute, N.I.H. Bethesda,
Belgium
Maryland, USA
Meletios Dimopoulos, Alexandra Hospital, Athens, Greece
Jae Hoon Lee, Gachon University Gil Hospital, Incheon, Korea
Angela Dispenzieri, Mayo Clinic, Rochester, Minnesota, USA
Xavier LeLeu, Hospital Huriez, CHRU Lille, France
Brian GM Durie, Cedars-Sinai Outpatient Cancer Center, Los
Suzanne
Lentzsch,
University
of
Pittsburgh,
Pittsburgh,
Angeles, California, USA
Pennsylvania, USA
Hermann Einsele, Universita¨tsklinik Wu¨rzburg, Wu¨rzburg,
Henk Lokhorst, University Medical Center Utrecht, Utrecht, The
Germany
Netherlands
Theirry Facon, Centre Hospitalier Regional Universitaire de
Sagar Lonial, Emory University Medical School, Atlanta,
Lille, Lille, France
Georgia, USA
Dorotea Fantl, Socieded Argentinade Hematolgia, Buenos Aires,
Heinz Ludwig, Wilhelminenspital Der Stat Wien, Vienna,
Argentina
Austria
Jean-Paul Fermand, Hopitaux de Paris, Paris, France
Angelo Maiolino, Rua fonte da Saudade, Rio de Janeiro,
Rafael Fonseca, Mayo Clinic Arizona, Scottsdale, Arizona, USA
Brazil
Leukemia
International Myeloma Working Group guidelines
A Palumbo et al
15
Maria Mateos, University of Salamanca, Salamanca, Spain
Jesus San Miguel, University of Salamanca, Salamanca, Spain
Jayesh Mehta, Northwestern University, Chicago, Illinois, USA
Chaim Shustik, McGill University, Montreal, Canada
GianPaolo Merlini, University of Pavia, Pavia, Italy
Seema Singhal, Northwestern University, Chicago, Illinois, USA
Joseph Mikhael, Mayo Clinic Arizona, Scottsdale, Arizona, USA
Pieter Sonneveld, Erasmus MC, Rotterdam, The Netherlands
Philippe Moreau, University Hospital, Nantes, France
Andrew Spencer, The Alfred Hospital, Melbourne, Australia
Gareth Morgan, Royal Marsden Hospital, London, England
Edward Stadtmauer, University of Pennsylvania, Philadelphia,
Nikhil Munshi, Dana-Farber Cancer Institute, Boston, Massa-
Pennsylvania, USA
chusetts, USA
Keith Stewart, Mayo Clinic Arizona, Scottsdale, Arizona, USA
Ruben Niesvizky, Weill Medical College of Cornell University,
Evangelos Terpos, University of Athens School of Medicine,
New York, New York, USA
Athens, Greece
Yana Novis, Hospital Si´rioLibane^s, Bela Vista, Brazil
Patrizia Tosi, Italian Cooperative Group, Istituto di Ematologia
Amara Nouel, Hospital Rutz y Paez, Bolivar, Venezuela
Seragnoli, Bologna, Italy
Robert Orlowski, MD Anderson Cancer Center, Houston, Texas,
Guido Tricot, Huntsman Cancer Institute, Salt Lake City, Utah,
USA
USA
Antonio Palumbo, Cathedra Ematologia, Torino, Italy
Ingemar
Turesson,
Department
of
Hematology,
Malmo
Santiago Pavlovsky, Fundaleu, Buenos Aires, Argentina
University, Malmo, Sweden
Linda Pilarski, University of Alberta, Alberta, Canada
Brian Van Ness, University of Minnesota, Minneapolis,
Raymond Powles, Leukaemia and Myeloma, Wimbledon,
Minnesota, USA
England
Ivan Van Riet, Brussels Vrija University, Brussels, Belgium
S Vincent Rajkumar, Mayo Clinic, Rochester, Minnesota, USA
Robert Vescio, Cedars-Sinai Cancer Center, Los Angeles,
Donna Reece, Princess Margaret Hospital, Toronto, Canada
California, USA
Tony Reiman, Cross Cancer Institute, Alberta, Canada
David Vesole, Loyola University Chicago, Illinois, USA
Paul Richardson, Dana Farber Cancer Institute, Boston,
Anders Waage, University Hospital, Trondheim, Norway
Massachusetts, USA
Michael Wang, M.D. Anderson, Houston, Texas, USA
Angelina Rodriquez Morales, Bonco Metro Politano de Sangre,
Donna Weber, MD Anderson, Houston, Texas, USA
Caracas, Venezuela
Jan Westin, Sahlgrenska University Hospital, Gothenburg,
Orhan Sezer, Department of Hem/Onc, Universitatsklinikum
Sweden
Charite, Berlin, Germany
Keith Wheatley, University of Birmingham, Birmingham, United
John Shaughnessy, M.I.R.T. UAMS, Little Rock, Arkansas, USA
Kingdom
Kazuyuki Shimizu, Nagoya City Midori General Hospital,
Dina B Yehuda, Department of Hematology, Hadassah
Nagoya, Japan
University Hospital, Hadassah, Israel
David Siegel, Hackensack, Cancer Center, Hackensack,
Jeffrey Zonder, SWOG, Department of Hem/Onc., Karmanos
New Jersey, USA
Cancer Institute, Michigan, USA
Leukemia

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