Mielomaaaaaaa

Seminar
Multiple myeloma
Christoph Röllig, Stefan Knop, Martin Bornhäuser
Multiple myeloma is a malignant disease characterised by proliferation of clonal plasma cells in the bone marrow and
typically accompanied by the secretion of monoclonal immunoglobulins that are detectable in the serum or urine.
Increased understanding of the microenvironmental interactions between malignant plasma cells and the bone
marrow niche, and their role in disease progression and acquisition of therapy resistance, has helped the development
of novel therapeutic drugs for use in combination with cytostatic therapy. Together with autologous stem cell
transplantation and advances in supportive care, the use of novel drugs such as proteasome inhibitors and
immunomodulatory drugs has increased response rates and survival substantially in the past several years. Present
clinical research focuses on the balance between treatment efficacy and quality of life, the optimum sequencing of
treatment options, the question of long-term remission and potential cure by multimodal treatment, the pre-emptive
treatment of high-risk smouldering myeloma, and the role of maintenance. Upcoming results of ongoing clinical
trials, together with a pipeline of promising new treatments, raise the hope for continuous improvements in the
prognosis of patients with myeloma in the future.
Epidemiology
Multiple myeloma is the malignant counterpart of
long-lived plasma cells with a strong tropism for bone
and bone marrow. Among other plasma cell dyscrasias,
such as Waldenström’s macroglobulinaemia and
primary amyloidosis, multiple myeloma is the second
most frequent haematological malignancy with an
age-adjusted incidence of six per 100 000 per year in the
USA and Europe. The incidence of multiple myeloma is
two to three times higher in African Americans, making
it the most common haematological malignancy in this
ethnic group.1
The median age at diagnosis of multiple myeloma is
69 years, with three-quarters of patients being diagnosed
above the age of 55 years and two of three patients being
men.2 With the advent of more effective therapeutic
strategies and improvements in supportive care, the
median survival has increased from 3 years to 6 years in
the past two decades. The age-adjusted death rate for
men and women between 2006 and 2010 in the USA was
3·4 in 100 000.2
Pathogenesis
Multiple myeloma cells are similar to long-lived,
post-germinal centre plasma cells, and are characterised
by strong bone marrow dependence, extensive somatic
hypermutation of immunoglobulin genes, and absence
of IgM expression. However, multiple myeloma cells
differ from healthy plasma cells because they retain the
potential to return to a lower proliferative state.3
Role of the microenvironment
Current research on the interaction between multiple
myeloma cells and their bone marrow microenvironment
focuses on cell–cell and cell–matrix interactions, and
growth factors and cytokines. Cellular components of the
microenvironment include bone marrow stromal cells,
osteoblasts, endothelial cells, and cells of the innate
and adaptive immune system, including regulatory
T cells. Crosstalk between multiple myeloma and its
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microenvironment seems to be bidirectional—eg, in the
case of tumour-promoting myeloid-derived suppressor
cells, which on the one hand induce the growth of
multiple myeloma cells by suppressing immune effector
cells but on the other hand are increased in number by
multiple myeloma cells.4
Myeloma progenitors and stem cells
Lancet 2015; 385: 2197–208
Published Online
December 23, 2014
http://dx.doi.org/10.1016/
S0140-6736(14)60493-1
Medizinische Klinik und
Poliklinik I,
Universitätsklinikum,
Carl Gustav Carus, Technische
Universität Dresden, Dresden,
Germany (C RÖllig MD,
Prof M Bornhäuser MD); and
Medizinische Klinik und
Poliklinik II,
Universitätsklinikum
Würzburg, Würzburg, Germany
(S Knop MD)
Correspondence to:
Dr Christoph Röllig, Medizinische
Klinik und Poliklinik I,
Universitätsklinikum Carl Gustav
Carus, Fetscherstraße 74,
01307 Dresden, Germany
christoph.roellig@
uniklinikum-dresden.de
Because all therapies established so far, including stem
cell transplantation, do not cure multiple myeloma,
research is ongoing to identify a way to target and
eradicate the subset of tumour cells that replenishes the
tumour, even after high-dose melphalan therapy. With
the use of serial transplantation models and clonogenic
in-vitro assays, it has been suggested that the multiple
myeloma stem cell is part of a subset of CD38CD19+CD27+ B cell precursors that do not express the
classic multiple myeloma markers CD38 or CD138.5 So
far, these investigations have not led to a clear structure
of the multiple myeloma stem and progenitor cell
network, which would however be necessary before
specific therapies targeting multiple myeloma stem cells
can be used.
Clonal evolution of multiple myeloma
Comprehensive high-resolution genomic studies have
shed new light on the clonal composition of multiple
myeloma at diagnosis and during disease progression.6,7
By contrast with what was postulated one or two decades
ago, tumours including multiple myeloma are not
derived from one single tumour stem cell, but composed
of clonally diverse subsets of tumour cells harbouring an
immense genetic diversity (figure 1). This theory is
supported by the clinical occurrence of biclonal disease
or even a class switch in the monoclonal immunoglobulin
in relapsing multiple myeloma patients. The waves of
different multiple myeloma clones evolving during the
natural course of disease and the shifts in dominant and
subdominant clones during therapy and relapse are a
fascinating area for novel research.
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Monoclonal gammopathy
of unknown significance
Myeloma
Progenitor clones competing
for bone marrow niche
Relapse or plasma cell leukaemia
Dominant diagnostic clone
Mutation x
Therapy
Tumour
initiating
cell
Mutation x
(A) clone with unique
mutations = diagnostic clone
Mutation x
Mutation xy
Minor diagnostic
subclone
Mutation z
Mutation xy
(B) dominant clone already
detectable as minor subclone
at diagnosis
Mutation z
(C) clone with unique
mutations = diagnostic clone
Figure 1: Clonal composition of multiple myeloma during disease progression and therapy
During the progression from monoclonal gammopathy to multiple myeloma, tumour initiating cells can give rise to subclones that are predominantly detected in
diagnostic samples and harbour unique mutations, x, which might also be detectable later on in relapsed disease. (A) Especially in high-risk disease, minor subclones
that might have been hardly detectable at the time of initial diagnosis might acquire additional driving mutations, xy, during therapy, which later dominate the clonal
composition at relapse. (B) Subclones derived from tumour-initiating cells not detectable at the time of initial diagnosis might awake from dormancy at a later point
in time and evolve as the dominating clone at relapse with a different founding mutation, z. (C) Whereas clones with unique non-linear mutations x or z are supposed
to be more susceptible to salvage therapy, subclones driven by newly acquired mutations (xy) are likely to be resistant to conventional therapies.
Test
Blood
Serum protein electrophoresis and immunofixation
Serum immunoglobulins quantitative
Serum free light chain assay
Total serum protein, serum albumin, creatinine, calcium, electrolytes, lactate dehydrogenase,
β2-microglobulin
Haemoglobin, white blood cell count, differential count, platelet count
Urine
Urine protein electrophoresis and immunofixation
24 h urine for total protein, light chains
Bone marrow
Aspirate and biopsy for plasma cell count, morphology, amyloid*
Cytogenetic evaluation and fluorescence in-situ hybridisation for the detection of del 13,
del 17p13, t(4;14), t(11;14), t(14;16), 1q+
Bones
Skeletal survey (conventional x-ray) or low-dose CT scan without contrast
Whole body
MRI*, PET-CT*
Tissue biopsy for solitary or extraosseous plasmacytoma*
*Useful under some circumstances.
Table 1: Diagnostic workup for multiple myeloma
Symptoms, diagnostic workup, and disease
monitoring
The most common clinical manifestations of symptomatic
multiple myeloma are anaemia, infections, lytic or
osteopenic bone disease, or renal failure, but patients with
multiple myeloma might be diagnosed at an asymptomatic
stage by chance. Generally, multiple myeloma is diagnosed
at an earlier stage today than in the past.8 Back pain,
particularly in older patients, or unclear anaemia should
prompt screening for the presence of multiple myeloma.
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The standard screening workup includes total serum
protein, serum and urine protein electrophoresis (SPEP
and UPEP), immunofixation in serum and urine, detection
of immunoglobulin free light chains (FLC) in serum, and
the following additional parameters: complete blood
count, serum creatinine, and electrolytes including
calcium, lactate dehydrogenase, and β2 microglobulin. In
a patient with suspected multiple myeloma, a bone
marrow sample should be obtained by aspiration or by
doing a biopsy. If a monoclonal protein is detected through
SPEP, UPEP, or by pathological FLC ratio and the plasma
cell count is higher than or equal to 10%, a diagnosis of
multiple myeloma is made. The same applies to patients
with less than 10% plasma cells but with a monoclonal
protein of more than or equal to 3 g/100 mL.9 In patients
with non-secretory multiple myeloma, the diagnosis is
based on the presence of more than 30% bone marrow
plasma cells or the detection of plasmacytoma in a biopsy.10
A singular plasma cell lesion in the bone or at an
extraosseous site with less than 10% plasma cell
infiltration in the bone marrow and low monoclonal
protein is defined as solitary plasmacytoma, a disorder
distinctively different from systemic multiple myeloma
both in terms of prognosis and treatment.
In patients diagnosed with multiple myeloma,
development of end-organ damage is the indication for
treatment. Multiple myeloma without end-organ damage
is referred to as smouldering multiple myeloma. Multiple
myeloma patients should have a full radiographic skeletal
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survey done to detect lytic lesions, severe osteopenia, or
pathological fractures.9 MRI or PET-CT can be used when
symptomatic areas show no abnormality on routine
radiographs.11 Table 1 summarises the diagnostic workup
for patients with multiple myeloma.
Patients with monoclonal gammopathy but with less
than 10% bone marrow plasma cells or low M-protein are
diagnosed with monoclonal gammopathy of unknown
significance, and do not need treatment but do need
regular follow-up because of the potential for progression
to multiple myeloma; however, the risk of progression is
only 1% per life-year.9 Disorders such as nephrotic
syndrome and heart failure, neuropathy in non-diabetic
patients, left ventricular hypertrophy on echocardiography
without consistent electrocardiographic evidence or low
limb lead voltages, hepatomegaly with normal imaging, or
albuminuria should be assessed carefully to not overlook
light-chain amyloidosis caused by free light-chain
secretion.12,13 The appendix shows the diagnostic criteria
for monoclonal gammopathy of unknown significance,
smouldering and active multiple myeloma.
To measure treatment response and monitor disease
activity, the serum M-protein is the preferred surrogate
marker. In patients with light chain secretion, the
Bence-Jones proteinuria in a 24 h urine specimen should
be used to monitor disease activity, and for patients with
oligosecretory multiple myeloma, the FLC assay is useful
to monitor disease activity, provided the FLC ratio is
abnormal and the involved FLC level is at least 100 mg/L.14
In the rare non-secretory multiple myeloma, only the
plasma cell count in the bone marrow and monitoring of
clinical manifestations of organ damage can be used for
response assessment and to monitor disease.15
Other techniques such as flow cytometry, fluorescent
in-situ hybridisation or PCR using allele-specific
oligonucleotides can contribute information on minimal
residual disease in myeloma, refine the complete
remission definition, and distinguish two response groups
(minimal residual disease positive and negative) with clear
differences in progression-free and overall survival.16
Disease management
Indication for treatment
Patients with smouldering multiple myeloma have no
treatment indication and should be monitored for
disease progression because early treatment with
conventional therapy has shown no benefit.17–19 The risk
of progression is highest in the first 5 years and decreases
subsequently. The overall risk of progression is 10% per
year for the first 5 years, about 3% per year for the next
5 years, and 1% per year for the next 10 years.17 Patients
with high-risk smouldering multiple myeloma should be
enrolled onto clinical trials
End-organ damage is defined mainly by the CRAB
criteria—hypercalcaemia, renal failure, anaemia, or bone
lesions, which are related to a plasma cell proliferative
disorder and cannot be explained by another unrelated
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disease or disorder. The appendix provides additional
information about criteria for active multiple myeloma.
Moreover, progressive myeloma-induced renal insufficiency should trigger initiation of treatment even
before the creatinine threshold of 2 mg/dL (177 μmol/L)
has been reached. Acute renal failure due to multiple
myeloma can be reversible if treated early. After the
confirmation of an underlying cast nephropathy,
appropriate treatment should be initiated without
delay.20,21 Once patients with renal impairment have
achieved a remission, their outcomes are similar to
patients with no renal insufficiency.22
Local disease control and systemic treatment
Solitary osseous and extraosseous plasmacytomas are
treated with curatively intended radiation therapy to the
involved field with cumulative doses of 45 Gy or more.23,24
Additionally, if necessary, extraosseous lesions can be
resected surgically. Although cure is the primary goal of
treatment in solitary plasmacytoma, a progression to
systemic multiple myeloma is possible and occurs in
30–60% of cases, therefore requiring regular follow-up.25
Patients diagnosed with systemic active multiple
myeloma characterised by end-organ damage should be
treated with systemic chemotherapy to prevent progression and reduce disease-induced symptoms.
A very good partial remission or complete remission
after systemic treatment is associated with an improved
long-term outcome. Therefore, the aim of new treatment
approaches is to increase response rates in all patients.
In elderly patients, this concept should be considered in
relation to possible side-effects and quality of life because
improved response rates do not necessarily translate into
a survival benefit.26–30 Surgery or radiotherapy might be
necessary if bone-related complications are present.
See Online for appendix
Autologous stem cell transplantation
Because myeloablative high-dose therapy with autologous
stem cell transplantation prolongs survival substantially
compared with conventional cytostatic treatments, it has
become an essential part of multiple myeloma management.31,32 Because of its toxic effects and the advanced age
of many multiple myeloma patients, the thorough assessment of eligibility is crucial.33 The most commonly used
criteria for eligibility are the patient’s preference, a
biological age up to 65–70 years, the absence of
substantial heart, lung, kidney, or liver dysfunction, or
other uncontrolled comorbidities such as diabetes.
Eligible patients should receive myeloablative treatment
with melphalan 200 mg/m² after remission induction by
standard first-line treatment. Older patients or patients
with substantially impaired organ function might receive
reduced doses of melphalan (100–140 mg/m²) before
infusion of autologous stem cells.34,35
Investigators in France showed that tandem transplantation was superior to single transplantation in a
randomised trial; however, this benefit was restricted to
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Age <65 years and dose level 0
Age 65–75 years and dose level –1
Age >75 years and dose level –2
Bortezomib
1·3 mg/m² on days 1, 4, 8, and
11 every 3 weeks
1·3 mg/m² on days 1, 8, 15, and
22 every 5 weeks
1·0 mg/m² on days 1, 8, 15, and
22 every 5 weeks
Cyclophosphamide
300 mg/m² orally on days 1, 8, 15,
and 22 every 4 weeks
50–100 mg/m² orally on days 1, 8, 15,
and 22 every 4 weeks
50 mg/m² orally every other day on
days 1–21 every 4 weeks
Dexamethasone
40 mg on days 1–4 and 15–18 or on
days 1, 4, 8, 15, and 22 every 4 weeks
20–40 mg on days 1, 4, 8, 15, and
22 every 4 weeks
10–20 mg on days 1, 4, 8, 15, and
22 every 4 weeks
Lenalidomide
25 mg on days 1–21 every 4 weeks
15 mg on days 1–21 every 4 weeks
10 mg on days 1–21 every 4 weeks
Melphalan
0·25 mg/kg on days 1–4 every 4–6 weeks
0·18 mg/kg on days 1–4 every 4–6 weeks
0·13 mg/kg on days 1–4 every 4–6 weeks
Prednisone
50 mg every other day
25 mg every other day
12·5 mg every other day
Thalidomide
200 mg/day continuously
100 mg/day continuously
50 mg/day continuously
Data from Ludwig and colleagues43 and Palumbo and Anderson.44
Table 2: Dose-adjustment recommendations depending on age and tolerability
patients who did not achieve at least a very good partial
remission after the first transplantation.36 The pooled
results from a systematic review showed no significant
difference between tandem and single autologous stem
cell transplantations for the outcome of overall survival,
but a superior event-free survival and response rate with
tandem transplantation.37 Current practice in most
centres is to do only one autologous stem cell transplantation initially. A reason for the use of this strategy is
that the proportion of patients achieving complete
remission after one high-dose chemotherapy has doubled
in the era of novel compounds used during induction
therapy. Moreover, stem cell transplantation might again
be effectively done in relapse, as suggested by data from
several non-randomised trials.38
Because the benefit of high-dose treatment has been
shown before the use of novel drugs and meta-analyses
showed an event-free survival advantage, but no clear
overall survival benefit,39 the value of autologous stem
cell transplantation has been a matter of debate for years.
However, preliminary results from randomised comparisons incorporating novel drugs have shown the
importance of high-dose treatment for sustained progression-free survival.40
Although immediate autologous stem cell transplantation in first-line treatment is the standard of care,
retrospective analyses suggest that in the era of novel
drugs its use could be postponed until the time of first
relapse with no prognostic disadvantage for patients.41
Currently, two large randomised trials (NCT01191060,
NCT01208766) are comparing immediate versus
delayed transplantation at the time of first relapse or
disease progression.
First-line treatment in patients not eligible for
transplantation
Most multiple myeloma patients will not be eligible for
high-dose therapy because of their older age. In this patient
group, emphasis should be placed on tolerability of
treatment to minimise excessive morbidity and mortality.
Treatment should be given for several cycles because
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response quality often increases over time.42 Generally,
however, this is only possible for treatments that have a
favourable tolerability profile. Quality of life is also a major
issue, particularly in a non-curable disease such as multiple
myeloma. To prevent excessive treatment toxic effects and
improve tolerability, age-adjusted dose reductions, modified
application schedules (table 2), and adequate supportive
measures are important considerations.
Figure 2 shows an overview of treatment approaches
used in newly diagnosed multiple myeloma patients.
Standard treatment options combine traditional drugs
such as melphalan and prednisone with novel treatments
such as immunomodulatory drugs and proteasome
inhibitors. The addition of the immunomodulatory drug
thalidomide to melphalan and prednisone has been
shown to increase response rates, progression-free
survival, and potentially overall survival in several trials
and a meta-analysis.45 Data from a large international
trial showed that the combination of the proteasome
inhibitor bortezomib and melphalan and prednisone had
a statistically significantly higher efficacy than melphalan
and prednisone alone and led to improved survival
outcomes.46 No data from randomised trials comparing
melphalan, prednisone, and thalidomide and melphalan,
prednisone, and bortezomib regimens are available.
However, findings from a recent meta-analysis suggested
higher response rates with the melphalan, prednisone,
and bortezomib regimen compared with the melphalan,
prednisone, and thalidomide regimen, but there were no
significant differences between the treatment regimens
in progression-free survival and overall survival.47
Another indirect meta-analysis of this comparison
showed no difference between melphalan, prednisone,
and bortezomib and melphalan, prednisone, and
thalidomide for all outcomes but a statistically significant
benefit for complete response and grade 3 or 4 adverse
events for melphalan, prednisone, and bortezomib.48 On
the basis of the survival benefit, compared with the
melphalan
and
prednisone
combination,
the
combinations of melphalan, prednisone, and thalidomide
and melphalan, prednisone, and bortezomib are the
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Patient with newly diagnosed multiple myeloma
CRAB criteria?
No
Watch and wait
Yes
Symptomatic osseus or
extraosseous lesion?
Yes
Consider radiotherapy or
surgical treatment
No
Systemic treatment
Assess comorbidities, age, patient’s preference
Transplantation-eligible patient
Three-drug regimen
Bortezomib, cyclophosphamide, and dexamethasone
Bortezomib, doxorubicin, and dexamethasone*
Bortezomib, lenalidomide, and dexamethasone*
Bortezomib, thalidomide, and dexamethasone*
Transplantation-ineligible patient
Two-drug regimen
Lenalidomide and
dexamethasone*
Bortezomib and
dexamethasone*
Three-drug regimen
Melphalan, prednisone, and bortezomib*
Melphalan, prednisone, and thalidomide*
Two-drug regimen
Lenalidomide and dexamethasone*
Bortezomib and dexamethasone*
Melphalan and prednisone*†
Bendamustine and prednisone*†
Dexamethasone†
Single autologous SCT*‡
Consider maintenance
Figure 2: Clinical management of patients with newly diagnosed multiple myeloma
The listed therapy combinations are selected and not inclusive of all regimens. *Treatment combinations with evidence from randomised-controlled trials.
†Melphalan + prednisone, bendamustine + prednisone, or dexamethasone can be used if novel drugs are not available or contraindicated. ‡Consider allogeneic
stem-cell transplantation in young patients with deletion 17p and HLA-identical siblings.
preferred first-line treatments if available and tolerated.
Data from two studies have shown that the combination
of lenalidomide and dexamethasone is an effective
treatment in elderly multiple myeloma patients.49,50
Preliminary data from a large randomised controlled
trial suggest higher response rates and similar
progression-free survival after first-line treatment with
lenalidomide plus low-dose dexamethasone for a fixed
number of cycles compared with melphalan, prednisone,
and thalidomide.51
Prophylactic antithrombotic measures should be taken
when thalidomide or lenalidomide are given,52,53 whereas
prophylactic aciclovir is recommended in patients
receiving bortezomib for the prevention of zoster
reactivation.54,55 Careful clinical monitoring and dose
adaptation is advisable to minimise the toxic effects of
treatment, ensure adherence to treatment and, hence,
provide the greatest opportunity for achievement of high
response rates and long-term remission. To minimise
toxicities of multiple myeloma treatments, dose reduction
might be necessary in patients receiving thalidomide and
lenalidomide, whereas laxatives might be needed for
patients receiving thalidomide. Moreover, there are
three main preventive strategies for bortezomib-induced
polyneuropathy: expansion of the application intervals
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from days 1, 4, 8, and 11 to days 1, 8, 15, and 22 per cycle;
use of the subcutaneous administration route as opposed
to intravenous application; and dose reduction.
First-line treatment in patients eligible for
transplantation
Patients eligible for high-dose treatment of multiple
myeloma tend to be younger and fitter than those who are
not eligible. Because there seems to be a positive
correlation between depth of response and survival,56–62
the goal with primary therapy is to achieve a maximum
response before high-dose treatment that translates into
even higher remission rates after autologous stem cell
transplantation. Accordingly, more effective and intensive
treatments are used to improve outcomes. Similarly to
non-transplantation-eligible patients, the combination of
novel drugs thalidomide,63 bortezomib,64 or lenalidomide49
with standard drugs for multiple myeloma treatment has
resulted in higher response rates than the historical
standard of vincristine plus doxorubicin (adriamycin)
plus dexamethasone.65,66 Therefore, combinations with
novel drugs should be used for primary treatment,
provided that they are available and not medically
contraindicated (figure 2). The triple combination
including either one or two novel drugs results in higher
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response rates than the combination of two drugs—eg,
bortezomib plus dexamethasone plus either cyclophosphamide67–70 or doxorubicin71,72 or thalidomide27,73 or
lenalidomide.69,74 The addition of a fourth drug to primary
treatment does not seem to further increase response
rates.28,69 On the basis of these findings, experts and
guidelines preferentially recommend the use of a triple
combination or if contraindications exist, a double
combination for three to six cycles for primary treatment
in transplant-eligible patients.43,44,65,75,76 There is a need for
high-level evidence from randomised-controlled trials
comparing different first-line regimens and two-drug
versus three-drug combinations, not only regarding
progression but also overall survival.
Consolidation and maintenance
To further reduce the tumour burden after autologous
stem cell transplantation, a limited number of treatment
cycles can be administered afterwards. This treatment is
referred to as consolidation and can improve the depth of
response.77,78 However, the emergence of novel agents
with a lower toxic effect profile than with more traditional
anti-multiple myeloma drugs led to a renaissance in the
concept of continuous treatment or maintenance.
Historical approaches with steroids79,80 or interferon81,82
showed little efficacy and serious limitations because of
long-term side-effects and low tolerability.
As thalidomide was the first of the novel drugs, the
largest number of patients has received thalidomide
continuously. Three meta-analyses of trial results in
transplantation-eligible patients showed a benefit in
progression-free survival and overall survival when
thalidomide maintenance was compared with no
maintenance.83–85 These positive results should be
considered in relation to substantial long-term toxic
effects, leading to a short treatment, mainly as a result of
peripheral polyneuropathy. In the large MRC IX trial of
thalidomide maintenance, patients with high-risk
cytogenetics had a statistically significantly shorter
overall survival after thalidomide maintenance than did
those without maintenance. This difference was caused
by a higher incidence of resistant disease that did not
respond to salvage treatment in the thalidomide
maintenance group.86 In four clinical trials administering
thalidomide after melphalan, prednisone, and
thalidomide in elderly patients,87–90 only one trial showed
a small statistically significant benefit in overall survival.88
The maintenance of lenalidomide, the second novel
drug, has been extensively studied in three large
randomised trials. As opposed to thalidomide, longterm application is feasible because of a more favourable
toxicity profile with mainly haematological side-effects.
The IFM 2005-0278 and CALGB 10010491 trials applied
lenalidomide maintenance after high-dose treatment in
a randomised placebo-controlled design until disease
progression. With a median follow-up of 45 months in
the IFM 2005-02 trial, progression-free survival was
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significantly prolonged with lenalidomide versus
placebo (41 months vs 23 months; p<0·001). After a
median follow up of 34 months in the CALGB 100104
trial, patients receiving maintenance with lenalidomide
versus placebo had a median time to progression of
46 months versus 27 months (p<0·001). Although the
IFM 2005–02 trial showed no significant benefit in
overall survival, a difference in 3-year overall survival of
88% versus 80% in favour of lenalidomide has been
shown in the CALGB 100104 trial (p=0·03). Another
trial explored lenalidomide maintenance in elderly
patients who were not eligible for high-dose treatment.
Patients were randomly assigned to receive either nine
cycles of melphalan and prednisone or melphalan and
prednisone plus lenalidomide or melphalan,
prednisone, and lenalidomide followed by lenalidomide
maintenance. Progression-free survival after melphalan,
prednisone, and lenalidomide was 14 months, but after
the same combination followed by lenalidomide
maintenance, it was 31 months. Overall survival in all
three study groups was not significantly different after a
median follow-up of 30 months.26 In all three trials, the
incidence of second primary malignancies was higher
in the treatment groups receiving continous
lenalidomide than in patients without lenlidomide
maintenance—between 7%26 and 9·5%91 versus about
3%26 to 4%.78,91 The preliminary results of the FIRST trial
showed a statistically significant improvement in
progression-free survival and overall survival when firstline lenalidomide plus dexamethasone treatment was
given continuously until progression compared with a
fixed number of cycles.51
Although the third established novel drug bortezomib
is given parenterally, its feasibility for continuous
treatment has been shown in a large Dutch-German
randomised trial, which compared bortezomib
maintenance after bortezomib-based induction and
thalidomide maintenance after induction with
vincristine,
doxorubicin,
and
dexamethasone.
Bortezomib was given intravenously every 2 weeks for
2 years. Bortezomib maintenance was better tolerated
than thalidomide. The main adverse events during
maintenance were infections, polyneuropathy, and
gastrointestinal symptoms. After a median follow-up of
41 months, progression-free survival was significantly
prolonged in the bortezomib group (35 months vs
28 months, p=0·002). An overall survival advantage
after 5 years was 61% versus 55% and became significant
only after adjustment for unbalanced risk factors in a
multivariate Cox regression model.72 No increased risk
of second primary malignancies was observed with
bortezomib maintenance.72 Investigators of a second
randomised trial explored the value of six cycles of
bortezomib consolidation after autologous stem cell
transplantation compared with no consolidation. After a
median follow-up of 38 months, the median progressionfree survival was 27 months versus 20 months (p=0·05)
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in favour of bortezomib consolidation and the 3-year
overall survival was 80% in both groups. Tolerability
was acceptable with more severe poly neuropathy after
bortezomib consolidation.92
Generally, the concept of maintenance is still a matter
of debate. Supporters emphasise the increased duration
of progression-free survival, a trend for an overall survival
benefit, and the acceptable tolerability with manageable
side-effects. Opponents argue in favour of a
treatment-free interval as an important factor for patients’
quality of life, and highlight the inconclusive results
regarding overall survival, the side-effects, the risk of
second primary malignancies and high costs. So far,
none of the drugs assessed has been approved for
maintenance therapy. Experts recommend that treatment
decisions for individual patients must carefully balance
potential benefits against risks because a widely agreed
on standard is not yet established (appendix).75,85
Allogeneic stem cell transplantation
Allogeneic stem cell transplantation has been done for
several decades in multiple myeloma patients. Despite
improvements in tolerability of conditioning regimens,
supportive care, and donor search, the more profound
antitumour efficacy of allogeneic stem cell transplantation
is partly offset by treatment-related complications that are
mainly due to graft-versus-host disease. Although clear
evidence for a graft-versus myeloma effect exists, as shown
by the efficacy of donor lymphocyte infusions in patients
relapsing after allogeneic stem cell transplantation, there is
so far no survival plateau in most reports, suggesting that
even allogeneic stem cell transplantation might not be a
definitive cure in a considerable proportion of patients.
Overall, the data tend not to support the routine use of
allogeneic stem cell transplantation as an upfront therapy
in unselected patients. Nevertheless, there is a small
number of patients in the age range of 30–40 years in
whom individualised decision making might favour the
use of allogeneic stem cell transplantation after
myeloablative conditioning therapy, since in these young
patients the prospect of a 5–10 year survival with
conventional strategies is unsatisfactory.
Treatment at relapse or progression
Treatment decisions in relapsed or progressive patients
should carefully weigh efficacy against risk and reduction
of patients’ quality of life. This is true not only for the
treatment regimen but also for the time when treatment
should be initiated. A clinical relapse characterised by
symptoms or CRAB criteria should be treated
immediately; however, a biochemical relapse—ie, a
solitary increase in protein markers in blood or urine
Patient with relapsed or progressive disease
Transplantation-eligible patient‡
Previous stem-cell transplantation
>12–18 months ago
<12–18 months ago
Consider re-induction
and autologous stem-cell
transplantation
Transplantation-ineligible patient
Previous treatment
Without novel drugs
With novel drugs
<6–9 months ago
>6–9 months ago
Change regimen
Consider repeating
previous regimen
Novel drug with or without steroid and with or without alkylator or anthracyclin
Previous treatment contained lenalidomide or thalidomide†
Bortezomib monotherapy*
Bortezomib and dexamethasone
Bortezomib and liposomal doxorubicin*
Pomalidomide and dexamethasone*
Bortezomib, cyclophosphamide, and dexamethasone
Bortezomib, bendamustine, and dexamethasone
Bortezomib, bendamustine, and prednisone
Previous treatment contained bortezomib†
Lenalidomide monotherapy
Lenalidomide and dexamethasone*
Pomalidomide and dexamethasone*
Thalidomide and dexamethasone
Lenalidomide, doxorubicin, and dexamethasone
Lenalidomide, cyclophosphamide, and dexamethasone
Lenalidomide, bendamustine, and dexamethasone
Thalidomide, bendamustine, and dexamethasone
Figure 3: Clinical management of patients diagnosed with relapsed or progressive multiple myeloma
The listed therapy combinations are selected and not inclusive of all regimens. *Treatment combinations with evidence from randomised-controlled trials. †Patients
refractory to lenalidomide or thalidomide and bortezomib are eligible for pomalidomide or carfilzomib or might benefit from cyclophosphamide, melphalan, or
bendamustine with or without steroids.‡Consider allogeneic stem-cell transplantation in young patients with deletion 17p and HLA-identical sibling.
www.thelancet.com Vol 385 May 30, 2015
2203
Seminar
A
Diagnosis after 1996
Diagnosis during or before 1996
100
Overall survival (%)
80
60
40
p<0·001
20
0
B
1971–76
1977–82
1983–88
1989–94
1995–2000
2001–06
100
Overall survival (%)
80
60
40
20
0
0
20
40
60
80
Time from diagnosis (months)
100
120
140
Figure 4: Overall survival after diagnosis in patients with multiple myeloma
The analysis is based on a cohort of 2981 patients with newly diagnosed multiple myeloma seen between
January, 1971, and December, 2006, at the Mayo Clinic, Rochester, MN, USA. (A) The Kaplan-Meier curves for
overall survival from diagnosis. The groups were divided based on the date of diagnosis: between Jan 1, 1997, to
Dec 31, 2006, versus on or before Dec 31, 1996. (B) The Kaplan-Meier curves for overall survival from the time of
diagnosis are grouped into 6-year intervals based on the date of diagnosis (with permission of Blood).108
without CRAB criteria in an asymptomatic patient,
should be observed for kinetics first, even in the presence
of formal criteria for relapse or progression. As a rule,
proliferative relapses should be treated more rapidly than
slowly relapsing multiple myeloma. If the doubling time
of the monoclonal protein is 2 months or less, treatment
is indicated even in the absence of CRAB criteria.43
Various treatment options are available in case of
relapse, ranging from conventional cytostatic agents
such as melphalan, cyclophosphamide, bendamustine,
liposomal doxorubicin, and steroids to novel drugs,
including thalidomide, bortezomib, and lenalidomide.
Most recommended treatment protocols comprise a
combination of these drugs. Figure 3 shows an overview
of treatment approaches in relapsed or progressive
multiple myeloma.
2204
The new immunomodulatory drug pomalidomide has
been approved by the US Food and Drug Administration
and by the European Medicines Agency for the treatment
of patients who have received at least two previous
therapies, including lenalidomide and bortezomib, and
have shown disease progression on or within 60 days of
completion of the last therapy. The drug is active even in
patients who are refractory to both lenalidomide and
bortezomib treatment and led to statistically significantly
higher response rates, progression-free survival, and
overall survival than high-dose dexamethasone in
randomised comparisons.93 The most frequently reported
side-effects were haematological toxic effects and febrile
neutropenia.93
Another approved drug carfi lzomib is a new
proteasome inhibitor displaying activity in heavily
pretreated patients with less neurotoxicity than
bortezomib.94,95 Carfi lzomib is approved by the Food and
Drug Administration for the treatment of patients who
have received at least two previous therapies, including
bortezomib and an immunomodulatory drug, and have
shown disease progression on or within 60 days of the
completion of the last therapy. The most frequent
adverse events in early trials were fatigue, anaemia,
nausea, and thrombocytopenia.94,95
The choice of a specific treatment protocol is determined
by patient-related factors (eg, age, performance status,
comorbidities, and pre-existing toxic effects), disease
characteristics such as quality and duration of response,
and aggressiveness of the disease.38,43
In patients with a history of recurrent or severe
thromboembolic events, thalidomide, lenalidomide, and
pomalidomide should be used with caution and with
adequate prophylaxis. In patients with clinically significant
neuropathy and gastrointestinal morbidity, bortezomib
and thalidomide should be avoided or used in dose-reduced
schedules. Renal insufficiency might restrict the applicable
dose of melphalan, cyclophosphamide, doxorubicin, and
lenalidomide. Steroids are part of most relapse protocols
and particularly useful as monotherapy in patients with
haematological insufficiency in whom most other drugs
must be used at a reduced dose or not at all.
Retreatment with a specific drug is generally feasible
and meaningful if the relapse or progress has occurred
after a prolonged treatment-free interval. Whereas this is
defined as more than 6 months in the USA,76,96 European
recommendations favour a treatment-free interval of
more than 12 months after the end of the previous
treatment.38,43 Many prospective and retrospective studies
showed that reusing bortezomib in later treatment lines is
feasible and can result in responses in a substantial
proportion of patients. Retreatment with immunomodulatory drugs, mainly lenalidomide, is also feasible
and can induce high response rates,38 even in relapse after
lenalidomide maintenance.97 A repeated high-dose
treatment with melphalan followed by autologous stem
cell transplantation seems to be a viable option for patients
www.thelancet.com Vol 385 May 30, 2015
Seminar
in good physical health with a time of at least 18 months98,99
to 24 months43 from treatment to relapse or progression or
if autologous stem cell transplantation was not given as
first-line therapy.100,101
Particularly in patients refractory to novel drugs,
sophisticated drug combinations and the participation in
clinical trials using experimental drugs should be
considered. Younger patients (age <50 years) with an
HLA-identical sibling donor are candidates for allogeneic
stem cell transplantation after dose-reduced conditioning
and should be assessed for such an intervention,
preferably in the first two years after initial diagnosis.102
Supportive care
The most important supportive measure in multiple
myeloma is the use of bisphosphonates in patients with
skeletal manifestations because they reduce pathological
vertebral fractures, skeletal related events, and bone pain.103
According to guidelines, bisphosphonates should be given
for at least 2 years after initial diagnosis.104,105 Combination
of bisphosphonates with vitamin D3 (cholecalciferol) and
calcium might be used. All patients should receive a dental
examination before initiation of bisphosphonates, and
invasive dental procedures should be done with caution
because of the risk of osteonecrosis of the jaw.106 The
appendix mentions other important supportive measures.
Future perspectives
The growing knowledge about pathogenic mechanisms,
the development of novel effective compounds that target
both multiple myeloma cells and the microenvironment,
and more effective supportive strategies have led to a
prolonged median overall survival of patients with multiple
myeloma over the past two decades.107 As shown in a single
treatment centre, 5-year overall survival improved from
37% in patients treated between 1971 and 1996, to 52%
between 1997 and 2006 (figure 4), and 66% between 2006
and 2010. These incremental increases in overall survival
can be attributed mainly to the introduction of autologous
stem cell transplantation, novel drugs and bisphosphonates.108,109 Nevertheless, multiple myeloma should still
be regarded as an incurable disease for most patients.
There is an ongoing cure-versus-control debate on
whether multiple myeloma should be treated with an
aggressive multidrug strategy targeting complete
response or whether a sequential disease control
approach should be pursued that emphasises quality of
life and overall survival.75 Although a multimodal
aggressive approach seems justified in younger patients
with adverse prognosis—eg, the deletion 17p or
extramedullary disease, treatment-related complications
should be kept in mind, together with the fact that only a
few long-term remissions and low (if any) survival
plateaus have been shown so far, questioning the
possibility of curing the disease. Moreover, it is not clear
whether sustained complete remission is caused by less
aggressive disease biology rather than therapy-induced
www.thelancet.com Vol 385 May 30, 2015
Search strategy and selection criteria
Data for this Seminar were identified by searches of PubMed,
Embase, Web of Science, and Cochrane Library for reports
published between Nov 1, 2008, and March 31, 2013, online
accessible abstract collections from 2012 annual meetings of
the American Society of Haematology, American Society of
Clinical Oncology, and European Society of Haematology.
Search terms used were “myeloma”, “pathogenesis”,
“diagnosis”, “treatment”, and “therapy”; MeSH terms and
filters for randomised trials were used if available.
Information from systematic reviews and meta-analyses,
randomised-controlled trials and evidence-based guidelines
was preferentially used; case reports, case studies and
non-English publications were excluded.
cure and might, therefore, be a prognostic factor post
hoc. Because cure or enduring remission is rare or
impossible even after intensive interventions, the
treatment goal in elderly, frail, or non-high-risk patients
should be disease control, such as achievement of a
stable plateau with transfusion independence, stable
renal function, and non-progression of bone disease with
low toxic effects, high quality of life, and improvement in
survival rather than to achieve a complete remission.
A major challenge in the near future will be to develop
rational algorithms and combination therapies for
biologically defined, distinct patient subgroups to prevent
overtreatment in low-risk patients or in those who do not
tolerate intensive interventions. However, more aggressive
strategies might be used in younger and physically fit
patients who are likely to derive long-term benefit from
tailored intervention. Such stratified approaches are
difficult to test for in prospective trials and need a
collaborative effort of large study groups and international
networks with state-of-the art molecular diagnostics.
Advances in our knowledge of when to use a particular
drug in the course of disease, together with the prospect of
several promising substances in clinical development, will
continue to improve the prognosis of multiple myeloma
patients in the future.
Contributions
CR, SK, and MB reviewed published work. CR and MB extracted data.
CR, SK, and MB wrote and revised the manuscript. CR and MB
contributed to the design of tables and figures. All authors approved the
final version of the manuscript.
Declaration of interests
CR has received speaker’s fees from Amgen, Celgene, Janssen, Novartis,
and Amgen. SK has received consultancies, honoraria, and speaker’s
fees from Celgene, Mundipharma, Janssen, Onyx, and travel or
accommodation payments from Celgene. MB has received speaker’s fees
from Celgene, Novartis, MedA, Genzyme, and Gilead, received a travel
grant from Astellas, and has served on an advisory board for Riemser.
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