Introduction
Multiple myeloma (MM) is an incurable malignant tumor of plasma cells [ 1 ], and typically starts as asymptomatic precursor conditions-either monoclonal gammopathy of undetermined significance or smouldering multiple myeloma-in which initiating genetic abnormalities [ 2 ]; Its pathogenesis has not yet been fully elucidated and it is most common in patients over 60 years of age. Due to significant advances in MM treatment, the overall survival of MM patients has increased over time. Immunosenescence refers to the overall dysfunction of the innate and adaptive immune system with aging, which impairs innate and adaptive immune responses and leads to tumorigenesis and cancer progression. Recent studies have shown that abnormalities in the immune system are closely related to the phenomenon of drug resistance in MM therapy and that immune senescence plays an important role in this process. Therefore, an in-depth understanding of the mechanisms of immune senescence in MM treatment resistance and the search for new therapeutic targets are important for developing new therapeutic strategies.
Manifestations and mechanisms of immunosenescence
Concepts and mechanisms of immune senescence
Aging is a natural process of growth and development in the human body, and the common features can be summarized as follows: genomic instability, telomere depletion, epigenetic alterations, loss of proteostasis, nutrient perception disorders, mitochondrial dysfunction, stem cell depletion, altered intercellular communication, and cellular senescence. When aging involves the immune system, it is called immunosenescence. Immune senescence is an extremely sophisticated and complex physiopathologic process whose function is influenced by intrinsic and extrinsic drivers. Intrinsic drivers mainly include inflammation and aging, while extrinsic drivers include antimyeloma therapy and microenvironmental changes due to various causes. Innate immune senescence is characterized by decreased antigen processing and presentation capacity and thus reduced response to stimuli. Adaptive immune senescence is characterized by loss of TCR diversity and impaired immune memory formation. One of the hallmarks of immune senescence is inflammation, and senescent immune cells exhibit a distinct senescence-associated secretory phenotype (SASP), secreting large amounts of soluble factors, including interleukin-1 (IL-1), IL-6, IL-8, IL-13, IL-18, and tumor necrosis factor (TNF) and its receptor, leading to an inflammatory phenotype. Senescent cells are characterized by cell cycle arrest, increased metabolic activity, upregulation of anti-apoptotic pathways, and senescence-associated secretory phenotypes (SASPs), which accumulate in several tissues during the aging process [ 3 ]. SASPs include the production of several pro-inflammatory cytokines and chemokines, which contribute to inflammation and the development of age-related diseases [ 4 ] SASP factors, Increased myeloid-derived suppressor cells (MDSCs), and T-cell senescence allow for abnormalities in the functioning of the innate and adaptive immune system, leading to immunosuppression, tumor proliferation, and decreased efficacy of immunotherapy.
Immune senescence in MM
Inflammation
One of the hallmarks of immune senescence is "inflammation", a systemic state of chronic low-grade inflammation characterized by the upregulation of blood inflammatory markers, which is considered to be a central pillar of aging [ 5 ]. Senescent cells in MM patients exhibit a unique aging-related secretion phenotype (SASP), secreting a large number of soluble factors, including interleukin-1 (IL-1), IL-6, IL-8, IL-13, IL-18, and tumor necrosis factor (TNF) and its receptors, leading to an inflammatory phenotype [ 6 – 9 ]. Not only that, age-related accumulation of senescent cells (including Mesenchymal Stem Cells (MSCs), bone macrophages, and long-lived osteoblasts) in the bone marrow may promote a pro-inflammatory microenvironment through SASP, favoring the differentiation of hematopoietic stem cells to myeloid progenitors [ 10 ] at the expense of lymphoid progenitors (adaptive immune B-cells, T-cells, and natural killer (NK) cells) [ 11 , 12 ]. CD8 + cytotoxic subsets show a significant decline in older adults, and differentiated T cells acquire certain characteristics with age, such as increased DNA damage, shortening of telomeres, and increased production of inflammatory cytokines [ 13 ]. DNA damage and the production of inflammatory cytokines not only induce cell senescence but also further accelerate the aging of immune function in MM patients.
Abnormalities in immune-related cell functions
Dysregulation of immune cells (e.g., NK cells, T cells, and dendritic cells (DCs)), as well as changes in the number of immunosuppressive cells (e.g., regulatory T cells and MDSCs), have been observed in patients with MM and may play a key role in disease progression.
NK cells are a central component of innate immunity, and studies have shown that NK cells are a central player in the immune surveillance of senescent cells, and their age-related accumulation is itself a possible factor in the development of chronic sterile low-grade inflammation with aging (inflammation formation) [ 14 ]. Thus, NK cell dysfunction is associated with an increased burden of infections, malignancies, inflammatory diseases, and senescent cells with age.
T cells are key to the body's immune function and can hit their targets with precision; the total number of T cells remains relatively stable in the elderly, but their immunophenotypic composition changes, most importantly in the form of shrinkage of the naïve T-cell pool and late differentiation and expansion of Tregs [ 15 ]. In addition, various T cell subpopulations show markedly heterogeneous changes with aging, characterized by the loss of naïve T cells and the increase of highly differentiated CD28 memory T cells or senescent cells. A study evaluating the expression of the suppressor molecules PD-1, CTLA-4, 2B4, CD160, the senescence markers CD57, and CD28 on T cells from myeloma patients in the bone marrow and peripheral blood found that T cell depletion and senescence were enhanced at the MM cell site and that the T cells in the bone marrow were more severely compromised than the peripheral T cells [ 16 ].
DCs, the classical antigen-presenting cells that link innate and adaptive immunity, are also affected by senescence [ 15 ]. Modern studies have shown that the antigen-presenting capacity of DCs in MM patients is impaired. In a study, single-cell transcriptome analysis of DCs and monocytes from 10 MM patients and 3 healthy volunteers showed that conventional DC2 (cDC2) and mono DC from MM patients exhibited impaired antigen processing and presentation, and reduced regulator activity of interferon regulatory factor 1 (IRF1), compared with healthy controls. This DC dysfunction may be due to abnormal cytokines released in the bone marrow of multiple myeloma, including IL-6, IL-10, and TGF-β [ 17 ]. Studies have shown that elevated pro-inflammatory serum IL6, RANKL, and BALP are typical of bony MM [ 18 ]. In addition, lower CTLA-4 levels in patients with newly diagnosed multiple myeloma (NDMM) or higher PD-1 expression in patients with recurrent and refractory multiple myeloma (RRMM) may predict early relapse [ 19 ].
B-cell dysfunction in MM patients leads to immune paralysis, hypogammaglobulinemia, and increased susceptibility to infections [ 13 ]. B-cells are critical for adaptive immunity through their antigen-presenting and antibody-producing capacities. It is widely recognized that during aging, B cells produce fewer antibodies with lower affinity, thereby impairing the ability of older adults to respond to new infections and vaccinations [ 20 ]. In addition to this, the production of B cells decreases gradually with age. Plasma cells derived from B cells are the sole producers of long-lasting protective antibodies and generate immune memory after infection or vaccination. Immune senescence leads to remodeling of the B-cell compartment. Reduced B-cell output, coupled with reduced expression of autoimmune modulators and autoantigen genes in thymic B cells, greatly impedes immune function in patients with MM.
MDSCs can impair T-cell function by affecting L-arginine metabolism leading to a deficiency of non-essential amino acids in bone marrow cells (BMCs). MDSC down-regulates CD62L levels on naïve T-cells through the membrane expression of ADAM17, decreasing the ability of T-cells to migrate to and be activated at the tumor site [ 21 , 22 ]. In addition to this, MDSC inhibits NK cell activity and crosstalks with tumor-associated macrophages (TAM), leading to the enrichment of immunomodulatory factors such as IL-10 and IL-6 in the microenvironment, which induces cancer cell proliferation and the development of drug resistance [ 15 ].
Overall, MM patients are often accompanied by changes in the number and function of immune cells. Among them, the number and function of T cells are suppressed, and the increase of immunosuppressive cells such as regulatory T cells (Treg) and MDSCs may lead to the development of a state of immune tolerance, where T cells in MM patients lose their ability to naturally control tumor progression. In addition, the function of NK cells and DCs is also impaired, and these changes may lead to a loss of immunosurveillance function, which promotes the development of immunoresistance and escape from MM disease.
Immunosuppression and immune dysfunction
Immunosuppressive cells aggregate in the bone marrow microenvironment of MM patients, and changes in the composition of the bone marrow microenvironment occur early in the progression of MM. Several changes in immune cells have been observed as early as the Monoclonal gammopathy of undetermined significance (MGUS) stage, with increased numbers of NK cells, T cells, and non-classical monocytes [ 15 ]. The interactions between the MM cells and the bone marrow (BM) microenvironment, in particular BM mesenchymal stem cells (BM-MSCs), play a critical role in the treatment of MM patients. A recent study showed that MM-BMSCs inhibit T cell proliferation and drive Th17 differentiation through the FAPα/TGF-β axis, leading to the development of myeloma and that FAPα-induced T cell senescence is mediated by the PI3K signaling pathway [ 23 ]. RRMM cells, through the up-regulation of inflammatory cytokines and close interactions with myeloid cells, form an immunosuppressive bone marrow microenvironment (BME) that is characterized by the formation of PD1 + γδ T cells, the aggregation of tumor-associated macrophages and depletion of hematopoietic progenitor cells [ 24 ].
Aging leads to immune dysfunction in the body, which further leads to immune dysfunction. Immune dysfunction is part of the pathogenesis of MM: abnormal Th1/Th2 ratios, increased T-cell senescence and depletion, and reduced levels of NK cells are seen in untreated MM patients [ 21 ]. In recent years, it has been shown that T cells in MM patients display features of immune senescence and depletion involved in suppressing the immune response. There is a loss of checkpoint expression of MM CD4 T cells (both effector (Teffs) and Tregs); relative defects in the secretory effector function of CD4 T cells are more pronounced in the context of myeloma relapse (e.g., Th1/Treg and Th17/Treg cell rates are decreased) [ 25 ]. The senescent CD4 + , CD28 T cell population found in MM is greatly increased, primarily in newly diagnosed MM subjects. These observations suggest that there are two dysfunctional states in MM CD4 T cells, with immune senescence predominating at disease diagnosis and immune exhaustion at relapse, thus implying different responsiveness to external receptor blockade depending on the disease stage.
Current status of MM treatment resistance
Drug resistance manifestation in MM patients
In recent years, therapies for MM mainly include Immunomodulatory Drugs (IMiDs), Protease inhibitors (PIs), Monoclonal Antibodies (mAbs), and Antibody–drug conjugate (ADC) for B-cell maturation antigen (BCMA)-directed therapy, bispecific antibodies, CAR-T cell therapy, and autologous stem cell transplantation (ASCT). Although much progress has been made in the treatment of MM, MM patients successively relapse or become refractory after one or more treatment regimens, mainly due to drug resistance. Therefore, drug resistance and relapse in MM is still a major challenge for researchers. The manifestations of immune resistance in MM patients mainly include decreased target expression and even target loss, increased complement proteins, decreased BCMA expression, and increased soluble B-cell maturation antigen (sBCMA) levels. Drug resistance in MM is mainly caused by the following reasons: mutation of the β5 subunit of the proteasome; upregulation of the efflux pump; induction of heat shock protein by proteasome inhibitors; downregulation of Cereblon protein (CRBN) expression; induction of heat shock protein by proteasome inhibitors; downregulation of CRBN expression; dysregulation of interferon regulatory factor 4 (IRF4) expression; mutations in the immunomodulatory drugs CRBN, Ikaros (IKZF1), and Aiolos (IKZF3), with decreased target expression; increase in complement proteins; increase in sBCMA; and decrease in monoclonal antibody BCMA expression [ 26 ]. Table 1 summarizes the mechanisms of action and resistance of drugs commonly used in multiple myeloma (Table 1 ).
Table 1
Mechanisms of action and resistance of drugs commonly used in multiple myeloma
| Drug type | Representative drug | Mode of action | Resistance mechanism |
| PIs | Bortezomib, carfilzomib and Isazzomib | The proteasome disrupts the natural degradation of intracellular proteins and induces the direct apoptosis of tumor plasma cells It exerts its biological activity by inhibiting cytokine secretion, inhibiting several adhesion molecules, and preventing angiogenesis [ 70 ] | MM cell gene variation: gene TP53 mutation; Up-regulation of proteasome system; MYC gene overexpression; [ 71 – 74 ] Drug transport and metabolic changes: up-regulation of P-gp [ 75 , 76 ] Apoptosis pathway changes: increased levels of multidrug transporter (ABCG2/BCRP) and enzyme activity ALDH1A1 stem cell-like phenotype; Activation of Hedgehog, Wnt, and Notch pathways; The BTK receptor and RARA are upregulated [ 77 – 79 ] |
| IMiDs | Thalidomide, lenalidomide and pomadomide | 1. Acts through brain-dependent degradation of IKZF1 and IKZF3, leading to direct myeloma cell apoptosis [ 80 , 81 ] 2. Favorable off-target effects are produced by stimulating the activity of T and NK cells. Enhances the production of Th1 cytokines (IL-2 and Interferon (IFN)-γ) and reduces the secretion of IL-10 by CD4 + and CD8 + T cells, leading to NK cell activation, expansion, and ADCC(antibody-dependent cellular cytotoxicity) [ 82 , 83 ]. 3. Inhibition of Treg amplification [ 84 ]. | 1. CRBN abnormalities CRBN genetic aberrations, CRBN protein loss, and CRBN-matrix binding defects [ 14 , 28 ] 2. The up-regulated IL-6/STATS signal drives IKZF1 independent IRF4 transcription; IKZF1/IKZF3 independent MYC transcription driven by upregulated Wnt/β-catenin signaling; The absence of IKZF1 and IKZF3 [ 28 , 29 ], CDK6 overexpression regulates protein targets associated with IMiD resistance [ 30 ]. 3. Changes in the bone marrow microenvironment include an increase in cell adhesion molecules such as CD44, an increase in T cell depletion and checkpoint inhibitors, and a decrease in IL-2 expression leading to a decrease in anti-tumor activity leading to the formation of an immunosuppressive microenvironment [ 31 ] |
| mAbs | CD38(daratumumab、isatuximab) and SLAM7(elotuzumab) | Establishing a link between tumor cells and immune effector cells leads to myeloma cell death through ADCC, Antibody-Dependent Cellular Phagocytosis (ADCP), and Complement-Dependent Cytotoxicity (CDC). mAb activates proteolytic enzymes that eventually rupture the tumor cell membrane [ 85 ] | 1. CD38 and SLAM7 expression decreased [ 32 ] 2. Increased expression of CD46, CD56, and CD59 blocked antibody-induced CDC [ 32 , 33 ] 3. Inflammation-mediated abnormal cytokine secretion, abnormal activation of signaling pathways, depletion of T cells, and increased checkpoint inhibitors |
| Therapy for BCMA targeted treatment | Antibody–drug conjugate ADC, biospecific antibody BsAb, CAR T cell therapy | 1. When it reaches a programmed target on the surface of myeloma, the chemotherapy drug is released, causing cell death [ 86 ]. Myeloma cells are killed by ADCC or ADCP [ 87 , 88 ] 2. Binding to two different epitopes on both T cells and tumor cells at the same time leads to T cell activation and simultaneous myeloma cell lysis [ 89 ] 3. The extracellular domain of BCMA scFv on CAR T cells binds to BCMA on the surface of MM cells, leading to the activation of CAR T cells, the release of cytotoxic cytokines, and the death of MM cells | Loss of BCMA, antigen downregulation, or antigen loss [ 34 , 90 , 91 ] Immune cells cannibalized, T cells exhausted, and the anti-tumor effect of CART cells decreased [ 35 , 36 ] |
PIs
Acquired resistance to proteasome inhibitor therapy is a major obstacle in the treatment of multiple myeloma. Proteasome inhibitors are commonly used as first-line therapy for MM. MM cells secrete large amounts of monoclonal immunoglobulins, which are highly dependent on the ubiquitin–proteasome system, to degrade intracellular misfolded proteins and maintain intracellular protein homeostasis. Previous studies have shown that proteasome inhibition enhances the anticancer efficacy of other chemotherapeutic agents by (i) decreasing the expression of anti-apoptotic proteins such as TNF-α and NF-kB, (ii) increasing the levels of the pro-apoptotic protein Noxa, (iii) activating caspase enzymes and inducing cell apoptosis, (iv) degrading pro-survival proteins, induced myeloid leukemia cell differentiation protein (MCL1) and (v) inhibition of drug efflux transporter proteins [ 27 ]. The main mechanisms of resistance are the following: genetic variation in MM cells; altered drug transport and metabolism; and altered apoptotic pathways.
IMiDs
IMiDs mainly include thalidomide, lenalidomide, and pomalidomide, which can act on MM cells and the bone marrow microenvironment, and play the dual roles of regulating the function of the immune system and anti-MM. IMiDs bring unprecedented hope to MM patients but not all patients can achieve good therapeutic effects. Research statistics show that about 20–30% of patients are not sensitive to IMiDs, which leads to treatment failure and disease recurrence. The resistance mechanisms are mainly as follows: 1. CRBN abnormality. Studies have shown that some patients with ineffective treatment with IMiDs have one or more CRBN genetic aberrations, CRBN protein loss, and CRBN substrate binding defects; disruption of CRBN activity leads to changes in the level and stability of the E3 ligase component, and changes in the strength of IMiD-induced ligase-substrate interactions, resulting in the development of immune-modulators resistance in patients [ 14 , 28 ]. In addition, there are a number of CRBN-independent mechanisms that also lead to treatment resistance in patients: up-regulated IL-6/STATS signaling driving IKZF1-independent IRF4 transcription, up-regulated Wnt/β-catenin signaling-driven IKZF1/IKZF3-independent MYC transcription, and deletion of IKZF1 versus IKZF3 [ 28 , 29 ], CDK6 overexpression regulates protein targets associated with IMiD resistance [ 30 ]. Alterations in the bone marrow microenvironment of MM patients include an increase in cell adhesion molecules such as CD44, T-cell depletion with an increase in checkpoint inhibitors, and a decrease in anti-tumor activity due to decreased IL-2 expression leading to the formation of an immune-suppressive microenvironment [ 31 ] thereby restricting the normal immune-suppressive action of IMiD drugs, which results in MM patients treatment is ineffective or relapse occurs.
mAbs
Aging of the BM microenvironment in MM patients leads to an imbalanced immune status in the bone marrow, inhibiting antibody- and complement-dependent cytotoxicity, and an abnormally high level of inflammatory factors affects the immunoregulatory function of Treg cells, which in turn affects the stimulation of T and NK cell activity, leading to a reduction in target expression [ 32 ]. These lead to abnormalities in the mAb pathway of action, ultimately leading to immune escape in MM patients. In addition, abnormal inflammation-mediated cytokine secretion, aberrant activation of signaling pathways, and depletion of T cells with an increase in checkpoint inhibitors in the bone marrow microenvironment of MM patients inhibit immunomodulators from normally driving T cell clonal expansion and NK cell activation [ 33 ], resulting in their inability to promote immune recognition and thus to kill MM cells.
Therapies directed against BCMA
Targeted therapies against B-cell maturation antigens (ADC, bispecific antibody (BsAb), Chimeric antigen receptor T (CAR-T) cell therapy) have shown favorable therapeutic efficacy in MM patients’ treatment. However, due to the depletion of BCMA in MM patients [ 34 ] the binding of anti-BCMA antibodies to tumor cells was continuously reduced and the functional BCMA on the surface of MM cells was significantly reduced. Moreover, the reduction of CD19 on MM cells by cell proliferation leads to internecine immune cells, T cell depletion, and decreased anti-tumor effect of CART cells [ 35 , 36 ], which has led to the emergence of drug resistance in MM patients. A meta-analysis collected individual data on response duration from studies with at least 12 months of follow-up and found a pooled prevalence of relapse within the first 12 months after CAR-T infusion of 61% (95% CI 43–78%); furthermore, one year after infusion, the analysis highlighted a relapse rate of 24% (95% CI 11–42%) [ 37 ].
Thus, although the emergence of immunotherapy has been a great boon to MM patients, patients who have undergone one or more therapies often develop drug resistance leading to disease recurrence, and the incidence of MM is closely related to aging and the state of the body's immune function. Therefore, there is an urgent need to overcome immunotherapy resistance and explore the causes of suppression and amelioration of immune senescence. Immune senescence, as a factor closely related to the pathogenesis of MM, is a promising direction for future research and is of great significance for changing the treatment resistance of MM patients.
Immune senescence and MM treatment resistance
The process of immune senescence leads to a decrease in the number and quality of immune cells, which affects the ability of the immune system to recognize and attack cancer cells. Immunotherapy is an important tool in the treatment of MM, which utilizes the body's own immune system to attack cancer cells. However, immune senescence may reduce the efficacy of immunotherapy and lead to increased patient resistance to treatment.
With age, the aging of hematopoietic stem cells leads to myeloid skew. Both adaptive and innate immune cells are derived from hematopoietic stem cell (HSC) progenitors in the bone marrow, which have been shown to undergo age-related changes and have limited replicative potency [ 38 ]. Harrison et al. demonstrated that bone marrow cells from aged mice transplanted into recipients showed a loss of stem cell repertoire capacity, suggesting that aging promotes HSC depletion or replicative senescence [ 39 ]. The transition from bone marrow hematopoiesis to myeloid hematopoiesis (as evidenced by an elevated myeloid-lymphoid ratio, a hallmark of immune system aging). Cellular senescence is associated with decreased function of HSCs and increased risk of hematological malignancies. Perturbation of HSCs also underlies myeloid-biased hematopoiesis as well as the increased incidence of myeloid malignancies with age [ 40 ].
Subjects over the age of 60 are more than twice as likely to develop progressive and invasive cancers compared to younger adults, making cancer both a disease of aging and the leading cause of death in men and women between the ages of 60 and 79 years [ 41 – 43 ]. The accumulation of DNA damage and epigenetic dysregulation facilitates cellular senescence and tumorigenesis, and in older patients, the persistence of chronic low-grade inflammation has been noted as a link between aging and cancer development [ 44 ]. Prolonged cellular exposure to plasma pro-inflammatory cytokines (e.g., IL-1β, IL-6, and TNFα) has been associated with a high risk of cancer development and progression, as these cytokines support tumor growth and metastatic spread [ 45 , 46 ]. Furthermore, the SASP phenotype of senescent cells has been identified as an important promoter of tumorigenesis during aging [ 47 ].
Intrinsic drivers of MM resistance include inflammation occurring in normal senescence and underlying senescence driven by the malignant clone itself, and extrinsic drivers include antimyeloma therapy. The result is an increase in SASP factors, MDSCs, and T-cell senescence, leading to immunosuppression, tumor proliferation, and decreased efficacy of immunotherapies [ 15 ]. The circuit between cellular senescence and inflammation promotes immune senescence and tumorigenesis. The gradual accumulation of senescent cells in the body is followed by an increase in SASP and a heightened inflammatory state, which activates immunosuppression. There appears to be a positive feedback regulatory loop between inflammation and cellular senescence, which impairs immunosurveillance and autophagy in senescent cells, thus permitting premature immunosenescence [ 48 ]. Thus, immune senescence may be a prerequisite for the increased incidence of autoimmune diseases.
In this context, the immune system has a dual role as it not only provides anti-tumor activity but is also closely linked to disease onset and progression [ 49 ]. In young and healthy tissues, effector cells (e.g., T cells, neutrophils, macrophages, and DCs) work together to prevent malignant tissue growth and remove damaged cells. In contrast, the progressive decline in overall immune function characteristic of immunosenescence is a direct contributor to SASP, inflammation, and tumor development [ 50 , 51 ]. This physiopathological network influences adaptive and innate immune function, increasing the recruitment of immune cells and their orientation towards immunosuppressive functions, thereby promoting greater susceptibility to cancer development [ 52 ].
Not only that, but MM also affects patients' immune function and accelerates immune senescence. One study observed enhanced T-cell depletion and senescence at the site of the tumor in MM patients. The percentage of senescent CD57 + CD28-CD8 + T cells was significantly lower in treated myeloma patients compared to untreated patients [ 16 ]. T cells from the bone marrow of myeloma patients are more severely damaged than peripheral T cells, and additional pathways are urgently needed to restore anti-myeloma T cell responses. Once MM cells enter the bone marrow, changes associated with immune senescence are observed in the immune tumor microenvironment (iTME), which are driven by malignant cells [ 15 ]. In vitro experiments revealed a senescence-like phenotype when pre-differentiated indirect MM exposure drove differentiated MSCs compared to normal donor MSCs, and the results suggest that MM cells can inhibit lipidogenic differentiation while stimulating the expression of SASP and other pro-myeloma molecules [ 52 ]. Recent results have shown that nearly two-thirds of CD8 + T cells from donors aged 60 years or older are senescent [ 53 ]. In addition, senescent CD8 + cells have significantly lower cytotoxicity compared to younger CD8 + cells, which may be due to a failure of immune surveillance leading to the accumulation of senescent cells in the elderly as well as an elevated risk of cancer, and thus an indirect involvement in inflammation. Figure 1 summarizes cellular senescence's developmental process and MM therapeutic resistance's emergence (Fig. 1 ).
Immunosenescence interventions in MM treatment
Three main anti-MM immunotherapeutic approaches have been developed: (i) drugs that remove breaks in the immune system, such as IMiDs and immune checkpoint inhibitors, (ii) drugs that target highly selective antigens on MM cells in the form of mAb, and (iii) drugs that stimulate immune cells to kill malignant cells selectively, such as CAR-T cells, bispecific T cell engagers (BiTE) [ 54 ].
Immunomodulators drive T-cell clonal expansion and NK-cell activation by triggering T-cell production of cytokines IFN γ, IL-2, and IL-10, and induce an increase in DC antigen presentation and activation of CD4 and CD8 T-cells, which promotes immune recognition and killing of MM cells. At the same time, immunomodulators work synergistically with immune checkpoint blocking to reduce the immune tolerance of MM cells.
Monoclonal antibodies intervene in the senescence and apoptosis of immune cells by regulating Treg cells as well as stimulating the activity of T cells and NK cells. BsAb is another brand new member in the field of MM immunotherapy with two binding structural domains that bind to tumor surface antigens (e.g., CD19, CD33, or BCMA) on one end, and receptors on the surface of T cells (e.g., CD3) on the other end, which recruit T cells are recruited to the vicinity of tumor cells, so that the T cells are not restricted by the major histocompatibility complex (MHC) but are directly activated, releasing perforin and granzyme to cause tumor cell lysis.
Immunotherapy is a new pillar of MM treatment, with therapies such as CAR-T and BsAb supporting the survival of long-lived cells and prompting immune cells to target MM cells for killing by targeted regulation of B-cell maturation and differentiation into plasma cells. T-cell senescence is a major obstacle to T-cell-based therapeutics, and a variety of strategies are being investigated for reversing T-cell senescence. Immunosuppression plays a key role in MM pathogenesis, so reversing this suppression may restore MM immune surveillance and improve disease control. A recent study [ 23 ] demonstrated that BSA/TPA-Erdn bovine serum albumin (BSA) nanoparticles mimic the maturation of human degenerate cells, activate functional T lymphocytes, and add additional polarization and differentiation signals, thereby reversing T-cell senescence restoring the immune microenvironment for MM treatment and providing promising immunotherapeutic performance. Figure 2 summarizes the mechanism of immunotherapy's action in treating multiple myeloma (Fig. 2 ).
It can be seen that immune cells play an extremely critical role in anti-MM therapy. Drugs stimulate and regulate various types of immune cells to intervene in the immune function of MM patients through a variety of pathways to ultimately achieve the role of recognizing and killing MM cells.
Rejuvenating the immune system has proven to be a promising avenue of research. One study improved thymic T-cell production by implanting young thymic epithelial cells into the thymus of middle-aged mice [ 55 ], demonstrating the importance of the tissue microenvironment, as well as the immune cells themselves, in maintaining immune function. Other strategies using induced thymic epithelial cell transplantation have shown that it is possible to generate a new intact and functional thymus in vivo [ 56 ], which can improve immune function in elderly patients.
Stimulating hematopoietic stem cell proliferation through depletion of senescent immune cells also seems promising, as rejuvenation of the B-cell lineage is achieved by complete depletion of B cells (e.g., treatment with the monoclonal anti-B-cell antibody rituximab), which triggers the expansion of progenitor cells; this rejuvenation is thought to be a result of the elimination of old long-lived B cells [ 57 ]. Induced pluripotent stem cells derived from aged HSC were also able to restore hematopoiesis to the level of young mice and also avoided biasing the bone marrow lineage [ 58 ].
Treating immune senescence by targeting drugs to the underlying biology of aging provides an important new avenue for ameliorating immune senescence and inflammation [ 59 ]. A major biological factor in senescence and inflammation is the accumulation of senescent cells that secrete pro-inflammatory SASP, which contributes to chronic inflammation with age. Therefore, the removal of senescent cells may prove helpful in reducing inflammation by reducing the source of SASP.
There is also a large number of studies exploring drug combination therapies and multi-targeted combination therapies to overcome treatment resistance and relapse due to immune senescence and depletion in clinical care. The results of a clinical trial showed that the combination of anti-BCMA and anti-CD19 CAR T cells induced a durable response in patients with RRMM with an overall efficacy rate of 92% (57/62) and complete remission or better in 37 cases (60%). The median progression-free survival was 18.3 months and had a manageable long-term safety profile [ 60 ]. Combining IMiDs with PIs enhanced NF-KB inhibition suppressed the inflammatory response in vivo, and achieved synergistic MM cell killing. In the phase 1 clinical trial of CSI-BCMA bispecific CAR, 81% ORR was observed [ 61 ]. In addition, in a limited patient cohort study, CAR-T cells targeting CD38 and BCMA showed significant efficacy with an ORR of 87.5%, although it was associated with an elevated incidence of grade 3 CRS [ 62 ]. What’s more, several other dual-targeted CAR-T cell therapies for MM are being explored, such as BCMA/CD19 [ 63 ] BCMA/GPRC5D CAR -T [ 64 ], and CD138/CD38 [ 65 ]. In addition, tri-specific antibodies such as CDR101 (BCMAxCD3xPD-L1) [ 66 ], ISB 2001 (BCMAxCD38xCD3) [ 67 ], and ISB1442 (CD38xCD47xCD3) [ 68 ] have been developed to augment myeloma cell killing and to overcome tumor escape mechanisms. Results from a phase II triple therapy ELOQUENT-3 trial ( NCT02654132 ) showed that in patients with RRMM treated with lenalidomide and a proteasome inhibitor (PI), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) and pomalidomide/dexamethasone (Pd) [ 69 ]. Combination therapies show promising research prospects. A variety of immunotherapeutic drugs and approaches are in clinical development (Table 2 ).
Table 2
Immunotherapeutic drugs and approaches in clinical trials
ORR overall remission rate, OS overall survival, DoCR duration of complete remission, PFS progression-free survival, IV intravenous injection, IH hypodermic injection, D or d day, sCR complete remission rate, PO oral administration, CI confidence interval
| Clinical trial number | Name of drug | Stages and types of clinical trials | Drug dose | Primary reaction | Major adverse reactions | References |
| NCT03958656 | Novel Anti-SLAMF7 CAR, + Dimerized drug Rimiducid (AP1903) | Phase I dose escalation trial | Initial dose level: 0.66 × 10^6 anti-SLAMF7-CAR + T cells/kg of recipient body weight. 0.4 mg/kg Rimiducid IV | Disease stabilization: 2 weeks; partial remission: 5 weeks; disease progression: 5 months and 23 days | Sinus tachycardia, fever, cytokine release syndrome | [ 92 ] |
| NCT03602612 | Novel Fully Human Anti-BCMA CAR | Phase I dose escalation test | Initial dose level: 0.75 × 10^6 CAR + T cells/kg recipient body weight | sCR:52%; PFS:78 weeks | Upper respiratory tract infection, cough, and dyspnea. The rate of adverse reactions increased progressively with dose increments | [ 93 ] |
| NCT04649359 | MagnetisMM-3: Elranatamab (PF-06863135) | Open-label, multicenter, non-randomized phase 2 study | Elranatamab IH, 12 mg d1, 32 mg d4, 76 mg d8 (each cycle = 28 days) | ORR (CI95%): cohort A 61.0%; cohort B 34.4% | Overall mortality: cohort A 34.96%; cohort B 46.88%. Cytokine release syndrome; COVID-19 pneumonia | [ 94 , 95 ] |
| NCT05565391 | elranatamab (PF-06863135) | Observations of the Cohort Review | Using data from a phase 2 clinical trial (MagnetisMM-3) to compare the experience of people receiving elranatamab with those treated with SOC | ORR(CI95%): in study C1071003 ( NCT04649359 ): 61.0%; COTA Cohort: 31.3%; Flatiron Health Cohort: 30.3% | [ 94 ] | |
| NCT03338972 | Autologous CD4 + and CD8 + T cells | Phase I Study of Relay Immunotherapy | Dose Level 1 (50 × 10^6 EGFRt cells); Dose Level 2 (150 × 10^6 EGFRt cells); Dose Level 3 (300 × 10^6 EGFRt cells); Dose Level 4 (450 × 10^6 EGFRt cells) | ORR was 100%. PFS: Dose level 1: 42.9%; Dose level 2: 62.5%; Dose level 3: 71.4%; Dose level 4: 66.7%. OS: Dose Level 1: 42.9%; Dose Level 2: 62.5%; Dose Level 3: 100%; Dose Level 4: 100% | Fever, febrile neutropenia | [ 96 ] |
| NCT03548207 | JNJ-68284528 | Phase 1b-2 open-label study | After lymphocyte clearance, JNJ-68284528 will be administered as a single infusion | PFS: 1b: 16.79 months; 2: 24.08 months (US), 11.17 months (Japan). OS: 1b: 27.24 months; 2: 32.2 months (US), 18.4 months (Japan) | All-cause mortality: 1b: 34.48%; 2: 36.76% (US), 33.33% (Japan). Cytokine release syndrome, pneumonia | [ 97 , 98 ] |
| NCT03525678 | Belantamab mafodotin Refrigerant; Belantamab mafodotin lyophilized powder | A phase II, open-label, randomized, two-arm study | Cryoliquid belantamab mafodotin: Group 1: 2.5 mg/kg IV; Group 2: 3.4 mg/kg IV. Separate cohort, lyophilized powder belantamab mafodotin 3.4 mg/kg IV | ORR (CI95%): 2.5 mg/kg: 30%; 3.4 mg/kg: 30%. OS: 2.5 mg/kg: 15.3 months; 3.4 mg/kg: 14.0 months; 3.4 mg/kg (lyophilized): 24.5 months. PFS: 2.5 mg/kg: 2.8 months; 3.4 mg/kg: 3.9 months; 3.4 mg/kg (lyophilized): 5.7 months | Thrombocytopenia; pneumonia; fever | [ 99 – 101 ] |
| NCT04177823 | Belantamab mafodotin | A Phase I Open-Label, Dose Escalation Study | Two dose groups, 2.5 mg/kg IV and 3.4 mg/kg IV, respectively | Objective remission rate ORR (CI95%): 16.7% | Bone marrow suppression; liver damage; platelet count reduction | [ 101 ] |
| NCT02336815 | Seleniso | A Phase 2b, Single-Arm, Open-Label, Multi-Center Study | Seleniso 80 mg PO plus low-dose dexamethasone 20 mg IV (twice a week) | Overall remission rate ORR (CI95%) 26.2%. PFS(CI95%) 4.7 months (part 1); 3.7 months (part 2). OS (CI95%) 7.3 months (part 1); 8.4 months (part 2) | Thrombocytopenia; pneumonia; influenza | [ 100 ] |
| NCT00566098 | ASCT + bone marrow infiltrating lymphocytes (MIL) | Phase I/II, open-label trial | d1 and d2: infusion of melphalan 100 mg/m^2; d3: infusion of activated marrow infiltrating lymphocytes (MILs) | OS: 112.1 months; PFS: 12.3 months | All-cause mortality is 45.45%. Syncope | [ 102 ] |
| NCT01245673 | MAGE-A3 vaccine and activated T cells | Phase 2, one-component formulation, open labeling | d2: anti-CD3/anti-CD28 co-stimulated autologous T cells. d 14, 42, 90: MAGEA3/GM-CSF (+ Hiltonol® Poly-ICLC) and PCV booster immunization. d100: Revlamid® (lenalidomide) maintenance therapy. d120, 150: MAGE-A3 and PCV immunization | The 2-year overall survival was 74% [95% confidence interval (CI), 54%-100%] and the 2-year event-free survival was 56% (95% CI, 37%-85%) | Pneumonia; fever; neutrophil count decreased | [ 103 ] |
| NCT03430011 | JCARH125 + anabolic acid | Open-label, multicenter, phase 1/2 study | Two doses of anabolic acid IH and one dose of JCARH125 IV. Received anabolic acid JCARH125 for 5 consecutive days after infusion | ORR (95% CI) for stages 2 and 2a were: 91.7%; 100%. DoCR for stages 2 and 2a were: 18.2 months; and 10.8 months. PFS for stages 2 and 2a were: 14.75 months; and 12.25 months | Cytokine release syndrome; thrombocytopenia; neutropenia; disseminated intravascular coagulation | [ 104 ] |
Conclusion and outlook
Immune senescence plays an important role in the occurrence and development of MM and is closely related to MM treatment resistance. An in-depth study of the mechanisms of immune senescence and the search for new immunotherapeutic targets are important for overcoming drug resistance in the immunotherapy of MM patients and developing more effective therapeutic strategies. Future research should focus on exploring the application of immunomodulation and immunotherapy in the treatment of MM and finding ways to delay or even reverse immune senescence in MM patients, delay and control the recurrence of MM, and thus improve the survival rate and quality of life of patients.
Author contributions
Authors: Yanan Jia, Lixiang Yan, Chenyang Fan, Hui Sun, Xinli Zhou, Zhexin Shi*. Yanan Jia searched and summarized the research. Lixiang Yan was responsible for the selection of literature. Chenyang Fan, Hui Sun, and Xinli Zhou were responsible for the execution of the study. Zhexin Shi put forward the concepts of the study. All the authors revised the manuscript. All the authors approved the final manuscript. The contents of this manuscript have not been copyrighted or published previously. We declare that there is no conflict of interest in this work.
Funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
Data Availability Statement
No datasets were generated or analysed during the current study.