Current status and updated recommendations for diagnosis and treatment of plasma cell myeloma in Switzerland.

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Review article | Published 21 February 2015, doi:10.4414/smw.2015.14100
Cite this as: Swiss Med Wkly. 2015;145:w14100
Current status and updated recommendations for
diagnosis and treatment of plasma cell myeloma in
Switzerland
Panagiotis Samarasa, Mario Bargetzib, Daniel C. Betticherc, Michel A. Duchosald, Dominik Heime, Urs Hessg, Nicolas Kettererh, Erika Lerchi,
Thomas Matthesj, Ulrich Meyk, Thomas Pabstl, Christian Tavernam, Thilo Zandern, Christoph Rennero
a Department of Medical Oncology, University Hospital Zurich, Switzerland
b Centre of Oncology/Haematology and Transfusion Medicine, Cantonal Hospital Aarau, Switzerland
c Clinics of Medical Oncology, HFR Fribourg Cantonal Hospital, Switzerland
d Service and Central Laboratory of Heamatology, University Hospital of Lausanne, Switzerland
e Department of Haematology, University Hospital Basel, Switzerland
g Division of Oncology/Haematology, Cantonal Hospital St. Gallen, Switzerland
h Clinic Bois-Cerf, Onco-haematology, Lausanne, Switzerland
i Oncology Institute of Southern Switzerland (IOSI), Ospedale San Giovanni, Bellinzona, Switzerland
j Division of Haematology, University Hospital Geneva, Switzerland
k Medical Oncology and Haematology, Cantonal Hospital Graubuenden, Chur, Switzerland
l Department of Medical Oncology, University Hospital of Berne, Switzerland
m Oncology/Haematology, Cantonal Hospital Münsterlingen, Switzerland
n Department of Medical Oncology, Cantonal Hospital Lucerne, Switzerland
o Oncology Centre Hirslanden & Zurich, Switzerland
Summary
The availability of drugs such as thalidomide, bortezomib
and lenalidomide changed the landscape in myeloma treat-
ment and has extended the median survival up to 10 years
with a substantial improvement in quality of life. This de-
velopment prompted a Swiss expert panel to re-evaluate
the current status and formulate updated clinical recom-
mendations for the diagnosis and treatment of plasma cell
myeloma. These recommendations should help clinicians
in their decision making to achieve the best outcome based
on currently available data.
Key words: plasma cell myeloma; multiple myeloma;
bortezomib; lenalidomide; stem cell transplantation;
relapsed/refractory
Introduction
Plasma cell myeloma is the second most common haemat-
ological malignancy and accounts for over 500 new cases
per year in Switzerland [1]. In most patients, it develops
from a precursor state called monoclonal gammopathy of
undetermined significance (MGUS) which has a mean risk
of progression to myeloma of 1% per year [2]. Plasma cell
myeloma is a disease of the elderly population: most pa-
tients are diagnosed in their seventh life decade [3]. The
clinical presentation may vary from asymptomatic disease
detected by laboratory work-up (asymptomatic myeloma)
to features dependent on the grade of the infiltration of
bone, bone marrow or other organs by myeloma cells, and
the amount of monoclonal protein produced by these cells.
Patients may develop one or more of the four leading
symptoms hyperCalcaemia, Renal failure, Anaemia and
Bone disease, summarised as the acronym CRAB criteria.
Bone involvement may cause progressive bone pain, which
often leads to the diagnosis of the disease. Other common
symptoms are fatigue, weight loss and recurrent infections
due to an underlying immune dysfunction. Some patients
with high levels of monoclonal protein may develop hyper-
viscosity symptoms, with vision impairment, neurological
symptoms, or heart failure. The prognosis of the patients
depends on numerous factors, including age, the stage at
diagnosis and genetic features of the myeloma cells. Today,
myeloma is considered an incurable disease, but long-term
remissions have been documented after more intense treat-
ment with high-dose chemotherapy and autologous stem
cell transplantations (ASCT) in about 10%–20% of the pa-
tients [4, 5]. Some promising results have been achieved
with allogeneic stem cell transplantation after reduced in-
tensity conditioning (RIC-allo) in selected patient popula-
tions and prompted some experts to consider this a curative
treatment approach in plasma cell myeloma [6, 7]. The cur-
rent status regarding diagnosis, staging, response assess-
ment and treatment of patients will be addressed in this
article. In addition, new and emerging drugs and their ex-
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pected impact on the treatment of myeloma patients will be
discussed briefly.
Staging
Laboratory assessment
For initial staging of patients with newly diagnosed my-
eloma the quantification of the monoclonal protein in ser-
um and light chains in 24-hour urine is still recommended.
In addition, quantification of immunoglobulins IgG, IgA
and IgM, immunofixation and measurement of serum free
light chains (FLC) with the corresponding ratio should be
performed. The panel agrees that the clinical relevance of
24-hour urine analysis has decreased owing to the high
sensitivity of available FLC assays (Freelite®, The Binding
Site Group, Birmingham, United Kingdom). Serum levels
of β2-microglobulin and albumin should be measured to
define the stage according to the International Staging Sys-
tem (ISS). The degree of bone marrow infiltration should
be assessed upfront, with a bone marrow biopsy and aspira-
tion, including cytogenetic analysis and, if possible, multi-
parameter flow cytometry (MFC). MFC may help to detect
minimal bone marrow involvement and could be useful for
differential diagnosis between normal plasma cells, plasma
cell myeloma, and other plasma cell disorders, as well as
for risk stratification of patients with asymptomatic myel-
oma and MGUS [8, 9]. MFC may also be considered for
the choice of consolidation or maintenance therapy, but it
is, as yet, not standard outside of a clinical trial.
Imaging
Plain radiographs are used for skeletal surveys to assess
the nature of bone disease in plasma cell myeloma. Con-
ventional radiographs are still considered the standard ima-
ging technique for myeloma despite the low sensitivity
compared with computed tomography (CT) and magnetic
resonance imaging (MRI). Low-dose CT and whole-body
MRI are more sensitive methods and may detect early act-
ive disease necessitating the initiation of myeloma treat-
ment. Therefore, low-dose CT and MRI are the preferred
and, thus, recommended imaging techniques for staging
plasma cell myeloma. In addition, positron emission
tomography-computed tomography (PET/CT) may provide
additional useful information to guide therapy, but it is
not standard in the diagnostic work-up of patients with
plasma cell myeloma. Patients in whom it is unclear wheth-
er active disease is present or the extent of the disease is
unclear (plasma cell myeloma or solitary plasmocytoma)
may particularly benefit from this imaging modality. MRI
has the advantage of detecting focal bone marrow infiltra-
tion even before bone lesions develop. New data are avail-
able which suggest that whole-body MRI may be used for
risk stratification of patients with MGUS and asymptomat-
ic/smouldering plasma cell myeloma. Moreover, the pres-
ence of more than one focal bone lesion as assessed by
MRI studies may help to distinguish symptomatic plasma
cell myeloma, considered suitable for treatment, from sol-
itary plasmocytoma or asymptomatic/smouldering plasma
cell myeloma[10–12].
Cytogenetic studies
Cytogenetic testing is especially recommended at diagnosis
and in younger patients, as it allows for risk stratification
and may thus facilitate individualised treatment decisions.
Fluorescence in situ hybridisation (FISH) is the method of
cytogenetic testing preferred over conventional cytogenet-
ic analysis, since it enables a comprehensive analysis of
proliferative as well as nonproliferative tumour cells. The
myeloma panel should include testing for ploidy status,
translocations t(4;14), t(14;16), t(11;14), t(14;20), chromo-
somal gains (1q gains), and deletions 13q and 17p [13]. For
risk stratification in transplant candidates, at least t(4;14),
t(14;16) and del17p should be determined. Recently, the
combination of FISH data with other prognostic factors
such as the ISS stage has been reported to allow precise risk
stratification in daily practice [14]. In a recent meeting of
the International Myeloma Working Group (IMWG), this
combination has been proposed as the current standard for
risk stratification and is therefore recommended [15].
Monitoring
The response assessment to treatment is being made based
on the IMWG uniform response criteria (table 1) [16]. The
panel agrees that the indispensable backbone of myeloma
patient follow-up is the measurement of serum M-protein
levels every 3 to 6 months. Immunofixation is indicated if
the M-protein is no longer (reliably) detectable by serum
electrophoresis to differentiate complete response (CR).
Accordingly, repeated serum FLC measurement is indic-
ated if the initial M-protein is <10 g/l or not reliably meas-
urable (provided that initially involved FLC levels are
>100 mg/l and the FLC ratio is abnormal). Otherwise, the
measurement of serum FLC levels is only useful to con-
firm a stringent complete response (sCR) in a patient ful-
filling all other criteria for CR. The repeated measurement
of Bence Jones protein in the 24-hour urine may be omit-
ted in patients with available serum parameters and if renal
function remains stable. Lytic bone lesions should be eval-
uated if clinically indicated with low-dose CT or MRI.
It has been shown in immunohistochemistry studies that
negative immunofixation in serum combined with a normal
serum FLC ratio are sensitive surrogate markers for a
myeloma-free bone marrow [17, 18]. Despite the reported
independent prognostic value of bone marrow examina-
tion, regular punctures may be therefore omitted and only
be reserved for patients with nonsecretory or dedifferenti-
ated myeloma, and for patients treated within clinical study
protocols demanding regular bone marrow assessment. It
has to be noted, however, that bone marrow assessment is
required for documentation of sCR or CR after treatment
according to the IMWG definition. Lacking the bone mar-
row data, at most only very good partial response (VGPR)
can be ascertained. A practical approach would be to val-
idate the achievement of sCR or CR with a bone marrow
puncture after ASCT and subsequently to follow up the pa-
tient with serum parameters if he or she remains stable.
In addition, monitoring of the remission status in the bone
marrow with more sensitive techniques such as polymerase
chain reaction or MFC to detect minimal residual disease
(MRD) after conventional treatment or after high-dose
chemotherapy with autologous or allogeneic stem cell
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transplantation may identify a patient subset with a lower
risk of relapse and a very favourable clinical outcome
[19–21]. However, these examinations are not standard and
await further validation in clinical trials.
First-line treatment
Monoclonal gammopathy of undetermined significance
(MGUS)
MGUS has a risk of progression to plasma cell myeloma of
1% per year, and patients may thus benefit from adequate
Table 1: International response criteria according to the International
Myeloma Working Group [16].
Response Criteria
sCR CR plus
normal FLC ratio AND
no MRD in the bone marrow as evaluated by
immunohistochemistry or MFC.
CR Negative immunofixation in serum and urine AND
disappearance of any soft tissue plasmocytoma AND
≤5% plasma cells in the bone marrow.
VGPR Serum and urine M protein detectable by immunofixation
but not electrophoresis OR
≥90% reduction of serum M protein plus urine M protein
<100 mg per 24 hours.
PR ≥50% reduction of serum M protein and reduction in
24-hour urinary M protein by ≥90% or to <200 mg per
24 hours.
If the serum and urine M protein are not assessable, a
≥50% reduction in the difference between involved and
uninvolved FLC levels is required in place of the M-
protein criteria.
If serum and urine M protein and serum FLC are not
assessable, ≥50% reduction in plasma cells is required,
provided that baseline bone marrow plasma cell
percentage was ≥30%.
≥50% reduction in the size of soft tissue plasmocytoma
is required if present at baseline.
SD Not meeting criteria for CR, VGPR, PR or PD
PD Requires one or more of the following:
Increase of ≥25% from baseline in
Serum M protein (absolute increase ≥0.5 g/dL) AND/OR
Urine M protein (absolute increase ≥200 mg/24 hours)
AND/OR
In patients without assessable serum or urine M protein:
difference between involved and uninvolved FLC
(absolute increase >10 mg/dl
Bone marrow involvement (absolute percentage ≥10%)
New bone lesions or soft tissue plasmocytoma OR
increase in size of known lesions/plasmocytomas
Development of hypercalcaemia attributed to the
myeloma
Clinical
relapse
Requires one or more of the following:
New soft tissue plasmocytomas or bone lesions
Increase in size of existing plasmocytomas or bone
lesions, defined as 50% (and at least 1 cm) increase
Hypercalcaemia of >11.5 mg/dl [2.65 mmol/l]
Decrease in haemoglobin of ≥2 g/dl [1.25 mmol/l]
Increase in serum creatinine of 2 mg/dl or more [177
µmol/l]
Relapse
from CR
Requires one or more of the following:
Reappearance of serum or urine M protein by
immunofixation or electrophoresis
Development of ≥5% plasma cells in the bone marrow
Appearance of any other sign of progression
CR = complete response; FLC = free light chains; PD = progressive
disease; MFC = multiparameter flow cytometry; MRD = minimal
residual disease; PR = partial response; SD = stable disease; sCR =
stringent complete response; VGPR = very good partial response
follow-up, depending on age and comorbidities. With the
laboratory parameters serum M-protein (<15 g/l vs ≥15
g/l), type of immunoglobulin (IgG vs non-IgG) and serum
FLC ratio (normal vs pathological), low-risk MGUS can be
distinguished from high-risk MGUS, which has a substan-
tially higher cumulative risk of progression. By using this
initial stratification, patient monitoring can be optimised
individually [22]. More recently, it has been shown that
MFC and whole-body MRI may also be of value for risk
stratification of newly diagnosed MGUS, but these tech-
niques are not yet standard outside of clinical trials [10, 23,
24]. No data are currently available supporting pre-emptive
treatment of patients with MGUS.
Asymptomatic/smouldering plasma cell myeloma
Patients with asymptomatic/smouldering plasma cell myel-
oma have a risk of progression to symptomatic plasma cell
myeloma of up to 40% per year, depending on the presen-
ce of various risk factors, and are subject to closer follow-
up [25]. Similarly to MGUS, various clinical parameters
may be used for risk stratification. The amount of the ser-
um M protein (<30 g/l vs ≥30 g/l), the number of bone mar-
row plasma cells (<10% vs ≥10%) and serum FLC ratio
(normal vs pathological) should be used to establish a risk
score for progression and allow optimised monitoring of
the patients [22, 25]. In the recent update of the criteria
for diagnosis of plasma cell myeloma, additional biomark-
ers have been defined in order to discriminate symptomat-
ic plasma cell myeloma without evidence of typical end-
organ damage from asymptomatic/smouldering plasma cell
myeloma: a percentage of clonal bone marrow plasma cells
of 60% or above, a serum FLC ratio above 100, or more
than one focal lesion on MRI studies [12]. In addition,
MFC may help to stratify patients better, but this needs to
be further validated in clinical trials and is not yet stand-
ard [24]. Early treatment of high-risk asymptomatic/smoul-
dering plasma cell myeloma with lenalidomide and dexa-
methasone with subsequent lenalidomide maintenance for
2 years has recently been shown to improve progression
free and overall survival [26]. The panel agrees that no gen-
eral recommendation for early treatment interventions can
be yet formulated. However, on the basis of this new data
on therapy and risk stratification, individualised treatment
strategies for asymptomatic myeloma patients may emerge
in the near future.
Symptomatic plasma cell myeloma
Transplant eligible (young) patients
The goal of treatment is to achieve the best possible re-
sponse (i.e. complete response) for a long period of time.
This is usually achieved with an intensive treatment al-
gorithm including induction, high-dose chemotherapy and
autologous stem cell transplantation, consolidation and, in
selected cases, maintenance therapy. The presence of risk
factors and treatment toxicity need to be considered on an
individual basis.
Induction therapy
Three to four cycles of a three drug regimen are used
in most cases. Based on the general correlation of depth
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of response and long-term outcome, the panel agrees that
a bortezomib-based triple combination (bortezomib, cyc-
lophosphamide, dexamethasone [VCD]; bortezomib,
thalidomide, dexamethasone [VTD]; or bortezomib, dox-
orubicin, dexamethasone [PAD]) achieves better pre- and
post-transplant responses than double therapy and should
be preferred for induction therapy if possible [27–31]. Re-
cently, a meta-analysis of all available phase III studies
using bortezomib-based induction demonstrated signific-
antly higher post-transplant CR/nCR rates (38% vs 24%, p
<0.001), improved median progression free survival (PFS;
36 months vs 29 months, p <0.001), and 3-year overall sur-
vival (OS; 80% vs 75%, p = 0.04) as compared with non-
bortezomib-based induction regimens. The benefit was
noted across all patient subgroups including patients with
high-risk cytogenetic features [32]. The VCD regimen, one
of the most frequently used induction regimens in Switzer-
land, is currently being evaluated in the ongoing interna-
tional phase III study EMN-02 by the European Myeloma
Network (clinicaltrials.gov identifier: NCT01208766).
Equal efficacy has been demonstrated for subcutaneously
and intravenously applied bortezomib in the relapsed set-
ting [33]. Although no randomised trial proved equivalent
activity in the first-line setting, many centres implemented
the subcutaneous administration of bortezomib on a routine
basis regardless of the treatment line, and this application
route is also being increasingly incorporated into prospect-
ive clinical studies.
In case of contraindications (i.e. neuropathy) for bortezom-
ib treatment, lenalidomide-based combinations should be
used [34, 35]. A possible triple combination is lenalidom-
ide, cyclophosphamide and dexamethasone (RCD) [36].
The treating physician should be aware of the potential
adverse impact on the ability to collect stem cells after
prolonged lenalidomide treatment. Therefore, early contact
with a transplantation centre and stem cell mobilisation
within the first four treatment cycles is recommended [37,
38]. Bortezomib has recently been approved for induction
therapy in Switzerland, in contrast to lenalidomide. Never-
theless, the treating physician has to apply to the respective
health insurance provider for cost coverage of either drug
before start of treatment.
High-dose chemotherapy and autologous stem cell
transplantation
High-dose chemotherapy (HDT) with melphalan followed
by autologous stem cell transplantation (ASCT) is still con-
sidered the consolidation treatment of choice for patients
who are eligible (age <65–75 years). The goal is to improve
the quality of response and achieve a sustained CR, as
this has been reported to correlate with improved survival
[39, 40]. The introduction of highly active antimyeloma
agents has markedly improved the results in the transplant
and nontransplant settings, and ongoing studies are cur-
rently challenging the classical strategy of upfront HDT
plus ASCT by using continued sequential treatment with
new drug combinations. Two very similar phase III studies
use four cycles of lenalidomide and low-dose dexa-
methasone (Rd) for induction and compare lenalidomide-
containing regimens with tandem high-dose melphalan
(MEL200) as consolidation. In one study, patients received
six cycles of lenalidomide, melphalan and prednisone
(MPR) and in the other study six cycles of lenalidomide,
cyclophosphamide and dexamethasone (RCD) for consol-
idation. The PFS was markedly better in patients after tan-
dem auto-transplant compared with patients who received
MPR consolidation (median PFS 43 months vs 22.4
months, p <0.001) or RCD consolidation (2-year PFS 72%
vs 61%, p = 0.02). In addition, OS was also improved in
the former trial (4-year OS 82% vs 65%, p = 0.02). These
two studies suggest that HDT with subsequent ASCT still
has an independent impact on patient outcome, despite the
availability of new compounds, and remains the standard
of care in the first-line setting [41, 42]. A recent report sug-
gests that tandem transplantation may improve outcome in
patients with advanced stage (ISS III), unfavourable cyto-
genetic features (t(4;14), del17p) or suboptimal response
to bortezomib induction therapy (i.e. not achieving a CR)
when compared with a single transplant [43]. In particular,
the presence of at least two adverse risk factors strongly fa-
voured the use of tandem transplantation. However, these
data have to be interpreted with caution owing to the ret-
rospective nature of the analysis. Therefore, single trans-
plant with melphalan 200 mg/m2 (MEL200) remains the
standard of care in Switzerland, but a second transplanta-
tion within 3–6 months should be considered in high-risk
patients or patients not achieving at least a VGPR after the
first transplant [44–46]. In patients older than 65 years or
with impaired kidney function the dose of melphalan may
be reduced to 100–140 mg/m2 (MEL100/140).
Eligibility for transplantation is assessed individually based
on organ function and patient age. Patients up to 65 years
are considered eligible for high-dose treatment, but older
patients up to 75 years with good performance status are
also increasingly offered transplantation. Excellent out-
comes with regard to response and survival have been
reported recently in patients over 65 years of age with
a bortezomib containing triple-combination as induction,
followed by tandem high-dose therapy with a reduced
melphalan dose (100 mg/m2, MEL100) and subsequent
ASCT, followed by lenalidomide-containing consolidation
and maintenance until progression [31].
Consolidation therapy
Convincing data have emerged supporting the introduction
of short-term chemotherapy consolidation after ASCT to
improve depth and duration of response.
In two phase III studies, VTD was compared with TD as
consolidation, and single-agent bortezomib consolidation
was compared with no consolidation. All patients benefited
from consolidation with bortezomib, and the improvement
of response was particularly evident in patients who did not
reach at least VGPR after ASCT [28, 47, 48].
In the placebo-controlled phase III study IFM-2005–02
which primarily evaluated maintenance therapy with low-
dose lenalidomide (10–15 mg daily) until progression, all
patients received additional consolidation after ASCT with
two cycles of lenalidomide at a dose of 25 mg at days
1–21 of a 28-day cycle. The rate of CR or VGPR was
improved from 58% before to 69% after consolidation (p
<0.001). In addition, response rates were further improved
by the maintenance treatment (p = 0.009) as compared with
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placebo [49]. Based on these results, patients with contrain-
dications for treatment with bortezomib may be considered
for two cycles of lenalidomide for consolidation therapy.
The outcome of two ongoing phase III studies – the
European EMN-02 and the American Blood and Marrow
Transplant Clinical Trials Network (BMT CTN) 0702, both
using bortezomib, lenalidomide and dexamethasone for
consolidation – have to be awaited before consolidation
therapy can be considered the standard of care. Based on
all available data thus far, the use of bortezomib- or
lenalidomide-containing consolidation, ideally the same re-
gimen successfully used for induction, initiated within the
first three months after ASCT, should be considered in pa-
tients with less than CR after ASCT.
Maintenance treatment
(a) Bortezomib-based maintenance
Two phase III studies evaluated bortezomib as maintenance
treatment after ASCT and three phase III studies are avail-
able for lenalidomide maintenance therapy.
The Dutch-Belgian Haemato-Oncology Cooperative
Group (HOVON) and the German Multicentre Myeloma
Group (GMMG) reported results of a study that used
bortezomib-containing triple therapy (PAD) for induction
and bortezomib alone as maintenance treatment for two
years after single or tandem transplantation, compared with
VAD induction and thalidomide maintenance for two years
after ASCT. This design was developed to assess sustained
bortezomib treatment during first-line therapy, as no
second randomisation was planned after ASCT. Higher re-
sponse rates and improved progression free and overall sur-
vival were achieved with bortezomib treatment. Patients
with myeloma-related renal failure and/or del(17p) muta-
tions seemed to benefit most from the prolonged bortezom-
ib treatment. Although not a preplanned analysis owing
to the lack of statistical power, patients receiving tandem
ASCT in German centres had longer OS as compared with
single transplanted patients in Dutch and Belgian centres (p
= 0.03), but additional comparative subgroup analyses have
not been performed in this context. The main adverse event
was neurotoxicity, but discontinuation of bortezomib due to
adverse events was necessary in only 11% of the patients as
compared with 30% of patients receiving thalidomide [28,
50].
(b) Lenalidomide-based maintenance
A study conducted by the Cancer and Leukaemia Group B
(CALGB) randomised patients after completion of induc-
tion chemotherapy and single ASCT to lenalidomide main-
tenance at a dose of 10–15 mg daily until progression or to
no maintenance. Patients without progression treated in the
placebo arm could cross over to lenalidomide during the
follow-up period. Assessment of cytogenetic features was
not mandatory and no data regarding cytogenetics have
been reported. The median time to progression was im-
proved from 27 months to 46 months (p <0.001) with len-
alidomide maintenance. Patients without CR after ASCT
seemed to benefit most from lenalidomide maintenance
with regard to time to progression. OS was also improved
in lenalidomide-treated patients (3-year OS 88% vs 80%,
p = 0.03). Interestingly, in a subgroup analysis there was a
greater difference in time to progression (p = 0.06) and OS
(p = 0.03) in patients with lenalidomide maintenance who
had already received lenalidomide as induction treatment,
suggesting a positive impact on survival with a strategy of
sustaining the exposure to the same agent during first line-
treatment. A higher rate of second primary malignancies
(SPM) was seen for lenalidomide-treated patients (7.8% vs
2.6%). More hematological and nonhematological adverse
events were observed with lenalidomide, and treatment dis-
continuation was necessary in 10% of the patients [51].
One study conducted by the Intergroupe Francophone du
Myélome (IFM) – the outcome of two cycles of lenalidom-
ide consolidation therapy was discussed above – showed
a marked improvement of PFS from median 23 months to
41 months (p <0.001) with lenalidomide maintenance until
progression. This benefit in PFS was seen across all patient
subgroups, including myeloma stage and type, cytogenet-
ic profile, induction regimen chosen, number of ASCTs re-
ceived, and response at randomisation. After documenting
an increased SPM risk in the lenalidomide group during the
follow-up period with an incidence of 3.1 versus 1.2 per
100 patient years (p = 0.002), lenalidomide was stopped
in all patients in accordance with the recommendation of
the Independent Data Monitoring Committee. Although a
marked difference in PFS was noted, OS was not different
between the two treatment arms [49]. One possible explan-
ation for this finding may be the high survival probability
of all patients as a result of the intensive treatment strategy
pursued, including the use of bortezomib induction in half
of the patients, induction reinforcement with polychemo-
therapy, tandem autotransplant in patients with less than
VGPR after the first ASCT, and two cycles of consolida-
tion with lenalidomide before randomisation. An updated
analysis suggests a shorter survival after progression under
maintenance with lenalidomid, eventually caused by ad-
verse impacts on the myeloma clone [52].
One phase III study comparing MPR consolidation with
tandem autotransplantation (as discussed above), also
tested the value of lenalidomide maintenance with a bi-
factorial 2x2 design. After completion of MPR consolid-
ation or tandem autotransplantation, respectively, patients
were randomised to receive lenalidomide maintenance or
no maintenance at all. The patients receiving lenalidomide
until progression had a significantly improved progression
free survival (median PFS 42 months vs 22 months, p
<0.001) [42, 53].
Based on trials performed on maintenance, the panel agrees
that maintenance therapy with lenalidomide or bortezomib
cannot be considered standard of care yet, but may be con-
sidered for patients on an individual basis based on the
underlying risk profile and response to treatment. High-
risk patients may benefit most from prolonged therapy with
bortezomib for 2 years. It has to be taken into account
that the optimal duration of maintenance therapy with len-
alidomide has not yet been defined, in particular consider-
ing the possible SPM risk. Therefore, maintenance therapy
with low doses of lenalidomide (10–15 mg daily) should
not be administered for more than 2 years. Maintenance
treatment should be initiated within 3 months after ASCT.
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Allogeneic stem cell transplantation
The concept of high-dose chemotherapy with autologous
stem cell transplantation followed by reduced intensity
conditioning with allogeneic stem cell transplantation
(auto/allo) has been evaluated in a few studies, with am-
biguous results. Two recently published meta-analyses of
all available data report that an auto/allo approach may
achieve higher response rates with the cost of higher treat-
ment related mortality rates than double autotransplanta-
tion, but without improving survival [54, 55]. This result
holds true also for patients with high-risk features such as
adverse cytogenetic abnormalities [55]. One recent update
of a large prospective study comparing tandem auto/RIC-
allo with tandem auto showed an improved long-term out-
come regarding PFS and OS after auto/RIC-allo [6]. The
panel agrees that allogeneic transplantation should not be
included within the routine standard first-line treatment for
myeloma patients and should be offered only to highly se-
lected patients as first-line treatment, ideally within clinical
study protocols.
Transplant ineligible patients
The goal of treatment is to achieve the best response pos-
sible for a long period of time, balancing treatment-related
toxicity against quality of life. This is usually achieved by a
prolonged treatment (up to 74 weeks) and dose adjustments
if necessary.
Patients not considered eligible for high-dose melphalan
are usually treated with regimens incorporating novel
agents. One large phase III trial added bortezomib to MP
(VMP), and demonstrated a marked improvement of re-
sponse, PFS and OS with the triplet combination (VISTA
trial). Patients received nine 6-week cycles of VMP or
MP. After a median follow-up time of 5 years, median OS
was improved from 43.1 to 56.4 months by the addition
of bortezomib (p <0.001). The survival benefit was seen
across all prespecified subgroups, including patient age
over 75 years, renal impairment and stage III disease. Im-
portantly, the survival benefit was maintained after VMP
was stopped, and despite the various salvage treatments
subsequently administered to relapsing patients. The OS
benefit could not be balanced by salvage treatment with
bortezomib in MP-treated patients, highlighting the import-
ance of upfront administration of bortezomib [56].
One study evaluated bortezomib-based induction combined
with bortezomib-based maintenance therapy. In a study us-
ing a bifactorial 2x2 design, the PETHEMA group com-
pared six 6-week cycles VMP with six 6-week cycles VTP
(bortezomib, thalidomide, prednisone) induction (first ran-
domisation) and bortezomib/thalidomide maintenance with
bortezomib/prednisone maintenance for up to three years
(second randomisation). In both arms, patients received
twice weekly doses of bortezomib in the first cycle only,
to achieve rapid tumour reduction. In the following cycles
bortezomib was administered only once weekly to reduce
toxicity and avoid early treatment discontinuation. No dif-
ferences were seen between the treatment arms regarding
response rate, PFS and OS for both the induction and the
maintenance therapy period. Patients treated with VTP ex-
perienced significantly more toxicities (p = 0.01) and dis-
continued treatment more frequently (p = 0.03) compared
with VMP. Importantly, the rate of neurological and
gastrointestinal toxicities with the weekly bortezomib
schedule was markedly lower compared with the data re-
ported in the VISTA trial, despite similar efficacy.
Moreover, maintenance therapy improved the CR rate of
the overall patient population from 24% after induction to
42%, which is higher than the 30% CR rate reported in the
VISTA trial. In addition, 22% of the patients achieved also
an immunophenotypic remission (MRD negativity) with a
3-year PFS rate of 90% [21].
Several randomised studies have demonstrated the advant-
age of thalidomide combined with melphalan and pred-
nisone (MPT) over the classical MP with regard to re-
sponse and PFS, but with conflicting results regarding OS.
A meta-analysis based on the individual data of all 1,685
patients included demonstrated a highly significant in-
crease of median OS from 32.7 months to 39.3 months (p
= 0.004) by the addition of thalidomide to MP. No benefit
for MPT was seen in frail patients and in patients with cast
nephropathy [57].
A recent retrospective case-match analysis compared VMP
with MPT in newly diagnosed elderly myeloma patients
and observed an advantage for VMP in terms of CR rates
(21% vs 13%, p = 0.007), median PFS (33 vs 23 months,
p <0.001), and median OS (80 vs 45 months, p <0.001).
The benefit was seen across all subgroups except in pa-
tients older than 75 years [58].
One randomised study assessed the impact of adding len-
alidomide to MP as first-line treatment (MPR). Induction
treatment was administered over 9 months in all patients
(nine 4-week cycles). Importantly, lenalidomide was given
in a low dose of 10 mg daily from start of induction.
In a third treatment arm, patients received additional len-
alidomide maintenance therapy after MPR induction until
progression (MPR-R). Both MPR-R and MPR resulted in
higher response rates compared with MP (77% and 68% vs
50% for MP, p <0.001 and p = 0.002, respectively), only
treatment with MPR-R significantly improved median PFS
compared with either MPR alone or MP alone (31 months
vs 14 months vs 13 months, p <0.001). The survival ad-
vantage was observed only in patients up to 75 years of
age, whereas older patients did not benefit from lenalidom-
ide. Interestingly, the use of lenalidomide during induction
alone did not result in a statistically significant improve-
ment of PFS compared with MP [59]. These data highlight
that mainly the prolonged treatment with lenalidomide is
able to further improve patient outcome after completion of
the induction period.
One study has been reported that evaluated lenalidomide in
combination with high-dose dexamethasone (RD) or low-
dose dexamethasone (Rd). Lenalidomide was administered
at a dose of 25 mg daily for 3 weeks of each 4-week
cycle; high-dose dexamethasone consisted of 480 mg and
low-dose dexamethasone of 160 mg per cycle. Treatment
could be continued until disease progression. The high-
dose dexamethasone arm achieved higher OR rates (79%
vs 68%, p = 0.008), but OS rate at 1 year was significantly
higher with the low-dose dexamethasone combination
(96% vs 87%, p = 0.0002), because of higher toxicities and
treatment-related mortality with RD [34]. Thus, lenalidom-
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ide combined with low doses of weekly dexamethasone is
the better tolerated and preferred regimen.
The FIRST trial compared lenalidomide plus low-dose
dexamethasone until progression (Rd) with lenalidomide
plus low-dose dexamethasone for 18 months (Rd18) or
MPT for 18 months. Continuous lenalidomide plus low-
dose dexamethasone until progression showed improved
PFS compared with MPT and Rd18 (25.5 vs 21.2 versus
20.7 months; Rd vs MPT, p = 0.00006) and improved
4-year OS compared with MPT (59.4% vs 51.4%, p =
0.0168). All subgroups benefited from continuous len-
alidomide plus low-dose dexamethasone. Haematological
and nonhaematological toxicities were as expected. No in-
creased risk of secondary primary malignancies was ob-
served with continuous lenalidomide plus low-dose dexa-
methasone. Rd until progression is another treatment op-
tion for elderly patients, especially in the case of pre-exist-
ing peripheral neuropathy or strong preference of an oral
therapy [60]. Selected regimens for either first or later lines
of therapy are shown in table 2.
In patients older than 75 years or younger patients with sig-
nificant comorbidities, upfront treatment dosage should be
carefully and individually adapted, since excessive toxicity
may result in therapy-related deaths and treatment interrup-
tion, and may consequently negatively affect survival [61].
The panel agrees that the dose of the most relevant antimy-
eloma agents may be modified in accordane with existing
recommendations (table 3).
Treatment of relapsed/refractory
disease
Treatment of relapsed and/or refractory myeloma aims at
reinducing a response and at maintaining it for as long
Table 2: Selected regimens.
Regimen Doses Schedule Setting
VCD
(clinicaltrials.gov:
01208766)
Bortezomib 1.3 mg/m2 i.v./s.c. d1,4,8,11
Cyclophosphamide 500 mg/m2 i.v. d1, 8
Dexamethasone 40 mg p.o. d1,2,4,5,8,9,11,12
Repeated every 21 days First line
pretransplant
VTD (27) Bortezomib 1.3 mg/m2 i.v./s.c. d1,4,8,11
Thalidomide 200 mg p.o. daily
Dexamethasone 40 mg p.o. d1–4 and 9–12
Repeated every 28 days First line
pretransplant
Rd (34) Lenalidomide 25 mg p.o. d1–21
Dexamethasone 40 mg p.o. d1,8,15,22
Repeated every 28 days First line pre-
or non-
transplant;
Relapsed/
refractory
RCD (35) Lenalidomide 25 mg p.o. d1–21 Cyclophosphamide 300 mg/m2 d1,8,15
Dexamethasone 40 mg p.o. d1,8,15,22
Repeated every 28 days First line
pretransplant
PAD (28) Bortezomib 1.3 mg/m2 i.v./s.c. d1,4,8,11
Doxorubicin 9 mg/m2 i.v. d1–4
Dexamethasone 40 mg p.o. d1–4, 9–12, 17–20
Repeated every 28 days First line
Pretransplant;
reinduction
before salvage
ASCT
VD (106) Bortezomib 1.3 mg/m2 i.v./s.c. d1,4,8,11
Dexamethasone 40 mg p.o. d1–4 (all cycles) and 9–12 (cycles 1 and 2)
Repeated every 21 days First line
pretransplant
MPT (107) Melphalan 0.25 mg/kg p.o. days 1–4
Prednisone 2 mg/kg p.o. days 1–4
Thalidomide 100–400 p.o. daily
Repeated every 6 weeks First line
nontransplant
VMP (21) Bortezomib 1.3 mg/m2 i.v./s.c. d1,4,8,11,22,25,29,32 (cycle 1); or d1,8,15,22 (cycle 2+)
Melphalan 9 mg/m2 p.o. days 1–4
Prednisone 60 mg/m2 p.o. days 1–4
Cycle 1: 6 weeks
From cycle 2 on: repeated every
5 weeks
First line
nontransplant
Pom Dex (77) Pomalidomide 4 mg/day p.o. d1–21
Dexamethasone 40 mg p.o. d1,8,15,22
Repeated every 28 days Relapsed/
refractory
i.v. = intravenously; p.o. = per os; s.c. = subcutaneously.
Table 3: Recommended dose modifications for elderly patients according to Palumbo and Anderson [61].
Drug Age <65 year Age 65–75 years Age >75 years
Dexamethasone 40 mg/day p.o. days 1–4, 15–18 every 4 weeks;
or 40 mg/day p.o. given on days 1, 8, 15, 22
every 4 weeks
40 mg/day p.o. on days 1, 8, 15, 22 every 4
weeks
20 mg/day p.o. on days 1, 8, 15, 22 every 4
weeks
Melphalan 0.25 mg/kg p.o. on days 1–4 every 6 weeks 0.25 mg/kg p.o. on days 1–4 every 6 weeks; or
0.18 mg/kg given p.o. on days 1–4 every 4
weeks
0.18 mg/kg p.o. on days 1–4 every 6 weeks; or
0.13 mg/kg given p.o. on days 1–4 every 4
weeks
Cyclophosphamide 300 mg/m2 p.o. on days 1, 8, 15, 22 every 4
weeks
300 mg/m2 p.o. on days 1, 8, 15, every 4 weeks;
or 50 mg/day p.o. on days 1–21 every 4 weeks
50 mg/day given p.o. on days 1–21 every 4
weeks; or 50 mg every other day p.o. on days
1–21 every 4 weeks
Thalidomide 200 mg/day p.o. continuously 100–200 mg/day p.o. continuously 50–100 mg/day p.o. continuously
Lenalidomide 25 mg/day p.o. on days 1–21 every 4 weeks 15–25 mg/day p.o. on days 1–21 every 4 weeks 10–25 mg/day p.o. on days 1–21 every 4 weeks
Bortezomib 1.3 mg/m2 i.v. or s.c. on days 1, 4, 8, 11 every 3
weeks
1.3 mg/m2 i.v. or s.v. On days 1, 4, 8, 11 every 3
weeks; or 1.3 mg/m2 i.v. or s.c. on days 1, 8, 15,
22 every 5 weeks
1.0–1.3 mg/m2 i.v. or s.c. on days 1, 8, 15, 22
every 5 weeks
p.o., per os; i.v., intravenously; s.c., subcutaneously.
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as possible. As in first-line treatment, various treatment
strategies may be considered according to the individual
patient situation, such as the use of new drugs or a rechal-
lenge with already administered regimens, or even salvage
autologous or allogeneic transplantation.
Unfortunately, the vast majority of successfully treated
cases of plasma cell myeloma will relapse. The treatment
approach is based on duration of the first-line therapy, the
level and duration of the first remission, age and comorbid-
ities of the patient and the clinical presentation at the onset
of relapse [62]. Criteria for relapse and disease progression
are shown in table 1 [16].
Transplant-ineligible patients who experienced remission
lasting at least 6 months may be retreated with the drugs
used in first-line therapy, especially when the initial treat-
ment was of short duration and stopped after achieving the
best response. In patients with prolonged first-line treat-
ment new drug combinations should be preferred.
Transplant-eligible patients not transplanted during first-
line therapy can benefit from high-dose melphalan plus
ASCT in second line after reinduction treatment. For pa-
tients who experienced a remission of at least 18-24 months
after the first autologous transplant a second, consolidating
autologous transplant after induction therapy is generally
proposed [63–66].
Two or three drug combinations including at least one nov-
el agent are preferred for reinduction. Approved drug com-
binations in this setting are bortezomib/dexamethasone and
lenalidomide/dexamethasone. The addition of an immun-
omodulatory drug (IMi)D or pegylated liposomal doxor-
ubicin to bortezomib/dexamethasone is another option
[67–69]. Response rates with four-drug combinations are
not superior compared with triple therapy [70]. It has been
shown that sequential therapy may be associated with less
toxicity [62, 69, 71–73].
Third-line treatment and beyond: bendamustine in combin-
ation with novel agents has been tested in several phase
II trials. With the combination of bendamustine, bortezom-
ib, dexamethasone ORRs ranging from 60%–70% are
achieved, which translate into PFS of 9.7–16 months [74,
75]. The combination of bendamustine with lenalidomide/
dexamethasone showed a lower ORR of 52% and a PFS of
6.5 months – most probably because of the need to tailor
lenalidomide dose to 10 mg [76]. Recently, the second gen-
Figure 1
Treatment algorithm.
eration irreversible proteasome inhibitor carfilzomib and
the third generation IMiD pomalidomide have been added
to the armamentarium for patients with multiple myeloma.
A prospective phase III study comparing pomalidomide,
a next generation IMiD, combined with low-dose dexa-
methasone to high dose dexamethasone alone in patients
with refractory or relapsed and refractory plasma cell my-
eloma pretreated with bortezomib and lenalidomide has
been reported. Both progression free and overall survival
were significantly increased with the combination therapy
as compared with dexamethasone alone. The documented
overall response rate was 31%. The most frequent toxicities
of grade ≥3 were infections, cytopenias and pneumonia
[77]. Pomalidomide has recently been approved by Swiss-
medic for patients with refractory or relapsed plasma cell
myeloma after at least two previous treatment lines, in-
cluding bortezomib and lenalidomide. Carfilzomib is a next
generation proteasome inhibitor that has been recently ap-
proved in the United States for treatment of patients with
refractory or relapsed and refractory plasma cell myeloma
who had received at least two previous therapies including
bortezomib and an IMiD. Three single-arm phase II studies
reported overall response rates of 17%–24% and a median
duration of response of about 7–8 months in bortezomib-
refractory patients [78–81]. The toxicity profile raised
some concerns since cardiac failure of grade ≥3 after onset
of treatment was seen in 7% of the patients, with some
cases of cardiac death occurring shortly after treatment
start [82]. Other relevant toxicities were fatigue, cytopeni-
as, diarrhoea, pyrexia and dyspnoea. It has to be noted that
carfilzomib is still not approved in Switzerland but may
be available within an early access programme for selec-
ted patients. Ideally, heavily pretreated patients in need and
ability of receiving treatment should be offered a clinical
trial, whenever possible. An overview on labelling and re-
imbursement of new drugs in Switzerland is shown in table
4.
Allogeneic transplantation is an additional option in the
relapsed/refractory setting. Graft versus myeloma reaction
leads to significantly lower relapse rates and long lasting
remissions compared to other salvage treatments. However,
this beneficial effect is put off by early transplant related
mortality resulting in overall survival rates similar to pa-
tients not transplanted from an allogeneic donor [83]. Fol-
low up in most trials however is too short to draw definitive
conclusions. Since the results remain controversial allogen-
eic HSCT is being performed preferentially within a clinic-
al trial.
An algorithm for first and later line treatment options is be-
ing depicted in the figure.
New drugs and future development
Various new promising drugs are currently being tested in
clinical trials and will be available for myeloma patients
in the near future. Small molecules include new,, orally
available, proteasome inhibitors (MLN9708), histone
deacetylase (HDAC) inhibitors (panobinostat), and the kin-
esin spindle inhibitor filanesib. New antibodies currently
undergoing clinical evaluation are daratumumab, targeting
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CD38, and elotuzumab, targeting the molecule CS1
[84–88].
Another promising approach, ‒ resensitising refractory my-
eloma cells to bortezomib ‒ has been reported with
nelfinavir, a protease inhibitor approved for the treatment
of human immunodeficiency virus. In a phase I study
nelfinavir has been shown to exhibit pan-proteasome inhib-
iting activity and to re-establish sensitivity to bortezomib
in bortezomib-refractory patients [89].
Supportive care
Bone disease
In 60% of patients, skeletal lytic lesions are present at time
of diagnosis. Pain, pathological fractures of the vertebrae,
and spinal cord compression are often associated with these
lesions, motivating specific therapies. Furthermore, verteb-
ral compression fractures occur frequently and may result
in decreased lung function associated with dyspnoea.
Vertebroplasty (percutaneous injection of bone cement in
the lytic lesion) or kyphoplasty (introduction of inflatable
bone tamps into the vertebral bone, which after inflation re-
store the height of the vertebra) are both techniques which
have been shown to induce pain relief [90–93]. In three
prospective phase II–III trials with kyphoplasty and/or ver-
tebroplasty, marked or complete pain relief was achieved
in 80–84% of patients with plasma cell myeloma. Despite
the fact that these procedures have never been examined
in randomised, placebo controlled, blinded trials in myel-
oma, they are used today with success in daily practice. The
choice between vertebroplasty and kyphoplasty depends on
the expertise of the orthopaedic surgeon or interventional
radiologist.
In up to 40% of patients, lytic lesions will require radio-
therapy for pain control. Myeloma cells are highly sensitive
to irradiation, thus irradiation is indicated for spinal cord
compression from plasmocytoma. Limited involved fields
should be preferred in order to limit the impact of irradi-
ation on future stem-cell harvest or on potential future my-
elotoxic treatments. Post-surgical radiation after stabilisa-
tion of impending fractures is rarely needed [94].
Myeloma patients with or without documented bone le-
sions should be treated with bisphosphonates (zoledronate,
pamidronate, or ibandronate) when receiving antimyeloma
therapy [95, 96]. The most frequent side effects are fever
occurring several hours after administration, acute renal
failure, osteonecrosis of the jaw (particularly in patients
with poor dental hygiene) and albuminuria (in particular
after pamidronate administration). This therapy signific-
antly reduces the number of skeletal events (pathological
fractures, need of irradiation, or surgery on bone and spinal
cord compression). Bisphosphonates should be given
monthly, continued in patients with active disease and re-
sumed in the case of myeloma relapse if discontinued in
patients achieving complete or very good partial response
with regularly monitoring of the renal function. In these
patients, the optimal treatment duration with bisphosphon-
ates is not clear, and experts and international guidelines
Table 4: Labelling and reimbursement of myeloma drugs in Switzerland (as of September 2014).
Drug Swissmedic-Approval Reimbursement Availability
Thalidomide TPL 1st line: no
Non-TPL 1st line: no
Later lines: no
No; individual application for cost coverage needed
No; individual application for cost coverage needed
No; individual application for cost coverage needed
Yes;
customised
importing for
named patient
use
Bortezomib TPL 1st line: yes, with standard chemotherapy
Non-TPL 1st line: yes, with melphalan/prednisone
Later lines: yes
Yes, with formal application
Yes, with formal application
Yes, with formal application
Yes
Lenalidomide TPL 1st line: no
Non-TPL 1st line: no
Later lines: yes, in combination with dexamethasone
No; individual application for cost coverage needed
No; individual application for cost coverage needed
Yes, with formal application
Yes
Bendamustine TPL 1st line: no
Non-TPL 1st line: no
Later lines: no
No; individual application for cost coverage needed
No; individual application for cost coverage needed
No; individual application for cost coverage needed
Yes
Pomalidomide TPL 1st line: no
Non-TPL 1st line: no
Later lines: yes, after at least two previous lines, including
lenalidomide and bortezomib
No; individual application for cost coverage needed
No; individual application for cost coverage needed
Yes, with formal application
Yes
Carfilzomib Not yet approved in Switzerland No; individual application for cost coverage needed Via EAP
Pegylated
Liposomal
Doxorubicin
TPL 1st line: no
Non-TPL 1st line: no
Later lines: yes, after at least one previous line
No; individual application for cost coverage needed
No; individual application for cost coverage needed
Yes, with formal application
Yes
EAP = early access programme; TPL = transplantation.
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propose that therapy should be administered for at least 12
months and up to 24 months.
Denosumab (a RANK-ligand inhibiting the osteoclast
function) has been compared with zolendronic acid in pa-
tients suffering from bone lesions due to various tumours:
denosumab was more active in solid tumour bone meta-
stases, but not in plasma cell myeloma lesions. In fact, in
the post-hoc analysis in 180 myeloma patients, denosumab
led to a significantly increased mortality as compared with
zoledronic acid [97, 98].
Infection
Infections are frequent in myeloma patients. Several pro-
phylactic therapies are indicated, in particular when dexa-
methasone and/or bortezomib are administered: Intraven-
ous immunoglobulin therapy should be considered for re-
current, life-threatening infections, particularly in patients
with very low immunoglobulin levels. The vaccination
schedule of the Swiss Health Department proposes
pneumococcal, influenza and varicella vaccine in patients
who are in clinical remission [99]. Pneumocystis jirovecii
(carinii) pneumonia (PCP), herpes, and antifungal prophy-
laxis is recommended if a high-dose regimen is used.
Herpes zoster prophylaxis is recommended in patients re-
ceiving bortezomib therapy [73, 100, 101].
Anticoagulation
Patients with plasma cell myeloma have an increased risk
of developing venous thromboembolism [102]. This results
from a combination of several factors including high
immmunoglobulin levels, inflammation secondary to cy-
tokines, hyperviscosity, and procoagulant activity of gam-
mopathies. The indication for primary thrombosis prophy-
laxis in patients with plasma cell myeloma has to be eval-
uated according to the presence of individual risk factors
[103]. Myeloma patients are not routinely preventively an-
ticoagulated. Importantly, combination treatments with
IMiDs can induce high rate of VTE and justify per se
primary prophylaxis. The type of prophylaxis is still de-
bated; nevertheless low risk patients should receive ASA,
whereas high-risk patients or those receiving high-dose
dexamethasone, anthracyclines, or polychemotherapy
should be treated with prophylactic doses of low molecular
weight heparin (LMWH) or oral anticoagulant therapy with
vitamin K antagonists [104].
Transfusion
In more than 90% of myeloma patients, anaemia (haemo-
globin <120 g/l) will be responsible for discomfort (fatigue,
loss of appetite, dyspnoea and other typical symptoms).
The initial evaluation should exclude other causes such as
iron (chronic bleeding) or vitamin deficiency.
The indication for anaemia therapy depends essentially on
the severity of the symptoms and on the level of haemo-
globin. In these cases, red blood cell (RBC) transfusions
(leucocyte-reduced, cross-matched red cells) are admin-
istered in order to increase the haemoglobin level to render
patients asymptomatic. However, RBC transfusions should
be administered carefully in patients with high levels of
monoclonal protein as they may aggravate an underlying
hyperviscosity syndrome.
Erythropoiesis-stimulating agents (ESAs) are usually re-
served for patients with symptomatic anaemia during the
plateau phase of the paraproteinaemia after chemotherapy.
In a double-blind phase of a randomised study comparing
erythropoietin to placebo, erythropoietin resulted in a sig-
nificantly lower incidence of transfusions (47% vs 28%),
and an increase of the haemoglobin concentration by 18 g/l
[105]. Seven preparations of ESA are available in Switzer-
land, with three approved in the context of chemotherapy.
Funding / potential competing interests: The process of
compiling this review was supported by an unrestricted grant
from beupdated. Beupdated has provided financial support for a
face-to-face meeting and a limited honorarium to authors. There
was no direct link between pharmaceutical industry and
authors.
Correspondence: Professor Christoph Renner, MD, Oncology
Centre Hirslanden & Zurich, CH-8038 Zurich, Switzerland,
christoph.renner[at]hirslanden.ch
References
1 Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh
JW, Comber H, et al. Cancer incidence and mortality patterns in
Europe: estimates for 40 countries in 2012. Eur J Cancer.
2013;49(6):1374–403. PubMed PMID: 23485231.
2 Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak
MF, et al. A long-term study of prognosis in monoclonal gammopathy
of undetermined significance. N Engl J Med. 2002;346(8):564–9.
PubMed PMID: 11856795.
3 Rodriguez-Abreu D, Bordoni A, Zucca E. Epidemiology of hemat-
ological malignancies. Annals of oncology: official journal of the
European Society for Medical Oncology / ESMO. 2007;18(Suppl
1):i3–i8. PubMed PMID: 17311819.
4 Martino M, Postorino M, Gallo GA, Messina G, Neri S, Piro E, et
al. Long-term results in multiple myeloma after high-dose melphalan
and autologous transplantation according to response categories in the
era of old drugs. Clin Lymphoma Myeloma Leuk. 2014;14(2):148–54.
PubMed PMID: 24417912.
5 Martinez-Lopez J, Blade J, Mateos MV, Grande C, Alegre A, Garcia-
Larana J, et al. Long-term prognostic significance of response in mul-
tiple myeloma after stem cell transplantation. Blood.
2011;118(3):529–34. PubMed PMID: 21482708.
6 Gahrton G, Iacobelli S, Bjorkstrand B, Hegenbart U, Gruber A, Greinix
H, et al. Autologous/reduced-intensity allogeneic stem cell transplanta-
tion vs autologous transplantation in multiple myeloma: long-term res-
ults of the EBMT-NMAM2000 study. Blood. 2013;121(25):5055–63.
PubMed PMID: 23482933.
7 Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schi-
anca F, et al. A comparison of allografting with autografting for newly
diagnosed myeloma. N Engl J Med. 2007;356(11):1110–20. PubMed
PMID: 17360989.
8 Paiva B, Almeida J, Perez-Andres M, Mateo G, Lopez A, Rasillo A, et
al. Utility of flow cytometry immunophenotyping in multiple myeloma
and other clonal plasma cell-related disorders. Cytometry Part B, Clin-
ical cytometry. 2010;78(4):239–52. PubMed PMID: 20155853.
9 Robillard N, Bene MC, Moreau P, Wuilleme S. A single-tube mul-
tiparameter seven-colour flow cytometry strategy for the detection of
malignant plasma cells in multiple myeloma. Blood cancer journal.
2013;3:e134. PubMed PMID: 23955589. Pubmed Central PMCID:
3763387.
10 Hillengass J, Weber MA, Kilk K, Listl K, Wagner-Gund B, Hillengass
M, et al. Prognostic significance of whole-body MRI in patients with
monoclonal gammopathy of undetermined significance. Leukemia.
2014;28(1):174–8. PubMed PMID: 23958921.
Review article Swiss Med Wkly. 2015;145:w14100
Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 10 of 15

11 Hillengass J, Fechtner K, Weber MA, Bauerle T, Ayyaz S, Heiss C, et al.
Prognostic significance of focal lesions in whole-body magnetic reson-
ance imaging in patients with asymptomatic multiple myeloma. Journal
of clinical oncology: official journal of the American Society of Clinic-
al Oncology. 2010;28(9):1606–10. PubMed PMID: 20177023.
12 Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G,
Mateos M, et al. International Myeloma Working Group updated cri-
teria for the diagnosis of multiple myeloma. The Lancet Oncology.
2014;15:e538–e47.
13 Ross FM, Avet-Loiseau H, Ameye G, Gutierrez NC, Liebisch P,
O’Connor S, et al. Report from the European Myeloma Network on
interphase FISH in multiple myeloma and related disorders. Haemat-
ologica. 2012 Aug;97(8):1272–7. PubMed PMID: 22371180. Pubmed
Central PMCID: 3409827.
14 Avet-Loiseau H, Durie BG, Cavo M, Attal M, Gutierrez N, Haessler
J, et al. Combining fluorescent in situ hybridization data with ISS sta-
ging improves risk assessment in myeloma: an International Myeloma
Working Group collaborative project. Leukemia. 2013;27(3):711–7.
PubMed PMID: 23032723. Pubmed Central PMCID: 3972006.
15 Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentz-
sch S, et al. IMWG consensus on risk stratification in multiple myel-
oma. Leukemia. 2014;28(2):269–77. PubMed PMID: 23974982.
16 Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson
K, et al. International uniform response criteria for multiple myeloma.
Leukemia. 2006;20(9):1467–73. PubMed PMID: 16855634.
17 Tatsas AD, Jagasia MH, Chen H, McCurley TL. Monitoring residual
myeloma: high-resolution serum/urine electrophoresis or marrow
biopsy with immunohistochemical analysis? Am J Clin Pathol.
2010;134(1):139–44. PubMed PMID: 20551278.
18 Chee CE, Kumar S, Larson DR, Kyle RA, Dispenzieri A, Gertz MA, et
al. The importance of bone marrow examination in determining com-
plete response to therapy in patients with multiple myeloma. Blood.
2009;114(13):2617–8. PubMed PMID: 19641191. Pubmed Central
PMCID: 2756122.
19 Martinelli G, Terragna C, Zamagni E, Ronconi S, Tosi P, Lemoli RM, et
al. Molecular remission after allogeneic or autologous transplantation
of hematopoietic stem cells for multiple myeloma. Journal of clinical
oncology: official journal of the American Society of Clinical Onco-
logy. 2000;18(11):2273–81. PubMed PMID: 10829048.
20 Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA,
et al. Multiparameter flow cytometric remission is the most relevant
prognostic factor for multiple myeloma patients who undergo autolog-
ous stem cell transplantation. Blood. 2008;112(10):4017–23. PubMed
PMID: 18669875. Pubmed Central PMCID: 2581991.
21 Mateos MV, Oriol A, Martinez-Lopez J, Gutierrez N, Teruel AI, de
Paz R, et al. Bortezomib, melphalan, and prednisone versus bortezom-
ib, thalidomide, and prednisone as induction therapy followed by main-
tenance treatment with bortezomib and thalidomide versus bortezomib
and prednisone in elderly patients with untreated multiple myeloma: a
randomised trial. The Lancet Oncology. 2010;11(10):934–41. PubMed
PMID: 20739218.
22 Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, Merlini G,
et al. Monoclonal gammopathy of undetermined significance (MGUS)
and smoldering (asymptomatic) multiple myeloma: IMWG consensus
perspectives risk factors for progression and guidelines for monitoring
and management. Leukemia. 2010;24(6):1121–7. PubMed PMID:
20410922.
23 Perez-Persona E, Mateo G, Garcia-Sanz R, Mateos MV, de Las Heras
N, de Coca AG, et al. Risk of progression in smouldering myeloma
and monoclonal gammopathies of unknown significance: comparative
analysis of the evolution of monoclonal component and multiparameter
flow cytometry of bone marrow plasma cells. Br J Haematol.
2010;148(1):110–4. PubMed PMID: 19821821.
24 Perez-Persona E, Vidriales MB, Mateo G, Garcia-Sanz R, Mateos MV,
de Coca AG, et al. New criteria to identify risk of progression in mono-
clonal gammopathy of uncertain significance and smoldering multiple
myeloma based on multiparameter flow cytometry analysis of bone
marrow plasma cells. Blood. 2007;110(7):2586–92. PubMed PMID:
17576818.
25 Dispenzieri A, Stewart AK, Chanan-Khan A, Rajkumar SV, Kyle RA,
Fonseca R, et al. Smoldering multiple myeloma requiring treatment:
time for a new definition? Blood. 2013;122(26):4172–81. PubMed
PMID: 24144641. Pubmed Central PMCID: 3952477.
26 Mateos MV, Hernandez MT, Giraldo P, de la Rubia J, de Arriba F,
Lopez Corral L, et al. Lenalidomide plus dexamethasone for high-risk
smoldering multiple myeloma. N Engl J Med. 2013;369(5):438–47.
PubMed PMID: 23902483.
27 Rosinol L, Oriol A, Teruel AI, Hernandez D, Lopez-Jimenez J, de
la Rubia J, et al. Superiority of bortezomib, thalidomide, and dexa-
methasone (VTD) as induction pretransplantation therapy in multiple
myeloma: a randomized phase 3 PETHEMA/GEM study. Blood.
2012;120(8):1589–96. PubMed PMID: 22791289.
28 Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U,
Salwender H, et al. Bortezomib induction and maintenance treatment
in patients with newly diagnosed multiple myeloma: results of the ran-
domized phase III HOVON-65/ GMMG-HD4 trial. Journal of clinical
oncology: official journal of the American Society of Clinical Onco-
logy. 2012;30(24):2946–55. PubMed PMID: 22802322.
29 Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, et al. Cyc-
lophosphamide, bortezomib and dexamethasone induction for newly
diagnosed multiple myeloma: high response rates in a phase II clin-
ical trial. Leukemia. 2009;23(7):1337–41. PubMed PMID: 19225538.
Pubmed Central PMCID: 2711213.
30 Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, et
al. Bortezomib with thalidomide plus dexamethasone compared with
thalidomide plus dexamethasone as induction therapy before, and con-
solidation therapy after, double autologous stem-cell transplantation in
newly diagnosed multiple myeloma: a randomised phase 3 study. Lan-
cet. 2010;376(9758):2075–85. PubMed PMID: 21146205.
31 Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo
F, et al. Bortezomib induction, reduced-intensity transplantation, and
lenalidomide consolidation-maintenance for myeloma: updated results.
Blood. 2013;122(8):1376–83. PubMed PMID: 23775712.
32 Sonneveld P, Goldschmidt H, Rosinol L, Blade J, Lahuerta JJ, Cavo M,
et al. Bortezomib-based versus nonbortezomib-based induction treat-
ment before autologous stem-cell transplantation in patients with pre-
viously untreated multiple myeloma: a meta-analysis of phase III ran-
domized, controlled trials. Journal of clinical oncology: official journal
of the American Society of Clinical Oncology. 2013;31(26):3279–87.
PubMed PMID: 23897961.
33 Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishun-
ina M, et al. Subcutaneous versus intravenous administration of
bortezomib in patients with relapsed multiple myeloma: a randomised,
phase 3, non-inferiority study. The Lancet Oncology.
2011;12(5):431–40. PubMed PMID: 21507715.
34 Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Wil-
liams ME, et al. Lenalidomide plus high-dose dexamethasone versus
lenalidomide plus low-dose dexamethasone as initial therapy for newly
diagnosed multiple myeloma: an open-label randomised controlled tri-
al. The Lancet Oncology. 2010;11(1):29–37. PubMed PMID:
19853510. Pubmed Central PMCID: 3042271.
35 Khan ML, Reeder CB, Kumar SK, Lacy MQ, Reece DE, Dispenzieri
A, et al. A comparison of lenalidomide/dexamethasone versus cyclo-
phosphamide/lenalidomide/dexamethasone versus cyclophosphamide/
bortezomib/dexamethasone in newly diagnosed multiple myeloma. Br
J Haematol. 2012;156(3):326–33. PubMed PMID: 22107129.
36 Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J,
et al. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for
newly diagnosed multiple myeloma: results from a phase 2 trial. Am J
Hematol. 2011;86(8):640–5. PubMed PMID: 21630308. Pubmed Cent-
ral PMCID: 3901994.
37 Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Gastineau
DA, et al. Impact of lenalidomide therapy on stem cell mobilization
and engraftment post-peripheral blood stem cell transplantation in pa-
tients with newly diagnosed myeloma. Leukemia. 2007;21(9):2035–42.
PubMed PMID: 17581613.
38 Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Ben-
singer W, et al. Mobilization in myeloma revisited: IMWG consensus
perspectives on stem cell collection following initial therapy with
thalidomide-, lenalidomide-, or bortezomib-containing regimens.
Blood. 2009;114(9):1729–35. PubMed PMID: 19561323.
Review article Swiss Med Wkly. 2015;145:w14100
Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 11 of 15

39 Harousseau JL, Avet-Loiseau H, Attal M, Charbonnel C, Garban F,
Hulin C, et al. Achievement of at least very good partial response is a
simple and robust prognostic factor in patients with multiple myeloma
treated with high-dose therapy: long-term analysis of the IFM 99–02
and 99–04 Trials. Journal of clinical oncology: official journal of the
American Society of Clinical Oncology. 2009;27(34):5720–6. PubMed
PMID: 19826130.
40 Barlogie B, Anaissie E, Haessler J, van Rhee F, Pineda-Roman M, Holl-
mig K, et al. Complete remission sustained 3 years from treatment ini-
tiation is a powerful surrogate for extended survival in multiple myel-
oma. Cancer. 2008;113(2):355–9. PubMed PMID: 18470907.
41 Gay F, Hajek, R., Diramondo, F., et al. Cyclophosphamide-
lenalidomide-dexamethasone vs autologous transplant in newly dia-
gnosed myeloma: a phase 3 trial. Clin Lymphoma Myeloma Leuk.
2013;13(suppl 1):S40.
42 Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci
MT, et al. Autologous transplantation and maintenance therapy in mul-
tiple myeloma. N Engl J Med. 2014;371(10):895–905. PubMed PMID:
25184862.
43 Cavo M, Salwender H, Rosiñol L, Moreau P, Petrucci MT, Blau IW,
et al. Double Vs Single Autologous Stem Cell Transplantation After
Bortezomib-Based Induction Regimens For Multiple Myeloma: An In-
tegrated Analysis Of Patient-Level Data From Phase European III Stud-
ies. ASH 2013 Annual Meeting. 2013:Abstract 767.
44 Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, et al.
Single versus double autologous stem-cell transplantation for multiple
myeloma. N Engl J Med. 2003;349(26):2495–502. PubMed PMID:
14695409.
45 Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, et al.
Prospective, randomized study of single compared with double autolog-
ous stem-cell transplantation for multiple myeloma: Bologna 96 clinic-
al study. Journal of clinical oncology: official journal of the American
Society of Clinical Oncology. 2007;25(17):2434–41. PubMed PMID:
17485707.
46 Kumar A, Kharfan-Dabaja MA, Glasmacher A, Djulbegovic B. Tandem
versus single autologous hematopoietic cell transplantation for the
treatment of multiple myeloma: a systematic review and meta-analysis.
J Natl Cancer Inst. 2009;101(2):100–6. PubMed PMID: 19141779.
47 Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma
D, et al. Bortezomib-thalidomide-dexamethasone is superior to
thalidomide-dexamethasone as consolidation therapy after autologous
hematopoietic stem cell transplantation in patients with newly dia-
gnosed multiple myeloma. Blood. 2012;120(1):9–19. PubMed PMID:
22498745.
48 Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes
K, et al. Bortezomib consolidation after autologous stem cell trans-
plantation in multiple myeloma: a Nordic Myeloma Study Group ran-
domized phase 3 trial. Blood. 2013;121(23):4647–54. PubMed PMID:
23616624. Pubmed Central PMCID: 3674665.
49 Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et
al. Lenalidomide maintenance after stem-cell transplantation for mul-
tiple myeloma. N Engl J Med. 2012;366(19):1782–91. PubMed PMID:
22571202.
50 Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der
Holt B, et al. Administration of bortezomib before and after autologous
stem cell transplantation improves outcome in multiple myeloma pa-
tients with deletion 17p. Blood. 2012;119(4):940–8. PubMed PMID:
22160383.
51 McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H,
Richardson PG, et al. Lenalidomide after stem-cell transplantation for
multiple myeloma. N Engl J Med. 2012;366(19):1770–81. PubMed
PMID: 22571201. Pubmed Central PMCID: 3744390.
52 Attal M L-CV, Marit G, et al. Lenalidomide maintenance after stem-cell
transplantation for multiple myeloma: Follow-up analysis of the IFM
2005–02 trial. 2013 ASH Annual Meeting. 2013:Abstract 406.
53 Boccadoro M, Cavallo F, Gay FM, Di Raimondo F, Nagler A, Monte-
fusco V, et al. Melphalan/prednisone/lenalidomide (MPR) versus high-
dose melphalan and autologous transplantation (MEL200) plus len-
alidomide maintenance or no maintenance in newly diagnosed multiple
myeloma (MM) patients. ASCO Annual Meeting 2013. Journal of clin-
ical oncology: official journal of the American Society of Clinical On-
cology. 2013;31(suppl; abstr 8509).
54 Kharfan-Dabaja MA, Hamadani M, Reljic T, Nishihori T, Bensinger
W, Djulbegovic B, et al. Comparative efficacy of tandem autologous
versus autologous followed by allogeneic hematopoietic cell transplant-
ation in patients with newly diagnosed multiple myeloma: a systematic
review and meta-analysis of randomized controlled trials. Journal of
hematology & oncology. 2013;6:2. PubMed PMID: 23289975. Pubmed
Central PMCID: 3548722.
55 Armeson KE, Hill EG, Costa LJ. Tandem autologous vs autologous
plus reduced intensity allogeneic transplantation in the upfront man-
agement of multiple myeloma: meta-analysis of trials with biological
assignment. Bone marrow transplantation. 2013;48(4):562–7. PubMed
PMID: 22964593.
56 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg
O, Kropff M, et al. Persistent overall survival benefit and no increased
risk of second malignancies with bortezomib-melphalan-prednisone
versus melphalan-prednisone in patients with previously untreated mul-
tiple myeloma. Journal of clinical oncology: official journal of the
American Society of Clinical Oncology. 2013;31(4):448–55. PubMed
PMID: 23233713.
57 Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksac M, et
al. Thalidomide for previously untreated elderly patients with multiple
myeloma: meta-analysis of 1685 individual patient data from 6 ran-
domized clinical trials. Blood. 2011;118(5):1239–47. PubMed PMID:
21670471.
58 Morabito F, Bringhen S, Larocca A, Wijermans P, Victoria Mateos M,
Gimsing P, et al. Bortezomib, melphalan, prednisone (VMP) versus
melphalan, prednisone, thalidomide (MPT) in elderly newly diagnosed
multiple myeloma patients: A retrospective case-matched study. Am J
Hematol. 2014;89(4):355–62. PubMed PMID: 24273190.
59 Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano
J, et al. Continuous lenalidomide treatment for newly diagnosed mul-
tiple myeloma. N Engl J Med. 2012;366(19):1759–69. PubMed PMID:
22571200.
60 Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch AR,
Hulin C, et al. Initial Phase 3 Results Of The First (Frontline Invest-
igation Of Lenalidomide + Dexamethasone Versus Standard Thalidom-
ide) Trial (MM-020/IFM 07 01) In Newly Diagnosed Multiple Myel-
oma (NDMM) Patients (Pts) Ineligible For Stem Cell Transplantation
(SCT). Blood. 2013;122:abstract 2.
61 Palumbo A, Anderson K. Multiple myeloma. N Engl J Med.
2011;364(11):1046–60. PubMed PMID: 21410373.
62 Lonial S, Mitsiades CS, Richardson PG. Treatment options for relapsed
and refractory multiple myeloma. Clinical cancer research: an official
journal of the American Association for Cancer Research.
2011;17(6):1264–77. PubMed PMID: 21411442.
63 Alvares CL, Davies FE, Horton C, Patel G, Powles R, Morgan GJ. The
role of second autografts in the management of myeloma at first re-
lapse. Haematologica. 2006;91(1):141–2. PubMed PMID: 16434386.
64 Lemieux E, Hulin C, Caillot D, Tardy S, Dorvaux V, Michel J, et
al. Autologous stem cell transplantation: an effective salvage therapy
in multiple myeloma. Biology of blood and marrow transplantation:
journal of the American Society for Blood and Marrow Transplantation.
2013;19(3):445–9. PubMed PMID: 23186983.
65 Olin RL, Vogl DT, Porter DL, Luger SM, Schuster SJ, Tsai DE, et
al. Second auto-SCT is safe and effective salvage therapy for relapsed
multiple myeloma. Bone marrow transplantation. 2009;43(5):417–22.
PubMed PMID: 18850013. Pubmed Central PMCID: 2757257.
66 Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden
JA, et al. High-dose chemotherapy plus autologous stem-cell trans-
plantation as consolidation therapy in patients with relapsed multiple
myeloma after previous autologous stem-cell transplantation (NCRI
Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase
3 trial. The Lancet Oncology. 2014;15(8):874–85. PubMed PMID:
24948586.
67 Jimenez-Zepeda VH, Reece DE, Trudel S, Chen C, Tiedemann R,
Kukreti V. Lenalidomide (Revlimid), bortezomib (Velcade) and dexa-
methasone for heavily pretreated relapsed or refractory multiple my-
eloma. Leukemia & lymphoma. 2013;54(3):555–60. PubMed PMID:
22881043.
Review article Swiss Med Wkly. 2015;145:w14100
Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 12 of 15

68 Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje
NS, et al. A phase 2 trial of lenalidomide, bortezomib, and dexa-
methasone in patients with relapsed and relapsed/refractory myeloma.
Blood. 2014;123(10):1461–9. PubMed PMID: 24429336.
69 Orlowski RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A,
et al. Randomized phase III study of pegylated liposomal doxorubi-
cin plus bortezomib compared with bortezomib alone in relapsed or re-
fractory multiple myeloma: combination therapy improves time to pro-
gression. Journal of clinical oncology: official journal of the American
Society of Clinical Oncology. 2007;25(25):3892–901. PubMed PMID:
17679727.
70 Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, et
al. Randomized, multicenter, phase 2 study (EVOLUTION) of com-
binations of bortezomib, dexamethasone, cyclophosphamide, and len-
alidomide in previously untreated multiple myeloma. Blood.
2012;119(19):4375–82. PubMed PMID: 22422823.
71 Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et
al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in
North America. N Engl J Med. 2007;357(21):2133–42. PubMed PMID:
18032763.
72 Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M,
Stadtmauer EA, et al. Long-term follow-up on overall survival from
the MM-009 and MM-010 phase III trials of lenalidomide plus dexa-
methasone in patients with relapsed or refractory multiple myeloma.
Leukemia. 2009;23(11):2147–52. PubMed PMID: 19626046.
73 Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA,
Facon T, et al. Bortezomib or high-dose dexamethasone for relapsed
multiple myeloma. N Engl J Med. 2005;352(24):2487–98. PubMed
PMID: 15958804.
74 Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, et al.
Bendamustine-bortezomib-dexamethasone is an active and well-toler-
ated regimen in patients with relapsed or refractory multiple myeloma.
Blood. 2014;123(7):985–91. PubMed PMID: 24227817. Pubmed Cen-
tral PMCID: 3924931.
75 Offidani M, Corvatta L, Maracci L, Liberati AM, Ballanti S, Attolico I,
et al. Efficacy and tolerability of bendamustine, bortezomib and dexa-
methasone in patients with relapsed-refractory multiple myeloma: a
phase II study. Blood cancer journal. 2013;3:e162. PubMed PMID:
24270324. Pubmed Central PMCID: 3880441.
76 Lentzsch S, O’Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL,
et al. Combination of bendamustine, lenalidomide, and dexamethasone
(BLD) in patients with relapsed or refractory multiple myeloma is feas-
ible and highly effective: results of phase 1/2 open-label, dose escala-
tion study. Blood. 2012;119(20):4608–13. PubMed PMID: 22451423.
Pubmed Central PMCID: 3392072.
77 San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, et
al. Pomalidomide plus low-dose dexamethasone versus high-dose dexa-
methasone alone for patients with relapsed and refractory multiple my-
eloma (MM-003): a randomised, open-label, phase 3 trial. The lancet
oncology. 2013;14(11):1055–66. PubMed PMID: 24007748.
78 Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh
K, et al. An open-label, single-arm, phase 2 study of single-agent car-
filzomib in patients with relapsed and/or refractory multiple myeloma
who have been previously treated with bortezomib. Br J Haematol.
2012;158(6):739–48. PubMed PMID: 22845873.
79 Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T,
et al. An open-label single-arm pilot phase II study (PX-171–003–A0)
of low-dose, single-agent carfilzomib in patients with relapsed and re-
fractory multiple myeloma. Clinical lymphoma, myeloma & leukemia.
2012;12(5):310–8. PubMed PMID: 23040437.
80 Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et
al. A phase 2 study of single-agent carfilzomib (PX-171–003–A1) in
patients with relapsed and refractory multiple myeloma. Blood.
2012;120(14):2817–25. PubMed PMID: 22833546.
81 Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK,
et al. An open-label, single-arm, phase 2 (PX-171–004) study of single-
agent carfilzomib in bortezomib-naive patients with relapsed and/or
refractory multiple myeloma. Blood. 2012;119(24):5661–70. PubMed
PMID: 22555973.
82 Herndon TM, Deisseroth A, Kaminskas E, Kane RC, Koti KM, Roth-
mann MD, et al. U.s. Food and Drug Administration approval: car-
filzomib for the treatment of multiple myeloma. Clinical cancer re-
search: an official journal of the American Association for Cancer
Research. 2013;19(17):4559–63. PubMed PMID: 23775332.
83 Patriarca F, Einsele H, Spina F, Bruno B, Isola M, Nozzoli C, et al. Al-
logeneic stem cell transplantation in multiple myeloma relapsed after
autograft: a multicenter retrospective study based on donor availability.
Biology of blood and marrow transplantation: journal of the Americ-
an Society for Blood and Marrow Transplantation. 2012;18(4):617–26.
PubMed PMID: 21820394.
84 Kumar SK BJ, Niesvizky R, Lonial S, Hamadani M, Stewart AK, et
al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral
Proteasome Inhibitor, in Combination with Lenalidomide and Dexa-
methasone in Patients with Previously Untreated Multiple Myeloma
(MM). ASH 2012 Annual Meeting. 2012 (Abstract 332).
85 Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE,
Gasparetto C, et al. PANORAMA 2: panobinostat in combination with
bortezomib and dexamethasone in patients with relapsed and
bortezomib-refractory myeloma. Blood. 2013;122(14):2331–7.
PubMed PMID: 23950178.
86 Lonial S SJ, Zonder J, Bensinger WI, Cohen AD, Kaufman JL, et
al. Prolonged Survival and Improved Response Rates With ARRY-520
(Filanesib) In Relapsed/Refractory Multiple Myeloma (RRMM) Pa-
tients With Low α-1 Acid Glycoprotein (AAG) Levels: Results From a
Phase 2 Study. ASH 2013 Annual Meeting. 2013 (Abstract 285).
87 Plesner T AT, Lokhorst H, Gimsing P, Krejcik J, Lemech C, et al. Pre-
liminary Safety and Efficacy Data Of Daratumumab In Combination
With Lenalidomide and Dexamethasone In Relapsed Or Refractory
Multiple Myeloma. ASH 2013 Annual Meeting. 2013 (Abstract 1986).
88 Richardson PG JS, Moreau P, Jakubowiak A, Raab MS, Facon T, et al. .
A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidom-
ide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/
Refractory Multiple Myeloma (R/R MM): Updated Results. ASH 2012
Annual Meeting. 2012 (Abstract 202).
89 Driessen C H, D, Pabst, T, Haile SR, Joerger M, von Moos R, et al.
SAKK 65/08: A Phase I Trial of the HIV Protease Inhibitor Nelfinavir
in Combination with Bortezomib Identifies Nelfinavir As FDA Ap-
proved, Oral Drug that Inhibits the Proteasome and Induces Proteotoxic
Stress in Vivo and has Potential Antimyeloma Activity. ASH 2012 An-
nual Meeting. 2012 (abstract 2956).
90 Dudeney S, Lieberman IH, Reinhardt MK, Hussein M. Kyphoplasty in
the treatment of osteolytic vertebral compression fractures as a result of
multiple myeloma. Journal of clinical oncology: official journal of the
American Society of Clinical Oncology. 2002;20(9):2382–7. PubMed
PMID: 11981012.
91 Fourney DR, Schomer DF, Nader R, Chlan-Fourney J, Suki D, Ahrar K,
et al. Percutaneous vertebroplasty and kyphoplasty for painful vertebral
body fractures in cancer patients. Journal of neurosurgery. 2003;98(1
Suppl):21–30. PubMed PMID: 12546384.
92 Lane JM, Hong R, Koob J, Kiechle T, Niesvizky R, Pearse R, et al.
Kyphoplasty enhances function and structural alignment in multiple
myeloma. Clin Orthop Relat Res. 2004(426):49–53. PubMed PMID:
15346051.
93 Hentschel SJ, Burton AW, Fourney DR, Rhines LD, Mendel E. Percu-
taneous vertebroplasty and kyphoplasty performed at a cancer center:
refuting proposed contraindications. J Neurosurg Spine.
2005;2(4):436–40. PubMed PMID: 15871483.
94 Lecouvet F, Richard F, Vande Berg B, Malghem J, Maldague B, Jamart
J, et al. Long-term effects of localized spinal radiation therapy on ver-
tebral fractures and focal lesions appearance in patients with multiple
myeloma. Br J Haematol. 1997;96(4):743–5. PubMed PMID: 9074416.
95 Terpos E, Morgan G, Dimopoulos MA, Drake MT, Lentzsch S, Raje N,
et al. International Myeloma Working Group recommendations for the
treatment of multiple myeloma-related bone disease. Journal of clinic-
al oncology: official journal of the American Society of Clinical Onco-
logy. 2013;31(18):2347–57. PubMed PMID: 23690408.
96 Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, et
al. First-line treatment with zoledronic acid as compared with clodron-
ic acid in multiple myeloma (MRC Myeloma IX): a randomised con-
trolled trial. Lancet. 2010 Dec 11;376(9757):1989–99. PubMed PMID:
21131037. Pubmed Central PMCID: 3639680.
Review article Swiss Med Wkly. 2015;145:w14100
Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 13 of 15

97 Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J,
et al. Randomized, double-blind study of denosumab versus zoledronic
acid in the treatment of bone metastases in patients with advanced can-
cer (excluding breast and prostate cancer) or multiple myeloma. Journal
of clinical oncology: official journal of the American Society of Clinic-
al Oncology. 2011;29(9):1125–32. PubMed PMID: 21343556.
98 Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH,
et al. Denosumab compared with zoledronic acid for the treatment of
bone metastases in patients with advanced breast cancer: a randomized,
double-blind study. Journal of clinical oncology: official journal of the
American Society of Clinical Oncology. 2010;28(35):5132–9. PubMed
PMID: 21060033.
99 Bundesamt für Gesundheit, Schweizerischer Impfplan 2013, page 20.
100 Chanan-Khan A, Sonneveld P, Schuster MW, Stadtmauer EA, Facon
T, Harousseau JL, et al. Analysis of herpes zoster events among
bortezomib-treated patients in the phase III APEX study. Journal of
clinical oncology: official journal of the American Society of Clinical
Oncology. 2008;26(29):4784–90. PubMed PMID: 18711175.
101 Mateos MV, Hernandez JM, Hernandez MT, Gutierrez NC, Palomera
L, Fuertes M, et al. Bortezomib plus melphalan and prednisone in
elderly untreated patients with multiple myeloma: results of a multi-
center phase 1/2 study. Blood. 2006;108(7):2165–72. PubMed PMID:
16772605.
102 Zamagni E, Brioli A, Tacchetti P, Zannetti B, Pantani L, Cavo M. Mul-
tiple myeloma, venous thromboembolism, and treatment-related risk of
thrombosis. Sem Thromb Hemost. 2011;37(3):209–19. PubMed PMID:
21455855.
103 http://myeloma.org/, IMWG guidelines for the prevention of thalidom-
ide- and Lenalidomide-associated thrombosis in myeloma.
104 Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F,
et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients
with multiple myeloma treated with thalidomide: a phase III, open-
label, randomized trial. Journal of clinical oncology: official journal
of the American Society of Clinical Oncology. 2011;29(8):986–93.
PubMed PMID: 21282540.
105 Osterborg A, Boogaerts MA, Cimino R, Essers U, Holowiecki J, Juli-
usson G, et al. Recombinant human erythropoietin in transfusion-de-
pendent anemic patients with multiple myeloma and non-Hodgkin's
lymphoma – a randomized multicenter study. The European Study
Group of Erythropoietin (Epoetin Beta) Treatment in Multiple Myel-
oma and Non-Hodgkin’s Lymphoma. Blood. 1996;87(7):2675–82.
PubMed PMID: 8639883.
106 Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty
M, et al. Bortezomib plus dexamethasone is superior to vincristine plus
doxorubicin plus dexamethasone as induction treatment prior to auto-
logous stem-cell transplantation in newly diagnosed multiple myeloma:
results of the IFM 2005–01 phase III trial. Journal of clinical onco-
logy: official journal of the American Society of Clinical Oncology.
2010;28(30):4621–9. PubMed PMID: 20823406.
107 Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al.
Melphalan and prednisone plus thalidomide versus melphalan and pred-
nisone alone or reduced-intensity autologous stem cell transplantation
in elderly patients with multiple myeloma (IFM 99–06): a randomised
trial. Lancet. 2007;370(9594):1209–18. PubMed PMID: 17920916.
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Figures (large format)
Figure 1
Treatment algorithm.
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