Editorial

From Biology to Clinical Practice: The Bone Marrow

Microenvironment in Multiple Myeloma
Despina Fotiou 1 and Eirini Katodritou 2, *

1 Department of Clinical Therapeutics, National and Kapodistrian University of Athens, 11528 Athens, Greece;
[email protected]
2 Department of Hematology, Theagenion Cancer Hospital, 54639 Thessaloniki, Greece
* Correspondence: [email protected]

1. Introduction
Multiple Myeloma (MM) is a complex hematological malignancy characterized by
the clonal proliferation of malignant plasma cells within bone marrow (BM) [1]. The
disease is also defined by the intricate interactions between these cells and their surround-
ing microenvironment, known as the bone marrow microenvironment (BMME) [2]. The
BMME comprises various cellular components, including stromal cells, immune cells,
and extracellular matrix (ECM) elements, which collectively create a supportive niche for
myeloma cells [3,4]. This editorial aims to summarize and introduce the multifaceted role
of the BMME in the pathogenesis and progression of MM, discuss current therapeutic
strategies targeting the microenvironment, and identify gaps in knowledge that warrant
further research.

1.1. The Role of the Bone Marrow Microenvironment in Multiple Myeloma

The BMME is a dynamic and interactive ecosystem that plays a significant role in
regulating the behavior of clonal plasma cells. Key factors mediating this interaction include
cytokines such as interleukin-6 (IL-6), B-cell activating factor (BAFF) and a proliferation-
inducing ligand (APRIL), alongside other molecular mediators like Receptor activator of NF-
kB (RANK) and Vascular Endothelial Growth Factor (VEGF). These factors, predominantly
produced by bone marrow stromal cells (BMSCs), promote the survival, migration, and
proliferation of myeloma cells [5,6]. IL-6, in particular, functions as a growth factor for
immature plasma cells, but does not induce terminal differentiation, a process essential for
Received: 6 December 2024
sustaining the malignant phenotype [7,8]. Furthermore, the secretion of IL-6 by osteoclasts
Accepted: 25 December 2024
Published: 8 January 2025
enhances the proliferation of myeloma cells but also promotes bone resorption through the
upregulation of RANKL. This dual activity establishes a vicious cycle of bone destruction
Citation: Fotiou, D.; Katodritou, E.
From Biology to Clinical Practice: The
and tumor expansion [9–11].
Bone Marrow Microenvironment in In addition to cytokines, adhesion molecules play a critical role in the interaction
Multiple Myeloma. J. Clin. Med. 2025, between myeloma cells and the BMME. The expression of CD11b and LFA-1, along with
14, 327. https://doi.org/10.3390/ the loss of CD56 and VLA-5, is associated with the migration of plasma cells from the bone
jcm14020327
marrow and the development of plasma cell leukemia [12]. Selectins also modulate the
Copyright: © 2025 by the authors. communication between plasma cells and neighboring stromal cells, further emphasizing
Licensee MDPI, Basel, Switzerland. the importance of adhesion in the pathophysiology of MM [13]. Adhesion molecules also
This article is an open access article
seem to play a role in treatment response [14]. These interactions facilitate the survival of
distributed under the terms and
myeloma cells, and contribute to treatment resistance, as evidenced by the phenomenon of
conditions of the Creative Commons
Attribution (CC BY) license
cell adhesion-mediated drug resistance (CAM-DR) [15].
(https://creativecommons.org/ The BMME is also characterized by the presence of various immune cells, including
licenses/by/4.0/). myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), which create

J. Clin. Med. 2025, 14, 327 https://doi.org/10.3390/jcm14020327

J. Clin. Med. 2025, 14, 327 2 of 6

an immunosuppressive environment conducive to tumor growth. MDSCs exert their im-

munosuppressive effects through the production of inhibitory cytokines such as IL-10 and
TGF-β, which inhibit the activation of effector T cells [16,17]. Additionally, MDSCs reduce
tryptophan levels in the tumor microenvironment, impairing further T cell function [18,19].
Moreover, the infiltration of M2 macrophages within the BMME has been associated with
a negative prognostic impact on treatment outcomes. These macrophages secrete pro-
tumoral immunosuppressive agents such as IL-10 and TGF-β1, as well as pro-angiogenic
factors like VEGF and FGF-2, which further promote an immunosuppressive environment
and promote tumor progression [20]. This underscores the importance of targeting immune
components within the BMME to improve therapeutic efficacy.
Regulatory T cells (Tregs), primarily identified as CD4+CD25+FoxP3+ cells, are in-
creasingly recognized for their complex role in the immune regulation of multiple myeloma.
They contribute to the maintenance of immune tolerance and the suppression of immune
responses against tumor cells [21,22]. Studies have shown that Treg populations are often
expanded in patients, particularly in the early stages of the disease, correlating with disease
burden and paraprotein levels [23]. This increase in Tregs may reflect a compensatory
mechanism to counteract the immune evasion strategies. Tregs have been shown to inhibit
the proliferation of effector T cells and secrete immunosuppressive cytokines such as TGF-β
and IL-10, which further modulate the immune response [22]. They have also been linked
with reduced immune surveillance, contributing to disease progression.
The therapeutic implications of targeting Tregs in MM are being actively explored,
as their immunosuppressive functions may hinder the efficacy of both conventional and
novel immunotherapies. Strategies aimed at depleting or inhibiting Tregs, such as the use
of monoclonal antibodies targeting specific surface markers like CTLA-4 and GITR, are
under investigation [22], with the aim of enhancing antitumor immunity by restoring the
function of effector T cells that are often suppressed in the presence of Tregs. Additionally,
the modulation of Treg activity could potentially improve the efficacy of bortezomib-
or lenalidomide-based therapy [23]. Overall, understanding the dual nature of Tregs
in MM—both as regulators of immune tolerance and as potential barriers to effective
therapy—remains a critical area of investigation in the quest to improve patient outcomes.

1.2. The Role of the Microenvironment in Drug Resistance

The BMME plays a crucial role in the development of drug resistance in MM. One
of the primary mechanisms is the secretion of cytokines and growth factors that promote
cell survival and proliferation. For example, IL-6 and IL-10, produced by BMSCs and
Tregs, respectively, have been shown to enhance the survival of myeloma cells and protect
them from the cytotoxic effects of chemoimmunotherapy [24]. Elevated IL-10 levels in
MM patients correlate with lower response rates and poor prognosis, highlighting the
importance of this cytokine in mediating drug resistance [25]. Additionally, the interaction
between myeloma cells and the BMME leads to the activation of survival pathways that
confer resistance to therapy. Clonal plasma cells can activate the AKT pathway through
interactions with MSC-derived extracellular vesicles (EVs), which inhibit pro-apoptotic
signaling pathways such as p38, p53, and c-Jun N-terminal kinase (JNK) [26,27]. This
activation of survival pathways not only promotes cell proliferation, but also enhances
resistance to various therapeutic agents, including proteasome inhibitors and immunomod-
ulatory drugs [28]. The phenomenon of CAM-DR is particularly relevant in the context of
drug resistance. Myeloma cells adhere to BMSCs through interactions involving adhesion
molecules such as VLA-4 and CD44, which promote cell survival but also reduce the
efficacy of chemotherapeutic agents [29]. This highlights the need for therapeutic strategies
that disrupt these interactions to enhance treatment efficacy.
J. Clin. Med. 2025, 14, 327 3 of 6

1.3. The Role of the Microenvironment in CAR-T and Bispecific Therapies

Recent advancements in cellular therapy, particularly CAR-T cell therapy and bispe-
cific T-cell engagers (BiTEs), have shown great promise in the treatment of MM. CAR-T cell
therapy involves the genetic modification of T cells to express chimeric antigen receptors
(CARs) that specifically target antigens on myeloma cells, such as B-cell maturation antigen
(BCMA) [30,31]. The BMME plays a significant role in the efficacy of CAR-T therapies, as
the immunosuppressive microenvironment can hinder T-cell function and persistence. The
BMME is characterized by the presence of Tregs and MDSCs, which can inhibit the activity
of CAR-T cells [32]. The upregulation of co-inhibitory molecules, such as PD-1, or ago-
nist molecules, such as T-cell immunoreceptors with immunoglobulin and ITIM domains
(TIGIT) on activated T cells in the BMME can protect clonal plasma cells from immune
attack [33,34]. Therefore, strategies aimed at modulating the BMME to enhance CAR-T cell
efficacy are crucial. Ongoing research explores the use of immune checkpoint inhibitors
or agonist proteins (such as TIGIT) in conjunction with CAR-T therapy to enhance T-cell
activation and persistence [35,36]. Bispecific T-cell engagers (BiTEs) are another innovative
therapeutic approach that harnesses the immune system to target myeloma cells. These
agents are designed to simultaneously bind to CD3 on T cells and an antigen on myeloma
cells, facilitating T-cell activation and cytotoxicity [37]. The efficacy of BiTEs is influenced
to a significant extent by the BMME. Immunosuppressive cells the microenvironment can
limit T-cell activation and function, thereby reducing the effectiveness of BiTEs [37]. Recent
studies have indicated that the combination of BiTEs with agents that target the BMME,
such as proteasome inhibitors, anti-CD38 monoclonal antibodies, or immune checkpoint
inhibitors, may be able to enhance their therapeutic efficacy [38]. This approach aims to cre-
ate a more favorable microenvironment for T-cell activity, ultimately improving treatment
outcomes for patients with MM.

1.4. Understanding the Heterogeneity of the Bone Marrow Microenvironment

A critical aspect of the BMME is its heterogeneity, which can vary significantly among
patients. This variability can influence response to treatment and long-term outcomes, un-
derscoring the need for personalized therapeutic approaches. For instance, the expression
of PD-L1, a key immune checkpoint molecule, has been associated with poor prognosis in
relapsed/refractory MM [39]. While anti-PD-L1 therapies have shown promise in other
malignancies, their efficacy in MM remains uncertain, as clinical studies have not demon-
strated the anticipated benefits [40]. This highlights the importance of understanding
the unique characteristics of the BMME in individual patients with MM and to adapt
the treatment approach to effectively target both clonal plasma cells and their supportive
microenvironment.
Moreover, the role of Bregs, a small B-cell subset with immunosuppressive properties,
in mediating the evasion of myeloma plasma cells from the immune system is an emerg-
ing area of research. Bregs promote an immunosuppressive microenvironment through
the production of IL-10 and the activation of the APRIL/TACI axis, which supports the
survival of malignant plasma cells [41]. Understanding the mechanisms underlying Breg
functions and their interactions with myeloma cells may provide valuable insights into
novel therapeutic strategies aimed at reversing immune suppression in MM. Recent stud-
ies have highlighted the importance of subclone-specific cellular interactions within the
BMME. For example, CD44 on myeloma cells interacts with LGALS9 on BMME cells, which
could be validated by emerging spatially resolved techniques [42,43]. To identify new
therapeutic targets, we need to understand the resistance mechanisms that occur secondary
to subclone-specific interactions.
J. Clin. Med. 2025, 14, 327 4 of 6

1.5. Gaps in Knowledge and Future Directions

Despite significant advancements in our understanding of the BMME’s role in MM,
several gaps remain that necessitate further investigation. A deeper understanding of the
molecular mechanisms governing the interactions between myeloma cells and various
components of the BMME is required. The roles of IL-6 and other cytokines are well-
documented, but the specific signaling pathways activated in response to these factors
remain to be fully elucidated. Another active area of research is the impact of hypoxia
within the BMME on myeloma cell behavior and treatment resistance, particularly given
the aberrant expression of hypoxia-inducible factors by myeloma cells [15,44].
The BMME also needs to be better characterized at the level of the individual. The
complexity of the BMME, influenced by factors such as genetic abnormalities and patient-
specific immune profiles, suggests that a one-size-fits-all approach may be inadequate. We
also need to identify biomarkers that can predict treatment response and resistance. A
personalized approach would enhance the efficacy of existing therapies and allow for novel
therapeutic strategies. The combinatory targeting of multiple components of the BMME
is another approach that could potentially overcome resistance and immune evasion and
improve outcomes.

2. Conclusions
The bone marrow microenvironment plays a pivotal role in the pathogenesis and
progression of multiple myeloma, influencing tumor growth, survival, and therapeutic
resistance. Understanding the intricate interactions within the BMME has significant
implications for clinical practice, particularly in the development of novel therapeutic
strategies. However, critical gaps in knowledge remain, particularly regarding the molecu-
lar mechanisms governing these interactions and the heterogeneity of the BMME among
patients. Addressing these gaps through focused research will be essential for advancing
the treatment of multiple myeloma and improving patient outcomes.

Author Contributions: Conceptualization, D.F. and E.K.; writing—original draft preparation, D.F.
and E.K.; writing—review and editing, supervision, E.K. All authors have read and agreed to the
published version of the manuscript.

Conflicts of Interest: D.F.: Honoraria: Sanofi and Janssen, E.K.: Janssen Cilag, Amgen, Abbvie, Pfizer,
GSK, Takeda, Sanofi, Karyopharm: Honoraria, Research Funding.

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