Multiple Myeloma - The Lancet

Seminar
Multiple myeloma
Niels W C J van de Donk, Charlotte Pawlyn, Kwee L Yong
Lancet 2021; 397: 410–27 Multiple myeloma is the second most common haematological malignancy in high-income countries, and typically
Amsterdam UMC, Vrije starts as asymptomatic precursor conditions—either monoclonal gammopathy of undetermined significance or
Universiteit Amsterdam, smouldering multiple myeloma—in which initiating genetic abnormalities, such as hyperdiploidy and translocations
Department of Hematology,
involving the immunoglobulin heavy chain, are already present. The introduction of immunomodulatory drugs,
Cancer Center Amsterdam,
Amsterdam, Netherlands proteasome inhibitors, and CD38-targeting antibodies has extended survival, but ultimately the majority of patients
(Prof N W C J van de Donk PhD); will die from their disease, and some from treatment-related complications. Disease progression and subsequent
The Institute of Cancer relapses are characterised by subclonal evolution and increasingly resistant disease. Patients with multiple myeloma
Research, The Royal Marsden
usually have hypercalcaemia, renal failure, anaemia, or osteolytic bone lesions—and a detailed diagnostic investigation
Hospital NHS Foundation
Trust, London, UK is needed to differentiate between symptomatic multiple myeloma that requires treatment, and precursor states. Risk
(C Pawlyn PhD); and University stratification using both patient-specific (eg, performance status) and disease-specific (eg, presence of high-risk
College London Cancer cytogenetic abnormalities) is important for prognosis and to define the best treatment strategy. Current research
Institute, London, UK
strategies include the use of minimal residual disease assays to guide therapy, refining immunotherapeutic
(Prof K L Yong PhD)
approaches, and intercepting disease early in smouldering multiple myeloma.
Correspondence to:
Prof Kwee Lan Yong, University
College London Cancer Institute, Introduction and produce M-protein (also known as monoclonal
London WC1E 6DD, UK In multiple myeloma research, there is increased focus immunoglobulin or paraprotein). Multiple myeloma is
[email protected]
on understanding disease evolution from precursor complicated by organ dysfunction: hypercalcaemia,
conditions, use of minimal residual disease for renal insufficiency, anaemia, and bone destruction
prognosis, and continued fast-paced development of (known as the CRAB criteria). Multiple myeloma
new therapies. Such therapies include both next- accounts for 1% of neoplastic diseases, and is the
generation agents of known classes of antimyeloma second most common haematological malignancy in
drugs, and agents with new mechanisms of action, high-income countries, with an incidence of 4·5–6 per
particularly new immuno therapies. Supportive care 100 000 per year and a median age of about 70 years
measures are of key importance in multiple myeloma when patients first visit their doctor with symptoms.
management, and need to keep pace with both Incidence is higher in western Europe, North America,
unfamiliar toxicities from new treatments and sur and Australasia than in Asia and sub-Saharan Africa,
vivorship challenges from extending survival without possibly because of variation in diagnosis.1 From 1990
cure. In this Seminar, we provide a practical approach to to 2016, there was a 126% increase in global incidence
understanding these latest develop ments and their of multiple myeloma, owing to population growth, an
implications for how clinicians manage this challenging aging world population, and increased age-specific
malignancy in the real world. incidence rates.1 Risk factors for multiple myeloma
include obesity, chronic inflammation, and exposure to
Epidemiology, risk factors, and clinical course pesticides, organic solvents, or radiation. Inherited
Multiple myeloma is a blood cancer of monoclonal genetic variants also contribute to the develop ment
plasma cells that accumulate in the bone marrow of multiple myeloma.2,3 A report published in 2020
summarises both inherited and societal influences
accounting for racial and ethnic disparities in incidence
Search strategy and selection criteria and outcomes of multiple myeloma and precursor
We searched PubMed on Feb 1, 2020, and the websites for the conditions.4
major conferences of the American Society of Hematology, The use of novel agents (eg, proteasome inhibitors,
the American Society of Clinical Oncology, and the European immunomodulatory drugs, and antibodies targeting
Haematology Association, on Feb 10, 2020, using the search cell surface molecules) and also high-dose therapy and
terms “myeloma”, “multiple myeloma”, “MGUS”, “monoclonal autologous stem-cell transplantation (ASCT) in younger
gammopathy of undetermined significance”, “smoldering patients, has markedly improved outcomes in patients
multiple myeloma”, and “primary plasma cell leukemia”. with multiple myeloma.5 Median overall sur vival in
We searched for papers and abstracts published in English, patients eligible for ASCT is estimated to be
without restriction on the earliest date of publication, which approximately 10 years, compared with 4–5 years in
reported preclinical or clinical studies in multiple myeloma or patients not eligible for transplantation.6,7 The majority
related plasma-cell disorders. The literature search was of patients with multiple myeloma experience numerous
updated on Aug 15, 2020, during the revision process for this relapses of their disease. Each subsequent remission is
Seminar. The final references list was generated on the basis of of increasingly shorter duration and ultimately patients
relevance and impact to the broad scope of this Seminar. will die from the disease itself or treatment-related
complications.
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Pathogenesis, genomics, and the marrow with adverse outcomes associated particularly with t(4;14),
microenvironment t(14;16), t(14;20), gain(1q), and del(17p).10,20 The loss of TP53
The initiating event driving malignant development is from both alleles—eg, owing to del(17p) and mutation of
either the acquisition of hyperdiploidy or a translocation the second allele, is associated with dismal outcomes.21
involving the immunoglobulin heavy chain gene locus.8 Major genetic change occurs early in disease evolution,
Such clonal events can occur in almost all cells, and are with fewer changes identified between smouldering
present in the precursor conditions monoclonal gam multiple myeloma and multiple myeloma than between
mopathy of undetermined significance (MGUS) and MGUS and smouldering multiple myeloma.22 Thus,
smouldering multiple mye loma. Aetiological transloca transition to disease requiring therapy might be partly
tions mean oncogenes are controlled by the strong driven by changes in the bone marrow microenvironment.
immunoglobulin heavy chain gene enhancer; the t(4;14) In this context, the bone marrow is the Darwinian selective
translocation dysregulates MMSET (also known as NSD2) pressure exerting influence over the clonal population.
and FGFR3, t(6;14) CCND3, t(11;14) CCND1, t(14;16) MAF, Ultimately, there is coevolution of the multiple myeloma
and t(14;20) MAFB.9 Additional genetic events are found in clone and the bone marrow microenvironment, with an
subclonal populations, and with increased frequency as the increase in tumour-promoting immune cells and a loss
disease evolves from a precursor condition into multiple of anti-tumour immunity as the disease evolves. The
myeloma. Acquired genetic events include copy number influence of the microenvironment is exemplified by
abnormalities, secondary translocations, and somatic studies showing spatial clonal differences in samples
mutations. Many of these genetic events converge to taken simultaneously from different bone marrow sites
dysregulate the cell cycle (figure 1).11 in a patient.23 There is also an association between
Copy number abnormalities result in chromosomal immunoparesis and disease progression from smoul
regions of loss or gain. Loss of tumour suppressor genes dering multiple myeloma to multiple myeloma, sug
results from a deletion (del) from the chromosome’s gesting loss of immune function and microenvironmental
short arm (p) or long arm (q); del(1p) results in the loss of control of clonal expansion.24 Multiple components of the
CDKN2C, FAF1, and FAM46C (also known as TENT5C), bone marrow microenvironment might be involved—eg,
del(11q) BIRC2 and BIRC3, del(13q) RB1 and DIS3, and mesenchymal stromal cells, B cells, T cells, osteoclasts,
del(17p) TP53.10 Gain in the long arm of chromosome 1 is and adipocytes.25,26
found in around 40% of patients, often in association
with t(4;14).12 Common secondary translocations Aetiological events
involve MYC, either via t(8;14) or without involving the t(11:14) t(4:14) t(14:16) t(14:20) t(6:14)
immunoglobulin heavy chain gene.12 Somatic mutation
rates are highly variable between patients,12 and occur Secondary events
MMSET MAF/B
most often in genes of the RAS/MAPK pathway; around MYC RAS
50% of patients have such a mutation (KRAS 22%, Hyperdiploidy
NRAS 17%, BRAF 8%). Other commonly mutated genes
include TENT5C (formerly known as FAM46C) and
CDK CDK CDK
DIS3, in around 10% of patients.13 CCND1 4/6
CCND2 4/6
CCND3 4/6
Other signalling pathways affected include the NF-κB
pathway (affected by copy number loss, mutation, and
translocations) and the PI3K pathway (dysregulated
CDKN2A Secondary events
in the absence of genetic change).14 Apoptotic pathway
INK4 Methylation
dysregulation occurs, with BCL2 dependency in patients CDKN2B
inhibitors Mutation
with t(11;14) and MCL1 dependency in other patients.15 Homozygous
CDKN2C
Normal plasma-cell differentiation signalling is altered, del(1p)
inactivation
with upregulation of IRF4, which occurs via a positive
CDK
autoregulatory loop and the loss of the negative feedback G1 CCNE 2
to MYC expression via PRDM1.16 Epigenetic dysregulation Mutation
is important in myeloma. MMSET, upregulated in the Secondary CIP/KIP Homozygous
CDKN1A TP53
15% of patients with the t(4;14) aetiological translocation, events Mutation E2F inhibitors inactivation
Homozygous RB1
is a histone 3 lysine 36 methyltransferase. Patients with inactivation del(17p)
t(4;14) have a distinct histone methylation and DNA del(1p)
methylation pattern, which might be responsible for P
P E2F
downstream gene expression differences.17 RB1 S
P
Acquired events collaborate with the background driver of P
pathogenesis, at differing frequencies in each aetiological Figure 1: Cell cycle dysregulation in myeloma
subgroup.18,19 Both initiating and acquired genetic events Both aetiological and secondary genetic events and other downstream effects help to dysregulate cell cycle control,
have important prognostic and therapeutic implications, leading to cell proliferation and clonal growth. Adapted from Pawlyn and Morgan (2017).10
www.thelancet.com Vol 397 January 30, 2021 411

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is fast and more sensitive than plain radiography.31

Monoclonal Smouldering myeloma Multiple myeloma
gammopathy of Imaging guidelines recommend functional imaging
undetermined techniques, such as ¹⁸F-fluorodeoxyglucose (FDG) PET
significance combined with CT, or diffusion-weighted MRI for
M-protein and clonal M-protein <30 g/l, M-protein ≥30 g/l, or Clonal bone marrow response assessment. Dedicated whole-spine MRI might
bone marrow plasma and urinary M-protein urinary M-protein plasma cells ≥10% or bony be required for evaluation of spinal cord compression.31
cells <500 mg/24 h, and clonal ≥500 mg/24 h, or clonal or extramedullary
bone marrow plasma bone marrow plasma plasmacytoma proved by
Bone marrow sampling is required to assess the amount
cells <10% cells ≥10 to <60% biopsy of infiltration, either by histopathology on the biopsy
Myeloma-defining No No Yes sample, or morphology, or flow cytometry on the bone
events: biomarker of marrow aspirate. Cytogenetic analysis by fluorescence in
malignancy* or situ hybridisation on purified multiple myeloma cells
end-organ damage†‡
should include tests for at least the high-risk lesions
FLC ratio=involved versus uninvolved serum free light chain ratio. *Biomarker of malignancy: clonal bone marrow t(4;14), t(14;16), and del(17p).32 Gene expression and
plasma cells of at least 60%, FLC ratio of at least 100, or more than 1 focal lesion on MRI (each lesion must be at least
5 mm in size). †End-organ damage that can be attributed to the underlying plasma cell disorder includes: mutation panels can assist prognosis, but are not
hypercalcaemia (serum calcium >0·25 mmol/L [>1 mg/dL] higher than the upper limit of normal or >2·75 mmol/L available routinely in most centres.
[>11 mg/dL]); renal insufficiency (creatinine clearance <40 ml/min or serum creatinine >177 µmol/L [>2 mg/dL]); Clinical outcomes for patients with multiple myeloma
anaemia (haemoglobin value of >20 g/L [>1·25 mM] below the lower limit of normal, or a haemoglobin value
<100 g/L [<6·2 mM]); lytic bone lesions (one or more osteolytic lesions on skeletal radiography, CT, or PET-CT [≥5 mm
depend on several factors (appendix p 3), including
in size]). If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from intrinsic tumour cell characteristics (cytogenetic abnor
solitary plasmacytoma with minimal marrow involvement. ‡Patients might have renal failure that is not related to the malities, gene expression profile, extramedullary growth,
plasma cell disorder, but which results from other underlying conditions, such as diabetes and hypertension, that are
lactate dehydrogenase levels),32,33 tumour burden (β2-
prevalent in patients older than 65 years. Similarly, consideration should be given to primary hyperparathyroidism in
case of hypercalcaemia, nutritional deficiencies for anaemia, and metastatic carcinoma for lytic bone lesions. microglobulin [B2M], low platelet count), and patient
features (age, comorbidities, frailty).34 Outcomes also
Table 1: Diagnostic criteria for monoclonal gammopathy of undetermined significance, smouldering depend on depth of response to therapy. Models
myeloma, and multiple myeloma29
combining patient and disease characteristics have been
created, because individual prognostic factors do not
Damage to the structure of bone itself is a major cause capture the full heterogeneity in outcome. The original
of morbidity in multiple myeloma, driven by disruption of multiple myeloma International Staging System, based
the balance between the bone-resorbing osteoclasts and on serum albumin and B2M concentrations, reflects
bone-repairing osteoblasts that constitute physiological tumour burden and patient condition.35 This staging
bone-remodelling processes.27 Tumour cells secrete oste system has been updated as the Revised International
oclast-activating factors (eg, RANK ligand [TNFSF11] and Staging System, which includes information on the
[interleukinIL]-6) and osteoblast inhibitory factors (eg, presence of high-risk genetic lesions—t(4;14), t(14;16), or
DKK1 and sclerostin [SOST]). This process leads to bone del(17p), either alone or in combination—or increased
loss and a feedback loop that drives further multiple lactate dehydrogenase con centration (appendix p 4).36
myeloma cell proliferation and immune suppression, Inclusion of more detailed genetic and molecular
resulting from the release of IGF1 and TGF-β during bone information could provide further prognostic information,
resorption.28 such as co-occurrence of multiple adverse cytogenetic
lesions (eg, biallelic disruption of TP53 that is associated
Symptoms, diagnostic investigation, and with particularly poor patient outcomes).18
prognostic models
Patients are sometimes identified on the basis of an Disease monitoring including assesment of
M-protein on routine blood testing, although most minimal residual disease
patients have signs and symptoms of organ damage Response to therapy is determined by measuring
(eg, bone pain and fractures, infections, anaemia, renal M-protein in serum and urine, combined with bone
failure, and hyperviscosity). A detailed diagnostic inves marrow assessment of plasma cells (appendix p 5).
tigation of patients with MGUS or smouldering multiple Minimal residual disease assessment of bone marrow
myeloma is needed to differentiate between multiple is generally only done in the context of clinical trials,
myeloma and asymptomatic precursor conditions, using but evidence from current trials supports its use in the
clinical, biochemical, and radiological criteria (table 1).29,30 near future to help direct treatment choice. Cross-
Indications for treatment are based on the presence of sectional imaging is repeated during follow-up if
end-organ damage or at least one biomarker of clinically indicated—eg, as part of response assessment
malignancy. in extra-osseous tumours, in patients with soft tissue
At the time of multiple myeloma diagnosis, a detailed plasmacytomas, or in cases with signs of disease
medical history, physical examination, and laboratory progression (eg, pain or increase in serological
See Online for appendix studies should be done (appendix p 2). Evaluation of parameters).
multiple myeloma bone disease requires cross-sectional Response to therapy is an important prognostic
imaging. Low-dose whole-body CT is recommended, as it factor, with complete response, or stringent complete

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response, signifying improved long-term survival.37,38 myeloma.31 To mitigate the risk of progression and enable
However, select patient subgroups, including people early diagnosis, long-term follow-up is advised, adjusted
with MGUS-like profiles, can have long-term survival according to risk and life expectancy52 (figure 2). Rarely,
without achieving complete response.38,39 As a refinement the MGUS or smouldering multiple myeloma clone
of complete response, sensitive methods for detecting itself is clinically relevant, for example, owing to cytokine
minimal residual disease in the bone marrow (eg, secretion (POEMS syndrome), the physicochemical
multiparameter flow cytometry or next-generation properties of the M-protein (light-chain amyloidosis,
sequencing) are increasingly used. Achieving negative monoclonal gammopathy of renal significance), or auto-
minimal residual disease status is consistently associated antibody activity (eg, IgM neuropathy).57 Clone-directed
with improved progression-free survival and overall therapy with anti-multiple myeloma agents might be
survival in patients with newly diagnosed multiple indicated in cases of aggressive and disabling disease.54
myeloma, regardless of having received a transplant or of In 2014, a small subset of patients with ultra high-risk
genetic risk.38,40–42 Because maintenance or continuous smouldering multiple myeloma was reclassified by
therapy can maintain negative minimal residual disease the International Myeloma Working Group as having
status,40,43 the effect of such status will differ, depending multiple myeloma, and recommended to start therapy
on whether patients remain on treatment. Although without waiting for organ damage to occur. These
there is no consensus on optimal timepoints or frequency patients had high risk (>80%) of disease progression
of minimal residual disease assessment, sustained within 2 years, and were identified by at least 60% bone
(ie, ≥12 months)44 negative status is probably the best marrow plasmacytosis, presence of more than one focal
surrogate for prolonged survival.44,45 Minimal residual lesion on MRI, or serum free light chain ratio of at
disease is now incorporated in the updated International least 100 (see biomarkers of malignancy, table 1).29
Myeloma Working Group response criteria (appendix Excluding patients with ultra high-risk disease, models
p 5).44 In the future, it is probable that regulatory to predict risk of progression in patients with MGUS55
authorities will consider minimal residual disease status and smouldering multiple myeloma56 are required
as a surrogate for estimating survival, thereby accelerating (figure 2). The 20–20–20 risk model for smouldering
approval of new drugs.46 Several trials are ongoing to multiple myeloma is based on cutoff values for serum
define the potential role of minimal residual disease M-protein (20 g/L), the involved to uninvolved serum
status to inform treatment decisions, such as assessing free light chain ratio (20), and bone marrow plasma cell
the need for consolidation, or to guide type and duration infiltration (20%), as independent risk factors. In this
of maintenance treatment. model, patients with at least two risk factors had a 2-year
However, minimal residual disease monitoring of progression rate of 46%, and might be candidates for
bone marrow fails to detect extramedullary disease, and clinical trials. Two studies in intermediate-risk or high-
can be falsely negative because of patchy involvement of risk smouldering multiple myeloma reported that early
bone marrow.46 Thus, functional imaging techniques intervention with lenalidomide (with or without
(eg, FDG PET combined with CT) are required to assess dexamethasone) delayed progression to symptomatic
residual disease outside the bone marrow, and com disease and resulted in longer overall survival, compared
plement bone marrow-based minimal residual disease with observation only.58,59 Several lenalidomide-based
assessment after therapy.47 However, PET scans can regimens, including antibody-based ones, are under
produce false positive (eg, infection, inflammation) or investigation in high-risk smouldering multiple mye
false negative results (hyperglycaemia or low expression loma. An alternative strategy of intensive combination
of hexokinase-2).48 therapy, followed by high-dose melphalan and ASCT,
resulted in a high rate of complete response and negative
MGUS and smouldering multiple myeloma: minimal residual disease status, though actual cure
management and risk models remains uncertain.60 As yet, no treatment is approved for
There is good evidence that multiple myeloma is always smouldering multiple myeloma.
preceded by the precursor conditions MGUS or
smouldering multiple myeloma.49 These precursors are Treatment of myeloma
characterised by the absence of signs or symptoms Proteasome inhibitors and immunomodulatory drugs are
related to multiple myeloma or other lymphoproliferative the current mainstay of myeloma therapy and in clinical
diseases. Only 5–7% of patients with MGUS, and around trials are usually the standard of care to which newer
50% of patients with smouldering myeloma, will develop drugs are added. Steroids, in the form of dexamethasone
multiple myeloma within 5 years of diagnosis.50,51 Careful or prednisolone, are invariably included. The fourth class
assessment of disease bulk and organ function, using of drug, which is becoming a key component of relapse
the same diagnostic investigations as for multiple and first-line therapies, is CD38-targeting antibodies
myeloma, is recommended, and cross-sectional imaging (appendix pp 6–7). The main drugs used, together with
with whole-body CT or MRI is advised for high-risk their licensed indications and main toxicities, are detailed
MGUS and for all patients with smouldering multiple in table 2.

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First-line therapy: use of ASCT in younger, fitter patients

Although no treatment for myeloma is truly curative, the
aim of first-line therapy is to induce a deep response,
A MGUS because depth of response correlates with longer time to
M-protein <30 g/L and BMPC
<10%; absence of end-organ relapse and overall survival.38 Evidence supports using
damage* induction therapy followed by ASCT to achieve a deep
response, hence this is standard of care in most countries
Perform risk stratification
in patients who are fit (ie, of good performance status, and
generally younger than 70 years).61,62 However, evidence is
accruing to support deferring ASCT until relapse,
especially in patients achieving a deep response.63 In a
Low-risk MGUS and life Non-low-risk MGUS and life MGUS and life expectancy randomised controlled trial to evaluate ASCT versus
expectancy ≥5 years expectancy ≥5 years <5 years
chemotherapy, patients in the ASCT group had longer
progression-free survival, although survival outcomes
Follow-up at 6 months and if Follow-up every 6 months for No further follow-up but were similar in both groups.61 Nevertheless, ASCT remains
stable every 1–2 years; or 2 years and annually thereafter additional investigations only in
discharge to primary care for case of symptoms suggestive of standard of care in many parts of the world. Patients are
follow-up with additional progression selected for ASCT on the basis of organ function, age,
investigations only in case of
symptoms suggestive of disease
performance status, and response to induction therapy,
progression because patients with refractory or progressive disease do
not benefit.64 Before ASCT, patients receive three to six
cycles of induction using a multidrug regimen, after which
Mayo Clinic risk stratification model for MGUS
haematopoietic stem cells are mobilised into the peripheral
Number of risk factors Risk of progression at 20 years Percentage of total
blood, harvested, and frozen down. These stem cells are
• M-protein ≥15 g/L
• Non-IgG subtype then reinfused 1–2 days after high-dose chemotherapy
• Abnormal FLC ratio (usually melphalan), hence the term autologous stem-cell
0: low risk 5% 39% transplantation. Many centres aim to harvest sufficient
stem cells to support a second ASCT, either as a tandem
1: low to intermediate risk 21% 37%
procedure or at relapse (see section on first relapse).
2: intermediate to high risk 37% 20%
3: high risk 58% 5% Induction regimens

Current standard of care is a bortezomib regimen,
B com bined with dexamethasone, and an immunomodu
SMM
M-protein ≥30 g/L, or BMPC ≥10 latory drug (thalidomide or lenalidomide, bortezomib–
to <60%, or both; FLC ratio <100; thalidomide–dexamethasone or bortezomib–lenalido
≤1 focal lesion on MRI; absence
of end-organ damage* mide–dexamethasone) or bortezomib–cyclophosphamide–
dexamethasone. Overall responses (defined as at least
Perform risk stratification
Figure 2: Risk stratification and follow-up of patients with MGUS and

Low-risk SMM Intermediate-risk SMM High-risk SMM smouldering myeloma
Follow-up of MGUS and smouldering myeloma is based on risk of progression to
symptomatic disease. (A) Recommendations for follow-up of patients with
Follow-up every 3 months for Follow-up every 3 months for Follow-up every 2–3 months, MGUS are based on IMWG criteria53 with some European Myeloma Network
1 year, and 6–12 months 2 years, and every 6 months or entry in a clinical trial modifications.52,54 Risk of progression to multiple myeloma, or other
thereafter thereafter If no progression after 5 years,
lymphoproliferative malignancies, is predicted by the Mayo Clinic risk
If no progression after 5 years, If no progression after 5 years, consider follow up every
consider annual follow-up consider annual follow-up 6–12 months stratification model.55 (B) Recommendations for follow-up of patients with
smouldering multiple myeloma are based on IMWG criteria,53 with some
modification according to risk.52 The IMWG prognostic scoring system gives an
estimate of the risk of progression.56 Follow-up should include laboratory testing
20–20–20 scoring system for smoldering multiple myeloma
for complete blood count, creatinine, calcium, M-protein, free light chains, and
Number of risk factors Risk of progression at 2 years Percentage of total urine (Bence Jones protein test, total protein), careful history, and directed
• Serum M-protein >20 g/L examination. If the free light-chain ratio is abnormal, with an increase of the
• FLC ratio >20 involved light chain, N-terminal pro B-type natriuretic peptide and urinary
• BMPC >20% albumin should be tested to exclude amyloid light chain amyloidosis. Repeat
0: low risk 5% 37% bone marrow biopsy and skeletal imaging31 are required if symptoms or signs of
progression (including abnormalities in laboratory results) develop. BMPC=bone
1: intermediate risk 17% 27% marrow plasma cells. FLC=serum free light chain. IMWG=International Myeloma
Working Group. MGUS=monoclonal gammopathy of undetermined
2–3: high risk 46% 36% significance. SMM=smouldering myeloma. *End-organ damage includes
hypercalcaemia, renal insufficiency , anaemia, and lytic bone lesions (see table 1).

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partial response, appendix p 5) to such regimens are Studies report high response rates to the second
generally more than 80% and around 40–50% of patients generation proteasome inhibitor carfilzomib, used in
also achieve at least a very good partial response. Following combination with lenalidomide and dexamethasone as
ASCT, responses increase by around 10–20%.61 induction before ASCT,65 but this drug remains unlicensed
Mode of action Route of Licensed Common regimens Common side-effects and

administration indications cautions
Alkylating drugs
Melphalan Induces DNA cross- Oral or Treatment of Melphalan (oral), prednisolone with or Bone marrow suppression,
linking and DNA double- intravenous myeloma; oral or without thalidomide or bortezomib infections, mucositis with
strand breaks intravenous (MPT, MPV); high-dose melphalan high-dose melphalan,
(200 mg/m² intravenously) as increased risk of second
conditioning for stem-cell primary malignancy, dose
transplantation, lower doses for reduction in renal
patients who are less fit (based on impairment
presence of comorbidities or Karnofsky
performance status <90%) and also as
part of conditioning in reduced intensity
allogeneic stem cell transplantation
Cyclophosphamide Formation of DNA Oral or First-line and Combination therapy with Bone marrow suppression,
crosslinks leading to intravenous relapse treatment dexamethasone and infections, haemorrhagic
apoptosis; at low and for peripheral immunomodulatory drugs (eg, CTD, cystitis; need for adequate
(metronomic) doses also blood stem cell CRD), and with proteasome inhibitors fluid intake, give mesna to
immune stimulatory mobilisation (eg, VCD, VCP, KCD) protect the bladder if giving
activity and high-dose (eg, 2 g/m²)
antiangiogenic effects cyclophosphamide, dose
modifications for neutropenia
and thrombocytopenia
Steroids
Dexamethasone Agonist of the GR Oral or First-line and Used in combination with almost all Infections, hyperglycaemia,
intravenous relapse therapy antimyeloma regimens, often as insomnia, psychiatric
pulsed (once per day for 4 days) or side-effects, dyspepsia,
once per week dosing; in acute spinal gastritis, gastric ulcer,
cord compression, can be used as duodenal ulcer
single agent
Prednisolone Agonist of the GR Oral First-line and In place of dexamethasone in patients With prolonged use:
relapse therapy not eligible for transplant—eg, MPT, suppression of the
MPV hypothalamic–pituitary axis,
avascular necrosis, myopathy
Anthracyclines
Doxorubicin Topoisomerase II Intravenous First-line and PAD, DT–PACE Heart failure, increased risk of
inhibitor infusion relapse therapy second primary malignancy,
myelosuppression and
infections, total cumulative
dose should not exceed
550 mg/m², discontinue
doxorubicin in patients who
develop cardiomyopathy
Proteasome inhibitors
Bortezomib First generation Intravenous or First-line therapy; First-line therapy: MPV, VCD, VRD, VTD, Peripheral neuropathy,
reversible boronic acid subcutaneous relapsed disease bortezomib–dexamethasone, dara– thrombocytopenia,
proteasome inhibitor injection VMP; for relapsed disease: bortezomib– diarrhoea, constipation,
dexamethasone, VCD, VTD, Pano–Vd, herpes zoster
dara–Vd, PVd
Carfilzomib Second generation Intravenous Relapsed disease KRd, carfilzomib–dexamethasone Hypertension, cardiac failure,
epoxyketone infusion acute renal failure;
proteasome inhibitor thrombotic
that binds selectively microangiopathy; anaemia,
and irreversibly to the neutropenia; low incidence of
constitutive proteasome treatment-emergent
and immunoproteasome neuropathy
Ixazomib Reversible boronic acid Oral Relapsed disease IRd Thrombocytopenia,
proteasome inhibitor gastrointestinal toxicity, rash,
lower incidence of neuropathy
compared with bortezomib
(Table 2 continues on next page)

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(Continued from previous page)
Immunomodulatory drugs
Thalidomide Binds to CRBN and Oral First-line and MPT, CTD, VTD Peripheral neuropathy,
thereby triggers relapse therapy venous thromboembolism,
proteasomal degradation somnolence, fatigue, rash,
of IKZF1 and IKZF3, constipation, teratogenic
leading to direct anti- effects
multiple myeloma
activity, and
immunomodulatory and
stromal-cell effects
Lenalidomide Similar mode of action Oral First-line therapy; First-line therapy: lenalidomide– Bone marrow suppression,
to thalidomide but with relapsed disease dexamethasone, dara–Rd, VRD; venous thromboembolism,
different CRBN-binding maintenance after ASCT; for relapsed rash, chronic diarrhoea or
affinity and properties disease: lenalidomide–dexamethasone, constipation, increased risk of
dara–Rd, elo-Rd, KRd, IRd second primary malignancies;
renally excreted, dose
reduction in renal
impairment; neuropathy and
somnolence are rare
Pomalidomide As for lenalidomide, but Oral Relapsed disease Pomalidomide–dexamethasone; dara– Bone marrow suppression,
degrades the target Pd; elo-Pd, PCd, PVd venous thromboembolism,
proteins IKZF1 and IKZF3 rash; neuropathy and
more potently, somnolence are rare
compared with
lenalidomide
Histone deacetylase inhibitors
Panobinostat Pan-deacetylase Oral Relapsed disease Pano–Vd Thrombocytopenia,
inhibitor diarrhoea, fatigue
Monoclonal antibodies
Elotuzumab Humanised monoclonal Intravenous Relapsed disease Elo-Rd, elo-Pd Infusion-related reactions,
antibody against infusion interference with response
SLAMF7, with anti- evaluation assays in patients
multiple myeloma with IgG kappa M-protein
activity via ADCC and
ADCP; also directly
activates natural killer
cells
Daratumumab Fully human CD38- Intravenous First-line therapy; First-line therapy: Dara–VMP, dara–Rd, Infusion-related reactions,
targeting antibody, which infusion or relapsed disease dara–VTD; for relapsed disease: interference with response
has classic Fc-dependent subcutaneous daratumumab monotherapy, dara–Rd, evaluation assays in patients
immune effector injection dara–Vd, dara–Pd, dara–Kd with IgG kappa M-protein,
mechanisms such as CDC, interference with blood
ADCC, and ADCP, but also group serological testing
immunomodulatory
effects via the elimination
of CD38-positive Tregs,
Bregs, and MDSCs
Isatuximab Chimeric CD38-targeting Intravenous Relapsed disease Isa–Pd, Isa–Kd Infusion-related reactions,
antibody, which can infusion interference with response
directly induce apoptosis evaluation assays in patients
and also has classic with IgG kappa M-protein,
Fc-dependent immune interference with blood
effector mechanisms, group serological testing
such as ADCC and ADCP,
and immunomodulatory
effects
(Table 2 continues on next page)
as a first-line therapy. The benefit of adding the CD38 vs 26% without) and improved progression-free survival.66
antibody daratumumab to bortezomib–thalidomide– This four-drug regimen was licensed by the US Food and
dexamethasone was reported in a trial, with higher Drug Administration (FDA; September, 2019) and by the
complete response rates (39% with added daratumumab European Medicines Agency (EMA; January, 2020) for

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(Continued from previous page)
Antibody–drug conjugates
Belantamab An anti-BCMA Intravenous Relapsed disease Single agent Keratopathy,
mafodotin immunoconjugate with infusion thrombocytopenia
an afucosylated,
humanised anti-BCMA
monoclonal antibody
conjugated by a protease-
resistant linker to a
microtubule-disrupting
drug (monomethyl
auristatin F)
Nuclear export inhibitors
Selinexor An orally bioavailable, Oral Relapsed disease Selinexor–dexamethasone Nausea, anorexia, diarrhoea,
selective XPO1 inhibitor hyponatraemia,
thrombocytopenia, fatigue
ADCC=antibody-dependent cellular cytotoxicity. ADCP=antibody-dependent cellular phagocytosis. ASCT=autologous stem-cell transplantation. BCMA=B-cell maturation
antigen. Breg=regulatory B cell. CDC=complement-dependent cytotoxicity. CRD=cyclophosphamide–lenalidomide–dexamethasone. CTD=cyclophosphamide–thalidomide–
dexamethasone. Dara–Pd=daratumumab–pomalidomide–dexamethasone. Dara–Rd=daratumumab–lenalidomide–dexamethasone. Dara–Vd=daratumumab–bortezomib–
dexamethasone. Dara–VMP=bortezomib–melphalan–prednisone plus daratumumab. Dara–VTD=daratumumab plus bortezomib–thalidomide–dexamethasone.
DIRA=daratumumab-specific immunofixation electrophoresis reflex assay. DT–PACE=dexamethasone–thalidomide–cisplatin–doxorubicin–cyclophosphamide–etoposide.
Elo–Pd=elotuzumab–pomalidomide–dexamethasone. Elo–Rd=elotuzumab–lenalidomide–dexamethasone. ESRD=end-stage renal disease. IRd=ixazomib–lenalidomide–
dexamethasone. Isa–Kd=isatuximab–carfilzomib–dexamethasone. Isa–Pd=isatuximab–pomalidomide–dexamethasone. KCD=carfilzomib–cyclophosphamide–dexamethasone.
KRd=carfilzomib–lenalidomide–dexamethasone. MDSC=myeloid-derived suppressor cell. MPT=melphalan–prednisone–thalidomide. MPV=melphalan–prednisone–
bortezomib. PAD=bortezomib–doxorubicin–dexamethasone. Pano–Vd=panobinostat–bortezomib–dexamethasone. PCd=pomalidomide–cyclophosphamide–
dexamethasone. PVd=pomalidomide–bortezomib–dexamethasone. SPEP=serum protein electrophoresis. TLS=tumour lysis syndrome. Treg=regulatory T cell.
VCD=bortezomib–cyclophosphamide–dexamethasone. VCP=bortezomib–cyclophosphamide–prednisone. VRD=bortezomib–lenalidomide–dexamethasone.
VTD=bortezomib–thalidomide–dexamethasone.
Table 2: Classes of drugs licensed for use in the treatment of multiple myeloma
treating transplantation-eligible newly diagnosed multiple contentious, with divergent evidence from randomised
myeloma. Adding daratumumab to bortezomib– trials,62,68 and are likely to depend on the induction
lenalidomide–dexamethasone in the phase II GRIFFIN regimen used and the depth of response achieved. An
trial produced deeper disease responses (mea sured as alternate strategy is to do a second transplantation
stringent complete response) compared with bortezomib– around 3 months after the first (known as tandem
lenalidomide–dexamethasone alone.67 ASCT), an approach that might benefit patients with
The benefit of using ASCT as part of a first-line regimen genetic high risk of disease, because such patients
has been revisited after a high rate of deep responses to respond well initially but relapse early with resistant
newer induction regimens, including the IFM2009/DFCI disease. However, the benefits of tandem ASCT in high-
phase 3 trial, and the EMN02 trial.61,62 Both trials used risk disease are not supported by all published studies.62,68
bortezomib-based induction, then randomisation to either Maintenance therapy, in the form of continuous
ASCT or chemotherapy as consolidation, and both studies treatment usually with a single drug, is used to improve
used lenalidomide maintenance. Both response depth and response, delay disease progression, and extend survival.
progression-free survival were superior in the ASCT group Lenalidomide is licensed for maintenance therapy after
compared with the chemotherapy group; however, overall ASCT, on the basis of several phase 3 studies that showed
survival for both groups was similar at the latest follow-up. statistically significant prolonged progression-free sur
vival and overall survival with lenalidomide compared
Consolidation and maintenance after ASCT with observation or placebo. There is some evidence that
The deepest measure of response—ie, negative minimal lenalidomide is effective even in genetically high-risk
residual disease status, is considered to be the aim of disease. This efficacy was not seen in earlier studies but
treatment, especially in the context of younger, fitter was apparent in the Myeloma XI study, which included a
patients undergoing ASCT.38,40,41 Thus, several approaches larger number of genetically characterised patients.69,70 A
to deepen and maintain disease response after ASCT meta-analysis of bortezomib as maintenance therapy
have been studied. revealed a benefit for both progression-free survival and
Consolidation consists of treatment of limited duration, overall survival.71 Ixazomib has shown efficacy as a single
using the same induction regimen to deepen response agent maintenance therapy.72 Outside of clinical trials,
and thereby improve progression-free survival and emerging practice is to add bortezomib to lenalidomide
overall survival. The benefits of consolidation remain maintenance therapy for patients at high risk of disease.63

Seminar
First-line treatment approaches without ASCT according to patient fitness, and the remarkably good
ASCT-sparing protocols have hitherto been generally tolerability of newer treatments such as the CD38
tailored to patients older than 65 years and not deemed antibodies, signal a step change in the prospects for
fit for high-dose chemotherapy. However, use of highly these patients.
effective first-line regimens has led to an increasing
trend to delay ASCT until relapse, especially in patients Treatment of relapse
achieving a deep response to initial therapy. In a series of For many patients, relapse is inevitable, and not all
1000 patients receiving bortezomib–lenalidomide–dexa patients remain candidates for further treatment.80
methasone induction, 18% were allocated to deferred Disease relapse is often signalled by a rise in the M-protein
ASCT, on the basis of achieving deep responses (ie, at or light chain, and is known as a biochemical relapse if
least a very good partial response), and had a progression- there are no clinical symptoms. Treatment should be
free survival of 74·3 months, compared with 63 months started if there are multiple myeloma-related symptoms
in the ASCT group, albeit with the majority of patients (CRAB features) or if a rapid M-protein increase
receiving maintenance with lenalidomide (bortezomib (ie, doubling in 2 months) occurs. With the growing
added for high-risk disease).63 number of therapeutic options available, treatment
Patients who are not deemed eligible for transplantation, selection and sequencing is chal lenging. The optimal
based on performance status or age, have not seen the sequence and choice of agents have not been established,
same improvements in outcomes as younger patients and choice of therapy depends on several factors,
during the last 10–15 years, largely owing to lower tolerance including patient features (age, frailty, bone marrow
of multidrug regimens.73 This difference is starting to reserve, comorbidities, performance status), disease
change, because of better supportive care, greater use of characteristics (cytogenetic risk, rapid increase in
frailty-adjusted treatment, and the development of more M-protein), patient preferences (oral or intravenous),
effective and tolerable regimens (eg, modification of previous treatment factors (response, toxicity), and
bortezomib scheduling and the use of the bortezomib– reimbursement and availability issues.81
lenalidomide–dexamethasone-lite regimen).74 The use of
ASCT in fitter, older patients (aged 65–75 years) continues First relapse
to be explored, and good results are seen with careful Lenalidomide–dexamethasone,82,83 bortezomib–dexametha
patient selection.75 Current non-ASCT regimens used in sone,84 and carfilzomib–dexamethasone85,86 are estab
fitter, older patients are generally triplet regimens (eg, lished doublet regimens for the treatment of relapsed and
bortezomib–lenalidomide–dexamethasone, bortezomib– refractory multiple myeloma. The ENDEAVOR study,85,86 a
cyclophosphamide–prednisone, bortezomib–melphalan– head-to-head comparison of bortezomib–dexamethasone
prednisone; table 2). The benefit of adding a CD38 versus carfilzomib–dexamethasone in patients at first to
antibody led to the quadruplet regimen daratumumab– third relapse, showed a higher response rate and longer
bortezomib–melphalan–prednisolone76 and the triplet progression-free survival and overall survival in patients in
regimen daratumumab–lenalidomide–dexamethasone77 the carfilzomib–dexamethasone group.
being licensed. One phase 3 randomised study found Randomised trials have shown that adding a third drug,
that substituting the second generation proteasome with a different mechanism of action, to these doublet
inhibitor carfilzomib for bortezomib (in bortezomib– regimens improves depth of response, progression-free
lenalidomide–dexamethasone) did not improve outcomes survival, and in some studies with a more mature follow-
in patients with standard-risk disease, hence bortezomib– up, also overall survival. There are currently four approved
lenalidomide–dexamethasone remains the proteasome lenalidomide-based triplet regimens, including two with
inhibitor–immunomodulatory drug triplet of choice in a proteasome inhi bitor (carfilzomib in carfilzomib–
standard-risk patients who are fit.78 Maintenance lenalidomide–dexamethasone87 and oral ixazomib in
approaches in the non-ASCT setting have also been ixazomib–lenalidomide–dexamethasone88). Monoclonal
studied, with some evidence to support lenalidomide, the antibodies can also be effectively combined with
CD38 anti body daratumumab, or the oral proteasome lenalidomide–dexamethasone. Elotuzumab, an antibody
inhibitor, ixazomib.63,76,79 directed against SLAMF7, has no single-agent activity,89
but improves progression-free survival in combination
Treatment of older patients who are frail with lenalidomide–dexamethasone, compared with the
Performance status outweighs genetic risk in relative doublet alone.90,91 Daratumumab, a first-in-class anti-
contribution to overall survival for older patients (aged CD38 antibody, has single-agent activity92 and improves
over 70 years).73 Attention to patients who are older and progression-free survival and response rates when
frail, and the use of frailty tools and geriatric assessments combined with lenalidomide–dexamethasone, compared
in this patient group, have provided data to support regi with the doublet alone.93
mens adjusted by dose and schedule, thereby improving Many patients experience first relapse while still
tolerability, treatment delivery, and clinical outcomes.34 receiving lenalidomide or lenalidomide-containing
Clinical trials that stratifed treatment intensity therapy, hence lenalidomide-based salvage is not

Seminar
Multiple myeloma patient with first relapse
Assess
1) Patient characteristics (presence of comorbidities, frailty, and patient preferences)
2) Tumour characteristics (cytogenetic risk and rapid increase in M-protein)
3) Previous treatment (response and toxicity)
4) Reimbursement and availability issues
Not lenalidomide-refractory Lenalidomide-refractory
Non-frail Frail Frail Non-frail
Lenalidomide-based Doublet Doublet Triplet

triplet
Dara–Rd Rd Vd Bortezomib-based Carfilzomib-based Pomalidomide-based

triplet triplet triplet
Or Or
Elo–Rd Kd Dara–Vd Dara–Kd PVd
Or Or Or Or
KRd Pano–Vd Isa–Kd Isa–Pd
Or Or
IRd SVd
Figure 3: Treatment algorithm for patients with multiple myeloma with first relapse
Treatment at the time of first relapse is dependent on patient and tumour characteristics, but type and response to previous therapy are also crucial for selection of
the next treatment regimen. Patients with lenalidomide-refractory disease benefit from proteasome inhibitor or pomalidomide-based regimens. Patients who
relapse without being lenalidomide-refractory, can be treated with a lenalidomide-based regimen. Retreatment with proteasome inhibitors can also be considered
for patients who received first-line treatment based on proteasome inhibitors with a treatment-free interval of more than 6 months. Doublet and triplet regimens
are shown that were evaluated in large randomised phase 3 trials. Triplet regimens have a better activity profile compared with doublet regimens; however, patients
with frailty might derive most benefit from a doublet regimen with a favorable toxicity profile. Dara–Kd=daratumumab–carfilzomib–dexamethasone.
Dara-Rd=daratumumab–lenalidomide–dexamethasone. Dara–Vd=daratumumab–bortezomib–dexamethasone. Elo-Rd=elotuzumab–lenalidomide–dexamethasone.
IRd=ixazomib–lenalidomide–dexamethasone. Isa–Kd=isatuximab–carfilzomib–dexamethasone. Isa–Pd=isatuximab–pomalidomide–dexamethasone. Kd=carfilzomib–
dexamethasone. KRd=carfilzomib–lenalidomide–dexamethasone. Pano–Vd=panobinostat–bortezomib–dexamethasone. PVd=pomalidomide–bortezomib–
dexamethasone. Rd=lenalidomide–dexamethasone. SVd=selinexor–bortezomib–dexamethasone. Vd=bortezomib–dexamethasone.
appropriate in such lenalidomide-refractory patients. Patients who relapse without being lenalidomide-
Three bortezomib-based triplets are approved for the refractory are typically treated at relapse with a regimen
treatment of relapsed and refractory multiple myeloma, containing lenalidomide, whereas patients who
on the basis of adding daratumumab,94 panobinostat95 develop progres sion during lenalidomide treatment
(a pan-deacetylase inhibitor), or pomalidomide96 to the are switched to a treatment based on proteasome
bortezomib–dexamethasone backbone. The carfilzomib– inhibitors (figure 3).81 In addition, there is increasing
dexamethasone combination also provides a backbone evidence that pomalidomide-based triplets, such as
for the incorporation of additional agents, such as pomalidomide combined with bortezomib–dexa
daratumumab or isatuximab.97,98 Details of these triplet methasone, are effective in patients with lenalidomide-
regimens are in the appendix (pp 8–9). refractory disease (figure 3).96 After reinduction
Cyclophosphamide-based triplets are not approved, but therapy, consolidation with high-dose therapy plus
are affordable and widely used—eg, the fully oral triplet ASCT should be considered at the time of first relapse
pomalidomide–cyclophosphamide–dexamethasone was in patients who did not receive upfront ASCT, or after a
effective and safe as second-line treatment in patients previous ASCT if initial response duration was at least
treated with lenalidomide–bortezomib–dexametha 24 months.101 Allogeneic stem-cell transplantation can
sone.99 Also, the triplet carfilzomib–cyclophosphamide– be considered in patients at high risk with early relapse
dexamethasone induces higher responses compared after ASCT, ideally in the context of a clinical trial.
with bortezomib–cyclophosphamide–dexa methasone in Patients relapsing early (≤12 months) after first-line
patients with first relapse.100 therapy tend to have resistant disease and a short

Seminar
overall survival of around 24 months.102,103 Many, but not extraosseus extension.116 Solitary extramedullary
all, such patients can be identified by the presence of plasmacytomas have no bone involvement, and occur
high-risk genetic lesions (often the presence of more most commonly in the head and neck, gastrointestinal
than one high-risk genetic lesion). tract, and lungs. Diagnosis is made on the basis of tissue
evidence of monoclonal plasma cell infiltrate; it is
Second relapse and beyond important to exclude the presence of occult multiple
Many patients suffer repeated relapses, responding to myeloma, hence investigations should include bone
retreatment often with a change in drug class.80 Patients marrow examination, and cross-sectional imaging
with disease that is double refractory (ie, to both (PET-CT or whole-body MRI). Around 50% of solitary
lenalidomide and bortezomib) have a poor prognosis, and bone plasmacytomas, but only 30% of solitary
might benefit from regimens containing pomalidomide, extramedullary plasmacytomas, will progress to multiple
daratumumab, or carfilzomib. Drug choice is largely myeloma within 10 years; such estimates might change
driven by type of prior therapy and duration of response. as techniques for detecting occult disease improve. Flow-
Pomalidomide–dexamethasone is effective in about cytometric detection of low levels of plasma cells with
30% of patients who are double-refractory,104 and responses aberrant phenotype in the bone marrow, for example,
are generally improved when combined with a third anti- correlates with increased risk of developing symptomatic
multiple myeloma drug (appendix, p 10).105–109 Combining multiple myeloma.117,118 Current standard of care remains
the doublet pomalidomide–dexamethasone with local radical radiotherapy, followed by watchful waiting.
daratumumab or elotuzumab is approved in this
setting,106,108 and the FDA and EMA also approved Extramedullary disease and plasma cell leukaemia
combining it with isatuximab.109 If antibodies are not Extramedullary involvement is rare in newly diagnosed
available, cyclophosphamide can be effectively com multiple myeloma, but more common in patients
bined with this doublet.105 Although daratumumab is with multiple relapses, and carries a poor prognosis.
increasingly combined with other drugs, it is also approved Extramedullary disease results from haematogenous
as monotherapy in patients with advanced multiple spread of multiple myeloma cells, and is characterised by
myeloma, and can benefit some patients with disease that the presence of soft tissue masses in extraosseous
has relapsed several times.92,110 Carfilzomib–dexamethasone locations (eg, in skin, lymph nodes, or brain), pleural
can also be effective in patients who are double-refractory.111 effusions, or leptomeningeal disease.119 Plasma cell
leukaemia can be considered to be the most aggressive
Triple-class refractory multiple myeloma variant of extramedullary multiple myeloma, and is
Patients who develop disease refractory to immuno characterised by the presence of greater than 2 × 10⁹/L
modulatory drugs, proteasome inhibitors, and CD38- peripheral blood multiple myeloma cells, or plasmacytosis
targeting antibodies (ie, are triple-class refractory) have accounting for more than 20% of the white cell count.
an overall survival of only a few months.112 Selinexor (an Primary plasma cell leukaemia arises de novo without
oral selective exportin 1 inhibitor) plus dexamethasone is evidence of pre-existing multiple myeloma, whereas
effective in about a quarter of patients who are triple- secondary plasma cell leukaemia is a leukaemic
class refractory, and has been approved by the FDA.113 transformation of end-stage multiple myeloma. Primary
These patients might also benefit from belantamab plasma cell leukaemia has an aggressive clinical
mafodotin (an antibody–drug conjugate that targets presentation and poor prognosis with high early mortality
BCMA [also known as TNFRSF17] that is approved by the due to disease-related com plications.120 Although the
FDA and EMA), which induces an overall response outcome of primary plasma cell leukaemia has improved
of 30%, with keratopathy and thrombocytopenia as the because of the introduction of ASCT and combination
most common adverse events.114 Patients who have been therapy with novel agents, survival is still inferior to that
heavily pretreated might also benefit from retreatment, observed in newly diagnosed multiple myeloma.120
which can be considered after long-lasting remission,
because previously used drugs can be given in different Supportive care
combinations. Novel agents can also be combined with Patients with myeloma have a considerable disease and
traditional cytotoxic agents, such as cyclophosphamide, treatment burden, causing morbidity and mortality.
anthracyclines, or bendamustine.115 Alternatively, patients Disease complications (eg, infections, bone disease, and
with advanced disease can be enrolled in clinical studies gastrointestinal upsets), lead to treatment delays or dis
evaluating new agents with novel mechanisms of action. continuation, reducing disease-free survival for patients
who suffer with such complications.121–124 Infections,
Solitary plasmacytoma and plasma cell cardiovascular disease, and renal failure are major
leukaemia causes of early death in multiple myeloma.125,126 Before
Solitary plasmacytoma the introduction of novel drugs, around 10% of patients
Solitary plasmacytomas usually arise in marrow-bearing died within 60 days of diagnosis because of complica
bone (ribs, vertebrae, pelvis, femurs) with or without tions caused by either the disease or therapy.125 Therapy

Seminar
Infections Thromboembolic and cardiovascular

• Increased risk of both bacterial (seven times) and • Frequent occurrence, especially during initial
viral (ten times) infections phase of treatment
• Occurs because of combined effects of: • Risk increased by immunomodulatory drugs
• multiple myeloma-related immunodeficiency therapy, especially in combination with
(deficits in humoral and cellular immunity) high-dose dexamethasone or other
• patient comorbidities chemotherapy
• anti-multiple myeloma therapy (steroids, • Patient-related risk factors:
multidrug combinations, drugs that suppress • obesity, immobility
bone marrow function and cellular immunity) • history of venous thromboembolism
• recent surgery
• comorbidities such as diabetes and infections
Bone disease
• Up to 80% of patients with multiple myeloma
suffer from osteolytic bone disease at diagnosis Renal disease
or at relapse • 20% of patients with multiple myeloma have
• Symptoms: bone and back pain; fractures serum creatinine ≥2 mg/dL (177 umol/L), and
(compression fractures of the spine may cause a minority will need dialysis
cord compression) • Causes of renal impairment include:
• Occurs as result of increased bone resorption • light-chain tubular cast nephropathy
and reduced bone formation (precipitation of light-chains with UMOD
in tubules)
• amyloidosis
Peripheral neuropathy • light-chain deposition disease
• Common in patients with multiple myeloma • dehydration (often associated with
• Caused by: hypercalcaemia)
• direct effects of disease (amyloid deposition, • infections
reactivity of the M-protein to nerve • use of nephrotoxic drugs
components, cytokine-mediated nerve • anti-multiple myeloma drugs can cause or
damage) precipitate renal injury (eg, thrombotic
• anti-multiple myeloma therapy (thalidomide, microangiopathy and tumour-lysis syndrome)
bortezomib)
Figure 4: Systemic effects of myeloma and its treatment

Complications of the disease and the many treatments result in a complex symptom burden in myeloma survivors affecting several organ systems. Some of the risks
and toxicities that should be carefully screened for are shown, treatment for which often requires coordinated management by a multidisciplinary team.
with novel drugs is associated with substantially reduced kyphoplasty, vertebroplasty) can provide pain relief in
early mortality, probably because of lower toxicity and patients with symptomatic vertebral fractures.129
greater efficacy.124 Prevention of unacceptable toxicity by
use of careful monitoring, plus dose adjustments in Infections
patients who are frail,34 is of crucial importance to Bacterial infections occur most often in patients with active
reduce early mortality and improve survival. Organs multiple myeloma who are starting therapy123,131 and
affected are shown and discussed in figure 4, and antibacterial prophylaxis should be considered, especially
interventions to manage end organ damage and drug during the first 3 months of treatment. A trial in patients
toxicity are discussed in the subsections that follow. with newly diagnosed multiple myeloma showed that
levofloxacin treatment for 12 weeks reduced febrile
Bone disease episodes and deaths, without development of antibiotic
Bisphosphonates or denosumab treatment is initiated in resistance, compared with placebo.132 Sulfamethoxazole–
patients with multiple myeloma with active myeloma trimethoprim prophylaxis is also com monly used, and
requiring therapy. Pamidronate and zoledronic acid, might also reduce febrile episodes and deaths.132 Although
taken intravenously, both have similar efficacy in neutropenia is rare at diagnosis,133 treatment might induce
reducing skeletal-related events,127 whereas clodronate substantial neutropenia, and cytopenias can develop in
taken orally is less effective.128 Osteonecrosis of the jaw is patients who have been heavily pretreated and require
a recognised toxicity associated with bisphosphonate use, schedule adjustment, with or without use of growth
and such drugs should be avoided in renal impairment factors. Immunoglobulin supplementation can be useful
(ie, creatinine clearance <30 ml/min).129 Denosumab, a in patients with recurrent bacterial infections and
RANKL-neutralising antibody, can be given to patients coexisting hypogammaglobulinaemia.134 Guidelines also
with renal failure, but increases the risk of osteonecrosis.130 recommend routine vaccination against influenza,
Local radiation therapy can help for painful bone lesions, Streptococcus pneumoniae, and Haemophilus influenzae
whereas surgery might be needed either to fix fractures, type B,135 ideally during periods of optimal disease control.135
or pre-emptively to prevent fractures in long bones with Live vaccines are generally contraindicated. Proteasome
large lytic lesions.129 Vertebral augmen tation (balloon inhibitors impair antigen-specific T-cell functions, and are

Seminar
associated with varicella zoster virus reactivation. inhibitors, because lenalidomide, pomalidomide,
Prophylaxis for this virus is mandatory during treatment carfilzomib, and ixazomib are associated with a low rate of
with proteasome inhibitors,135 and should also be neurotoxicity.85 Pharmacological interventions for neurop
considered with monoclonal antibody-based therapy, with athy include neuroleptic agents, antidepressants, anti
immunomodulatory drug therapy, and after ASCT. epileptic medications, or topical pain medication.
Hepatitis B reactivation is also recognised after therapy
using proteasome inhibitors, immunomodulatory drugs, Renal impairment
or daratumumab, and all patients with multiple myeloma The presence of renal failure at diagnosis is associated
should have serology tests before treatment starts. Patients with shorter survival,121,125 probably because of an asso
with active hepatitis should be managed in conjunction ciation with more advanced disease, lower recommended
with a hepatologist, and people with evidence of past starting doses of anti-multiple myeloma agents, and
infection (eg, hepatitis B core antibody positive) require higher toxicity leading to dose reductions, or drug
prophylaxis to prevent reactivation. Novel diseases, such as discontinuations, or both.146 Reversal of renal impairment
COVID-19, pose a particular threat to immunosuppressed is associated with improved prognosis. In patients with
patients with multiple myeloma until vaccines become acute renal impairment, anti-multiple myeloma therapy
available. Steps to avoid exposure to infection are crucial should be initiated without delay to rapidly reduce the
and might require alterations to anti-multiple myeloma light chain load on the kidneys. Bortezomib pharma
therapy and prophylaxis.136 cokinetics are unaffected in renal failure, and bortezomib-
based therapy improves survival and renal function in
Thromboembolic and cardiovascular disease patients with multiple myeloma who have renal failure,
Thromboprophylaxis is recommended for patients on including people requiring dialysis.121,146,147 Other anti-
immunomodulatory drugs treatment—aspirin in multiple myeloma drugs can also be effective in renal
patients at low risk and, in patients with more than one failure, but dose reduction is required for several of these
risk factor, low-molecular weight heparin or direct oral agents (table 2). The evidence base remains unclear for
anticoagulants, with a switch to aspirin being considered plasma exchange or the use of mechanical filters to
after 4 months.137–139 If a patient has a thromboembolic rapidly reduce free light chain levels.148–150
event, anticoagulation therapy should be started. Direct
oral anticoagulants are reported to be non-inferior to low- New agents and future therapies
molecular-weight heparin regarding the composite New therapies with novel mechanisms of action are still
outcome of recurrent venous thromboembolism or needed for patients with disease that is refractory to all
major bleeding in patients with cancer.140 available approved drugs, and for patients with high-risk
Cardiovascular disease can be related to the underlying disease. Improved understanding of molecular abnor
plasma cell disorder (amyloid light chain amyloidosis, malities related to disease initiation and progression,
anaemia, and renal dysfunction) or to therapy. Cardio and of how tumour cells interact with the protective
toxicity is more frequently observed in patients aged at microenvironment, enabled the development of new
least 75 years or who have pre-existing cardiovascular drugs, including interventions based on biomarkers for
disorders.137 Anthracyclines can reduce cardiac con personalised therapeutic treatment of specific molecular
tractility and immunomodulatory drugs might induce subtypes. Com bining these novel drugs with either
arrhythmias.137 Carfilzomib is associated with an increased conventional drugs or other new drugs with com
risk of hypertension, pulmonary hypertension, and plementary modes of action will be crucial to prevent
cardiac failure,85,141 and patients on this therapy should be development of resistant clones.
monitored for hypertension and fluid overload.137 New anti-multiple myeloma treatment approaches of
particular promise include several innovative immuno
Peripheral neuropathy therapies, such as chimeric antigen receptor T-cells,
Treatment-related peripheral neuropathy usually has antibody-drug conjugates, and bispecific antibodies.
symptoms of tingling, pain, or numbness in the hands and Some of these drugs have shown notable activity as single
feet. Prompt identificiation, and cessation or modulation of agents (appendix p 11). Many of these new drugs target
treatment, can prevent permanent damage. First-in-class B-cell maturation antigen, a TNF receptor superfamily
immunomodulatory agents and proteasome inhibitors member that is highly and spe cifically expressed on
(thalidomide and bortezomib) are often implicated, and plasma cells, including multiple myeloma cells.151
can cause both sensorimotor and autonomic neuropathy.142
A change of clinical practice, from intravenous to Managing myeloma in the real world
subcutaneous bortezomib and from a twice per week to a Rapid pharmacological and technological developments
once per week schedule, has resulted in a lower rate of have markedly improved patient survival, albeit with
neuropathy,143,144 and concomitant dexamethasone dosing increasing treatment costs and clear global differences in
might also help.145 Fortunately, neuropathy is not a class the availability and reimbursement of the newer drugs
effect of either immunomodulatory drugs or proteasome because of economic constraints.1 Clinical trial data can

Seminar
help to advance clinical practice and product licensing, but 8 González D, van der Burg M, García-Sanz R, et al. Immunoglobulin
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Contributors
Blood 1998; 92: 3025–34.
All authors contributed equally to the design, writing, and revision of
18 Shah V, Sherborne AL, Walker BA, et al. Prediction of outcome in
this Seminar.
newly diagnosed myeloma: a meta-analysis of the molecular profiles
Declaration of interests of 1905 trial patients. Leukemia 2018; 32: 102–10.
KLY declares research grants from Janssen Pharmaceuticals, Amgen, 19 Walker BA, Leone PE, Chiecchio L, et al. A compendium of
Sanofi Genzyme Oncology, and Takeda Oncology; consultancy fees, myeloma-associated chromosomal copy number abnormalities and
honoraria, and travel support from Takeda Oncology, Janssen their prognostic value. Blood 2010; 116: e56–65.
Pharmaceuticals, Sanofi Genzyme Oncology, and Roche 20 Boyd KD, Ross FM, Chiecchio L, et al. A novel prognostic model in
Pharmaceuticals; and consultancy fees from Autolus. CP declares myeloma based on co-segregating adverse FISH lesions and the
consultancy fees Amgen, Celgene Corporation, Janssen, Takeda ISS: analysis of patients treated in the MRC Myeloma IX trial.
Leukemia 2012; 26: 349–55.
Oncology; honoraria from Amgen, Celgene Corporation, and Janssen;
and travel support from Amgen, Celgene Corporation, Takeda Oncology 21 Weinhold N, Ashby C, Rasche L, et al. Clonal selection and double-
hit events involving tumor suppressor genes underlie relapse in
and Janssen. NWCJvdD declares research grants from Janssen
myeloma. Blood 2016; 128: 1735–44.
Pharmaceuticals, Amgen, Celgene, Cellectis, Novartis, and Bristol Myers
22 Bolli N, Maura F, Minvielle S, et al. Genomic patterns of progression
Squibb; and serves on advisory boards for Janssen Pharmaceuticals,
in smoldering multiple myeloma. Nat Commun 2018; 9: 3363.
Amgen, Celgene, Bristol Myers Squibb, Takeda, Roche, Novartis, Bayer,
23 Rasche L, Chavan SS, Stephens OW, et al. Spatial genomic
and Servier.
heterogeneity in multiple myeloma revealed by multi-region
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Seminar
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Seminar

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is fast and more sensitive than plain radiography.31

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First-line therapy: use of ASCT in younger, fitter patients

3: high risk 58% 5% Induction regimens

Figure 2: Risk stratification and follow-up of patients with MGUS and

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Mode of action Route of Licensed Common regimens Common side-effects and

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Mode of action Route of Licensed Common regimens Common side-effects and

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Mode of action Route of Licensed Common regimens Common side-effects and

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Multiple myeloma patient with first relapse

Not lenalidomide-refractory Lenalidomide-refractory

Non-frail Frail Frail Non-frail

Lenalidomide-based Doublet Doublet Triplet

Dara–Rd Rd Vd Bortezomib-based Carfilzomib-based Pomalidomide-based

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Infections Thromboembolic and cardiovascular

Figure 4: Systemic effects of myeloma and its treatment

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