Clinical Review & Education

JAMA Oncology | Review

Moving From Cancer Burden to Cancer Genomics

for Smoldering Myeloma
A Review
Francesco Maura, MD; Niccolò Bolli, MD, PhD; Even H. Rustad, MD, PhD; Malin Hultcrantz, MD, PhD;
Nikhil Munshi, MD; Ola Landgren, MD, PhD

Supplemental content
IMPORTANCE All patients who develop multiple myeloma have a preceding asymptomatic
expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of
undetermined significance or smoldering multiple myeloma (SMM). During the past decade,
significant progress has been made in the classification and risk stratification of SMM.

OBSERVATIONS This review summarizes current clinical challenges and discusses available
models for risk stratification in the context of SMM. Owing to several novel, more effective,
and less toxic drugs, these aspects are becoming increasingly important to identify patients
eligible for early treatment. However, all proposed criteria were built around indirect markers
of disease burden and therefore are generally able to identify a fraction of patients with SMM
in whom transformation to multiple myeloma and genomic subclonal diversification are
already happening. In contrast, next-generation sequencing approaches have the potential to
identify myeloma precursor disease that will progress even before the major clonal expansion
and progression, providing a potential base for more effective treatment and better precision
regarding the optimal timing of treatment initiation. Author Affiliations: Author
affiliations are listed at the end of this
CONCLUSIONS AND RELEVANCE Owing to modern technologies, in the near future, prognostic article.
models derived from genomic signatures independent of the disease burden will allow better Corresponding Authors: Ola
identification of the optimal timing to treat a plasma cell clonal disorder at the very early Landgren, MD, PhD (landgrec@
stages, when the chances of eradication are higher. mskcc.org), and Francesco Maura,
MD (mauraf@mskcc.org), Myeloma
Service, Department of Medicine,
JAMA Oncol. doi:10.1001/jamaoncol.2019.4659 Memorial Sloan Kettering Cancer
Published online December 12, 2019. Center, 1275 York Ave, New York, NY
10065.

M
any cancers develop through a Darwinian evolution
model along preferred evolutionary trajectories in which
different driver events accumulate over time and con-
fer a proliferation and survival advantage to a given subclone, pro-
gressively shaping the genomic profile and the clinical behavior of
that cancer.1 One of the fields in which the concept of premalignant
clonal evolution was described for the first time is gammopathies.
Almost all patients who develop multiple myeloma have a preced-
ing asymptomatic expansion of clonal plasma cells, clinically recog-
nized as monoclonal gammopathy of undetermined significance
(MGUS) or smoldering myeloma (SMM).2-6 For more than 20 years,
the definition and differentiation between these 2 clonal entities
have been based on indirect measurements of the clonal burden
(Box).3,4,7,8 These precursor conditions (ie, MGUS and SMM) pro-
vide an extraordinary opportunity to study the multistep evolution
of cancer and to design preventive and early treatment strategies.
In the past 10 years, the introduction of new drugs has substan-
tially changed and improved the treatment of multiple myeloma
(eFigure 1 in the Supplement).9 Many of these new drugs are more
effective and less toxic than traditional chemotherapy, providing for
the first time attractive agents for early treatment strategies. By com-
bining these novel regimens with modern technologies, such as next-
generation sequencing, we have the opportunity to identify patients
with myeloma precursors who might benefit from early interven-
tion. In this article, we review the current criteria for risk stratifica-
tion in SMM and highlight new research and clinical perspectives in
light of novel discoveries in the era of genomics.
Diagnosis and Assessment
In an investigation of a retrospective cohort of 276 patients with
SMM, Kyle et al10 reported an overall risk of progression to multiple
myeloma of 10% per year for the first 5 years, approximately 3% per
year for the next 5 years, and 1% per year for the last 10 years
(Figure 1A). That study was the first to report that different serum
markers were associated with the risk of SMM progression to mul-
tiple myeloma. The ability to estimate the risk of progression was a
turning point in the study of SMM, stimulating many different groups
to develop translational studies and clinical trials.
After these preliminary observations, different markers were
subsequently reported to be associated with an increased risk of
SMM progression, and 2 major models for SMM risk stratification
were developed based on combinations of these markers (Figure 1B
and eTable 1 in the Supplement)12-16: (1) the Mayo Clinic model, mostly
focused on serum protein abnormalities as surrogate measures of

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 Clinical Review & Education Review
tumor burden,10 and (2) the Programa para el Tratamiento de
Hemopatias Malignas (PETHEMA) model, using multiparametric flow
cytometry to phenotype bone marrow plasma cells.17 A head-to-
head comparison11 of the Mayo Clinic and PETHEMA models in a pro-
spective cohort of 77 patients with SMM found a significant discor-
dance in the overall risk stratification, with only 28.6% of patients
overlapping on specific risk categories: low risk vs high risk, low risk
vs non–low risk, and high risk vs non–high risk (Figure 1C). Further-
more, in the Swedish Myeloma Registry, only 30% of SMM cases that
progressed met the Mayo Clinic criteria for high-risk disease.18 Over-
all, this finding highlights the need for more robust strategies to iden-
tify individuals with myeloma precursor disease who are at high risk
of progression.
Owing to technological advances, several different ap-
proaches have been tested to allow an earlier and more accurate
identification of patients with high-risk SMM. The application of
imaging approaches, such as magnetic resonance imaging of the
spine and pelvis and whole-body positron emission tomography–
computed tomography, were used to estimating the risk of progres-
sion to multiple myeloma.19-21 Specifically, patients with focal le-
sions and/or bone marrow abnormalities were characterized by
a higher risk of progression.22 However, these approaches still re-
flect the SMM disease burden and end-organ damage.
Of importance, alternative efforts have been attempted to
identify markers of SMM progression that are not measures of the
disease burden but rather are more intrinsically linked to the under-
lying biological features of the disease. In the past 20 years, several
studies23,24 reported recurrent translocations and copy number
abnormalities (CNAs) in patients with multiple myeloma using
karyotype and fluorescence in situ hybridization, with some of these
translocations and CNAs having associations with prognosis
(Figure 2). On the basis of these efforts, recurrent CNAs and trans-
locations were investigated by fluorescence in situ hybridization in
several different clinical trials and retrospective cohort studies, which
showed that the presence of del17p13 (TP53), t(4;14)(MMSET;IGH),
and/or 1q21 gain were associated with shortened time to multiple
myeloma progression in SMM and MGUS.30,31 Using a different ap-
proach, Dhodapkar et al32 identified a 70-gene expression signa-
ture in SMM (GEP70) that was independently associated with the
risk of progression to multiple myeloma. However, similar to many
prognostic models based on gene expression, the application of this
approach into daily clinical practice has been limited by low stan-
dardization and low reproducibility.
Prognosis
Overall, when progression curves of SMM are considered, 3 main pat-
terns can be identified based on the rate of transformation, likely re-
flecting differences in underlying biological characteristics10 (Figure 1).
The first pattern is a group characterized by ongoing transforma-
tion already at the time of SMM diagnosis who will meet transfor-
mation criteria within a few months or years. These patients have
likely already acquired the key driver events associated with pro-
gression and likely have a genomic and microenvironment land-
scape similar to the one of multiple myeloma. A second group will
experience progression after several years of an indolent and asymp-
tomatic clinical course. This group of patients with SMM likely has a
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Moving From Cancer Burden to Cancer Genomics for Smoldering Myeloma
Box. Definition of Multiple Myeloma Based on 2014 International
Myeloma Working Group Criteria
Criteria for Multiple Myeloma
Clonal bone marrow plasma cells of at least 10% or biopsy-proven
bony or extramedullary plasmacytoma and any 1 or more of the
following myeloma-defining events:
1. Evidence of end-organ damage that can be attributed to the
underlying plasma cell proliferative disorder, specifically:
• Hypercalcemia: serum calcium level greater than 1 mg/dL
higher than the upper limit of normal or greater than 11 mg/dL
(to convert to micromoles per liter, multiply by 0.25)
• Renal insufficiency: creatinine clearance <0.67 mL/s/m2
(to convert to milliliters per minute per 1.73 m2, multiply by
0.0167) or serum creatinine level greater than 2 mg/dL
(to convert to micromoles per liter, multiply by 88.4)
• Anemia: hemoglobin value greater than 2.0 g/dL below the
lower limit of normal or a hemoglobin value less than 10.0
g/dL (to convert to grams per liter, multiply by 10)
• Bone lesions: 1 or more osteolytic lesions on skeletal
radiography, computed tomography, or positron emission
tomography–computed tomography
2. Any 1 or more of the following biomarkers of malignancy:
• Clonal bone marrow plasma cell percentage of 60% or
greater
• Involved-uninvolved serum free light-chain ratio of 100 or
greater
• More than 1 focal lesion on magnetic resonance imaging
Definition of Smoldering Multiple Myeloma
1. Serum monoclonal protein (IgG or IgA) level of 3000 mg/dL or
greater (to convert to grams per liter, multiply by 0.01) or
urinary monoclonal protein level of 500 mg/24 hours or
greater and/or clonal bone marrow plasma cell count of 10% to
60%
2. Absence of myeloma-defining events or amyloidosis
genomic background more prone to acquire new lesions and mi-
croenvironment changes with the potential to lead to an aggressive
evolutionary trajectory and consequently to a shift in clinical behav-
ior. In contrast to the first group, the key driver events associated with
progression to multiple myeloma have not yet been acquired in this
intermediate group. The third group is characterized by a clinical
course compatible with that of MGUS despite meeting clinical crite-
ria for SMM diagnosis (ie, they have a recognizable burden of dis-
ease in terms of plasma cell bone marrow infiltration and serum M-
component). In this last group of patients, the genomic predisposition
to acquire new driver events associated with progression is low, the
clone is stable, and the clinical course is indolent in the long term. Al-
though these patterns can be identified by careful scrutiny of pro-
gression curves, to date, we do not have any direct evidence of the
biological events causally linked to disease progression, and it is there-
fore currently not possible to assign a patient to a group at the time
of SMM diagnosis. However, the identification of biological markers
to estimate MGUS and SMM progression before the onset of end-
organ damage has always been a main goal of multiple myeloma re-
search. Thanks to the wide availability of next-generation sequenc-
ing platforms, we now have the means to address this critical task.
In general, MGUS and SMM shared some recurrent genomic
aberrations with multiple myeloma (Figure 2 and eTable 2 in the
Supplement); however, others, such as 13q and 17p deletions,
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 Moving From Cancer Burden to Cancer Genomics for Smoldering Myeloma Review Clinical Review & Education

Figure 1. Clinical Outcome of Multiple Myeloma Precursors

A Evolution trajectories

100
1 2 Established ongoing transformation
3
and ongoing clinical progression
High predisposition to genomic
80
Probability of Progression, %

transformation
SMM Low predisposition to genomic
transformation
60

40
4

20
MGUS

0
0 5 10 15 20 25
C Risk of SMM
Years
1.0
PETHEMA
B Myeloma progression risk
Low
0.8 Intermediate
PETHEMA
High
Low
0.6

Proportion
Intermediate

High
0.4
Mayo
Low
0.2
Intermediate

High
0
0 20 40 60 80 100 Mayo Mayo Mayo
5-y SMM Progression, % Low Intermediate High

A, Three evolution trajectories for monoclonal gammopathy of undetermined
significance (MGUS) and smoldering multiple myeloma (SMM) progression
(adapted from Kyle et al10), potentially reflecting 3 different biological and
genomic profiles. The first trajectories reflect an ongoing transformation and
progression. The second reflect patients and clones with high predisposition to
acquire new driver events and progress over the time. The third is characterized
by low predisposition to acquire new driver events and progress over the time,
with a clinical outcome similar to MGUS. B, Risk of SMM or MGUS progression
according to the Mayo Clinic model or Programa para el Tratamiento de
Hemopatias Malignas (PETHEMA) prognostic model. C, Comparison between
the Mayo Clinic and PETHEMA risk models for the identification of patients with
high-risk SMM. Adapted from Cherry et al.11

were observed at lower prevalence compared with multiple
myeloma.25-29,31,33,34 Furthermore, all but t(11;14)(CCND1;IGH)
recurrent cytogenetic and structural aberrations have been
reported at lower frequency among MGUS cases compared with
multiple myeloma and SMM cases (Figure 2 and eTable 2 in the
Supplement). This finding confirms the existence of a chronologic
order of acquisition of cytogenetic aberrations potentially
involved in the clone progression from MGUS to SMM and from
SMM to multiple myeloma.35
Using whole genome sequencing and whole exome sequenc-
ing data, different groups have recently found that multiple my-
eloma has a complex and heterogeneous genomic profile.36-41 Sig-
nificant efforts have been made to characterize the landscape of
driver mutations in multiple myeloma genes.36,37,39,42,43 However,
several reports39,42,43 suggest that driver mutations are secondary
events and not directly involved in the cancer initiation and early pro-
gression. To confirm this theory, initial whole exome sequencing and
whole genome sequencing studies28,44-46 have found a lower preva-
lence of these driver mutations in MGUS and SMM compared with
what has been reported among newly diagnosed multiple my-
eloma (Figure 3A and B). Overall, these observations suggest that
the MGUS and SMM genomic landscape is less complex than that
of multiple myeloma and the identification of secondary events in-
volved in progression could represent an important early and accu-
rate prognostic marker. However, such identification is not an easy
task in multiple myeloma. Some hematologic malignant tumors, such
as acute myeloid leukemia, are usually characterized by a low ge-
nomic complexity, and the characterization of their genomic land-
scape based on targeted and/or exome-based approaches has been
relatively straightforward.47 Similar approaches have been at-
tempted in multiple myeloma40,43,48,49; however, its genomic land-
scape is more complex and heterogeneous (Figure 3C).42 The first
whole genome sequencing characterization of 10 non–high-risk
SMM cases that progressed to multiple myeloma highlighted the
great genomic complexity and heterogeneity of this premalignant
entity.44 Two different progression models were reported based on
gene mutations, translocations, CNAs, and mutational signatures in
paired SMM and multiple myeloma samples (eFigure 2 in the Supple-
ment): (1) the static model, in which the same subclonal architec-
ture was retained as the disease progressed to multiple myeloma,
and (2) the spontaneous evolution model, in which the subclonal
composition of SMM changed without any external selective

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 Clinical Review & Education Review
Figure 2. Multiple Myeloma (MM) Cytogenetic Precursor
0.6
MGUS SMM MM
0.5
Proportion of Patients
0.4
0.3
0.2
0.1
0
t(11;14) t(4;14) t(14;16) HRD
or t(14;14)
The prevalence of the main cytogenetic aberration evaluated by fluorescence
in situ hybridization or single-nucleotide polymorphism array among different
published cohorts of monoclonal gammopathy of undetermined significance
(MGUS), smoldering multiple myeloma (SMM), and newly diagnosed MMs.25-29
pressure. Although patients included in the first group generally
experienced progression in less than 1 year, reflecting an already
ongoing transformation process, the second had a longer time to
progression. Although the identification of robust novel prog-
nostic markers of SMM progression was beyond the scope of the
study, additional studies 42,44,46,50-52 confirmed that several
genomic lesions only explorable by whole genome sequencing
might be involved in SMM progression. Aside from mutations,
CNAs, and translocations, analysis of mutational signatures can
also provide clues to disease progression. In particular, aberrant
activity of the APOBEC family of DNA deaminases, a mutational
process particularly active in aggressive multiple myeloma,41,50
was mostly present in late SMM subclones, suggesting a role in
progression to multiple myeloma.
The ability to identify biological hallmarks of disease aggres-
siveness among patients with MGUS and SMM has been further con-
firmed by a recent single-cell RNA sequencing study53 in which the
authors found small clonal populations in patients with MGUS that
were indistinguishable at the molecular level from those in individu-
als with multiple myeloma.
One limitation of genomic studies is that they are focused on
the cancer (ie, myeloma) cells and thus blind to the complex inter-
action with microenvironment. The cancer-naive niche is not suited
for cancer cell growth. Cancer cells may, however, acquire the abil-
ity to induce phenotypic changes in the microenvironment, pro-
moting the production of cellular and humoral factors that may sus-
tain cancer proliferation, as well as escape from immune tumor
surveillance to make it permissive to cancer cell seeding.54,55 Over-
all, the microenvironment can influence the myeloma genesis in dif-
ferent ways: (1) by creating the condition for the cancer initiations
within the germinal center, (2) by inducing a selective pressure lim-
iting the expansion of premalignant entities, and (3) by promoting
the premalignant clonal expansion and progression into sympto-
matic disease. The role of the microenvironment in multiple my-
eloma has been extensively studied, and comparative studies56,57
have highlighted changes that may be associated with progression
from asymptomatic and symptomatic stages. A direct, in vivo dem-
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Moving From Cancer Burden to Cancer Genomics for Smoldering Myeloma
onstration of the role of the microenvironment in progression of
monoclonal gammopathies came from the study of a humanized
mouse model,58 in which xenografts from patients with asymptom-
atic gammopathies showed progressive growth, suggesting that the
clinical stability of these conditions may be in part caused by
extrinsic growth restriction of tumor cells from the host microen-
vironment. Of interest, progression occurred after a Darwinian
competition during which a minor subclone in the patient
acquired clonal dominance in the xenograft. This finding is an
example of how the heterogeneous genomic landscape of plasma
cell disorders can dynamically adapt to different microenviron-
ments in an interplay required for tumor progression. This con-
cept was also supported by a study59 on simultaneous biopsies in
13q del 17p del 1q gain newly diagnosed multiple myeloma that revealed an extensive
heterogeneity among spatially distinct lesions, possibly reflecting
the influence of different microenvironmental contexts on sub-
clonal selection within tumor cells.
Recently, the first large, population-based prospective screen-
ing study60 from myeloma precursor disease to multiple myeloma
provided novel insight on how serum immune markers—indicators
of disease burden—can change over time, emphasizing the impor-
tance of repeated blood tests and reassessment of risk annually. A
logical extension of the results from the population-based prospec-
tive screening study60 is the application of genomic assays on lon-
gitudinally collected samples, with the aim of defining key evolu-
tionary and clinical trajectories involved in the progression from
myeloma precursor disease to multiple myeloma.
The integration of cell-intrinsic and cell-extrinsic analyses will
offer the opportunity to design new prognostic models that are as-
sociated with biological features of the disease rather than with its
burden. Harnessing the selective evolutionary pressure from the
microenvironment for therapeutic purposes, before a more active
subclone takes over and the disease (eventually) becomes symp-
tomatic, will also be a relevant challenge for the future.
Treatment
The current standard of care for patients with multiple myeloma pre-
cursors is watchful waiting. The rationale for this approach comes
from unsuccessful early treatment approaches using melphalan-
prednisone, thalidomide, or bisphosphonates.61-67
Because of the increased access to novel drugs that are highly
effective and generally safe, early high-risk SMM treatment is in the
spotlight again. Rationale for early treatment of patients with SMM
consists of better potential of disease control, if not cure, in the early
stages in which the subclonal complexity (and hence drug resis-
tance) could be lower. Furthermore, patients may better tolerate
treatment in the absence of end-organ damage. However, there is
a risk of overtreating a fraction of patients who would otherwise be
stable for years. In addition, treatment could represent an early
bottleneck of evolution for cancer cells, thereby promoting earlier
expansion of more aggressive and refractory clones compared with
conventional watch-and-wait approaches. Furthermore, although
the antimyeloma activity of chemotherapeutical agents is widely
accepted, their short- and long-term toxic effects would still be con-
cerning in the context of SMM.
The 2014 updated diagnostic criteria for multiple myeloma sug-
gested that ultra–high-risk SMM (now defined as multiple my-
eloma) should be treated even if asymptomatic, owing to a 80% risk
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 Moving From Cancer Burden to Cancer Genomics for Smoldering Myeloma Review Clinical Review & Education

Figure 3. Genomic Landscape of Multiple Myeloma (MM) Precursors

A Next-generation sequencing studies B CoMMpass AI11

Mailankody Bolli Walker

et al45 et al44 et al46 Mikulasova et al27,28
SMM SMM SMM/MGUS MGUS

ACTG1 ACTG1
BRAF BRAF
CYLD CYLD
DIS3 DIS3
FAM46C FAM46C
HIST1H1E HIST1H1E
IRF4 IRF4
KRAS KRAS
LTB LTB
MAX MAX
NRAS NRAS
PRDM1 PRDM1
RB1 RB1
TP53 TP53
TRAF3 TRAF3

C PD26400a

Y 1
X

22
21
20 2

19

18

17 3

16

15 4

14

13

12 6

11
7

10
9 8

A-B, Heatmap showing the prevalence of recurrent MM mutations among
monoclonal gammopathy of undetermined significance (MGUS), smoldering
multiple myeloma (SMM), and MMs according to the 4 main next-generation
sequencing studies and among newly diagnosed MM enrolled within the
CoMMpass (Relating Clinical Outcomes in MM to Personal Assessment of
Genetic Profile) trial.28,44-46 The CoMMpass data were generated as part of the
Multiple Myeloma Research Foundation Personalized Medicine Initiatives
(https://research.themmrf.org and http://www.themmrf.org). C, Example of
SMM whole genome landscape. All main genomic events are reported in this
genome plot: mutations (external circle), indels (middle circle; dark green and
brown lines represent insertion and deletion respectively), copy number
variants (red indicates deletions, green indicates gain) and rearrangements
(blue indicates inversion, red indicates deletions, green indicates tandem
duplication, black indicates translocation). This patient had non–high-risk
SMM10 that progressed after 42 months.

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 Clinical Review & Education Review Moving From Cancer Burden to Cancer Genomics for Smoldering Myeloma

of developing end-organ damage in the subsequent 2 years.22 For

Figure 4. The Rationale of Early Treatment in Patients With Smoldering
patients with SMM who have a high risk of progression, who do not Multiple Myeloma (SMM) and Monoclonal Gammopathy of
fit the new criteria for multiple myeloma, several attempts have Undetermined Significance (MGUS)
been made to challenge this practice since the advent of novel
drugs. In 2013, Mateos et al68,69 published, to our knowledge, the A Step 1

first phase 3 trial, in which patients with high-risk SMM were ran- Early Late Multiple First
Initiation expansion expansion myeloma Treatment relapse
domized between the watch-and-wait approach and treatment
with lenalidomide-dexamethasone for 9 cycles, followed by a fixed
2-year maintenance regimen. The authors reported a survival
advantage in the experimental arm of 94% vs 80% for patients
alive at 3 years.
In the early 2010s,45,70 studies of the combination of carfil-
B Step 2
zomib, lenalidomide, and dexamethasone, the first 3-drug combi-
Early Late First
nation therapy targeting patients at high risk of multiple myeloma, Initiation expansion expansion Treatment relapse
showed a high rate of minimum residual disease negativity (92%).
Despite results from these trials, follow-up is still short, and the
paradigm of SMM treatment has not changed in routine clinical
practice; however, several clinical trials targeting patients with
high-risk SMM are currently ongoing, and considering the efficacy
of novel agent combinations in newly diagnosed patients, most of C Step 3
these have been designed without standard chemotherapy Early
Initiation expansion Treatment Remission or eradication
(eTable 3 in the Supplement).
Before treatment of SMM can be accepted as standard prac-
tice, several biological and clinical questions must be addressed. Clini-
cal and laboratory markers associated with risk of progression are
mainly based on surrogate measures of disease burden, and the cho-
sen cutoffs are generally based on arbitrary values extracted from Multiple myeloma pathogenesis is characterized by a typical Darwinian
retrospective series; it is a common experience of practitioners that evolution model characterized by accumulation over time of different driver
events along preferred evolutionary trajectories. A, When multiple myeloma is
these risk scores are inaccurate for some patients. We believe that treated, most patients achieve a good response and durable remission.
through genomic studies, we will, in the future, detect aggressive However, a significant fraction still experience progression, generally after a
disease cases in asymptomatic phases, also allowing for control of clonal or subclonal competition and selection induced by treatment. This clonal
heterogeneity and genomic complexity represent the main reasons why it is
subclonal diversification and long-term toxic effects on the hema-
difficult to completely eradicate this cancer. B, A significant fraction of high-risk
topoietic stem cells from treatment (Figure 4). SMM already has the key driver events and has already expanded its clonal and
subclonal architecture, reducing chance to eradicate the disease. C, Conversely,
at the very early stage of MGUS and SMM clonal expansion, the genomic and
clonal complexity is likely lower, potentially increasing the premalignant clone
Conclusions eradication chances.

In the coming years, we need to better understand the biological de-

terminants and the dynamics of evolution of myeloma precursor dis- the current genomic era and will potentially allow practitioners to bet-
ease to identify more robust genomic prognostic markers to be ter identify the optimal timing to treat a plasma cell clonal disorder at
combined within current risk models. This goal is finally achievable in the very early stages, when the chances of eradication are higher.

ARTICLE INFORMATION
Accepted for Publication: August 8, 2019.
Published Online: December 12, 2019.
doi:10.1001/jamaoncol.2019.4659
Author Affiliations: Myeloma Service, Department
of Medicine, Memorial Sloan Kettering Cancer
Center, New York, New York (Maura, Rustad,
Hultcrantz, Landgren); Cancer Genome Project,
Wellcome Trust Sanger Institute, Cambridgeshire,
United Kingdom (Maura); Department of Oncology
and Hemato-Oncology, University of Milan, Milan,
Italy (Bolli); Department of Hematology,
Fondazione IRCCS Istituto Nazionale dei Tumori,
Milan, Italy (Bolli); Jerome Lipper Multiple Myeloma
Center, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, Massachusetts (Munshi);
Veterans Administration Boston Healthcare
System, West Roxbury, Massachusetts (Munshi).
Author Contributions: Dr Maura had full access to
all the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
Concept and design: Maura, Bolli, Munshi,
Landgren.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Maura, Bolli, Landgren.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Maura, Hultcrantz.
Obtained funding: Landgren.
Administrative, technical, or material support:
Maura, Bolli, Munshi, Landgren.
Supervision: Maura, Bolli, Landgren.
Conflict of Interest Disclosures: Dr Hultcrantz
reported receiving grants from the Multiple
Myeloma Research Foundation and the Swedish
Research Council outside the submitted work.
Dr Munshi reported receiving grants from Celgene,
receiving personal fees from Oncopep outside the
submitted work, and having a patent to Oncopep
issued and licensed. Dr Landgren reported
receiving grants and personal fees from Amgen,
Janssen, Celgene, and Karyopharm; receiving
personal fees from Adaptive Biotech; and serving
on independent data monitoring committees for
Merck, Theradex, and Takeda outside the
submitted work. No other disclosures were
reported.
Funding/Support: This study was funded by core
grant P30 CA008748 from Memorial Sloan
Kettering Cancer Center (Drs Maura and Landgren),
the Perelman Family Foundation in collaboration
with the Multiple Myeloma Research Foundation
(Drs Maura and Landgren), and grant 817997 from
the European Research Council under the European

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 Moving From Cancer Burden to Cancer Genomics for Smoldering Myeloma
Union’s Horizon 2020 research and innovation
program (Dr Bolli).
Role of the Funder/Sponsor: The funding sources
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
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