Abstract
The basic idea of modulating the immune system to better recognize and fight tumor cells has led to the successful introduction of adoptive cellular immunotherapy (ACT). ACT-based treatment regimens, in which the patient's own immune cells are isolated and subsequently expanded (ex vivo) and reinfused, have also contributed significantly to the development of a personalized treatment strategy. Complementing this, the unprecedented advances in ACTs as chimeric antigen receptor (CAR)-T cell therapies and their derivatives such as CAR-NK, CAR-macrophages, CAR-γδT and CAR-NKT have further maximized the therapeutic outcomes. Herein, we provide a comprehensive overview of the development of ACTs in multiple myeloma (MM) and outline how they have evolved from an experimental form to a mainstay of standard clinical settings. Besides, we provide insights into cytokine-induced killer cell (CIK) therapy, an alternative form of ACT that (as CIK or CAR-CIK) has enormous potential in the clinical spectrum of MM. We also summarize the results of the major preclinical and clinical studies of adoptive cell therapy in MM and address the current challenges (such as cytokine release syndrome (CRS) and neurotoxicity) that limit its complete success in the cancer landscape.
Supplementary Information
The online version contains supplementary material available at 10.1186/s40164-024-00576-6.
Keywords: Multiple myeloma, Cell therapy, Immunotherapy, CAR-T, CAR-NK, CIK
Introduction
Multiple myeloma (MM) is a malignancy of plasma cells in the bone marrow, comprising around 10% of all hematologic cancers. This disorder arises from the genetic alteration of stem cells, which causes normal B lymphocytes to morph into malignant myeloma cells. These cells produce dysfunctional M proteins, which contribute to disease progression and associated symptoms such as severe bone damage, kidney dysfunction, anemia, and elevated calcium levels [1–3] (Fig. 1A). In the U.S., MM predominantly affects older adults, typically beginning around age 69, with a prevalence rate of 7 per 100,000 people annually [4]. It often develops from conditions like monoclonal gammopathy of undetermined significance (MGUS) or smoldering MM, found in 3% of those over 50 [5, 6]. MM is notably more prevalent among individuals of African descent and in industrialized areas such as the U.S., where it constitutes 1.8% of all cancer cases [7]. In 2022, there were about 34,470 new cases and 12,640 deaths due to MM in the U.S., and men are 1.5 times more likely to be affected than women. Over the past two decades, the treatment landscape for MM has been transformed through the widespread adoption of autologous stem cell transplantation (ASCT) and the approval of innovative medications and strategies. A variety of new drugs, including histone deacetylase inhibitors, proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and other targeted therapies, have been developed. These advances have not only improved the five-year survival rate but also shifted treatment approaches towards more intricate combinations, such as triple therapy, and extended treatment durations to enhance patient outcomes. Notably, the tumor microenvironment (TME) in MM plays a crucial role in disease pathogenesis, progression, and therapeutic resistance [8, 9] (Fig. 1A). Targeting the TME offers a promising strategy to enhance treatment outcomes for MM patients. Current research aims to understand the complexities of the TME and develop new therapies to exploit its weaknesses [10]. Despite advances in these areas, MM remains incurable, with current treatments often limited by resistance and relapse. This highlights the urgent need for innovative therapeutic approaches to achieve a cure [11–16].
Fig. 1.
A The process of normal immune cell development versus the development of MM. In healthy bone marrow, stem cells develop into B lymphocytes which then mature into plasma cells, producing normal antibodies. In contrast, in multiple myeloma, genetic damage to stem cells leads to the formation of abnormal B lymphocytes, which evolve into myeloma cells. These cancerous cells produce an abnormal protein known as M protein, disrupting normal blood cell production and immune functions. Immunosuppressive Tumor Microenvironment (TME): The TME consists of tumor cells, stroma, and various immune cells, such as dendritic cells (DCs), T cells, NK cells, B cells, and macrophages, which often become exhausted and contribute to the immunosuppressive nature of the environment. B Timeline of significant milestones in CAR-T cell therapy development. Beginning with the use of adoptive transfer of tumor-infiltrating lymphocytes (ATILs) for metastatic cancer in 1993, significant milestones include the introduction of various generations of CAR constructs, such as CD3ζ (first generation) and 4-1BB-CD3ζ (second generation). Noteworthy is the FDA's approval of the first CAR-T cell therapies: Kymriah in 2017 for ALL and Yescarta for NHL, followed by approvals for multiple myeloma treatments, Abecma in 2021, and Carvykti in 2022. Additionally, the figure notes the ide-cel (bb2121) receiving breakthrough therapy designation, highlighting the ongoing innovation and regulatory endorsement in the CAR-T field. Each milestone in this timeline underscores the rapid evolution and increasing complexity of CAR-T cell therapies, showcasing both clinical and regulatory advancements that have significantly impacted cancer treatment paradigms. Figure created with BioRender.com
Over recent decades, advancements in adoptive cellular immunotherapy (ACT) have not only revolutionized the therapeutic landscape but have also progressively redefined the paradigms of clinical care for MM [17]. This review delves into the transformative journey of cell therapy in MM, tracing its origins from an experimental stratagem to its status as a cornerstone in the management of this challenging disease. Initially, the adoption of ASCT marked a significant breakthrough, enhancing survival rates and setting a new benchmark for care [18–20]. The introduction of ASCT in the late twentieth century heralded the first wave of innovations that provided a glimmer of hope against a once grim prognosis [21–23]. Building on this foundation, the emergence of chimeric antigen receptor (CAR)-T cell therapies catalyzed a seismic shift in the treatment modalities available for MM [24, 25] (Fig. 1B). Particularly, the development of CAR-T cells targeting the B cell maturation antigen (BCMA) has demonstrated remarkable efficacy in treating patients with relapsed/refractory multiple myeloma (RRMM), offering unprecedented response rates and opening new avenues for remission [26–28].
Further, this review explores the burgeoning role of alternative cell-based therapies, such as natural killer (NK) cells and T cell receptor (TCR) engineered cells [29–32]. These therapies are not merely adjuncts to existing treatments but are pivotal in addressing ongoing challenges such as antigen escape and resistance to CAR-T cell therapy [28, 33]. Moreover, we address the critical management of adverse effects, including cytokine release syndrome (CRS) and neurotoxicity [34–36], which are significant considerations in the deployment of these potent therapeutic options.
As we stand on the brink of significant advancements, this review anticipates future innovations, including combination therapies and genetically tailored approaches designed to improve efficacy, safety, and personalized treatment outcomes. By integrating historical achievements with current research directions, we endeavor to shed light on the path toward achieving durable remissions and, ultimately, a cure for MM or RRMM. This review outlines key historical milestones and emphasizes the transformative potential of cell therapy in MM. The evolution of cell therapies, illustrated in Fig. 2 and elaborated in the text, shows great promise for MM treatment. Additionally, Table 1 and Supplementary Table 1 summarize the results from major pre-clinical and clinical adoptive cell therapy studies for MM.
Fig. 2.
Cell therapies for multiple myeloma (MM). A Autologous stem cell transplantation, remains the cornerstone of treatment for MM; B T cell receptor (TCR) gene engineered cells enhance a patient’s T cells by incorporating a receptor designed to target specific antigens, such as NY-ESO-1, and MAGE-A3, present on myeloma cells. These targeted antigens, derived from proteins commonly found in cancer cells, enable the modified T cells to recognize and destroy tumor cells that exhibit these antigens once reintroduced into the patient; C Chimeric antigen receptor (CAR) T cells, a groundbreaking advancement in MM, designed to enhance the body’s immune response against malignant cells; D CAR-NK cells/genetically engineered NK cells, which express engineered receptors targeting one or more antigens, facilitate the activation of immune cells against MM cells; E Bispecific immune cell engagers (BiCEs)/Trispecific immune cell engagers (TriCEs) are a form of immunotherapy that targets cancer cells. By binding to both immune cells (NK cells or T cells) and MM cells, BiCEs or TriCEs bring these cells into close contact, enabling NK or T cells to effectively kill the MM cells; F Lymphokine-activated killer (LAK) cells, are a promising immunotherapy for MM, but further research and clinical trials are needed to fully explore and optimize their therapeutic potential; G γδ T cells from tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMCs), a subset of T cells with non-MHC‐restricted cytotoxic activity, are notable for their ability to directly kill MM cells and modulate the immune response. This dual function can promote tumor eradication or facilitate tumor immune evasion; H Dendritic cell (DC) vaccination involves using autologous dendritic cells that have been loaded with peptides or tumor-derived proteins to activate cytotoxic T cell responses in MM patients. Figure created with BioRender.com
Table 1.
Clinical studies of adoptive cell therapies for MM treatment
| Type | Phase | Clinical design | Clinical response | Most common grade 3/4/5 toxicities | References |
|---|---|---|---|---|---|
| TCR gene engineered T cells | I/II (NCT01352286) |
Treatment: Received NY-ESO-1-specific TCR-engineered T cells after ASCT Protocol: Twenty patients with antigen-positive MM received an average 2.4 × 109 NY-ESO-1-LAGE-1 TCR-engineered T cells for 2 days after ASCT |
CR: 80%; PFS: 19.1 months | GVHD (17.4%), rash (6%), hypotension (6%) | [37] |
| CAR-T cells | I (NCT02658929) |
Treatment: BCMA-targeted CAR-T cell (Idecabtagene vicleucel; Bb2121) Protocol: CTX + FAMP + 150 or 450 × 106 cells/pt |
ORR: 75.8%; CR: 38.7%; mPFS: 18.1 months | Neutropenia (88.7%), anemia (56.5%), infection (22.6%), CRS (6.5%), thrombocytopenia (56.5%), leukopenia (61.3%), lymphopenia (35.5%), ICANS (1.6%), second primary malignancy (3.2%) | [38] |
| I/II (NCT03090659) |
Treatment: BCMA-targeted CAR-T cell (LCAR-B38M) Protocol: CTX + avg 0.5 × 106 cells/kg 3 split infusions |
ORR: 87.8%; CR: 73%; MRD negativity: 67.6%; 5-year PFS: 21%; 5-year OS: 49.1% | Neutropenia (85.3%), thrombocytopenia (58.8%), and hepatic disorder (38.3%) | [39] | |
| Ib/II (NCT03548207) |
Treatment: BCMA-targeted CAR-T cell (JNJ-4528) Protocol: CTX + FAMP + avg 0.75 × 106 cells/kg |
ORR: 97.9%; sCR: 82.5%; 27-month PFS: 54.9%; 27-month OS: 70.4% | Neutropenia (94.8%), anemia (68%), thrombocytopenia (59.8%), leukopenia (60.8%), lymphopenia (50.5%), metabolism and nutrition disorders (18.5%), CRS (5.1%), ICANS (12.3%) | [40] | |
| Ib (NCT02546167) |
Treatment: BCMA-targeted CAR-T cell (CART-BCMA) Protocol: None or CTX + 1–5 × 107 or 1–5 × 108 cells/pt |
ORR: 48%; CR: 8%; VGPR: 20%; PR: 20% | Leukopenia (44%), neutropenia (44%), lymphopenia (36%), CRS (32%), ICANS (12%) | [41] | |
| I (NCT03070327) |
Treatment: BCMA-targeted CAR-T cell (MCARH171) Protocol: CTX + FAMP + 72, 137, 475 or 818 × 106 cells/pt (1 or 2 doses) |
ORR:64% | CRS (23%), ICANS (36%) | [42] | |
| I (NCT03455972) |
Treatment: CD19-targeted CAR-T cell and BCMA-targeted CAR-T cell Protocol: anti-CD19 CAR-T cells were infused at a fixed dose of 1.0 × 107/kg body weight on day 0, followed by 2.0 × 107/kg of anti-BCMA CAR-T cells on day 1 and 3.0 × 107/kg of anti-BCMA CAR -T cells on day 2 |
ORR: 100%; sCR: 90%; CR: 10% | Neutropenia (20%), lymphopenia (100%), thrombocytopenia (70%), anemia (50%), elevated bilirubin (10%), hypotension (10%), respiratory infection (50%) | [43] | |
| II (ChiCTR17011272) |
Treatment: CD19-targeted CAR-T cell and BCMA-targeted CAR-T cell Protocol: CTX + FAMP + humanized anti-CD19 CAR-T cells (1 × 106 cells/kg) and murine anti-BCMA CAR-T cells (1 × 106 cells/kg) |
ORR: 95%; sCR: 43%; CR: 14%; VGPR: 24%; PR: 14% | Neutropenia (86%), anaemia (62%), thrombocytopenia (62%), CRS (4%) | [44] | |
| I/II (ChiCTR2000033567) |
Treatment: Bispecific BC19 CAR-T cell targeting BCMA/CD19 Protocol: Not found |
ORR: 92%; mPFS: 19.7 months; mOS: 19.7 months | Neutropenia (98%), anemia (64%), thrombocytopenia (66%), leukopenia (96%), AST increased (24%), Pyrexia (24%), CRS (8%) | [45] | |
| I (ChiCTR1800018143) |
Treatment: Bispecific BM38 CAR-T cell targeting BCMA/CD38 Protocol: CTX + FAMP + anti BM38 CAR-T cells (0.5, 1.0, 2.0, 3.0 and 4.0 × 106 cells/kg) |
ORR: 87%; CR: 52% | CRS (22%), neutropenia (87%), anemia (13%), thrombocytopenia (47%), leukopenia (83%) | [46] | |
| I (ChiCTR1900026286) |
Treatment: Bispecific BM38 CAR-T cell targeting BCMA/CD38 Protocol: CTX + FAMP + anti BM38 CAR-T cells |
ORR: 88%; CR: 81% | Anemia (37.6%), thrombocytopenia (25%), leukopenia (93.8%), CRS (31.3%) | [47] | |
| I (ChiCTR1800017051) |
Treatment: CD38-targeted CAR-T cell and BCMA-targeted CAR-T cell Protocol: CTX + FAMP + humanised anti-BCMA CAR-T cells (2 × 106 cells/kg) and murine anti-CD38 CAR-T cells (2 × 106 cells/kg) |
ORR: 90.9%; CR: 54.5% | Fever (36.4%), leukopenia (36.4%), anemia (27.3%), CRS (27.3%) | [48] | |
| I/IIa (NCT04662099) |
Treatment: Bispecific CS1 CAR-T cell targeting CSI/BCMA Protocol: CTX + FAMP + bispecific CS1-BCMA CAR-T cells (0.75 × 106, 1.5 × 106 and 3.0 × 106 cells/kg) |
ORR: 81%; sCR: 38% | CRS (6%), pain (19%), infection (31%), leukopenia (100%), neutropenia (94%), lymphopenia (100%), anemia (13%), thrombocytopenia (31%) | [49] | |
| I (NCT04555551) |
Treatment: GPRC5D-targeted CAR-T cell (MCARH109) Protocol: GPRC5D-targeted CAR-T cells (25 × 106 to 450 × 106 cells in total) |
ORR: 71%; CR: 35%; MRD negativity: 47% | CRS (5.9%), ICANS (5.9%) | [50] | |
| I (NCT04674813) |
Treatment: GPRC5D-targeted CAR-T cell (BMS-986393) Protocol: GPRC5D-targeted CAR-T cells (25 × 106 to 450 × 106 cells in total) |
Patients with assessable efficacy: ORR: 86%; CR: 38%; patients refractory to prior BCMA-directed therapy: ORR: 85%; CR: 46% | Neutropenia (69%), anemia (31%), thrombocytopenia (30%), CRS (4.3%), ICANS (3%) | [51] | |
| I (NCT05016778) |
Treatment: GPRC5D-targeted CAR-T cell (OriCAR-017) Protocol: GPRC5D-targeted CAR-T cells (1 to 6 × 106 CAR-T cells/kg) |
ORR: 100%; sCR: 60% | Neutropenia (100%), thrombocytopenia (90%), leukopenia (90%), anemia (70%) | [52] | |
| CAR-NK cells | I/II (NCT03940833) |
Treatment: BCMA-specific CAR-NK 92 cell Protocol: Not found |
Not found | Not found | Not found |
| I (NCT05182073) |
Treatment: Allogenic CAR NK cells with BCMA expression (FT576) Protocol: CTX + FAMP + Daratumumab + Bendamustine + FT576 |
Not found | Not found | Not found | |
| LAK cells | I/II |
Treatment: rIL-2 Protocol: 9 × 106 IU/m2 twice daily on day 1 and 2, then 0.9 × 106 IU/m2 twice daily from day 3 to 56, every 12 weeks until disease progression |
ORR: 35.3% | Not found | [53] |
| I |
Treatment: rIL-2 Protocol: 0.3 to 4.5 × 106 IU/m2 daily from day 1 to 5, then 0.3 × 106 IU/m2 daily from day 12 to 21 |
Not found | Most patients exhibited mild to moderate fever, nausea, diarrhea, and/or skin rash | [54] | |
| γδ T cells | II |
Treatment: Zoledronate + IL-2 Protocol: IL-2: 2 × 106–8 × 106 IU/day (increased by 25% each time until toxicity was observed); 4 mg of zoledronic acid were administered on day 2 of each cycle |
CR: 18% | Treatment was well tolerated without G3 or 4 toxicities | [55] |
| I |
Treatment: Pamidronate + IL-2 Protocol: Pamidronate on day 1 followed by increasing dose levels of IL-2 from day 3 to day 8 (0.25–3 × 106 IU/m2); pamidronate on day 1, followed directly by IL-2 administration from day 1 to day 6 |
PR: 33% | Thrombosis (10%) | [56] | |
| I |
Treatment: Zoledronate + IL-2 activated allogeneic γδ T cells from healthy donors Protocol: On average, patients received 2.17 × 10⁶/kg (range 0.9–3.48) γδ T cells. All patients received prior lymphopenia-inducing chemotherapy (FAM 20–25 mg/m2 day -6 until day -2 and CTX 30–60 mg/kg day -6 and -5) and were treated with 4 mg zoledronate on day 0 and 1.0 × 10⁶ IU/m2 IL-2 on day + 1 until day + 6 for the induction of γδ T cell proliferation in vivo |
CR: 75% (patients with plasma cell leukaemia) | Neutropenia (100%) | [57] | |
| I (NCT04688853) |
Treatment: TEG002 cells (autologous T cells transduced with a specific γδTCR) Protocol: Not found |
Ongoing | Not found | Not found | |
| DC vaccination | II (NCT02728102) |
Treatment: DC/MM fusion vaccine + lenalidomide (Revlimid) + GM-CSF Protocol: DC/MM fusion vaccine was given on day 1 of cycles 2, 3, and 4 of lenalidomide maintenance therapy, starting 90–100 days after auto-HSCT, and continued for 2 years. GM-CSF was given daily for a total of 4 days of each cycle (each cycle lasted 28 days) |
CR: Vaccine group vs control group (52.9% vs 50%); VGPR: Vaccine group vs control group (85.3% vs 77.8%) | Blood and lymphatic disorders (52.9%), gastrointestinal disease disorders (14.7%), nervous system disorders (16.2%), metabolism and nutrition disorders (10.3%) | [58] |
MM: multiple myeloma; ORR: overall response rate; sCR: stringent complete response; MRD: minimal residual disease; CR: complete responses; VGPR: very good partial response; PR: partial response; OS: overall survival; mOS: median overall survival; PFS: progression-free; mPFS: median progression-free; GVHD: Graft Versus Host Disease; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; CTX: cyclophosphamide; FAM: fludarabine; pt: per test; data sourced from the clinicaltrials.gov site and the chictr.org.cn site
Preclinical and clinical applications of adoptive cell therapies for MM
Autologous stem cell transplantation
Autologous stem cell transplantation (ASCT) remains the cornerstone of treatment for MM, especially in younger patients under 65 years old who are in good health [59]. This treatment follows a multi-phase therapeutic path that includes induction, high-dose melphalan (HDM) with ASCT, consolidation, and maintenance therapy, the combination of high-dose chemotherapy and ASCT provides the maximum therapeutic benefit in eligible MM patients by leveraging the cytotoxic effects of chemotherapy while ensuring recovery of bone marrow function through stem cell reinfusion. While ASCT itself does not directly target myeloma cells, it enables the use of more aggressive chemotherapy, leading to improved long-term outcomes [18, 60]. ASCT achieves high response rates and significantly extends both progression-free (PFS) and overall survival (OS), outperforming standard chemotherapy regimens [18, 61, 62]. Recent guidelines advocate for induction therapy with bortezomib, thalidomide, and dexamethasone (VTd) or bortezomib, lenalidomide, and dexamethasone (VRd) combined with the anti-CD38 monoclonal antibody daratumumab, followed by HDM-ASCT and lenalidomide maintenance [63]. Additionally, ongoing research suggests the early application of ASCT following induction therapy enhances outcomes [64–66]. With the introduction of new immunotherapies, including monoclonal antibodies and CAR-T cell therapy targeting MM cells, the role of ASCT may evolve, integrating these advances to improve response rates and minimize relapse [67, 68]. These newer strategies aim to reactivate the immune system, either passively or actively, providing deep and durable responses and raising the potential for their inclusion earlier in the treatment regimen [69]. For transplant-eligible newly diagnosed multiple myeloma (NDMM) patients, HDM plus ASCT remains the standard of care recommended by international guidelines from organizations such as the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and European Bone Marrow Transplantation (EBMT) [12, 63, 70]. Until recently, induction therapy typically involved a three-drug regimen of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and dexamethasone. However, the treatment landscape has shifted with the introduction of anti-CD38 monoclonal antibodies, daratumumab and isatuximab, leading to the adoption of four-drug regimens (quadruplets) in place of the previous three-drug regimens (triplets) [71, 72].
Induction regimens for ASCT
Daratumumab, a human IgG/kappa monoclonal antibody targeting CD38, is approved for treating RRMM and NDMM [73–76]. It has become a new standard of care in transplant-eligible NDMM, as shown in the phase III CASSIOPEIA trial (NCT02541383), where adding daratumumab to VTd improved stringent complete response (sCR) rates and PFS, with 64% achieving minimal residual disease (MRD) negativity [77, 78]. The phase II GRIFFIN study (NCT02874742) further demonstrated the efficacy of daratumumab with VR, showing higher sCR and MRD negativity rates than VRd alone [79, 80]. These findings were confirmed by the phase III PERSEUS study (NCT03710603), where daratumumab plus VRd significantly improved PFS and MRD negativity rates [81]. Additionally, the phase II MASTER trial (NCT03224507) highlighted the potential of MRD-driven therapy adjustments with the Dara-KRd regimen (daratumumab, carfilzomib, lenalidomide, dexamethasone), offering a treatment-free state for MRD-negative patients [82]. These studies collectively affirm the benefits of incorporating daratumumab into standard treatment regimens for NDMM.
Isatuximab, a chimeric IgG monoclonal antibody targeting a unique epitope on CD38, exerts anti-myeloma effects through mechanisms including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, direct induction of apoptosis, and inhibition of CD38 enzyme activity [83, 84]. Approved for RRMM, it is also being explored for NDMM in transplant-eligible patients [85–88]. In the phase III GMMG-HD7 trial (NCT03617731), 660 transplant-eligible NDMM patients received either isatuximab plus bortezomib, lenalidomide, and dexamethasone (Isa-VRd) or standard VRd. The trial reported a 50% MRD negativity rate in the isatuximab group compared to 36% in the control group (p = 0.00017) [89]. The phase II GMMG-CONCEPT trial (NCT03104842) evaluated isatuximab with carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in high-risk NDMM patients. Post-consolidation, 72.8% achieved complete or stringent complete responses, 18.2% very good partial responses, and an overall response rate of 94.9%. MRD negativity was achieved by 67.7% after consolidation and 81.8% at some point. Sustained MRD negativity for 6 and 12 months was 72.7% and 62.6%, respectively. With a median follow-up of 44 months, the median PFS had not been reached, highlighting Isa-KRd's potential in high-risk NDMM [90].
Advancements in stem cell mobilization and collection techniques
Mobilizing CD34+ stem cells from bone marrow to peripheral blood is essential for harvesting adequate hematopoietic stem cells (HSC) for ASCT. A minimum of 2 × 106/kg CD34+ cells is required, with optimal targets of > 3 × 106/kg for one ASCT and > 6 × 106/kg for two ASCTs. While the optimal mobilization strategy remains debated, current methods include granulocyte colony-stimulating factor (G-CSF), optionally preceded by Cyclophosphamide (1.5–4 g/m2) [91–93]. Plerixafor, a selective CXCR4 antagonist, enhances mobilization by preventing HSC adherence to the marrow, reducing procedure failure, and minimizing adverse events like neutropenia [94–96]. Anti-CD38 monoclonal antibodies used in induction therapy for NDMM have shown reduced HSC mobilization efficiency, as seen in the CASSIOPEIA trial, which reported lower CD34+ cell yields with the D-VTd regimen compared to VTd (6.7 vs. 10.0 × 106/kg), higher plerixafor use (21.7% vs. 7.9%), and increased collection failures (24.6% vs. 11.4%) [97–99]. The MASTER and GRIFFIN trials also indicated high plerixafor use with daratumumab-containing regimens but found no negative impact on ASCT feasibility or safety [100]. Another study on 179 NDMM patients from the GMMG-HD6 and GMMG-HD7 trials (NCT02495922, NCT03617731) showed successful mobilization (> 6 × 106/kg CD34+ cells) with VRd, I-VRd, and elotuzumab-VRd, confirming that isatuximab addition does not negatively affect mobilization [101–103]. These findings underscore that despite varying yields and increased plerixafor use, integrating daratumumab or isatuximab into induction regimens does not hinder successful stem cell collection or ASCT outcomes.
T cell receptor (TCR) gene engineered T cells
The TCR is essential for the specific activation and clonal expansion of T cells in response to antigens. TCRs are generally heterodimers, composed of α and β chains, each featuring constant and variable domains. The variable domain undergoes somatic recombination, creating a vast diversity of TCR clonotypes, essential for recognizing antigens presented on cells by major histocompatibility complex (MHC) molecules [104, 105]. Unlike CARs, TCRs lack an intrinsic signaling domain and require the CD3 complex to transmit activation signals through phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs). This interaction initiates various signaling pathways, leading to T cell activation [106, 107]. TCRs are highly sensitive; a few interactions with peptide-MHC (pMHC) complexes can trigger T cell responses, including cytokine production and target cell killing. High avidity TCRs, which bind strongly to pMHC, typically induce stronger immune responses and are more effective at lower antigen concentrations [108, 109]. However, T cells with lower-affinity TCRs are also crucial, maintaining immune effectiveness across a range of conditions and contributing to long-term immune memory, especially in chronic infections and cancer [110, 111]. Co-stimulation is necessary for optimal TCR signaling, provided by interactions with co-receptors and ligands that modulate T cell responses. This modulation influences T cell differentiation, proliferation, and longevity, which are key for effective immune responses and potential therapeutic interventions [109, 112, 113]. Understanding the integration of these signals can enhance T cell-based therapies by adjusting co-stimulation to improve T cell functionality in diverse disease settings.
TCR therapy for MM involves engineering patient T cells to target specific antigens such as NY-ESO-1 [37, 114], MAGE-A3 [115, 116], and BCMA [117], which are either unique to or overexpressed by MM cells. This strategy enables the modified T cells, upon reintroduction into the patient, to specifically identify and eradicate malignant cells. The effectiveness of this therapeutic approach largely depends on the selection of appropriate target antigens [67]. NY-ESO-1 is often selected due to its restricted expression in normal tissues, enhancing its safety profile [118, 119]. MAGE-A3 is chosen for its tumor-specific expression, providing a high degree of cancer selectivity [120, 121]. Additionally, BCMA, a target commonly utilized in CAR-T cell therapies [27, 122, 123], is increasingly being considered for TCR-based strategies due to its prevalent expression in MM cells [124]. However, BCMA itself, as a protein expressed on the surface of B cells, is not typically a target for TCR therapies because TCRs recognize peptides presented by MHC molecules on the surface of cells, rather than whole proteins or antigens directly exposed on the cell surface. This precision in antigen targeting is crucial for the success of TCR therapies in treating MM.
TCR‐engineered T cells targeting NY-ESO-1 tumor antigen
NY-ESO-1, a cancer-testis antigen, is primarily expressed in a variety of cancers but is absent in normal tissues with the exception of the testis. The testis lacks expression of the MHC, enabling evasion of immune detection. The restricted expression and immunogenic properties of NY-ESO-1 render it an ideal target for cancer immunotherapy [125–127]. In the context of oncological research, NY-ESO-1 mRNA has been identified in 20–40% of tumors, including those of the esophageal, gastric, melanoma, prostate, and several other carcinomas [128–131]. Its expression is notably associated with advanced cancer stages and correlates with poorer survival outcomes, emphasizing its potential as a prognostic marker. This antigen's relevance is particularly pronounced in MM, where NY-ESO-1 expression is predominantly observed in advanced stages of the disease [132]. The progression from diagnosis to relapse often sees an increase in NY-ESO-1 levels, mirroring broader malignancy trends where progression correlates with the upregulation of cancer/testis antigen (CTA) genes such as NY-ESO-1. This upregulation is likely a consequence of global hypomethylation events within the genome [133]. Mastaglio et al. demonstrated that single TCR gene editing using the clinical-grade HLA-A2 restricted NY-ESO-1157-165-specific TCR can quickly generate large quantities of tumor-specific T cells. These cells effectively target and eliminate cancer cells, showing a strong and safe performance compared to traditional TCR-transferred cells. The edited cells also have a better safety profile, minimizing risks like graft-versus-host disease in mice models. This approach offers a promising and safer method for advancing cancer immunotherapy treatments [118]. Moreover, Rapoport et al. conducted a study (NCT01352286) on 20 MM patients using engineered T cells targeted at cancer antigens NY-ESO-1 and LAGE-1. The treatment was well-tolerated, with no severe side effects, and the T cells showed effective targeting and persistence in the marrow. The presence of these T cells correlated with better clinical outcomes, leading to promising responses in 80% of the patients, with a median PFS of 19.1 months [37]. These studies confirmed that these engineered T cells are safe and effective for treating MM.
TCR‐engineered T cells targeting MAGE-A3 tumor antigen
MAGE-A3 is a member of the melanoma antigen gene (MAGE) family, which are typically not expressed in normal tissues except in testicular germ cells but are expressed in various types of cancers, including melanoma, non-small cell lung cancer, and others. This makes MAGE-A3 an attractive target for cancer immunotherapy [134–136]. Jungbluth et al. showed that MAGE-A3 serves as a promising antigen associated with myeloma, potentially valuable for vaccine-based immunotherapy. Additionally, the widespread expression and its association with cellular proliferation imply a pathogenic role for this gene in MM development [121]. Atanackovic et al. demonstrated that MAGE-A3 significantly enhances the survival of myeloma cells and their clonogenic precursors by diminishing the rates of both spontaneous and chemotherapy-induced apoptosis. Consequently, MAGE-A3 may serve as a promising target for the development of novel, myeloma-specific therapeutic strategies [120]. However, Linette et al. reported two patients with MAGE-A3-positive tumors received T cells modified to target an HLA-A*01-restricted peptide but died within a week from severe myocardial damage caused by an off-target reaction. Autopsies revealed no MAGE-A3 in the heart, but studies showed the T cells reacted to an unrelated cardiac peptide (NCT01350401 and NCT01352286) [137]. This highlights the risks of off-target effects with enhanced TCRs, emphasizing the need for careful analysis and early intervention in TCR-based therapies.
Chimeric antigen receptor (CAR) T cells
CARs are genetically engineered receptors designed to recognize specific antigens, and are expressed on the surface of immune cells (Fig. 3B). The extracellular domain of a CAR typically consists of a single-chain variable fragment (scFv) that binds to antigens overexpressed on tumor cells. This scFv is connected via a hinge domain (e.g., CD8, CD28, IgG1, or IgG4) to a transmembrane domain (e.g., CD28, 4-1BB, or CD8). Intracellularly, CARs include one or more costimulatory domains (e.g., CD28, 4-1BB, or OX40, absent in first-generation CARs) and a CD3ζ activation domain [138, 139] (Fig. 3A). This configuration enables full T-cell activation upon antigen recognition. CAR-T cell therapy has significantly advanced cancer immunotherapy, demonstrating substantial efficacy in treating hematological malignancies, including MM [28, 140, 141].
Fig. 3.
A Structure of different CAR generations. The core structure of a CAR is delineated by its primary components: the extracellular domain, the transmembrane domain, and the intracellular domain. The development of CAR-T cells has evolved significantly across generations. First-generation CARs featured only a signaling domain in the intracellular region. This was followed by second-generation CARs, which incorporated one co-stimulatory molecule. Third-generation CARs included an additional co-stimulatory molecule, enhancing their efficacy. Fourth-generation CARs, also known as TRUCKs (T cells redirected for universal cytokine-mediated killing), are based on second-generation designs but also express cytokines like IL-12 either constitutively or inducibly. The latest, fifth generation, builds further on the second-generation framework by adding intracellular domains of cytokine receptors, such as the IL-2Rβ chain fragment, which includes a STAT3/5 binding motif, to enhance signaling and T cell activity. B CARs can be engineered to be expressed on various immune cells, including T cells, NK cells, and macrophages, enabling these cells to recognize specific tumor antigens without reliance on MHC presentation. This overview encapsulates the array of molecules currently under investigation as potential CAR targets in MM. These include BCMA, CD19, CD38, CD138, SLAMF7, GPRC5D, FcRH5, NKG2D, k light chain, NY-ESO-1, CD44V6, CD46, CD56, CD70, CD74, CD229, integrin β7, ILT3, MUC1, CCR10, Lewis Y antigen and SEMA4A. Figure created with BioRender.com
BCMA targeted CAR‐T cells
BCMA, or B-cell maturation antigen is crucial in MM pathogenesis, largely due to its interactions with the ligands APRIL (a proliferation-inducing ligand) and BAFF (B-cell activating factor) [142–144]. These interactions support the survival and proliferation of MM cells [145]. BCMA is mainly found on plasma cells, which are central to MM, and is significantly overexpressed in myeloma cells compared to normal ones [122, 146]. Upon binding with APRIL and BAFF, BCMA triggers various signaling pathways, notably the NF-κB pathway, enhancing gene transcription that supports cell survival, growth, and chemotherapy resistance [147, 148]. This relationship also modifies the bone marrow environment, further facilitating myeloma cell growth. Given its specific overexpression in myeloma cells and limited presence in normal cells, BCMA is an effective target for therapies like antibody–drug conjugates, bispecific T-cell engagers (TCEs), and CAR-T cell therapies [27, 67, 149, 150]. These treatments focus on selectively eliminating myeloma cells with minimal impact on healthy cells.
In the preclinical phase, BCMA targeted CAR-T cells demonstrated potent cytotoxic activity in vitro and in vivo against myeloma cells. These studies often involve testing the CAR-T cells against human myeloma cell lines in mice models to observe the efficacy and safety of the treatment [151–156]. Safety is a critical aspect of preclinical trials. CAR-T cell therapy can lead to CRS and neurotoxicity, which are significant concerns [157, 158]. Preclinical models have been used to study these effects and refine the cell manufacturing process and dosing strategies to minimize adverse effects. Moreover, further advancements in CAR-T cell designs are ongoing in preclinical studies to enhance their effectiveness and reduce side effects. This includes modifications like the inclusion of suicide genes [159], dual-targeting CARs [160], or using different co-stimulatory domains to improve cell persistence and function [161, 162]. These preclinical findings are foundational for advancing BCMA targeted CAR-T therapy into clinical settings, where the real-world efficacy and safety can be evaluated in patients with MM. This research is crucial in potentially offering a new and effective treatment for patients who have RRMM.
In the clinical phase, Idecabtagene vicleucel (Abecma), also known as Bb2121, is the first CAR-T cell therapy approved by the U.S. Food and Drug Administration (FDA) for adults with RRMM in March 2021. This therapy targets patients whose MM has either recurred or failed to respond to prior treatments [163]. Lin et al. conducted a phase I multicenter study (CRB-401) on 62 patients with RRMM, followed for a median of 18.1 months. The study (NCT02658929) primarily assessed safety and showed low rates of serious side effects, with 6.5% experiencing severe CRS and 1.6% severe neurotoxicity. The overall response rate (ORR) was 75.8%, with 64.5% achieving a very good partial response (VGPR) or better, and 38.7% reaching CR or sCR. Secondary measures included median durations of CR, PFS, and OS at 10.3, 8.8, and 34.2 months, respectively. Furthermore, the expansion of Bb2121 in blood and bone marrow was linked to clinical effectiveness and a decrease in soluble BCMA. Notably, patients with longer PFS (≥ 18 months) had T cells that were less exhausted and showed a more robust functional phenotype [38]. These findings support the safety, tolerability, and effectiveness of Bb2121, highlighting specific T cell characteristics associated with durable responses. LCAR-B38M (JNJ-68284528) is a second-generation, bispecific CAR-T cell therapy targeting two distinct BCMA epitopes, enhancing its binding affinity. This differentiates it from other BCMA-directed CAR-T therapies. The therapy is being evaluated in the LEGEND-2 phase I/II trial (NCT03090659) in China for patients with RRMM. The study reported a 5-year PFS of 21.0% and OS of 49.1%, noting a stabilization of survival curves over time. Participants achieving CR demonstrated notably higher 5-year PFS and OS rates of 28.4% and 65.7%, respectively. Notably, 12 patients (16.2%) maintained relapse-free status despite high-risk cytogenetic abnormalities and all had restored normal humoral immunity. A sustained CR was associated with favorable prognostic factors including good performance status, IgG subtype, absence of extramedullary disease, and a lymphodepletion regimen combining cyclophosphamide (CTX) and fludarabine (FAM). Among the patients, 83.8% experienced disease progression or death; however, 61.1% of those responded to subsequent therapies, particularly proteasome inhibitor-based treatments. Safety profiles showed comparable recovery of hematologic and hepatic functions across groups, with a low incidence of secondary malignancies (5.4%) and no severe viral infections. One patient in persistent remission exhibited a sustainable CAR-T population characterized by a predominance of indolent, low-cytotoxicity CD4/CD8 double-negative T cells [39]. The CARTITUDE-1 phase Ib/II study (NCT03548207) evaluated ciltacabtagene autoleucel (cilta-cel) in patients with relapsed/refractory multiple myeloma, demonstrating sustained, profound responses after 12 months. Updated results, with a median follow-up of 27.7 months (N = 97), show a remarkable ORR of 97.9% and a sCR rate of 82.5%. Patients, including high-risk subgroups, received a single cilta-cel infusion following lymphodepletion. Median PFS and OS were not reached, with 27-month PFS and OS rates at 54.9% and 70.4%, respectively. Response durations were reduced in high-risk patients. The treatment's safety profile remained manageable, with stable adverse events. These findings, at around 28 months, confirm cilta-cel's robust efficacy and favorable risk/benefit ratio in treating advanced MM [40]. In a phase Ib study (NCT02546167), Cohen et al. evaluated autologous T cells modified with a lentiviral BCMA-specific CAR, incorporating CART-BCMA, in 25 patients with RRMM. Participants were assigned to three cohorts: 1) 1–5 × 108 CART-BCMA cells, 2) 1–5 × 107 CART-BCMA cells plus CTX at 1.5 g/m2, and 3) 1–5 × 108 CART-BCMA cells plus CTX at the same dose. BCMA expression was not a criterion for inclusion. All patients received the engineered T cells, which expanded successfully. Significant adverse effects were CRS and neurotoxicity, observed as grade 3–4 in 32% and 12% of patients, respectively, but these were reversible. One death occurred due to candidemia and advancing MM on day 24 after severe complications. Therapeutic responses varied across cohorts, with efficacy rates of 44% in cohort 1, 20% in cohort 2, and 64% in cohort 3. Outcomes included five partial, five very good partial, and two complete responses. Three responses were maintained for up to 32 months. Response and T cell expansion correlated with the CD4:CD8 ratio and CD45RO−CD27+CD8+ T cell prevalence in the pre-treatment leukapheresis product. CART-BCMA treatment, with or without lymphodepleting chemotherapy, showed clinical activity in extensively treated MM patients [41]. The phase I dose-escalation trial (NCT03070327) assessed MCARH171 in RRMM patients. Participants underwent a FAMP and CTX conditioning regimen before receiving 1–2 doses of MCARH171. Four escalating doses tested range from 72 × 106 to 818 × 106 CAR-T cells. As of July 16, 2018, 11 patients, having previously failed an average of six myeloma treatments, were treated, achieving an ORR of 64% with a median duration of response (mDOR) of 106 days. Patients in high-dose cohorts exhibited greater peak expansion, prolonged persistence of MCARH171, and more sustained clinical responses compared to those in low-dose cohorts. CRS was reported in six patients, with two experiencing grade 3 severity. Additionally, one patient developed transient grade 2 encephalopathy that resolved within 24 h. No dose-limiting toxicities (DLTs) were observed [42]. CART-BCMA therapies, have demonstrated significant efficacy in RRMM, though they are associated with severe neurological toxicities, primarily immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS typically occurs within the first week of treatment and presents with a range of symptoms, including headache, confusion, delirium, aphasia, tremors, and seizures. In more severe cases, it can progress to encephalopathy, coma, or cerebral edema, which may be fatal. Motor dysfunction, such as tremors and muscle weakness, and seizures have also been reported. While ICANS often occurs alongside CRS, it can manifest independently. Prompt recognition and management of these neurotoxic effects, typically with corticosteroids or other immunosuppressive agents, are critical to preventing life-threatening complications [164]. Despite these risks, studies consistently highlight the potential of BCMA-targeted CAR-T therapies in advanced MM, demonstrating both robust efficacy and a manageable safety profile across diverse patient cohorts.
CD19 targeted CAR‐T cells
CD19 is typically not targeted in MM treatments because it is mainly found on B cells and their precursors, while MM primarily arises from plasma cells, which do not usually express CD19 [165–168]. Consequently, CD19-targeted CAR-T cell therapy, effective in other B-cell malignancies, has limited applicability in MM [169, 170]. However, emerging research indicates that a small subset of MM cells might express CD19 or that combining CD19 with other antigens could enhance treatment efficacy [28]. The infusion of anti-CD19 and anti-BCMA CAR-T cells in patients with NDMM or RRMM has shown promising results and manageable side effects [43, 44], despite not conclusively preventing progression post-anti-BCMA therapy. There are indications of its potential benefit, particularly in dual-targeted strategies. For instance, early studies have begun to explore dual-targeting CAR-T cells aimed at both BCMA and CD19, though these are less prevalent than BCMA-focused therapies [171]. A recent Phase I/II trial in China (ChiCTR2000033567) investigating a BCMA-CD19 bispecific CAR-T cell therapy showed that BC19 CAR T cells are feasible, safe, and effective for treating patients with RRMM, demonstrating promising early responses [45].
CD38 targeted CAR‐T cells
CD38, a glycoprotein found abundantly on the surface of MM cells, serves as an ideal target for therapeutic interventions, such as monoclonal antibodies (daratumumab and isatuximab) [83, 172–174]. This molecule is integral to various cellular processes including cell adhesion, signal transduction, calcium signaling, and the regulation of apoptosis—a key mechanism in cancer treatment [175, 176]. Its high and uniform expression on plasma cells and other lymphoid cells highlights its potential as a focal point for novel therapeutic strategies in MM [177, 178]. Several research groups have developed anti-CD38 CAR-T cells and tested them in preclinical studies [179–182]. These cells often lack CD38 expression, likely due to the elimination of CD38-positive cells among them, a process known as fratricide. Despite this, the anti-CD38 CAR-T cells effectively target myeloma cells, supporting previous findings that CD38 is not essential for T cell functionality [183]. Notably, Glisovic-Aplenc et al. reported the anti-CD38 CAR-T cells they produced did not experience fratricide, potentially because of a protective mechanism within the CAR construct. These CAR-T cells can deplete CD34+ CD38+ hematopoietic progenitors in vitro and in vivo; however, they appear to spare other hematopoietic lineages, indicating that the CD34+CD38− low/negative cells can sustain hematopoiesis [180, 182]. As these therapies progress to clinical trials, it is crucial to monitor their impact on the immune and hematopoietic systems in patients.
In the clinical phase, Mei et al. developed a CAR-T cell with dual targeting domains for CD38 and BCMA, and a 4-1BB co-stimulatory domain, selecting a scFv with lower CD38 affinity to minimize hematopoietic toxicity (ChiCTR1800018143) [46]. This construct was administered to 23 patients, resulting in an ORR of 87%, with 52% achieving CR. Common toxicities included CRS in 87% of patients and significant cytopenias in 96%, with severe cases (grade ≥ 3) in 17% and 87% respectively. Two fatalities occurred due to infection and cerebral hemorrhage. The duration of response (DOR) reached 76% over one year. Another study with a similar dual-targeted CAR-T cell construct reported on 16 RRMM patients, showing comparable toxicities and an ORR of 88% with 81% CR. Notably, one patient died from an infection during prolonged CRS and persistent cytopenias related to hemophagocytic lymphohistiocytosis [47]. Moreover, Zhang et al. administered separate anti-CD38 and anti-BCMA CAR-T cells to 22 patients, achieving an ORR of 91% and CR rate of 55%. However, two deaths occurred due to CRS [48]. In summary, the primary challenge in analyzing these studies is determining the specific toxicity and responses caused by the anti-CD38 therapy component, as it was always used in combination with anti-BCMA constructs.
SLAMF7 targeted CAR‐T cells
The glycoprotein cell surface receptor signaling lymphocytic activation molecule family member 7 (SLAMF7), also known as CD319 or CS1, is a receptor found primarily on MM cells, natural killer cells, and some T cell subsets [184, 185]. Its high expression on malignant plasma cells and crucial role in plasma cell survival has led to the development of targeted therapies [186]. One such therapy, the anti-SLAMF7 antibody elotuzumab, has been FDA-approved for use with lenalidomide and dexamethasone in treating RRMM [187]. Additionally, using CAR-T cells to target SLAMF7 offers a promising approach to treat MM.
Several groups have developed anti-SLAMF7 CAR-T cells, showing promise in preclinical models for treating MM. Gogishvili et al. engineered CAR T cells with elotuzumab's target-binding domain and a CD28 co-stimulatory domain, effectively targeting myeloma in patient-derived and murine models [188]. Although SLAMF7 is also present on various immune cells, leading to potential fratricide, post-manufacture CAR T cells mostly lacked SLAMF7 expression, mitigating this issue. They also spared SLAMF7-low immune cells while depleting high expressers. Furthermore, Roders et al. enhanced anti-myeloma efficacy by using CRISPR/Cas9 to eliminate CD38 in T cells, creating a dual CAR system targeting CD38 and SLAMF7 [189]. This approach showed robust responses without the toxicity seen in anti-CD38 CAR T therapy, suggesting a safer alternative. O'Neal et al. utilized a different SLAMF7-binding epitope and a third-generation co-stimulatory domain, producing mainly CD4+ CAR-T cells due to CD8+ T cell fratricide [190]. They further applied CRISPR/Cas9 to prevent fratricide, achieving a balanced CD4/CD8 ratio without enhancing efficacy significantly. Collectively, these studies indicate the potential of anti-SLAMF7 CAR-T cells in myeloma treatment, though the implications of fratricide require more research. In a phase I/IIa clinical trial initiated based on preclinical studies of a dual-targeted single-chain CAR featuring anti-BCMA and anti-SLAMF7 domains, results from 16 treated patients were recently published [49]. The trial reported toxicities including CRS in 38% of cases, 6% of which were grade 3 or higher, but no instances of Immune effector cell-associated neurotoxicity syndrome (ICANS). All patients experienced cytopenias, with 100% encountering severe (grade ≥ 3) cases. Infections occurred in 38% of the patients, with severe infections (grade ≥ 3) in 31%. Efficacy was notable, with an ORR of 81% and sCR rate of 38%.
GPRC5D targeted CAR‐T cells
G protein-coupled receptor class C group 5 member D (GPRC5D) is a protein predominantly expressed on the surface of MM cells but with limited expression in normal tissues [191–193]. This makes it an attractive target for CAR-T therapy because therapies directed against it can potentially kill myeloma cells while sparing most healthy cells [194]. In murine and nonhuman primate models, CAR-T cells targeting GPRC5D showed effective anti-MM activity in vivo, including in BCMA escape models, without on-target, off-tumor toxicity [195, 196]. This success has spurred the clinical development of therapeutic agents that target GPRC5D for MM treatment. In a 2022 phase I study by Mailankody et al. [50], 17 RRMM patients, all previously treated with at least three lines of therapy including proteasome inhibitors (PIs), IMiDs, anti-CD38, and BCMA-targeted therapies, received infusions of MCARH109. This CAR-T cell therapy features a humanized anti-GPRC5D scFv target-binding domain and a 4-1BB co-stimulatory domain. Doses ranged from 25 to 450 × 106 CAR T-cells. The study established 150 × 106 CAR-T cells as the maximum tolerated dose after observing severe adverse events, including grade 4 CRS and ICANS in one patient, and grade 3 cerebellar disorder in two patients at the highest dose level. These neurological effects were likely due to low-level, off-target GPRC5D expression. Among patients who received 25 to 150 × 106 CAR-T cells, no severe CRS or neurotoxicity was reported, and ORR was 71%, with 58% for those administered up to the maximum tolerated dose. Other mild side effects included grade 1 nail changes in 65% of patients and grade 1 taste alterations or dry mouth in 12%. Moreover, BMS-986393 is an autologous CAR-T cell therapy targeting GPRC5D, evaluated in a phase I, first-in-human trial (CC-95266-MM-001, NCT04674813) [51]. This multi-center study involved patients with three or more prior lines of therapy, including PIs, IMiDs, anti-CD38 therapy, and ASCT, alongside previous BCMA-targeted therapies. In the dose expansion cohort of 70 patients, BMS-986393 doses ranged from 25 to 450 × 106 CAR-T cells. Of these patients, 46% had prior BCMA-targeted therapy, and 36% had prior BCMA-directed CAR-T cell therapy. The ORR was 86%, with a 38% CR rate in patients with assessable efficacy, and 85% ORR with a 46% CR in those refractory to prior BCMA-targeted therapies. Common severe side effects included neutropenia (69%), anemia (31%), and thrombocytopenia (30%). There were no severe adverse events related to skin, nails, or taste. CRS occurred in 84% of patients, mostly mild; however, severe CRS led to one death and affected three additional patients. Neurological toxicities were noted, with 11% experiencing ICANS, and other neurological symptoms like cerebellar toxicity and headache occurring in a few patients. This data supports the potential of BMS-986393 as a treatment for RRMM, with further investigations ongoing. Furthermore, OriCAR-017, another GPRC5D-targeted autologous CAR T-cell therapy, features the proprietary Ori signal activation domain to enhance memory immune cells' expansion efficiency, boosting the anti-tumor effectiveness and longevity of CAR T-cells in vivo [191]. In the phase I POLARIS trial in China (NCT05016778) [52], 10 RRMM patients received OriCAR-017 in doses from 1 to 6 × 106 CAR-T cells/kg. All patients experienced hematologic toxicities, such as neutropenia (100%), thrombocytopenia (90%), leukopenia (90%), and anemia (70%). Ninety percent encountered grade 1 CRS, 10% had grade 2 CRS, and there were no cases of neurologic toxicities. ORR was 100%, with 60% achieving sCR. After a median follow-up of 7.8 months, disease progression occurred in two patients. However, mechanisms underlying resistance to anti-GPRC5D CAR-T cell therapy are becoming clearer. Mailankody et al. showed that unlike relapse after anti-BCMA CAR-T cell therapy, where BCMA loss is rare, four out of six patients who initially responded and then relapsed showed complete loss of GPRC5D expression. Notably, one patient exhibited biallelic deletions at the GPRC5D loci [50]. Additional studies have identified complex GPRC5D deletions and mutations during relapse following anti-GPRC5D bispecific TCE therapy, pointing to genetic alterations that reduce GPRC5D expression [197]. Moreover, Derrien et al. reported a patient with decreased chromatin accessibility at the GPRC5D promoter and distant enhancer regions, suggesting epigenetic silencing [198]. These findings underscore the intricate tumor biology of myeloma and the need for comprehensive treatment strategies to overcome resistance.
GPRC5D-targeted therapies have shown promise, particularly for patients who have previously failed BCMA therapies, offering reduced infection risks [194]. Common side effects include skin and oral issues such as rash and dry mouth, which are generally manageable with standard care, though taste changes remain a challenge. These therapies are associated with fewer such side effects compared to TCE therapies, possibly due to different tissue distributions and dosing regimens [199]. Some unique side effects of CAR-T cell therapies include dizziness at high doses. Recent studies, including dual-targeted BCMA and GPRC5D therapies, suggest potential for significant improvements in treatment outcomes for MM, highlighting GPRC5D's role in advancing MM treatment strategies [200]. Future clinical trials and novel approaches like dual-targeting constructs and combination therapies are currently being explored, indicating a robust pipeline for enhancing therapeutic efficacy and safety.
CD138 targeted CAR-T cells
CD138 (Syndecan-1), a transmembrane proteoglycan, is primarily expressed on terminally differentiated B cells and is essential for plasma cell survival [201, 202]. However, its expression on other cell types such as epithelial and endothelial cells theoretically limits its utility as a therapeutic target [203]. Despite these challenges, anti-CD138 CAR-T cells have been developed and preclinically tested. These cells, as demonstrated by Sun et al., did not affect endothelial or epithelial cells in co-culture experiments [204]. Ongoing clinical and preclinical studies, including a U.S. trial (NCT03672318), aim to optimize this therapy. Notably, a novel dual-split CAR construct targeting both CD38 and CD138 antigens showed efficacy in eliminating malignant plasma cells while sparing hematopoietic precursors. Additionally, a phase I trial (NCT01886976) involving a CD138-directed CAR-T cell with a 4-1BB domain in RRMM patients reported manageable side effects and detectable CAR-T cells up to three months post-treatment. Despite CD138 expression in normal tissues, no off-target effects have been reported in ongoing trials, though the limited efficacy of these constructs raises questions about the potential safety of more potent CD138-targeted therapies.
FcRH5 targeted CAR-T cells
Fc receptor-homolog 5 (FcRH5) is predominantly expressed on plasma cells, marking it as a promising target for MM immunotherapy [205]. Its expression is limited primarily to certain B cell subsets and is notably heightened in MM patients with a 1q21 amplification, a known adverse prognostic factor [206]. Cevostamab, a bispecific TCE targeting FcRH5, is currently in early clinical trials and has demonstrated promising efficacy with minimal toxicity [207]. Additionally, preclinical developments include an anti-FcRH5 CAR-T cell therapy that effectively eradicates myeloma cells both in vitro and in vivo [208]. This includes a model of myeloma resistant to BCMA-targeted therapies. A dual-targeted CAR-T therapy combining anti-BCMA and anti-FcRH5 has also shown potential. While no clinical trials for anti-FcRH5 CAR-T cells are ongoing, their future exploration is anticipated. However, more comprehensive clinical data are required to fully assess the safety and efficacy of FcRH5-directed therapies.
Other potential targets for MM
Several clinical trials have evaluated other targeted CAR-T cell therapies in myeloma with limited success. Trials with anti-κ light chain CAR-T cells aimed at the κ light chain found in many B cell tumors showed no positive responses in myeloma patients [209]. Similarly, trials using anti-NKG2D ligand CAR-T cells, which target widely expressed NKG2D ligands on various tumors, also failed to show effectiveness [210, 211]. Additionally, trials with anti-NY-ESO-1 TCR-engineered T cells post-ASCT indicated some biological activity, but the results were mixed and the effectiveness of the CAR-T cells themselves remains unclear [37, 212]. Preclinical studies have also identified several other potential targets for CAR-T cell therapy in myeloma, including CD44 splice variants [213], CD46 [214], CD56 [215], CD70 [216], CD74 [217], CD229 [218, 219], integrin β7 [220], Lewis Y antigen [221], ILT3 [222], SEMA4A [223], CCR10 [224], and Mucin 1 (MUC1) [225].
CAR-NK cells or genetically engineered NK cells
Engineering of natural killer (NK) cells has emerged as a promising cancer therapy, offering an alternative to conventional methods [226–228]. NK cells, which are part of the innate immune system, can be activated without antigen presentation or strict matching of human leukocyte antigens (HLAs), unlike T cells. This allows the development of CAR-NK cells, which are less likely to induce graft-versus-host disease (GVHD), making them suitable for "off-the-shelf" use [229, 230]. CAR-NK cells can be sourced from established NK cell lines like NK92 or from induced pluripotent stem cells (iPSCs), bypassing the need for cells from the actual patient [231, 232]. Additionally, NK cells kill cancer cells by releasing perforin and granzyme, and expressing ligands such as FasL and TRAIL, significantly reducing the risk of CRS often associated with CAR-T cell therapies [233, 234]. NK cells can be derived from various sources, including peripheral and cord blood, as well as iPSCs, allowing for allogeneic use that does not require donor-patient HLA matching. This versatility could potentially lower the costs of CAR cell therapies. CAR-NK therapy is appealing because it is less likely to cause CRS and GVHD and can counteract the tumor's resistance mechanisms [235]. However, challenges remain, such as lower transduction efficiency and expansion issues, particularly with peripheral blood-derived NK cells. Cord blood-derived NK cells tend to minimize these problems but are relatively immature, which is a drawback [236, 237]. NK92, an IL-2-dependent immortalized cell line derived from a lymphoma patient, requires irradiation before clinical use due to safety concerns, despite the general safety of infusion. The primary advantages of NK92 are its ease of expansion and availability, which reduce both treatment initiation time and costs. However, while NK-92 cell lines are readily manipulable and expandable, they pose safety risks and exhibit poor long-term survival [238, 239]. Enhancing the survival, cytotoxicity, and tumor-targeting of CAR-NK cells are critical areas of ongoing research in improving the effectiveness of CAR-NK cell therapies.
Ren et al. and Cao et al. developed BCMA-specific CAR-NK cells targeting MM, enhancing cytotoxicity and survival in mouse models [240, 241], with ongoing clinical trials (NCT03940833 and NCT05182073) exploring their therapeutic potential. Jiang et al. demonstrated that CD138-specific CAR-NK cells target CD138-positive malignancies, potentially improving remission outcomes post-chemotherapy [242]. Chu et al. advanced SLAMF7-specific CAR-NK cell therapy, showing significant tumor inhibition and survival extension in MM models, indicating its promising treatment prospects [243]. Additionally, studies revealed that NKG2D-CAR NK cells, engineered from autologous NK cells of MM patients, safely enhance antimyeloma activity [244]. Reiser et al. developed the iPSC-derived FT555 CAR-NK cell product targeting GPRC5D and CD38, used alongside daratumumab, providing a scalable, off-the-shelf therapeutic option for broad MM patient access [245]. These innovations highlight significant advances in NK cell therapies for MM, focusing on dual targeting and engineered enhancements to improve efficacy and patient outcomes.
CAR-NK cell therapy, inspired by CAR-T methods, requires sophisticated cell processing facilities and trained personnel. Optimizing CAR properties and NK cell metabolism is key to combating drug-resistant MM. NK cells, with their inherent anti-tumor abilities, are enhanced to improve lifespan and activation for better MM response. CAR-NK targets multiple stable antigens to avoid issues like antigen shedding and off-target effects seen with CAR-T therapies. Additionally, off-the-shelf NK cell therapies are being developed to reduce costs and widen patient access. Unlike T cell therapies, repeated NK cell doses are necessary for a sustained and effective anti-MM response, offering a promising alternative for improving MM patient outcomes.
Bi- and trispecific immune cell engagers for cell therapy of MM
Bi- and trispecific T cell and NK cell engagers are emerging targeted immunotherapies aimed at enhancing the antitumor response against MM [246–249]. These molecules typically consist of single-chain variable fragments that bind simultaneously to CD3 on T cells and a tumor-associated antigen like BCMA or CD19, commonly overexpressed in MM cells [149, 250]. By forming an immunological synapse between T cells and cancer cells, these engagers facilitate targeted tumor cell killing. Trispecific engagers further enhance this approach by incorporating an additional binding domain, boosting specificity and immune attack potency [251]. NK cell engagers activate NK cells by targeting receptors such as CD16, alongside a tumor-specific antigen, directing NK cell cytotoxicity towards MM cells [252–254]. These dual and triple targeting strategies amplify the immune response and mitigate antigen escape, a common challenge in MM treatment [140, 255, 256]. However, these engagers can induce severe side effects like CRS, necessitating ongoing optimization to balance efficacy with safety [246, 257]. Current clinical trials are promising, indicating potential in achieving sustained responses in MM, particularly in cases resistant to conventional treatments [258]. Integrating these novel engagers with other therapies could enhance outcomes through a robust, precisely targeted immune approach.
As mentioned previously, BCMA is a crucial target in MM treatment due to its role in cell proliferation and survival. It is primarily expressed on malignant and normal plasma cells, but not on hematopoietic stem cells or most non-hematopoietic tissues, making it an ideal target for T cell-redirecting therapies. Elevated levels of soluble BCMA (sBCMA) are associated with disease progression. The FDA has approved several BCMA-targeted therapies, including CAR-T products Abecma and cilta-cel, and the antibody–drug conjugate belantamab mafodotin, which was withdrawn in 2022 after failing a phase III trial [259]. In October 2022, subcutaneous teclistamab was approved for patients with RRMM who had previously failed multiple treatments, marking it the first anti-BCMA × anti-CD3 TCE bispecific antibody (BsAb) to receive approval [260]. Teclistamab showed an ORR of 63% and CR rate of 39.4% in clinical trials (NCT03145181, NCT04557098). Despite a lower response rate compared to some CAR-T treatments, teclistamab offers a safer profile and easier production [261, 262]. Other promising BCMA-targeted BsAbs like elranatamab and linvoseltamab are undergoing FDA review or clinical trials with favorable preliminary results [263, 264]. Emerging treatments for MM include talquetamab and cevostamab. Talquetamab targets GPRC5D, a novel receptor expressed on MM cells. Cevostamab (RG6160) is an FcRH5 × CD3 TCE that binds to a membrane-proximal epitope of FcRH5, promoting efficient synapse formation and MM cell killing. Clinical studies have demonstrated high efficacy for both treatments [265, 266]. Other strategies include targeting CD38 and SLAMF7 with TCE BsAbs and exploring trispecific antibodies (TsAbs) combining multiple targets for enhanced efficacy [246].
It is worth noting that redirecting NK cells to kill tumors is a potential alternative to T cell based therapies, which, though effective, often cause severe side effects like CRS. Clinical responses observed with anti-CD19 CAR-NK cells, without major toxic effects, illustrate the potential of NK cell based immunotherapy [267]. Most NK cell engagers (NKCEs) display an antibody fragment directed against CD16a, similar to the CD3-targeting moiety of TCE [268]. NKCEs like AFM13, a chimeric tandem diabody (TandAb) with anti-CD30 and anti-CD16a domains, have shown potent ADCC and promising results in clinical trials, especially when combined with allogenic NK cells [269]. Advanced NKCEs such as antibody-based NKCE technology and trispecific NKCE therapies platforms incorporate multiple binding domains to enhance NK cell activation and tumor cell killing. For example, the trispecific NKCE (IPH6401/SAR445514) targets BCMA, NKp46, and CD16a, showing potent antitumor activity in preclinical studies and ongoing phase I trials [270]. IL-15-based trifunctional NK cell engagers (TriKEs) like GTB-5550 enhance NK cell activation and proliferation, showing promising preclinical results in treating MM [271]. Overall, bi- and trispecific T cell and NK cell engagers represent a significant advancement in MM therapy, offering targeted, potent, and potentially safer alternatives to existing treatments. Ongoing clinical trials and optimization efforts are crucial to fully realizing their therapeutic potential and integrating them into standard MM treatment regimens.
Other adoptive cell therapies for MM
Lymphokine-activated killer (LAK) cells
Lymphokine-activated killer (LAK) cells, primarily derived from NK cells and T-lymphocytes, are activated by interleukin-2 (IL-2) and exhibit potent cytotoxic activity against tumor cells [272, 273]. LAK cells express NK markers such as CD3−CD56+ and NKG2D, allowing for HLA-independent killing mechanisms [274, 275]. A phase I/II trial assessed low-dose recombinant interleukin-2 (rIL-2) in advanced MM patients who failed standard chemotherapy [53]. Eighteen patients received subcutaneous rIL-2. Tumor response occurred in 6 of 17 patients: 2 had tumor reduction, and 4 achieved stable disease. Eosinophil counts increased 15-fold, CD4+ T cells activated, and CD56+ NK cells expanded. The CD4+/CD8+ ratio normalized, and NK/LAK cell activities enhanced. Endogenous rIL-2 production and soluble rIL-2 receptor levels also increased. In another clinical trial, 16 patients received rIL-2 and LAK cells to reduce relapse rates after autologous bone marrow transplantation (ABMT) [54]. Common side effects included fever, nausea, and rash. Dose-limiting but reversible toxicities were hypotension and thrombocytopenia. Higher rIL-2 doses enhanced NK and LAK cell activity, indicating a strong immunomodulatory effect. These results suggest that rIL-2 and LAK cells warrant further investigation for reducing relapse in advanced hematological malignancies. While low-dose rIL-2 can boost immune function in MM, its efficacy is limited in advanced stages due to tumor-induced immunodeficiency. Future studies should explore the role of rIL-2 in maintaining remission post-chemotherapy. Interestingly, Gottlieb et al. found rIL-2 enhanced cytotoxicity in plasma cell lines and malignant cells from MM patients [276]. Healthy donors' PBMCs showed minimal killing ability, increasing slightly with rIL-2. MM patients' PBMCs induced significant lysis of malignant cells post-rIL-2 exposure. rIL-2-stimulated monocytes released TNF and interferon-γ (IFNγ), reducing malignant cell survival in culture. In vivo, four MM patients received seven rIL-2 courses post-ABMT without serious side effects. rIL-2 increased NK and LAK cell activities and TNF and IFNγ production. These results suggest rIL-2 administration in MM warrants further evaluation, especially for controlling minimal residual disease. However, LAK cell therapy has been replaced by more specific immunotherapies [277, 278].
γδ T cells from TILs and PBMCs
Γδ T cells, a distinct subset of T cells abundant in mucosal organs, constitute less than 5% of peripheral blood lymphocytes [279–281]. They are non-HLA-restricted cytotoxic cells playing a crucial role in both innate and adaptive immunity by directly recognizing and killing pathogens and activating T and B lymphocytes through cytokine release [282, 283]. γδ T cells kill cancer cells through direct recognition via TCRs and natural killer cell receptors (NKRs). They induce apoptosis using TRAIL, FAS ligand (FASL), and the granule exocytosis pathway, releasing perforin and granzymes. γδ T cells also mediate ADCC when tumor-specific antibodies are present. They enhance antitumor immunity by producing IFNγ and acting as antigen-presenting cells to activate αβ T cells. Additionally, they express the 4-1BB ligand (4-1BBL) to stimulate NK cells and induce antibody class switching in B cells. γδ T cells produce granulocyte–macrophage colony-stimulating factor (GM-CSF) to regulate dendritic cell (DC) infiltration. Their antitumor activity is further enhanced by IL-2, IL-15, IL-18, and IL-21 [284, 285] (Fig. 4). In MM, γδ T cells are activated by non-peptide antigens and stress-induced ligands, exhibiting cytotoxic activity by killing MM cells via perforin, granzyme, and death receptor pathways, and recognizing stress-induced ligands such as MICA/B and ULBP1-4 via the NKG2D receptor [286–289]. Additionally, they produce pro-inflammatory cytokines like IFN-γ and TNF-α, enhancing the immune response, and modulate the tumor microenvironment to promote anti-tumor immunity [285]. Therapeutically, γδ T cells can be expanded ex vivo for adoptive cell therapy and combined with monoclonal antibodies, checkpoint inhibitors, or chemotherapy to boost anti-tumor effects [290]. Challenges include achieving sufficient ex vivo expansion, overcoming the immunosuppressive microenvironment, and ensuring safety [291]. Preclinical and clinical trials are exploring the efficacy and safety of γδ T cell-based therapies in MM [55, 56, 292]. In hematological malignancies, Wilhelm et al. reported the infusion of allogeneic γδ T cells from healthy donors in patients with advanced refractory MM who were not eligible for allogeneic transplantation [57]. While CAR-γδ T cells showed promise, their limited proliferation and diversity led researchers to develop αβ T cells expressing γδ TCRs, known as TEGs [291]. These TEGs can target various hematological tumors, exhibiting potent antitumor activity, strong proliferation, and preserved CD4+ and CD8+ effector functions, leading to tumor eradication in the leukemia patient derived xenograft (PDX) model [293]. A phase I clinical trial (NCT04688853) is currently testing TEG002, an autologous T cell transduced with a specific γδ TCR, in patients with RRMM. In general, these cells hold significant potential as a therapeutic option, with further research needed to realize their full potential in improving patient outcomes.
Fig. 4.
Antitumour γδ T cell functions and their regulation. γδ T cells recognize and kill tumor cells via their TCRs and NKRs, mediating tumor cell killing through TRAIL, FASL, and the granule exocytosis pathway, which involves perforin and granzyme secretion. Additionally, they engage in antibody-dependent cellular cytotoxicity when tumor-specific antibodies are present. γδ T cells enhance antitumor immune responses by producing IFNγ and acting as antigen-presenting cells, which activate αβ T cells. They also express the 4-1BBL to stimulate NK cells and induce antibody class switching in B cells, bolstering the humoral response. Moreover, γδ T cells produce GM-CSF to regulate DC infiltration. The antitumor activity of γδ T cells is further enhanced by IL-2, IL-15, IL-18, and IL-21. FcγRIII, Fcγ receptor III; HLA-DR, human leukocyte antigen-DR; LDL, low-density lipoprotein; MHC, major histocompatibility complex; NKG2D, natural killer group 2D; TRAIL-R, TRAIL receptor. Figure created with BioRender.com
Dendritic cell (DC) vaccination
Dendritic cell (DC) vaccines work by inducing and supporting an immune response to eradicate tumor cells. Autologous DCs, when pulsed with peptides or proteins derived from tumor lysates, can stimulate the production of cytotoxic T cells in MM patients [294–296] (Fig. 5). There are four main methods for using DCs as cell-based vaccines against cancer: co-culturing DCs with isolated autologous tumor tissues, co-culturing DCs with synthetic peptides or recombinant proteins of a tumor antigen, transfecting DCs with a specific plasmid to express tumor antigens, and fusing DCs with complete tumor cells using polyethylene glycol [297–299]. These methods enhance the ability of DC vaccines to stimulate a targeted immune response against MM. Han et al. showed that lentiviral-induced overexpression of calnexin (CNX) in DCs of MM patients enhanced MM-specific CD4 and CD8 T-cell responses, overcoming immune suppression [300]. CNX overexpression did not impact regulatory T cell (Treg) expansion. This suggests that improving antigen processing in DCs can lower the activation threshold of immune effector cells, potentially bypassing Treg-mediated suppression. Currently, the phase I clinical trial (NCT06435910) for this study is also ongoing. Genetically engineering DCs may thus enhance cancer immunotherapy. A randomized phase II trial (NCT02728102) found that combining DC/MM fusion vaccination with lenalidomide did not significantly increase CR rates one year post-transplant [58]. However, it did lead to a notable rise in circulating MM-reactive lymphocytes, suggesting enhanced tumor-specific immunity.
Fig. 5.
Immune activation of DCs in MM. The process begins with isolating DCs from the patient's blood via leukapheresis. These cells are then cultured with specific growth factors to differentiate into immature DCs, which are subsequently matured with stimuli like TNF-α. The mature DCs are loaded with myeloma-specific antigens from sources such as tumor lysates, peptides, or mRNA/DNA encoding myeloma antigens. Once loaded, these antigen-presenting DCs are injected back into the patient, typically intradermally or subcutaneously. The DCs then migrate to germinal centers (like lymph nodes), where they activate naïve T cells, leading to the generation of cytotoxic T lymphocytes (CTLs) that specifically target and kill MM cells. Additionally, helper T cells support the immune response by secreting cytokines. Some activated T cells become memory T cells, offering long-term surveillance against MM recurrence. Figure created with BioRender.com
Cytokine-induced killer (CIK) cells
Cytokine-Induced Killer (CIK) cells are a diverse group of effector cells derived from PBMCs and expanded in vitro using IFN-γ, anti-CD3 antibody, and IL-2 [301, 302]. First described over 30 years ago, CIK cells are an innovative cancer immunotherapy strategy. They involve modifying and utilizing autologous or allogeneic CD3+CD56− T cells and CD3+CD56+ NK-T cells, which can recognize tumor cells without HLA restriction [303, 304].
CIK cells possess potent antitumor activity due to their combined T cell (CD3+) and NK cell (CD56+) characteristics [305, 306]. They can be used in various therapeutic approaches (Fig. 6), including: combining with immune checkpoint inhibitors, antibody-mediated interventions to counter tumor ligand shedding, adoptive transfer of CIK cells engineered with CARs, ADCC, tri-specific CIK engagers, dendritic cell-CIK combinations (DC-CIK) and epigenetic inhibitors [307–313]. These mechanisms enable CIK cells to target MM cells through direct cytotoxicity and cytokine release. In the preclinical phase, Pu et al. demonstrated that combining HDAC inhibitors (HDACis) with CIK cells significantly enhances cytotoxicity against MM. This combination shows potential as a promising treatment option for MM patients. Additionally, Poles et al. showed that BCMA-CARs or affinity-optimized CD38-CARs with CIK cells not only spared normal hematopoietic cells but also exhibited a Th1-like cytokine profile, further supporting their therapeutic utility in MM [314].
Fig. 6.
Approaches for CIK cell immunotherapy. CIK therapy employs various mechanisms to enhance its efficacy, such as combining with immune checkpoint inhibitors or epigenetic inhibitors, using antibody-mediated intervention to address tumor ligand shedding, and adopting the transfer of CIK cells engineered with CARs. It also includes ADCC, the use of tri-specific CIK engagers, and DC-CIK combinations. These approaches collectively improve the therapeutic potential of CIK cells in targeting and eliminating cancer cells. Figure created with BioRender.com
Clinical trials in China have demonstrated that DC/CIK cells are safe and can induce clinical responses in MM patients, both as a standalone therapy and in combination with chemotherapy and other immunotherapies [315]. However, other clinical trials (NCT00477035, NCT00185757, NCT00460694) in the world have been completed without relevant clinical effect evaluations being reported. CIK cell therapy is notable for its broad antitumor activity, low risk of graft-versus-host disease (GVHD), and ease of expansion in vitro. Interest is growing in understanding the role of CIK cell therapy within the current and future landscape of immuno-oncology [316]. Ongoing research focuses on optimizing expansion protocols, exploring combination therapies, and developing personalized treatments. CIK cells present a promising immunotherapeutic approach for MM, with further research needed to solidify their role in clinical practice.
Conclusion and future perspectives
This manuscript reviews the evolution of cell therapy for MM, highlighting recent advancements and future perspectives. Cell therapies have emerged as transformative options in MM treatment, demonstrating significant promise, particularly for patients with refractory or relapsed disease. Recent preclinical and clinical studies have underscored the efficacy of CAR-T cells, NK cells, and other immune effector cells. However, notable challenges persist in ensuring the safety and efficacy of these therapies, including CRS, neurotoxicity, and antigen escape, which complicate clinical outcomes.
Further investigation is essential to assess the durability of responses and the long-term safety profiles of these therapies. Each ACT approach for MM offers distinct strengths and limitations. CAR-T therapy, particularly targeting BCMA, currently demonstrates the highest efficacy and durability. BiTEs show significant promise in terms of accessibility and safety, while TCR therapy, NK cell therapy and other therapies are still in exploratory stages but may contribute to a more personalized treatment landscape in the future.
Off-the-shelf CAR-T and NK cell therapies are emerging as promising options for MM, offering advantages over traditional approaches. Their pre-manufactured nature allows for immediate availability, reduced costs, and consistent quality. Initial clinical trials targeting antigens like BCMA have shown high response rates in patients with RRMM. Nevertheless, challenges such as GVHD and antigen escape necessitate careful monitoring and innovative strategies.
Ongoing research aims to enhance the efficacy of these therapies through combination strategies and the identification of new therapeutic targets. Optimizing CAR-T cell design and delivery to minimize adverse effects and enhance persistence is critical. Developing next-generation CAR constructs, dual-targeting CARs, and safety switches is essential. Moreover, integrating cell therapy with other therapeutic modalities—such as immunomodulators, proteasome inhibitors, and monoclonal antibodies—could yield synergistic effects and address resistance mechanisms.
Exploring alternative immune effector cells, such as CAR-NK cells and TCR-engineered T cells, presents further avenues for effective treatment. Establishing robust biomarkers for patient selection and response monitoring is vital for personalizing treatment strategies.
Adoptive cellular immunotherapy has opened new therapeutic avenues for patients with MM, especially those with limited options. While CAR-T cell therapies demonstrate transformative potential, challenges such as manufacturing complexity, toxicities, and immune evasion remain. Emerging strategies, including NK cell therapies, cytokine-induced killer (CIK) cell therapies, and bispecific antibodies, hold promise for overcoming the limitations of existing therapies. Future research should prioritize optimizing these strategies, reducing associated toxicities, and exploring novel targets to achieve sustained and widespread responses. Collaborative efforts among clinicians, researchers, and industry stakeholders will be pivotal in translating these advances from bench to bedside, ultimately leading to more effective and durable treatments for patients with MM.
Supplementary Information
Acknowledgements
This work was supported by the Open Access Publication Fund of the University of Bonn. The CIO Aachen Bonn Köln Düsseldorf is kindly supported by the Deutsche Krebshilfe. JJP and TL are supported by the China Scholarship Council (CSC) from the Ministry of Education, China.
Abbreviations
- MM
Multiple myeloma
- ACT
Adoptive cellular immunotherapy
- ASCT
Autologous stem cell transplantation
- CAR
Chimeric antigen receptor
- BCMA
B-cell maturation antigen
- NK
Natural killer
- TCR
T-cell receptor
- MGUS
Monoclonal gammopathy of undetermined significance
- TME
Tumor microenvironment
- RRMM
Relapsed/refractory multiple myeloma
- FDA
The United States Food and Drug Administration
- DCs
Dendritic cells
- ATILs
Adoptive transfer of tumor-infiltrating lymphocytes
- BiCEs
Bispecific immune cell engagers
- TriCEs
Trispecific immune cell engagers
- LAK
Lymphokine-activated killer
- TILs
Tumor-infiltrating lymphocytes
- PBMCs
Peripheral blood mononuclear cells
- HDM
High-dose melphalan
- PFS
Progression-free
- mPFS
Median progression-free
- OS
Overall survival
- mOS
Median overall survival
- VTd
Bortezomib, thalidomide, and dexamethasone
- VRd
Bortezomib, lenalidomide, and dexamethasone
- D-VTd
VTd combined with daratumumab
- D-VRd
VRd combined with daratumumab
- I-VRd
VRd combined with isatuximab
- ASCO
American Society of Clinical Oncology
- ESMO
European Society for Medical Oncology
- EBMT
European Bone Marrow Transplantation
- PI
Proteasome inhibitor
- IMiD
Immunomodulatory drug
- NDMM
Newly diagnosed multiple myeloma
- CR
Complete response
- sCR
Stringent complete response
- MRD
Minimal residual disease
- KRd
Carfilzomib, lenalidomide and dexamethasone
- D-KRd
KRd combined with daratumumab
- I-KRd
KRd combined with isatuximab
- ADCC
Antibody-dependent cellular cytotoxicity
- HSC
Hematopoietic stem cells
- G-CSF
Granulocyte colony-stimulating factor
- MHC
Major histocompatibility complex
- pMHC
Peptide-MHC
- ITAMs
Immunoreceptor tyrosine-based activation motifs
- CTA
Cancer/testis antigen
- MAGE
Melanoma antigen gene
- scFv
Single-chain variable fragment
- APRIL
A proliferation-inducing ligand
- BAFF
B-cell activating factor
- CRS
Cytokine release syndrome
- ICANS
Immune effector cell-associated neurotoxicity syndrome
- ORR
Overall response rate
- VGPR
Very good partial response
- CTX
Cyclophosphamide
- FAM
Fludarabine
- pt
Per test
- mDOR
Median duration of response
- DOR
Duration of response
- DLTs
Dose-limiting toxicities
- SLAMF7
Signaling lymphocytic activation molecule family member 7
- ICANS
Immune effector cell-associated neurotoxicity syndrome
- GPRC5D
G protein-coupled receptor class C group 5 member D
- PIs
Proteasome inhibitors
- FcRH5
Fc receptor-homolog 5
- TCEs
T-cell engagers
- TRUCKS
T cells redirected for universal cytokine-mediated killing
- GVHD
Graft-versus-host disease
- HLAs
Human leukocyte antigens
- iPSCs
Induced pluripotent stem cells
- sBCMA
Soluble BCMA
- BsAb
Bispecific antibody
- TsAbs
Trispecific antibodies
- NKCEs
NK cell engagers
- TandAb
Tandem diabody
- TriKEs)
Trifunctional NK cell engagers
- IL-2
Interleukin-2
- rIL-2
Recombinant interleukin-2
- ABMT
Autologous bone marrow transplantation
- IFNγ
Interferon-γ
- NKRs
Natural killer cell receptors
- FASL
FAS ligand
- 4-1BBL
4-1BB ligand
- GM-CSF
Granulocyte–macrophage colony-stimulating factor
- PDX
Patient derived xenograft
- CNX
Calnexin
- Tregs
Regulatory T cells
- CTLs
Cytotoxic T lymphocytes
- CIK
Cytokine-Induced killer
- DC-CIK
Dendritic cell-CIK combinations
- HDACis
Histone deacetylase inhibitors
- BMMCs
Bone marrow mononuclear cells
- MM Id-Ig
Multiple myeloma-specific idiotype immunoglobulins
Author contributions
JJP, TL, AS, LPJ, FW, XBR, IGHS-W and JH contributed to conceive, design and revision of the manuscript sections. JJP wrote the manuscript. JJP and TL designed figures and created Tables. JJP, XBR, IGHS-W and JH supervised the manuscript by providing critical feedbacks and revisions. The authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. Not applicable.
Availability of data and materials
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
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.
Jingjing Pu and Ting Liu contributed equally.
Contributor Information
Xiubao Ren, Email: renxiubao@tjmuch.com.
Ingo G. H. Schmidt-Wolf, Email: ingo.schmidt-wolf@ukbonn.de
Jian Hou, Email: houjian@medmail.com.cn.
References
- 1.Cowan AJ, Green DJ, Kwok M, et al. Diagnosis and management of multiple myeloma: a review. JAMA. 2022;327:464–77. [DOI] [PubMed] [Google Scholar]
- 2.Rollig C, Knop S, Bornhauser M. Multiple myeloma. Lancet. 2015;385:2197–208. [DOI] [PubMed] [Google Scholar]
- 3.Kumar SK, Rajkumar V, Kyle RA, et al. Multiple myeloma. Nat Rev Dis Primers. 2017;3:17046. [DOI] [PubMed] [Google Scholar]
- 4.Garfall AL. New biological therapies for multiple myeloma. Annu Rev Med. 2024;75:13–29. [DOI] [PubMed] [Google Scholar]
- 5.Kyle RA, Larson DR, Therneau TM, et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Engl J Med. 2018;378:241–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Mateos MV, Kumar S, Dimopoulos MA, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 2020;10:102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Landgren O, Weiss BM. Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis. Leukemia. 2009;23:1691–7. [DOI] [PubMed] [Google Scholar]
- 8.Garcia-Ortiz A, Rodriguez-Garcia Y, Encinas J, et al. The role of tumor microenvironment in multiple myeloma development and progression. Cancers. 2021;13:217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Uckun FM. Overcoming the immunosuppressive tumor microenvironment in multiple myeloma. Cancers. 2021;13:2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hervas-Salcedo R, Martin-Antonio B. A journey through the inter-cellular interactions in the bone marrow in multiple myeloma: implications for the next generation of treatments. Cancers. 2022;14:3796. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Pu J, Liu T, Wang X, et al. Exploring the role of histone deacetylase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future perspectives. Exp Hematol Oncol. 2024;13:45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Mikhael J, Ismaila N, Cheung MC, et al. Treatment of multiple myeloma: ASCO and CCO joint clinical practice guideline. J Clin Oncol. 2019;37:1228–63. [DOI] [PubMed] [Google Scholar]
- 13.Soekojo CY, Chng WJ. Treatment horizon in multiple myeloma. Eur J Haematol. 2022;109:425–40. [DOI] [PubMed] [Google Scholar]
- 14.Holstein SA, Grant SJ, Wildes TM. Chimeric antigen receptor T-cell and bispecific antibody therapy in multiple myeloma: moving into the future. J Clin Oncol. 2023;41:4416–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Tanenbaum B, Miett T, Patel SA. The emerging therapeutic landscape of relapsed/refractory multiple myeloma. Ann Hematol. 2023;102:1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Cengiz Seval G, Beksac M. A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma. Expert Opin Drug Saf. 2019;18:563–71. [DOI] [PubMed] [Google Scholar]
- 17.Elnair RA, Holstein SA. Evolution of treatment paradigms in newly diagnosed multiple myeloma. Drugs. 2021;81:825–40. [DOI] [PubMed] [Google Scholar]
- 18.Bazarbachi AH, Al Hamed R, Malard F, Bazarbachi A, Harousseau JL, Mohty M. Induction therapy prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma: an update. Blood Cancer J. 2022;12:47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Minnie SA, Hill GR. Immunotherapy of multiple myeloma. J Clin Invest. 2020;130:1565–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Joshua DE, Bryant C, Dix C, Gibson J, Ho J. Biology and therapy of multiple myeloma. Med J Aust. 2019;210:375–80. [DOI] [PubMed] [Google Scholar]
- 21.Goldschmidt H, Egerer G, Ho AD. Autologous and allogeneic stem cell transplantation in multiple myeloma. Bone Marrow Transplant. 2000;25(Suppl 2):S25-26. [DOI] [PubMed] [Google Scholar]
- 22.Gahrton G, Bjorkstrand B. Progress in haematopoietic stem cell transplantation for multiple myeloma. J Intern Med. 2000;248:185–201. [DOI] [PubMed] [Google Scholar]
- 23.Majolino I, Scime R, Indovina A. Autologous blood stem cell transplantation in hematologic malignancies. Haematologica. 1990;75:555–66. [PubMed] [Google Scholar]
- 24.Rosenblatt J, Avigan D. Role of immune therapies for myeloma. J Natl Compr Canc Netw. 2015;13:1440–7. [DOI] [PubMed] [Google Scholar]
- 25.Atanackovic D, Radhakrishnan SV, Bhardwaj N, Luetkens T. Chimeric Antigen Receptor (CAR) therapy for multiple myeloma. Br J Haematol. 2016;172:685–98. [DOI] [PubMed] [Google Scholar]
- 26.Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20:359–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Yu B, Jiang T, Liu D. BCMA-targeted immunotherapy for multiple myeloma. J Hematol Oncol. 2020;13:125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.van de Donk N, Usmani SZ, Yong K. CAR T-cell therapy for multiple myeloma: state of the art and prospects. Lancet Haematol. 2021;8:e446–61. [DOI] [PubMed] [Google Scholar]
- 29.Roshandel E, Ghaffari-Nazari H, Mohammadian M, et al. NK cell therapy in relapsed refractory multiple myeloma. Clin Immunol. 2023;246: 109168. [DOI] [PubMed] [Google Scholar]
- 30.Kriegsmann K, Kriegsmann M, Cremer M, et al. Cell-based immunotherapy approaches for multiple myeloma. Br J Cancer. 2019;120:38–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Tomaipitinca L, Russo E, Bernardini G. NK cell surveillance of hematological malignancies. Therapeutic implications and regulation by chemokine receptors. Mol Aspects Med. 2021;80: 100968. [DOI] [PubMed] [Google Scholar]
- 32.San Miguel JF, Paiva B, Lasarte JJ. Engineering Anti-myeloma responses using affinity-enhanced TCR-engineered T cells. Cancer Cell. 2015;28:281–3. [DOI] [PubMed] [Google Scholar]
- 33.Majzner RG, Mackall CL. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 2018;8:1219–26. [DOI] [PubMed] [Google Scholar]
- 34.Ludwig H, Terpos E, van de Donk N, et al. Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European Myeloma Network. Lancet Oncol. 2023;24:e255–69. [DOI] [PubMed] [Google Scholar]
- 35.Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Sadek NL, Costa BA, Nath K, Mailankody S. CAR T-Cell therapy for multiple myeloma: a clinical practice-oriented review. Clin Pharmacol Ther. 2023;114:1184–95. [DOI] [PubMed] [Google Scholar]
- 37.Rapoport AP, Stadtmauer EA, Binder-Scholl GK, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21:914–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Lin Y, Raje NS, Berdeja JG, et al. Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial. Nat Med. 2023;29:2286–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Xu J, Wang BY, Yu SH, et al. Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial. J Hematol Oncol. 2024;17:23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene autoleucel, an anti-b-cell maturation antigen chimeric antigen receptor T-Cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-Year follow-up. J Clin Oncol. 2023;41:1265–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Cohen AD, Garfall AL, Stadtmauer EA, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129:2210–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Jain T, Knezevic A, Pennisi M, et al. Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies. Blood Adv. 2020;4:3776–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Shi X, Yan L, Shang J, et al. Anti-CD19 and anti-BCMA CAR T cell therapy followed by lenalidomide maintenance after autologous stem-cell transplantation for high-risk newly diagnosed multiple myeloma. Am J Hematol. 2022;97:537–47. [DOI] [PubMed] [Google Scholar]
- 44.Yan Z, Cao J, Cheng H, et al. A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial. Lancet Haematol. 2019;6:e521–9. [DOI] [PubMed] [Google Scholar]
- 45.Shi M, Wang J, Huang H, et al. Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial. Nat Commun. 2024;15:3371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Mei H, Li C, Jiang H, et al. A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma. J Hematol Oncol. 2021;14:161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Tang Y, Yin H, Zhao X, et al. High efficacy and safety of CD38 and BCMA bispecific CAR-T in relapsed or refractory multiple myeloma. J Exp Clin Cancer Res. 2022;41:2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Zhang H, Liu M, Xiao X, et al. A combination of humanized anti-BCMA and murine anti-CD38 CAR-T cell therapy in patients with relapsed or refractory multiple myeloma. Leuk Lymphoma. 2022;63:1418–27. [DOI] [PubMed] [Google Scholar]
- 49.Li C, Xu J, Luo W, et al. Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma. Leukemia. 2024;38:149–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Mailankody S, Devlin SM, Landa J, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med. 2022;387:1196–206. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Bal S, Htut M, Nadeem O, et al. BMS-986393 (CC-95266), a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Multiple Myeloma (RRMM): updated results from a phase 1 study. Blood. 2023;142:219. [Google Scholar]
- 52.Zhang M, Wei G, Zhou L, et al. GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial. Lancet Haematol. 2023;10:e107–16. [DOI] [PubMed] [Google Scholar]
- 53.Peest D, Leo R, Bloche S, et al. Low-dose recombinant interleukin-2 therapy in advanced multiple myeloma. Br J Haematol. 1995;89:328–37. [DOI] [PubMed] [Google Scholar]
- 54.Higuchi CM, Thompson JA, Petersen FB, Buckner CD, Fefer A. Toxicity and immunomodulatory effects of interleukin-2 after autologous bone marrow transplantation for hematologic malignancies. Blood. 1991;77:2561–8. [PubMed] [Google Scholar]
- 55.Fazzi R, Petrini I, Giuliani N, et al. Phase II trial of maintenance treatment with IL2 and zoledronate in multiple myeloma after bone marrow transplantation: biological and clinical results. Front Immunol. 2020;11: 573156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Wilhelm M, Kunzmann V, Eckstein S, et al. Gammadelta T cells for immune therapy of patients with lymphoid malignancies. Blood. 2003;102:200–6. [DOI] [PubMed] [Google Scholar]
- 57.Wilhelm M, Smetak M, Schaefer-Eckart K, et al. Successful adoptive transfer and in vivo expansion of haploidentical gammadelta T cells. J Transl Med. 2014;12:45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Chung DJ, Shah N, Wu J, et al. Randomized phase II trial of dendritic cell/myeloma fusion vaccine with lenalidomide maintenance after upfront autologous hematopoietic cell transplantation for multiple myeloma: BMT CTN 1401. Clin Cancer Res. 2023;29:4784–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial. Lancet. 2007;370:1209–18. [DOI] [PubMed] [Google Scholar]
- 60.Ntanasis-Stathopoulos I, Gavriatopoulou M, Kastritis E, Terpos E, Dimopoulos MA. Multiple myeloma: role of autologous transplantation. Cancer Treat Rev. 2020;82: 101929. [DOI] [PubMed] [Google Scholar]
- 61.More S, Corvatta L, Manieri VM, et al. Autologous stem cell transplantation in multiple myeloma: where are we and where do we want to go? Cells. 2022;11:606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Devarakonda S, Efebera Y, Sharma N. Role of stem cell transplantation in multiple myeloma. Cancers. 2021;13:863. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Dimopoulos MA, Moreau P, Terpos E, et al. Multiple myeloma: EHA-ESMO clinical practice guidelines for diagnosis. Treat Follow-up Hemasphere. 2021;5: e528. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Soekojo CY, Kumar SK. Stem-cell transplantation in multiple myeloma: how far have we come? Ther Adv Hematol. 2019;10:2040620719888111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Kumar S, Baizer L, Callander NS, et al. Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: consensus recommendations of the NCI Multiple Myeloma Steering Committee. Blood Cancer J. 2022;12:98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Holstein SA, Richardson PG, Laubach JP, McCarthy PL. Management of relapsed multiple myeloma after autologous stem cell transplant. Biol Blood Marrow Transplant. 2015;21:793–8. [DOI] [PubMed] [Google Scholar]
- 67.Lancman G, Sastow DL, Cho HJ, et al. Bispecific antibodies in multiple myeloma: present and future. Blood Cancer Discov. 2021;2:423–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Lakshman A, Kumar SK. Chimeric antigen receptor T-cells, bispecific antibodies, and antibody-drug conjugates for multiple myeloma: an update. Am J Hematol. 2022;97:99–118. [DOI] [PubMed] [Google Scholar]
- 69.Dimopoulos MA, Jakubowiak AJ, McCarthy PL, et al. Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma. Blood Cancer J. 2020;10:17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Snowden JA, Sanchez-Ortega I, Corbacioglu S, et al. Indications for haematopoietic cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2022. Bone Marrow Transplant. 2022;57:1217–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Goel U, Usmani S, Kumar S. Current approaches to management of newly diagnosed multiple myeloma. Am J Hematol. 2022;97(Suppl 1):S3–25. [DOI] [PubMed] [Google Scholar]
- 72.Mo CC, Hartley-Brown MA, Midha S, Richardson PG. Upfront or deferred autologous stem cell transplantation for newly diagnosed multiple myeloma in the era of triplet and quadruplet induction and minimal residual disease/risk-adapted therapy. Cancers. 2023;15:5709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Gozzetti A, Ciofini S, Simoncelli M, et al. Anti CD38 monoclonal antibodies for multiple myeloma treatment. Hum Vaccin Immunother. 2022;18:2052658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Kim K, Phelps MA. Clinical pharmacokinetics and pharmacodynamics of daratumumab. Clin Pharmacokinet. 2023;62:789–806. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Hill E, Morrison C, Kazandjian D. Daratumumab: a review of current indications and future directions. Semin Oncol. 2022;49:48–59. [DOI] [PubMed] [Google Scholar]
- 77.Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394:29–38. [DOI] [PubMed] [Google Scholar]
- 78.Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22:1378–90. [DOI] [PubMed] [Google Scholar]
- 79.Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136:936–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10:e825–37. [DOI] [PubMed] [Google Scholar]
- 81.Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390:301–13. [DOI] [PubMed] [Google Scholar]
- 82.Costa LJ, Chhabra S, Medvedova E, et al. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. Lancet Haematol. 2023;10:e890–901. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Frampton JE. Isatuximab: a review of its use in multiple myeloma. Target Oncol. 2021;16:675–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Moreno L, Perez C, Zabaleta A, et al. The mechanism of action of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma. Clin Cancer Res. 2019;25:3176–87. [DOI] [PubMed] [Google Scholar]
- 85.Martin T, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study. Blood Cancer J. 2023;13:72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86.Richardson PG, Perrot A, San-Miguel J, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022;23:416–27. [DOI] [PubMed] [Google Scholar]
- 87.Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394:2096–107. [DOI] [PubMed] [Google Scholar]
- 88.Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397:2361–71. [DOI] [PubMed] [Google Scholar]
- 89.Goldschmidt H, Mai EK, Bertsch U, et al. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial. Lancet Haematol. 2022;9:e810–21. [DOI] [PubMed] [Google Scholar]
- 90.Leypoldt LB, Tichy D, Besemer B, et al. Isatuximab, carfilzomib, lenalidomide, and dexamethasone for the treatment of high-risk newly diagnosed multiple myeloma. J Clin Oncol. 2024;42:26–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Hoy SM. Motixafortide: first approval. Drugs. 2023;83:1635–43. [DOI] [PubMed] [Google Scholar]
- 92.Lanza F, Marchetti M, Zannetti BA. Overview on novel strategies and current guidelines for hematopoietic stem cell mobilisation and collection. Transfus Apher Sci. 2023;62: 103830. [DOI] [PubMed] [Google Scholar]
- 93.Swinn T, Butler A. Plerixafor use in New Zealand 2016–2019: an observational study. Intern Med J. 2023;53:970–7. [DOI] [PubMed] [Google Scholar]
- 94.Giralt S, Stadtmauer EA, Harousseau JL, et al. International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia. 2009;23:1904–12. [DOI] [PubMed] [Google Scholar]
- 95.Jantunen E, Partanen A, Turunen A, Varmavuo V, Silvennoinen R. Mobilization strategies in myeloma patients intended for autologous hematopoietic cell transplantation. Transfus Med Hemother. 2023;50:438–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Wang J, Tannous BA, Poznansky MC, Chen H. CXCR4 antagonist AMD3100 (plerixafor): from an impurity to a therapeutic agent. Pharmacol Res. 2020;159: 105010. [DOI] [PubMed] [Google Scholar]
- 97.Zappaterra A, Civettini I, Cafro AM, et al. Anti-CD38 monoclonal antibody impairs CD34+ mobilization and affects clonogenic potential in multiple myeloma patients. Blood Transfus. 2024;22:328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98.Venglar O, Kapustova V, Anilkumar Sithara A, et al. Insight into the mechanism of CD34(+) cell mobilisation impairment in multiple myeloma patients treated with anti-CD38 therapy. Br J Haematol. 2024;204:1439–49. [DOI] [PubMed] [Google Scholar]
- 99.Hulin C, Offner F, Moreau P, et al. Stem cell yield and transplantation in transplant-eligible newly diagnosed multiple myeloma patients receiving daratumumab + bortezomib/thalidomide/dexamethasone in the phase 3 CASSIOPEIA study. Haematologica. 2021;106:2257–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Chhabra S, Callander N, Watts NL, et al. Stem cell mobilization yields with daratumumab- and lenalidomide-containing quadruplet induction therapy in newly diagnosed multiple myeloma: findings from the MASTER and GRIFFIN trials. Transplant Cell Ther. 2023;29:174. [DOI] [PubMed] [Google Scholar]
- 101.Kauer J, Freundt EP, Schmitt A, et al. Stem cell collection after lenalidomide, bortezomib and dexamethasone plus elotuzumab or isatuximab in newly diagnosed multiple myeloma patients: a single centre experience from the GMMG-HD6 and -HD7 trials. BMC Cancer. 2023;23:1132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 102.Mai EK, Goldschmid H, Miah K, et al. Elotuzumab, lenalidomide, bortezomib, dexamethasone, and autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GMMG-HD6): results from a randomised, phase 3 trial. Lancet Haematol. 2024;11:e101–13. [DOI] [PubMed] [Google Scholar]
- 103.Mai EK, Hielscher T, Bertsch U, et al. Predictors of early morbidity and mortality in newly diagnosed multiple myeloma: data from five randomized, controlled, phase III trials in 3700 patients. Leukemia. 2024;38:640–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104.Tendeiro Rego R, Morris EC, Lowdell MW. T-cell receptor gene-modified cells: past promises, present methodologies and future challenges. Cytotherapy. 2019;21:341–57. [DOI] [PubMed] [Google Scholar]
- 105.Johnson LA, June CH. Driving gene-engineered T cell immunotherapy of cancer. Cell Res. 2017;27:38–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106.James JR. Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density. Sci Signal. 2018;11: eaan1088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Mukhopadhyay H, Cordoba SP, Maini PK, van der Merwe PA, Dushek O. Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity. PLoS Comput Biol. 2013;9: e1003004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Schumacher TN. T-cell-receptor gene therapy. Nat Rev Immunol. 2002;2:512–9. [DOI] [PubMed] [Google Scholar]
- 109.Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110.Ping Y, Liu C, Zhang Y. T-cell receptor-engineered T cells for cancer treatment: current status and future directions. Protein Cell. 2018;9:254–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111.Shah K, Al-Haidari A, Sun J, Kazi JU. T cell receptor (TCR) signaling in health and disease. Signal Transduct Target Ther. 2021;6:412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112.Schlom J, Hodge JW. The diversity of T-cell co-stimulation in the induction of antitumor immunity. Immunol Rev. 1999;170:73–84. [DOI] [PubMed] [Google Scholar]
- 113.Pourakbari R, Hajizadeh F, Parhizkar F, Aghebati-Maleki A, Mansouri S, Aghebati-Maleki L. Co-stimulatory agonists: an insight into the immunotherapy of cancer. EXCLI J. 2021;20:1055–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.Ishihara M, Kitano S, Kageyama S, et al. NY-ESO-1-specific redirected T cells with endogenous TCR knockdown mediate tumor response and cytokine release syndrome. J Immunother Cancer. 2022;10: e003811. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115.Moeller I, Spagnoli GC, Finke J, Veelken H, Houet L. Uptake routes of tumor-antigen MAGE-A3 by dendritic cells determine priming of naive T-cell subtypes. Cancer Immunol Immunother. 2012;61:2079–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Wang L, Jin N, Schmitt A, et al. T cell-based targeted immunotherapies for patients with multiple myeloma. Int J Cancer. 2015;136:1751–68. [DOI] [PubMed] [Google Scholar]
- 117.Wachsmann TLA, Meeuwsen MH, Remst DFG, et al. Combining BCMA-targeting CAR T cells with TCR-engineered T-cell therapy to prevent immune escape of multiple myeloma. Blood Adv. 2023;7:6178–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118.Mastaglio S, Genovese P, Magnani Z, et al. NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease. Blood. 2017;130:606–18. [DOI] [PubMed] [Google Scholar]
- 119.Schuberth PC, Jakka G, Jensen SM, et al. Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma. Gene Ther. 2013;20:386–95. [DOI] [PubMed] [Google Scholar]
- 120.Atanackovic D, Hildebrandt Y, Jadczak A, et al. Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells. Haematologica. 2010;95:785–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121.Jungbluth AA, Ely S, DiLiberto M, et al. The cancer-testis antigens CT7 (MAGE-C1) and MAGE-A3/6 are commonly expressed in multiple myeloma and correlate with plasma-cell proliferation. Blood. 2005;106:167–74. [DOI] [PubMed] [Google Scholar]
- 122.Shah N, Chari A, Scott E, Mezzi K, Usmani SZ. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia. 2020;34:985–1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Yang J, Zhou W, Li D, Niu T, Wang W. BCMA-targeting chimeric antigen receptor T-cell therapy for multiple myeloma. Cancer Lett. 2023;553: 215949. [DOI] [PubMed] [Google Scholar]
- 124.Bezverbnaya K, Moogk D, Cummings D, et al. Development of a B-cell maturation antigen-specific T-cell antigen coupler receptor for multiple myeloma. Cytotherapy. 2021;23:820–32. [DOI] [PubMed] [Google Scholar]
- 125.Raza A, Merhi M, Inchakalody VP, et al. Unleashing the immune response to NY-ESO-1 cancer testis antigen as a potential target for cancer immunotherapy. J Transl Med. 2020;18:140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Thomas R, Al-Khadairi G, Roelands J, et al. NY-ESO-1 based immunotherapy of cancer: current perspectives. Front Immunol. 2018;9:947. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 127.Zhou H, Ma Y, Liu F, et al. Current advances in cancer vaccines targeting NY-ESO-1 for solid cancer treatment. Front Immunol. 2023;14:1255799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 128.Park TS, Groh EM, Patel K, Kerkar SP, Lee CC, Rosenberg SA. Expression of MAGE-A and NY-ESO-1 in primary and metastatic cancers. J Immunother. 2016;39:1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129.Fujiwara S, Wada H, Kawada J, et al. NY-ESO-1 antibody as a novel tumour marker of gastric cancer. Br J Cancer. 2013;108:1119–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130.Ishihara M, Kageyama S, Miyahara Y, et al. MAGE-A4, NY-ESO-1 and SAGE mRNA expression rates and co-expression relationships in solid tumours. BMC Cancer. 2020;20:606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 131.Goydos JS, Patel M, Shih W. NY-ESO-1 and CTp11 expression may correlate with stage of progression in melanoma. J Surg Res. 2001;98:76–80. [DOI] [PubMed] [Google Scholar]
- 132.van Rhee F, Szmania SM, Zhan F, et al. NY-ESO-1 is highly expressed in poor-prognosis multiple myeloma and induces spontaneous humoral and cellular immune responses. Blood. 2005;105:3939–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133.Julve M, Kennedy O, Frampton AE, Bagwan I, Lythgoe MP. Gene of the month: cancer testis antigen gene 1b (NY-ESO-1). J Clin Pathol. 2023;77:1–7. [DOI] [PubMed] [Google Scholar]
- 134.Chinnasamy N, Wargo JA, Yu Z, et al. A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer. J Immunol. 2011;186:685–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 135.Esfandiary A, Ghafouri-Fard S. MAGE-A3: an immunogenic target used in clinical practice. Immunotherapy. 2015;7:683–704. [DOI] [PubMed] [Google Scholar]
- 136.Schafer P, Paraschiakos T, Windhorst S. Oncogenic activity and cellular functionality of melanoma associated antigen A3. Biochem Pharmacol. 2021;192: 114700. [DOI] [PubMed] [Google Scholar]
- 137.Linette GP, Stadtmauer EA, Maus MV, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122:863–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 138.Pan K, Farrukh H, Chittepu V, Xu H, Pan CX, Zhu Z. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. J Exp Clin Cancer Res. 2022;41:119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 139.Tokarew N, Ogonek J, Endres S, von Bergwelt-Baildon M, Kobold S. Teaching an old dog new tricks: next-generation CAR T cells. Br J Cancer. 2019;120:26–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 140.Parikh RH, Lonial S. Chimeric antigen receptor T-cell therapy in multiple myeloma: a comprehensive review of current data and implications for clinical practice. CA Cancer J Clin. 2023;73:275–85. [DOI] [PubMed] [Google Scholar]
- 141.Manier S, Ingegnere T, Escure G, et al. Current state and next-generation CAR-T cells in multiple myeloma. Blood Rev. 2022;54: 100929. [DOI] [PubMed] [Google Scholar]
- 142.Day ES, Cachero TG, Qian F, et al. Selectivity of BAFF/BLyS and APRIL for binding to the TNF family receptors BAFFR/BR3 and BCMA. Biochemistry. 2005;44:1919–31. [DOI] [PubMed] [Google Scholar]
- 143.Tai YT, Acharya C, An G, et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood. 2016;127:3225–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 144.Mulazzani M, Huber M, Borchard S, et al. APRIL and BAFF: novel biomarkers for central nervous system lymphoma. J Hematol Oncol. 2019;12:102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.Tai YT, Li XF, Breitkreutz I, et al. Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res. 2006;66:6675–82. [DOI] [PubMed] [Google Scholar]
- 146.Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19:2048–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Demchenko YN, Glebov OK, Zingone A, Keats JJ, Bergsagel PL, Kuehl WM. Classical and/or alternative NF-kappaB pathway activation in multiple myeloma. Blood. 2010;115:3541–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 148.He C, Zhang M, Liu L, et al. Cellular membrane-based vesicles displaying a reconstructed B cell maturation antigen for multiple myeloma therapy by dual targeting APRIL and BAFF. Acta Biomater. 2022;143:406–17. [DOI] [PubMed] [Google Scholar]
- 149.Ravi G, Costa LJ. Bispecific T-cell engagers for treatment of multiple myeloma. Am J Hematol. 2023;98(Suppl 2):S13–21. [DOI] [PubMed] [Google Scholar]
- 150.Mishra AK, Gupta A, Dagar G, et al. CAR-T-Cell therapy in multiple myeloma: B-Cell Maturation Antigen (BCMA) and beyond. Vaccines. 2023;11:1721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151.Harush O, Asherie N, Kfir-Erenfeld S, et al. Preclinical evaluation and structural optimization of anti-BCMA CAR to target multiple myeloma. Haematologica. 2022;107:2395–407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 152.Lin L, Cho SF, Xing L, et al. Preclinical evaluation of CD8+ anti-BCMA mRNA CAR T cells for treatment of multiple myeloma. Leukemia. 2021;35:752–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 153.Perez-Amill L, Sune G, Antonana-Vildosola A, et al. Preclinical development of a humanized chimeric antigen receptor against B cell maturation antigen for multiple myeloma. Haematologica. 2021;106:173–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 154.Sommer C, Boldajipour B, Kuo TC, et al. Preclinical evaluation of allogeneic CAR T cells targeting BCMA for the treatment of multiple myeloma. Mol Ther. 2019;27:1126–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 155.Lin RJ, Sutton J, Bentley T, et al. Constitutive Turbodomains enhance expansion and antitumor activity of allogeneic BCMA CAR T cells in preclinical models. Sci Adv. 2023;9: ead8694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 156.Buonato JM, Edwards JP, Zaritskaya L, et al. Preclinical efficacy of BCMA-directed CAR T cells incorporating a novel D domain antigen recognition domain. Mol Cancer Ther. 2022;21:1171–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 157.Freyer CW, Porter DL. Cytokine release syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies. J Allergy Clin Immunol. 2020;146:940–8. [DOI] [PubMed] [Google Scholar]
- 158.Morris EC, Neelapu SS, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol. 2022;22:85–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 159.Rana PS, Murphy EV, Kort J, Driscoll JJ. Road testing new CAR design strategies in multiple myeloma. Front Immunol. 2022;13: 957157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 160.Larson RC, Kann MC, Graham C, et al. Anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma. Nat Commun. 2023;14:7509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 161.Tan J, Jia Y, Zhou M, et al. Chimeric antigen receptors containing the OX40 signalling domain enhance the persistence of T cells even under repeated stimulation with multiple myeloma target cells. J Hematol Oncol. 2022;15:39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 162.Rujirachaivej P, Siriboonpiputtana T, Luangwattananun P, et al. Therapeutic potential of third-generation chimeric antigen receptor T cells targeting B cell maturation antigen for treating multiple myeloma. Clin Exp Med. 2024;24:90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 163.Anderson LD Jr. Idecabtagene vicleucel (ide-cel) CAR T-cell therapy for relapsed and refractory multiple myeloma. Future Oncol. 2022;18:277–89. [DOI] [PubMed] [Google Scholar]
- 164.Reyes KR, Huang CY, Lo M, et al. Safety and efficacy of BCMA CAR-T cell therapy in older patients with multiple myeloma. Transplant Cell Ther. 2023;29:350–5. [DOI] [PubMed] [Google Scholar]
- 165.Wang K, Wei G, Liu D. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol. 2012;1:36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 166.Li X, Ding Y, Zi M, et al. CD19, from bench to bedside. Immunol Lett. 2017;183:86–95. [DOI] [PubMed] [Google Scholar]
- 167.Del Nagro CJ, Otero DC, Anzelon AN, Omori SA, Kolla RV, Rickert RC. CD19 function in central and peripheral B-cell development. Immunol Res. 2005;31:119–31. [DOI] [PubMed] [Google Scholar]
- 168.Hasegawa M, Fujimoto M, Poe JC, Steeber DA, Tedder TF. CD19 can regulate B lymphocyte signal transduction independent of complement activation. J Immunol. 2001;167:3190–200. [DOI] [PubMed] [Google Scholar]
- 169.Sadelain M. CAR therapy: the CD19 paradigm. J Clin Invest. 2015;125:3392–400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 170.Boardman AP, Salles G. CAR T-cell therapy in large B cell lymphoma. Hematol Oncol. 2023;41(Suppl 1):112–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 171.Kang L, Zhang J, Li M, et al. Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma. Biomark Res. 2020;8:14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 172.van de Donk N, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131:13–29. [DOI] [PubMed] [Google Scholar]
- 173.Nooka AK, Kaufman JL, Hofmeister CC, et al. Daratumumab in multiple myeloma. Cancer. 2019;125:2364–82. [DOI] [PubMed] [Google Scholar]
- 174.Bonello F, D’Agostino M, Moscvin M, Cerrato C, Boccadoro M, Gay F. CD38 as an immunotherapeutic target in multiple myeloma. Expert Opin Biol Ther. 2018;18:1209–21. [DOI] [PubMed] [Google Scholar]
- 175.Wu HT, Zhao XY. Regulation of CD38 on multiple myeloma ANd NK cells by monoclonal antibodies. Int J Biol Sci. 2022;18:1974–88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 176.Frerichs KA, Nagy NA, Lindenbergh PL, et al. CD38-targeting antibodies in multiple myeloma: mechanisms of action and clinical experience. Expert Rev Clin Immunol. 2018;14:197–206. [DOI] [PubMed] [Google Scholar]
- 177.Morandi F, Horenstein AL, Costa F, Giuliani N, Pistoia V, Malavasi F. CD38: a target for immunotherapeutic approaches in multiple myeloma. Front Immunol. 2018;9:2722. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 178.Zannetti BA, Faini AC, Massari E, et al. Novel insights in anti-CD38 therapy based on CD38-receptor expression and function: the multiple myeloma model. Cells. 2020;9:2666. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 179.Mihara K, Bhattacharyya J, Kitanaka A, et al. T-cell immunotherapy with a chimeric receptor against CD38 is effective in eliminating myeloma cells. Leukemia. 2012;26:365–7. [DOI] [PubMed] [Google Scholar]
- 180.Drent E, Groen RW, Noort WA, et al. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. Haematologica. 2016;101:616–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 181.An N, Hou YN, Zhang QX, et al. Anti-multiple myeloma activity of nanobody-based anti-CD38 chimeric antigen receptor T cells. Mol Pharm. 2018;15:4577–88. [DOI] [PubMed] [Google Scholar]
- 182.Glisovic-Aplenc T, Diorio C, Chukinas JA, et al. CD38 as a pan-hematologic target for chimeric antigen receptor T cells. Blood Adv. 2023;7:4418–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 183.Partida-Sanchez S, Cockayne DA, Monard S, et al. Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat Med. 2001;7:1209–16. [DOI] [PubMed] [Google Scholar]
- 184.Malaer JD, Mathew PA. CS1 (SLAMF7, CD319) is an effective immunotherapeutic target for multiple myeloma. Am J Cancer Res. 2017;7:1637–41. [PMC free article] [PubMed] [Google Scholar]
- 185.Boudreault JS, Touzeau C, Moreau P. The role of SLAMF7 in multiple myeloma: impact on therapy. Expert Rev Clin Immunol. 2017;13:67–75. [DOI] [PubMed] [Google Scholar]
- 186.Wang Y, Sanchez L, Siegel DS, Wang ML. Elotuzumab for the treatment of multiple myeloma. J Hematol Oncol. 2016;9:55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 187.Elotuzumab MA. First global approval. Drugs. 2016;76:397–403. [DOI] [PubMed] [Google Scholar]
- 188.Gogishvili T, Danhof S, Prommersberger S, et al. SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7(+) normal lymphocytes. Blood. 2017;130:2838–47. [DOI] [PubMed] [Google Scholar]
- 189.Roders N, Nakid-Cordero C, Raineri F, et al. Dual chimeric antigen receptor T cells targeting CD38 and SLAMF7 with Independent signaling demonstrate preclinical efficacy and safety in multiple myeloma. Cancer Immunol Res. 2024;12:478–90. [DOI] [PubMed] [Google Scholar]
- 190.O’Neal J, Ritchey JK, Cooper ML, et al. CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells. Leukemia. 2022;36:1625–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 191.Rodriguez-Otero P, van de Donk N, Pillarisetti K, et al. GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review. Blood Cancer J. 2024;14:24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 192.Nath K, Costa BA, Mailankody S. GPRC5D as a novel immunotherapeutic target in multiple myeloma. Nat Rev Clin Oncol. 2023;20:281–2. [DOI] [PubMed] [Google Scholar]
- 193.Atamaniuk J, Gleiss A, Porpaczy E, et al. Overexpression of G protein-coupled receptor 5D in the bone marrow is associated with poor prognosis in patients with multiple myeloma. Eur J Clin Invest. 2012;42:953–60. [DOI] [PubMed] [Google Scholar]
- 194.Smith EL, Harrington K, Staehr M, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11: eaau7746. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 195.Fernandez de Larrea C, Staehr M, Lopez AV, et al. Defining an optimal dual-targeted CAR T-cell therapy approach simultaneously targeting BCMA and GPRC5D to prevent BCMA escape-driven relapse in multiple myeloma. Blood Cancer Discov. 2020;1:146–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 196.Simon S, Riddell SR. Dual targeting with CAR T cells to limit antigen escape in multiple myeloma. Blood Cancer Discov. 2020;1:130–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 197.Mi X, Penson A, Abdel-Wahab O, Mailankody S. Genetic basis of relapse after GPRC5D-targeted CAR T cells. N Engl J Med. 2023;389:1435–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 198.Derrien J, Gastineau S, Frigout A, et al. Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation. Nat Cancer. 2023;4:1536–43. [DOI] [PubMed] [Google Scholar]
- 199.Zhou X, Yang Y, Hu X, et al. Identification of LPAR1/LPAR5 as novel GPCR partners of GPRC5D for the efficient CAR-T therapy of multiple myeloma. Blood. 2023;142:4679. [Google Scholar]
- 200.Hou J, Li Y, Lin Q. Bispecific antibodies and dual-targeting CAR-T cells for multiple myeloma: latest updates from the 2023 ASCO annual meeting. Exp Hematol Oncol. 2023;12:74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 201.McCarron MJ, Park PW, Fooksman DR. CD138 mediates selection of mature plasma cells by regulating their survival. Blood. 2017;129:2749–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 202.Couchman JR. Syndecan-1 (CD138), carcinomas and EMT. Int J Mol Sci. 2021;22:4227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 203.Palaiologou M, Delladetsima I, Tiniakos D. CD138 (syndecan-1) expression in health and disease. Histol Histopathol. 2014;29:177–89. [DOI] [PubMed] [Google Scholar]
- 204.Sun C, Mahendravada A, Ballard B, et al. Safety and efficacy of targeting CD138 with a chimeric antigen receptor for the treatment of multiple myeloma. Oncotarget. 2019;10:2369–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 205.Li J, Stagg NJ, Johnston J, et al. Membrane-proximal epitope facilitates efficient T cell synapse formation by anti-FcRH5/CD3 and is a requirement for myeloma cell killing. Cancer Cell. 2017;31:383–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 206.Schmidt TM, Fonseca R, Usmani SZ. Chromosome 1q21 abnormalities in multiple myeloma. Blood Cancer J. 2021;11:83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 207.Zhao J, Ren Q, Liu X, Guo X, Song Y. Bispecific antibodies targeting BCMA, GPRC5D, and FcRH5 for multiple myeloma therapy: latest updates from ASCO 2023 Annual Meeting. J Hematol Oncol. 2023;16:92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 208.Jiang D, Huang H, Qin H, et al. Chimeric antigen receptor T cells targeting FcRH5 provide robust tumour-specific responses in murine xenograft models of multiple myeloma. Nat Commun. 2023;14:3642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 209.Ramos CA, Savoldo B, Torrano V, et al. Clinical responses with T lymphocytes targeting malignancy-associated kappa light chains. J Clin Invest. 2016;126:2588–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 210.Baumeister SH, Murad J, Werner L, et al. Phase I trial of autologous CAR T cells targeting NKG2D ligands in patients with AML/MDS and multiple myeloma. Cancer Immunol Res. 2019;7:100–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 211.Sallman DA, Kerre T, Havelange V, et al. CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial. Lancet Haematol. 2023;10:e191–202. [DOI] [PubMed] [Google Scholar]
- 212.Stadtmauer EA, Faitg TH, Lowther DE, et al. Long-term safety and activity of NY-ESO-1 SPEAR T cells after autologous stem cell transplant for myeloma. Blood Adv. 2019;3:2022–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 213.Casucci M, Nicolis di Robilant B, Falcone L, et al. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood. 2013;122:3461–72. [DOI] [PubMed] [Google Scholar]
- 214.Sherbenou DW, Aftab BT, Su Y, et al. Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells. J Clin Invest. 2016;126:4640–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 215.Cottini F, Rodriguez J, Hughes T, et al. Redefining CD56 as a biomarker and therapeutic target in multiple myeloma. Mol Cancer Res. 2022;20:1083–95. [DOI] [PubMed] [Google Scholar]
- 216.Shaffer DR, Savoldo B, Yi Z, et al. T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood. 2011;117:4304–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 217.Burton JD, Ely S, Reddy PK, et al. CD74 is expressed by multiple myeloma and is a promising target for therapy. Clin Cancer Res. 2004;10:6606–11. [DOI] [PubMed] [Google Scholar]
- 218.Atanackovic D, Panse J, Hildebrandt Y, et al. Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma. Haematologica. 2011;96:1512–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 219.Radhakrishnan SV, Luetkens T, Scherer SD, et al. CD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide. Nat Commun. 2020;11:798. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 220.Hosen N, Matsunaga Y, Hasegawa K, et al. The activated conformation of integrin beta(7) is a novel multiple myeloma-specific target for CAR T cell therapy. Nat Med. 2017;23:1436–43. [DOI] [PubMed] [Google Scholar]
- 221.Peinert S, Prince HM, Guru PM, et al. Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen. Gene Ther. 2010;17:678–86. [DOI] [PubMed] [Google Scholar]
- 222.Di Meo F, Iyer A, Akama K, et al. A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma. Cell Rep Med. 2023;4: 101110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 223.Anderson GSF, Ballester-Beltran J, Giotopoulos G, et al. Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma. Blood. 2022;139:2471–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 224.Ferguson ID, Patino-Escobar B, Tuomivaara ST, et al. The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance. Nat Commun. 2022;13:4121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 225.Yin L, Tagde A, Gali R, et al. MUC1-C is a target in lenalidomide resistant multiple myeloma. Br J Haematol. 2017;178:914–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 226.Gong Y, Klein Wolterink RGJ, Wang J, Bos GMJ, Germeraad WTV. Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. J Hematol Oncol. 2021;14:73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 227.Lamers-Kok N, Panella D, Georgoudaki AM, et al. Natural killer cells in clinical development as non-engineered, engineered, and combination therapies. J Hematol Oncol. 2022;15:164. [DOI] [PMC free article] [PubMed]
- 228.Laskowski TJ, Biederstadt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer. 2022;22:557–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 229.Xie G, Dong H, Liang Y, Ham JD, Rizwan R, Chen J. CAR-NK cells: a promising cellular immunotherapy for cancer. EBioMedicine. 2020;59: 102975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 230.Heipertz EL, Zynda ER, Stav-Noraas TE, et al. Current perspectives on “off-the-shelf” allogeneic NK and CAR-NK cell therapies. Front Immunol. 2021;12: 732135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 231.Li Y, Hermanson DL, Moriarity BS, Kaufman DS. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell. 2018;23(181–192): e185. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 232.Lin X, Sun Y, Dong X, Liu Z, Sugimura R, Xie G. IPSC-derived CAR-NK cells for cancer immunotherapy. Biomed Pharmacother. 2023;165: 115123. [DOI] [PubMed] [Google Scholar]
- 233.Zhang L, Meng Y, Feng X, Han Z. CAR-NK cells for cancer immunotherapy: from bench to bedside. Biomark Res. 2022;10:12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 234.Ebrahimiyan H, Tamimi A, Shokoohian B, et al. Novel insights in CAR-NK cells beyond CAR-T cell technology; promising advantages. Int Immunopharmacol. 2022;106: 108587. [DOI] [PubMed] [Google Scholar]
- 235.Valeri A, Garcia-Ortiz A, Castellano E, et al. Overcoming tumor resistance mechanisms in CAR-NK cell therapy. Front Immunol. 2022;13: 953849. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 236.Wang L, Dou M, Ma Q, Yao R, Liu J. Chimeric antigen receptor (CAR)-modified NK cells against cancer: opportunities and challenges. Int Immunopharmacol. 2019;74: 105695. [DOI] [PubMed] [Google Scholar]
- 237.Maalej KM, Merhi M, Inchakalody VP, et al. CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances. Mol Cancer. 2023;22:20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 238.Klingemann H. The NK-92 cell line-30 years later: its impact on natural killer cell research and treatment of cancer. Cytotherapy. 2023;25:451–7. [DOI] [PubMed] [Google Scholar]
- 239.Maddineni S, Silberstein JL, Sunwoo JB. Emerging NK cell therapies for cancer and the promise of next generation engineering of iPSC-derived NK cells. J Immunother Cancer. 2022;10: e004693. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 240.Ren Q, Zu Y, Su H, et al. Single VHH-directed BCMA CAR-NK cells for multiple myeloma. Exp Hematol Oncol. 2023;12:98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 241.Cao Z, Yang C, Wang Y, et al. Allogeneic CAR-NK cell therapy targeting both BCMA and GPRC5D for the treatment of multiple myeloma. Blood. 2022;140:7378–7378. [Google Scholar]
- 242.Jiang H, Zhang W, Shang P, et al. Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Mol Oncol. 2014;8:297–310. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 243.Chu J, Deng Y, Benson DM, et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia. 2014;28:917–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 244.Leivas A, Valeri A, Cordoba L, et al. NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma. Blood Cancer J. 2021;11:146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 245.Reiser J, Chan SR, Mathavan K, et al. FT555: off-the-shelf CAR-NK cell therapy co-targeting GPRC5D and CD38 for the treatment of multiple myeloma. Blood. 2022;140:4560–1. [Google Scholar]
- 246.Tapia-Galisteo A, Alvarez-Vallina L, Sanz L. Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies. J Hematol Oncol. 2023;16:83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 247.Goebeler ME, Bargou RC. T cell-engaging therapies - BiTEs and beyond. Nat Rev Clin Oncol. 2020;17:418–34. [DOI] [PubMed] [Google Scholar]
- 248.Zhou S, Liu M, Ren F, Meng X, Yu J. The landscape of bispecific T cell engager in cancer treatment. Biomark Res. 2021;9:38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 249.Tapia-Galisteo A, Compte M, Alvarez-Vallina L, Sanz L. When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy. Theranostics. 2023;13:1028–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 250.Letouze E, Moreau P, Munshi N, Samur M, Minvielle S, Touzeau C. Mechanisms of resistance to bispecific T-cell engagers in multiple myeloma and their clinical implications. Blood Adv. 2024;8:2952–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 251.Yao Y, Hu Y, Wang F. Trispecific antibodies for cancer immunotherapy. Immunology. 2023;169:389–99. [DOI] [PubMed] [Google Scholar]
- 252.Giang KA, Boxaspen T, Diao Y, et al. Affibody-based hBCMA x CD16 dual engagers for NK cell-mediated killing of multiple myeloma cells. N Biotechnol. 2023;77:139–48. [DOI] [PubMed] [Google Scholar]
- 253.Li W, Zhang B, Cao W, et al. Identification of potential resistance mechanisms and therapeutic targets for the relapse of BCMA CAR-T therapy in relapsed/refractory multiple myeloma through single-cell sequencing. Exp Hematol Oncol. 2023;12:44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 254.Kakiuchi-Kiyota S, Ross T, Wallweber HA, et al. A BCMA/CD16A bispecific innate cell engager for the treatment of multiple myeloma. Leukemia. 2022;36:1006–14. [DOI] [PubMed] [Google Scholar]
- 255.Wang C, Wang W, Wang M, et al. Different evasion strategies in multiple myeloma. Front Immunol. 2024;15:1346211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 256.Einsele H, Borghaei H, Orlowski RZ, et al. The BiTE (bispecific T-cell engager) platform: development and future potential of a targeted immuno-oncology therapy across tumor types. Cancer. 2020;126:3192–201. [DOI] [PubMed] [Google Scholar]
- 257.Khattak ZE, Hashmi H, Khan SI, et al. Dawn of a new era of antibody-drug conjugates and bispecific T-cell engagers for treatment of multiple myeloma: a systematic review of literature. Ann Hematol. 2021;100:2155–72. [DOI] [PubMed] [Google Scholar]
- 258.Minakata D, Fujiwara SI, Yokoyama D, et al. Relapsed and refractory multiple myeloma: a systematic review and network meta-analysis of the efficacy of novel therapies. Br J Haematol. 2023;200:694–703. [DOI] [PubMed] [Google Scholar]
- 259.Belantamab Mafodotin. LiverTox: Clinical and research information on drug-induced liver injury. Bethesda (MD); 2012. [PubMed]
- 260.Firestone R, Lesokhin AM, Usmani SZ. An embarrassment of riches: three FDA-approved bispecific antibodies for relapsed refractory multiple myeloma. Blood Cancer Discov. 2023;4:433–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 261.Usmani SZ, Garfall AL, van de Donk N, et al. Teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet. 2021;398:665–74. [DOI] [PubMed] [Google Scholar]
- 262.Moreau P, Garfall AL, van de Donk N, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387:495–505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 263.Bahlis NJ, Tomasson MH, Mohty M, et al. Efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma Naïve to B-cell maturation antigen (BCMA)-directed therapies: results from cohort a of the magnetismm-3 study. Blood. 2022;140:391–3. [Google Scholar]
- 264.Panowski SH, Kuo T, Chen A, et al. Preclinical evaluation of a potent anti-Bcma CD3 bispecific molecule for the treatment of multiple myeloma. Blood. 2016;128:383. [Google Scholar]
- 265.Verkleij CPM, Broekmans MEC, van Duin M, et al. Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma. Blood Adv. 2021;5:2196–215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 266.Lesokhin AM, Richter J, Trudel S, et al. Enduring responses after 1-year, fixed-duration cevostamab therapy in patients with relapsed/refractory multiple myeloma: early experience from a phase I study. Blood. 2022;140:4415–7. [Google Scholar]
- 267.Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382:545–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 268.Pinto S, Pahl J, Schottelius A, Carter PJ, Koch J. Reimagining antibody-dependent cellular cytotoxicity in cancer: the potential of natural killer cell engagers. Trends Immunol. 2022;43:932–46. [DOI] [PubMed] [Google Scholar]
- 269.Wu J, Fu J, Zhang M, Liu D. AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy. J Hematol Oncol. 2015;8:96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 270.Tang A, Gauthier L, Beninga J, et al. The novel trifunctional anti-BCMA NK cell engager SAR’514 has potent in-vitro and in-vivo anti-myeloma effect through dual NK cell engagement. Blood. 2022;140:9985–6. [Google Scholar]
- 271.Miller JS, Zorko N, Merino A, et al. 755P B7H3-targeted tri-specific killer engagers deliver IL-15 to NK cells but not T-cells, and specifically target solid tumors as a pan-tumor antigen strategy mediated through NK cells. Ann Oncol. 2022;33:S889. [Google Scholar]
- 272.Lindemann A, Herrmann F, Oster W, Mertelsmann R. Lymphokine activated killer cells. Blut. 1989;59:375–84. [DOI] [PubMed] [Google Scholar]
- 273.Richards JM. Therapeutic uses of interleukin-2 and lymphokine-activated killer (LAK) cells. Blood Rev. 1989;3:110–9. [DOI] [PubMed] [Google Scholar]
- 274.Morris DG, Pross HF. Studies of lymphokine-activated killer (LAK) cells. I. Evidence using novel monoclonal antibodies that most human LAK precursor cells share a common surface marker. J Exp Med. 1989;169:717–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 275.Lobo PI, Chang MY, Mellins E. Mechanisms by which HLA-class II molecules protect human B lymphoid tumour cells against NK- and LAK-mediated cytolysis. Immunology. 1996;88:625–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 276.Gottlieb DJ, Prentice HG, Mehta AB, et al. Malignant plasma cells are sensitive to LAK cell lysis: pre-clinical and clinical studies of interleukin 2 in the treatment of multiple myeloma. Br J Haematol. 1990;75:499–505. [DOI] [PubMed] [Google Scholar]
- 277.Paucek RD, Baltimore D, Li G. The cellular immunotherapy revolution: arming the immune system for precision therapy. Trends Immunol. 2019;40:292–309. [DOI] [PubMed] [Google Scholar]
- 278.Labanieh L, Mackall CL. CAR immune cells: design principles, resistance and the next generation. Nature. 2023;614:635–48. [DOI] [PubMed] [Google Scholar]
- 279.Sun L, Su Y, Jiao A, Wang X, Zhang B. T cells in health and disease. Signal Transduct Target Ther. 2023;8:235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 280.Kabelitz D, Peters C, Wesch D, Oberg HH. Regulatory functions of gammadelta T cells. Int Immunopharmacol. 2013;16:382–7. [DOI] [PubMed] [Google Scholar]
- 281.Vroom TM, Scholte G, Ossendorp F, Borst J. Tissue distribution of human gamma delta T cells: no evidence for general epithelial tropism. J Clin Pathol. 1991;44:1012–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 282.Mensurado S, Blanco-Dominguez R, Silva-Santos B. The emerging roles of gammadelta T cells in cancer immunotherapy. Nat Rev Clin Oncol. 2023;20:178–91. [DOI] [PubMed] [Google Scholar]
- 283.Dong C. Cytokine regulation and function in T cells. Annu Rev Immunol. 2021;39:51–76. [DOI] [PubMed] [Google Scholar]
- 284.Silva-Santos B, Mensurado S, Coffelt SB. gammadelta T cells: pleiotropic immune effectors with therapeutic potential in cancer. Nat Rev Cancer. 2019;19:392–404. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 285.Hu Y, Hu Q, Li Y, et al. gammadelta T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct Target Ther. 2023;8:434. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 286.Rimailho L, Faria C, Domagala M, Laurent C, Bezombes C, Poupot M. gammadelta T cells in immunotherapies for B-cell malignancies. Front Immunol. 2023;14:1200003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 287.Caccamo N, La Mendola C, Orlando V, et al. Differentiation, phenotype, and function of interleukin-17-producing human Vgamma9Vdelta2 T cells. Blood. 2011;118:129–38. [DOI] [PubMed] [Google Scholar]
- 288.Wu YL, Ding YP, Tanaka Y, et al. gammadelta T cells and their potential for immunotherapy. Int J Biol Sci. 2014;10:119–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 289.Obeidy P, Sharland AF. NKG2D and its ligands. Int J Biochem Cell Biol. 2009;41:2364–7. [DOI] [PubMed] [Google Scholar]
- 290.Kabelitz D, Serrano R, Kouakanou L, Peters C, Kalyan S. Cancer immunotherapy with gammadelta T cells: many paths ahead of us. Cell Mol Immunol. 2020;17:925–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 291.Sebestyen Z, Prinz I, Dechanet-Merville J, Silva-Santos B, Kuball J. Translating gammadelta (gammadelta) T cells and their receptors into cancer cell therapies. Nat Rev Drug Discov. 2020;19:169–84. [DOI] [PubMed] [Google Scholar]
- 292.de Weerdt I, Lameris R, Scheffer GL, et al. A Bispecific antibody antagonizes prosurvival CD40 signaling and promotes Vgamma9Vdelta2 T cell-mediated antitumor responses in human B-cell malignancies. Cancer Immunol Res. 2021;9:50–61. [DOI] [PubMed] [Google Scholar]
- 293.Marcu-Malina V, Heijhuurs S, van Buuren M, et al. Redirecting alphabeta T cells against cancer cells by transfer of a broadly tumor-reactive gammadeltaT-cell receptor. Blood. 2011;118:50–9. [DOI] [PubMed] [Google Scholar]
- 294.Verheye E, Bravo Melgar J, Deschoemaeker S, et al. Dendritic cell-based immunotherapy in multiple myeloma: challenges, opportunities, and future directions. Int J Mol Sci. 2022;23:904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 295.Allegra A, Penna G, Innao V, et al. Vaccination of multiple myeloma: Current strategies and future prospects. Crit Rev Oncol Hematol. 2015;96:339–54. [DOI] [PubMed] [Google Scholar]
- 296.Weinstock M, Rosenblatt J, Avigan D. Dendritic cell therapies for hematologic malignancies. Mol Ther Methods Clin Dev. 2017;5:66–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 297.Cancer vaccine--Antigenics. BioDrugs. 2002;16:72–74. [DOI] [PubMed]
- 298.Mumper RJ, Ledebur HC Jr. Dendritic cell delivery of plasmid DNA. Applications for controlled genetic immunization. Mol Biotechnol. 2001;19:79–95. [DOI] [PubMed] [Google Scholar]
- 299.Koida S. Dendritic-tumor fusion cell-based cancer vaccines. Int J Mol Sci. 2016;17:828. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 300.Han S, Wang B, Cotter MJ, et al. Overcoming immune tolerance against multiple myeloma with lentiviral calnexin-engineered dendritic cells. Mol Ther. 2008;16:269–79. [DOI] [PubMed] [Google Scholar]
- 301.Introna M. CIK as therapeutic agents against tumors. J Autoimmun. 2017;85:32–44. [DOI] [PubMed] [Google Scholar]
- 302.Jiang J, Wu C, Lu B. Cytokine-induced killer cells promote antitumor immunity. J Transl Med. 2013;11:83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 303.Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med. 1991;174:139–49. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 304.Mata-Molanes JJ, Sureda Gonzalez M, Valenzuela Jimenez B, Martinez Navarro EM, Brugarolas MA. Cancer immunotherapy with cytokine-induced killer cells. Target Oncol. 2017;12:289–99. [DOI] [PubMed] [Google Scholar]
- 305.Introna M, Golay J, Rambaldi A. Cytokine Induced Killer (CIK) cells for the treatment of haematological neoplasms. Immunol Lett. 2013;155:27–30. [DOI] [PubMed] [Google Scholar]
- 306.Meng Y, Yu Z, Wu Y, et al. Cell-based immunotherapy with cytokine-induced killer (CIK) cells: from preparation and testing to clinical application. Hum Vaccin Immunother. 2017;13:1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 307.Poh SL, Linn YC. Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts. Cancer Immunol Immunother. 2016;65:525–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 308.Ferrari de Andrade L, Kumar S, Luoma AM, et al. Inhibition of MICA and MICB shedding elicits NK-Cell-mediated immunity against tumors resistant to cytotoxic T cells. Cancer Immunol Res. 2020;8:769–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 309.Biondi M, Tettamanti S, Galimberti S, et al. Selective homing of CAR-CIK cells to the bone marrow niche enhances control of the acute myeloid leukemia burden. Blood. 2023;141:2587–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 310.Dalla Pieta A, Cappuzzello E, Palmerini P, et al. Innovative therapeutic strategy for B-cell malignancies that combines obinutuzumab and cytokine-induced killer cells. J Immunother Cancer. 2021;9: e002475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 311.Zhang Y, Wu X, Sharma A, et al. Anti-CD40 predominates over anti-CTLA-4 to provide enhanced antitumor response of DC-CIK cells in renal cell carcinoma. Front Immunol. 2022;13: 925633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 312.Wang S, Wang X, Zhou X, Lyerly HK, Morse MA, Ren J. DC-CIK as a widely applicable cancer immunotherapy. Expert Opin Biol Ther. 2020;20:601–7. [DOI] [PubMed] [Google Scholar]
- 313.Pu J, Sharma A, Liu T, Hou J, Schmidt-Wolf IG. Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine-induced killer cell efficiency in multiple myeloma via the NKG2D pathway. Clin Transl Immunol. 2024;13: e1500. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 314.Poels R, Drent E, Lameris R, et al. Preclinical evaluation of invariant natural killer T cells modified with CD38 or BCMA chimeric antigen receptors for multiple myeloma. Int J Mol Sci. 2021;22:1096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 315.Wang Y, Lv B, Li K, Zhang A, Liu H. Adjuvant immunotherapy of dendritic cells and cytokine-induced killer cells is safe and enhances chemotherapy efficacy for multiple myeloma in China: a meta-analysis of clinical trials. Drug Des Devel Ther. 2017;11:3245–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 316.Sharma A, Schmidt-Wolf IGH. 30 years of CIK cell therapy: recapitulating the key breakthroughs and future perspective. J Exp Clin Cancer Res. 2021;40:388. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
No datasets were generated or analysed during the current study.