Review

How to Manage Neutropenia in Multiple Myeloma

Antonio Palumbo,1 Jon Bladé,2 Mario Boccadoro,1 Carmela Palladino,1
Faith Davies,3 Meletios Dimopoulos,4 Anna Dmoszynska,5 Hermann Einsele,6
Philippe Moreau,7 Orhan Sezer,8 Andrew Spencer,9 Pieter Sonneveld,10
Jesus San Miguel11

Abstract
Neutropenia is a hematologic adverse event characterized by an absolute neutrophil count (ANC) lower than 1500
cells/mL. This reduction may be due to decreased neutrophil production, accelerated use, a shift in compartments
of neutrophils, or a combination of these factors. Neutropenia is often associated with infections, which are major
causes of morbidity and mortality in patients with cancer. In patients with multiple myeloma, the novel agents
thalidomide, lenalidomide, and bortezomib have improved outcome, but chemotherapy-related neutropenia should
be carefully considered. Chemotherapy-related high-risk factors for severe neutropenia include regimens with an
expected neutropenia rate of ⬎ 50%, such as the 3-drug combinations including lenalidomide plus alkylating agents
or doxorubicin, whereas low-risk regimens include combinations of the novel agents with dexamethasone alone.
Patient characteristics, disease stage, type of current and previous treatment, and ANC ⬍ 1000 cells/mL at baseline
are additional factors that define the risk of severe neutropenia.
Granulocyte-colony stimulating factor (G-CSF) should be used to manage chemotherapy-related neutropenia so
that patients may stay on treatment for a longer time and benefit from it. Primary G-CSF prophylaxis should be used
when high-risk regimens are administered or when low/intermediate-risk regimens are used and additional risk
factors are present. Reactive G-CSF treatment is indicated when patients undergoing low-risk chemotherapy
experience grade 3/4 neutropenia. If ANC restores to ⬎ 1000 cells/mL, therapy can be resumed with no dose
modifications. In case of persistence of severe neutropenia, treatment should be delayed until ANC reaches ⬎ 1000
cells/mL, and dose reductions are necessary.

Clinical Lymphoma, Myeloma & Leukemia, Vol. 12, No. 1, 5-11 © 2012 Elsevier Inc. All rights reserved.
Keywords: Absolute neutrophil count, Granulocyte colony-stimulating factor, Multiple myeloma,
Myelosuppression, Neutropenia

Definition and Classification of trophils originate from pluripotential stem cells in the bone mar-
Neutropenia row.1 Two hematopoietic growth factors, namely granulocyte colo-
Neutropenia is a blood disorder related to neutrophilic white cells, ny-stimulating factor (G-CSF) and granulocyte-macrophage colony-
which are essential to prevent bacterial and fungal infections. Neu- stimulating factor, regulate the production and deployment of
neutrophils.2 Healthy adults have an absolute neutrophil count
(ANC) of about 1500-7000 cells/mL (1.5-7.0 ⫻ 109/L). According
1
Myeloma Unit, Division of Hematology, University of Torino, AOU San Giovanni to the National Cancer Institute Common Terminology Criteria for
Battista, Torino, Italy
2
Department of Hematology, Hospital Clinic, Barcelona, Spain Adverse Events (NCI CTCAE) V3.0, it is classified as mild (ANC
3
Institute of Cancer Research and Royal Marsden Hospital, London, United
Kingdom
4
Department of Clinical Therapeutics, University of Athens School of Medicine, 10
Department of Hematology, University Hospital Rotterdam, Rotterdam,
Alexandra General Hospital, Athens, Greece Netherlands
5
Department of Haematooncology and Bone Marrow Transplantation, Medical 11
Servicio de Hematología, Hospital Universitario de Salamanca, and CIC, IBMCC
University of Lublin, Lublin, Poland (USAL-CSIC), Salamanca, Spain
6
Department of Internal Medicine II, University Hospital Würzburg, Würzburg,
Germany Submitted: Aug 4, 2011; Revised: Oct 14, 2011; Accepted: Nov 9, 2011
7
Hematology Department, University Hospital Hôtel-Dieu, Nantes, France
8
Department of Hematology and Oncology, University Medical Center, Hamburg, Address for correspondence: Antonio Palumbo, Myeloma Unit, Division of
Germany Hematology, University of Torino, AOU San Giovanni Battista, Torino, Italy
9
Malignant Hematology and Stem Cell Transplantation Service, Alfred Hospital, Fax: ⫹39 01 1696 3737; e-mail contact: appalumbo@yahoo.com
Melbourne, Australia

2152-2650/$ - see frontmatter © 2012 Elsevier Inc. All rights reserved.

doi: 10.1016/j.clml.2011.11.001 Clinical Lymphoma, Myeloma & Leukemia February 2012 5
 How to Manage Neutropenia in Multiple Myeloma
Table 1 Neutropenia Severity According to the National
Cancer Institute Common Toxicity Criteria
Grade ANC (cells/mL)
0 Within normal limits
1 ⱖ 1500 to ⬍ 2000
2 ⱖ 1000 to ⬍ 1500
3 ⱖ 500 to ⬍ 1000
4 ⬍ 500
Abbreviation: ANC ⫽ absolute neutrophil count.
1000-1500 cells/mm3), moderate (ANC 500-1000 cells/mm3), and
severe (ANC ⬍ 500 cells/mm3) (Table 1).
Febrile neutropenia is classified as an ANC lower than 1000 cells/
mm3 (⬍ 1.0 ⫻ 109/L) and with fever higher than 38.3°C (101°F) or
a sustained temperature of ⱖ 38°C (100.4°F) for more than 1 hour
(NCI CTCAE V4.0).
Severe neutropenia can lead to serious problems and requires im-
mediate and careful care because the patient could potentially ac-
quire a bacterial, fungal, or mixed infections at any time. Symptoms
depend on the level and grade of neutropenia. The lower the neutro-
phil count, the greater the grade of neutropenia (Table 1) and con-
sequently the higher the risk of infection. This risk normally in-
creases if the neutrophil count remains less than the normal level for
more than 3 days. Types of infection include otitis media, tonsillitis,
sore throat, mouth ulcers, gum infection, and skin abscesses. Any
fever (body temperature ⬎ 38.5°C or 101.3°F) must be taken very
seriously into account and the physician should be informed. Signs of
infection, such as swelling and warmth, are not usually present in
neutropenia-associated infections.3
Neutropenia in Multiple Myeloma
Multiple myeloma is the second most common hematologic ma-
lignancy. It accounts for 1% of all cancers and 13% of hematologic
neoplasms; it is typically seen in the elderly, and the median age at
diagnosis is 70 years,4 – 6 Although the disease remains incurable, the
introduction of novel agents such as the immunomodulatory drugs
thalidomide and lenalidomide and the proteasome inhibitor bort-
ezomib, has markedly changed the treatment paradigm of myeloma
and considerably improved outcomes.7 The efficacy of these drugs
should always be balanced against their toxicity profile. Therapy-
related toxicities may in fact negatively affect outcome and lead to
early treatment discontinuation. Neutropenia is a hematologic side
effect commonly associated with chemotherapy.8,9
In myeloma patients receiving new drugs, constant monitoring
may predict occurrence of neutropenia. Neutropenia can also be
managed with appropriate supportive case management, dose adjust-
ment, and growth factor support. In the era of novel agents, neutro-
penia is less common, especially with thalidomide and bortezomib,
unless they are combined with conventional agents, such as alkylat-
ing agents. By contrast, lenalidomide-induced neutropenia should
always be considered because neutropenia is one of the most frequent
side effects of lenalidomide. The reported incidence of grade 3/4
neutropenia with lenalidomide is approximately 35%,10,11 and it is
about 11% and 1% with bortezomib and thalidomide, respec-
6 Clinical Lymphoma, Myeloma & Leukemia February 2012
tively.12,13 These drugs, particularly when used in association with
standard chemotherapy in elderly and transplant-ineligible patients,
may cause severe myelosuppression.14 Since severe neutropenia is a
relevant side effect of lenalidomide, a group of experts has provided
some clinical guidance for the management of cytopenia. In general,
the blood count should be monitored on a biweekly basis during
lenalidomide treatment, but weekly monitoring is recommended in
patients with cytopenia at baseline. In case of cytopenia, G-CSF or
erythropoietin stimulating agents may be necessary, and in some
cases dose reductions or interruptions may be needed.15 Routine
antibiotic use is recommended for all patients on initiation of lena-
lidomide treatment.16
This article focuses on neutropenia in multiple myeloma and aims
to provide clinicians with a simple algorithm to deal with this side
effect. This article is based on the consensus achieved among the
authors. Amgen has provided support to write the guidelines but did
not provide any comment on the content, data analysis, or
interpretation.
Risk Factor Assessment
Low ANC before starting treatment is the primary risk factor for
the development of severe neutropenia and neutropenic complica-
tions after chemotherapy.17–19 Additional risk factors can be identi-
fied. They can be classified as patient-specific, cancer-specific, or
treatment-specific (Table 2). Patient-specific risk factors are female
sex, a small body surface area (BSA) (⬍ 2 m2) and age ⬎ 65 years.
These factors represent a major risk for chemotherapy-related toxic-
ity in oncology and are associated with severe myelosuppression be-
cause of high systemic absorption of drugs resulting in increased
toxicity. Comorbidities such as diabetes mellitus and cardiovascular
disease as well as the presence of open wounds and altered hepatic or
renal function, which are typical of the elderly, poor nutritional sta-
tus with low serum albumin levels, and low performance status
highly increase the risk of neutropenic complications.17,18,20 –22
Cancer-specific risk factors for neutropenia include type and status
of cancer. The more the abnormal process of growth involves the
bone marrow, the higher the severity and grade of cytopenia in pe-
ripheral blood, and the slower the recovery after chemotherapy. Pa-
tients who have already received chemotherapy and have aggressive
or relapsed/refractory disease are at higher risk for the development
of grade 3/4 neutropenia.17,19 Treatment-specific risk factors in-
clude previous exposure to chemotherapy or radiation therapy,
which contributes to cytopenia and neutropenia. Of note, all patients
who are treated with chemotherapy are at risk for neutropenic com-
plications.17,19 The type of chemotherapeutic regimen is one of the
primary determinants of the risk of neutropenia in multiple my-
eloma. Some chemotherapeutic regimens are more myelotoxic than
others. High-dose alkylating agents and novel agent– containing
therapies for multiple myeloma can cause myelosuppression, espe-
cially when used in combination.23
Based on the risk of chemotherapy-induced neutropenia in pa-
tients with multiple myeloma, 4 categories of risk regimens can be
identified: low, low/intermediate, intermediate, and high (Table 3).
Overall, in patients who receive chemotherapy for the first time and
have no other risk factors, low-risk regimens include novel agents in
association with dexamethasone, such as lenalidomide in association
 Antonio Palumbo et al
Table 2 Risk Factors for Neutropenia

Patient-Related Cancer-Related Treatment-Related

Age > 65 years Heavy marrow infiltration History of severe neutropenia with previous chemotherapy
Comorbidities
Female Sex Advanced/uncontrolled disease High-risk chemotherapy
Poor Nutritional Status (low albumin)
Decreased Immune Function Relapsed/refractory disease Extensive previous chemotherapy
Low Performance Status
Small Body Surface Area < 2 m2 Preexisting neutropenia Concurrent or previous radiation therapy

Table 3 Neutropenia Risk Associated with Each Regimen
Grade 3/4 < 50% Grade 3/4 > 50%
Low Risk
Low/Intermediate Intermediate
High Risk
Risk Risk
RD MPT PAD RAD
VD CTD CVD MPR
TD MPV CRD
VTD
VRD
Abbreviations: CRD ⫽ cyclophosphamide-lenalidomide-dexamethasone; CTD ⫽ cyclophosph-
amide-thalidomide-dexamethasone; CVD ⫽ cyclophosphamide-bortezomib-dexamethasone;
MPR ⫽ melphalan-prednisone-lenalidomide; MPT ⫽ melphalan-prednisone-thalidomide;
MPV ⫽ melphalan-prednisone-bortezomib; PAD ⫽ bortezomib-Adriamycin-dexamethasone;
RAD ⫽ lenalidomide-Adriamycin-dexamethasone; RD ⫽ lenalidomide-dexamethasone;
TD ⫽ thalidomide-dexamethasone; VD ⫽ bortezomib-dexamethasone; VRD ⫽ bortezomib-
lenalidomide-dexamethasone; VTD ⫽ bortezomib-thalidomide-dexamethasone.
with dexamethasone (RD),24 bortezomib plus dexamethasone
(VD),25 and thalidomide plus dexamethasone (TD).26 Low/inter-
mediate-risk regimens include thalidomide plus melphalan and
prednisone (MPT)27 and thalidomide plus cyclophosphamide and
dexamethasone (CTD). Intermediate-risk regimens include bort-
ezomib-doxorubicin-dexamethasone (PAD),28 cyclophosphamide-
bortezomib-dexamethasone (CVD), bortezomib-melphalan-predni-
sone (VMP),29 and the combinations of bortezomib with
dexamethasone plus either thalidomide (VTD)30 or lenalidomide
(VRD). High-risk regimens include the 3-drug combinations con-
taining lenalidomide plus doxorubicin-dexamethasone (RAD),31
melphalan-prednisone (MPR), cyclophosphamide-dexamethasone
(CRD), or melphalan-prednisone (MPR),32 in which the expected
incidence of neutropenia is higher than 50%.
Besides the neutropenia risk associated with the specific regimen,
patient and disease characteristics remain fundamental to assess the
final risk category. In particular, patients with preexisting cytopenia
and high tumor burden in the bone marrow are at higher risk of
severe neutropenia.14,33
Febrile Neutropenia
Febrile neutropenia is defined as a single oral temperature reading
higher than 38.3°C (101°F) or a sustained (more than 1 hour) tem-
perature of ⱖ 38°C (100.4°F) in a patient with an ANC lower than
1000 cells/mm3 (⬍ 1.0 ⫻ 109/L) (NCI CTCAE V4.0). In the past
few years, the mortality rate due to febrile neutropenia has decreased
steadily, but it remains significant. In some hematologic malignan-
cies, overall mortality from febrile neutropenia reaches 14%, whereas
for multiple myeloma it is around 8%.34 Neutropenia alters the
host’s inflammatory response, making it difficult to detect the usual
signs and symptoms of infection. A careful history and a detailed and
repeated physical examination are thus necessary. In patients with
central venous catheters, at least 2 sets of blood cultures from the
catheters and from a peripheral site, as well as cultures from other
sites (eg, urine, stool, throat), should be obtained before starting
empirical antibiotic therapy. Cultures should be repeated daily while
patients remain febrile. Chest radiography followed by imaging tech-
niques such as high-resolution computed tomography (CT) is essen-
tial to detect pulmonary lesions. CT, magnetic resonance imaging,
ultrasonography, and radionuclide imaging of any potential site of
infection must be performed. Invasive procedures such as broncho-
scopic examination and lung, liver, or skin biopsy are also useful to
detect infections.
It is hard to predict the risk of complications related to febrile neutro-
penia. Differentiating between high- and low-risk patients has a signifi-
cant impact on the patients’ quality of life and outcome, as well as on
medical costs for hospitalization.8,35 The degree of neutropenia and its
duration are important aspects to consider. Patients who are expected to
recover their granulocyte counts in ⬍ 1 week are generally considered at
low risk of complications after onset of fever. High-risk patients experi-
ence prolonged neutropenia lasting ⬎ 7 days.36
An internationally validated scoring system to classify patients
with cancer according to the risk of febrile neutropenia has been
developed by the Multinational Association of Supportive Care in
Cancer (MASCC) and is shown in Table 4. This numerical risk score
takes into account different features that are likely to contribute to a
favorable outcome. A high global score indicates a high probability of
fever resolution with no serious complications. A MASCC risk score
ⱖ 21 identifies low-risk patients with a positive predictive value of
91%, a specificity of 68%, and a sensitivity of 71%.37
Based on this score index, high-risk patients have a global risk
score ⬍ 21. G-CSF is not routinely indicated as an adjunct to anti-
biotic therapy in uncomplicated fever and neutropenia. However the
use of G-CSF should be considered in patients at high risk for com-
plications, or when prognostic factors are predictive of poor clinical
outcome, including expected prolonged (⬎ 10 days) and profound
(ANC ⬍ 1000 cells/mL) neutropenia, age ⬎ 65 years, uncontrolled
primary disease, pneumonia, hypotension and multiorgan dysfunc-

Clinical Lymphoma, Myeloma & Leukemia February 2012 7

 How to Manage Neutropenia in Multiple Myeloma
Table 4 Multinational Association of Supportive Care in
Cancer Index
Variables
Burden of Illness
No or mild symptoms
Moderate symptoms
Severe symptoms
No Hypotension (Systolic blood pressure
> 90 mm Hg)
No Chronic Obstructive Pulmonary Disease
Solid Tumor/Lymphoma With No Previous
Fungal Infection
No Dehydration
Outpatient Status (at Onset of Fever)
Age < 60 Years
A global score ⱖ 21 denotes low risk of complications. Points attributed to the variable “burden
of illness” are not cumulative. The maximum theoretical score is therefore 26.
tion (sepsis syndrome), invasive fungal infection, and hospitalization
at the time of development of fever.20,38 – 42
Recommendations for the Management of Novel
Therapy–related Neutropenia In Multiple Myeloma
In patients with multiple myeloma who are treated with novel
agent– containing chemotherapy, the risk of severe neutropenia and
neutropenic complications should be carefully taken into account.
Particular attention should be paid to febrile neutropenia, since it
requires hospitalization, involves substantial costs, and has mortality
rates that are not negligible.43
To limit and manage neutropenia and the related complications, sim-
ple guidelines for physicians to appropriately use G-CSF are needed.
G-CSF is a glycoprotein that stimulates survival, proliferation, differen-
tiation, and function of neutrophil granulocyte progenitor cells and ma-
ture neutrophils. The two forms of recombinant human G-CSF in clin-
ical use (filgrastim and lenograstim) are potent stimulants of neutrophil
granulopoiesis and have demonstrated efficacy in preventing infectious
complications of some neutropenic states.41
Two major strategies for the use of G-CSF are recommended, as
either primary or reactive prophylaxis. Primary G-CSF prophylaxis is
recommended when using chemotherapy regimens associated with a
high risk of the development of grade 3/4 neutropenia, when the
expected neutropenia rate is ⬎ 50%. Thus G-CSF prophylaxis is
recommended with 3-drug regimens containing lenalidomide, such
as MPR, CRD, and RAD. In addition, primary G-CSF prophylaxis
should be used with low/intermediate-risk regimens with an ex-
pected severe neutropenia incidence ⬍ 50%, such as the 2-drug
regimens RD, VD, and TD and the 3-drug combinations MPT,
CTD, PAD, MPT, VMP, VTD, and VRD, only if 1 or more pa-
tient- or cancer-related risk factors are also present and ANC is ⬍
1000 cells/mL at the start of chemotherapy (Table 3). Moreover it is
strongly recommended that the dose be adjusted correctly based on
BSA when using chemotherapy regimens with a high risk for the
development of grade 3/4 neutropenia.
8 Clinical Lymphoma, Myeloma & Leukemia February 2012
Clinical data support the use of primary G-CSF prophylaxis in
patients receiving chemotherapy regimens with an expected febrile
neutropenia rate higher than 20%, as well as in those with a febrile
Score neutropenia rate of 10%-20% when at least 1 patient-related risk
factor for febrile neutropenia is present.20,44
A different approach is recommended when severe neutropenia
5
occurs in a patient with multiple myeloma who has been treated
3
with chemotherapy with a low or low/intermediate risk of severe
0 neutropenia and who does not present with any other risk factors.
In these patients, reactive G-CSF prophylaxis should be used, that
5
is to say prophylaxis is administered only after the occurrence of
4 the adverse event. If neutropenia resolves and ANC restores to ⬎
4 1000 cells/mL after G-CSF administration, therapy can be re-
sumed and no dose modifications are needed (Figure 1). On the
3 contrary, if ANC remains lower than 1000 cells/mL, treatment
3 should be delayed until ANC recovers to ⬎ 1000 cells/mL, and
2 dose reductions are necessary (Table 5). If the patient experiences
another severe neutropenic event after the first dose reduction,
treatment should be suspended again. It can be resumed when the
ANC rises to ⬎ 1000 cells/mL and treatment can be resumed
with further dose reductions (Table 5). Finally, in patients with
high tumor burden in the bone marrow, full-dose chemotherapy
is recommended; consequent myelosuppression is not to be
treated with G-CSF administration, but monitoring until recov-
ery is suggested, unless complications occur (fever, infection).
Dose and Timing of G-CSF
Since the kinetics and recovery of bone marrow function vary
between cytotoxic agents and regimens, it is difficult to provide gen-
eral recommendations on dose and timing.
G-CSF is contraindicated within 24 hours of chemotherapy, when
stimulation of progenitor cells in the presence of cytotoxic agents
may worsen the myelotoxicity of the regimen. For cytotoxic drugs
with a long half-life, a longer interval may be required to avoid in-
creased myelotoxicity.39,42
Subcutaneous and intravenous G-CSF have equivalent potency, but
subcutaneous injection is generally recommended, as it is suitable for
outpatients.45
Lenograstim 150 ␮g/m2 once daily by subcutaneous injection
(vial/syringe size 105 ␮g and 263 ␮g) is commonly used in practice
in a daily dose of 263 ␮g (patients with BSA ⬎ 1.8 m2 may be given
an additional 105 ␮g daily, either initially or if they have an inade-
quate response to the standard daily dose).20
Filgrastim 5 ␮g/kg is used once daily by subcutaneous injection
(vial/syringe size 300 ␮g and 480 ␮g). It is common practice for a
daily dose of 300 ␮g to be given; however patients who weigh ⬎ 90
kg may be given the 480-␮g syringe either initially or if they have
inadequate response to the standard dose.
Lenograstim and filgrastim should be started not before 24 hours
and not later than 72 hours after cytotoxic treatment is completed. In
this way the stimulus provided by G-CSF will be present at a time
when the bone marrow is regenerative and able to respond. G-CSF
injections should continue until ANC has recovered to at least 1000
cells/mL on 2 consecutive days.46
Filgrastim is recommended to manage febrile neutropenia. It should
be administered at the standard dose of 5 ␮g/kg daily, starting the day
 Antonio Palumbo et al
Figure 1 Algorithm for the Use of G-CSF in Patients with Myeloma Who are Receiving Chemotherapy

Grade 3-4 neutropenia observed

action
Add G-CFS and maintain doses

Does patient recover to ANC > 1000 ?

YES NO
action

action
Delay therapy until ANC ≥1000
Continue therapy at the same doses +
Resume treatment at reduced doses*

Abbreviations: ANC ⫽ absolute neutrophil count; G-CSF ⫽ granulocyte-colony stimulating factor. * Dose reductions are reported in Table 5.

Table 5 Suggested Dose Reductions When Grade 3/4 Events Do Not Resolve Despite G-CSF

Drug Full Dose Suggested Dose Reduction Further Reduction, if Needed

Melphalan 0.25 mg/kg days 1-4 for 4-6 weeks 0.18 mg/kg days 1-4 for 4-6 weeks 0.13 mg/kg days 1-4 for 4-6 weeks
Thalidomide 100 mg/day 50 mg/day 50 mg every other day
Lenalidomide 25 mg/day days 1-21 for 4 weeks 15 mg/day days 1-21 for 4 weeks 10 mg/day days 1-21 for 4 weeks
1.3 mg/m2 twice weekly days 1, 4, 8, 1.3 mg/m2 once weekly days 1, 8, 15, 22 for 5 1.0 mg/m2 once weekly days 1, 8, 15, 22 for
Bortezomib
11 for 3 weeks weeks 5 weeks
100 mg/day days 1-21 for 4 weeks or
50 mg/day days 1-21 for 4 weeks or 150 mg/m2/ 50 mg every other day days 1-21 for 4 weeks
Cyclophosphamide 300 mg/m2/day days 1, 8, 15 for 4
day days 1, 8, 15 for 4 weeks or 75 mg/m2/day days 1, 8, 15 for 4 weeks
weeks

after chemotherapy and finishing after 10-14 days, when the postnadir
neutrophil level has recovered to 1000 cells/mL. G-CSF is repeated with
each cycle of chemotherapy.47
In patients receiving autologous bone marrow transplantation, the
starting dose of G-CSF is 5 ␮g/kg daily, starting within 24-120 hours
after administration of high-dose therapy and tapering the dose accord-
ing to neutrophil levels during the postnadir neutrophil recovery.
The recommended dose of G-CSF for peripheral blood stem cell
mobilization is 10 ␮g/kg daily subcutaneously starting 4 days before
the first leukopheresis and ending after the last one.
Pegylated G-CSF (pegfilgrastim/pegG;) has recently been intro-
duced. It is a novel G-CSF with double molecular weight and an
attenuated systemic clearance. It can be used to obtain sustainable
G-CSF levels in particularly myelotoxic regimens at the dose of 6 mg
once in each chemotherapy cycle, in unique administration, 24 hours
after completion of chemotherapy (Table 6).20,39,40 – 42,47
Conclusion
The combination of novel agents with conventional chemother-
apy or dexamethasone has substantially changed the treatment par-
adigm of patients with multiple myeloma, prolonging disease-free
and overall survival. Treatment-related toxicities remain a main con-
cern in the era of new drugs as well. Neutropenia is a main concern
with lenalidomide, and caution is suggested when thalidomide and
bortezomib are used for the treatment of frail patients.14
A simple algorithm to manage neutropenia associated with novel
therapies for multiple myeloma may help physicians to deal with this
adverse event appropriately. G-CSF prophylaxis is an optimal strat-

Clinical Lymphoma, Myeloma & Leukemia February 2012 9

 How to Manage Neutropenia in Multiple Myeloma
Table 6 Recommendations for G-CSF Use
Growth Factor Setting
Myelotoxic
chemotherapy
High-dose therapy and
G-CSF (filgrastim)
ASCT rescue
PBSC mobilization
Pegylated G-CSF Myelotoxic
(pegfilgrastim) chemotherapy
Abbreviations: ANC ⫽ absolute neutrophil count; ASCT ⫽ autologous stem cell transplantation; G-CSF ⫽ granulocyte-colony stimulating factor; PBSC ⫽ peripheral blood stem cell.
egy to maintain chemotherapy at the desired dose intensity and min-
imize delays. G-CSF prophylaxis is suggested with chemotherapy
regimens with a high risk of neutropenia.
G-CSF should be used as a reactive treatment if severe neutropenia
occurs after chemotherapy in order to reduce the duration of neutro-
penia and related complications. If neutropenia does not resolve de-
spite the use of G-CSF, treatment should be delayed until ANC
restores to ⬎ 1000 cells/mL. Treatment can then be resumed with
appropriate dose reductions. This approach may reduce the risk of
early treatment discontinuation for severe neutropenia, thus en-
abling patients to derive the highest benefit from the therapy.
Acknowledgement
This study was supported by Amgen. The authors thank the edi-
torial assistant Giorgio Schirripa.
Disclosures
Antonio Palumbo has received honoraria from Celgene, Jans-
sen-Cilag, Merck, and Amgen, and is on the advisory committees
of Celgene and Janssen-Cilag; Jon Bladé has received honoraria
from and has served on the advisory boards of Jansen-Cilag, Cel-
gene, Novartis, and Pharmamar and has received research grants
from Jansen-Cilag and Celgene; Faith Davies has participated in
advisory boards and spoken at meetings for Celgene, Novartis,
and Ortho-Biotech and has received travel support to attend
meetings from Celgene and Ortho Biotech; Meletios Dimopoulos
has received honoraria from Celgene and Ortho-Biotech; Mario
Boccadoro has received research support from and served on the
consultancy and the scientific advisory boards of Celgene and
Janssen-Cilag; Anna Dmoszynska has received honoraria from
Celgene and Janssen-Cilag and has served on the advisory com-
mittees of Amgen and Mundipharma; Hermann Einsele has re-
ceived research support from and has served on the advisory
boards of Celgene and Janssen-Cilag and has served on the speak-
er’s bureaus of Celgene, Janssen-Cilag, and Novartis; Hermann
Einsele has served on the advisory boards of Celgene, Novartis,
and Janssen-Cilag; Orhan Sezer has received honoraria from Cel-
gene, Janssen-Cilag, Amgen, and Novartis and has received re-
search funding from Janssen-Cilag and Novartis; Andrew Spencer
has received honoraria from Celgene, Janssen-Cilag, and Amgen
and has served on the advisory committees of Celgene, Janssen-
Cilag, Novartis, and Amgen; Pieter Sonnveld has received re-
10 Clinical Lymphoma, Myeloma & Leukemia February 2012
Start Duration Dose
24-72 hours after administration of 5 ␮g/kg/day
Until ANC ⱖ 1000/mL
chemotherapy subcutaneously
Dose tapering according to
24-120 hours after administration of 5 ␮g/kg/day
neutrophil levels during the post
high-dose therapy subcutaneously
nadir neutrophil recovery
10 ␮g/kg/d
ⱖ 4 days before first leukopheresis Continue until last leukopheresis
subcutaneously
Once per each chemotherapy
24 hours after end of chemotherapy 6 mg
cycle
search support from Celgene, Janssen-Cilag, and Onyx and has
served on the advisory boards of Celgene, Janssen-Cilag, Millen-
nium, and Onyx; Jesus San Miguel has served on the advisory
boards of Millennium, Celgene, and Johnson & Johnson.
References
1. Metcalf D. Cellular hematopoiesis in the twentieth century. Semin Hematol 1999;
36:5-12.
2. Hannen M, Banning U, Bonig H, et al. Cytokine-mediated regulation of granulo-
cyte colony-stimulating factor production. Scand J Immunol 1999; 50:461-8.
3. Schwartzberg LS. Neutropenia: Etiology and pathogenesis. Clin Cornerstone; 2006;
8:S5-11.
4. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin 2010;
60:277-300.
5. Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of
younger patients with multiple myeloma. Blood 2008; 111:2521-6.
6. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple my-
eloma and the impact of novel therapies. Blood 2008; 111:2516-20.
7. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004; 351:1860-73.
8. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for
Supportive Care in Cancer risk index: a multinational scoring system for identifying
low-risk febrile neutropenic cancer patients. J Clin Oncol 2000; 18:3038-51.
9. Leong DC, Kinlay S, Ackland S, et al. Low-risk neutropenia in a medical oncology
unit. Aust N Z J Med 1997; 27:403-7.
10. Pérez Persona E, Mesa MG, García Sánchez PJ, et al. Lenalidomide treatment for
patients with multiple myeloma: diagnosis and management of most frequent ad-
verse events. Adv Ther 2011;28:11-6.
11. Palumbo A, Miguel JS, Sonneveld P, et al. Lenalidomide: a new therapy for multiple
myeloma. Cancer Treat Rev 2008; 34:283-91.
12. San Miguel J, Bladé J, Boccadoro M, et al. A practical update on the use of bort-
ezomib in the management of multiple myeloma. Oncologist 2006; 11:51-61.
13. Perri AJ 3rd, Hsu S. A review of thalidomide’s history and current dermatological
applications. Dermatol Online J 2003; 9:5
14. Palumbo A, Mateos MV, Bringhen S, et al. Practical management of adverse events
in multiple myeloma: can therapy be attenuated in older patients? Blood Rev 2011;
25:181-91.
15. Sonneveld P, Dimopoulos M, San Miguel J, et al. Recommended management of
cytopenia for len/dex in MM. Haematologica 2007; 92(s2):217: abstract PO-1122.
16. Attal M, Dimopoulos M, San Miguel J, et al. Management of non-haematological
toxicity of len/dex. Haematologica 2007;92(s2):217-8: abstract PO-1123.
17. Friese C. Chemotherapy induced neutropenia: important new data to guide nursing
assessment and management. Cancer Ther Supportive Care 2006;4:21-5.
18. Aapro MS, Cameron DA, Pettengell R, et al. EORTC guidelines for the use of
granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-
induced febrile neutropenia in adult patients with lymphomas and solid tumours.
Eur J Cancer 2006; 42:2433-53.
19. Lyman GH, Lyman CH, Agboola O; ANC Study Group. Risk models for predict-
ing chemotherapy-induced neutropenia. Oncologist. 2005; 10: 427-37.
20. Smith T, Khatcheressian J, Lyman G, et al. 2006 update of recommendations for
the use of white blood cell growth factors: an evidence-based clinical practice guide-
lines. J Clin Oncol 2006; 24:3187-205.
21. NCCN Clinical Practice Guidelines in Oncology Myeloid Growth Factors
(Version 1.2010). Available at: http://www.nccn.org/professionals/physician_gls/
f_guidelines.asp. Accessed November 21, 2011.
22. Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia risks, con-
sequences, and new directions for its management. Cancer 2004; 100:228-37.
23. Miceli T, Colson K, Gavino M, et al. Myelosuppression associated with novel
therapies in patients with multiple myeloma: consensus statement of the IMF Nurse
Leadership Board. Clin J Oncol Nurs 2008; 12:13-20.

24. Rajkumar SV, Jacobus S, Callander N, et al. Phase III trial of lenalidomide plus
high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in
newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern
Cooperative Oncology Group. J Clin Oncol 2007; 25(suppl):abstract LBA8025.
Available at: www.asco.org. Accessed November 21, 2011.
25. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexa-
methasone for relapsed multiple myeloma. N Engl J Med 2005; 352:2487-98.
26. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus
dexamethasone compared with dexamethasone alone in newly diagnosed multiple
myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group.
J Clin Oncol 2006; 24:431-6.
27. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemo-
therapy plus thalidomide compared with melphalan and prednisone alone in elderly
patients with multiple myeloma: randomised controlled trial. Lancet 2006; 367:
825-31.
28. Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-341/bort-
ezomib, doxorubicin and dexamethasone) for previously untreated patients with
multiple myeloma. Br J Haematol 2005; 129:755-62.
29. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and
prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359:
906-17.
30. Palumbo A, Gay F. How to treat elderly patients with multiple myeloma: combi-
nation of therapy or sequencing. Hematology Am Soc Hematol Educ Program 2009:
566-77.
31. Caravita T, Siniscalchi A, Tendas A, et al. Safety and efficacy of a combination
therapy with Revlimid, Adriamycin and dexamethasone (RAD) in relapsed/refrac-
tory multiple myeloma (MM): a single-centre experience. Ann Hematol 2011; 90:
115-6.
32. Palumbo A, Falco P, Corradini P, et al. Melphalan, prednisone, and lenalidomide
treatment for newly diagnosed myeloma: a report from the GIMEMA–Italian Mul-
tiple Myeloma Network. J Clin Oncol 2007; 25:4459-65.
33. Hattori Y, Kakimoto T, Okamoto S, et al. Thalidomide-induced severe neutropenia
during treatment of multiple myeloma. Int J Hematol 2004; 79:283-8.
34. Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated
with febrile neutropenia in adult cancer patients. Cancer 2006; 106:2258-66.
Antonio Palumbo et al
35. Innes H, Lim SL, Hall A, et al. Management of febrile neutropenia in solid tumours
and lymphomas using the Multinational Association for Supportive Care in Cancer
(MASCC) risk index: feasibility and safety in routine clinical practice. Support Care
Cancer 2008; 16:485-91.
36. Cullen M, Baijal S. Prevention of febrile neutropenia: use of prophylactic antibiot-
ics. Br J Cancer 2009;101:S11-4.
37. Sharma A, Lokeshwar N. Febrile neutropenia in haematological malignancies. J
Postgrad Med 2005; 51:S42-8.
38. Pagliuca A, Carrington PA, Pettengell R, et al. Guidelines on the use of colony-
stimulating factors in haematological malignancies. Br J Haematol 2003; 123:22-33.
39. Scott SD, Chrischilles EA, Link BK, et al. Days of prophylactic filgrastim use to
reduce febrile neutropenia in patients with non-Hodgkin’s lymphoma treated with
chemotherapy. J Manag Care Pharm 2003; 9:15-21.
40. Guidelines for the use of G-CSF following chemotherapy, Surrex, West Sussex and
Hampshire cancer network, NHS. Available at: http://www.swshcn.nhs.uk/
healthcare-professionals/clinical-policies-and-protocols/supportive-care/g-csf_
network_policy. Accessed June 22, 2011.
41. Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-
macrophage colony-stimulating factor. N Engl J Med 1992; 327:28-35.
42. Weycker D, Hackett J, Edelsberg J, et al. Duration of G-CSF therapy and risk of
hospitalization for neutropenia or infection. J Clin Oncol 2004; 22(suppl):abstract
6731.
43. Rolston KV. New trends in patient management: risk-based therapy for febrile
patients with neutropenia. Clin Infect Dis 1999; 29:515-21.
44. Adams JR, Angelotta C, Bennett CL. When the risk of febrile neutropenia is 20%,
prophylactic colony-stimulating factor use is clinically effective, but is it cost-effec-
tive? J Clin Oncol 2006; 24:2975-7.
45. Petros WP. Pharmacokinetics and administration of colony-stimulating factors.
Pharmacotherapy 1992; 12:32S-8S.
46. Crawford J, Armitage J, Balducci L, et al. Myeloid growth factors. J Natl Compr
Canc Network 2009; 7:64-83.
47. 2006 update of ASCO Practice Guideline Recommendations for the Use of White
Blood Cell Growth Factors: Guideline Summary. J Oncol Pract 2006; 2:
196-201.
Clinical Lymphoma, Myeloma & Leukemia February 2012 11