haematologica | 2015; 100(10)Introduction Multiple myeloma (MM) is characterized by bone destruc- tion, anemia, renal and immunological impairment…. [612712]

1254GUIDELINE ARTICLE
haematologica | 2015; 100(10)Introduction
Multiple myeloma (MM) is characterized by bone destruc-
tion, anemia, renal and immunological impairment. These
complications may lead to severe impairment of the quality of
life of myeloma patients and may deteriorate their life
expectancy. Therefore, prophylaxis and supportive treatment
for osteolytic disease, pain, anemia, renal insufficiency, infec-
tions, pain, thromboembolic events and peripheral neuropa-
thy are essential for the management of myeloma patients.
The aim of this paper of the European Myeloma Network
(EMN) is to provide useful guidelines for the management of
the most common myeloma-related complications.Methods
An interdisciplinary panel of myeloma experts on behalf of
the EMN reviewed all published randomized clinical studies,
guidelines, meta-analyses, systematic reviews, observational
studies and case reports on the management of complications
in MM. The research was performed in PubMed and ISI until
the 28thAugust 2014. The Grading of Recommendations
Assessment Development and Evaluation (GRADE) system
was used for the grading of recommendations (Table 1). In
cases of lack of sufficient data, an expert consensus was used
to develop recommendations. The paper was circulated
among the panel members; initial discussion took place at the
©2015 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2014.117176
Manuscript received on January 26, 2015. Manuscript accepted on June 29, 2015.
Correspondence: [anonimizat] European Myeloma Network provides recommendations for the management of the most common compli-
cations of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional
radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of
lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis
should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on
conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients
with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma,
bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear
if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment
with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemo-
globin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be
stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based
regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neu-
ropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination
against streptococcus pneumonia andhemophilus influenza is appropriate, but efficacy is not guaranteed due to subop-
timal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving
proteasome inhibitors, autologous or allogeneic transplantation (grade 1A). European Myeloma Network Guidelines for the Management
of Multiple Myeloma-related Complications
Evangelos Terpos,1*Martina Kleber,2,3*Monika Engelhardt,2*Sonja Zweegman,4Francesca Gay,5Efstathios Kastritis,1
Niels W.C.J. van de Donk,6Benedetto Bruno,5Orhan Sezer,7Annemiek Broijl,8Sara Bringhen,5Meral Beksac,9
Alessandra Larocca,5Roman Hajek,10Pellegrino Musto,11Hans Erik Johnsen,12Fortunato Morabito,13 Heinz Ludwig,14
Michele Cavo,15Hermann Einsele,16Pieter Sonneveld,8Meletios A. Dimopoulos,1and Antonio Palumbo5on behalf of
the European Myeloma Network
1Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Greece; 2Department of
Hematology and Oncology, University of Freiburg Medical Center, Germany; 3Clinic for Internal Medicine, University Hospital Basel,
Switzerland; 4Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands; 5Division of Hematology, S.
Giovanni Battista Hospital, University of Turin, Italy; 6Department of Hematology, University Medical Center, Utrecht, the Netherlands;
7Department of Hematology, Memorial Sisli Hospital, Istanbul, Turkey; 8Department of Hematology, Erasmus University Medical Center
Rotterdam, the Netherlands; 9Department of Hematology, Ankara University, Turkey; 10Department of Hemato-Oncology, University
Hospital Ostrava and Faculty of Medicine OU, Ostrava, Czech Republic; 11Centro di Riferimento Oncologico della Basilicata, Istituto di
Ricovero e Cura a Carattere Scientifico, Rionero in Vulture, Italy; 12Department of Hematology, Aalborg University Hospital, Denmark;
13Department of Hematology, Azienda Ospedaliera dell'Annunziata, Cosenza, Italy; 14Department of Medicine I, Center of Oncology,
Hematology and Palliative Care, Wilhelminenspital, Vienna, Austria; 15“Seràgnoli” Institute of Hematology and Medical Oncology,
University of Bologna, Italy; and 16Department of Internal Medicine II, University Hospital Würburg, Würzburg, Germany
*ET, MK, ME contributed equally to this work.
ABSTRACT

6thEMN Trialist meeting (Baveno, Italy, 15th-16thSeptember
2013) and the recommendations were approved by the
panel members and the participants at the 7thEMN Trialist
meeting (Baveno, 14th-15thSeptember 2014). Subsequently,
the manuscript underwent two-round revisions between
the panel members.
Bone disease
Osteolytic bone disease is one of the most prominent
features of myeloma, and is present in up to 80% of
patients at diagnosis.1Bone destruction leads to skeletal-
related events (SREs), i.e. vertebral and other pathological
fractures, a need for radiotherapy or surgery to the bone
and/or spinal cord compression. It is mainly due to an
increased osteoclastic activity which is accompanied by
low osteoblastic function.1Bisphosphonates, radiotherapy,
balloon kyphoplasty and surgery are the main therapies
used for the management of bone disease in MM.
Imaging for the diagnosis and follow up of myeloma
patients
Skeletal survey based on conventional radiography
(WBXR) is currently considered to be the standard tech-
nique for the detection of lytic lesions in MM patients and
is recommended for the detection of bone disease in the
CRAB criteria that are used for the definition of myeloma
defining events.2,3However, novel techniques can detect
more lytic lesions compared to conventional radiography.
Whole-body, multi-detector, low-dose computed tomogra-
phy (WBLD-CT) is more sensitive for the detection of lytic
lesions in myeloma compared to conventional radiogra-
phy, it is very easy to perform (the examination is per-
formed in 2 min or less), it has a more accurate evaluation
of areas with instability or at risk of fracture, and is superi-or regarding the planning for radiotherapy or surgical inter-
ventions.
4,5Similarly, positron emission tomography in
combination with CT (PET/CT) is superior to conventionalradiography in the detection of lytic disease, while whole-
body magnetic resonance imaging (MRI) accurately depicts
the marrow involvement in MM patients.
6,7We stress that
MRI depicts bone marrow involvement, while CT and
skeletal survey reveals lytic lesions. However, there aresome issues that need to be clarified when using such sen-
sitive techniques. For example, the issue of the importanceof the detection of 2 or 3 small lesions of 3-4 mm of diam-
eter by WBLD-CT or by MRI or PET/CT in a patient with
no CRAB criteria has not yet been solved (i.e. whether this
patient will develop symptomatic disease earlier than
those without such lesions). Furthermore, we do not knowthe prognostic value of the WBCT, i.e. what the difference
is between an MM patient with 4 lytic lesions detected by
conventional radiography and another patient with 14 lytic
lesions detected by WBLD-CT. Although these questions
have not been conclusively answered, data so far support
the substitution of conventional radiography by WBLD-
CT for the detection of lytic disease in MM. Positive
lesions in WBLD-CT are considered those with a diameter
of 5 mm or more.
Regarding the definition of myeloma defining events,
there are important studies which suggest that asympto-
matic patients with more than 1 focal lesions on MRI have
a higher risk (more than 70% within 2 years) for progres-
sion to symptomatic myeloma.
8,9These patients need to be
treated as having symptomatic disease.10Furthermore, MRI
correlates with survival in myeloma patients.11PET/CT
findings have also been correlated with response to thera-
py and survival.12,13Prospective comparisons between MRI
and PET/CT in patients with asymptomatic disease have
not yet been published. In symptomatic patients there is
evidence that MRI achieves better results than PET/CT in
the staging and disease recurrence, while PET/CT has
shown faster changes in imaging findings than MRI in
patients who respond to therapy.14However, in the post-
treatment setting, MRI may often be false positive because
of persistent non-viable lesions and thus PET/CT might be
more suitable for the determination of remission status.15
Recommendation: WBLD-CT is the novel standard procedure
for the diagnosis of lytic disease in patients with MM (grade 1A).
Conventional radiography can also be used if WBLD-CT is not
available. In asymptomatic patients with no lytic disease in
WBLD-CT, whole body MRI (or spine and pelvic MRI if WB-
MRI is not available) has to be performed and in the presence of
more than 1 focal lesion the patients are characterized as having
symptomatic disease that needs therapy (grade 1A). PET/CT maybe useful for the better definition of complete or stringent complete
response (CR or sCR) and for the progression of the disease (grade
2B). Figure 1 presents the imaging algorithm which is proposed by
the EMN for use in myeloma-related bone disease.
Bisphosphonates
Based on phase III studies, both pamidronate and zole-
dronic acid (ZA) have been found to reduce SREs com-
pared to placebo.16-18There are only three randomized stud-
ies comparing the effect of two different bisphosphonates
(BP) or two different dosages of the same BP. In the first
study, ZA was as effective as pamidronate in reducing
SREs in the era of conventional chemotherapy.18,19In the
second, two doses of intravenous pamidronate (30 mg vs.Guidelines for myeloma complications
haematologica | 2015; 100(10) 1255Table 1.Grade recommendations for grading levels of evidence.
Grade
1 Evidence strongly suggests that the A Consistent evidence from systemic reviews of high-quality randomized
benefit of the procedure outweighs potential risks studies or from high-quality randomized studies or from high-quality
or risks of the procedure outweigh potential benefits observational studies
2 Evidence suggests the benefit and risk of a procedure B Evidence from randomized and observational studies with important
is finely balanced or uncertain methodological flaws
C Evidence from randomized and observational studies with major
methodological flaws or other sources of evidence (e.g. case series)

90 mg, monthly) had comparable results regarding time to
SRE and SRE-free survival time.20The major flaw of this
study was that it was powered to show differences in qual-
ity of life and not in SREs.20Finally, the third study, which
compared intravenous ZA with oral clodronate, found that
ZA reduced the SRE risk compared to clodronate in all
patients, irrespective of the presence of lytic lesions at diag-
nosis, but furthermore, improved overall survival (OS) by
ten months in MM patients with lytic lesions at diagno-
sis.21,22These effects continued in patients who received ZA
for more than two years.23However, there was no sub-
analysis according to the response status of the patients,
and thus it is not clear if the continuous use of ZA produces
similar results in patients who have achieved a CR, sCR,
very good partial response (VGPR) or PR. A recent meta-
analysis was not able to confirm superiority of ZA over
pamidronate, but remarkably revealed a survival advantage
of ZA versusplacebo.24This analysis also showed that in
order to prevent one SRE, we need to treat 6-15 MM
patients with BP.
Recommendations: all MM patients with adequate renal func-
tion (creatinine clearance >30 mL/min) and osteolytic disease at
diagnosis should be treated with ZA (4 mg, over an at least 15-
min infusion, every 3-4 weeks) or pamidronate (90 mg, in a 2-4-
h infusion, every 3-4 weeks), intravenously, in addition to specific
anti-myeloma therapy (grade 1A). Symptomatic patients, without
bone disease assessed by conventional radiography, can be treatedwith ZA (grade 1B). The advantage is not clear for patients with-
out bone involvement on MRI or PET/CT. In asymptomatic MM,
BPs are not recommended (grade 1A); in cases of osteoporosis orvertebral fractures that are not due to myeloma, bisphosphonates
should be given in asymptomatic patients with doses as given for
osteoporosis (i.e. 5 mg ZA per year). ZA should be given continu-
ously (grade 1B). However, it is currently unknown whether
patients who achieve VGPR or better have benefits from the con-
tinuous use of ZA. Regarding pamidronate, there are no data to
support its continuous use; thus it should be given for two years
and then at the physician’s discretion (grade 2C).
Side-effects of bisphosphonates and their management
Side-effects of intravenous BPs include acute phase reac-
tions, inflammatory reactions at the injection site, hypocal-
cemia, hypophosphatemia, renal impairment (RI) and
osteonecrosis of the jaw (ONJ).25-27For the prevention of
hypocalcemia, all patients under BPs should receive calci-
um and vitamin D3 supplementation (600 mg calcium per
day and 400 IU vitamin D3 per day); interestingly, approx-
imately 60% of myeloma patients are vitamin D-deficient
or -insufficient.25The treating physicians are encouraged to
perform vitamin D measurements at least once a year and
manage their patients accordingly.
RI due to acute tubular damage and deterioration of renal
function can be observed with both pamidronate and ZA,
but the true incidence of this adverse event remains
unknown, as RI is also a common complication of
MM.21,25,26Thus patients with moderate RI need dose reduc-
tions of ZA, according to the summary of product charac-
teristics of the drug.25Regarding pamidronate, its elimina-
tion is slower when the CrCl is below 30 mL/min.26
ONJ is an uncommon but sometimes severe complica-E. Terpos et al.
1256 haematologica | 2015; 100(10)
Figure 1. Algorithm for imag-
ing in multiple myeloma
(MM). In the case of spinal
cord compression an urgent
MRI or CT is obligatory in
order to assess the better
management (radiotherapy
or surgery in the cases on thepresence of bone fracture
segments into the spinal
canal). In the suspicion of a
plasmacytoma a CT of the
area and a needle biopsy is
needed. In the case of myelo-
ma the WBLD-CT (or the stan-dard conventional radi-
ographic evaluation of the
skeleton if a WBLD-CT is not
available) may reveal or not
lytic lesions. If lytic lesions
are present then the patient
fulfils the criteria for sympto-
matic disease and needs sys-
tematic therapy. If not, then a
WB-MRI (or a spinal and
pelvic MRI if a WB-MRI is notavailable) has to be per-
formed. In the presence of
more than one focal lesion
(more than 5 mm of diame-
ter) in MRI the treating physi-cian should treat the patient
as having symptomaticmyeloma. To date data do notjustify the initiation of treat-
ment in asymptomatic
patients with diffuse MRI pat-
tern of marrow involvement.

tion of BP. Retrospective studies suggest that ONJ is
observed more often with ZA, after dental procedures, and
is associated with the prolonged administration of the BP.27
It seems that the use of preventive dental measures leads to
the reduction of ONJ incidence.28There are conflicting rec-
ommendations regarding precautions before dental extrac-
tion in patients who are treated with BP. The most recent
American Dental Association (ADA) recommendations do
not support the discontinuation of BP in these cases in the
absence of any convincing data and because BP remain inthe bones for years.
29However the International Myeloma
Working Group (IMWG) guidelines suggest the temporary
discontinuation of BP for 90 days before and after invasive
dental procedures.25
Recommendations: for the prevention of hypocalcemia, calcium
and vitamin D3 supplementation should be given in all patients
under intravenous BP (grade 1A). The treating physicians are
encouraged to perform vitamin D measurements at least once a
year and manage their patients accordingly. Renal function should
be closely monitored by measuring CrCl, serum electrolytes and
urinary albumin in all patients under BP therapy; CrCl should be
evaluated before the administration of each intravenous infusion
(grade 1A). Patients with CrCl 30-60 mL/min should receive
reduced doses of ZA with no change to infusion time (grade 1A),
while pamidronate should be given via 4-h infusion (grade 1C).
Pamidronate and ZA should not be given in patients with CrClless than 30 mL/min (grade 1A); alternatively clodronate can begiven in patients with a CrCl more than 12 mL/min (grade 2C).
Treatment with BP should be discontinued if a patient experiences
deterioration of renal function until CrCl returns to within 10% of
base-line values (grade 1B). Patients on chronic dialysis without
possibility of renal failure reversal should also receive monthly BPs
(grade 2C); treating physicians should closely monitor thesepatients due to high risk for hypocalcemia. For all other patients
on dialysis, BPs should be avoided until their independence from
dialysis and the reversal of RI to CrCl more than 30 mL/min
(grade 2C). Before BP administration, patients should have a
thorough dental examination and all major dental problems (i.e.
dental extractions or other traumatic dental procedures) should be
resolved (grade 2C). In cases of ONJ, BP should be discontinued
and can later be re-administered if ONJ has healed, at the physi-
cian's discretion (grade 2C).
Denosumab: denosumab has not yet been licensed for
myeloma patients. A large phase III study comparing deno-sumab with ZA is ongoing. Denosumab can currently begiven in myeloma patients only in the rare cases of resist-
ant hypercalcemia to BPs.
Radiotherapy: radiotherapy is mainly used in the cases of
solitary plasmacytoma, symptomatic spinal cord compres-
sion, extremely painful lytic lesions and for the prevention
of pathological fractures. For painful osteolytic lesions, a
dose of 3000 cGy in 10-15 fractions is usually adequate.
Radiotherapy may cause delays in applying systemic anti-
myeloma therapies with radiosensitizing drugs, such as
anthracyclinse and proteasome inhibitors.
Balloon kyphoplasty and vertebroplasty: these techniques are
mainly used for the management of painful vertebral com-
pression fractures, where almost 80% of patients with
pain, non-responsive to pain killers, experience pain relief.30
All recent data, including a phase III study and a large
meta-analysis, suggest that balloon kyphoplasty is thetreatment of choice for the reduction of pain due to can-
cer-related vertebral fractures and is associated with
reduced rates of cement leakage
30,31(grade 1A).
Surgery: the administration of very effective novel anti-
myeloma regimens has reduced the need for surgery dur-
ing the last decade. Currently, surgery should be used in
the following cases: i) to fix pathological fractures of thelong bones; ii) to prevent and restore axial skeleton in cases
of unstable spinal fractures; and iii) for spinal cord com-
pression with bone fragments within the spinal route
(grade 2C).
Anemia
Anemia, which is usually normochromic and normocyt-
ic, is another common complication of MM. It is present in
approximatley 75% of patients at diagnosis32,33and in
almost all patients with uncontrolled disease. Several fac-
tors contribute to the development of anemia in MM
patients: the BM infiltration by the myeloma itself leads to
reduced numbers of erythroid precursors, erythropoietin
deficiency (in patients with RI), decreased responsiveness
of the pro-erythroblasts and CFU-E cells to erythropoietin,
impaired iron utilization due to increased production ofGuidelines for myeloma complications
haematologica | 2015; 100(10) 1257Table 2.Incidence of adverse events in multiple myeloma patients treated with different therapy regimens.
Regimens Neutropenia (%) VTE (%) PN (%) Infection (%) SPM (%)
Induction
MPT 16-48 3-12 6-23 4-28 NA
CTD NA 16 7 13 NA
VMP 40 1 22 10 6
VMPT 38 5 15 13 NA
VTP 22 29 1 NA
VRd 95 6 5 NA
Rd 20 12 29 NA
MPR 66 50 13 2
Salvage
V 14 08 13 NA
RD 41 15 2 22 NA
CTD: cyclophosphamide-thalidomide-dexamethasone; MPR: melphalan-prednisone-lenalidomide; NA: not available, Rd: lenalidomide plus low-dose dexamethasone; RD: lenalido-
mide plus high-dose dexamethasone; SPM: second primary malignancy; V: bortezomib;VMP: bortezomib-melphalan-thalidomide; VMPT: bortezomib-melphalan-prednisone-thalido-
mide;VTE: venous thromboembolism; VTP: bortezomib-melphalan-prednisone (adapted according Palumbo et al.100).

hepcidin because of chronic inflammation, and parapro-
tein-induced increase of the plasma volume.33However,
the major cause of anemia in myeloma is the induction of
apoptosis of erythroblast by myeloma cells.34Furthermore,
anti-myeloma therapy and radiotherapy can either cause
anemia or exacerbate pre-existing anemia.35
Red blood cell transfusions are helpful for patients who
need rapid improvement of their anemic condition.
Moreover, several prospective studies have shown that
erythropoiesis-stimulating agents (ESAs), such as erythro-
poietin (Epo)- a and βas well as darbepoetin are able to
increase hemoglobin (Hb) levels by 2 g/dL or more in 60%
to 75% of myeloma patients with symptomatic anemia.
ESAs mainly reduce transfusion requirements and improve
quality of life.36-40Predictors of response to ESAs include the
ratio of observed to expected Hb (<0.9) and the preserved
BM function, reflected by the platelet counts(>150×109/L).33,38,41A systematic review of the use of ESAs
in more than 20,000 cancer patients confirmed that theiruse reduced the relative risk of transfusions due to increase
of erythroid responses, but there was evidence that ESAs
increased mortality during ESA administration and thus
decreased OS.
42Although anemia is common in MM
patients, no clear consensus exists as to the use and impact
of ESAs on outcome in MM and randomized studies in
MM patients are still limited. However, one randomized
study (VISTA sub-analysis) showed no evidence of inferior
outcome after ESA treatment, albeit patient numbers were
very limited and, therefore, statistically under-powered.43
The most recent guidelines from the American Society of
Hematology (ASH) and American Society of Clinical
Oncology (ASCO) recommend the administration of ESAs
at the lowest possible dose to avoid transfusions. In case of
iron deficiency, which is indicated by low transferrin satu-E. Terpos et al.
1258 haematologica | 2015; 100(10)Table 3. Management of hematologic and non-hematologic complication in myeloma patients treated with novel agents.
Complication MM agents AE grade Dose recommendations Management
Neutropenia L-based Uncomplicated 25–50% reduction G-CSF until neutrophil recovery
grade 4
(ANC: 500/mm3)
or grade 2–3
(ANC: 500-1000/mm3)
complicated by infection
Anemia B- and L-based Grade 2–4 (Hb ≤ 10 g/dL) 25–50% reduction Erythropoietin or darbepoietin
(only grade 3-4)
Bone disease Analgesics to treat uncontrolled pain, low-dose radiotherapy of limited involved fields should be used in case of pain not responding
to therapy. Bisphosphonates for preventing and management of SREs. Monitoring of renal function is mandatory.
Renal toxicity L CrCL: 30–60 mL/min 10 mg/d Correct precipitant factors:
dehydration, hypercalcemia,
CrCL<30 mL/min; no dialysis 15 mg every other d hyperuricemia, urinary infections,
and concomitant use
CrCL<30mL/min; dialysis 5 mg/d after dialysis of nephrotoxic drugs
Neuropathy Thal-based Grade 2 PN 50% dose reduction Neurological assessment before
(from 100 mg to 50 mg) and during treatment; consider
Grade 3–4 PN Treatment discontinuation symptomatic treatment with
until PN resolves to grade 1; gabapentin, pregabalin, vitamin B
restart at 50% dose reduction complex,amitryptilin, or L-carnitin
B-based Grade 1 with pain 25–50% dose reduction:
or grade 2 PN 1.3 mg/m2once per
week reduced to
1.0 mg/m2+ subs. to 0.7 mg/m2,
(s.c preferred)
Grade 2 with pain Dose interruption until
or grade 3 PN PN resolves to grade 1 or more;
restart at 50% dose reduction
Grade 4 PN Treatment discontinuation
Infections B-/L-or Thal-based Grade 3–4 25–50% reduction Trimetoprin-cotrimoxazole for PJP
during HD-Dex.; aciclovir or valacyclovir for HVZ
prophylaxis during PI-based therapy; consider
antibiotic prophylaxis, seasonal
influenca vaccination
ThromboembolismThal + L-based All grades Temporary drug discontinuation 0-1 individual risk:
and full anticoagulation, aspirin 100 mg; ≥2 individuals risk or
then validate re-treatment HD-Dex/ multiagent CTx:
LMWH or full-dose warfarin
MM: multiple myeloma; AE: adverse event; B-based: bortezomib-based; CTx: chemotherapy; Dex: dexamethasone; HD-Dex: high-dose dexamethasone; Hb: hemoglobin; HVZ: herpes-
varicella-zoster; L-based: lenalidomide-based; LMWH: low-molecular-weight heparin; PI: proteasome inhibitor; PJP: Pneumocystis jirovecii ; PN: peripheral neuropathy; Thal-based:
thalidomide-based; SREs: skeletal-related events, s.c.: subcutaneous (adapted according Gay et al.78and Metha et al.85).

ration (<20%) and/or high numbers of hypochromic red
cells (>5%), the iron should be given intravenously.44
Important side-effects of ESAs include thromboembolic
complications, hypertension and possibly increased mor-
tality.42,45Here, it is important to stress that nowadays, with
very effective combination therapies that rapidly control
the disease, the systematic need of ESAs in myeloma is a
subject of debate.
Recommendations: treatment with ESAs may be initiated in
patients with persistent symptomatic anemia (usually Hb levels
<10 g/dL) in whom other causes of anemia (i.e. iron or B12 defi-
ciency, hemolysis, etc.) have been excluded (grade 1B). The stan-
dard dose of Epo- ais 40,000 U/week, of Epo- β30,000 U/week
and of darbepoetin 150 μg/week or 500 μg every three weeks. Hb
levels should not increase more than 12 g/dL. ESAs should be
stopped after 6-8 weeks if adequate Hb response is not achieved.
True or functional iron deficiency during treatment with an ESA
should be treated with intravenous iron (grade 1A).Renal Impairment
Incidence and assessment of renal impairment
Mild renal impairment (RI) (estimated glomerular filtra-
tion rate [eGFR] <60 mL/min/1.73 m2), if carefully moni-
tored, can be observed in at least 25%-50% of patients dur-
ing the course of their disease.46The pathophysiology of RI
in MM is complex and associated with various underlying
processes. The principal renal mechanism is tubulointersti-
tial lesions, such as cast nephropathy, a direct consequence
of the high serum concentration of immunoglobulin free
light chains (SFLCs; Figure 2), characterized by tubular
atrophy and tubular-interstitial fibrosis and the most fre-
quent (approx. 90%) form of renal damage.47-51FLCs can
also cause functional impairment, resulting in Fanconi’s
syndrome, characterized by failure of the reabsortive
capacity of the proximal renal tubules resulting in gluco-
suria, aminoaciduria, hypophosphatemia andGuidelines for myeloma complications
haematologica | 2015; 100(10) 1259
Figure 2. Mechanisms of FLC-induced acute kidney injury. Serum FLCs are primarily cleared by the kidneys through glomerular filtration, endo-
cytosed by the proximal tubule cells and degraded within lysosomes.50In MM, the Ig light chains are produced in excess and absorption mech-
anisms in the proximal tubule are overwhelmed. Thus, the excessive light chains reach the distal tubules, where they form tubular casts with
Tamm-Horsfall protein (THP), subsequently leading to tubular obstruction.51Additionally, excess FLCs can cause direct injury to proximal tubu-
lar cells through the induction of pro-inflammatory cytokine production and other pathways leading to tubular cell death.52The very high con-
centrations of FLCs present in the ultrafiltrate of patients with MM can result in direct injury to PTCs. Activation of redox pathways occurs, with
increased expression of NFκB and MAPK, which in turn leads to the transcription of both inflammatory and profibrotic cytokine. In the distal
tubules, FLCs can bind to a specific binding domain on THPs and co-precipitate to form casts. These casts result in tubular atrophy proximal
to the cast and lead to progressive interstitial inflammation and fibrosis. CCL2: hemokine (C-C motif) ligand 2; CDR: complementarity deter-
mining region; FLC: free light chain; IL: interleukin; MAPK: mitogen-activated protein kinase; NFκB: nuclear factor κB; PTC: proximal tubule kid-
neys; TGF-β1: transforming growth factor β1; THP: Tamm-Horsfall protein (adapted to Hutchison et al.49).

hypouricemia.52Moreover, deposition of monoclonal light
chains can occur in several organs (kidney, heart, liver,
small intestine), leading to the development of amyloid
light chain (AL) amyloidosis or light chain deposition dis-
ease (LCDD). A variety of other nephrotoxic processes
may also contribute to renal damage, including dehydra-
tion, hypercalcemia, infections, amyloidosis, and concomi-
tant exposure to nephrotoxic medications, such as non-
steroidal anti-inflammatory drugs.46,53
According to Durie & Salmon staging system, serum cre-
atinine-levels of 2 mg/dL or more (sCr) define RI and rep-
resent one of the ‘CRAB’ diagnostic criteria for sympto-
matic MM.54However, serum creatinine is not a suitable
factor for the reflection of GFR.54-55Therefore predictive of
GFR equations based on serum creatinine [Cockcroft-Gaultequation and the Modification of Diet in renal Disease
(MDRD)] are often used to define the degree of RI.
46,55,56The
IMWG has recommended the use of the MDRD equation
for the estimation of GFR in MM patients,56and the Kidney
Disease Improving Global Outcomes (KDIGO) classifica-
tion for the classification of RI in MM patients.57Recently,
the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) formulas, with or without cystatin C, has been
used for the accurate detection of manifest RI,58,59and espe-
cially the CKD-EPI-cystatin C equation seems to provide
an independent prognostic value, which needs to be fur-
ther elucidated and formally compared to currently used
equations both in newly diagnosed and relapsed patients.58
The improved prognostic ability and more sensible detec-
tion of RI by the CDK-EPI compared to the MDRD estima-
tion therefore enlarges the arsenal of eGFR formulas and
should lead to a broader use of CKD-EPI formulas for the
estimation of GFR in patients with myeloma.59,60Supportive care and mechanical approaches
MM patients with RI at presentation should be consid-
ered a medical emergency. Management of patients with
RI include adequate hydration, urine alkalinization, and
treatment off hypercalcemia. High fluid intake alone will
at best reduce the urine concentration of the pathogenic
light chains and should be combined with prompt anti-
myeloma therapy, including agents without nephrotoxic
potency. Therapeutic plasma exchange (TPE) has been
suggested to impact the outcome of the renal failure by
promoting rapid reduction in the levels of free light
chain,61but its role remains controversial.62The largest
prospective randomized trial performed so far found no
impact of TPE on the composite end point of death, dial-
ysis dependence, and GFR less than 30 mL/min/1.73 m2in
MM patients with RI.62A small series of 14 patients with
confirmed or presumed cast nephropathy treated with
bortezomib, dexamethasone, and TPE reported normal-
ization of serum creatinine in 43% of patients.61A defini-
tive answer on the role of TPE in MM patients with RI
will require larger prospective trials with, for example,
proteasome-inhibitor-based uniform pharmacological
therapy. The removal of FLCs with dialysis is another
method. The issue of whether an extended duration of
dialysis with high cut off dialyzers is more effective than
plasma exchange at removing FLCs or reversing renal fail-ure is not established but should be solved in the near
future and this method can also be combined with borte-
zomib or other anti-myeloma therapies.
63-65
Antimyeloma therapy in multiple myeloma patients with
renal impairment
High-dose chemotherapy with autologous stem cellE. Terpos et al.
1260 haematologica | 2015; 100(10)
Figure 3. Algorithm for the initial
workup of myeloma patients with
renal impairment.

transplantation (ASCT) may be performed in patients with
severe RI or under dialysis using melphalan at a reduced
dose (140 mg/m2) albeit immediately reconstitution of RI is
essential and ASCT may not always be readily applicable;
therefore, immediate initiation of effective chemotherapies
is recommended.56Therapy with bortezomib-based regi-
mens plus high-dose dexamethasone [either alone or with
the addition of a third agent such as thalidomide (VTD),
doxorubicin (PAD) or cyclophosphamide (VCD)] should be
used as first choice.56The prospective, randomized phase
III (HOVON-65/GMMG-HD4) trial, including 81 of 827
patients with RI (serum-creatinine ≥2 mg/dL) and investi-
gating PAD versusVAD followed by ASCT and mainte-
nance with thalidomide or bortezomib, showed a substan-
tial improved OS at three years for the patients with
serum-creatinine of 2 mg/dL or more of 74% with PAD-ASCT-bortezomib versus34% with VAD-ASCT-thalido-
mide (P<0.001).
66In addition, it was also worthy of note
that both OS and progression-free (PFS) survival were sim-
ilar with base-line serum-creatinine of 2 mg/dL or more or
less than 2 mg/dL in the PAD-ASCT-bortezomib arm.
These results indicated that bortezomib-containing treat-
ment before and after ASCT may overcome the negative
prognostic impact of RI.66In elderly or comorbid patients
with RI, the combination with bortezomib with melpha-
lan and prednisone (VMP) may be preferred.67The second
proteasome inhibitor which has been licensed for MM,
carfilzomib, has also shown encouraging results in a small
phase II study with 38 relapsed/refractory patients with RI
(8 on chronic dialysis); responses were similar among
patients with different severity of renal dysfunction.68
More studies are needed to reveal the role of carfilzomib
in RI.
Immunomodulatory drugs (IMiDs) can also been admin-
istered in myeloma patients with RI. Thalidomide and
lenalidomide are very effective especially in patients with
mild to moderate RI; lenalidomide should be used with therecommended reduced doses based on renal function.56,69
Finally, responses to the combination of pomalidomide and
low-dose dexamethasone were similar between patients
with relapsed/refractory myeloma, irrespective of renal
function.70Bendamustine in combination with thalidomide
or bortezomib and prednisone is also feasible and safe,
even in patients with end-stage renal disease.71,72
Analyses of newly diagnosed MM patients with at least
moderate renal dysfunction showed that bortezomib-based regimens were the most effective in the reversibilityof renal function. Time to major renal response (renalCR or
renalPR) for thalidomide, bortezomib and lenalidomide-
based regimes was 2, 1.12 and 1.25 months, respectively.
73
Recommendations: every myeloma patient with RI needs a thor-
ough workup for the determination of the cause of RI (Figure 3).
For the evaluation of RI, the MDRD formula is recommended in
patients with stabilized serum creatinine. Patients with renal fail-
ure should be classified according to the KDIGO classification
(grade 1B). Novel formulas, such as the CKD-EPI, with or with-
out cystatin C, should be further assessed in clinical trials and in
large patient cohorts to evaluate their utility and prognostic impact.
Available data support the safety and efficacy of bortezomib-
based therapies in MM patients with RI and thus bortezomib
combined with dexamethasone (with or without thalidomide, dox-
orubicin or cyclophosphamide) is the recommended treatment
(grade 1A). Lenalidomide is a feasible and effective therapy option
with mild to moderate RI and is recommended with dose adjust-
ment according to renal function (grade 1B).
Peripheral neuropathy
Peripheral neuropathy (PN) is a significant complication
of MM that can be caused by the disease itself or by certain
therapies, including thalidomide- and bortezomib-based
therapies. Thorough clinical evaluation has shown that up
to 20% of MM patients have PN at diagnosis and up toGuidelines for myeloma complications
haematologica | 2015; 100(10) 1261Table 4.Total Neuropathy Scores.
Parameter Score
012 3 4
Sensory symptoms None Symptoms limited Symptoms extend Symptoms extend Symptoms above
to fingers or toes to ankle or wrist to knee or elbow knees or elbows, or
functionally disabling
Motor symptoms None Slight difficulty Moderate difficulty Require help or assistance Paralysis
Number of autonomic symptoms None One Two Three Four or five
Pin sensibility Normal Reduced in Reduced up to Reduced up Reduced above
fingers and/or toes wrist and/or ankle to elbow and/or knee elbow and/or knee
Vibration sensibility Normal Reduced in Reduced up to Reduced up to Reduced above
fingers and/or toes wrist and/or ankle elbow and/or knee elbow and/or knee
Strength Normal Mild weakness Moderate weakness Severe weakness Paralysis
Tendon reflex Normal Ankle reflex reduced Ankle reflex absent Ankle reflex absent, All reflexes absent
others reduced
Vibration sensation Normal to 125% 126-150% of ULN 151-200% of ULN 201-300% of ULN >300% of ULN
(QST vibration)* of ULN
Sural amplitude** Normal or reduced 76-95% of LLN 51-75% of LLN 26-50% of LLN 0-25% of LLN
to <5% of LLN
Peroneal amplitude** Normal or reduced 76-95% of LLN 51-75% of LLN 26-50% of LLN 0-25% of LLN
to <5% of LLN
*Used only in whole Total Neuropathy Score. **Used only in the Total Neuropathy Score-reduced. QST: quantitative sensory test; ULN: upper limit of normal; LLN: lower limit of nor-
mal. Score 0 is suggestive of no peripheral neuropathy (PN); score 1-9 is suggestive of mild PN; score 10-19 defines moderate PN, while score ≥20 defines severe PN.

75% may experience treatment-emergent PN during ther-
apy.74MM-associated PN is primarily sensory or sensori-
motor, and symptoms are predominantly symmetric,
including paresthesia, numbness, burning sensation and
weakness, often with mild intensity, but rarely with the
potency to be inactivating or life-threatening. Treatment-
induced PN symptoms are usually symmetric and distal
with some differences among therapies.75PN from thalido-
mide is cumulative, dose dependent and often permanent,
and may also occur after treatment has already stopped.74,75
Bortezomib-induced PN is related to dose, schedule and
mode of administration and is mostly reversible.
Symptoms of bortezomib-induced PN may start distally
and may progress proximally.74,75A randomized trial of sub-
cutaneous compared to intravenous administration of
bortezomib showed a significant decrease in PN of all
grades (38% vs. 53%) and grade 3 or 4 (6% vs.16%) with
the former, leading to its universal use.76Based on these
data, the up-dated US prescribing information added thatstarting subcutaneous bortezomib may be considered forpatients with pre-existing PN or at high-risk of PN (Table
3). The incidence of treatment-emergent PN with the
newer proteasome inhibitors is relatively low. Experience
from 526 relapsed/refractory MM patients in 4 phase II
studies with carfilzomib reported an overall incidence of
PN of 13.9%, grade 3 PN of 1.3% and no grade 4 or more;
moreover all of the grade 3 PN occurred in patients with
grade 1 or 2 at baseline.
77
Careful attention to the development of PN is essential,
while patients are on therapy and prompt dose reductionsare required. Lower doses of bortezomib, weekly adminis-
tration or different schedules (4- instead of 3-week cycles)may also be used. Regular monitoring for treatment-emer-
gent PN, sensible detection and intervention are relevant to
prevent the development of more severe PN (Table 3).
74,78
The NCI CTC definition of PN is commonly used in clini-
cal routine, but should be used with neuropathy-specificpatient-completed questionnaires, such as the whole or thereduced Total Neuropathy Score (Table 4).
79However, a
need remains for more sensitive assessment tools that
focus on MM patients with PN.
Several interventions have been investigated for treat-
ment-induced PN, but prospective analyses are lacking.
Acetyl-L-carnitin and alpha lipoic acid has shown activity
in the treatment of chemotherapy-induced PN.74Although
the neuropathic pain may often be poorly responsive to
standard analgesic treatment, opioids can be effective,
which should be combined with other pain modulating
drugs.44,74In addition, calcium channel blocker (e.g.
gabapentin and pregabalin), sodium channel blockers, such
as oxcarbazepine and serotonin-norepinephrine reuptakeinhibitors (e.g. duloxetine) can be very effective, especially
in painful PN.
44,74Recent studies in a mouse model with
anti-TNF- ashowed protection against neuropathy
induced by bortezomib, but future studies are essential toelucidate the etiopathogenesis of neuropathy, the role of
TNF- apathway and how bortezomib differentially regu-
lates NF- κB in tumoral and neuronal cells.
80
Recommendations: in the treatment for chemotherapy-induced
PN, prevention is a key strategy for patients’ quality of life and
ongoing treatment options (grade 2C). All MM patients withpotential neurotoxic drugs should be routinely and clinically
assessed for signs of PN before undergoing treatment; it is advis-
able that PN is graded with validated tools, such as the Total
Neuropathy Score (grade 2C). The use for dose modifications forthe management of bortezomib- or thalidomide-induced PN
remains the ‘gold standard’ of care (grade 1C). Reduction of PN
induced by bortezomib can be achieved by: a) prompt dose modi-
fication (1.3
→1.0→0.7 mg/m2); b) once a week instead of twice
weekly application; and c) subcutaneous rather than intravenous
administration (Table 3).
Infections
Myeloma is associated with increased rate of infections,
which is the main cause of death for myeloma patients. A
recent population-based study on 9253 myeloma patients
showed that the risk of developing a bacterial infection
was 7-fold higher and for viral infections 10-fold higher
compared to healthy individuals of the same sex and age.
At one year of follow up, infection was the underlying
cause in 22% of deaths in MM patients.81Haemophilus
influenzae,streptococcus pneumoniae , Gram negative bacilli
and viruses (influenza and herpes zoster) are the most fre-
quent causes of infection in myeloma patients.81
The increased susceptibility of patients to infections
results from the myeloma itself, therapies and/or age- and
disease-related conditions. Myeloma-related innate
immunodeficiency involves various parts of the immune
system and includes B-cell dysfunction as well as function-
al abnormalities of dendritic-, T- and natural killer (NK)-
cells.82Myeloma- and treatment-associated organ dysfunc-
tion, such as renal and/or pulmonary impairment, alimen-
tary mucosal damage and multiorgan involvement by
myeloma-associated deposition disease also increase the
risk for infections.83Finally, MM affects older patients who
frequently experience age-related frailty, geriatric condi-
tions and physical dysfunctions making them more suscep-
tible to infections (Figure 3).84
Multiple myeloma patients require thorough infection
monitoring and appropriate use of antibiotics (Table 3).85
There are only a few prospective studies evaluating the
role of prophylactic antibiotics in MM patients. In a ran-
domized, phase II study in 157 patients who underwent
ASCT, the administration of ciprofloxacin and vancomycin
reduced the incidence of neutropenic fever, without affect-
ing, however, the total interval of hospitalization, time to
engraftment, or all-cause mortality.86In another study, 212
myeloma patients who received initial chemotherapy were
randomized on a 1:1:1 basis to daily ciprofloxacin (500 mg
twice daily), trimethoprim-sulfamethoxazole (DS twice
daily) or observation. The incidence of severe bacterial
infections was similar among the three groups: 12.5%,
6.8% and 5.9%, respectively ( P=0.218). Similarly, the inci-
dence of any infection during the first two months of ther-
apy was also comparable (20%, 23% and 22%, respective-
ly; P=0.954).87
Regarding the incidence of infections with different
therapies, this has been reported to be 14% of patients
treated with lenalidomide and dexamethasone in MM-
009 and -010 trials88and approximately 30% (grade 3 and
4) of patients treated with pomalidomide plus low-dosedexamethasone, mainly during the first three months of
therapy.
89For this reason, routine antibiotic prophylaxis
should be considered for the first three months of therapy
with these IMiDs and is particularly recommended for
patients with aggressive disease, history of infectious com-
plications or neutropenia.88,89The available data do not sup-
port the use of any specific antibiotic regimen to use andE. Terpos et al.
1262 haematologica | 2015; 100(10)

thus clinicians should follow their institutional guidelines
for antibiotic prophylaxis. In patients who receive poma-
lidomide, quinolones must be used with caution due to
common metabolic pathways that can increase pomalido-
mide exposure.
The use of prophylactic immunoglobulin replacement
has shown no advantage in reducing infection rates in
newly diagnosed myeloma patients.90Regarding vaccina-
tions, myeloma patients show suboptimal antibody
responses to several vaccines; the responses seem to be
worse for polysaccharide than protein antigens.91In addi-
tion, all patients who undergo allogeneic SCT should
receive vaccinations for Haemophilus influenzae type b, per-
tussis, pneumococci, meningococci, tetanus, diphtheria,
hepatitis A and B, measles, mumps and rubella, influenza,
poliomyelitis, varicella-zoster virus, human papilloma
virus, and tick-borne encephalitis with a particular focus on
vaccination of patients with active chronic graft- versus-host
disease (GvHD).92
Recommendations: vaccination against influenza virus is appro-
priate and is recommended for both patients and their contacts.
Moreover vaccination against Streptococcus pneumonia and
Haemophilus influenzae is recommended, but efficacy for all
vaccines is not guaranteed, due to suboptimal immune response
(grade 1C). In general, live vaccines should be avoided in myelo-
ma patients (grade 2C). Aciclovir or valacyclovir for herpes-zostervirus prophylaxis is recommended for patients receiving protea-
some inhibitor-based therapies (grade 1A) or during ASCT/allo-
geneic-SCT, mainly in those with positive serology (grade 1C).Antiviral drugs should be continued for six weeks after discontin-
uation of the proteasome inhibitor. Due to increased infection rateduring lenalidomide or pomalidomide administration, antibiotic
prophylaxis is recommended at least for the first three months of
therapy (grade 2C). Prophylactic immunoglobulin replacement is
not routinely recommended; however, it may be useful in a subset
of patients with severe, recurrent bacterial infections and
hypogammaglobulinemia (grade 2C).
Venous thromboembolism
Myeloma itself, antimyeloma therapies, the presence of
infections, the history of previous venous thromboem-
bolism (VTE), immobility, obesity, paraplegia, ESA treat-
ment, comorbidities, dehydration and renal failure are all
important factors for the development of VTE. The inci-
dence of VTE is approximately 8-22/1000 person years.
Disease-related risk factors include the hyperviscosity, the
inhibition of natural anticoagulants and the hypercoagula-
bility status induced by inflammatory cytokines (i.e.
increased von Willebrand factor, fibrinogen and factor VIII
levels, acquired activated protein C resistance, decreased
protein S levels, etc.).93The incidence of VTE during front-
line therapy is 1%-2% with conventional therapies such as
melphalan and prednisone, and it is doubled by the use of
doxorubicin or other chemotherapeutic agents, while the
use of IMiDs in combination with dexamethasone or
chemotherapeutic agents produces a VTE risk of up to
70% in the absence of anticoagulation.94The risk for a VTE
is higher during the first four months of therapy with
lenalidomide or pomalidomide and then seems to be
reduced.88,89Aspirin and low molecular weight heparinGuidelines for myeloma complications
haematologica | 2015; 100(10) 1263
Figure 4. Special considerations prior to therapy in elderly or frail
patients. In multiple myeloma patients with newly diagnosed or refrac-
tory disease a detailed geriatric and functional assessment helps to
define more precisely 'fit' versus 'frail' patients and to evaluate
patients' risk for treatment toxicity and treatment discontinuation.
These definitions of fit, unfit and frail patients are anticipated to influ-
ence selection of therapeutics, as well as the correct allocation to
intensive or non-intensive treatment should reduce side-effects/SAEs
and treatment toxicity.

(LMWH) have been used in myeloma patients under
IMiDs. In a prospective, randomized, study, which com-
pared aspirin 100 mg/day and enoxaparin 40 mg/day in
342 newly diagnosed patients who received lenalidomide
and low-dose dexamethasone induction and melphalan-
prednisone-lenalidomide consolidation, the incidence of
VTE was 2.3% in the aspirin group and 1.2% in the enoxa-
parin group.95Thus, aspirin can be considered as adequate
anticoagulation therapy in patients who have no or one
risk factor for VTE (i.e. hyperviscosity, personal or family
history of VTE, obesity (Body Mass Index ≥30), co-mor-
bidities: cardiac, diabetes, RI, chronic inflammatory dis-
ease, immobility , thrombophilias, concomitant presence
of myeloproliferative disorders, hemoglobinopathies,
recent surgery (within 6 weeks), medications: ESAs, hor-
mone replacement therapy, tamoxifen/stilboestrol, dox-
orubicin, high-dose steroids ( ≥480mg of
dexamethasone/month). Otherwise LMWH or full-dose
warfarin can be used. The risk for bleeding has also to be
taken into account in the choice of anticoagulation.94
Recommendations: patients who are due to start IMiD therapy
should have a risk assessment for VTE and receive appropriate
anticoagulation during the treatment duration (grade 1A). In these
patients, aspirin (100 mg) is enough for VTE prophylaxis in low-
risk patients (i.e. without risk factors, or only one myeloma/individ-
ual risk factor present), unless contraindicated (grade 1B).
Otherwise, LMWH or full-dose warfarin has to be used (grade 1B).
The use of LMWH has to be continued for at least four months and
then patients may be switched to aspirin prophylaxis (grade 2C).
Treatment of confirmed VTE has to be according to international or
national guidelines96(grade 1A). In cases of VTE, despite the use of
full anticoagulation, the treating physician should consider the dis-
continuation of the responsible anti-myeloma drug (grade 2C).
Pain management recommendations
Pain is a considerable problem for many patients with
MM. Regarding bone disease, the use of BPs along with anti-
myeloma therapy, radiation or balloon kyphosplasty in spe-
cific indications may control the pain of the patients. The
treating physician should take into account that, in severalpatients, pain, and especially back pain, may be due to other
reasons, and not to myeloma itself. Regarding the relief of
pain using pain killers or other drugs, on the basis of avail-
able data we suggest the following.97-100Paracetamol can be
administered at a dose of up to 1 g qid for the control of mild
pain (grade 1B). In general, non-steroidal anti-inflammatory
drugs should be avoided in MM (grade 2C). Oral tramadol
or codeine can be given for the control of mild-moderate
pain (grade 1C). In cases of chronic moderate to severe pain,
fentanyl or buprenorphine patches or oxycodone are recom-
mended (grade 1B). For severe chronic pain, nervous block
with anesthetic drugs can be performed, while neurolytic
block using chemicals, heat and freezing, may produce long-
lasting blockade with pain relief for weeks, months or indef-
initely. For the management of acute severe pain, subcuta-
neous opioid (i.e. oxycodone or morphine injection) can be
used for the rapid relief of symptoms (grade 2B). Patients on
opioids should be also given laxatives (grade 1A). All
patients with chronic pain may be also considered as candi-
dates for calcium channel blockers (gabapentin or prega-
balin), for sodium channel blocker (lidocaine, oxcar-
bazepine) or a serotonin-norepinephrine reuptake inhibitors
(duloxetine or amitryptiline) (grade 1B).
Conclusion
In conclusion, complications related to disease and/or
anti-myeloma drugs contribute to increased mobility and
mortality of myeloma patients. Furthermore, such compli-
cations also alter the performance status of the patients to
define fit versusfrail patients and consequently select
and/or dose-reduce therapy (Figure 4). Therefore, the
appropriate management of these complications is crucial
for both patient quality of life and survival, and treating
physicians must pay special attention to their manage-
ment.
Authorship and Disclosures
Information on authorship, contributions, and financial & other
disclosures was provided by the authors and is available with the
online version of this article at www.haematologica.org.E. Terpos et al.
1264 haematologica | 2015; 100(10)References
1. Terpos E, Dimopoulos MA. Myeloma bone
disease: pathophysiology and management.
Ann Oncol. 2005;16(8):1223-1231.
2. Dimopoulos M, Terpos E, Comenzo RL, et al.
International myeloma working group con-sensus statement and guidelines regarding the
current role of imaging techniques in the
diagnosis and monitoring of multiple
Myeloma. Leukemia. 2009;23(9):1545-1556.
3. Terpos E, Moulopoulos LA, Dimopoulos
MA. Advances in imaging and the manage-
ment of myeloma bone disease. J Clin Oncol.
2011;29(14):1907-1915.
4. Regelink JC, Minnema MC, Terpos E, et al.
Comparison of modern and conventional
imaging techniques in establishing multiple
myeloma-related bone disease: a systematic
review. Br J Haematol. 2013;162(1):50-61.
5. Pianko MJ, Terpos E, Roodman GD, et al.
Whole-body low-dose computed tomogra-
phy and advanced imaging techniques for
multiple myeloma bone disease. Clin CancerRes. 2014;20(23):5888-5897.
6. Walker R, Barlogie B, Haessler J, et al.
Magnetic resonance imaging in multiple
myeloma: diagnostic and clinical implica-
tions. J Clin Oncol. 2007;25(9):1121-1128.
7. Waheed S, Mitchell A, Usmani S, et al.
Standard and novel imaging methods for
multiple myeloma: correlates with prognostic
laboratory variables including gene expres-
sion profiling data. Haematologica.2013;98(1):71-78.
8. Hillengass J, Fechtner K, Weber MA, et al.
Prognostic significance of focal lesions in
whole-body magnetic resonance imaging inpatients with asymptomatic multiple myelo-
ma. J Clin Oncol. 2010;28(9):1606-1610.
9. Kastritis E, Moulopoulos LA, Terpos E, et al.
The prognostic importance of the presence of
more than one focal lesion in spine MRI of
patients with asymptomatic (smoldering)
multiple myeloma. Leukemia. 2014;28(12):
2402-2403.
10. Rajkumar SV, Dimopoulos MA, Palumbo A,
et al. International Myeloma Working Groupupdated criteria for the diagnosis of multiple
myeloma. Lancet Oncol. 2014;15(12):e538-
548.
11. Moulopoulos LA, Dimopoulos MA,
Christoulas D, et al. Diffuse MRI marrow
pattern correlates with increased angiogene-sis, advanced disease features and poor prog-
nosis in newly diagnosed myeloma treated
with novel agents. Leukemia. 2010;24(6):1206-1212.
12. Zamagni E, Patriarca F, Nanni C, et al.
Prognostic relevance of 18-F FDG PET/CT in
newly diagnosed multiple myeloma patients
treated with up-front autologous transplanta-
tion. Blood. 2011;118(23):5989-5995.
13. Spinnato P, Bazzocchi A, Brioli A, et al.
Contrast enhanced MRI and (1)(8)F-FDG
PET-CT in the assessment of multiple myelo-
ma: a comparison of results in different phas-
es of the disease. Eur J Radiol. 2012;81(12):
4013-4018.
14. Derlin T, Peldschus K, Munster S, et al.
Comparative diagnostic performance of
(1)(8)F-FDG PET/CT versus whole-body MRI

for determination of remission status in mul-
tiple myeloma after stem cell transplantation.
Eur Radiol. 2013;23(2):570-578.
15. Kleber M, Udi J, Metzke B, et al. Challenging
the current approaches to multiple myeloma-
and other cancer-related bone diseases: from
bisphosphonates to targeted therapy. Leuk
Lymphoma. 2012;53(6):1057-1061.
16. Berenson JR, Lichtenstein A, Porter L, et al.
Efficacy of pamidronate in reducing skeletal
events in patients with advanced multiple
myeloma. Myeloma Aredia Study Group. N
Engl J Med. 1996;334(8):488-493.
17. Berenson JR, Rosen LS, Howell A, et al.
Zoledronic acid reduces skeletal-related
events in patients with osteolytic metastases.
Cancer. 2001;91(7):1191-1200.
18. Rosen LS, Gordon D, Kaminski M, et al.
Zoledronic acid versus pamidronate in the
treatment of skeletal metastases in patients
with breast cancer or osteolytic lesions of
multiple myeloma: a phase III, double-blind,
comparative trial. Cancer J. 2001;7(5):377-
387.
19. Rosen LS, Gordon D, Kaminski M, et al.
Long-term efficacy and safety of zoledronic
acid compared with pamidronate disodium
in the treatment of skeletal complications in
patients with advanced multiple myeloma or
breast carcinoma: a randomized, double-
blind, multicenter, comparative trial. Cancer.
2003;98(8):1735-1744.
20. Gimsing P, Carlson K, Turesson I, et al. Effect
of pamidronate 30 mg versus 90 mg on phys-
ical function in patients with newly diag-
nosed multiple myeloma (Nordic Myeloma
Study Group): a double-blind, randomised
controlled trial. Lancet Oncol. 2010;11(10):973-982.
21. Morgan GJ, Davies FE, Gregory WM, et al.
First-line treatment with zoledronic acid as
compared with clodronic acid in multiple
myeloma (MRC Myeloma IX): a randomisedcontrolled trial. Lancet. 2010;376(9757):1989-
1999.
22. Morgan GJ, Child JA, Gregory WM, et al.
Effects of zoledronic acid versus clodronic
acid on skeletal morbidity in patients with
newly diagnosed multiple myeloma (MRC
Myeloma IX): secondary outcomes from a
randomised controlled trial. Lancet Oncol.
2011;12(8):743-752.
23. Morgan GJ, Davies FE, Gregory WM, et al.
Effects of induction and maintenance plus
long-term bisphosphonates on bone disease
in patients with multiple myeloma: the
Medical Research Council Myeloma IX Trial.
Blood. 2012;119(23):5374-5383.
24. Mhaskar R, Redzepovic J, Wheatley K, et al.
Bisphosphonates in multiple myeloma: a net-
work meta-analysis. Cochrane Database Syst
Rev. 2012;5:CD003188.
25. Terpos E, Morgan G, Dimopoulos MA, et al.
International Myeloma Working Group rec-
ommendations for the treatment of multiple
myeloma-related bone disease. J Clin Oncol.
2013;31(18):2347-2357.
26. Berenson JR, Rosen L, Vescio R, et al.
Pharmacokinetics of pamidronate disodium
in patients with cancer with normal or
impaired renal function. J Clin Pharmacol.
1997;37(4):285-290.
27. Dimopoulos MA, Kastritis E,
Anagnostopoulos A, et al. Osteonecrosis of
the jaw in patients with multiple myelomatreated with bisphosphonates: evidence of
increased risk after treatment with zoledronic
acid. Haematologica. 2006;91(7):968-971.
28. Dimopoulos MA, Kastritis E, Bamia C, et al.
Reduction of osteonecrosis of the jaw (ONJ)after implementation of preventive measuresin patients with multiple myeloma treated
with zoledronic acid. Ann Oncol. 2009;20(1):
117-120.
29. Hellstein JW, Adler RA, Edwards B, et al.
Managing the care of patients receiving
antiresorptive therapy for prevention and
treatment of osteoporosis: executive summa-
ry of recommendations from the American
Dental Association Council on Scientific
Affairs. J Am Dent Assoc. 2011;142(11):1243-
1251.
30. Berenson J, Pflugmacher R, Jarzem P, et al.
Balloon kyphoplasty versus non-surgical frac-
ture management for treatment of painful
vertebral body compression fractures in
patients with cancer: a multicentre, ran-
domised controlled trial. Lancet Oncol.
2011;12(3):225-235.
31. Bhargava A, Trivedi D, Kalva L, Tumas M,
Hooks M, Speth J. Managment of cancer-
related vertebral compression fracture:
Comparison of treatment options-A literaturemeta-analysis. J Clin Oncol.
2009;27(15S):e20529.
32. Kyle RA, Gertz MA, Witzig TE, et al. Review
of 1027 patients with newly diagnosed mul-
tiple myeloma. Mayo Clin Proc.
2003;78(1):21-33.
33. König C, Kleber M, Ihorst G, et al. Prevalence
of iron overload vs iron deficiency in multiple
myeloma: resembling or different from MDS-
-and stem cell transplant (SCT)–patients?
Clin Lymphoma Myeloma Leuk.
2013;13(6):671-680.
34. Silvestris F, Cafforio P, Tucci M, Dammacco F.
Negative regulation of erythroblast matura-
tion by Fas-L(+)/TRAIL(+) highly malignant
plasma cells: a major pathogenetic mecha-
nism of anemia in multiple myeloma. Blood.
2002;99(4):1305-1313.
35. Birgegard G, Gascon P, Ludwig H. Evaluation
of anaemia in patients with multiple myelo-
ma and lymphoma: findings of the European
CANCER ANAEMIA SURVEY. Eur JHaematol. 2006;77(5):378-386.
36. Cazzola M, Messinger D, Battistel V, et al.
Recombinant human erythropoietin in the
anemia associated with multiple myeloma or
non-Hodgkin's lymphoma: dose finding and
identification of predictors of response.
Blood. 1995;86(12):4446-4453.
37. Dammacco F, Castoldi G, Rodjer S. Efficacy
of epoetin alfa in the treatment of anaemia of
multiple myeloma. Br J Haematol.
2001;113(1):172-179.
38. Osterborg A, Brandberg Y, Molostova V, et al.
Randomized, double-blind, placebo-con-
trolled trial of recombinant human erythro-
poietin, epoetin Beta, in hematologic malig-
nancies. J Clin Oncol. 2002;20(10):2486-2494.
39. Hedenus M, Adriansson M, San Miguel J, et
al. Efficacy and safety of darbepoetin alfa inanaemic patients with lymphoproliferative
malignancies: a randomized, double-blind,
placebo-controlled study. Br J Haematol.
2003;122(3):394-403.
40. Beguin Y, Maertens J, De Prijck B, et al.
Darbepoetin-alfa and intravenous iron
administration after autologous hematopoiet-
ic stem cell transplantation: a prospective
multicenter randomized trial. Am J Hematol.
2013;88(12):990-996.
41. Osterborg A, Brandberg Y, Hedenus M.
Impact of epoetin-beta on survival of patients
with lymphoproliferative malignancies: long-
term follow up of a large randomized study.Br J Haematol. 2005;129(2):206-209.
42. Tonia T, Mettler A, Robert N, et al.
Erythropoietin or darbepoetin for patients
with cancer. Cochrane Database Syst Rev.
2012;12:CD003407.43. Richardson P, Schlag R, Khuageva N, et al.
Characterization of haematological parame-
ters with bortezomib-melphalan-prednisone
versus melphalan-prednisone in newly diag-
nosed myeloma, with evaluation of long-
term outcomes and risk of thromboembolic
events with use of erythropoiesis-stimulating
agents: analysis of the VISTA trial. Br J
Haematol. 2011;153(2):212-221.
44. Snowden JA, Ahmedzai SH, Ashcroft J, et al.
Guidelines for supportive care in multiple
myeloma 2011. Br J Haematol. 2011;154(1):
76-103.
45. Katodritou E, Zervas K, Terpos E, Brugnara C.
Use of erythropoiesis stimulating agents and
intravenous iron for cancer and treatment-
related anaemia: the need for predictors and
indicators of effectiveness has not abated. Br
J Haematol. 2008;142(1):3-10.
46. Kleber M, Ihorst G, Deschler B, et al.
Detection of renal impairment as one specific
comorbidity factor in multiple myeloma:
multicenter study in 198 consecutive patients.
Eur J Haematol. 2009;83(6):519-527.
47. Davenport A, Merlini G. Myeloma kidney:
advances in molecular mechanisms of acute
kidney injury open novel therapeutic oppor-tunities. Nephrol Dial Transplant. 2012;27
(10):3713-3718.
48. Dimopoulos MA, Kastritis E, Rosinol L, Blade
J, Ludwig H. Pathogenesis and treatment ofrenal failure in multiple myeloma. Leukemia.
2008;22(8):1485-1493.
49. Hutchison CA, Batuman V, Behrens J, et al.
The pathogenesis and diagnosis of acute kid-
ney injury in multiple myeloma. Nat Rev
Nephrol. 2011;8(1):43-51.
50. Huang ZQ, Sanders PW. Biochemical interac-
tion between Tamm-Horsfall glycoprotein
and Ig light chains in the pathogenesis of cast
nephropathy. Lab Invest. 1995;73(6):810-817.
51. Sengul S, Zwizinski C, Simon EE, Kapasi A,
Singhal PC, Batuman V. Endocytosis of light
chains induces cytokines through activation
of NF-kappaB in human proximal tubule
cells. Kidney Int. 2002;62(6):1977-1988.
52. Ma CX, Lacy MQ, Rompala JF, et al. Acquired
Fanconi syndrome is an indolent disorder in
the absence of overt multiple myeloma.
Blood. 2004;104(1):40-42.
53. Bird JM, Owen RG, D'Sa S, et al. Guidelines
for the diagnosis and management of multi-
ple myeloma 2011. Br J Haematol. 2011;154
(1):32-75.
54. IMWG Criteria for the classification of mon-
oclonal gammopathies, multiple myeloma
and related disorders: a report of theInternational Myeloma Working Group. Br JHaematol. 2003;121(5):749-757.
55. Kleber M, Cybulla M, Bauchmuller K, Ihorst
G, Koch B, Engelhardt M. Monitoring of renal
function in cancer patients: an ongoing chal-
lenge for clinical practice. Ann Oncol.
2007;18(5):950-958.
56. Dimopoulos MA, Terpos E, Chanan-Khan A,
et al. Renal impairment in patients with mul-
tiple myeloma: a consensus statement on
behalf of the International Myeloma Working
Group. J Clin Oncol. 2010;28(33):4976-4984.
57. Levey AS, Eckardt KU, Tsukamoto Y, et al.
Definition and classification of chronic kid-ney disease: a position statement fromKidney Disease: Improving Global Outcomes
(KDIGO). Kidney Int. 2005;67(6):2089-2100.
58. Terpos E, Christoulas D, Kastritis E, et al. The
Chronic Kidney Disease Epidemiology
Collaboration cystatin C (CKD-EPI-CysC)
equation has an independent prognostic
value for overall survival in newly diagnosedpatients with symptomatic multiple myelo-
ma; is it time to change from MDRD toGuidelines for myeloma complications
haematologica | 2015; 100(10) 1265

CKD-EPI-CysC equations? Eur J Haematol.
2013;91(4):347-355.
59. Kleber M, Koch B, Wäsch R, Engelhardt M.
Estimation of GFR with different EGFR equa-
tions in multiple myeloma patients receiving
lenalidomide treatment. Blood. 2013;122
(Abstract 5324).
60. Dimopoulos M, Terpos E, Symeonidis A, et
al. Estimated Glomerular Filtration Rate
Calculated By The CKD-EPI Formula HasImproved Prognostic Ability Over MDRD
Formula In Patients With Newly Diagnosed,
Symptomatic, Multiple Myeloma: AnalysisIn 1937 Patients. Blood 2013;122(Abstract
1867).
61. Burnette BL, Leung N, Rajkumar SV. Renal
improvement in myeloma with bortezomib
plus plasma exchange. N Engl J Med.2011;364(24):2365-2366.
62. Clark WF, Stewart AK, Rock GA, et al. Plasma
exchange when myeloma presents as acute
renal failure: a randomized, controlled trial.
Ann Intern Med. 2005;143(11):777-784.
63. Hutchison C, Bridoux F, Fermand JP. Renal
improvement in myeloma with plasma
exchange. N Engl J Med. 2011;365(11):1061;
author reply 2.
64. Heyne N, Denecke B, Guthoff M, et al.
Extracorporeal light chain elimination: high
cut-off (HCO) hemodialysis parallel to
chemotherapy allows for a high proportion
of renal recovery in multiple myeloma
patients with dialysis-dependent acute kid-
ney injury. Ann Hematol. 2012;91(5):729-735.
65. Zannetti BA, Zamagni E, Santostefano M, et
al. Bortezomib-based therapy combined with
high cut-off hemodialysis is highly effective
in newly diagnosed multiple myeloma
patients with severe renal impairment. Am JHematol. 2015; doi: 10.1002/ajh.24035
66. Scheid C, Sonneveld P, Schmidt-Wolf IG, et
al. Bortezomib before and after autologous
stem cell transplantation overcomes the neg-
ative prognostic impact of renal impairment
in newly diagnosed multiple myeloma: a sub-
group analysis from the HOVON-65/GMMG-HD4 trial. Haematologica.2014;99(1):148-154.
67. Dimopoulos MA, Richardson PG, Schlag R,
et al. VMP (Bortezomib, Melphalan, and
Prednisone) is active and well tolerated in
newly diagnosed patients with multiple
myeloma with moderately impaired renal
function, and results in reversal of renal
impairment: cohort analysis of the phase IIIVISTA study. J Clin Oncol. 2009;27(36):6086-
6093.
68. Badros AZ, Vij R, Martin T, et al. Carfilzomib
in multiple myeloma patients with renal
impairment: pharmacokinetics and safety.
Leukemia. 2013;27(8):1707-1714.
69. Dimopoulos MA, Terpos E, Goldschmidt H,
Alegre A, Mark T, Niesvizky R. Treatment
with lenalidomide and dexamethasone in
patients with multiple myeloma and renal
impairment. Cancer Treat Rev. 2012;38(8):
1012-1019.
70. Weisel K, Dimopoulos MA, Cavo M, et al.
Pomalidomide + low-dose dexamethasone in
patients with refractory or relapsed and
refractory multiple myeloma and renal
impairment: analysis of patients from the
phase 3b Stratus trial (MM-010). Blood.
2014;124(21)(Abstract)4755.71. Ramasamy K, Hazel B, Mahmood S,
Corderoy S, Schey S. Bendamustine in com-
bination with thalidomide and dexametha-sone is an effective therapy for myeloma
patients with end stage renal disease. Br J
Haematol. 2011;155(5):632-634.
72. Pönisch W, Moll B, Bourgeois M, et al.
Bendamustine and prednisone in combina-
tion with bortezomib (BPV) in the treatmentof patients with relapsed or refractory multi-
ple myeloma and light chain-induced renal
failure. J Cancer Res Clin Oncol.
2013;139(11):1937-1946.
73. Dimopoulos MA, Roussou M,
Gkotzamanidou M, et al. The role of novel
agents on the reversibility of renal impair-
ment in newly diagnosed symptomatic
patients with multiple myeloma. Leukemia.
2013;27(2):423-429.
74. Richardson PG, Delforge M, Beksac M, et al.
Management of treatment-emergent periph-
eral neuropathy in multiple myeloma.
Leukemia. 2012;26(4):595-608.
75. Delforge M, Bladé J, Dimopoulos MA, et al.
Treatment-related peripheral neuropathy in
multiple myeloma: the challenge continues.
Lancet Oncol. 2010;11(11):1086-1095.
76. Moreau P, Pylypenko H, Grosicki S, et al.
Subcutaneous versus intravenous administra-
tion of bortezomib in patients with relapsed
multiple myeloma: a randomised, phase 3,
non-inferiority study. Lancet Oncol. 2011;12
(5):431-440.
77. Siegel D, Martin T, Nooka A, et al. Integrated
safety profile of single-agent carfilzomib:
experience from 526 patients enrolled in 4phase II clinical studies. Haematologica.
2013;98(11):1753-1761.
78. Gay F, Palumbo A. Multiple myeloma: man-
agement of adverse events. Med Oncol.
2010;27(3):646-653.
79. Richardson PG, Briemberg H, Jagannath S, et
al. Frequency, characteristics, and reversibility
of peripheral neuropathy during treatment of
advanced multiple myeloma with borte-
zomib. J Clin Oncol. 2006;24(19):3113-3120.
80. Ale A, Bruna J, Morell M, et al. Treatment
with anti-TNF alpha protects against the neu-
ropathy induced by the proteasome inhibitor
bortezomib in a mouse model. Exp Neurol.
2014;253:165-173.
81. Blimark C, Holmberg E, Mellqvist UH, et al.
Multiple myeloma and infections: a popula-
tion-based study on 9253 multiple myeloma
patients. Haematologica. 2015;100(1):107-
113.
82. Tete SM, Bijl M, Sahota SS, Bos NA. Immune
defects in the risk of infection and response to
vaccination in monoclonal gammopathy of
undetermined significance and multiple
myeloma. Front Immunol. 2014;5:257.
83. Nucci M, Anaissie E. Infections in patients
with multiple myeloma. Semin Hematol.
2009;46(3):277-288.
84. Kleber M, Ihorst G, Gross B, et al. Validation
of the Freiburg Comorbidity Index in 466
multiple myeloma patients and combination
with the international staging system are
highly predictive for outcome. Clin
Lymphoma Myeloma Leuk. 2013;13(5):541-
551.
85. Mehta J, Cavo M, Singhal S. How I treat eld-
erly patients with myeloma. Blood.
2010;116(13):2215-2223.86. Eleutherakis-Papaiakovou E, Kostis E,
Migkou M, et al. Prophylactic antibiotics for
the prevention of neutropenic fever in
patients undergoing autologous stem-cell
transplantation: results of a single institution,
randomized phase 2 trial. Am J Hematol.
2010;85(11):863-867.
87. Vesole DH, Oken MM, Heckler C, et al. Oral
antibiotic prophylaxis of early infection in
multiple myeloma: a URCC/ECOG random-
ized phase III study. Leukemia. 2012;26(12):
2517-2520.
88. Dimopoulos MA, Palumbo A, Attal M, et al.
Optimizing the use of lenalidomide in
relapsed or refractory multiple myeloma:
consensus statement. Leukemia. 2011;25(5):
749-760.
89. Dimopoulos MA, Leleu X, Palumbo A, et al.
Expert panel consensus statement on the
optimal use of pomalidomide in relapsed and
refractory multiple myeloma. Leukemia.
2014;28(8):1573-1585.
90. Salmon SE, Samal BA, Hayes DM, Hosley H,
Miller SP, Schilling A. Role of gamma globulin
for immunoprophylaxis in multiple myelo-
ma. N Engl J Med. 1967;277(25):1336-1340.
91. Robertson JD, Nagesh K, Jowitt SN, et al.
Immunogenicity of vaccination against
influenza, Streptococcus pneumoniae and
Haemophilus influenzae type B in patientswith multiple myeloma. Br J Cancer.
2000;82(7):1261-1265.
92. Hilgendorf I, Freund M, Jilg W, et al.
Vaccination of allogeneic haematopoietic
stem cell transplant recipients: report fromthe international consensus conference on
clinical practice in chronic GVHD. Vaccine.
2011;29(16):2825-2833.
93. De Stefano V, Za T, Rossi E. Venous throm-
boembolism in multiple myeloma. Semin
Thromb Hemost. 2014;40(3):338-347.
94. Palumbo A, Rajkumar SV, Dimopoulos MA,
et al. Prevention of thalidomide- and lenalido-mide-associated thrombosis in myeloma.
Leukemia. 2008;22(2):414-423.
95. Larocca A, Cavallo F, Bringhen S, et al. Aspirin
or enoxaparin thromboprophylaxis for
patients with newly diagnosed multiple
myeloma treated with lenalidomide. Blood.
2012;119(4):933-939.
96. Kuderer NM, Lyman GH. Guidelines for
treatment and prevention of venous throm-
boembolism among patients with cancer.
Thromb Res. 2014;133 Suppl 2:S122-127.
97. Davis MP, Walsh D, Lagman R, LeGrand SB.
Controversies in pharmacotherapy of pain
management. Lancet Oncol. 2005;6(9):696-
704.
98. Snowden JA, Ahmedzai SH, Ashcroft J, et al.
Guidelines for supportive care in multiple
myeloma 2011. Br J Haematol. 2011;154(1):
76-103.
99. Yan PZ, Butler PM, Kurowski D, Perloff MD.
Beyond neuropathic pain: gabapentin use in
cancer pain and perioperative pain. Clin J
Pain. 2014;30(7):613-629.
100.Palumbo A, Rajkumar SV, San Miguel JF, et al.
International myeloma working group con-
sensus statement for the management, treat-
ment, and supportive care of patients with
myeloma not eligible for standard autologous
stem-cell transplantation. J Clin Oncol. 2014;
32(6):587-600.E. Terpos et al.
1266 haematologica | 2015; 100(10)