diagnostics
Review
Autoimmune Diseases and Plasma Cells Dyscrasias:
Pathogenetic, Molecular and Prognostic Correlations
Laura Giordano 1,† , Rossella Cacciola 2,† , Paola Barone 1 , Veronica Vecchio 1 , Maria Elisa Nasso 1 ,
Maria Eugenia Alvaro 1 , Sebastiano Gangemi 3 , Emma Cacciola 4,‡ and Alessandro Allegra 1, *,‡
Citation: Giordano, L.; Cacciola, R.;
Barone, P.; Vecchio, V.; Nasso, M.E.;
Alvaro, M.E.; Gangemi, S.; Cacciola, E.;
Allegra, A.. Autoimmune Diseases and
Plasma Cells Dyscrasias: Pathogenetic,
Molecular and Prognostic Correlations.
Diagnostics 2024, 14, 1135. https://
doi.org/10.3390/diagnostics14111135
Academic Editor: Evangelos Terpos
Received: 13 April 2024
Revised: 23 May 2024
Accepted: 27 May 2024
Published: 29 May 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Diagnostics 2024, 14, 1135. https://doi.org/10.3390/diagnostics14111135
1 Hematology Unit, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”,
University of Messina, Via Consolare Valeria, 98125 Messina, Italy; laura.giordano@polime.it (L.G.);
paola.barone@polime.it (P.B.); vero.vecchio99@gmail.com (V.V.); maria.nasso@studenti.unime.it (M.E.N.);
m.eugenia983@gmail.com (M.E.A.)
2 Hemostasis/Hematology Unit, Department of Experimental and Clinical Medicine, University of Catania,
95123 Catania, Italy; rcacciol@unict.it
3 School and Operative Unit of Allergy and Clinical Immunology, Department and Experimental Medicine,
University of Messina, 98125 Messina, Italy; gangemis@unime.it
4 Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of
Catania, 95123 Catania, Italy; ecacciol@unict.it
* Correspondence: aallegra@unime.it
† These authors contributed equally to this work.
‡ These authors contributed equally to this work.
Abstract: Multiple myeloma and monoclonal gammopathy of undetermined significance are plasma
cell dyscrasias characterized by monoclonal proliferation of pathological plasma cells with uncon-
trolled production of immunoglobulins. Autoimmune pathologies are conditions in which T and
B lymphocytes develop a tendency to activate towards self-antigens in the absence of exogenous
triggers. The aim of our review is to show the possible correlations between the two pathological
aspects. Molecular studies have shown how different cytokines that either cause inflammation or
control the immune system play a part in the growth of immunotolerance conditions that make it
easier for the development of neoplastic malignancies. Uncontrolled immune activation resulting in
chronic inflammation is also known to be at the basis of the evolution toward neoplastic pathologies,
as well as multiple myeloma. Another point is the impact that myeloma-specific therapies have on the
course of concomitant autoimmune diseases. Indeed, cases have been observed of patients suffering
from multiple myeloma treated with daratumumab and bortezomib who also benefited from their
autoimmune condition or patients under treatment with immunomodulators in which there has been
an arising or worsening of autoimmunity conditions. The role of bone marrow transplantation in the
course of concomitant autoimmune diseases remains under analysis.
Keywords: autoimmune disease; multiple myeloma; MGUS; monoclonal gammopathies; systemic
lupus erythematosus; psoriasis; rheumatoid arthritis
1. Introduction
Multiple myeloma (MM) is the second most prevalent hematologic malignancy, found
in the spectrum of plasma cell dyscrasias [1]. Neoplastic transformation of a plasma
cell clone causes hyperproduction of identical immunoglobulins (Figure 1), resulting in
monoclonal gammopathy of undetermined significance (MGUS) and, due to the occurrence
of additional mutations, leading to multiple myeloma. It is classically a pathology of the
elderly, although cases have been observed in the young population, usually with a poor
prognosis [2–5].
MGUS is defined as an increase in monoclonal immunoglobulin (Ig) in blood or urine
of less than 3 g/dL, clonal plasma cells less than 10% in the bone marrow and the absence
https://www.mdpi.com/journal/diagnostics
 Diagnostics 2024, 14, 1135 2 of 20

s 2024, 14, x FOR PEER REVIEW of any clinical signs. MGUS is present in 3% of individuals aged 502 and
of 21above, and its
occurrence becomes more common as age advances [6–8].

Figure 1. Pathogenetic mechanisms

Figure 1. Pathogeneticofmechanisms
myeloma. Created withCreated
of myeloma. BioRender.com (accessed (accessed
with BioRender.com on 28 on 28 Febru-
February 2024). ary 2024).

MGUS is defined Whileas the

an increase
exact cause in monoclonal
of MGUS and immunoglobulin
MM is not well (Ig) in bloodthere
understood, or is evidence
urine of less than 3 g/dL, clonal
suggesting plasma cells less
that immunological than 10%orinprolonged
dysfunction the bone immune
marrow system
and theactivation may
absence of any be crucial
clinical factors
signs. MGUS in the development
is present in 3% of of both disorders.
individuals aged Monoclonal
50 and above, immunoglobulin
is commonly found in chronic
and its occurrence becomes more common as age advances [6–8]. inflammatory illnesses, including chronic infection and
While the autoimmune
exact cause ofdisorders
MGUS and [9–12].
MM is Thenotinfluence of these two
well understood, thereentities on immunological
is evidence
suggesting that homeostasis
immunological is particularly
dysfunction significant
or prolongedwhen immune
taking into account
system the increased
activation may vulnerability
to severe
be crucial factors infectious complications,
in the development even during
of both disorders. times free
Monoclonal from myelotoxicistherapies. This
immunoglobulin
commonly found is due to a change
in chronic in the humoral
inflammatory immunity’s
illnesses, includingeffector arm.infection
chronic The progressive
and au- accumulation
of dysfunctional plasma cells in the bone marrow
toimmune disorders [9–12].The influence of these two entities on immunological home- results in a direct suppression of B
lymphocytopoiesis and non-clonal immunoglobulin production.
ostasis is particularly significant when taking into account the increased vulnerability to In fact, a characteristic
severe infectious complications, even during times free from myelotoxic therapies. This is absence of,
marker of multiple myeloma is the decrease in, and occasionally the complete
physiological immunoglobulins. This immune paralysis results in a decrease in the patient’s
due to a change in the humoral immunity’s effector arm. The progressive accumulation
capacity to develop an effective primary defense against infections and an incapacity to
of dysfunctional plasma cells in the bone marrow results in a direct suppression of B
create a strong secondary defense [13–15].
lymphocytopoiesis and non-clonal immunoglobulin production. In fact, a characteristic
An autoimmune disease (AD) is a clinical illness that occurs when T cells and/or B
marker of multiple myeloma is the decrease in, and occasionally the complete absence of,
cells are activated in the absence of an ongoing infection or any other recognized cause.
physiological immunoglobulins. This immune paralysis results in a decrease in the pa-
The basis for autoimmune diseases (ADs) lies in the failure to distinguish between self
tient’s capacity and
to develop
non-selfan and effective primaryofdefense
the disruption against infections
immunological tolerance. and Duringan inca-
these pathological
pacity to create situations,
a strong secondary defense [13–15].
T cells cause damage to tissues by directly destroying target cells, attracting
An autoimmune diseasecells
inflammatory (AD) andis releasing
a clinical various
illness that occursAutoantibodies
cytokines. when T cells and/or (autoAbs)B may trigger
cells are activated in the absence of an ongoing infection or any other recognized
tissue injury by forming immune complexes, causing cytolysis or phagocytosis of target cause.
The basis for autoimmune diseasescellular
cells and disrupting (ADs) function
lies in the failure
(Figure 2).to distinguish between self
and non-self and theCentral
disruption of immunological tolerance.
and peripheral immune tolerance controls During these pathological
the activity of T cells and B cells.
situations, T cells cause damage
Nevertheless, to tissues
certain by directly
autoreactive T and destroying target
B cells migrate cells,
to the attracting
outer regions, where they
inflammatory cells
remainanddormant
releasing various
until cytokines.
an external Autoantibodies
stimulus disrupts the (autoAbs)
tolerance and may trig-
stimulates the innate
ger tissue injuryandbyadaptive
formingimmuneimmunecells complexes, causingwith
in an individual cytolysis
geneticorsusceptibility
phagocytosis of
[16–18].
target cells and disrupting cellular function (Figure 2).
tics 2024, 14, x FOR PEER
Diagnostics 2024,REVIEW
14, 1135 3 of 21 3 of 20

Figure 2. Pathogenetic
Figure mechanism of autoimmunity.
2. Pathogenetic mechanism of autoimmunity.

Central and peripheral immune tolerance

Chronic inflammation controls
is known the activity
to have a role inofthe T cells and B cells.
development of hematological
Nevertheless, certain autoreactive
malignancies and otherT and B cells
forms migrateDifferent
of cancer. to the outer regions, where
inflammatory they are implicated
pathways
remain dormant in Buntil
cellan externalThey
survival. stimulus disrupts the
are mediated tolerance and
by interleukin stimulates
6 (IL-6), the in- 13 (IL-13) and
interleukin
tumor
nate and adaptive necrosis
immune factor
cells in an(TNF)-α.
individualToll-like
withreceptor (TLR) and its ligands
genetic susceptibility [16–18].stimulate the growth
of B cells, while
Chronic inflammation B-cell activating
is known to have a role factor
in (BAFF) and the subsequent
the development activation of nuclear
of hematological
factor κ-B (NF-κB) are associated with B cell neoplasias.
malignancies and other forms of cancer. Different inflammatory pathways are implicated
In recent
in B cell survival. They years, different
are mediated studies have
by interleukin suggested
6 (IL-6), a connection
interleukin 13 (IL-13) between
and plasma cell
tumor necrosisdyscrasias and ADs.
factor (TNF)-α. It has been
Toll-like hypothesized
receptor (TLR) andthat its prolonged exposure
ligands stimulate theto antigen stim-
ulation
growth of B cells, while could cause
B-cell plasmafactor
activating cells’ (BAFF)
malignant andtransformation
the subsequentby leading to
activation ofpro-oncogenic
mutations
nuclear factor κ-B (NF-κB) inare
rapidly dividing
associated with cells [19–22].
B cell neoplasias.
Increased activity of
In recent years, different studies have suggestedB cells is a characteristic
a connection feature of these
between autoimmune
plasma cell disorders,
and there is evidence to suggest that immune-related
dyscrasias and ADs. It has been hypothesized that prolonged exposure to antigen stim- conditions may be linked to an
increased risk of MGUS and MM. A significant
ulation could cause plasma cells’ malignant transformation by leading to pro-oncogenicincidence of MGUS has been seen in a
cohort dividing
mutations in rapidly of patients with
cells immunological diseases or persistent infections. Nevertheless, the
[19–22].
precise mechanism connecting
Increased activity of B cells is a characteristic benign inflammatory
feature conditions disorders,
of these autoimmune and the development of
and there is evidence to suggest that immune-related conditions may be linked to an and
genetically clonal cells is still uncertain [9]. An increased risk for MGUS in- MM has been
found in families with a positive history for ADs
creased risk of MGUS and MM. A significant incidence of MGUS has been seen in a co- [23]. In particular, a correlation between
a personal history of giant cell arteritis (GCA) and
hort of patients with immunological diseases or persistent infections. Nevertheless, the polymyalgia rheumatica and a higher
risk of MGUS and MM has been under study
precise mechanism connecting benign inflammatory conditions and the development of[24]. The exact causes are unknown, but a
possible role of the long-term immunological activation
genetically clonal cells is still uncertain [9]. An increased risk for MGUS and MM has has been suggested. Furthermore,
been found inthe connection
families with abetween
positive ADs history andforMGUS
ADs [23]. seems stronger than
In particular, that between ADs and
a correlation
MM [25,26].
between a personal history of giant cell arteritis (GCA) and polymyalgia rheumatica and
McShane et al. discovered that a 42% higher incidence of MGUS was associated with
a higher risk of MGUS and MM has been under study [24]. The exact causes are un-
any autoimmune condition. Patients with detectable autoantibodies and organ involvement
known, but a possible role of the long-term immunological activation has been suggest-
showed a higher risk, while those with non-detectable autoantibodies showed a less
ed. Furthermore, the connection between ADs and MGUS seems stronger than that be-
significant elevated risk [25].
tween ADs and MM [25,26].
Eight families were subjected to genetic analysis, which demonstrated that hyperphos-
McShane et al. discovered that a 42% higher incidence of MGUS was associated with
phorylated paratarg-7 was transmitted as a dominant character and that carriers had an
any autoimmune condition. Patients with detectable autoantibodies and organ involve-
almost eight-fold greater risk of multiple myeloma and IgA or IgG MGUS.
ment showed a higher risk, while those with non-detectable autoantibodies showed a less
In addition, greater correlations were identified in patients with MGUS rather than
significant elevated risk [25].
with MM (42% vs. 13%) [27–29].
Eight families were subjected to genetic analysis, which demonstrated that hyper-
phosphorylated 2. paratarg-7 was transmitted
Physiopathology of Autoimmuneas a dominant
Diseases character and thatMyeloma
and Multiple carriers had
an almost eight-fold greater risk of
2.1. Hematological Conditionsmultiple myeloma and IgA or IgG MGUS.
In addition, greater correlations were identified in patients with MGUS rather than
Anemia is one of the CRAB criteria and it is frequently present at the moment of MM
with MM (42% vs. 13%) [27–29].
diagnosis. It has a complex base regarding the inflammatory environment caused by MM
itself, the invasion of the bone marrow by plasma cells and the erythropoietin deficiency
Diagnostics 2024, 14, 1135 4 of 20

following renal impairment. Nonetheless, other causes of anemia have been reported: pure
red cell aplasia, pernicious anemia and autoimmune hemolytic anemia (AIHA) [19,30].
ADs and plasma cell diseases seem to be closely related to a number of blood crasis
changes. The potential connections between certain illnesses, including AIHA, idiopathic
thrombocytopenia purpura (ITP), autoimmune neutropenia (AIN), acquired hemophilia
(AHA) and coagulation problems with monoclonal gammopathies, will be assessed in
this section.
While some research indicates that AIHA is extremely infrequently related with MM,
others assert that 4% of individuals with MM also have AIHA. A recent study revealed
the presence of antibodies against erythrocyte surface antigens in 10.6% of the population
under analysis, suggesting that the production of autoantibodies could be facilitated by
concurrent immunological abnormalities in patients affected by MM [31–33].
ITP has also been reported in MM patients, although rarely, with a similar pathogenic
cause [34,35].
AIN is defined by an absolute neutrophil count (ANC) of less than 1500 cells/mL. It
could have secondary causes such as rheumatological diseases, ITP, AIHA and cancer. In
MM, neutropenia is typically the consequence of treatment. Up to 35% of patients develop
neutropenia (grades 3 and 4) brought on by lenalidomide [19,30].
Some aspects point to MM as the most likely underlying cause of AIN: neutrophil anti-
bodies, the absence of other possible causes, the timing of AIN’s diagnosis and its resolution
with the control of MM. Despite the fact that the precise cause of AIN in MM is still unknown,
MM and immunological dysregulation are related. Immunological dysregulation in MM may
cause AIN, or AIN may cause immunological dysregulation in MM [36].
AHA is a rare autoimmune disease responsible for an increased bleeding tendency
due to the presence of autoantibodies initiating the activity of coagulation factor VIII. Ap-
proximately half of AHA cases are associated with an underlying condition, such as cancer,
ADs or pregnancy complications. In the remaining cases, AHA’s cause is still unknown.
AHA can arise as a result of hematological malignancies or be associated with them.
Among these cancers, lymphoproliferative diseases are the most prevalent. Only 14% of
AHA cases associated with a hematological malignancy are specifically related to plasma
cell neoplasms (PCNs) [36].
Coagulation system abnormalities pose a substantial problem in patients with plasma
cell disorders. Approximately 6–7% of patients with MGUS and 10% of individuals with
primary amyloidosis experience venous thromboembolisms. Immunomodulatory drugs
used to treat MM, such as thalidomide, lenalidomide or pomalidomide, greatly increase
the risk of thrombotic events. However, patients with plasma cell abnormalities do develop
bleeding tendencies due to impaired platelet production, altered platelet function caused by
paraproteins and vascular injury resulting from hyperviscosity syndrome. Some cases have
demonstrated that therapy for MM decreases the occurrence of coagulopathy by lowering
the paraproteins in the blood.
These findings imply that paraproteins are a major factor in the aberrant coagulation
observed in MM patients, working as neutralizing antibodies for certain coagulation
factors [37–40].

2.2. Rheumatological Conditions

According to the literature, there are several pathologies of rheumatological interest
associated with MM. The dysregulation of the immune response resulting from the state of
chronic inflammation and the consequent alteration of immunological surveillance up to
the release of cytokines by pathological plasma cells seem to be common hypotheses [19].
In patients affected by systemic lupus erythematosus (SLE), tolerance mechanisms
such as elimination of the plasma cells producing autoantibodies and editing their receptor
to create non-self-reacting immunoglobulins are overridden by B cell hyperactivity. The
main targets of these pathogenic plasma cells are nuclear components, including DNA
Diagnostics 2024, 14, 1135 5 of 20

and histone. Both humans with SLE and lupus-prone mice exhibit a tendency towards
excessive activity of B cells [41].
There is evidence to suggest that individuals with autoimmune conditions have an
increased risk of developing cancer. According to a recent study, even in the absence of
cytotoxic therapies, individuals with SLE had a higher chance of having a tumor. Among
the neoplasms associated with SLE, lymphomas—particularly non-Hodgkin’s lymphomas—
are the most often reported forms. Plasma cell dyscrasias, including macroglobulinemia
and MGUS, have also been linked to SLE (11% of patients) [19], even though it is uncommon
for SLE and MM to coexist [42].
In patients affected by SLE, it has been suggested that B cell hyperactivity facilitates
the escape of atypical B cell clones from the regulatory systems. Mice with spontaneous
lupus-like symptoms had a high frequency of plasma cell dyscrasias [43]. There may be a
direct link between MM and chronic inflammatory diseases, as evidenced by the finding
that both conditions may be associated with an increase in bone marrow plasma cell counts.
An alternate theory is that SLE patients’ compromised immune surveillance, which makes
them more susceptible to cancer overall, encourages the emergence of MM [44].
A similar pathogenetic mechanism was hypothesized in patients affected by Sjögren’s
syndrome (SS), a chronic autoimmune disease of unknown etiology which is characterized
by a progressive infiltration of lymphocytes and plasma cells in the salivary and lacrimal
glands [45]. Patients with primary SS have an increased relative chance of having B cell
lymphoproliferative disorders compared to the normal population. It has been estimated
that one-third of patients with SS develop a B cell lymphoma. Polyclonal B cell activation
is the central immunoregulatory aberration in SS, although T cells represent the majority
of the lymphoid cells invading these glands. Hyperglobulinemia and the development of
many autoantibodies against both organ-specific and non-organ-specific autoantigens are
manifestations of this activity. Treatment for MM in a patient who was also affected by
SS resulted in a reduction in SS symptoms, such as xerostomia and xerophthalmia. While
the involvement of a hyperimmune reaction in the development of lymphoma in SS is
recognized, the potential link between chronic inflammation in SS and the onset of MM
remains to be determined [46].
Furthermore, the idea of impaired immune surveillance as a cause of both immune
and neoplastic components could explain the association between MM and another AD,
primary biliary cirrhosis (PBC) [47,48]. PBC is an autoimmune disease causing a persistent
state of hepatic inflammation, leading to the gradual loss of small interlobular bile ducts.
This progresses to the onset of cholestasis, liver damage and eventually the development of
fibrosis and cirrhosis [49]. It has been linked to higher levels of immunoglobulins, the pres-
ence of circulating immune complexes and a greater likelihood of developing extrahepatic
malignancies. There have been four reported instances of a connection between multiple
myeloma and PBC. In two patients who had targeted treatment for the hematological
condition, there was a decrease in cholestasis indices and immunoglobulins, indicating a
potential correlation between the two disorders [50,51].
Following the case of neurological involvement, two conditions appear to have a sig-
nificant clinical role: chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
and giant cell arteritis (GCA). CIDP is a peripheral neuropathy characterized by both distal
and proximal sensory impairments, often related to lymphoproliferative diseases [52–54].
Multiple myeloma has been associated with many forms of neuropathy, including axonal
demyelinating. Neuropathy in MM typically manifests as a mild, symmetrical sensorimotor
deficit, characterized by greater sensory impairment than motor impairment, and with a
preference for affecting the distal parts of the body over the proximal parts. Idiopathic
CIDP cannot be distinguished from CIDP associated with monoclonal gammopathies. At
the time of diagnosis, clinical signs of neuropathy are observed in 33% of individuals with
multiple myeloma. More than 50% of multiple myeloma cases exhibit detectable subclinical
neuropathy. Certain cases display an elevated level of antibodies against neural antigens,
despite the absence of clinical neuropathy [55].
Diagnostics 2024, 14, 1135 6 of 20

GCA, a chronic inflammation of blood vessels responsible for the irroration of scalp
and head, has been correlated to MM, suggesting that they might share a mutual inflam-
matory mechanism. Specifically, GCA may be associated with an immunological response
that occurs as a result of cytokine release in MM, or it may be caused by amyloid deposits
that are subsequent to MM [56].
It is not possible to report an estimate of the incidence of some conditions such as PBC,
CIDP and GCA as we referred to studies with scant case series, but they were carefully
considered to support our association between ADs and MM.

3. A Closer Look: Molecular Aspects

Focusing our attention on the molecular basis, several soluble and biological factors
play a key role in the pathogenesis of MM and ADs. B lymphocytes are found in an
inflammatory microenvironment, supported by pathways involving IL-6, IL-10 and tumor
necrosis factor alpha [57].
Among the pro-inflammatory cytokines, the leading role was attributed to IL-6. Inflam-
mation has been linked to both monoclonal B cell neoplasia and polyclonal B cell activation.
Individuals who have a history of chronic inflammations also tend to have polyclonal
hypergammaglobulinemia and often develop lymphomas or plasma cell neoplasias. When
combined, these findings indicate that the development of autoantibodies and polyclonal B
cells is closely linked to the chronic-inflammation-induced IL-6 production [58].
Regarding a deeper prospect, different proteins have been studied. Tumor necrosis
factor (TNF) family proteins participate in the control of vital cell functions such as differ-
entiation, proliferation, survival and cell death. Changes in the expression of TNF family
members are frequently linked to pathological states such as cancer and autoimmune dis-
eases. First reported in 1998, the TNF-like ligand APRIL (a proliferation-inducing ligand)
received its name from its ability to promote tumor cell proliferation in vitro. Originally
discovered in hematopoietic cells under normal circumstances, APRIL is overexpressed in
several tumor tissues [59].
From a biological perspective, regulatory B lymphocytes appear to play an essential
part. They are in charge of controlling the immune response by undermining T cells’
defenses and helping them transform into regulatory T cells (Tregs). The inflammatory
aspect of the MM environment stimulates angiogenesis, adaptive immunity and the growth
and survival of malignant cells, all of which have a profound effect on the regulatory
cells’ ability to operate. It is commonly known that immunological abnormalities in MM
are seen not only in B cells but also in natural killer (NK), T cells and dendritic cells
(DCs) [60] (Table 1).

Table 1. Cytokines and other factors in ADs and MM.

Cytokines and Other Factors Role in ADs Role in MM

Activation of B cells → abnormal growth → Plasmablasts growth, maturations of
Interleukin 6
autoantibodies production plasmablasts in pathological PCs
Interleukins 13 and 4 Anti-apoptotic effect, IgE production B cells proliferation
Survival of MM cells
Chronic inflammation (activation of
APRIL and BAFF Inhibition of apoptosis
keratinocytes in Ps and joint erosion in RA)
Ig class-switch recombination
Progression of MM
Interleukin 10 Immunosuppression
B cells differentiation in MM PCs
Interleukin 35 B- and Tregs expansion B cells differentiation in MM PCs

3.1. IL-6
Interleukin 6 (IL-6) is a versatile cytokine responsible for the development of B cells
as well as playing a role in the immune response, hematopoiesis and inflammation. The
Diagnostics 2024, 14, 1135 7 of 20

hypothesis that IL-6 is implicated in autoimmunity was advanced while studying patients
affected by cardiac myxoma. In fact, the cardiac myxoma cells were found to produce IL-6
and the patients exhibited autoimmune symptoms [61].
Elevated levels were also discovered in the synovial fluid of patients diagnosed with
rheumatoid arthritis (RA), and it is essential for the induction of autoimmune disorders
and autoimmunity in experimental settings. These facts indicate that IL-6 has a significant
role in the B cell abnormalities linked to the inflammatory process. In line with this concept,
inflammation has been linked to both widespread activation of B cells and the development
of abnormal growth of a single clone of B cells [62]. Individuals who have pre-existing
chronic inflammation often exhibit an excessive production of multiple types of antibodies
(polyclonal hypergammaglobulinemia) and are prone to developing abnormal growths of
plasma cells (PCs) or lymphoma. Collectively, these findings indicate that the synthesis
of IL-6 that results from chronic inflammation is strongly associated with the activation
of multiple B cells and the formation of autoantibodies. The underlying cause of SLE
is believed to be the improper activation of B cells, which are responsible for producing
antibodies. This abnormal activation is assumed to be caused by a dysregulated IL-6/IL-6R
pathway in B cells. In the absence of T cells, B cells derived from individuals with SLE
exhibit autonomous production of substantial quantities of IgGs, including IgG antibodies
targeting single-stranded DNA (ssDNA). Activated B cells respond to IL-6 by generating
IgGs and IgG anti-ssDNA antibodies. Significant IL-6 production and B cell expression of
IL-6R have been linked to SLE and a number of other autoimmune disorders. While regular
T and B cells do not express IL-6, B cells associated with SLE produce larger quantities
of IL-6. IL-6 transgenic mice exhibit a significant increase in the production of polyclonal
plasma cells, together with the generation of autoantibodies and the development of
glomerulonephritis characterized by the proliferation of mesangial cells. The concept that
dysregulated IL-6 gene expression can initiate polyclonal plasmacytosis and subsequently
lead to the development of a malignant monoclonal plasmacytoma is well supported by
the available data [63–65]. IL-6-deficient mice do not develop plasmacytoma, which aligns
with this concept [58].

3.2. Differentiation of Plasma Cells

PCs are B cells that have been activated by antigen and undergone a transformation
that enables them to produce substantial amounts of neutralizing antibodies. They are
quiescent, terminally differentiated cells which remain in the niches of the bone marrow
(BM) for a few days or possibly years. Two forms of PCs can be distinguished: short-lived
and long-lived plasma cells. When B cells encounter antigens with the assistance of T
cells through the process of CD40 ligation (known as T-dependent responses), the B cells
generate prolonged responses [66].
Activated B cells in the germinal center (GC), known as centroblasts, proliferate rapidly
and undergo processes of isotype switching and somatic hypermutation. These events
alter the hypervariable regions of the Ig genes, hence modifying the specificity of the B cell
receptor (BCR) [67,68].
The cells resulting from this process are centrocytes, which subsequently go through
an affinity maturation phase: their survival is dictated by their affinity to the BCR. They can
then leave the germination center and become memory B cells or long-lived PCs. Multiple
cell surface indicators are downregulated in long-lived PCs [69]. Surface CD45, B220, MHC
class II, CD19 and, most significantly, the BCR are all lost in this process. The ability of
long-lived PCs to make antigen-specific antibodies over prolonged periods of time is, of
course, their most remarkable feature. Long-lived PCs endure for at least a year, whereas
short-lived PCs could barely last a few days [70]. The sequential expression and silencing
of transcription factors that regulate B cell destiny can be utilized for tracking the progress
of B cell development. B lymphocyte-induced maturation protein 1 (BLIMP-1) is essential
to the PC transformation process, as several investigations have demonstrated. Bcl-6 and
B cell lineage-specific activator (BSAP, encoded by PAX5) are both repressed by BLIMP-1
Diagnostics 2024, 14, 1135 8 of 20

expression and are necessary for the early phases of B cell maturation. Numerous additional
genes are also repressed by BLIMP-1, such as MHC class II transactivator (CIITA), which is
necessary for MHC class II expression, and activation-induced cytidine deaminase (AID),
which is necessary for SHM and isotype class switching. PC formation is lost when BLIMP-
1 expression is suppressed. Therefore, the type of B cell activation and the anatomical site
of residency have a major impact on the final quality and size of a PC population. The
interplay between early developmental phases and environmental management will play a
key role in the establishment of a PC population. PCs’ unique microenvironment has been
linked to factors that affect cellular survival and lifetime and, consequently, their ability
to generate Ig over extended periods of time. Chemokines and their receptors regulate
migration to particular microenvironmental niches. The interaction between PC and BM
stroma also appears to affect plasma cells’ lifespan [71].
Dysregulation of B cells’ maturation and differentiation is the base of autoimmune
diseases and certain hematological cancers. The first step is the immortalization of PCs,
resembling long-lived plasma cells. Expression of BLIMP-1, oct-2, PU.1 and Spi-B was
detected in myeloma cells; they are essential for the differentiation of plasma cells and
enhancing the production of immunoglobulins. In particular, PU.1 controls the expression
of many integrins necessary for stem cell homing and engraftment onto bone marrow
stroma [72,73]. The presence of PU.1 in pathological plasma cells can indicate their level of
development and help explain the mechanism by which MM is mainly located in the bone
marrow [74].

3.3. APRIL: A Proliferation Inducing Ligand

The TNF family of ligands and receptors plays a crucial role in controlling several
cellular processes, including activation, survival and cell death. A proliferation induc-
ing ligand (APRIL) and B-cell activating factor belonging to the TNF family (BAFF) are
two strongly associated constituents of the TNF ligand superfamily [75]. APRIL was first
defined in 1998 and given its name due to its ability to promote the growth of cancer cells
in both laboratory settings and living organisms. APRIL is manifested by a diverse range of
immune cell subsets. The production of APRIL by monocytes, macrophages and dendritic
cells relies on the presence of specific cytokines in the environment, such as interferon
(IFN) gamma and IFN alpha. The expression of APRIL receptors on B lymphocytes varies
depending on their stage of maturity and activity. APRIL and BAFF, previously recog-
nized as B cell modulators under normal settings, were hypothesized to play a role in
supporting the survival of chronic lymphocytic leukemia (CLL) cells. They were found
in both MM cell lines and in the bone marrow of MM patients, and elevated levels of
circulating APRIL and BAFF are also observed in the blood of MM patients. In the bone
marrow of multiple myeloma patients, MM cells, CD14+ cells and osteoclasts all express
both ligands. In particular, osteoclasts appear to be the major producers of APRIL/BAFF.
Osteolytic bone disease affects 70–80% of MM patients. This condition is mostly caused by
increased osteoclast activation and interactions between MM cells and the bone marrow
microenvironment. Plasma cells co-cultured with osteoclasts show an enhanced viability.
Thus, it can be suggested that APRIL and BAFF, generated from osteoclasts, have a role in
the proliferation of MM cells. This further suggests that APRIL and BAFF participate in B
cell malignancies [59].

3.4. The Role of Innate Lymphoid Cells in ADs and MM

In recent years, the anti-tumor properties previously attributed to tumor-infiltrating
leukocytes have been rediscussed, and it is now common knowledge how they are indeed
responsible for tumor progression and the development of metastases. It is precisely in this
scenario that innate lymphoid cells (ILCs) make their appearance: they are lymphocyte-like
cells of the innate immune system with a significant role in inflammatory and neoplastic
processes. In a neoplastic environment, ILCs evade immune surveillance mechanisms and
Diagnostics 2024, 14, 1135 9 of 20

release pro-neoplastic factors [76]. They have a lymphoid morphology and lack specific
antigen receptors and phenotypic markers of myeloid cells and dendritic cells (DCs) [77].
They are distinguished in three categories on the basis of phenotypic features: ILC
Group 1, including NK and ILC1 cells; Group 2 with ILC2 and Group 3 including lymphoid
tissue inducer (LTi) and ILC3 cells [78]. Group 1 NK cells are fundamental in cancer
surveillance. Previous studies demonstrated that patients with MGUS and newly diagnosed
MM have higher levels of CD56+ CD3− NK cells in their blood and bone marrow and that
these patients have a worse prognosis [79].
ILCs are also an important source in the production of cytokines. ILC1s secrete IFN-
γ, which is thought to have a protective effect against cancer. IFN-γ in fact inhibits the
proliferative activity of MM cells by suppressing IL-6, which is a critical growth factor
for MM. Another important cytokine is IL-10. In a malignant environment, it acquires a
negative prognostic value: IL-10 inhibits the release of pro-inflammatory IFN-γ and TNF-α
and enhances the emergence of NK-resistant tumor phenotypes. ILC1s maintained the
capacity to release lineage-specific cytokines (IFN-γ) in individuals with MGUS, whereas
this ability was notably diminished in those with asymptomatic MM [80].
ILC2 is regarded as a cell subtype with pro-tumor features. It in fact secretes cytokines
that promote tumor growth and inhibit anti-tumor immunity in the microenvironment.
ILC2s in patients with MGUS were shown to secrete IL-13 [81].
The role of ILC3s in MM and MGUS is not entirely clear due to the limited research
available. However, their involvement in the development and progression can be hypoth-
esized: ILC3s have exhibited pro-tumor activity in several cancers by releasing cytokines
such as IL-17, IL-22 and IL-23, which are implicated in the development of inflammatory
illnesses [82].
Moreover, ILCs seem to also have a role in the pathogenesis of ADs. Different studies
have discovered evidence of ILCs’ alterations in human psoriasis. Investigators utilized
immunofluorescence in situ staining to demonstrate the distribution of ILCs in psoriatic
skin, particularly at the epidermis and in close proximity to T cells, indicating a direct
contact between these cell types [83].
Research indicates an increase in ILC3s and ILC1s but a decrease in ILC2s in psoriatic
skin lesions, suggesting that ILC1s and ILC3s may contribute to the disease, whereas ILC2s
could have a protective effect in psoriasis development [84,85]. The pathogenetic role of
ILC3s in Ps may be attributed to the production of crucial pro-inflammatory cytokines such
as IL-17 and IL-22 [83].

3.5. The Role of Multi-Omics Analysis in MGUS and ADs

Numerous biomarkers of human diseases can be found and quantified using novel
omics approaches such as transcriptome, proteome and metabolome profiling. Thus,
this integrative multi-omics analysis can aid in our methodical understanding of the
molecular pathways that underlie disease and biological function. Our understanding of the
pathophysiology of autoimmune diseases will grow with the integration of transcriptome,
proteome and metabolome studies data [86].
For instance, omics techniques are widely used in SLE research. These techniques
help the identification of beneficial compounds and signal transduction pathways. Scien-
tists have found through transcriptomics that patients with SLE have abnormal mRNA
expression of biomarkers mediated by immune response and inflammatory signals, cell
proliferation and differentiation signals and type I interferon signaling [87].
Proteomics approaches have revealed abnormal autoantibodies, chemokines, com-
plement system, cytokines and novel protein biomarkers such as VCAM-1 and C-reactive
protein in SLE patients [88]. Researchers have found, thanks to metabolomics, that energy-
producing, purine nucleotide, oxidative stress and fat-related metabolic signals are aberrant
in SLE [88].
Furthermore, a study identified IFN-driven changes in the composition and phenotype
of T and NK cells that are consistent with systemic immune activation. This was achieved
Diagnostics 2024, 14, 1135 10 of 20

by using a targeted single-cell multi-omics approach that combined protein and mRNA
quantification to generate a high-resolution map of the T lymphocyte and natural killer (NK)
cell populations in blood from SLE patients [89]. The study of monoclonal gammopathies
is also pertinent to omics approaches. After being developed, a transcriptome-based
response predictor model demonstrated encouraging predictive accuracy in MM patients
undergoing first-line therapy [90]. By employing multi-omics techniques, it will be possible
to uncover novel pathogenetic mechanisms and perhaps diverge from current therapeutic
approaches, as well as identify new shared pathways between autoimmune illnesses and
monoclonal gammopathies. Future research and clinical trials will illustrate the value of
various multi-omics expression analysis platform components as biomarker finding tools
for the diagnosis, prognosis and therapy of autoimmune entities [91]

4. Impact of Autoimmune Disease on Multiple Myeloma Prognosis

The connection between ADs and plasma cell dyscrasias has now been established.
However, what the burden is on patients who have both conditions must be questioned.
Some investigations have tried to find an answer, discovering an increased risk of concur-
rent MGUS but not MM in patients with previous ADs [25]. Individuals having a personal
history of giant cell arteritis, polymyalgia rheumatica or autoimmune hemolytic anemia
were found to have an elevated risk of multiple myeloma [92]. The precise biological
mechanisms underlying these observations remain unclear; however, it has been suggested
that they may arise from a shared genetic predisposition or persistent antigen stimulation,
which in turn triggers the formation of plasma cell dyscrasias [25]. Focusing on the risk of
progression from MGUS to MM, there has been proven to be a lower risk of developing
MM, particularly in patients without detectible autoantibodies in blood [93].
A population-based study revealed a 17% lower risk of progression, also indicating
that while MGUS is more prevalent in patients with ADs, it tends to have a less severe
evolution [94].
Other analyses confirmed similar deductions; thus, it has been hypothesized that
MGUS in patients also affected by ADs has a different biological base. Even patients
affected by smoldering multiple myeloma (SMM) and concomitant ADs appear to have
better prognostic features. However, the risk remains: a higher prevalence of MGUS in this
population leads to a higher probability to develop MM, even if with a slower course [92].
Potential underlying causes of the lower risk of progression may be that MGUS in
a setting with chronic low-level antigen stimulation is biologically less likely to undergo
the genetic events that trigger progression. Additionally, the use of immunosuppressive
therapies for the autoimmune conditions may delay or prevent progression [95].
Nevertheless, when considering prognosis and survival, individuals with MM and a
prior history of autoimmune diseases exhibited an elevated mortality rate. Possible expla-
nations encompass the existence of common genetic factors, the likelihood that individuals
with a history of autoimmunity encounter more severe cases of MM or a combination of
comorbidity in each patient [96,97].

5. Psoriasis, Multiple Myeloma and Impaired Immune Tolerance

Psoriasis (Ps), a papulosquamous skin disease, was originally thought to be a disorder
primarily of epidermal keratinocytes but is now recognized as one of the most common
immune-mediated disorders. An immune dysregulation seems to be the cause of both
Ps and MM, resulting in an impaired balance of effector and regulatory cells, such as B
regulatory lymphocytes (Bregs) [98–100].
Specific attention was placed on the progenitor population of the regulatory cells,
CD19+CD24hiCD38hi Bregs lymphocytes, which is also implicated in the production of
cytokines with regulatory activity on the immune system, such as IL-10, and therefore
responsible for the autoimmune process, which is advantageous in the case of Ps but also
of tumorigenesis, which appears to be facilitated by such immunosuppressive mecha-
nisms [101].
Diagnostics 2024, 14, 1135 11 of 20

Regulatory B Cells
ADs are caused by a breakdown of immunological “tolerance” and a failure to distin-
guish self from non-self. Under these pathogenic conditions, T cells cause damage to tissues
through cytolysis of target cells by enlisting the help of inflammatory cells and producing
various cytokines. Additionally, autoantibodies (autoAbs) can form immune complexes,
induce phagocytosis or cytolysis of target cells and interfere with cellular function. T cells
and B cells are under the influence of both central and peripheral immunological tolerance.
Nonetheless, a portion of autoreactive T and B cells go to the periphery, where they stay
inactive until an external stimulus breaks tolerance and activates innate and adaptive
immune cells in a genetically susceptible individual. Even some Tregs may be induced to
generate pro-inflammatory cytokines as a result of inflammation [16,102].
Regulatory B cells (Bregs) are essential to the pathophysiology of neoplasms and
autoimmune disorders. They are responsible for producing immunological tolerance by
generating inhibitory molecules such as programmed cell death ligand 1 (PDL1) and
suppressive cytokines such as interleukin-10 (IL-10) and interleukin-35 (IL-35). Bregs’ IL-10
production level does, in fact, reflect their regulating role [103,104].
They cause effector T lymphocytes to die by binding to CD40 on the surface of Bregs
and to its ligand CD40L on T cells, which reduces the response to the autoantigen.
Autoimmune and autoinflammatory diseases may be exacerbated by an imbalance in
these immune effector actions. However, the overexpression of regulatory cells might play
in favor of the onset of tumors [105,106].
The microenvironment is crucial in the development of MM; inflammation promotes
angiogenesis and the growth and survival of cancerous cells. Other immune cell abnormali-
ties have also been noted. The development of the illness may be linked to myeloid-derived
suppressor cells, which create a repressive environment in the bone marrow [107]. At this
stage, MM develops into relapsed/refractory MM (RRMM) and immunotherapy becomes
ineffective [108–110].
Even though B cells minimize T effector cell responses during chronic inflammation,
which may be advantageous in psoriasis (Ps), malignant cells thrive in this environment.
The mechanism appears to be self-sustaining: the pathogenic plasma cells enhance the
survival of Bregs by reducing their programmed cell death, and the resulting IL-10 facilitates
immunosuppression [111]. The percentage of regulatory B lymphocytes appears to be lower
in Ps-affected patients, but CD19+CD24hiCD38hi Bregs, ancestors of Bregs, are higher in
percentage. Following Ps immunosuppressive therapy, this equilibrium appears to shift in
favor of a higher concentration of B regulatory cells [60,112].
In MM, the production of IL-10 in CD19+CD24hiCD38hi Bregs appears to be correlated
to the severity of the disease, and it was in fact found to be elevated in patients with ISS
stage III.
Indeed, IL-10 has an immunosuppressive role in MM, which aids in the disease’s
development. It may also promote B cells’ differentiation into pathogenic plasma cells,
which is associated with a worse prognosis [113].
In one study, the percentages of CD19+CD24hiCD38hi Bregs were considerably lower
after daratumumab therapy. Remarkably, the proportions of CD19+CD24hiCD38hi Bregs
dropped very quickly following the first treatment cycle. Nonetheless, there was no
discernible difference in RRMM patients’ plasma levels of IL-10 before and after daratu-
mumab therapy, suggesting other potential sources of IL-10. However, the study’s findings
showed that daratumumab therapy for RRMM resulted in an instantaneous reduction in
CD19+CD24hiCD38hi Bregs [101,114].

6. Role of Multiple Myeloma Therapy in Autoimmune Diseases

In the therapeutic scenario of MM, there are different approaches built on the biologi-
cal characteristics of the disease and patient characteristics such as comorbidity, age and
performance status. To date, daratumumab, bortezomib, dexamethasone and immunomod-
Diagnostics 2024, 14, 1135 12 of 20

ulators such as thalidomide and lenalidomide used in combination are the first line of
treatment for newly diagnosed transplant-eligible patients [115].
Regarding the treatment of ADs, a challenge arises: the pathological target is repre-
sented by a peculiar type of plasma cells, found in MM and also in ADs. They are in fact
long-lived plasma cells, resident in specialized niches of the marrow and therefore not
easily attacked by the therapeutic means available to us. This has generated interest in the
search for molecules capable of acting against this type of plasma cell, and numerous ideas
come from the therapy against multiple myeloma [116,117].

6.1. Daratumumab
Daratumumab is a human immunoglobulin G kappa monoclonal antibody targeting
CD38. Daratumumab-based regimens improved the depth of response, including MDR
negativity, in newly diagnosed cases of multiple myeloma as well as in relapsed/refractory
MM [118–121]. The production of autoantibodies is carried out by a specific type of
plasma cell: long-lived, non-dividing plasma cells. They provide a therapeutic challenge
since they are found in specific niches inside the bone marrow and are shown to resist
immunosuppressive treatments.
A recent study on patients with SLE found that daratumumab successfully decreased
the number of plasma cells in patients’ peripheral blood and also suppressed the activity of
CD38 on the remaining plasma cells [122].
A subgroup of lupus patients were recently found to have an expanded CD38highCD8+
T cell type with decreased cytotoxic capacity in association with an increased propensity
to infections, despite the fact that the circulating plasmablasts in those patients had CD38
expression levels comparable to those of healthy individuals [107]. It was discovered that
the usage of daratumumab was linked to excellent clinical and serologic responses in
two patients with refractory lupus and in patients affected by SS [123].
Given that anti-CD38 therapy with daratumumab is effective in MM and that long-
lived plasma cells exhibit elevated levels of CD38, there is a possibility that this treatment
will lead to the therapeutically meaningful elimination of pathogenic long-lived plasma
cells. Indeed, a considerable (about 60%) decrease in pathogenic anti-dsDNA antibodies
was related to daratumumab. Improvements in many clinical characteristics, including
pericarditis, autoimmune hemolytic anemia, lupus nephritis and mucocutaneous symptoms
in SLE patients, were attributed to the use of daratumumab [124].
It has been suggested that daratumumab may have additional effects such as blocking
T cells co-expressing CD38 which are responsible for lupus nephritis and depleting plasma-
cytoid dendritic cells, also expressing elevated levels of CD38, hence reducing interferon
type I activity. The majority of patients with SLE display an increased expression of type I
interferon (IFN)-regulated genes, lacking proper negative feedback mechanisms and thus
becoming one of the driving forces behind the disease [125].
Daratumumab also reduces CD19 B cells by 50%, depleting the autoreactive B cell
components, and it plays a role in the transcriptional profile of CD4 and CD8 cells, down-
regulating the gene transcripts linked to the repeated antigenic stimulation [126].

6.2. Bortezomib
Degradation of redundant and misfolded proteins, along with a range of regulatory
proteins, is made possible by the 26S proteasome, a proteolytic complex found in the cytosol
and nucleus of eukaryotic cells. The 26S proteasome complex is thought to be responsible
for the processing of more than 80% of all cellular proteins, including nuclear factor kappa
B (NF B) and inhibitor protein kappa B (I B), both of which are crucial for the onset
of cancer and inflammation. There have been numerous autoimmune and inflammatory
illnesses linked to the proteasomal system. Serum samples from patients with SLE, myositis,
rheumatoid arthritis and Sjögren’s syndrome showed a correlation between the levels of
circulating proteasomes and the severity of their conditions [127].
Diagnostics 2024, 14, 1135 13 of 20

The approved medication for MM, bortezomib, selectively and reversibly inhibits the
26S proteasome. Its ability to reduce inflammation is linked to its suppression of NFB. In a
human skin graft, bortezomib decreased the psoriatic lesions’ size, thickness, keratinocyte
proliferation and leukocyte infiltration. These findings offered convincing evidence for
investigating bortezomib’s potential application in the management of psoriasis [128].
In MM, apoptosis occurs when the neoplastic plasma cells’ proteasome catalytic
sites are inhibited. By affecting dendritic cells and T and B cells and blocking the NF-kB
pathway, proteasome inhibition suppresses the immune system by lowering the generation
of pro-inflammatory cytokines. Short-lived and long-lived plasma cells (SLPCs, LLPCs) are
impacted by BTZ, which also lowers autoAbs, essential for the development of autoimmune
disorders [16,129,130].

6.3. Lenalidomide
An Italian retrospective study reported an elevated occurrence of autoimmune diseases
subsequent to lenalidomide therapy. Autoimmune cytopenias were the most common
manifestation of ADs. Additionally, cases of polymyositis, Graves’ illness, optic neuritis
and vasculitis were noted, and thyroid problems have been reported to occur in up to 6%
of patients receiving lenalidomide therapy in the past [131].
The evolution toward an autoimmune dysfunction might suggest the existence of an
underlying immunological imbalance that lenalidomide, with its powerful immunostimu-
latory qualities, can turn on in favor of its autoreactive component to an overt AD [132,133].

6.4. Effect of Transplantation for Multiple Myeloma on Autoimmune Disease

It has been demonstrated that when high-dose chemotherapy is paired with autolo-
gous stem cell transplantation (HSCT) rather than just conventional chemotherapy alone,
patients with myeloma have improved overall survival, event-free survival and even qual-
ity of life [115]. There are numerous cases of long-term remission of concurrent autoimmune
diseases following autologous or allogeneic stem cell transplantation in individuals with
hematological malignancies [134]. Due to these findings, there is growing interest in the
combination of autologous stem cells and high-dose chemotherapy for the treatment of
different forms of autoimmune diseases. To improve their management, a rigorous prepar-
ative immunoablative regimen is thought to be able to eliminate the patient’s immune cells,
including autoreactive lymphocyte clones. Nonetheless, there have also been reports of
autoimmune disorder recurrence following autologous stem cell transplantation in some
hematologic malignancy coexisting with an autoimmune disease.
Coexisting cases of RA have frequently temporarily improved with autologous SCT
for hematological malignancy; however, the RA typically relapses shortly after transplanta-
tion. The reason why patients with myeloma have a greater rate of post-transplantation
autoimmune condition recurrence is still unknown [135].
Shaikh H. et al. monitored a patient with concurrent ankylosing spondylitis (AS)
and MM who had a long-lasting remission after HSCT. One explanation could be that the
patient’s melphalan conditioning altered the autoimmune T cell clone, which led to the
rheumatological process’s remission. Given the potential that AS in these cases may be
a paraneoplastic condition, it is possible that the MM treatment caused the concomitant
remission of the autoimmune disease [136].

7. Conclusions and Future Prospectives

MM and ADs share complex and heterogeneous pathogenetic bases. We attempted
to bring to light the possible mechanisms that explain their connection, concluding that
a correlation between the two pathologies is possible: it is expressed in the context of
the inflammatory medullary microenvironment, the production of long-lived PCs capa-
ble of producing autoantibodies and becoming immortal and the set of cytokines and
proliferation/anti-apoptotic factors that control their survival [9,11,44,137,138]
Diagnostics 2024, 14, 1135 14 of 20

The possibility of treatments aimed at controlling both pathologies remains to be

discussed. The potential of bone marrow transplantation in eradicating them is weighted
by collateral factors that are not always predictable such as the selection of clones of
autoreactive lymphocyte due to the delayed recovery of CD4+ cells [134,135].
Current therapies available for MM such as daratumumab and bortezomib have
proven useful in controlling ADs by acting against long-lived PCs located in specialized
niches of the bone marrow that are often difficult to reach for common AD treatments,
leaving hope for a common therapeutic approach and further strengthening the hypothesis
that the two pathologies have a close connection, with pathogenetic bases capable of
influencing each other [44,95].
The newest frontier in the treatment of MM is represented by bispecific antibodies
(bsAbs). They are proteins against two targets: the tumor cell and an effector cell, typically
a T cell. The bsAb activates the T cell, which forms a cytolytic synapse with the tumor cells,
causing the release of cytotoxic molecules responsible for tumor apoptosis [115].
Studies have demonstrated the possibility of using bsAbs also in the context of au-
toimmune diseases [139,140]. Currently, two bsAbs, blinatumomab (CD19 × CD3) and
emicizumab (Factor IX/Factor X), have been authorized in the treatment of oncological
and hematological malignancies [141]. BsAbs for autoimmune diseases are still in the early
phases of research, even though significant developments have been made in the treatment
of rheumatoid arthritis, SLE, asthma, Ps and other autoimmune diseases. All these results
provide a further contribution to the knowledge of these pathologies and could constitute
a substrate for the development of new treatment strategies [141].

Author Contributions: Conceptualization, A.A. and S.G.; methodology, L.G. and P.B.; formal analysis,
L.G., P.B., V.V., M.E.N. and M.E.A.; data curation, L.G., P.B., V.V., M.E.N. and M.E.A.; writing—original
draft preparation, L.G. and P.B.; writing—review and editing, L.G., P.B. and A.A.; supervision, A.A.,
S.G., R.C. and E.C. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflicts of interest.

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