Leukemia

https://doi.org/10.1038/s41375-019-0660-0

REVIEW ARTICLE

Multiple myeloma gammopathies

Extramedullary multiple myeloma

Manisha Bhutani1 David M. Foureau2 Shebli Atrash
● ●
1 ●
Peter M. Voorhees1 Saad Z. Usmani1
●

Received: 9 April 2019 / Revised: 31 July 2019 / Accepted: 12 August 2019

© The Author(s), under exclusive licence to Springer Nature Limited 2019

Abstract
Extramedullary multiple myeloma (EMM) is an aggressive subentity of multiple myeloma, characterized by the ability of a
subclone to thrive and grow independent of the bone marrow microenvironment, resulting in a high-risk state associated with
increased proliferation, evasion of apoptosis and treatment resistance. Despite improvement in survival for most patients
with multiple myeloma over recent decades, outcomes are generally poor when EMM develops. Understanding the
molecular underpinnings leading to homing of plasma cells in ecosystems outside the bone marrow will be crucial for
therapeutically manipulating the microenvironment and targeting key signaling pathways. Herein, we discuss the
evolutionary biology of EMM, underscore the importance of a uniform definition, discuss prognostic significance, and
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provide current and emerging treatment strategies for managing this rare subentity of multiple myeloma.

Introduction myeloma, the diagnosis of EMM is typically made by the

Multiple myeloma is characterized by clonal proliferation of
neoplastic plasma cells within the bone marrow resulting in
anemia, myelosuppression and bone destruction, as well as
clinical consequences from the paraproteinemia on kidney
function and other organ systems [1]. Extramedullary
multiple myeloma (EMM) is a less frequent manifestation
of multiple myeloma, where myeloma cells become inde-
pendent of bone marrow microenvironment, infiltrate other
organs and/or circulate freely in the blood [2, 3]. Patients
present with involvement of lymph nodes, skin, soft tissues,
central nervous system (CNS), thoracoabdominal organs,
effusions, or any other anatomic sites, either at initial
diagnosis (primary EMM) or at the time of relapse (sec-
ondary EMM) [2, 4]. Rare cases evolve to or present with a
leukemic phase termed plasma cell leukemia (PCL) [5],
which we consider as the most aggressive type of EMM as
discussed in this review. Occasionally there is involvement
of multiple extramedullary sites without bone marrow
involvement [6]. In patients with confirmed multiple
presence of pathologic soft tissue masses on imaging
[computed tomography (CT)-scan, PET/CT, magnetic
resonance imaging (MRI), or ultrasound], biopsy or physi-
cal examination [7]. EMM is inherently a high-risk stage
with a poor prognosis. The molecular mechanisms under-
lying the development of EMM have not been fully defined.
Various cytogenetic abnormalities are observed, and few
studies have generated gene sequencing profiles in small
patient cohorts that discriminate EMM from classic multiple
myeloma [8–11]. Treated the same way, the outcomes for
patients with EMM are different from multiple myeloma
without extramedullary manifestations [11]. While PCL and
CNS EMM portend a poor prognosis, the outcomes can be
very heterogeneous for other manifestations. Sensitive
imaging including PET/CT and MRI are important part of
diagnosis and response evaluation. The purpose of therapy
is to eradicate the myeloma clone from bone marrow and
extramedullary compartments. We consider these points
while reviewing the pathobiology, diagnosis, prognosis and
therapeutic options of EMM.

Controversies surrounding the definition

* Saad Z. Usmani
saad.usmani@atriumhealth.org
There is no uniform definition of EMM. A three-stage
1
Department of Hematologic Oncology and Blood Disorders, anatomic classification was first proposed in 1969 by Pas-
Levine Cancer Institute/Atrium Health, Charlotte, NC, USA mantier and Azar [12] based on review of 57 autopsied
2
Immune Monitoring Core Laboratory, Levine Cancer Institute/ cases of multiple myeloma: Stage I or intraskeletal, in
Atrium Health, Charlotte, NC, USA which myeloma nodules were confined to the skeleton;

Stage II or paraskeletal, implying spread to adjoining tis-
sues; stage III or extraskeletal, with gross spread to distant
sites. Earlier studies described a higher incidence of EMM
in younger patients and in those with IgD myeloma and
nonsecretory myeloma [13, 14]. The definitions of EMM
vary greatly. Some groups restrict the definition solely to
soft tissue masses in extraosseous locations resulting from
hematogenous spread, referred to here as extramedullary-
extraosseous (EM-E) [4, 7, 11]. Others have used a broader
definition inclusive of bone-related plasmacytomas that
extend via disruption of cortical bones into contiguous soft
tissues, referred to in this paper as extramedullary-bone
related (EM-B) [15]. It is important to differentiate between
the two types, as the outcome is worst for patients with EM-
E compared with those with EM-B [16, 17]. Moreover,
studies suggest that plasma cells extending from the bone
into the adjacent soft tissues are simply an extension of the
same “biological compartment” as the bone itself, whereas
plasma cells at distant anatomical sites carry different bio-
logical characteristics [4, 18]. Importantly, the definition of
EMM must explicitly exclude ‘solitary extramedullary
plasmacytoma’ and ‘solitary bone plasmacytoma’ (Table 1)
[19, 20]. PCL can be considered an extreme variant of
aggressive EMM characterized by rapid progression, drug
resistance and short survival [5]. Even lower levels of cir-
culating clonal plasma cells, with a cutoff ≥5% portend a
similar adverse prognostic impact as traditionally defined
PCL [21]. Although PCL fulfills the definition of EMM,
some authors reason that PCL is a well-defined pathologic
entity and should be excluded from the EMM spectrum [7].
We recommend restricting the definition of EMM to the
presence of extramedullary disease in a patient meeting the
definition of multiple myeloma, excluding those with soli-
tary extramedullary/bone plasmacytoma (Table 1). To have
a better understanding of the behavior of contiguous versus
hematogenous spread, it is important to collect prospective
data in EMM with respect to EM-E and EM-B subtypes.
We propose that both secondary and primary PCL be
included in the definition of EMM as it is not uncommon
for these patients to have concomitant or subsequent
extraosseous involvement of liver, spleen, lymph nodes,
and other soft tissues [5, 22, 23].
Evolutionary biology
There are important biological differences between multiple
myeloma and EMM that might explain the propensity for
dissemination and a more aggressive clinical course in the
latter. Multiple myeloma cells primarily grow in the bone
marrow and are dependent upon the microenvironment for
their growth and survival. The presence of multiple bone
lytic lesions suggests an efficient trafficking of myeloma
M. Bhutani et al.
cells along the entire bone marrow compartment. The dis-
semination of myeloma cells from bone marrow ecosystem
to blood and distant tissues (organ-specific ecosystems)
involves multiple processes. The precise sequence of events
and the extent to which these processes are activated at
various stages of extramedullary progression remain poorly
understood; however, few principles have emerged that
unify our understanding of biologic evolution to a high- risk
state of EMM and PCL.
The primary genetic events endow tumor-initiating
abilities in a clone of plasma cells critical for progression
from precursor states to active multiple myeloma, while
acquisition of secondary and terminal genetic events, in
collaboration with microenvironment influence, intra and
extracellular signaling, epigenetic changes and immune
evasion, potentially trigger egress to ecosystems outside the
bone marrow (Fig. 1). Plasma cells that invade into the
marrow neo-vasculature or into the vasculature of adjacent
normal tissues encounter physical challenges en route to
distant tissues, which include failure to attach to a substrate,
hydrodynamic flow, and shear stress. In addition, immune
interactions can target circulating malignant cells for elim-
ination. Once in the circulation, few plasma cells manage to
extravasate, seed into new tissue microenvironment, adapt
to survival signals and colonize into the extramedullary
ecosystem.
In the following sections, we focus on the molecular
mechanisms and adhesion molecules that play a role in the
pathogenesis of EMM. Epigenetic and immune changes
also play a role, but these factors have been studied less
extensively.
Cytogenetic and molecular hallmarks
The cytogenetics, FISH, gene expression profiling (GEP)
and deep sequencing studies comparing samples taken from
different individuals who have multiple myeloma, EMM or
PCL have identified gradual accumulation of genetic events
as the disease transitions to a more aggressive phenotype. In
the context of a disease model where EMM and PCL are
considered as one extreme of the myeloma spectrum, mul-
tistep transformation includes acquisition of sequential
genetic hits leading to generation of branching evolutionary
pathways, with better adaptation of clonal cells to their
microenvironment leading to ‘fitter’ clones that outcompete
dominant clones [24]. Spatiotemporal comparisons of bone
marrow and targeted biopsies of EMM and multiple focal
lesions reveal enrichment of pathways in EMM sites that
were not identified in original bone marrow biopsies, sup-
porting a model for progression with clonal sweeps in the
early phase and regional evolution in advanced disease [25].
The time at which two subclones evolve at extramedullary
Table 1 Defining features of EMM and other relevant plasma cell dyscrasias
Plasma cell dyscrasia
Extramedullary multiple
myeloma (EMM)
Extramedullary multiple myeloma-
extraosseous (EM-E)
Extramedullary multiple myeloma- bone • Extramedullary plasma cell mass arising from the underlying bone (e.g. Some authors do not consider EM-B in the definition of EMM.
related (EM-B)
Solitary extramedullary plasmacytoma
Solitary bone plasmacytoma
Primary plasma cell leukemia
Secondary plasma cell leukemia
Definition Comments
• Presence of extramedullary disease in a patient meeting the definition of Diagnosis can be made by imaging (PET/CT and/or MRI) in a patient with
multiple myeloma confirmed multiple myeloma either at the time of diagnosis (primary EMM)
• Diagnostic (IMWG) criteria for multiple myeloma must be fulfilled or at relapse/progression (secondary EMM).
• Does not include solitary extramedullary plasmacytoma or solitary bone Pathologic confirmation is recommended wherever possible.
plasmacytoma (discussed below)
• EMM involving soft tissue or viscera in extraosseous locations resulting Examples include involvement of lymph nodes, liver, pleura, testis, skin,
from hematogenous spread, not contiguous to involved bone CNS, kidneys, blood.
Extramedullary multiple myeloma
ribs, vertebrae, skull, sternum, pelvis) with extension to contiguous To have a better understanding of the behavior of contiguous versus
paraskeletal area or soft tissue via cortical disruption hematogenous spread, we believe it is important to collect prospective data
in patients with EMM with respect to both EM-E and EM-B subtypes.
• A distinct diagnostic entity that must not be confused with EMM. Most common site is upper aerodigestive tract, but other sites have been
• Biopsy -proven localized monoclonal plasma cell mass localized to a described such as gastrointestinal tract, urinary bladder, thyroid, breast,
SINGLE extramedullary site in the absence of other defining events for testes, parotid glands or lymph nodes.
multiple myeloma Treatment involves surgical resection and/or radiotherapy. Estimated
• No evidence of clonal plasma cells in bone marrow disease-free survival, about 80% at 10 years.
• No more than one primary lesion on low dose whole-body CT, PET/CT
or MRI of the whole body or of spine and pelvis
• Absence of end-organ damage (CRAB) or systemic amyloidosis that can
be attributed to the plasma cell proliferative disorder
• A distinct diagnostic entity that must not be confused with EMM The common affected sites are vertebra, pelvis, ribs, upper extremities, face,
• Biopsy -proven localized monoclonal plasma cell mass localized to a skull, femur, or sternum.
SINGLE bone with or without extension to adjacent soft tissue, in the The primary treatment is definitive local radiation therapy. Surgical
absence of other defining events for multiple myeloma. intervention may be necessary in patients with vertebral instability or
• No evidence of clonal plasma cells in bone marrow (or <10% in the case pathologic fracture of a long bone.
of solitary bone plasmacytoma with minimal marrow involvement) Estimated disease-free survival about 50% at 10 years.
• No more than one primary lesion on low dose whole-body CT, PET/CT Patients with minimal marrow involvement (up to 10% plasma cells) treated
or MRI of the whole body or of spine and pelvis like solitary bone plasmacytoma have a higher risk of progression to
• Absence of end-organ damage (CRAB) or systemic amyloidosis that can symptomatic myeloma with a 60% chance of recurrence or progression
be attributed to the plasma cell proliferative disorder. within three years.
Patients with SPB with 10% or more clonal plasma cells in the bone
marrow are considered to have multiple myeloma and treated as such.
• An extreme variant of EMM, defined by the presence of 20% and/or an We propose both secondary and primary PCL be included in the definition
absolute number >2 × 10e9/L of (clonal) plasma cells in the peripheral of EMM.
blood without a prior history of multiple myeloma
• Even lower levels of circulating clonal plasma cells, with a cutoff ≥5%
portend a similar adverse prognostic impact as traditionally defined PCL,
indicating that a lower-cut off may be adapted in future consensus
• Clonality establishment by flow-cytometry must be given consideration,
as polyclonal plasma cells can be detected in blood in other conditions
• Plasma cell leukemia, which occurs in a patient with a previously
diagnosed multiple myeloma, generally as a progressive/transformation
event during relapsed/refractory course of illness.

Fig. 1 Model illustrating central drivers in pathogenesis of EMM and
plasma cell leukemia. Genetic and microenvironment mechanisms are
important for biologic evolution to a high-risk state of EMM and PCL.
Primary immunoglobulin heavy chain (IgH) translocations with five
recurrent chromosomal partners (4p16, 6p21, 11q13, 16q23, and
20q11) and hyperdiploidy (typically with trisomies of chromosomes 3,
5, 7, 9, 11, 15, 19, and 21) are considered initiating genetic events that
endow tumor-initiating abilities in a clone of plasma cells critical for
progression from precursor states to active multiple myeloma.
Acquisition of secondary chromosomal abnormalities (such as dele-
tions of chromosomes) or terminal events (secondary chromosomal
translocations and mutations involving individual genes) are critical to
progression to aggressive forms of multiple myeloma, such EMM or
plasma cell leukemia. The evolution takes place within the bone
sites may be temporarily synchronous (primary EMM) or
develop at different time intervals (secondary EMM).
The primary genetic events such as hyperdiploidy, del
(13)q(14) and recurrent translocations of immunoglobulin
heavy chain (IgH) loci with five chromosomal partners
(4p16, 6p21, 11q13, 16q23, and 20q11) are typically clonal
[24, 26], and lead to upregulation of cyclin D1, D2, and D3
thereby triggering G1/S checkpoint cell cycle progression
and downstream driving of cellular proliferation [27].
Consequently, there is phenotypic transition and evolution
M. Bhutani et al.
marrow ecosystem with complex network signals emanating from
plasma cells and various components of their microenvironment, such
as osteoclasts, endothelial cells, stromal cells, and cells of the immune
system. The balance is delicate and tightly regulated. A variety of
genetic (and epigenetic) changes endow critical phenotype traits to
malignant plasma cells that allow territorial expansion to outside
organ-specific ecosystems, via proliferative self-renewal, adhesion,
angiogenesis, migration, and invasion. Important chemokines, adhe-
sion molecules and growth factors crucial to each step are shown in the
green box. The process of clonal evolution is not as simple, and the
exact sequence of events is not known. Progression is also accom-
panied by altered interactions of the tumor cells with various com-
ponents of their microenvironment, such as osteoclasts, endothelial
cells, and cells of the immune system
of a clone that can both proliferate and self-renew. Some
translocations confer high-risk features, for example, t(4;14)
leads to epigenetic dysregulation via expression of MMSET
[28], and t(14;16) and t(14;20) cause an aberrant tran-
scriptional program via overexpression of the oncogenes
MAF and MAFB, respectively. Secondary acquired events
(amplification of 1q21 ≥ 4 copies and loss of 17p) or late
terminal events (MYC translocation or 8q24 copy number
changes, mutation of the MAPK signaling pathway or the
nuclear factor-κB pathway) occur in a divergent manner at
Extramedullary multiple myeloma
subclonal level during disease progression and cause
enhanced DNA damage and genome instability. The high-
risk features alter tumor cell biology and allow propagating
cells to cross the bone marrow boundary leading to
aggressive forms of multiple myeloma, such as EMM and
PCL (Fig. 1) [26]. Compared with classic multiple mye-
loma, EMM and PCL are molecularly distinguished by a
high prevalence of high-risk chromosomal abnormalities, a
more complex genomic profile, and immunophenotypic
features related to adhesion and chemokine molecules
expression (Table 2) [4, 9, 10, 29–37].
EMM
Small case series have described cytogenetic/FISH features
in diagnostic marrow samples of patients who subsequently
relapse/progress with EMM, In a series of 19 patients who
progressed to EMM, the most frequent cytogenetic
abnormality at diagnosis was 13q deletion, seen in 11/19
cases followed by t(4;14) in 10/19 (52%) and deletion 17p
in 4/19 (21%) [8]. In a retrospective study of 117 multiple
myeloma patients treated on bortezomib-based protocols,
the presence of t(11;14), del 13/13q by FISH and del(17p)
at diagnosis did not predict for development of EMM at
relapse, but all patients who did develop EMM lacked t
(11;14) at diagnosis [38]. Evaluation of cytogenetic differ-
ences between multiple myeloma patients with and without
EM-E at presentation showed particularly high incidence of
p53 deletion in EM-E, 34.5% (10/29) vs. 11.9% (29/243),
respectively [32]. A case report described a newly acquired
TP53 deletion in the EM-E lesion, but wild type TP53 in the
bone marrow with a marked dissociation between response
obtained in bone marrow and that achieved in soft tissue
[39]. Although the reported incidence of TP53 mutation is
10-30% in marrow localized multiple myeloma, it was
detected in tissues from 8/9 (89%) patients with CNS EMM
[40]. In another series of 12 patients, 75% of EMM biopsy
specimens revealed increased p53 immunostaining, whereas
only 8% of bone marrow specimens showed nuclear accu-
mulation of p53 [41]. Thus the tumor suppressor gene TP53
seems to be an important driver associated with EMM.
Analysis of extramedullary tissue biopsies in 19 patients
with EM-E and 11 with EM-B revealed no significant dif-
ference in recurrent cytogenetic abnormalities between the
two types: del(17p13) 32% vs. 27%, del(13q14) 35% vs.
27%, MYC-overexpression 28% vs. 18% and t(4;14) 37%
vs. 18%, respectively [42].
Using GEP by both 70-gene and 80-gene models, EMM
was linked to high-risk molecular subgroups defined by the
MF subgroup often associated with t(14;16) and t(14;20),
and the PR subgroup representing highly proliferative dis-
ease [11]. Haart et al. [37] characterized molecular altera-
tions between paired bone marrow and soft tissue biopsies
in 14 patients with EMM using DNA sequencing for a
targeted panel of 50 tumor suppressor and oncogenes that
revealed a high frequency of activating RAS mutations in
67% bone marrow samples (6/9 patients) and in 64%
extramedullary samples (7/11 patients). The incidence of
RAS mutations in this cohort was close to PCL [43] but
much higher than previously reported 23–44% in newly
diagnosed and relapsed multiple myeloma [44]. In three of
six patients with identical IgH sequences in intramedullary
and extramedullary plasma cells, RAS mutations were only
observed in plasma cells from extramedullary sites, thus
suggesting a role of RAS mutations in transition to EMM
[37]. Egan et al. reported an acquired truncating mutation of
cereblon as well as point mutations in proteasome subunit
G2 and the glucocorticoid receptor as an explanation of
drug resistance in a patient presenting with progressive,
multi-drug refractory EMM [45]. Whole-exome, whole-
genome and RNA sequencing of a biopsy taken from the
neck mass revealed a highly disturbed genome including
271 nonsynonymous, somatic point mutations in genes
including KRAS, PIK3CA, ATM, and NFKB2, suggesting
the role of these candidate genes in extramedullary trans-
formation and potential exploitation with MEK and PI3K
inhibitors.
PCL
Although a higher frequency of t(11;14) using FISH probes
for targeted sequences is identified in primary PCL
(Table 1), this abnormality often associated with other high-
risk molecular events explain an inferior outcome for PCL
in contrast to favorable prognosis associated with this iso-
lated abnormality seen in multiple myeloma [9, 22].
Number and patterns of somatic variants in PCL are
higher and more complex than multiple myeloma. Com-
parison of GEP of patients with primary PCL (n = 20) and
multiple myeloma (n = 1096) treated on ‘total therapy’ (TT)
protocols revealed a signature of 203 genes predominantly
belonging to the lipid-metabolism and myeloid differentia-
tion pathway that distinguished primary PCL and non-PCL
cases [36]. PET data, available at baseline for 724 patients,
revealed a higher incidence of extramedullary involvement
in the primary PCL group than in multiple myeloma (21%
versus 6%; P = 0.05). In another GEP study, primary
immunoglobulin translocations were identified in 63% (12/
19) of patients with PCL, including MAF t(14;16) in 32%,
t(14;20) in 10%, t(11;14) in 16%, and t(4;14) in 10% [46].
Furthermore, 32% (6/19) of patients had at least one MYC
translocation, which are known to strongly correlate with
disease progression. In another cohort of patients, whole-
exome sequencing on primary PCL cells identified 14
candidate cancer driver genes involved in cell-matrix
adhesion and membrane organization (SPTB, CELA1), cell
Table 2 Important biologic features that distinguish EMM and primary PCL from multiple myeloma
Characteristics Multiple myeloma EMM Primary PCL References

Immunophenotype of aberrant Bone marrow plasma cells: Positive or Extramedullary site plasma cells: Positive or strong Circulating plasma cells: Positive or strong Jelinek et al. [29], Jelinek et al.
plasma cells strong positive expression of CD28, CD33, positive expression of CD44, CD81, nestin positive expression of CD19, CD20, CD23, [30], Rihova et al. [31]
CD38, CD56, CD117, CD138, BCMA, CS1 Negative or weak expression of CD19, CD27, CD44, CD45.
(CD319), and CD200. CD56, CD117 Negative or weak expression of CD27, CD56,
Negative or weak expression of CD19, CD71, CD117, and HLA-DR.
CD20 CD27, CD45, and CD81 Expression of CD23 has been associated with t
(11;14)
Adhesion molecule, chemokine Adhesion molecule downregulation (CD56, P- Surface integrin downregulation (CD11a, Reviewed in Weinstock and
receptors selectin, VLA-4) CD11c, CD29, CD49d, CD49e) Ghobrial [4] and Jelinek et al.
Migration molecule upregulation (CD44 isoforms) Adhesion molecule downregulation (CD33, [29]
Angiogenesis upregulation (VEGF, MMP-9, CD56, CD117, CD138)
angiopoietin-1, CD31) Activation molecules downregulation (CD28,
Chemokine receptor downregulation (CCR1, CCR2, CD38, CD81)
CXCR4/SDF-1alpha)
Cytogenetic abnormalities Chang et al. [9], Deng et al. [32],
Royer et al. [33], Avet-Loiseau
et al. [34]
t(11;14) 13% (19/145) 14% (4/28) 27% (6/22)
t(4;14) 13% (24/179) 23% (7/31) 29% (8/28)
t(14;16) 3% (32/1003) 8% (2/26) 17% (11/70)
del(13q) 41% (65/158) 59% (17/29) 63% (22/35)
del(17p) 11% (17/155) 34.5% (10/29) 37% (13/35)
Amp (1q21) 34% (45/133) 54% (14/26) 51% (20/39)
Del (1p21) 18% (36/203) 33% (13/40)
GEP and NGS mutational panel Neri et al. [35], Usmani et al.
[11], Usmani et al. [36], Cifola
et al. [10], de Haart et al. [37]
TP53 3.1% (4/129) 25% (6/24)
DIS3 18.5% (24/130) 25% (6/24)
FAM46C 11.7% (15/128) 4.2% (1/24)
NRAS 26.5% (35/132) 4.2% (1/24)
KRAS 32.6% (43/132) 16.7% (4/24)
BRAF 10.6% (14/132) 20.8% (5/24)
GEP 70 high risk 19% (216/1140) 46% (12/26) 44% (7/16)
GEP 80 high risk 13.7% (156/1140) 42% (11/26) 31% (5/16)
Mutations in TP53, RB1, KRAS, FAK have been Lipid-metabolism and myeloid differentiation
described in up to 50% of patients with EMM genes overexpressed: (CD14(cell membrane
Chr 17p deletion and nonhyperdiploid status are both LPS receptor), TRAF2 and CCL2).
over-represented in EMM Enrichment of Cadherin/Wnt signaling, ECM-
Angiogeneis related genes overexpressed receptor, and G2/M cell cycle checkpoint
(angiopoietin 1, SPARC, NOTCH3, thrombospondin
2, TIMP3, PDGF-alpha, PDGF-beta, and
fibronectin1)
Adhesion molecule genes overexpressed (CD31,
ENG, SPARC)
M. Bhutani et al.
Extramedullary multiple myeloma
cycle and apoptosis (CIDEC), genome stability (KIF2B),
RNA metabolism (DIS3, RPL17), and protein folding
(CMYA5) being the most affected, with enrichment of
functional pathways, including cadherin and Wnt signaling,
extracellular matrix (ECM)-receptor interaction, ECM
organization, and G2/M cell cycle checkpoint [10].
Role of adhesion and chemokine molecules
The multiple myeloma cells within the bone marrow eco-
system engage with stromal cells, endothelial cells, hema-
topoietic cells, immune cells, osteoblasts, osteoclasts,
extracellular matrix, and liquid milieu to facilitate autocrine
and paracrine signaling [47, 48]. Adhesion of myeloma
cells to bone marrow stromal cells is mediated by mole-
cules, including CD44 isoforms, neuronal adhesion mole-
cule (NCAM), beta-1 integrins [very late antigen (VLA) 4,
VLA5] and beta-2 integrins [leukocyte function-associated
antigen 1 (LFA-1), intercellular adhesion molecule
(ICAM1)] and chemokine receptors (Fig. 1) [49]. Adhesion
favors secretion of cytokines, chemokines and other factors
that promote angiogenesis and an immune suppressive
milieu.
A significant effort has been devoted to finding mole-
cules that direct plasma cells to extramedullary sites. Stu-
dies have shown that plasma cells derived from EMM are
characterized by decreased expression of CD56, the beta 5
integrin adhesion molecule [50–52] and an increased
expression of CD44 isoforms involved in cell proliferation
and migration (Table 2) [51]. Specifically, expression of
CD44 variant isoform 6 (CD44v6) and CDv9 are associated
with plasma cell motility and poor prognosis in multiple
myeloma [53, 54]. Decreased expression of other adhesion
molecules (P-selectin, VLA-4) has also been associated
with EMM in various murine model studies [55]. It remains
unclear whether loss of these receptors alters the adhesive
potential of the tumor cell and/or allows escape from
immune surveillance. The chemokine receptor CXCR4 is a
transmembrane, G-protein coupled receptor that is expres-
sed on both normal and malignant plasma cells and is
involved in plasma cell homing to the bone marrow where
its ligand SDF-1 (also known as CXCL12) is secreted by
osteoblasts and stromal cells. Impairment of SDF-1/
CXCR4 signaling has been associated with extramedullary
transformation [2]. Concomitant downregulation of CXCR5
and CCR7 have shown to promote plasma cell motility by
decreasing their sensitivity to B and T zone chemokines
CXCL13, CCL19, and CCL21 [56]. In addition, an upre-
gulation of epithelial–mesenchymal transition-like tran-
scriptional activity that leads to higher CXCR4 expression
may play role in extramedullary dissemination [57]. Bone
marrow hypoxia, which induces a metabolic switch to
aerobic glycolysis via upregulation of HIF1alpha and lactate
dehydrogenase A has been associated with egress of plasma
cells to extramedullary sites [58]. Focal adhesion kinase
(FAK), a protein whose activation can affect cell survival,
migration, and invasion via interaction with the phosphatase
and tensin homolog (PTEN) pathway has shown to play a
role in EMM. In a series of 55 MM patients, 12 with EMM
had significantly higher expression level of FAK mRNA in
their bone marrow nuclear cells in contrast to those without
EM infiltration [59].
Angiogenesis is a central component of the bone marrow
vascular microenvironment. Experiments have shown that
cells within the marrow release soluble “angiocrine” factors
that promote plasma cell expansion. Bone marrow stromal
cells from multiple myeloma patients express multiple
proangiogenic molecules such as vascular endothelial
growth factor (VEGF), angiopoietin 1 (Ang-1), basic-FGF
(bFGF), platelet-derived growth factor (PDGF), hepatocyte
growth factor (HGF), transforming growth factor-alpha
(TGF-α), and IL-1 [60]. Many genes involved in angio-
genesis, such as TIE2, NOTCH3, and several factors that
promote angiogenesis, including VEGF, matrix
metalloproteinase-9 (MMP-9), Ang-1, and CD31, appear to
be upregulated in EMM compared with MM [61].
Incidence
The reported incidence of EMM is generally underestimated
given the inconsistencies in definitions and method of eva-
luation. Most studies predated the era of novel therapies and
more routine application of sensitive imaging modalities
(Table 3) [8, 11, 15, 16, 32, 38, 62–69]. The reported inci-
dence of EM-E at diagnosis ranges from 1.7 to 4.5%
[11, 66, 67]. EM-B involvement is more frequent and varies
from 7 to 34.2% [2, 15]. At relapse, the incidence of EM-E
ranges from 3.4 to 10% while EM-B involvement from 6 to
34% [15, 16, 38]. In the largest series evaluating 3744
multiple myeloma patients from a European registry, 14.5%
had EM-B and 3.7% had EM-E at diagnosis [63]. Hypo-
thetical concerns have been raised about an increased inci-
dence of secondary EMM in the era of novel agents, however
whether this is truly a consequence of exposure to novel
agents is contentious, as some studies have shown an
increased risk with these agents [70, 71], whereas others have
not [15, 38]. Currently, there are no evidence-based data to
support that the risk of EMM is influenced by the choice of
the initial treatment. As patients are being followed‐up over
longer periods of time, their probability of eventually relap-
sing with EMM increases. Autopsy studies in the past
revealed the presence of extraskeletal involvement in
approximately 70% of patients, suggesting that EMM
represents a natural evolution of the disease [12]. A higher
incidence of EMM has been reported in patients after
Table 3 Incidence and survival of EMM in select retrospective studies
Incidence of EMM No. of MM Diagnostic strategy Treatment PFS (EMM OS (EMM vs. MM) Remarks Reference
patients (period vs. MM)
covered)

11% primary EMM 2332 Imaging per study Three trials for transplant- Median PFS (25.3 Median OS (63.5 vs. This is a meta-analysis of Montefusco
(91% EM-B and protocol; skeletal survey, eligible, and five trials for vs. 25.2 mo). 79.9 mo). 5-y OS eight treatment trials. et al. [62]
4% EM-E) MRI, or CT. And/or transplant-ineligible 5-y PFS (19% vs. (51% vs. 59%, p = In multivariate analysis
physical examination. patients. 22%, p = 0.46) 0.01) the presence of EMM
Three trials included an did not impact PFS,
IMiD (lenalidomide in while it was associated
almost all cases), three trials with a reduced OS (HR
a PI, and four trials both. Six 1.41, 95% CI 1.16-1.71;
out of eight trials-included p < 0.001).
maintenance.
14.5% primary EM-B, 3744 Patients who had full data All patients received an up- EM-B: 3-y PFS EM-B: 3-y OS (77.7% Between 2005 and 2014, Gagelmann
3.7% primary EM-E (2005–2014) available on front single ASCT within (50% vs.47.9%, p vs. 80.1%, P = 0.09) the EMM incidence per et al. [63]
extramedullary 12 months of diagnosis or a = 0.78) EM-E: 3-y OS (58% year increased from
involvement (yes or no) tandem ASCT within EM-E: 3-y PFS vs. 80.1%, P < 0.001) 6.5% to 23.7%.
at time of diagnosis, its 6 months from first ASCT (39.9% vs. 47.9%,
location, and the number as first-line therapy. P = 0.001)
of sites were included.
14% 456 Skeletal survey, whole Induction included first- Median OS 3.1 y Secondary plasma cell Mangiacavalli
primary EMM (2000–2010) body low dose CT, generation novel agents primary EMM, leukemia was also et al. [64]
28% secondary EMM MRI, PET/CT (Thalidomide, 2 y secondary EMM included in the definition
(36% EM-B, 52% EM-E, Lenalidomide, Bortezomib), vs. 11 y p < 0.001) of secondary EM-E
both 12%) and ASCT EM-E vs. EM-B (1.6 y
vs. 2.4 y, P = 0.006)
16.2% primary EMM 271 MRI, PET/CT, and/or Induction using novel Median PFS (18 vs. Median OS (32 vs. Kumar et al.
biopsy/cytology agents, VAD, or alkylating 44 mo, P < 0.001) 100 mo, P < 0.001) [65]
agents. All patients
underwent ASCT.
4.8% primary EMM 834 Xray, ultrasound, CT, Induction therapy with Median TTP (11.5 Median OS (16.5 vs. Deng et al. [32]
3.4% secondary EMM (1993–2013) physical exam. Histologic novel agents-based vs. 25 mo, 40 mo, P < 0.001)
confirmation was regimens (Thalidomide, P < 0.001)
performed whenever Bortezomib or
possible. Lenalidomide), alkylating-
based regimens, or
dexamethasone-based
regimens. After induction
only five patients (12.5%)
received ASCT.
32.5% primary EMM-B, 117 Radiological imaging Eight clinical trials of first- Secondary EMM: PCL was also classified Varga et al. [38]
1.7% primary EM-E (2003–2012) (CT, PET/CT, MRI), line treatment with Median OS was 0.9 y as EMM.
27.4% secondary EM-B, biopsy, and/or physical bortezomib-based regimens, (0.1–4.8 y) for EM-E. The rate of development
16.2% secondary EM-E examination. with or without of secondary EMM at
M. Bhutani et al.
Table 3 (continued)
Incidence of EMM No. of MM Diagnostic strategy Treatment PFS (EMM OS (EMM vs. MM) Remarks Reference
patients (period vs. MM)
covered)

lenalidomide. Throughout Median OS was 2.47 y truncated follow up of

the follow-up period, 57 (0.1–8.7 y) for EM-B 5 y and 7 y was not
patients (48·7%) received an influenced by induction
ASCT and four patients therapy (bortezomib with
(3·4%) received an alloSCT lenalidomide vs. without
Extramedullary multiple myeloma

lenalidomide)
8.3% secondary EMM-E 663 Pathologic or radiologic All 55 patients with EMM Median OS from Weinstock et al.
(2005–2011) evidence of EMM at any were treated with a median EMM diagnosis was [66]
time following initial of four different regimens 1.3 y (0.8–2.3 y)
diagnosis. prior to development of
EM-B were excluded EMM. All underwent ASCT
from definition of EMM. and 15 also underwent
Only patients with alloSCT
biopsy-proven clonal
plasma cell infiltrates
were included.
14% secondary EMM-E. 226 Ultrasound, CT, or MRI. Conventional Median TTP after Median OS from Pour et al. [16]
10% secondary EMM-B (2005–2008) Biopsies were carried out chemotherapy, novel agents EM relapse was diagnosis (38 vs. 109
if the lesion was (Thalidomide or Bortezomib 5.4 mo. mo, P < 0.001)
accessible. containing regimens), Median OS EM-E vs.
ASCT, Interferon alfa. EM-B (30 vs. 45 mo,
P = 0.022)
Primary EMM: 2.41% of 1965 Baseline PET/CT ASCT within the context of Primary EMM: 5-y Primary EMM: 5-y OS The cumulative Usmani et al.
TT, 4.35% of non-TT, (2000–2010) performed at diagnosis TT protocols, non-TT PFS (21% vs. 50%, (31% vs. 59%, P < incidence of EMM was [11]
and 4.5% of non- for all patients protocols, and non-protocol P < 0.001) 0.001) significantly increased in
protocol patients. patients. patients who had GEP-
Secondary EMM: 3.43% defined high-risk disease
of TT, 5.2% of non-TT, at baseline and baseline
and 7.24% of non- cytogenetic
protocol patients abnormalities.
6.7% secondary EMM 357 Cytologically proven ASCT, ASCT-alloSCT, Median PFS of Median OS of CNS involvement in 5/ Rasche et al. [8]
(2007–2010) malignant effusion, or a alloSCT, novel agents. 2 months (95% CI 7 months (95% CI 24 cases
biopsy-proven plasma Treatments post EMM 0.08–3.92) 3.56–10.43)
cell tumor outside the included RT, dose-intense
bone marrow, and not chemotherapy including
originating from skeletal novel agents, and ASCT-
structures alloSCT.
9.2% secondary EMM-E. 174 PET/CT, MRI. Within the context of a Not provided Median OS This study specifically Short et al. [67]
(2007–2010) Of note, EM-B were phase II trial of (16 months versus not assessed the incidence of
excluded pomalidomide and low-dose reached, P = 0.002) EMM that develops
dexamethasone during the progression of
Table 3 (continued)
Incidence of EMM No. of MM Diagnostic strategy Treatment PFS (EMM OS (EMM vs. MM) Remarks Reference
patients (period vs. MM)
covered)

MM in patients who did

not have EMM at
diagnosis
7% primary EMM (85% 1003 MRI, PET, X-ray, Conventional chemotherapy Median PFS (18 vs. Median OS (36 vs. 43 Most patients (64 of 76, Varettoni et al.
EM-B and 15% EM-E) (1971–2007) physical examination (1971–1993), up front 30 mo, P = 0.003) mo, P = 0.36) 84%) had a single [15]
6% secondary EMM ASCT for age <65 year plasmacytoma.
(1994–1999), novel agents By time-dependent
(2000–2007) analysis, the presence of
EMM at any time
(primary or secondary)
was associated with
significantly shorter OS
(HR 3.26, P < 0.0001)
and PFS (HR 1.46, P =
0.04).
In the 208 MM patients
treated with ASCT, the
presence of EMM did
not significantly affect
PFS (P = 0.08) and OS
(P = 0.17).
20.4% secondary EMM 172 Sequential ASCT-alloSCT. Median PFS after 1-y OS after alloSCT Minnema et al.
Treatment of EMM included alloSCT not (61% vs. 73% for [68]
DLI, radiotherapy, or significantly relapsed MM without
chemotherapy different between EM) disease,
patients with and P = 0.494)
without EMM at
relapse
14.2% secondary EMM 70 Imaging guided by ASCT-alloSCT or alloSCT NA NA Of 70 patients included Perez-Simon
(1999–2004) symptoms with reduced-intensity in the study, 27 patients et al. [69]
conditioning relapsed (of which 10
were EMM).
EMM extramedullary multiple myeloma, EM-E extraosseous EMM, EM-B bone-related EMM, MM multiple myeloma, IMiD immunomodulatory drug, PI proteasome inhibitor, VAD (vincristine,
doxorubicin, dexamethasone), ASCT autologous stem cell transplant, alloSCT allogeneic stem cell transplant, TT total therapy, RT radiation therapy, PFS progression-free survival, OS overall
survival, TTP time to progression, y years, mo months, CI confidence interval, NA not available
M. Bhutani et al.
Extramedullary multiple myeloma
allogeneic stem cell transplantation (alloSCT) than auto-
logous stem cell transplantation (ASCT) [68, 69, 72, 73].
Graft versus myeloma effect may not be as effective in cer-
tain extramedullary sites due to lower infiltration of tumor-
specific lymphocytes into these sites relative to the bone
marrow. Another possibility is that patients with high-risk
features and multiply relapsed advanced disease are more
likely to undergo alloSCT.
An important question is whether increased use of PET/
CT imaging would detect more cases of EMM. In few
studies incorporating PET/CT at diagnosis, the reported
incidence of EMM from 3.4 to 10% seems not to reflect an
increase [11, 67, 74]. The recent International Myeloma
Working Group guidelines recommend the use of PET/CT
for both newly diagnosed and relapsed/refractory multiple
myeloma to determine the extent of bone damage and
extramedullary involvement [75]. PET/CT is being
employed in several novel therapy studies. As results of
prospective studies become available, the role of PET/CT in
determining the true incidence of EMM will be subject to
continual reassessment.
Prognosis
Tumor burden is generally high in patients with EMM, and
they usually present with severe anemia, thrombocytopenia,
hypercalcemia, and high rates of renal impairment. Elevated
serum lactate dehydrogenase, serum β2 microglobulin
level ≥ 5.5 g/dL and light chain escape are also typical fea-
tures of EMM, often associated with plasmablastic mor-
phology or PCL [7]. Historically, the outlook for patients
with EMM has been poor, with a median OS of <1 year for
patients who are refractory to standard therapies or relapse
after ASCT [16]. Even with ASCT or alloSCT, survival is
usually not longer than 3 years [15, 38]. Table 3 sum-
marizes outcome of EMM in various informative studies. In
a cumulative analysis that included 1965 patients with
multiple myeloma treated with ASCT on TT and non-TT
protocols, those with EMM diagnosed on PET/CT
(excluding EM-B) had significantly inferior OS at 5 years
relative to patients with multiple myeloma (31% vs. 59%,
p 0.001) [11]. Similarly, PFS at 5 years was 21% in EMM
compared with 50% in multiple myeloma (p = 0.001). In a
study defining EMM strictly restricted to biopsy-proven
EM-E, the median OS from the time of extramedullary
diagnosis was 1.3 years [66]. In a prospective study eval-
uating the role of RVD+/− ASCT for frontline therapy,
EMM (defined as an FDG-avid mass that arose in the soft
tissue and not contiguous to the bone) at diagnosis was an
independent prognostic factor for both PFS and OS [74].
In general, the prognosis for EM-E is worse compared
with EM-B. The presence of EMM in the setting of
confirmed MM progression/relapse was associated with a
median OS of 5 months for EM-E and 12 months for EM-B
[16]. In a retrospective series, 226 patients with EMM
between 2010 and 2017 were analyzed [76]. Among the
primary EMM who underwent ASCT, the median PFS was
38.9 months for EM-E and 51.7 months for EM-B (p =
0.034), whereas OS was 46.5 months for EM-E and not
reached for EM-B (p = 0.002). However, for secondary
EMM, PFS was 11.4 months for EM-E and 20.9 months for
EM-B (p = 0.249), whereas OS was 13.6 months for EM-E
and 39.8 months for EM-B (p = 0.093). The presence of
EMM at certain anatomic sites such as blood, CNS, liver,
lung, and muscles has been associated with earlier deaths
than when these sites were not involved. EMM with mul-
tiple involved sites carries a poor prognosis. Patients with
multiple site EMM had shorter 3-year PFS after first-line
ASCT, 22.7% versus 49.4%, than with one involved site or
multiple myeloma (p = 0.001), but both one and multiple
involved sites showed worse 3-year OS in comparison to
patients with multiple myeloma [63]. The prognosis for
patients who have PCL is extremely poor. An analysis of
the Surveillance, Epidemiology, and End Results database
that included 445 patients with primary PCL diagnosed
between 1973 and 2009 reported median OS of 5, 6, 4, and
12 months, during the time periods of 1973–1995,
1996–2000, 2001–2005, and 2006–2009, respectively [77].
Current and emerging treatment strategies
Given the relative infrequency of EMM, exclusion of
patients with nonsecretory EMM, PCL, and CNS myeloma
from clinical trials, as well as lack of proper documentation
regarding presence of EMM in prospective studies, infor-
mation regarding treatment is derived from retrospective
series. A variety of strategies like that for molecularly
defined high-risk multiple myeloma patients have been
used, but a standard therapy has not been established.
EMM
Several case series have reviewed the role of novel therapies
and ASCT in EMM in a retrospective manner, often
including secondary EMM, which is a terminal event in a
previously diagnosed multiple myeloma (Table 3). More-
over, the definitions of EMM are not consistent and the data
have been collected over long periods with heterogeneous
drug combinations and transplant procedures reflecting
changing clinical practices and approved therapies of that
period. Overall, these studies suggest that regimens that
contain bortezomib and/ or IMiDs have improved outcome;
however, the gains in PFS and OS are less pronounced
compared with classic multiple myeloma. In a meta-analysis

of eight treatment trials (three for transplant eligible and five
for transplant-ineligible patients), patients with EMM (91%
EM-B) treated with IMiDs, mainly lenalidomide, or borte-
zomib had PFS akin to multiple myeloma patients, sug-
gesting that novel agents improved outcome regardless of
presence of EMM [62]. Several clinical reports demonstrate
effectiveness of bortezomib [78, 79], as well of lenalido-
mide and pomalidomide [80, 81]. Thalidomide, on the other
hand, has shown conflicting efficacy. While a report
described three patients with secondary EMM who
achieved CR [82], other reports observed poor efficacy of
this agent [83, 84].
Few studies suggest that ASCT can overcome the poor
prognostic impact of EMM, whereas most studies con-
sistently show an inferior outcome despite the use of ASCT
(Table 3). In a recent retrospective multi-institutional study
from Europe, a total of 100 patients with EMM received
ASCT, of which 51.5% had primary EMM [76]. Overall,
ASCT imparted a survival benefit for both EM-E and EM-
B. Among patients who underwent an ASCT, the median
PFS from diagnosis was 49 months (EM-B: 51.7 months
and EM-E: 46.5 months; p = NS) and for those who did
not receive an ASCT the median PFS was 28.1 months
(p < 0.001).
Weighing the effect of double versus single ASCT, the
superiority of tandem ASCT cannot be convincingly
established. In the landmark analyses, tandem ASCT
showed similar 3-year PFS and OS with HR of 0.83 and
0.74 (p = 0.13), respectively compared with single ASCT
[63]. Whereas in another study comparing the outcome of
single ASCT (n = 373) versus tandem ASCT (n = 84) in
EMM patients with high-risk cytogenetics (present in 40%),
OS was 70% for single ASCT versus 83% for tandem
ASCT (p = 0.06) and corresponding PFS was 43% vs. 52%,
respectively (p = 0.30) [85]. In multivariable analysis,
patients receiving a tandem ASCT were less likely to die
than were patients who received single ASCT with hazard
ratio of 0.46 (0.24–0.89; p = 0.02).
The data in EMM with incorporation of carfilzomib, an
irreversible second-generation proteasome inhibitor, are not
readily available. In a retrospective study investigating
carfilzomib alone or in combination as salvage therapy in
relapsed/refractory multiple myeloma, the presence of
EMM resulted in a strong trend towards shorter duration of
response compared with absent EMM (3.9 months vs.
9.3 months, respectively; p = 0.06) [86]. Espanol et al.
reported a case with pleuropericardial EMM treated with a
combination of carfilzomib and dexamethasone, along with
pericardiocentesis and thoracentesis, resulting in quick CR
[87]. Based on efficacy of carfilzomib in high molecular risk
patients enrolled on ENDEAVOR study [88] and ASPIRE
study [89], it can be speculated that carfilzomib may also
prove effective in the setting of EMM.
M. Bhutani et al.
Daratumumab, an anti-CD38 monoclonal antibody with
direct antimyeloma and immune-modulatory effects, is
approved for treatment of newly diagnosed and relapsed
multiple myeloma. However, there are limited data
regarding the efficacy of daratumumab, either alone or in
combination, in EMM. An updated pooled analysis of phase
I/II trials that led to accelerated approval of daratumumab
monotherapy in heavily pretreated patients reported that
12% of patients had at least one extramedullary plasmacy-
toma [90]. The overall response rates for patients with and
without extramedullary plasmacytomas were 16.7% (n =
18) and 33.1% (n = 130), respectively. In a retrospective
study involving 30 heavily pretreated advanced multiple
myeloma “real-world” patients, daratumumab-based ther-
apy yielded an overall response rate of 36.6% and a median
PFS and OS of 2.3 and 6.6 months, respectively, with
particular poor results in those with EMM (n = 9); only two
achieved partial remission, and both progressed shortly (50
and 85 days) after treatment initiation [91].
Ongoing front-line randomized trials in transplant-eligible
multiple myeloma evaluating the addition of daratumumab
(Cassiopea IFM-HOVON study, NCT02541383) or elotuzu-
mab (GMMG-HD6 study, NCT02495922) and in transplant-
ineligible patients evaluating the addition of daratumumab
(Alcyone study, NCT02195479; Maia study, NCT02252172)
or elotuzumab (ELOQUENT-1 study, NCT01335399) are
incorporating PET-CT at diagnosis and during patient follow-
up and may therefore inform an optimal strategy for EMM
patients.
PCL
Table 4 provides a summary of treatment outcome of pri-
mary PCL with the use of novel agents and transplant in
various informative studies [33, 36, 92–99]. There are two
prospective phase II studies [33, 92], while other studies are
retrospective. In general, these studies provide evidence for
the activity of bortezomib-based regimens. In a prospective
study, bortezomib, dexamethasone plus doxorubicin or
cyclophosphamide induction followed by transplantation
(alloSCT, double ASCT, or ASCT-alloSCT) in patients
with PCL demonstrated median PFS and OS of 15.1 and
36.3 months, respectively [33]. Among immunomodulatory
drugs, the combination of lenalidomide and dexamethasone
was prospectively evaluated in 23 patients with primary
PCL, 14 patients completed the initial 4 planned cycles with
achievement of PR in 61%, and ≥VGPR in 35%, 9 patients
underwent ASCT after induction. After a median follow-up
of 34 months, median PFS was 14 months and median OS
was 28 months, with superior survival in patients who
underwent ASCT than in those who did not [92].
Registry studies have explored the role of ASCT in PCL.
The European Group for Blood and Marrow
Table 4 Outcomes for primary PCL in select prospective and retrospective studies after treatment with novel agents and stem cell transplant
Number of primary Treatment plan Median PFS OS Comments Reference
PCL patients (period
covered)

40 (2010–2013) Induction with PAD/VCD. Consolidation 15.1 mo (not reached with double ASCT 36.3 mo (not reached with Prospective phase II study. Royer et al. [33]
with ASCT-alloSCT (n = 17), if matched vs. 17.9 mo with ASCT-alloSCT). double ASCT vs. 36.3 mo with ASCT-alloSCT did not show IFM study group
donor available, otherwise tandem ASCT ASCT-alloSCT). improvement in survival compared with
(n = 7). double ASCT.
Maintenance (for 1 year) with Bz, Dex and
Len in tandem (double) ASCT group.
23 (2009–2011) Induction with Len + Dex. 14 months (27 mo with ASCT vs. 2 mo 28 mo (not reached with ASCT Prospective phase II study. Musto et al. [92]
Extramedullary multiple myeloma

Consolidation with ASCT in eligible without ASCT). vs. 12 mo without ASCT). Survival advantage was exclusively GIMEMA study group
patients. confined to patients who
underwent ASCT
38 (2005–2016) Bz based induction 100%, Bz + IMiD 92%; 20 mo (25 mo with ASCT vs. 6 mo 33 mo (36 mo with ASCT vs. 26 The median PFS was significantly longer Mina et al. [93]
ASCT 74%, and maintenance 61%. without ASCT; 27 mo with ASCT and mo without ASCT) in patients who received ASCT upfront as Single center study
maintenance vs. 11 mo with ASCT (38 mo with ASCT and compared with those who did not.
without maintenance). maintenance vs. 22 mo with The receipt of maintenance therapy after
ASCT without maintenance). ASCT significantly prolonged survival.
Greatest survival benefit was observed
among patients who underwent PI plus
IMiD induction, ASCT, and a 3-drug
maintenance.
23 (2000–2016) PI or IMiDs prior to ASCT 100%; 5.5 mo (18.6 mo with maintenance vs. 18.1 mo (31.8 mo with Gowda et al. [94]
maintenance 52% 3.8 mo without maintenance) maintenance vs. 16.1 mo Single center study
without maintenance)
50 (2000–2016) Novel treatment (mostly Bz based) 80%; 12 mo (18 mo with Bz + ASCT vs. 9 mo 18 mo (48 mo with Bz + ASCT Inclusion of Bz based therapy on the Katodritou et al. [95]
ASCT 40%. in others) vs. 14 mo in others) backbone of ASCT improved OS Greek myeloma
study group
117 (2006–2016) Novel treatment 76%; upfront ASCT 64% NA 23 mo (35 mo with ASCT vs. 13 Better survival with ASCT than without Jurczyszyn et al. [96]
mo without ASCT) International
multicenter study
37 (2002–2016) Bz 77%, IMiDs 67%, cyclophosphamide NA 15 mo (35.5 mo with ASCT) Ganzel et al. [97]
67%, anthracycline 26%, melphalan 13%. Israeli MM study group
SCT 49%- 1/3 of these alloSCT
69 (1998–2015) Novel agents + ASCT 25%, conventional 12.2 mo (26.4 mo with novel agents + 16.1 mo (31.1 mo with novel Jung et al. [98]
chemotherapy + ASCT 12%, novel therapies ASCT vs. 9 mo without ASCT) agents + ASCT vs. 12.3 mo Korean MM
only 36%, conventional chemotherapy without ASCT) working party
only 27%
38 (2001–2012) 64% treated with vincristine, doxorubicin Median PFS not reported 34.2 mo (53.4 mo with Iriuchishima et al. [99]
and dexamethasone, 34% treated with novel maintenance vs. 34.2 mo Japanese
agents +/− ASCT-alloSCT without maintenance Myeloma Society
after ASCT)
27 (not provided) TT1 (n = 7) and TT2 (n = 12) did not 0.8 y vs. 5.4 y (for MM) 1.3 y vs. 8.8 y for MM Usmani et al. [36]
include novel agents. TT3 (n = 8) included Single Center Study
novel agents.

PCL plasma cell leukemia, PFS progression-free survival, OS overall survival, PAD (Bortezomib, Doxorubicin, Dexamethasone), VCD (Bortezomib, Cyclophosphamide, Dexamethasone), ASCT
autologous stem cell transplant, alloSCT allogeneic stem cell transplant, Bz bortezomib, Len lenaldiomide, Dex dexamethasone, IMiD immunomodulatory drug, PI proteasome inhibitor, TT total
therapy, y years, mo months, MM multiple myeloma, NA not available

Transplantation registry reported the outcomes of 272
patients with primary PCL who underwent an ASCT
between 1980 and 2006 [100], quoting a median PFS and
OS of 14.3 months and 25.7 months, respectively. Simi-
larly, the Center for International Blood and Marrow
Transplant Research (CIBMTR) showed a survival benefit
with upfront ASCT for 97 patients with primary PCL
treated between 1995 and 2006 [101]. The 3-year PFS and
OS were 34 and 64%, respectively. In addition, there
appeared to be a trend toward a superior OS in patients who
received a tandem ASCT as opposed to single ASCT, with
OS at 3 years being 84 and 56%, respectively. Since the
analyzed cohorts represent a selected group of patients that
had survived long enough to undergo transplantation and
had demonstrated chemotherapy-sensitive disease, the
observed outcome is likely expected to be better than for an
unselected group of patients with EMM and PCL. In a more
recent study, patients with primary PCL who received an
intensive strategy including proteasome inhibitor plus IMiD
induction regimen, consolidation with a single ASCT, and
followed by a 3‐drug maintenance regimen, the median PFS
was 33 months, and the median OS was 63 months, with 3‐
year PFS and OS rates of 47 and 58%, respectively [93].
The role of alloSCT has been described in small retro-
spective studies. In the CIBMTR series, the outcome of 97
patients who received ASCT was compared with 50 patients
who received alloSCT between 1995 and 2006. Although
the cumulative incidence of relapse at 3 years was sig-
nificantly lower in the allogeneic group (38% vs. 61%),
transplant-related mortality at 3 years was considerably
higher in patients who received an alloSCT (41% vs. 5%)
versus ASCT. This resulted in a 3-year OS of 64% for
ASCT group and 39% for the alloSCT group, respectively.
While a comparison between ASCT and alloSCT is difficult
owing to relatively small numbers of alloSCT and lack of
randomized studies, the available evidence does not suggest
that alloSCT is superior to ASCT, despite decreased rates of
disease relapse.
The European Myeloma Network study (EMN12/
HOVON 129 PCL) is analyzing the role of carfilzomib and
lenalidomide containing induction regimen, followed by
tandem ASCT and alloSCT, the latter involving semi-
intensive conditioning with melphalan 140 mg/m2 + flu-
darabine, as well as carfilzomib and lenalidomide in con-
solidation and maintenance in primary PCL. Venetoclax
(BCL2 inhibitor) has shown significant activity in patients
with t(11;14) + multiple myeloma, a translocation fre-
quently reported in primary PCL, thus providing the ratio-
nale for exploring this drug in PCL in combination with
other agents. Monoclonal antibodies directed against CD38
and SLAMF7, exportin 1 inhibitors (e.g., selinexor), anti-
BCMA antibodies, and bispecific T-cell engagers have
shown efficacy in high-risk multiple myeloma, and
M. Bhutani et al.
therefore merit investigation for treatment of EMM and
PCL, often harboring high-risk molecular abnormalities.
Emerging cellular therapies including CAR-T cell therapy
also hold promise to improve the prognosis, therefore it
would be desirable to enroll patients with EMM and PCL in
prospective studies designed for multiple myeloma.
Management approach
PET/CT imaging plays an integral role in diagnosis and
monitoring of treatment response at various extramedullary
sites [7]. Biopsy of EMM lesion must be considered for
acquisition of molecular information, and to establish
diagnosis in nonsecretory cases with no marrow involve-
ment. The main goal of therapy is to rapidly debulk the
disease in both bone marrow and extramedullary sites and
to reverse end-organ complications, to prevent early mor-
tality and eventually prolong survival.
The current treatment approach is tailored to patient age
and fitness, with fit patients receiving intensive induction
therapy, consolidation ASCT and maintenance, whereas
unfit patients are treated with several cycles of combination
chemotherapy and extended maintenance. Radiation ther-
apy is employed in selected cases with bulky disease to
improve local control and palliate symptoms. Where pos-
sible, patients should be considered for enrollment in clin-
ical trials.
In younger/fit patients with proliferative/ bulky EMM or
PCL, more intensive combination regimens incorporating a
proteasome inhibitor and alkylators, such as V(or K)RD-
PACE (bortezomib or carfilzomib, lenalidomide, dex-
amethasone, cisplatin, doxorubicin, cyclophosphamide, and
etoposide) may be utilized to provide rapid reduction in
disease burden (Fig. 2). Echocardiographic estimation of
cardiac function is recommended prior to starting therapy.
Treating EMM is analogous to treating aggressive lym-
phomas or acute leukemia, with propensity for tumor cells
to rapidly grow and develop drug resistance during inter-
current periods of suboptimal treatment, prolonged treat-
ment breaks or delays. Avoiding low-intensity suboptimal
treatment is the crux. Patients must receive tumor lysis
prophylaxis with hydration and allopurinol. In patients with
underlying renal disease, and/or history of allopurinol
intolerance, the use of febuxostat (a new xanthine oxidase
inhibitor) may be considered. Rasburicase is preferred in
patients whose baseline uric acid is higher than 8 mg/dL
(476 mmol/L) or those who develop evidence of active
tumor lysis. Intensive supportive care is critical with careful
monitoring of cytopenia and nearly all patients will require
blood product support. Febrile neutropenia is a frequent
complication, particularly after PACE based therapies, and
patients must be counseled to seek immediate medical
Extramedullary multiple myeloma

Fig. 2 Management approach

for EMM or primary PCL.
**Consider for patients who are
fit enough to receive aggressive
chemotherapy. In the absence of
PR or better, approach as
primary refractory and switch to
2nd line regimen. *Consider
reduced-intensity allogeneic
stem cell transplant for young/fit
patients in the context of a
clinical trial only. PCL plasma
cell leukemia, EMM
Extramedullary multiple
myeloma, RVd lenalidomide,
bortezomib, dexamethasone,
KRd carfilzomib, lenalidomide,
dexamethasone, V(K)-RD-
PACE bortezomb(carfilzomib)-
lenalidomide, dexamethasone,
cisplatin, doxorubicin,
cyclophosphamide, etoposide,
PR partial response, CR
complete response, CSF
cerebrospinal fluid, CNS central
nervous system

attention with fever. Antibiotic prophylaxis directed against
gram-negative bacteria, and antifungal prophylaxis should
be considered if neutropenia is anticipated for a long
duration. Adequate antithrombotic prophylaxis is also cru-
cial. Finally, for all patients with EMM, we recommend the
use bisphosphonate therapy or denosumab (for patients with
renal impairment) to decrease the risk of future skeletal-
related events.
In cases with less bulky or low-volume EMM lacking the
features of PCL, or for those with pre-existing organ dys-
function, or significant comorbidities, we prefer frontline
therapy with a triplet regimen that includes a proteasome
inhibitor and an IMiD, such as RVd (lenalidomide, borte-
zomib, and dexamethasone) or KRd (carfilzomib, lenali-
domide, and dexamethasone). In the very elderly population
and in frail patients, treatment efficacy should be carefully
weighed against the risk of life-threatening adverse events
that may significantly impair quality of life. In these situa-
tions, dose reductions could be adopted, or in selected cases
a palliative approach could be offered upfront.
Patients failing to achieve a partial response after two
cycles of induction therapy or breaking through the treat-
ment, if remain eligible, should be timely switched to a
more aggressive regimen to minimize risk of organ failure
and death.
After induction therapy, in transplant-eligible patients, an
upfront ASCT is recommended to achieve a deeper
response and likely longer disease control. Based on limited
data showing efficacy, a tandem ASCT could be considered
[63, 101]. An alloSCT may be considered and performed
preferably only in the setting of a clinical trial. In the
posttransplant period, our group minimizes the period with
no therapy to 60 days rather than the conventional 100 days
for the initiation of consolidation/maintenance therapy, as is
done in the total therapy program from Arkansas. The
maintenance regimens typically include a proteasome
inhibitor and an IMiD combination, given promising results
with this strategy in high-risk multiple myeloma [102]. The
approach of prolonged administration of RVD-based
maintenance forms the basis for the current ongoing
Southwest Oncology Group clinical trial for high risk as the
control arm (elotuzumab plus RVD vs. RVD for high risk
only with maintenance until progression in each arm;
SWOG S1211, NCT01668719).
CNS EMM
The CNS is an immunologically privileged site that is iso-
lated from the blood system by the blood–brain barrier

(BBB) and the blood–cerebrospinal fluid (CSF) barriers.
Although the process by which lymphoid or myeloid leu-
kemic cells traffic into the CNS has been studied, this
process is less well understood in the context of malignant
plasma cells. CNS is an exceedingly rare location of EMM
involvement, diagnosed at an incidence of less than
1%, with an overall survival reported less than 6 months
[103–105]. Most patients are diagnosed with CNS invol-
vement at relapse/progression. Diagnosis is made by pre-
sence of atypical plasma cells in the CSF by conventional
cytology and flowcytometry or direct tissue sampling and/or
imaging evidence of intraparenchymal lesions or leptome-
ningeal/dural enhancement. A correct and timely diagnosis
still represents a challenge as neurological symptoms and
signs may be subtle, and sometimes attributed to other
clinical situations, such as hyperviscosity, metabolic ence-
phalopathy from hypercalcemia or AKI, treatment-related
neuropathy, stroke or opportunistic infections. The fact that
many patients with CNS EMM have PCL or other extra-
medullary localizations suggests that the hematologic route
plays a major role for spreading [106]. Besides hemato-
genous spread, CNS EMM can arise from direct invasion
from skull or vertebral lesions into the CNS. MRI with
gadolinium contrast has a superior sensitivity than cranial
CT to assess for CNS EMM, whereas PET/CT is best suited
to localize involvement of sites outside the CNS.
Management of CNS EMM represents a unique chal-
lenge. Most published reports describe dismal survival with
traditional use of intrathecal chemotherapy and radiation
therapy with or without systemic therapy [106, 107]. In the
largest retrospective multi-institutional study of 172 CNS
EMM cases, the median OS from the onset of CNS invol-
vement for the entire group was 7 months; untreated and
treated patients had median OS of 2 and 8 months,
respectively [104]. Despite the use of novel agents, or
aggressive therapies, in combination with ASCT or
alloSCT, the outcomes after CNS EMM diagnosis are
uniformly dismal [103, 108, 109].
Alkylating agents penetrate the CSF poorly, and con-
ventional agents like high-dose methotrexate and cytar-
abine, known to cross the BBB, have minimal to no
antimyeloma activity. IMiDs, including thalidomide, lena-
lidomide, and pomalidomide have shown CNS penetrance
and effectiveness in clearance of myeloma cells from CSF
[110, 111]; however, IMiD resistance is not uncommon in
this group of patients. Although proteasome inhibitors
(bortezomib, carfilzomib, and ixazomib) cannot cross the
BBB, marizomib, an irreversible proteasome inhibitor has
shown to distribute uniformly within the brain parenchyma,
thus making it a suitable agent to be tested in clinical trials
[112]. The anti-CD38 antibody daratumumab and anti-CS1
elotuzumab have not been tested in CNS EMM as CNS
involvement was an exclusion criterion in the registration
M. Bhutani et al.
trials. It is unknown whether these antibodies can get
through the blood–brain barrier or be used intrathecally.
Engineered CAR-T cells targeting BCMA antigens were
found in CSF of several patients recruited to dedicated
trials, suggesting these might have a role in eradicating CNS
disease. Our approach for CNS EMM includes IT che-
motherapy, CNS radiotherapy in selected cases, and sys-
temic IMiD-based combination therapy.
Conclusions
Despite greatly improved prognosis for multiple myeloma
in general, our current standard therapies have not suffi-
ciently improved outcomes for patients with EMM. The
rarity of this disease and the lack of prospective trials make
it difficult to generate solid data and treatment guidelines.
Although it will be challenging to have trials adequately
powered to investigate outcomes in this uncommon group
of patients, trials targeting ‘high-risk multiple myeloma’
could allow inclusion of these patients for assessment of
reported subgroup effect estimates with a priori hypotheses.
Capturing information regarding EM-B and EM-E at diag-
nosis and at the time of relapse in clinical trials incorpor-
ating sensitive imaging modalities will be a key to
evaluating outcomes for EMM prospectively. International
collaborative studies are warranted to better understand the
risk factors, the biological and genetic features and the
impact of novel therapeutic modalities. As more data are
accumulated from clinical trials evaluating next wave of
antimyeloma therapies, including selinexor, checkpoint
inhibitors, CAR T cells, antibody-drug conjugates and
bispecific antibodies, a better understanding of how to
sequence and cycle therapies will be critical to further
improving outcomes in EMM.
Acknowledgements This work is supported by the Carolinas Mye-
loma Research Fund, Heinemann Foundation of Charlotte, the
Freedland Fund, the Leukemia Lymphoma Society and NCI Grant
5R01CA201634.
Author contributions SZU and MB conceived and designed the study.
MB wrote the first draft of the manuscript with input from SZU and
PMV. DMF, MB and SA prepared the figures. All authors were
involved in researching data, discussion of content and critical revision
of the paper and approval of the submitted manuscript.
Compliance with ethical standards
Conflict of interest MB has received speaker’s fees from Amgen.
DMF has no conflict of interest. SA has received consulting fees from
Takeda, Amgen and Celgene, and speaker’s fees from Takeda and
Celgene. PMV has received consulting fees from Amgen, BMS,
Celgene, Janssen, Novartis, Oncopeptides, Takeda and TeneoBio.
SZU has received consulting fees from Abbvie, Amgen, BMS, Cel-
gene, EdoPharma, GSK, Janssen, Sanofi, Seattle Genetics, Skyline Dx,
Extramedullary multiple myeloma
Takeda and TeneoBio, and research funding from Amgen, Array
Biopharma, BMS, Celgene, Janssen, Pharmacyclics, Prothena, Sanofi,
Seattle Genetics, Skyline Dx and Takeda.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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