Immune Landscape in Multiple Myeloma

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Niyati Seshagiri Sharma	--	4856	2023-11-15 06:45:17	\|
2	format change	Peter Tang	+ 2 word(s)	4858	2023-11-15 09:41:33	\|

This entry is adapted from the peer-reviewed paper 10.3390/biom13111629

Multiple myeloma (MM) is a dyscrasia of plasma cells (PCs) characterized by abnormal immunoglobulin (Ig) production. The disease remains incurable due to a multitude of mutations and structural abnormalities in MM cells, coupled with a favorable microenvironment and immune suppression that eventually contribute to the development of drug resistance. The bone marrow microenvironment (BMME) is composed of a cellular component comprising stromal cells, endothelial cells, osteoclasts, osteoblasts, and immune cells, and a non-cellular component made of the extracellular matrix (ECM) and the liquid milieu, which contains cytokines, growth factors, and chemokines. The bone marrow stromal cells (BMSCs) are involved in the adhesion of MM cells, promote the growth, proliferation, invasion, and drug resistance of MM cells, and are also crucial in angiogenesis and the formation of lytic bone lesions. Classical immunophenotyping in combination with advanced immune profiling using single-cell sequencing technologies has enabled immune cell-specific gene expression analysis in MM to further elucidate the roles of specific immune cell fractions from peripheral blood and bone marrow (BM) in myelomagenesis and progression, immune evasion and exhaustion mechanisms, and development of drug resistance and relapse.

multiple myeloma tumor microenvironment hematopoiesis immune profiling immunotherapy

1. Introduction

B-cell development and maturation is a tightly regulated process. Throughout adult life, the bone marrow (BM) serves as the primary hotspot for a finite number of pluripotent hematopoietic stem cells (HSCs) to sequentially give rise to all the blood cell types through a process called hematopoiesis (Figure 1).

Figure 1. Hematopoiesis is the process by which all the blood cell types are produced through differentiation from increasingly lineage-committed precursor cells in the adult BM. Broadly, the cells can be classified as myeloid or lymphoid in origin. The myeloid lineage gives rise to thrombocytes (platelets), erythrocytes, granulocytes (mast cells, basophils, neutrophils, eosinophils), macrophages, and myeloid-derived dendritic cells (DCs). The lymphoid lineage produces T- and B-lymphocytes, natural killer (NK) cells, and lymphoid DCs.

Immature plasma cells (PCs) originate from the lymphoid progenitor lineage ^[1]^[2], express a surface B-cell immunoglobulin receptor (BCR), and move to secondary lymphoid organs ^[3]^[4]. Here, the B-cells start to mature while remaining non-proliferative and transcriptionally dormant but primed for antigen recognition through the toll-like receptors (TLR) or the BCR ^[3]^[5]. B-cell activation can then occur in a T-cell-independent or dependent manner to generate acute or long-term immunity. The latter process involves complex activation by cytokines and affinity maturation in the germinal center of the lymph nodes. During activation and differentiation, B-cells are equipped to express a host of antibodies through the physiological process of class-switch recombination and somatic hypermutation ^[3]^[5]^[6]. However, these processes are highly error-prone and can cause the accumulation of genomic changes such as chromosomal translocations and aneuploidies ^[3]^[5]. Such translocations can place proto-oncogenes under the control of powerful enhancers in the Ig gene locus which can create aberrant PCs that can establish multiple myeloma (MM) precursor conditions such as monoclonal gammopathy of uncertain significance (MGUS) and smoldering MM (SMM) ^[5]^[7]^[8]^[9].

In MM, a clonal subset of these transformed post-germinal-center B-cells undergoes malignant proliferation in the favorable microenvironment of the BM (Figure 2) to produce abnormal levels of Igs that are secreted into the serum and urine and termed as Bence-Jones proteins ^[9]^[10]. Monoclonal antibody accumulation in the BM can cause anemia, hypercalcemia and lytic bone lesions with accompanying bone pain and fractures, and impaired kidney function leading to renal failure ^[6]^[8]^[9]. These bone- and organ-damaging events are characteristic features of MM, often abbreviated as “CRAB” which stands for hyperCalcemia, Renal involvement, Anemia, and Bone lesions ^[8]^[9].

Figure 2. Normal B-cell development and myelomagenesis. Upon BCR activation by antigenic stimulus, B-cell precursors migrate from the BM to peripheral lymph nodes to elicit a short-term immune response and the remaining cells differentiate into long-lived circulating plasma and memory cells, eventually becoming resident cells in the tissue niches. Some of the post-germinal-center B-cells carrying oncogenic mutations enter the circulation as plasmablasts and memory B-cells that migrate to the BM as pre-malignant cells to establish MGUS. Further advantageous oncogenic mutations and the favorable BMME drive malignancy and MM development after which the cells become niche-independent and re-enter the circulation, resulting in extramedullary plasmacytoma.

Epidemiology, Diagnosis, and Cytogenetics in Multiple Myeloma

As of 2020, 176,404 new cases of MM were reported globally, accounting for close to 1% of all newly diagnosed cancer cases and 1.2% of all cancer-related deaths ^[11]. MM is often labelled as a neoplasm of ageing, with the age at diagnosis often being ≥ 65 years ^[9]^[12]^[13]. Very rarely, MM has been reported in individuals younger than 30 years of age at frequencies of 0.02% to 0.3% of all diagnosed cases ^[14]. In 1979, the Durie-Salmon staging system was developed for evaluating MM based on the presence of anemia and bone disease ^[15]^[16]. The International Myeloma Working Group defines the International and Revised International Staging systems (ISS and R-ISS) for MM based on either clinical and laboratory parameters only (ISS) or in combination with cytogenetic abnormalities (R-ISS) ^[17]^[18]. Chromosomal aneuploidy is a complex yet distinguishing feature in MM, with the disease often presenting as hyperdiploid or non-hyperdiploid, involving translocations with the IgH locus ^[19]^[20]. Fluorescent in situ hybridization (FISH) is most commonly employed to detect cytogenetic abnormalities in MM ^[19]^[20]^[21]. Hyperdiploidy is observed in nearly half of MM cases and is associated with a good prognosis ^[5]^[22]^[23]. Primary reciprocal translocations specific to B-cell chromosomal rearrangements, observed in nearly half the MGUS and MM cases, are early events in myeloma pathogenesis and are considered high-risk (HR) abnormalities as they bring oncogenes, mainly cyclins, fibroblast growth factor receptor (FGFR) 3, multiple myeloma SET domain (MMSET), and musculoaponeurotic fibrosarcoma (c-MAF), under the control of powerful IgH enhancers ^[5]^[22]^[24]^[25]^[26]. Secondary genetic alterations indicate disease progression, generally do not involve the IgH locus, and may or may not be clonal. Further, these changes are seen in a non-hyperdiploid background with reduced dependence on the BMME and often indicate a poor prognosis (Figure 3) ^[5]^[25]. Detailed classification and staging based on clinical and cytogenetic parameters are listed in Table 1.

Figure 3. Cytogenetic abnormalities and involvement of the BMME in myeloma initiation and progression. Abnormal PCs in the BM harbor chromosomal abnormalities such as translocations and aneuploidy which could establish the precursor condition of monoclonal gammopathy of uncertain significance (MGUS). BM involvement and modification of the immune landscape by myeloma cells sets off myeloma genesis, first as smoldering MM (SMM), and with the accumulation of secondary genetic abnormalities such as CNVs and epigenetic changes as well as oncogenic driver mutations, active MM is established which eventually progresses to aggressive extramedullary plasmacytoma upon bone lysis and egress from the marrow to peripheral blood.

Table 1. Staging of myeloma based on myeloma-defining events, cytogenetic abnormalities, and prognosis ^[27]^[28]^[29]^[30]^[31]^[32]^[33]^[34]^[35]^[36]^[37]^[38]. * CRAB criteria defined by the International Myeloma Working Group (IMWG) refer to organ involvement based on hyperCalcemia (serum calcium > 10.5 mg/dL), Renal impairment (serum creatinine > 2 mg/dL), Anemia (hemoglobin < 10 g/dL), and Bone lesions (osteolysis or osteoporosis on any skeletal examination). LR = Low Risk, SR = Standard Risk, IR = Intermediate Risk, HR = High Risk, IS = Improved Survival, AP = Adverse Prognosis for progression-free/overall survival.

Myeloma Stage	Clinical Parameters	Cytogenetic Abnormalities	Prognosis
MGUS	Serum M-protein ≤ 30 mg/l, <10% BM clonal PC, no organ damage evidence (CRAB *)	Hyperdiploidy (HD) (chromosomes 3, 5, 7, 9, 11, 15, 17)	SR
		IgH translocations (IgHT)—t(11;14), t(4;14), t(6;14), t(14;16) and t(14;20) and involved partner genes—4p16: FGFR3/MMSET, 11q13: CCND1, 16q23: MAF, 6p21: CCND3, 20q11: MAFB	HR, AP
		monosomy 13/del(13q)	SR/IR
SMM	Serum M-protein ≥ 30 mg/l (IgG or IgA), >10% BM clonal PC, no organ damage evidence (CRAB)	MGUS abnormalities	SR
SMM		MUGUS + secondary abnormalities—monosomy17/del(17p) (gene P53), gain 1q21	HR
MM	Serum M-protein ≥ 30 mg/l (IgG or IgA), >10% BM clonal PC, and organ damage evidence (CRAB)	HD, HD (chromosomes 3, 5) + gain 5q31	IS
		Hypoploidy, IgHT + non-HD	HR, AP
		del(17p), gain 1q21 (gene CSK1B), MYC translocations, del(1p)	AP
Extramedullary MM (not including solitary/bone plasmacytoma)	MM criteria and involvement of skeleton or soft tissue or lymph node(s), BM-independence, drug resistance	del(17p13), del(13q14), MYC-over-expression, t(4;14)	AP
		Mutations in TP53, RB1, KRAS, FAK	HR
		del(17p) + non-HD	AP
RRMM	Reappearance of M-protein, ≥5% BMPCs, new lytic bone lesions and/or soft tissue plasmacytomas, increase in size of residual bone lesions, and/or development of hypercalcemia > 11.5 mg/dL not attributable to another cause	del(17p), t(4;14) or t(14;16)	HR, AP
		gain 1q21	AP
		t(4;14): overexpression of FGFR3, t(14:16): overexpression of c-maf, t(14:20): overexpression of c-maf, del(17p): deletion of p53	AP

2. Marrow, Microenvironment, and Multiple Myeloma

The BMME comprises an extracellular matrix (ECM), blood vessels, cells from the hematopoietic lineage, supporting cells required for the regulation of hematopoiesis, and cells from the osteo-lineage ^[39]^[40]^[41]. Normal hematopoiesis occurs in two distinct niches in the BM: the central niche which is in the core of the BM and the endosteal niche which is close to the surface of the bone and the terminal epiphysis containing the trabecular marrow (Figure 4) ^[40]^[42].

Figure 4. Anatomy of the BMME and niche interactions of BM-resident cells during hematopoiesis. Two major niches can be described in the bone marrow: vascular and endosteal. The vascular niche is at the core of the bone marrow comprising both arteriolar and sinusoidal vessels and is associated with LepR+ or nestin+ BMSCs and CXAR cells, macrophages, megakaryocytes, sympathetic nerve fibers, Schwann cells, endothelial cells, and adipocytes. The endosteal niche is closer to terminal bone and comprises osteolineage cells—osteoblasts and osteoclasts—involved in bone formation and recycling. Secreted growth factors, cytokines, CAMs, and ECM molecules participate in an intricate signaling network to regulate HSC quiescence and differentiation/proliferation programs. The major factors involved are CXCL-12, TGF-β, G-CSF, GM-CSF, MMPs, collagens, and integrins. Particularly, the Schwann cells and stromal cells associated with the vasculature help in the regulation of HSC migration and differentiation while cells at the endosteal surface promote HSC quiescence and maintenance of their self-renewal capacity. ★ Activation of hematopoiesis. ▲ proliferation. ⧪ retention in the BM ↝ mobilization ♻ recycling.

Hematopoiesis starts in the embryonic stage, primarily to produce red blood cells from transitory, non-renewing erythroid progenitor cells that carry oxygen to tissues during growth and development. This is the “primitive” phase of hematopoiesis ^[43]^[44]. As embryonic development progresses, the primitive wave allows definitive hematopoiesis to begin in various fetal niches, giving rise to erythroid-myeloid progenitor cells ^[43]^[44]. HSCs progressively move into the fetal liver and then the BM, which is the primary site for adult hematopoiesis ^[1]^[44]. The HSCs generate increasingly lineage-committed progenitor cells that give rise to all the blood cells (Figure 1). The first line of cells are the common lymphoid progenitors (CLP) and the common myeloid progenitors (CMP) ^[45]. Subsequent differentiation of CLP gives rise to B and T lymphocytes, which are integral for antigen-specific adaptive immunity, and to natural killer (NK) ^[46] cells, which are part of the innate immune system. CMPs differentiate into erythroid/platelet progenitors which produce the red blood cells (erythrocytes) and platelets (thrombocytes), and granulocyte-macrophage progenitors which produce granulocytes (neutrophils, eosinophils, basophils, and mast cells), dendritic cells (DCs), and monocytes, which differentiate into macrophages ^[45]^[47].

Disruptions to genome integrity, transcription efficiency, and cell-specific protein expression capacity affect several cellular processes including hematopoiesis ^[48]. Such events can drive the malignant transformation of BM cells and alter the environment in a manner disruptive to normal cells but favorable for their own survival and proliferation ^[49]. A double-edged hypothesis is suggested by several studies whereby both the microenvironment and the hematopoietic cells themselves are suggested to initiate or promote malignancy ^[42]^[50]^[51]^[52]. Cells of the hematological lineage and the BMME can co-evolve to promote tumorigenesis, cancer progression, and the development of drug resistance. In MM, the BMME exhibits distinct, stage-specific profiles (Figure 5).

Figure 5. Immune cell function in myeloma BM is altered by secreted factors from the MMPCs and the cells lose their normal immune surveillance capacity. An immunosuppressive state is then established, helping MMPCs evade immune system detection. The immune cells show features of exhaustion and anergy. Myeloma cells primarily use secreted IL-6 and TGF-β to disrupt normal immune system activation and express cell adhesion molecules (CAMs) such as PSGL-1, ICAM-1, and VLA-4 which helps in attachment to various immune cells as well as the BMSCs or ECM. PD-L1 is another surface-expressed ligand on MMPCs that can bind NK- and T-cell programmed cell death protein (PD)-1 to suppress their cytotoxic functions and cause immune exhaustion. MMPCs also express CXCL-12 which results in macrophage polarization to M2 or the tumor-associated macrophage phenotype. MMPC-derived cytokines including IL-6 and IL-10, along with secreted M-CSF and VEGF, affect DC maturation and proliferation in the BM. PC = plasma cell, TC = T-cell, NKT = natural killer-like T-cell, Nφ = neutrophil, NK = natural killer cell, MMPC = multiple myeloma plasma cell, Mφ = macrophage, MKφ = megakaryocyte, TAMφ = tumor-associated macrophage, tMKφ = transformed megakaryocyte, DC = dendritic cell, mDC = monocytic DC, pDC = plasmacytoid DC, ExNK = exhausted NK, AnNφ = anergic Nφ, AnTC = anergic TC.

3. Immune Profiling Using Single-Cell Transcriptome Sequencing in Multiple Myeloma

In hematological malignancies, immune system dysfunction is well-established, and a deeper understanding of the immune landscape can inform precision diagnostics, drug response prediction, and targeted treatment. Recent technological advancement has seen an influx of several non- and minimally invasive approaches for individualized immune profiling from limited samples to obtain gene/protein expression information from bulk immune cells and single cells ^[53]. In this section, the researchers attempt to review the application of one of the most promising technologies in this area—single-cell transcriptome sequencing (SCTS)—in immune profiling of hematological malignancies, focusing on MM. Table 2 provides a detailed list of recent single-cell sequencing studies in MM focusing on the immune microenvironment.

Table 2. Recent single-cell sequencing studies in MM exploring the role of immune cells and the BMME in myelomagenesis, progression, and drug response. NA = not available.

Disease Stage	Type of Samples and Number of Cells	Number of Samples	Type of Sequencing	Key Findings	Year and Reference
MGUS, SMM, MM, primary light chain amyloidosis (AL)	PCs from peripheral blood (3540) and BM (20,586)	MGUS = 7, SMM = 6, MM = 12, AL = 4, controls = 11	scRNA-seq	Use of single cell transcriptomics for prognostic prediction and personalized therapy based on unique subclonal structures within individuals, detection of tumor cell populations in MRD stages matching those from active MM.	2018 ^[54]
5TGM1 murine myeloma	NA	NA	scRNA-seq	Identification of myeloma-specific transcriptome signature enriched for genes associated with immune function and myeloid cell differentiation, loss of dormancy related gene expression such as AXL	2019 ^[55]
MGUS, SMM	Patient BM aspirates, 19,000 CD45+/CD138− cells	MGUS = 5, LR-SMM = 3, HR-SMM = 8, NDMM = 7, healthy donors = 9	scRNA-seq	Immune profile-based patient risk stratification: increased NK cell abundance in early stages, loss of cytotoxic T cells in SMM, MHC-II dysregulation in CD14+ monocytes causing T-cell suppression.	2020 ^[56]
NDMM to relapse follow-up samples	Patient BM aspirates, CD138+ sorted and unsorted cells: 17,267 PCs and 57,719 immune cells	14 patients across stages for a total of 29 samples	scRNA-seq and 10x WGS	Three distinct patterns identified with stability from precancer to diagnosis and gain or loss from diagnosis to relapse involving B-cell type PCs, inflammation regulated gene expression changes in IL6 and IL1B	2021 ^[57]
Across MM stages	Patient BM aspirates. CD138+ and CD138− sorted BM cells	18 patients across stages	scRNA-seq, CyTOF, and CITE-seq	Advanced stage MM patients had reduced CD4+ T/CD8+ T cells ratio, overexpression of RAC2 and PSMB9 observed in NK cells of progressors compared to non-progressors, rapid progression-specific markers identified for MM	2022 ^[58]
MM before and after 2 cycles of bortezomib-cyclophosphamide-dexamethasone (VCD) treatment	Patient and control BM and peripheral blood samples, 25,231 plasma cells and 216,209 immune cells	MM patients = 10, healthy controls = 3	scRNA-seq	In response to drug treatment, reduced unfolded protein response and metabolic signaling, increased stress and immune-reactive signaling; reduced checkpoint molecules expression, T-cell, NK cell and monocyte exhaustion in MM indicating immunosuppression in the BMME and related to poor prognosis	2023 ^[59]
Across MM stages	NA	NA	scRNA-seq	Progression associated with immunosuppressive tumor microenvironment, with increased levels of exhausted CD8+ T-cells, NK cells and reprogrammed TAMs showing both M1 and higher M2 phenotypes with impaired phagocytic activity demonstrated in vitro	2023 ^[60]
NDMM followed by 2 cycles of VCD	BM and peripheral blood samples, DCs = 1429, monocytes = 42,464	MM patients = 10, healthy volunteers = 3	scRNA-seq	Dysfunctional conventional DC2 (cDC2), mono-DC, and intermediate monocytes through downregulation of interferon regulatory factor (IRF)-1 signaling with reduced antigen presentation capacity in MM compared to controls	2023 ^[61]

SCTS is an emerging technology used to resolve gene expression differences between cell populations of a heterogeneous tumor sample, and it has been employed in hematological malignancies to understand aberrant immune cell frequency and function. Many SCTS studies have been carried out for MM in recent years, focusing on the BM tumor microenvironment, the immune landscape and immune evasion, and the development of drug resistance and relapse.

Single-cell sequencing of around 75,000 cells from 14 MM patients by Liu et al. provided insights into the malleability of the tumor microenvironment and its role in tumor heterogeneity and MM progression, as demonstrated by co-clustering patient immune and PCs with similar genetic backgrounds ^[57]. The authors also traced the journey of PCs from SMM to active myeloma and relapse using somatic alteration, cell type-specific marker expression, and gene expression data in relation to the tumor microenvironment. Unlike the malignant cells, the clustering of non-malignant cells was independent of tumor stage or origin. However, patient-specific differences in expression were observed, further underscoring the involvement of the tumor microenvironment’s interaction with the genetic background ^[57]. BM cells from different stages of MM progression and healthy donors were used for SCTS, revealing that NK cell abundance increases early in the disease along with altered chemokine receptor expression. In this study, the authors found that granzyme K+ cytotoxic T-memory cells were lost as early as SMM and could play a critical role in MM immunosurveillance in mouse models. Additionally, major histocompatibility complex (MHC)-class II dysregulation in CD14+ monocytes leads to T-cell suppression in vitro ^[56]. A compromised tumor microenvironment was also demonstrated in a study combining SCTS with validation using bulk RNA sequencing (RNAseq), flow cytometry, and functional experiments ^[60]. Results showed enrichment of exhausted NK cells and CD8+ T cells, macrophage reprogramming to a mixed M1-M2 phenotype, and two TAM clusters present only in the MM stage with increased M2 scores. Interaction analysis showed enrichment for two ligand–receptor pairs between macrophages and malignant PCs involving phagocytosis suppression and the macrophage inhibitory factor, which alters macrophage phenotype, and these alterations correlated with disease progression and adverse outcomes. In a multi-omics study that included SCTS as part of the MMRF immune atlas pilot project, 18 MM patient BM samples were used to compare immune cell profiles using scRNA-seq, cytometry by time-of-flight (CyTOF), and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq). The techniques exhibited differences in identifying T-cell, macrophage, and monocyte numbers. Overall, ISS stage 3 patients had decreased CD4+ T/CD8+ T-cell ratios, and ras-related C3 botulinum toxin substrate 2 (RAC2) and proteasome 20S subunit beta 9 (PSMB9) expression was upregulated in NK cells of progressive versus non-progressive MM ^[58]. SCTS of 10 MM individuals pre and post two cycles of a bortezomib-cyclophosphamide-dexamethasone (VCD) regimen revealed increased immune-reactive and stress-associated pathways while unfolded-protein response (UPR) and metabolic-related programs were reduced. Low immune-reactive gene expression indicated poor survival and non-responsiveness to drugs, likely by reduced MHC-class I-mediated antigen presentation capacity (APC) and immune surveillance, and upregulation of immune escape genes. The authors also found a connection between the tumor-intrinsic immune reactive program and the immunosuppressive microenvironment arising from immune cell exhaustion and checkpoint molecule expression in T-cells, NK cells, and monocytes ^[59]. Another study focusing specifically on SCTS of DCs and monocytes from 10 MM patients found five distinct clusters for each cell type ^[61]. Using trajectory analysis, one subset—monocyte-derived DCs (mono-DCs)—was shown to be generated from intermediate monocytes. Compared to healthy controls, conventional DC2 (cDC2), mono-DC, and intermediate monocytes of MM patients exhibited impaired APC. Additionally, the regulatory function of interferon regulatory factor 1 (IRF1) was shown to be decreased in the cDC2, mono-DC, and intermediate monocytes of MM patients.

4. Immunotherapy in Multiple Myeloma

Immunotherapy has come a long way from the Nobel Prize-winning first documented use of allogeneic bone marrow hematopoietic cell transplantation in 1968 by Edward Donnall Thomas for leukemia treatment ^[62]. The primary immunotherapies for hematological cancers are checkpoint inhibitors, vaccines, cell-based antibodies, and oncolytic viruses ^[63]. Here, the researchers will review the antibody- and cell-based methods. In cancer, immunotherapy refers to either activating or rescuing an anti-tumor immunogenic response or suppressing an undesirable immune dysfunction state to destroy existing cancer cells or control the progression. This is often achieved by identifying and targeting specific proteins usually expressed only by malignant cells using antibody- or cell-based methods. Monoclonal or bispecific antibodies are designed against the malignant cell proteins to destroy cancer cells while leaving healthy cells untouched. Similarly, healthy immune cells (mainly T- or NK-cells) derived from the patient are engineered in the laboratory to express specific antibodies or peptides against cancer cell-specific proteins and termed chimeric antigen receptor (CAR) cells, which can home onto cancer cells and kill them via cell-mediated cytotoxic responses. The patient’s immune function can also be rescued using specific recombinant cytokines and growth factors. Immunotherapy can be used as a monotherapy or in combination with a cytotoxic/chemotherapeutic drug to eliminate cancer cells while minimizing off-target effects.

Bispecific T-cell engagers (BiTEs) have two specific variable region chains—one for the immune cell receptor and one for the cancer-specific target antigen—to improve specificity and reduce off-target action.

MM’s standard-of-care treatment has remained relatively the same since autologous stem cell transplantation (ASCT) was developed in the 1980s and, later, PIs in the 2000s (Figure 6). MM remains an incurable disease with high relapse and drug resistance rates ^[64]^[65]^[66]^[67]^[68]. Cell- and antibody-based immunotherapy are emerging as invaluable tools in MM treatment, with clinical trials showing great promise. B-cell maturation antigen (BCMA) and SLAMF7 are the two novel targets in MM immunotherapy. BCMA is an important member of the TNFR superfamily expressed by all malignant MMPCs and required for survival, proliferation, and myeloma progression. At the same time, SLAMF7 is thought to play a role In BM stromal interactions with MMPCs to promote survival and is also highly expressed by all stages of MMPCs ^[69]^[70]. The landmark advancement in MM therapy was the development and approval of the monoclonal antibodies elotuzumab (anti-SLAMF7) and daratumumab (anti-CD38) in 2015 for both monotherapy and combination forms, particularly in the case of RRMM ^[71]^[72]^[73]^[74]^[75]^[76]. The first anti-BCMA CAR-T cells were made by lentiviral vector-mediated transfection in 2013 using a single-chain variable fragment from mouse anti-BCMA antibody combined with hinge and transmembrane regions of human CD8α, CD3ζ T-cell activation domain, and a costimulatory molecule (CD28), and the first clinical trial took place in 2016 to show potent cytotoxicity in refractory MM ^[77]^[78]. Since then, a wide array of immunotherapies have been developed, including chimeric antigen receptor-T (CAR-T) cells, bispecific antibodies, antibody-drug conjugates, and immune checkpoint inhibitors ^[64]^[65]^[79]. A combination of the PI3K inhibitor with BCMA was used to develop the Bb2121 CAR T-cell therapy, designed to improve the memory phenotype for RRMM. In clinical trials, this showed minimal residual disease (MRD) negativity and median progression-free survival (PFS) of 17.7 months ^[80]. LCAR-B38M, a dual epitope anti-BCMA-targeting CAR-T therapy, underwent a Phase 1 clinical trial and showed a median duration of response (DOR) of 16 months, median PFS of 15 months, and median PFS for patients achieving CR of 24 months ^[81]. The CARAMBA Phase 1/2A clinical trial employs CAR-T cells targeting SLAMF7, utilizing a novel virus-free transient mRNA expression system to minimize the incidence of cytokine release syndrome (CRS) in the first European virus-free CAR-T clinical trial ^[82]. CAR-NK cell therapy has also been developed against SLAMF7, which was shown to eliminate human MM cells in a mouse xenograft model and is currently under phase 1 clinical trial evaluation (NCT03710421) ^[83]. A majority of MMPCs express CD56—required for MM cell peripheral blood egress and setup of extramedullary disease—which is also an emerging CAR cell therapy target showing positive results in a mouse model and currently in clinical trials (NCT03473496, NCT03271632) ^[84]^[85]. Another exciting target is CD19, which is rarely expressed by MMPCs but could potentially be expressed by “stem” clones in some patients. It has also been tested in two clinical trials with no conclusive results ^[84]. Other important targets in CAR cell therapy are CD138, κ-light chain, G-protein coupled receptor (GPRC) 5D, NKG2D, and New York Esophageal Squamous Cell Carcinoma (NY-ESO)-1, also being investigated in several clinical trials ^[84]. Table 3 lists successful ongoing and completed clinical trials for immunotherapy in MM at various stages of the disease. An anti-BCMA antibody, erlanatamab, is currently in a Phase 1 dose escalation clinical trial (NCT03269136) for RRMM post-PI or anti-CD38 treatment over an 8.1 month follow-up, with 67% of participants showing Grade 1 or 2 CRS, 31% complete remission (CR), 64% overall response rate (ORR), and 91% probability of event-free status at 6 months ^[86]. Several other anti-BCMA BiTEs and BsAbs are in various stages of clinical trials, and more targets are being explored, including CD138, CD38, CD19, SLAMF7, Fc receptor-like 5 (FcRL5), CS1-NKG2D, GPRC5D, and NY-ESO-1 ^[87].

Figure 6. Timeline of therapeutic developments in MM. Historically, corticosteroids were the first drugs to be used in MM treatment, and in the late 1970s, BM stem cell transplantation became one of the most promising treatments in eligible patients. Discovery of the proteasome inhibitor (PI) bortezomib was a significant advancement in MM treatment and remains the standard first-line therapy in most MM regimens today. The last decade has witnessed significant research into targeting the dysregulated immune landscape as well as myeloma cell-specific markers through development of antibody- and cell-based immunotherapeutic approaches.

Table 3. Ongoing immunotherapy clinical trials for MM {adapted from the NCBI Clinical Trials Registry. Source: ^[88]}.

NCT Number	Study Title	Conditions	Targets	Type of Immunotherapy	Expected Outcome	Phases
NCT00090493	Study of MAGE-A3 and NY-ESO-1 Immunotherapy in Combo with DTPACE Chemo and Auto Transplantation in Multiple Myeloma	MM	Myeloma cells expressing MAGE-A3 and NY-ESP-1 proteins	Peptide vaccine against MAGE-A and NY-ESP-1	Generation of anti-myeloma T cells to kill myeloma cells	Phase 2, Phase 3
NCT00006244	Melphalan, Peripheral Stem Cell Transplantation, and Interleukin-2 Followed by Interferon Alfa in Treating Patients with Advanced Multiple Myeloma	Refractory MM, Stage I, Stage II and Stage III MM	Activating patient WBC response	Recombinant IL-2 (Aldsleukin), IFN-α	Stimulate patient WBCs with IL-2 to kill myeloma cells and arrest proliferation with IFN-α	Phase 2
NCT03525678	A Study to Investigate the Efficacy and Safety of Two Doses of GSK2857916 in Participants with Multiple Myeloma Who Have Failed Prior Treatment with an Anti-CD38 Antibody	MM	BCMA on myeloma cells	Antibody-drug conjugate (ADC)—belantamab mafodotin	Anti-BCMA antibody belantamab will target myeloma cells and the conjugate mafodotin is a cytotoxic agent to effect cell cycle arrest and ADCC of myeloma cells	Phase 2
NCT02336815	Selinexor Treatment of Refractory Myeloma	MM	Exportin-1 (XPO-1)—overexpressed in myeloma cells	Inhibitor of nuclear export	Arrest cell cycle and proliferation of myeloma cells by blocking nuclear to cytoplasmic transport and signaling	Phase 2
NCT03958656	T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma	MM, plasma cell (PC) MM	SLAMF7	Anti-SLAMF7 CAR-T cell	Targeting myeloma cell SLAMF7 using CAR-T cell and T cells along with a stop gene to limit toxicity	Phase 1
NCT03602612	T Cells Expressing a Novel Fully Human Anti-BCMA CAR for Treating Multiple Myeloma	MM, PCMM	BCMA on myeloma cells	Anti-BCMA CAR-T cells	Patient- derived T-cells cultured to express anti-BCMA CAR to kill BCMA expressing myeloma cells	Phase 1
NCT02215967	Study of T Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma	PCMM, MM	BCMA on myeloma cells of treated patients	Anti-BCMA CAR-T cells	Patient- derived T-cells cultured to express anti-BCMA CAR to kill BCMA expressing myeloma cells	Phase 1
NCT03338972	Immunotherapy with BCMA CAR-T Cells in Treating Patients with BCMA Positive Relapsed or Refractory Multiple Myeloma	Recurrent PCMM, refractory PCMM	BCMA on myeloma cells of relapsed or refractory MM patients	Autologous Anti-BCMA-CAR-expressing CD4+/CD8+ T-lymphocytes	Patient- derived T-cells cultured to express anti-BCMA CAR to kill BCMA expressing myeloma cells	Phase 1
NCT00566098	Activated White Blood Cells with ASCT for Newly Diagnosed Multiple Myeloma	MM and PC neoplasm	Newly diagnosed MM cells	Activated patient-derived WBCs	Use patient-derived, cultured WBCs to study MM cell cytotoxicity and side effects	Phase 1, Phase 2
NCT01245673	Combination Immunotherapy and Autologous Stem Cell Transplantation for Myeloma	MM	Myeloma cells	MAGE-A3 vaccine + activated T-cells	To test if this combination: (i) provides “immunity” against myeloma cells and (ii) prevents progression	Phase 2
NCT00439465	Adoptive Cellular Immunotherapy Following Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) for Multiple Myeloma	Transplant eligible MM patients	Myeloma cells in post-APBSCT patients	Cytotoxic T-cells + IL-2 + recombinant GM-CSF	Combination of Cytotoxic T-cells + IL-2 + recombinant GM-CSF to enhance anti-tumor immune reconstitution and improve outcome of MM patients.	Phase 2
NCT05652530	Clinical Study of the Safety and Efficacy of BCMA CAR-NK	MM	BCMA on myeloma cells	Anti-BCMA CAR-NK cells	Targeting myeloma cells expressing BCMA using CAR-NK cells in relapsed/refractory MM patients	Early Phase 1
NCT03940833	Clinical Research of Adoptive BCMA CAR-NK Cells on Relapse/Refractory MM	MM	BCMA on myeloma cells	Anti-BCMA CAR-NK 92 cells	To kill myeloma cells expressing BCMA using NK 92 cells in MM patients	Phase 1, Phase 2
NCT05182073	FT576 in Subjects with Multiple Myeloma	MM	BCMA on myeloma cells	FT576 (Allogeneic BCMA CAR-NK cells)	FT576 as monotherapy and in combination with the monoclonal antibody daratumumab in MM	Phase 1
NCT06045091	To Evaluate the Safety and Efficacy of Human BCMA Targeted CAR-NK Cells Injection for Subjects With R/R MM or PCL	MM, PC leukemia	BCMA on myeloma cells	Anti-BCMA CAR-NK cells	Targeting myeloma cells expressing BCMA using CAR-NK cells in MM and PC leukemia patients	Early Phase 1
NCT05008536	Anti-BCMA CAR-NK Cell Therapy for the Relapsed or Refractory Multiple Myeloma	Refractory MM	BCMA on myeloma cells	Umbilical and cord blood derived, anti-BCMA engineered CAR-NK cells	Targeting malignant myeloma cells expressing BCMA using engineered CAR-NK cells in refractory MM patients	Early Phase 1

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