Identification and transformation of novel targets for immunotherapy in multiple myeloma.

Introduction

Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the progressive growth of clonal plasma cells, excessive accumulation of M protein, and terminal end-organ damage. [ 1 ] The progression of MM is closely associated with progressive immune dysfunction, which is attributable to exhausted immune cells, MM-associated immunosuppressive cells, and soluble mediators within the immunosuppressive microenvironment. [ 2 , 3 ] Numerous studies of MM pathogenesis have led to the development of immunotherapies targeting immune system dysfunction and evasion, which have led to improved 5-year overall survival (OS) rates over the past two decades. [ 4 , 5 ] Currently available immunotherapies, including immunomodulatory imide drugs (IMiDs) and monoclonal antibodies (mAbs), are now standard treatments for both newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (R/RMM). Recent work has furthered the development of novel immunotherapies such as immune checkpoint inhibitors (ICIs), chimeric antigen receptor T cell (CAR-T) therapy, bispecific antibodies, and antibody–drug conjugates (ADCs), which have been widely studied in multiple clinical trials. Despite these developments, MM remains incurable and will almost certainly relapse. In addition, triple-class refractory disease (refractory to proteosome inhibitors [PIs], IMiDs, and CD38 mAbs) or penta-class refractory disease (refractory to 2 PIs, 2 IMiDs, and a CD38 mAb) is more difficult to treat than other forms due to target loss or antigen escape. [ 6 , 7 ] Therefore, new therapies for MM with novel targets are urgently needed to improve clinical responses and avoid disease relapse. Here, we review the currently available immunotherapies, focusing on the novel targets and products of each type of therapy, and provide a perspective on future directions for MM.

Pivotal Role of the Immune Microenvironment in MM Development

MM forms a robust connection with the immune microenvironment in the bone marrow (BM), which substantially contributes to disease progression and exacerbation through intricate dynamic interactions. [ 8 – 12 ] The key mutations required for MM progression are present in early stages of the disease, which include monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). MM progression is characterized by changes in the clonal structure that begin before the MGUS/SMM stage, rather than by the appearance of entirely new subclones. [ 13 , 14 ] Our single-cell sequencing analysis of bone marrow mononuclear cells (BMNCs) confirmed that, in addition to intrinsic tumor cell characteristics, the tumor microenvironment, particularly the immune microenvironment, has a substantial influence on MM cell proliferation. [ 12 ] Within the BM microenvironment, increased concentrations of inflammatory cytokines, such as interleukin (IL)-6 and transforming growth factor (TGF)-β, lead to shifts in the T cell population, facilitating tumor growth and promoting immune evasion and immunoediting. [ 2 , 8 , 14 ] Regulatory T cells (Tregs) interfere with anti-tumor responses through immunosuppression. The ratio of CD8 + T cells to Tregs in the BM reflects the strength of the anti-tumor immune response and thus can predict the response to immune checkpoint blockade (ICB) therapy. A higher CD8 + /Treg ratio indicates greater robustness. [ 15 ] Infiltrating MM cells disrupt the normal differentiation of CD8 + T cells, contributing to the formation of an immunosuppressive microenvironment. This disruption is linked to the abnormal expression of PIM kinase and KLRB1, as well as metabolic dysregulation driven by MM. [ 12 ] CD57 + CD8 + T cells represent a terminally differentiated, senescent, and functionally exhausted subset characterized by diminished proliferative capacity, attenuated cytotoxicity, and reduced interferon-γ production. [ 8 , 16 – 19 ] Senescence was shown to be independent of telomeres, while various immune checkpoints, including programmed death (PD)-1, cytotoxic T-lymphocyte-associated protein-4, lymphocyte activation gene (LAG)-3, and T-cell immunoreceptor with immunoglobulin and T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domains (TIGIT), have been frequently associated with immune cell exhaustion. [ 14 , 18 , 20 – 24 ] The presence of pre-existing exhausted-like CD8 + T cell clones (e.g., granzyme K + or thymocyte selection-associated high mobility group box protein + ) before T cell engager (TCE) therapy has been associated with clinical response failure. [ 25 ]

The cytotoxic activity of natural killer (NK) cells is frequently compromised in MM due to receptor dysregulation, e.g., a decrease in the expression of activating receptors alongside increases in the expression of inhibitory receptors and immune checkpoints. [ 8 , 14 ] Human leukocyte antigen (HLA)-E expression is regulated by the transcription factor cAMP-responsive element-binding protein 1 (CREB1), which directly binds to its promoter region. HLA-E interacts with NKG2A to convey inhibitory signals to NK cells. Importantly, CREB1 inhibitor treatment was shown to effectively restore NK cell-mediated cytotoxicity against MM cell lines and patient samples. [ 26 ] Extracellular adenosine is linked to MM progression: Its level was found to correlate with decreases in the cytotoxic activity of CD8 + T cells and NK cells, as well as an increase in the proportion of Tregs. [ 27 ] Myeloid-derived suppressor cells (MDSCs) are abundant in the BM of MM patients; [ 28 , 29 ] these cells inhibit immune responses primarily by inducing Treg differentiation, decreasing T cell proliferation, and promoting MM cell proliferation and angiogenesis. [ 8 ] In MM cells, increased expression of leukocyte immunoglobulin-like receptor B4 (LILRB4) promotes the generation of MDSCs, contributing to the establishment and maintenance of an immunosuppressive microenvironment. [ 28 ] Granulocytic MDSCs enhance tumor progression and immune suppression in MM by promoting the expression of Piwi-interacting RNA (piRNA)-823, which facilitates DNA methylation and increases the tumorigenic potential and cancer stem cell characteristics of MM cells. [ 30 ]

Multiple studies have confirmed the expression of the M2 macrophage markers CD163 and CD206 in tumor-associated macrophages from the BM of patients with MM at both diagnosis and relapse. [ 31 – 33 ] Interaction between P-selectin glycoprotein ligand-1 and selectins and between intercellular adhesion molecule-1 and lymphocyte function-associated antigen 1 on macrophages and MM cells, respectively, activate the Src and Erk1/2 kinases and c-Myc pathway, ultimately suppressing chemotherapy drug-induced caspase. [ 34 ] IL-32γ promotes drug resistance in MM by driving macrophage polarization toward the M2 phenotype via partial reliance on the upregulation of colony-stimulating factor 1 (CSF1). [ 35 ] As CSF-1 enhances metastatic potential, inhibiting CSF-1/CSF-1R activity may not only slow cancer progression but also target metastasis and prevent malignant transformation. [ 36 , 37 ] Indoleamine 2,3-dioxygenase, an inducible enzyme that converts tryptophan into kynurenine metabolites, is overexpressed in MM, where it helps suppress anti-myeloma immunity and promotes the establishment of an immunosuppressive microenvironment in the BM. [ 38 ]

Immunotherapy: Concept, Categories, and History

Immunotherapy for MM focuses on manipulating the immune system to specifically recognize, target, and eradicate MM cells. By augmenting the immune system’s capacity to identify malignant cells as threats, immunotherapy aims to initiate a more precise and effective attack. The goal of this approach is not only to enhance the targeting capabilities of the immune system but also to facilitate sustained immune responses that may prevent disease recurrence and improve patient outcomes.

During the 1960s, the combination of oral melphalan, an alkylating agent, and prednisone was considered the standard first-line treatment for MM. [ 39 , 40 ] Together with the introduction of daunorubicin, a combination therapy comprising vincristine, adriamycin, and dexamethasone was developed in 1983 for the treatment of refractory MM, and its efficacy has been demonstrated in clinical trials. [ 41 ] In the 1980s, autologous BM transplantation and allogeneic BM transplantation were introduced in conjunction with high-dose chemotherapy. These strategies have enabled extended disease management through an immune-mediated graft-versus-myeloma effect, while simultaneously promoting the restoration of immune balance. [ 42 – 45 ] The introduction of proteasome inhibitors (PIs) in 2003 marked a significant advancement in patient care and led to considerable increases in progression-free survival (PFS). [ 46 ] Following the success of bortezomib, additional PIs, including carfilzomib and ixazomib, were approved for the treatment of MM. Thalidomide, an IMiD, was first administered in 1997 and was approved by the United States Food and Drug Administration (FDA) in 2006. The FDA subsequently approved the use of lenalidomide in 2006 and pomalidomide in 2013. [ 47 ]

The current MM treatment landscape era is dynamic and characterized by the rapid advancement of immune-based therapies [Figure 1 ]. Immunotherapies can be broadly categorized into four primary components. The first component is the targeting of specific antigens present on MM cells via mAbs. The second component is the disruption of immune tolerance mechanisms via agents such as checkpoint inhibitors. The third component is the enhancement of both the quantity and efficacy of immune effector cells, specifically aimed at eradicating MM cells via therapies such as CAR-T, CAR-NK, and vaccines. The fourth component is the integration of dual mechanisms via therapeutic platforms such as bispecific T cell engagers (BiTEs) and ADCs, which simultaneously target tumor antigens and exert cytotoxic or immunomodulatory effects [Figure 2 ]. The aim of this multifaceted approach is to refine the anti-MM immune response and improve patients’ treatment outcomes. [ 18 , 47 , 48 ]

Immunotherapies Targeting Novel Pathways

Immunomodulatory imide drugs (IMiDs)

IMiDs play a crucial role in combination therapy for both NDMM and R/RMM. These drugs are also used for maintenance therapy following autologous stem cell transplantation (ASCT). The success of thalidomide has instilled new hope regarding the treatment of MM, leading to a series of clinical trials based on its use. However, thalidomide is associated with substantial adverse effects and has been gradually supplanted by the thalidomide derivatives lenalidomide and pomalidomide, which offer improved tolerance and efficacy.

IMiDs exhibit a range of anti-myeloma effects, including anti-angiogenic properties, apoptosis induction, and cell growth inhibition. [ 49 ] The mechanism of these drugs remained unclear until the 2010s, when cereblon (CRBN) was identified as a key target of thalidomide. [ 50 , 51 ] IMiDs act as a molecular glue: These drugs bind CRBN and link neosubstrates to the CRL4CRBN complex, leading to polyubiquitination and subsequent proteasomal degradation. In MM, the primary neosubstrates are the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are crucial to plasma cell development and proliferation. IMiD-mediated degradation of IKZF1 and IKZF3 by the CRL4CRBN complex results in the downregulation of interferon response factor 4 expression in MM cells, ultimately triggering apoptosis. In addition to direct cytotoxicity, IMiDs modulate the immune response by promoting IL-2 secretion from T cells and interferon-γ production by NK cells, thus boosting the activity of both cell populations. [ 52 ] Recent studies have demonstrated that IMiDs can enhance the cytotoxicity of NK and T cells through ZAP-70-mediated, CRBN-independent mechanisms, suggesting potential targets for the development of novel MM therapies. [ 53 ]

Next-generation cereblon E3 ligase modulators (CELMoDs) were recently developed based on a similar mechanism. CELMoDs exhibit over 20-fold higher affinity for CRBN than conventional IMiDs, leading to significantly enhanced degradation of IKZF1 and IKZF3. This has resulted in promising clinical outcomes for patients with R/RMM who have received multiple lines of therapy, including lenalidomide and pomalidomide. Iberdomide is a novel and effective CELMoD shown to exert potent antiproliferative and pro-apoptotic activity against MM cells in preclinical studies. [ 54 ] A multicenter, multicohort, open-label, phase I/II trial evaluated the clinical effects of iberdomide in combination with dexamethasone in a cohort of 197 patients with R/RMM who had received at least three previous lines of therapy. [ 55 ] The overall response rate (ORR) was 32% (95% confidence interval [CI] 23–43%; 29 of 90 patients) in the dose-escalation cohort and 26% (95% CI 18–36%; 28 of 107 patients) in the dose-expansion cohort. Although the ORR associated with this combination therapy was not as remarkable as those observed with B-cell maturation antigen (BCMA)-directed treatments for R/RMM, the combination therapy was associated with a lower incidence of grade 3 or worse non-hematological adverse effects, suggesting a more manageable safety profile and improved tolerability. The analysis of biological samples from trial participants with R/RMM revealed that iberdomide exerted antimyeloma effects through not only CRBN-dependent degradation of IKZF1 and IKZF3 but also immune stimulation, inducing T cells to transition into an activated memory phenotype. [ 56 ] Mezigdomide (CC-92480), a novel compound classified as a CELMoD, has demonstrated an even higher binding affinity for CRBN than iberdomide. In MM cell lines, mezigdomide exerts antimyeloma effects through mechanisms similar to those of other IMiDs but achieves a greater downregulation of interferon response factor 4 and c-Myc. Furthermore, T cell lymphoma research has shown that mezigdomide can overcome lenalidomide resistance by targeting IKZF1 and ZFP91. [ 54 ] Recently, the efficacy of mezigdomide in combination with dexamethasone and bortezomib was evaluated in the ongoing phase I/II clinical trial (No. CC-92480-MM-002). [ 57 ] Of the 19 patients with R/RMM who had received two to four prior therapies, including lenalidomide, the ORR across all doses was 73.7% (14 of 19) and was accompanied by manageable adverse effects. These findings indicate promising preliminary clinical outcomes for this combination therapy and support the further development of mezigdomide for the management of R/RMM.

Monoclonal antibodies (mAbs)

In recent years, mAbs have become a cornerstone in the treatment of MM. Over the past decade, the FDA has approved three mAbs—daratumumab, isatuximab, and elotuzumab—for the management of MM. These agents specifically target antigens that are highly and exclusively expressed on MM cells, inducing cytotoxicity through various mechanisms.

Anti-CD38 mAbs

Daratumumab monotherapy has demonstrated promising clinical activity, with a 29% ORR and a favorable safety profile in patients with heavily pretreated MM, offering new hope for the treatment of R/RMM. [ 58 ] Given these encouraging effects, daratumumab has been evaluated in combination with standard-of-care regimens across various subgroups of MM patients. In patients with R/RMM, the combination of daratumumab with either IMiDs or PIs, alongside dexamethasone, resulted in prolonged OS and stronger clinical responses than standard treatment alone. [ 59 – 62 ]

In transplant-ineligible patients with NDMM, daratumumab-based combinations have shown superior clinical efficacy. In the ALCYONE trial, the primary analysis showed that daratumumab combined with bortezomib, melphalan, and prednisone (D-VMP) significantly prolonged the median PFS compared with bortezomib, melphalan, and prednisone (VMP) alone. This significant improvement in the median PFS was maintained after a median follow-up of 40 months (hazard ratio [HR] 0.42 [95% CI 0.34–0.51]; P <0.0001). In transplant-eligible patients with NDMM, daratumumab was incorporated into the bortezomib, thalidomide, and dexamethasone regimen (D-VTd) during both the induction and consolidation phases before and following ASCT. When administered before and after ASCT, D-VTd conferred clinical advantages in terms of the median PFS (83.7 vs . 52.8 months), stringent complete response rate (sCR) (29% vs . 20%; HR 1.60, 95% CI 1.21–2.12, P = 0.0010), and rate of minimal residual disease (MRD) negativity (64% vs . 44%) compared with VTd alone. [ 63 ] Furthermore, daratumumab maintenance therapy after consolidation led to a significant improvement in PFS compared with standard VTd alone (median not reached [95% CI 79.9–not estimable (NE)] vs . 45.8 months [41.8–49.6 months]; HR 0.49 [95% CI 0.40–0.59]; P <0.0001). [ 64 ] However, intravenous daratumumab administration requires a prolonged infusion time and may lead to infusion-related reactions, which can adversely affect patients’ quality of life. Recently, a new formulation of daratumumab for subcutaneous injection was developed to reduce both the administration time and the incidence of allergic reactions. In a randomized phase III trial, subcutaneous daratumumab was found to have an improved safety profile while maintaining non-inferior efficacy and pharmacokinetics compared with intravenous daratumumab. [ 65 ]

Isatuximab is an immunoglobulin G1 (IgG1) mAb that targets a specific CD38 epitope distinct from the target of daratumumab. The clinical efficacy of isatuximab has also been evaluated in clinical trials incorporating isatuximab into standard treatment regimens. The findings from the ICARIA-MM and IKEMA trials have led to the approval of combination therapy comprising isatuximab and dexamethasone with pomalidomide or carfilzomib for patients with R/RMM. [ 66 , 67 ] Analogously to daratumumab, isatuximab, administered in combination with lenalidomide, dexamethasone, and bortezomib, has led to clinical improvements in both transplant-eligible and transplant-ineligible patients diagnosed with NDMM. [ 68 , 69 ] However, few studies have directly compared the clinical effects of daratumumab and isatuximab. The results of a phase I/II study assessing the safety and efficacy of isatuximab in patients with daratumumab-refractory disease suggest that isatuximab has no clinical effect in this specific patient population. Specifically, isatuximab did not elicit any objective responses in patients with daratumumab-refractory MM. This finding suggests that isatuximab has no clinical efficacy in patients with R/RMM who were previously treated with daratumumab. [ 70 ]

Anti-CS1 mAb

Elotuzumab is a humanized IgG1 mAb that specifically targets signaling lymphocytic activation molecule F7 (SLAMF7), also known as CS1 or CD319. SLAMF7, a cell surface glycoprotein, is predominantly expressed on MM cells and normal plasma cells, as well as on NK cells and CD8 + T cells. [ 71 ] Elotuzumab exerts its antitumor effect by stimulating Fcγ receptor (FcγR)-mediated antibody-dependent cellular cytotoxicity via NK cells and antibody-dependent cellular phagocytosis via macrophages. [ 72 , 73 ] Elotuzumab exhibited limited antitumor activity as a monotherapy but substantial clinical efficacy when combined with IMiDs.

The randomized phase III ELOQUENT-2 trial evaluated the combination of elotuzumab, lenalidomide, and dexamethasone (ERd) in patients with R/RMM who had received one to three prior lines of therapy. Long-term follow-up results revealed an increased ORR (79% vs . 66%), prolonged median PFS (19.4 vs . 14.9 months), and a significant OS benefit (48.3 vs . 39.6 months, HR 0.82 [95.4% CI 0.68–1.00]) compared with lenalidomide and dexamethasone (Rd) alone. [ 74 ] When combined with pomalidomide and dexamethasone, elotuzumab demonstrated significant improvements in the median PFS, from 4.7 to 10.3 months, and in OS, from 17.4 to 29.8 months (HR 0.59 [95% CI 0.37–0.93]; P = 0.0217) in patients with R/RMM who had been pre-treated with lenalidomide and a PI compared with pomalidomide and dexamethasone (Pd) alone. [ 74 ]

Emerging targets of mAbs

CD98 heavy chain (CD98hc) is a promising therapeutic target in MM due to its crucial role in MM cell proliferation and survival. [ 75 ] However, the ubiquitous expression of CD98hc on both normal hematopoietic and non-hematopoietic cells poses significant challenges for selectively targeting MM cells. Recently, Hasegawa et al [ 76 ] identified a mAb, R8H283, which specifically recognizes CD98hc expressed on MM cells without interacting with normal tissues. This specificity is attributed to the distinct glycoform of CD98hc expressed on MM cells compared with normal cells, suggesting that CD98hc is a viable target for mAb-based therapy in MM.

IL-6, a critical growth factor for MM cell survival, can be targeted by the mAb siltuximab. A randomized, double-blind, multicenter study evaluated the efficacy of siltuximab in delaying progression from high-risk SMM to symptomatic MM. The results demonstrated significantly improved PFS (not reached vs . 23.5 months, HR 0.50 [95% CI 0.24–1.04]; P = 0.0597) and a favorable safety profile compared with placebo, suggesting the potential clinical benefit of siltuximab in delaying disease progression. [ 77 ]

Immune checkpoint inhibitors (ICIs)

T cells and NK cells express a variety of immune checkpoint receptors, such as PD-1, TIGIT, and LAG-3. [ 79 ] As the disease progresses and these immune cells interact with the tumor microenvironment, the expression levels of immune checkpoint receptors increase, leading to immune cell senescence or exhaustion. This process facilitates tumor immune evasion. [ 47 , 78 – 80 ] By blocking the interactions between inhibitory receptors and their ligands, ICIs have led to remarkable advancements in the treatment of both solid and hematologic malignancies. However, in the context of MM, ICIs have shown limited efficacy as monotherapies. [ 79 ] In recent studies, combining ICIs with IMiDs, mAbs, or other ICIs has yielded promising outcomes. [ 47 ] However, in 2017, the FDA suspended three ongoing phase III clinical trials involving IMiDs (pomalidomide or lenalidomide) and dexamethasone in combination with ICIs (pembrolizumab or nivolumab) due to severe adverse effects and high mortality rates. [ 47 , 81 ] This decision subsequently affected other studies on combination therapies involving ICIs, leading to the discontinuation of several projects.

The results of current clinical trials suggest that monotherapies targeting single immune checkpoints, such as PD-1/PD-ligand 1 (L1) blockade, [ 82 ] or simplistic combinations of ICIs often fail to achieve optimal therapeutic outcomes. [ 83 , 84 ] Identifying precise biomarkers and elucidating synergistic mechanisms are essential to enhance treatment efficacy. [ 45 , 82 – 85 ] A study (No. NCT04150965 ) evaluated the combination of anti-TIGIT or anti-LAG3 antibodies with pomalidomide and dexamethasone in patients with R/RMM who had previously been treated with a PI or IMiD. The study demonstrated that this combination regimen was well tolerated and achieved durable clinical responses in both treatment arms. Specifically, three of six participants responded in the anti-TIGIT arm, while two of six responded in the anti-LAG3 arm. The immune response profiles differed between the two groups: Anti-LAG3 responders exhibited higher levels of naive CD4 + T cells and lower PD-1 expression, whereas anti-TIGIT responders showed increased CD226 expression and enhanced NK cell activity. [ 86 ]

Patients with R/RMM who had received at least three prior lines of therapy, including a PI, an IMiD, and an anti-CD38 mAb, were enrolled in a study to evaluate the efficacy and safety of treatment with 2.5 mg/kg belantamab mafodotin in combination with pembrolizumab. Among 34 patients receiving this combination therapy, the ORR was 47% (95% CI 29.8–64.9%). Three of 10 patients who achieved a very good partial response (VGPR) or better were MRD-negative. In the subgroup of patients previously treated with anti-BCMA therapies, five of eight achieved at least a partial response (PR), including two patients with BCMA-refractory disease. The regimen was well tolerated, with manageable adverse events that did not significantly impact quality of life. These findings highlight the potential of combination immunotherapies to overcome treatment resistance in R/RMM. [ 87 ]

The combination of cobimetinib (a MEK inhibitor), venetoclax (a BCL-2 inhibitor), and atezolizumab (a PD-L1 inhibitor) exhibited moderate efficacy and favorable safety profiles in patients with R/RMM who had received three to five prior lines of therapy, including a PI and an IMiD. Patients harboring the t(11;14) translocation demonstrated particularly promising responses. Specifically, the response rates were 0 for cobimetinib monotherapy, 27.3% for cobimetinib–venetoclax dual therapy, and 28.6% for the full combination. In t(11;14)-positive patients, the response rates increased to 50% for cobimetinib–venetoclax and 100% for the full combination. These results underscore the potential of targeted therapies for subgroups with genetically defined MM. [ 88 ] A phase I/II study (No. NCT05289492 ) evaluating the efficacy of EOS884448, a TIGIT inhibitor, both as a monotherapy and in combination with iberdomide in patients with R/RMM was terminated due to a corporate strategic decision. Advanced technologies such as multi-omics analyses will enable a deeper understanding of immune evasion mechanisms and the development of personalized immunotherapy strategies to improve outcomes in patients with R/RMM. [ 89 ]

Antibody-drug conjugates (ADCs)

ADCs are a promising therapeutic strategy for treating MM. They combine the tumor-targeting specificity of mAbs with the cytotoxic potency of chemotherapeutic agents, enabling the targeted elimination of MM cells while minimizing damage to normal tissues. [ 90 ] Belantamab mafodotin, the first FDA-approved (now withdrawn) ADC targeting BCMA for the treatment of R/RMM, received approval in 2020 for patients who had undergone four or more prior therapies. [ 91 ] This approval has sparked considerable interest in applying ADCs to MM, subsequently driving the development of a diverse array of therapeutic candidates targeting antigens expressed on myeloma cells [Table 1 ]. ADCs comprise three core components: A mAb, a linker, and a cytotoxic payload. Upon binding to tumor-associated antigens on the surfaces of MM cells, ADCs are internalized through endocytosis. Inside the cells, the linkers are cleaved, releasing the cytotoxic payload to precisely target and eradicate MM cells. [ 92 ]

B-cell maturation antigen (BCMA) as a key therapeutic target

BCMA, also known as TNFRSF17, is a member of the tumor necrosis factor (TNF) receptor superfamily. It is predominantly expressed on both malignant and normal plasma cells, with minimal expression in other normal tissues. [ 91 ] This restricted expression pattern reduces the risk of off-target toxicity, making BCMA an attractive target for the development of ADCs.

In the BCMA-targeting ADC belantamab mafodotin, a mAb is linked to the cytotoxic agent monomethyl auristatin E (MMAE) via a specialized linker. [ 93 , 94 ] Although the FDA withdrew the biologics license of this ADC in February 2023 due to unfavorable clinical outcomes in the DREAMM-3 trial, [ 87 ] subsequent studies, including the DREAMM-7 and DREAMM-8 trials, have demonstrated its therapeutic potential in MM. [ 96 , 97 ]

The phase III DREAMM-7 trial evaluated the efficacy and safety of a regimen combining belantamab mafodotin, bortezomib, and dexamethasone (BVd) in patients with MM who had progressed after at least one prior therapy. With a median follow-up of 28.2 months, the BVd regimen demonstrated a median PFS of 36.6 months (95% CI 28.4 months – not reached), significantly surpassing the 13.4 months observed in the daratumumab, bortezomib, and dexamethasone (DVd) group (HR 0.41; 95% CI 0.31–0.53; P <0.001). The OS at 18 months reached 84% in the BVd group vs . 73% in the DVd group; and 25% of the BVd group achieved MRD-negative status with a CR or better vs . 10% of the DVd group. However, grade 3 or higher adverse events were observed in 95% of patients receiving BVd and 78% of those receiving DVd. Eye-related events were more frequent in the BVd group (79% vs . 29%) but were generally manageable with dose modifications. Importantly, most cases of visual acuity decline resolved over time, demonstrating the feasibility of the regimen in clinical practice. [ 96 ] In the DREAMM-8 phase III trial, the combination of belantamab mafodotin, pomalidomide, and dexamethasone (BPd) demonstrated superior efficacy compared with the combination of pomalidomide, bortezomib, and dexamethasone (PVd) in lenalidomide-exposed patients with R/RMM who had received at least one line of therapy. Among patients receiving BPd, 71% (95% CI 63–78%) achieved a PFS of 12 months ( vs . 51%, 95% CI 42–60% for PVd), 77% attained at least a PR ( vs . 72% for PVd), and 40% achieved a CR or better ( vs . 16% for PVd). Despite its robust efficacy, grade 3 or higher adverse events occurred in 94% vs . 76% of patients. Ocular adverse events were reported in 89% of BPd patients but were manageable, with only 9% discontinuing due to toxicity. [ 97 ]

HDP-101 is an innovative ADC targeting BCMA. This ADC comprises an anti-BCMA mAb conjugated to alpha-amanitin, a toxin that specifically inhibits RNA polymerase II. Preclinical studies have demonstrated that HDP-101 exerts substantial cytotoxicity against BCMA-positive MM cells in both proliferative and quiescent states in vitro . In vivo , this ADC showed robust antitumor potential, with a single dose leading to favorable therapeutic effects in MM models, including murine xenograft and cynomolgus monkey models. [ 102 ] Currently, HDP-101 is undergoing clinical evaluation in a phase I/IIa trial. Among 18 patients with R/RMM enrolled in the first five dose-escalation cohorts, 17 were evaluable for dose-limiting toxicities. The first four dose cohorts demonstrated good tolerability, with no dose-limiting toxicities observed. In Cohort 5, four patients showed encouraging results after three to four cycles of treatment: Two achieved a PR and two maintained stable disease (SD). [ 103 ] These preliminary results highlight the potential of HDP-101 to address currently unmet therapeutic requirements in MM, warranting further exploration in advanced clinical trials.

MEDI2228 is an ADC that combines a fully humanized BCMA-targeting antibody with a pyrrolobenzodiazepine dimer. The efficacy of MEDI2228 was evaluated in a phase I clinical trial involving patients with R/RMM who had previously received three or more lines of therapy, including PIs, IMiDs, and mAbs. In this trial, MEDI2228 demonstrated encouraging efficacy, achieving an ORR of 56.1% (95% CI 39.7–71.5%) in the maximum tolerated dose cohort and 53.3% (16 of 30) among patients with triple-refractory disease. However, the development of this agent has been impeded by significant adverse events, particularly ocular toxicities such as photophobia, which limit its clinical application. [ 99 ] AMG 224 is another BCMA-targeting ADC, consisting of an anti-BCMA IgG1 antibody conjugated to the anti-tubulin agent mertansine. As a monotherapy, this agent has shown efficacy in heavily pretreated R/RMM patients, achieving an ORR of 23% (95% CI 11–39%) in clinical trials. Although the toxicity profile of AMG 224 was generally manageable, thrombocytopenia emerged as the most prominent adverse event. Notably, the modest ORR of AMG 224 relative to other BCMA-targeted therapies underscores its limitations as a monotherapy for R/RMM. [ 98 ]

CC-99712 is another BCMA-targeting ADC that has been evaluated to determine its therapeutic potential in R/RMM patients. A phase I clinical trial (No. NCT04036461 ) was launched to evaluate its efficacy; however, the study was prematurely terminated due to difficulties in patient recruitment.

Expanding the ADC target landscape: Novel targets in MM

In recent years, the advancement of ADCs has expanded beyond the conventional target of BCMA to include novel targets such as G-protein coupled receptor family C group 5 member D(GPRC5D), CD38, CD46, and Fc receptor-like (FCRL)5, thereby broadening the therapeutic landscape for MM.

GPRC5D

Among these targets, GPRC5D has emerged as a promising therapeutic candidate due to its elevated expression in MM cells. [ 104 ] AZD0305, the first-in-class ADC specifically designed to target GPRC5D, has shown potent antitumor activity in preclinical studies. Currently, the efficacy and safety of AZD0305 are being assessed in a phase I clinical trial involving patients with R/RMM (No. NCT06106945 ), with active patient enrollment ongoing. [ 105 ] Another novel GPRC5D-targeting ADC, LM-305, has demonstrated strong preclinical antitumor activity in MM models. LM-305 exhibited high binding affinity for GPRC5D, efficient internalization, and strong cytotoxicity in MM cell lines. In xenograft mouse models, LM-305 induced dose-dependent tumor regression and achieved CRs in GPRC5D-high tumors at a dose of 3 mg/kg, while maintaining a favorable safety profile. These preclinical findings support the further development of LM-305 as a promising therapeutic option for patients with R/RMM characterized by GPRC5D expression. [ 106 ]

CD38

CD38 is a transmembrane glycoprotein abundantly expressed on the surfaces of MM cells. It plays a crucial role in tumor proliferation, immune suppression, and immune evasion, making it a pivotal therapeutic target of MM treatment. STI-6129 is an ADC comprising the fully humanized anti-CD38 antibody STI-5171 linked to the microtubule inhibitor duostatin-5.2 (Duo-5.2) via a proprietary non-polyethylene glycol-based linker. Preclinical studies have demonstrated that STI-6129 exhibits robust antitumor activity in CD38 + hematologic models, both in vitro and in vivo . [ 107 ] Two clinical trials (Nos. NCT05565807 [recruiting] and NCT05308225 [active, not recruiting]) are currently underway, and both aim to evaluate the safety, pharmacokinetics, and preliminary efficacy of STI-6129 in patients with R/RMM. MT-0169, also known as TAK-169, is another ADC composed of a CD38 antibody fragment conjugated to a de-immunized Shiga-like toxin A subunit payload. Preclinical studies have demonstrated that MT-0169 exerts potent cytotoxicity against MM cells, including newly diagnosed, drug-resistant, and R/RMM cells. In vivo studies have further confirmed its significant antitumor activity. [ 108 ] A phase I clinical trial (No. NCT04017130 ) has been initiated to evaluate the safety and efficacy of MT-0169 in patients with R/RMM. [ 109 ] The early results indicate that at a dose of 50 mcg/kg, MT-0169 effectively binds to its CD38 target and significantly reduces NK cell counts. [ 109 , 110 ] However, two cases of cardiac adverse events led the FDA to impose a partial clinical hold. This restriction was lifted following the submission of updated safety data, allowing the trial to proceed.

CD46

CD46 is frequently overexpressed in MM patients harboring a 1q chromosomal gain and those with refractory disease, with levels further elevated following IMiD treatment. FOR46, which comprises an ADC targeting CD46 conjugated to vc-MMAE, has shown favorable efficacy in clinical trials. Among patients with triple-refractory MM enrolled in dose-escalation cohorts (1.8 and 2.4 mg/kg), three of six evaluable participants achieved a PR. In addition, FOR46 demonstrated an acceptable toxicity profile, supporting its potential as a viable therapeutic option for this patient population. [ 111 ]

FcRL5

FcRL5, also known as FcRH5, is a cell surface receptor and immunoglobulin superfamily member. Its expression is upregulated in the B-cell lineage, with high levels observed on both normal and malignant plasma cells. DFRF4539A, an MMAE-conjugated ADC targeting FcRH5, has been clinically evaluated in the context of R/RMM. However, in a phase I trial, its efficacy was limited, with 5% of patients achieving PRs, 3% demonstrating minimal responses, 46% maintaining SD, and 41% experiencing disease progression. Adverse events were reported in 95% of patients, with serious adverse events occurring in 21% and grade 3 or higher events in 39%. Anemia, the most frequently reported adverse event, was observed in 26% of participants. Despite its tolerability, DFRF4539A failed to demonstrate a substantial clinical benefit in this context. [ 101 ] Several other ADCs targeting surface antigens on MM cells are currently under evaluation, including STRO-001 (targeting CD74, incorporating monomethyl auristatin F), indatuximab ravtansine (targeting CD138, incorporating maytansinoid DM4), lorvotuzumab mertansine (targeting CD56, incorporating mertansine), [ 92 , 112 ] and SGN-CD48A (targeting CD48, incorporating MMAE). [ 113 ]

Balancing efficacy and safety: Challenges and future directions for ADCs in MM

The therapeutic dynamics of ADCs in MM are characterized by a dichotomy. While some ADCs exhibit strong anti-myeloma efficacy, their clinical utility is often limited by severe adverse effects. [ 96 , 97 ] Conversely, ADCs with more favorable safety profiles frequently fail to achieve the desired therapeutic efficacy, particularly in heavily pretreated R/RMM cohorts. [ 98 ] This ongoing trade-off between efficacy and tolerability underscores the urgent need to further investigate MM pathogenesis and clarify the molecular and cellular mechanisms underlying ADC-based therapies. Such insights will be essential for informing the rational design of next-generation ADCs that can effectively balance potent anti-myeloma efficacy with manageable safety profiles.

CAR-T cell therapy

Recently, CAR-T cell therapy has emerged as one of the most innovative and promising strategies in cancer treatment, demonstrating unprecedented efficacy, particularly in hematological malignancies. CAR-T cell therapy begins with leukapheresis, a process that isolates CD3 + T cells from patients or healthy donors. The isolated T cells are then expanded and activated ex vivo , followed by transduction with a vector to express CARs capable of recognizing tumor-specific antigens. These CARs, expressed on T cells, consist of several structural components. The single-chain variable fragment (scFv), which forms the ectodomain of the CAR, is responsible for recognizing tumor-associated antigens independent of HLA presentation. Linked by a hinge and a transmembrane domain, the intracellular domain of the CAR contains a CD3ζ signaling domain (first generation), a costimulatory domain (second generation), or two costimulatory domains (third generation) to induce T cell expansion and enhance persistence. [ 114 , 115 ] Following manufacturing, CAR-T cells are infused back into patients after lymphodepleting chemotherapy.

In MM, an ideal target for CAR-T cells would exhibit selective and abundant expression on MM cells while being absent from normal tissues. Currently, BCMA is the most widely studied CAR-T target in MM due to its exclusive distribution on plasma cells and MM cells. BCMA-targeted CAR-T cell therapy has demonstrated remarkable effectiveness in patients with R/RMM, significantly prolonging their OS. [ 116 , 117 ] To date, the FDA has approved two anti-BCMA CAR-T cell therapies, idecabtagene vicleucel (ide-cel, bb2121, by Celgene) and ciltaca- btagene autoleucel (cilta-cel, JNJ-4528, by Janssen Biotech), for the treatment of R/RMM patients. Despite its remarkable efficacy, BCMA-targeted CAR-T cell therapy faces challenges such as total antigen loss and antigen escape, which compromise antitumor outcomes and ultimately result in relapse. Therefore, identifying novel targets on the MM cell surface is crucially important. Numerous targets on MM have been discovered, and the efficacy of CAR-T cells specific for these targets has been demonstrated in preclinical models and clinical trials [Table 2 ]. These targets include CD19, CD38, CD138, CD229, GPRC5D, SLAMF7/CS1, a proliferation-inducing ligand (APRIL), transmembrane activator and CAML interactor (TACI), NKG2D ligands, integrin β7, and FcRL5. [ 118 – 121 ] This review highlights the clinical efficacy and safety of CAR-T cell therapies targeting both BCMA and non-BCMA antigens, with a particular focus on novel targets that demonstrate favorable safety profiles, as well as compelling therapeutic potential for R/RMM.

BCMA-targeted CAR-T cell therapy

BCMA, a member of the TNF receptor superfamily, is continuously expressed on MM cells, plasma cells, and mature B cell subsets at varying levels of intensity but is not present on hematopoietic stem cells or normal tissue. This makes BCMA an optimal target for CAR-T cell therapy. [ 137 ] BCMA interacts with B-cell activating factor (BAFF) and APRIL, which are integral to MM cell survival, proliferation, and differentiation. [ 137 – 139 ] In 2021, the FDA approved the anti-BCMA CAR-T cell therapies ide-cel and cilta-cel for patients with R/RMM who have undergone four or more prior therapies. Encouraged by the substantial clinical outcomes of anti-BCMA CAR-T cell therapy, clinical trials are increasingly evaluating these therapies.

The first-in-human study of BCMA-targeting CAR-T cells was conducted by the US National Cancer Institute (NCI). A total of 24 patients R/RMM who had received a median of 7.5 prior lines of therapy received varying doses of anti-BCMA CAR-T cells (ranging from 0.3 × 10 6 cells/kg to 9 × 10 6 cells/kg) following lymphodepleting chemotherapy. Among the 16 patients receiving the highest dose, the ORR was 81%, and the VGPR or better rate was 63%. These results underscore the significant efficacy of BCMA-targeting CAR-T cells in heavily pretreated patients with R/RMM. [ 140 , 141 ] This study was the first to demonstrate the potent clinical efficacy of non-CD19 CAR-T cells, profoundly changing the landscape of CAR-T cell development.

Ide-cel, the most advanced anti-BCMA CAR-T cell product, has been extensively studied in R/RMM. Ide-cel incorporates a similar scFv as the NCI product, along with a 4-1BB co-stimulatory domain. A phase I study demonstrated favorable clinical effectiveness in patients with R/RMM who had received at least three prior lines of therapy, paving the way for phase II and subsequent studies to evaluate the safety and efficacy of ide-cel. [ 142 ] In the phase II KarMMa-2 trial, ide-cel elicited significant and durable responses in patients with triple-class-exposed R/RMM. The ORR reached 73%, with 33% of patients achieving a CR or better. At a median follow-up of 13.3 months, the median OS was 19.4 months, and the median PFS was 8.8 months (95% CI 5.6–11.6 months), suggesting robust efficacy with a single ide-cel infusion. The incidence of grade 3 or higher toxic effects was no more than 6%, with grade 3 neurotoxic effects occurring in 3%. [ 143 ] The phase III KarMMa-3 trial evaluated the clinical efficacy of ide-cel compared with standard regimens in patients with R/RMM who had received two to four prior lines of therapy. At a median follow-up of 18.4 months, ide-cel significantly prolonged the PFS (13.3 vs . 4.4 months, HR 0.49; 95% CI 0.38–0.65; P <0.001) and achieved ORR benefit (compared with standard regimens in R/RMM patients). [ 144 , 145 ]

Cilta-cel, the second CAR-T cell therapy approved by the FDA for the treatment of MM, specifically targets BCMA. [ 146 , 147 ] Multiple trials have consistently demonstrated its clinical efficacy, particularly in patients with R/RMM. [ 123 , 148 – 153 ] In the phase I/II CARTITUDE-1 trial (No. NCT03548207 ), 97 patients with R/RMM received cilta-cel at the recommended target dose of 0.75 × 10 6 CAR-positive viable T cells per kg of body weight. The ORR reached 98% (95% CI 92.7–99.7%), with 83% of patients achieving an sCR. The median PFS was 34.9 months (95% CI 25.2 months–not estimable). Among the 49 patients evaluable for MRD, 26 maintained MRD negativity for over 12 months, and 20 achieved both MRD negativity and a sCR. Cytokine release syndrome (CRS) occurred in 92% of patients, with grade ≥3 CRS observed in 9%. Neurotoxicity was reported in 21% of patients and was generally manageable, suggesting a generally controllable safety profile. [ 148 ] The efficacy of cilta-cel was further substantiated in the phase III CARTITUDE-4 trial (No. NCT04181827 ), a randomized controlled study involving patients with lenalidomide-refractory MM. Among the 208 patients who received cilta-cel, the 12-month PFS rate was 75.9% (95% CI 69.4–81.1%), significantly higher than the 48.6% rate observed in the standard therapy group (95% CI 41.5–55.3%). The ORR was 84.6%, with 73.1% of patients achieving a CR or better, and 60.6% reaching MRD negativity—all of which were statistically superior to outcomes in the control arm (67.3%, 21.8%, and 15.6%, respectively). Although CRS was observed in most patients, grade 3–4 CRS occurred in only 1.1%, and neurotoxic events were predominantly mild to moderate in severity. [ 123 ]

Cilta-cel has been extensively investigated in clinical settings, with its applications evolving from monotherapy to combination regimens and across an increasingly broad range of disease stages. [ 149 , 154 , 155 ] Despite these significant advances, challenges remain, particularly concerning disease relapse and treatment-related adverse events such as CRS. [ 150 , 156 , 157 ] Further mechanistic studies are warranted to elucidate the underlying causes of resistance and toxicity, thereby optimizing the clinical benefits and long-term outcomes of cilta-cel therapy for MM. [ 158 , 159 ]

Equecabtagene autoleucel (eque-cel) is a fully humanized anti-BCMA CAR-T product that received regulatory approval in China in 2023 for the treatment of R/RMM in patients who have received at least three prior lines of therapy. In the pivotal FUMANBA-1 study, eque-cel demonstrated robust clinical efficacy, achieving an ORR of 96.0% and a CR or better rate of 74.3% among evaluable patients. The 12-month PFS rate was 78.8% (95% CI 68.6–86.0%), and MRD negativity was observed in 95% of patients. Notably, eque-cel induced clinical responses in 75% of patients who had previously experienced failure with other CAR-T therapies, underscoring its potential to overcome CAR-T resistance. The most frequently reported adverse event was CRS, which occurred in 93.2% of patients; the majority of cases had a severity of grade 1–2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was rare, affecting only 1.9% of patients, and was limited to grade 1–2 events. Overall, eque-cel exhibited a favorable safety and tolerability profile. [ 160 ] Clinical investigation of eque-cel is ongoing to further validate its therapeutic efficacy and expand its indications. Current clinical trials are evaluating its applications in various settings, including R/RMM (No. NCT05698303 ), in combination with selinexor for R/R extramedullary myeloma (No. NCT05201118 ), in autoimmune neurological disorders (CARTinNS, No. NCT04561557 ), and as part of frontline treatment for newly diagnosed high-risk MM (FUMANBA-2, No. NCT05181501 ). [ 161 ] These studies aim to further elucidate the clinical utility and broaden the therapeutic landscape of eque-cel.

Non-BCMA targeted CAR-T cells

GPRC5D

GPRC5D is primarily expressed on BM plasma cells in patients with MM. In normal tissue, GPRC5D expression is largely restricted to hair follicles. Preclinical studies in mice have demonstrated that GPRC5D-targeted CAR-T cells effectively eliminate MM xenografts and prolong survival without inducing alopecia or other GPRC5D-mediated toxicities, even in BCMA antigen escape models. [ 119 ]

These results have led to the rapid development of GPRC5D-targeted CAR-T cell products and their evaluation in clinical trials, which have demonstrated encouraging efficacy. In a phase I study, MCARH 109, a GPRC5D-targeted CAR-T cell product, was administered to patients with R/RMM at four dose levels. Overall, 71% (12 of 17) of patients and 58% (7 of 12) of patients receiving doses without overt side effects (25 × 10 6 to 150 × 10 6 cells) achieved a clinical response. [ 162 ] OriCAR-017, another CAR-T cell product based on GPRC5D, demonstrated remarkable potency, with a 100% (10 of 10) ORR in a phase I clinical trial, without severe adverse events. These positive responses may be attributable to the characteristics of OriCAR-017, which include a high level of humanization, dual epitope recognition, and low tonic signaling induction. [ 129 ] Similarly, a phase II study reported a high ORR of 91% (95% CI 76–98%; 30 of 33 patients), which may be related to the shorter follow-up time and less heavily pretreated patients than reported for other studies. [ 131 ]

These studies also assessed the safety of GPRC5D-targeted CAR-T cells. CRS occurred at a high frequency but low-grade levels. The most common grade 3 or 4 adverse events included hematological toxicities such as neutropenia, thrombocytopenia, and anemia, which were observed in more than 90% of patients. These toxicities were primarily associated with lymphodepletion chemotherapy. The on-target, off-tumor effects were transient and manageable, often requiring minimal or no intervention. Furthermore, patients pretreated with BCMA-targeted therapy or those who relapsed after BCMA CAR-T cell treatment demonstrated impressive responses to GPRC5D CAR-T cells, indicating that GPRC5D expression on MM cells is independent of BCMA. However, all studies reported relapses in patients who had initially responded to GPRC5D CAR-T cells. [ 129 , 131 , 162 ] Similar to BCMA, these relapses might be associated with the biallelic loss of GPRC5D mediated by chromosomal alteration. [ 163 ] These studies had small sample sizes, and therefore, the mechanisms underlying GPRC5D relapse remain elusive and require further validation.

To improve the long-term clinical effects of CAR-T cell therapy and reduce antigen escape, an anti-BCMA/GPRC5D bispecific CAR-T cell was designed and tested in R/RMM patients. In a phase I clinical trial involving 21 patients, this bispecific CAR-T therapy demonstrated a favorable safety profile and potent anti-myeloma activity. The ORR was 86%, with 62% of patients achieving a CR or better and 81% reaching MRD negativity. The anti-BCMA/GPRC5D bispecific CAR-T cell therapy was generally well-tolerated, with the most common grade ≥3 adverse events being hematologic toxicities. CRS occurred in 71% of patients, with all cases being grade 1 or 2. Only one case of grade 1 ICANS was observed, and no severe neurotoxicity or organ toxicity was reported at or below the maximum tolerated dose. [ 132 ] These findings suggest that anti-BCMA/GPRC5D bispecific CAR-T cells provide a promising treatment option for patients with R/RMM, including those with single-antigen negative expression, and may overcome the challenge of antigen escape while maintaining a manageable safety profile.

CS1 (SLAMF7)

CS1, also known as SLAMF7, is highly expressed on MM cells. Compared with BCMA, CS1 is detected in a larger proportion of MM patients. The FDA has approved the anti-CS1 mAb elotuzumab (huLuc63 the FDA has approved the anti-CS1 mAb elotuzumab), which has shown potent efficacy when combined with IMiDs and PIs for the treatment of R/RMM. [ 164 ] Consequently, CS1 has emerged as a promising target in MM treatment, and CS1 CAR-T cell therapy has advanced to a phase I clinical trial (No. NCT03710421 ). However, preclinical research has indicated that while single-input CS1 CAR-T cells demonstrated a tumor lytic effect, their antitumor activity is less robust than that of BCMA CAR-T cells. [ 165 ] Due to the limited expression of CS1 on NK cells, CD8 + T cells, and other lymphocytes, single-input CS1 CAR-T cells were found to induce selective fratricide of normal lymphocytes in a preclinical study. [ 166 ] To leverage the unique expression of CS1 while minimizing off-tumor toxicity, bispecific CS1-BCMA CAR-T cells have been developed and evaluated both in vitro and in vivo . Preclinical analysis has shown that these novel single-chain bispecific CARs, which can target either CS1 or BCMA, exert potent antitumor effects on MM resistant to single-input BCMA or CS1 CAR-T cells. [ 165 ] Recently, a single-arm phase I/IIa clinical trial was conducted to assess the safety and efficacy of bispecific CS1/BCMA CAR-T cells in patients with R/RMM (No. NCT04662099 ). The trial reported that of the 16 evaluable patients, 13 (81%) achieved a clinical response, and 6 (38%) attained a sCR. Notably, severe infections (6/13, 38%) and lymphopenia (16/16, 100%), potentially related to selective fratricide, were also observed in this study. [ 136 ]

CD38

CD38 is widely but not specifically expressed on MM cells, which raises concerns about the potential for on-target/off-tumor toxicity when targeting CD38 with CAR-T cells. Consequently, CD38 is currently being investigated in bispecific CAR-T cell therapies alongside BCMA, with promising results. Bispecific CD38 and BCMA CAR-T cells have demonstrated potent antitumor effects in preclinical studies. [ 133 , 134 ] This CAR therapy has advanced to a phase I clinical trial to evaluate its safety and efficacy. Mei et al [ 133 ] evaluated BM38 CAR in a phase I clinical study involving patients with R/RMM (No. ChiCTR1800018143). At a median follow-up of 9 months, 20 patients (87%) had achieved a clinical response and MRD negativity, among whom 12 patients (52%) achieved a sCR and four patients (17%) achieved a VGPR. The most common adverse events were CRS (20/23, 87%) and hematological toxicity (22/23, 96%), and these were mild and manageable in most cases. Neurotoxicity was not observed. [ 133 ] In another single-arm, single-center clinical study, 16 patients with R/RMM received infusions of CD38 and BCMA bispecific CAR-T cells; of the 14 patients (87.5%) who responded to the treatment, 13 achieved an sCR and one achieved a PR during a median follow-up of 11.5 months. [ 134 ] Although patients in both studies relapsed after treatment with CD38 and BCMA bispecific CAR-T cells, most relapses involved persistent CD38 and BCMA positivity in the BM. This suggests a lower selective pressure on BCMA compared with BCMA alone and highlights the importance of improving CAR-T cell persistence.

CD138

Similar to CD38, CD138 is highly expressed on both MM cells and normal hematopoietic and non-hematopoietic tissues. Due to the unique co-expression of CD38 and CD138 on MM cells, dual CAR-T cells targeting both markers have been developed in several preclinical studies. Globerson Levin et al [ 167 ] incorporated CD138 and CD38 recognition domains into the CD28 and CD8 chains, respectively, allowing activation and co-stimulation signals to be provided separately by two distinct polypeptide chains within a single CAR. Consequently, the CD138/CD38 dual-targeting CAR-T cell (dCAR138-38) is activated exclusively by recognizing both CD138 and CD38 concurrently, resulting in a pronounced antitumor effect in preclinical models with minimal toxicity to normal cells. [ 167 ] Despite the potent cytotoxicity elicited by dCAR138-38, the tumor specificity of this CAR-T cell therapy remained suboptimal. Another CAR-T cell co-targeting CD138 and CD38 was generated using a similar strategy involving a distinct combination approach and the incorporation of binding domains with varying affinity. This dual CAR-T cell was developed with a low-affinity stimulatory CD138 CAR (sCD138CAR) and a high-affinity costimulatory CD38 CAR (cCD38CAR) to enhance antigen-specific cytotoxicity in MM. The study results showed that the sCD138CAR/cCD38CAR-T cells exhibited substantial cytotoxicity in MM cells, even in daratumumab-pretreated models. [ 168 ] Several clinical trials of CAR-T cells are currently targeting CD138 alone or in combination with other targets (Nos. NCT03672318 , NCT03196414 , and NCT01886976 ) and may provide valuable clinical insights into the use of CAR-T cells to target CD138 in the future.

FcRL5

FcRL5 (CD307, IRTA2) is an immunoglobulin-like cell surface receptor specifically expressed in the B-cell lineage. [ 169 ] Compared with normal plasma cells, its expression is upregulated in MM cells, particularly those with chromosome 1q21 amplification. [ 170 ] FcRL5 is thus a promising target in MM therapy; consequently, CAR-T cells targeting FcRL5 have been developed and evaluated in both preclinical models and clinical trials. Anti-FcRL5 CAR-T cells, which consist of an anti-FcRL5 scFv, a CD8 hinge domain, and a CD28-CD3ζ intracellular domain, exhibited potent effects in preclinical models, even those with BCMA deficiency. [ 171 ] Building on this structure, an advanced anti-FcRL5 CAR-T cell product was developed by incorporating an IL-15 secretion module in the intracellular domain; this product enhanced T cell persistence and improved antitumor efficacy in preclinical studies. [ 118 ] Furthermore, a bispecific CAR-T cell targeting both FcRL5 and BCMA has been developed, demonstrating a superior antitumor effect compared with monospecific CAR-T cells and showcasing substantial potential for future CAR-T cell development. [ 171 ] In addition, an open-label, single-arm, phase II clinical trial (No. NCT06196255 ) is underway to evaluate the safety and efficacy of anti-FcRL5 CAR-T therapy in patients with R/RMM.

TACI

Similar to BCMA, TACI is a member of the TNF receptor superfamily and plays critical roles in B-cell maturation and survival. TACI is expressed in the B-cell lineage and is detected at elevated levels in the majority of MM cells. The natural ligand of TACI is APRIL, which also serves as the ligand for BCMA. [ 139 ] Consequently, APRIL-based CAR-T cells have been generated in which APRIL is used as the tumor-targeting domain to simultaneously recognize both BCMA and TACI. [ 172 ] Although APRIL-based CAR-T cells manufactured with a single moiety of APRIL have demonstrated potent antimyeloma effects even in tumor escape models, the clinical response observed in a phase I clinical trial (No. NCT03287804 , AUTO2) was minimal. [ 172 , 173 ] To enhance the binding of APRIL to both BCMA and TACI, CAR-T cells with a trimeric APRIL-binding domain, known as TriPRIL, have been developed and are currently being assessed in a clinical trial (No. NCT05020444 ). [ 174 ] More recently, a second generation of TACI-targeting CAR-T cells was developed using a different approach. Unlike the previous approach that used APRIL as the tumor-targeting domain, this new approach incorporates an anti-TACI scFv derived from TACI-immunizing mice to improve antigen-binding specificity. In addition, bispecific CAR-T cells targeting both BCMA and TACI have been developed to increase cytotoxicity and prevent antigen escape. [ 175 ]

CD229

CD229, a member of the SLAM family, plays a crucial role in MM cell survival. [ 176 ] Although CD229 is universally expressed at low levels on normal T and B lymphocytes, it is highly expressed on MM cells, making it a promising target for MM CAR-T cell therapy. CAR-T cells targeting CD229 have been developed and shown to exert a robust ability to eliminate MM cells, including those that propagate the disease. However, despite the absence of fratricide in CD229 low/negative T cells, anti-CD229 CAR-T cells were found to target normal T cells with high CD229 expression. This resulted in on-target, off-tumor toxicity and compromised T cell persistence. [ 177 ] To address the unintended killing of normal cells and enhance CAR-T cell selectivity, Vander Mause et al [ 178 ] screened multiple binding domains and developed FH9Q/c-Jun CAR-T cells with reduced CD229 binding affinity. This low-affinity design effectively mitigated on-target, off-tumor toxicity while maintaining T cell persistence through c-Jun overexpression. This modification achieved an optimal balance between the efficacy and safety of CAR-T cells.

LILRB4

LILRB4 is an immune checkpoint receptor expressed exclusively on myeloid cells, including dendritic cells and macrophages. [ 179 ] LILRB4 is also highly expressed in hematological malignancies, particularly acute myeloid leukemia (AML) and MM. [ 180 ] In AML, LILRB4 is predominantly expressed on the surfaces of tumor cells with monocytic differentiation, where it suppresses T cell activation and promotes leukemic infiltration and survival. Targeting LILRB4 has shown promising effects in preclinical AML models, with anti-LILRB4 CAR-T cell therapies demonstrating antitumor activity by reversing immune suppression and directly eliminating AML cells. [ 181 ] Similar to AML, recent studies have shown that LILRB4 promotes bone lesions and facilitates cell proliferation in MM, underscoring its essential role in disease development. [ 182 , 183 ] In addition to tumor cells, LILRB4 is also detected on MDSCs, where it functions as an immune checkpoint receptor that exerts immunosuppressive effects. [ 184 ] Given the dual effects of LILRB4 on both MM cells and the tumor microenvironment, a novel TCR-based CAR-T cell, STAR-T, was developed to target LILRB4 on both MM cells and MDSCs simultaneously. Preclinical studies of STAR-T demonstrated its strong cytotoxic activity and ability to enhance cytokine secretion in MM cell lines and xenograft MM models, with no significant off-tumor effects. These findings highlight LILRB4 as a promising target for future MM immunotherapies. [ 28 ]

The development of CAR-T therapies targeting novel antigens represents a key frontier in MM treatment. These approaches may improve the durability of responses, expand treatment options for patients with low BCMA expression, and reduce relapse rates. Future efforts will focus on optimizing the CAR designs, minimizing off-tumor toxicity, and exploring combinations with ICIs or other agents. As more clinical data emerge, novel-target CAR-T therapies are expected to become integral components of personalized, effective, and durable MM treatment strategies.

BiTEs

BiTEs, an emerging class of immunotherapies, have been rapidly developed to treat multiple hematological malignancies. BiTEs are engineered proteins designed to redirect the cytotoxic potential of T cells toward cancer cells. These molecules consist of two scFvs linked together: one binding domain targets a tumor-associated antigen on malignant cells, while the other engages CD3, a crucial component of the T cell receptor complex. This simultaneous binding facilitates the formation of an immunologic synapse, leading to T cell activation and direct cytotoxicity against the tumor cell, independent of major histocompatibility complex presentation. [ 185 ] However, BiTEs typically have a short half-life, necessitating continuous infusion to sustain their therapeutic effectiveness. [ 186 ] The efficacy of BiTEs relies on the quality and functionality of the patient’s activated T cells, and the toxicity profile is similar to that of CAR-T cells, including CRS and ICANS. [ 187 ]

Most BiTEs currently in development for the treatment of MM target BCMA, which has emerged as a leading therapeutic target; these BiTEs deliver strong, durable responses in patients with R/RMM. Recently, BiTEs aimed at novel targets, including GPRC5D and FcRL5, have been developed for heavily pretreated patients [Table 3 ]. These innovations are expanding the therapeutic landscape and providing renewed hope for patients with limited treatment options.

BCMA-directed BiTEs

The BCMA-targeted BiTEs teclistamab and elranatamab have been FDA-approved for treating R/RMM in patients with more than three prior lines of therapy. Their safety and efficacy have been evaluated in several clinical trials, which have yielded promising results and favorable safety profiles in heavily pretreated patients with MM.

The MajesTEC-1 study was a phase I/II single-agent clinical trial of teclistamab. In this trial, patients with R/RMM who had received at least three prior lines of treatment were administered teclistamab (1.5 mg/kg) subcutaneously per week, following a step-up dosing regimen. During a median follow-up of 14.1 months, the ORR was 65% (95% CI 48−79%), with 39.4% of patients achieving a complete response (CR) or better. The median PFS was 11.3 months, indicating sustained, substantial clinical benefits. [ 201 ] Teclistamab was shown to exert activity in patients previously treated with BCMA-targeting therapies. In one cohort, the ORR was 52.5% (95% CI 36.1–68.5%), with 30% of patients (95% CI 16.6–46.5%) achieving a CR or better, suggesting the potential utility of this agent even after prior BCMA-directed treatments. [ 202 ] Elranatamab exhibits similar clinical efficacy as teclistamab in heavily pretreated patients with R/RMM. In phase I of the MagnetisMM-1 clinical trial, elranatamab monotherapy was administered to 88 patients with R/RMM patients who had received at least three prior lines of therapy, including 55 patients who had received efficacious doses (≥215 μg/kg). After a median follow-up of 12 months, the ORR was 63.6% (35/55; 95% CI 50.4–75.1%), with 38.2% of patients achieving a CR or better, indicating a strong and sustained response in patients with R/RMM. [ 190 ] Based on the encouraging results from phase I of the MagnetisMM-1 study, patients with triple-class-exposed R/RMM received subcutaneous injections of elranatamab (76 mg) weekly, following two step-up priming doses. The results showed an ORR of 61% (95% CI 51.8–69.6%), with a CR or better rate of 35%, showcasing the efficacy of elratanamab in this challenging patient population. [ 191 ] In addition, patients with fewer prior lines of therapy or less refractory disease had better response rates than those with multiple prior therapies or advanced disease in both the MajesTEC-1 and MagnetisMM-1 studies, indicating improved benefits for both teclistamab and elranatamab when administered in earlier treatment lines.

The most common adverse events associated with anti-BCMA BiTEs are infections, cytopenia, and CRS. Most patients exhibit low-grade CRS, along with grade 3 or higher infections and cytopenia. The mitigation of CRS following anti-BCMA BiTE treatment is strongly associated with the step-up priming dose, as confirmed in trials of both teclistamab and elranatamab. [ 191 , 202 ] Moreover, in the ongoing phase II MagnetisMM-3 clinical trial, persistent responders receiving elranatamab weekly were shifted to biweekly dosing after six cycles, resulting in a reduction in grade 3/4 adverse events. Therefore, transitioning to biweekly dosing of both teclistamab and elranatamab is a potential strategy for improving long-term safety.

GPRC5D-directed BiTEs

Talquetamab, a first-in-class bispecific antibody targeting GPRC5D and CD3, has shown significant promise in the treatment of R/RMM. In a phase I study (MonumenTAL-1), talquetamab was administered subcutaneously at two doses recommended for phase II evaluation: 405 µg/kg weekly and 800 µg/kg every other week. The ORRs were 70% (95% CI 51–85%) and 64% (95% CI 48–78%), respectively, with responses strengthening over time. The median response durations were 10.2 months and 7.8 months, respectively. Common adverse events included CRS (77–80%, primarily grades 1–2), skin-related events (67–70%), and dysgeusia (57–63%). Serious adverse events were infrequent, and treatment discontinuation due to toxicity was rare. [ 193 ] These findings establish talquetamab as a novel therapeutic option for heavily pretreated R/R MM, with substantial antitumor activity and an acceptable safety profile.

Forimtamig, another bispecific antibody targeting GPRC5D and CD3, uses a 2 + 1 molecular format to optimize binding affinity and therapeutic efficacy against MM. Preclinical models have demonstrated the ability of forimtamig to induce potent T-cell activation, facilitate stable immunological synapse formation, and achieve robust tumor cell killing. [ 203 ] Early-phase clinical data suggest significant efficacy in the treatment of R/RMM, with notable anti-tumor activity even in heavily pretreated patients. Forimtamig has shown rapid tumor clearance in orthotopic mouse models and demonstrated enhanced efficacy when combined with standard-of-care therapies, such as anti-CD38 mAbs, IMiDs, and PIs. Its safety profile indicates manageable CRS, with step-up dosing strategies effectively mitigating severe adverse events. Furthermore, the synergistic potential of forimtamig with emerging agents, such as BCMA-targeted bispecific TCEs and CELMoDs, reduces the likelihood of GPRC5D-negative tumor relapse. [ 203 , 204 ] Currently under investigation in phase I clinical trials (No. NCT04557150 ), forimtamig holds promise as both a monotherapy and a combination regimen component, addressing key resistance mechanisms in MM while offering a new avenue for durable disease control.

FcRL5-directed BiTEs

Cevostamab is the first FcRL5-targeted therapy to demonstrate significant anti-myeloma activity in patients with R/RMM. In an ongoing clinical trial, cevostamab has shown encouraging efficacy, particularly in heavily pretreated patients with R/RMM. The ORR was ~50%, with responses observed even in patients who were refractory to prior BCMA-targeted therapies, highlighting its potential as an alternative treatment option. [ 204 , 205 ]

BiTEs have emerged as a transformative approach to immunotherapy for R/RMM, demonstrating potent anti-myeloma activity by redirecting T cells to target malignant cells. While BCMA remains the best-validated target, BiTEs such as teclistamab and elranatamab have received FDA approval and are yielding high response rates and manageable safety profiles in heavily pretreated patients. Despite these successes, challenges such as relapse and resistance necessitate the pursuit of alternative antigens. Emerging BiTE products targeting GPRC5D, FcRL5, or other novel targets are exhibiting encouraging efficacy and tolerability, offering a promising route for patients with limited treatment options and bringing new hope that antigen escape and treatment resistance can be overcome.

Conclusions

Over the past two decades, substantial progress has been made in the field of immunotherapy for MM, transforming the treatment paradigm for this complex malignancy. Advancements in immunotherapy, including IMiDs, mAbs, and cutting-edge therapies such as CAR-T cell therapies and BiTEs, have significantly improved patient outcomes, particularly among those with R/RMM. However, MM remains incurable, with relapse and treatment resistance continuing to pose major challenges, especially among heavily pretreated patients.

The identification of novel therapeutic targets, such as BCMA, GPRC5D, and FcRL5 and the development of new modalities such as CELMoDs and ADCs, offer hope that these challenges can be overcome. Despite the impressive efficacy of these therapies, issues such as antigen escape, immune-related toxicities, and limited response durability underscore the need for innovative approaches. Emerging strategies, including combination regimens and next-generation therapies, are paving the way for safer, more durable therapeutic options.

Acknowledgment

Professional english language editing support was provided by AsiaEdit (asiaedit.com).

Funding

This study was funded by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2023ZD0501300), the National Natural Science Foundation of China (Nos. 82370210, 82341211, and 82170194), Tianjin Natural Science Foundation Key Project (No. 25JCZDJC00530), and the CAMS Innovation Fund for Medical Sciences (Nos. CIFM 2023-I2M-2-007, CIFMS 2021-I2M1-040, and CIFMS 2022-I2M1-022).

Conflicts of interest

None.

Footnotes

Yijie Wang and Yonghuan Wang contributed equally to this work.

How to cite this article: Wang YJ, Wang YH, Ma JY, Jing HQ, Liu LT, Qiu LG, Hao M. Identification and transformation of novel targets for immunotherapy in multiple myeloma. Chin Med J 2025;138:3404–3424. doi: 10.1097/CM9.0000000000003869

References

1. Liu J Liu W Mi L Cai C Gong T Ma J, et al. Burden of multiple myeloma in China: An analysis of the Global Burden of Disease, Injuries, and Risk Factors Study 2019. Chin Med J 2023;136:2834–2838. doi: 10.1097/cm9.0000000000002600.

2. Nakamura K, Smyth MJ, Martinet L. Cancer immunoediting and immune dysregulation in multiple myeloma. Blood 2020;136:2731–2740. doi: 10.1182/blood.2020006540.

3. Liu L Gong D Sun H Feng F Xu J Sun X, et al. DNp73 enhances tumor progression and immune evasion in multiple myeloma by targeting the MYC and MYCN pathways. Front Immunol 2024;15:1470328. doi: 10.3389/fimmu.2024.1470328.

4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:7–30. doi: 10.3322/caac.21590.

5. Yu T Du C Ma X Sui W Yu Z Liu L, et al. Polycomb-like protein 3 induces proliferation and drug resistance in multiple myeloma and is regulated by miRNA-15a. Mol Cancer Res 2020;18:1063–1073. doi: 10.1158/1541-7786.Mcr-19-0852.

6. Bal S Malek E Kansagra A Usmani SZ Vij R Godby KN, et al. Treatment outcomes of triple class refractory multiple myeloma: A benchmark for new therapies. Leukemia 2022;36:877–880. doi: 10.1038/s41375-021-01471-3.

7. Mateos MV Weisel K De Stefano V Goldschmidt H Delforge M Mohty M, et al. LocoMMotion: A prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma. Leukemia 2022;36:1371–1376. doi: 10.1038/s41375-022-01531-2.

8. Garcia-Ortiz A Rodriguez-Garcia Y Encinas J Maroto-Martin E Castellano E Teixido J, et al. The role of tumor microenvironment in multiple myeloma development and progression. Cancers (Basel) 2021;13:217. doi: 10.3390/cancers13020217.

9. Wang Y Zhang W Li T Liu M Gao M Li X, et al. Identification of potential immune-related mechanisms related to the development of multiple myeloma. Chin Med J 2024;137:1603–1613. doi: 10.1097/cm9.0000000000003116.

10. Gong L, Qiu L, Hao M. Novel insights into the initiation, evolution, and progression of multiple myeloma by multi-omics investigation. Cancers (Basel) 2024;16:498. doi: 10.3390/cancers16030498.

11. Wei X Yu Z Tang P Sun H Gong L Liu L, et al. Multiple myeloma-derived miR-27b-3p facilitates tumour progression via promoting tumour cell proliferation and immunosuppressive microenvironment. Clin Transl Med 2023;13:e1140. doi: 10.1002/ctm2.1140.

12. Lv J Sun H Gong L Wei X He Y Yu Z, et al. Aberrant metabolic processes promote the immunosuppressive microenvironment in multiple myeloma. Front Immunol 2022;13:1077768. doi: 10.3389/fimmu.2022.1077768.

13. Dutta AK Fink JL Grady JP Morgan GJ Mullighan CG To LB, et al. Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterised by clonal stability. Leukemia 2019;33:457–468. doi: 10.1038/s41375-018-0206-x.

14. Malard F Neri P Bahlis NJ Terpos E Moukalled N Hungria VTM, et al. Multiple myeloma. Nat Rev Dis Primers 2024;10:45. doi: 10.1038/s41572-024-00529-7.

15. Larrayoz M Garcia-Barchino MJ Celay J Etxebeste A Jimenez M Perez C, et al. Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma. Nat Med 2023;29:632–645. doi: 10.1038/s41591-022-02178-3.

16. Zelle-Rieser C Thangavadivel S Biedermann R Brunner A Stoitzner P Willenbacher E, et al. T cells in multiple myeloma display features of exhaustion and senescence at the tumor site. J Hematol Oncol 2016;9:116. doi: 10.1186/s13045-016-0345-3.

17. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 2015;15:486–499. doi: 10.1038/nri3862.

18. Minnie SA, Hill GR. Immunotherapy of multiple myeloma. J Clin Invest 2020;130:1565–1575. doi: 10.1172/JCI129205.

19. Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape. Curr Opin Immunol 2014;27:16–25. doi: 10.1016/j.coi.2014.01.004.

20. Braga WM da Silva BR de Carvalho AC Maekawa YH Bortoluzzo AB Rizzatti EG, et al. FOXP3 and CTLA4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4(+) T regulatory cells. Cancer Immunol Immunother 2014;63:1189–1197. doi: 10.1007/s00262-014-1589-9.

21. Chung DJ Pronschinske KB Shyer JA Sharma S Leung S Curran SA, et al. T-cell exhaustion in multiple myeloma relapse after autotransplant: Optimal timing of immunotherapy. Cancer Immunol Res 2016;4:61–71. doi: 10.1158/2326-6066.Cir-15-0055.

22. Guillerey C Harjunpää H Carrié N Kassem S Teo T Miles K, et al. TIGIT immune checkpoint blockade restores CD8(+) T-cell immunity against multiple myeloma. Blood 2018;132:1689–1694. doi: 10.1182/blood-2018-01-825265.

23. Rosenblatt J Glotzbecker B Mills H Vasir B Tzachanis D Levine JD, et al. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother 2011;34:409–418. doi: 10.1097/CJI.0b013e31821ca6ce.

24. Minnie SA Kuns RD Gartlan KH Zhang P Wilkinson AN Samson L, et al. Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade. Blood 2018;132:1675–1688. doi: 10.1182/blood-2018-01-825240.

25. Friedrich MJ Neri P Kehl N Michel J Steiger S Kilian M, et al. The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients. Cancer Cell 2023;41:711–725.e716. doi: 10.1016/j.ccell.2023.02.008.

26. Ismael A Robinette AJ Huric L Schuetz J Dona K Benson D, et al. CREB1 promotes expression of immune checkpoint HLA-E leading to immune escape in multiple myeloma. Leukemia 2024;38:1777–1786. doi: 10.1038/s41375-024-02303-w.

27. Horenstein AL Quarona V Toscani D Costa F Chillemi A Pistoia V, et al. Adenosine generated in the bone marrow niche through a CD38-mediated pathway correlates with progression of human myeloma. Mol Med 2016;22:694–704. doi: 10.2119/molmed.2016.00198.

28. Gong L Sun H Liu L Sun X Fang T Yu Z, et al. LILRB4 represents a promising target for immunotherapy by dual targeting tumor cells and myeloid-derived suppressive cells in multiple myeloma. Haematologica 2024;109:3650–3669. doi: 10.3324/haematol.2024.285099.

29. Giannotta C, Autino F, Massaia M. The immune suppressive tumor microenvironment in multiple myeloma: The contribution of myeloid-derived suppressor cells. Front Immunol 2022;13:1102471. doi: 10.3389/fimmu.2022.1102471.

30. Ai L Mu S Sun C Fan F Yan H Qin Y, et al. Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation. Mol Cancer 2019;18:88. doi: 10.1186/s12943-019-1011-5.

31. Andersen MN, Andersen NF, Rødgaard-Hansen S, Hokland M, Abildgaard N, Møller HJ. The novel biomarker of alternative macrophage activation, soluble mannose receptor (sMR/sCD206): Implications in multiple myeloma. Leuk Res 2015;39:971–975. doi: 10.1016/j.leukres.2015.06.003.

32. Beider K Bitner H Leiba M Gutwein O Koren-Michowitz M Ostrovsky O, et al. Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype. Oncotarget 2014;5:11283–11296. doi: 10.18632/oncotarget.2207.

33. De Beule N De Veirman K Maes K De Bruyne E Menu E Breckpot K, et al. Tumour-associated macrophage-mediated survival of myeloma cells through STAT3 activation. J Pathol 2017;241:534–546. doi: 10.1002/path.4860.

34. Zheng Y Yang J Qian J Qiu P Hanabuchi S Lu Y, et al. PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma. Leukemia 2013;27:702–710. doi: 10.1038/leu.2012.272.

35. Yan H He D Qu J Liu Y Xu R Gu H, et al. Interleukin-32γ promotes macrophage-mediated chemoresistance by inducing CSF1-dependent M2 macrophage polarization in multiple myeloma. Cancer Immunol Immunother 2023;72:327–338. doi: 10.1007/s00262-022-03241-1.

36. Lin EY, Nguyen AV, Russell RG, Pollard JW. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 2001;193:727–740. doi: 10.1084/jem.193.6.727.

37. Wang Q Lu Y Li R Jiang Y Zheng Y Qian J, et al. Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma. Leukemia 2018;32:176–183. doi: 10.1038/leu.2017.193.

38. Bonanno G Mariotti A Procoli A Folgiero V Natale D De Rosa L, et al. Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma. J Transl Med 2012;10:247. doi: 10.1186/1479-5876-10-247.

39. Poczta A, Rogalska A, Marczak A. Treatment of multiple myeloma and the role of melphalan in the era of modern therapies-current research and clinical approaches. J Clin Med 2021;10:1841. doi: 10.3390/jcm10091841.

40. Bergsagel DE, Sprague CC, Austin C, Griffith KM. Evaluation of new chemotherapeutic agents in the treatment of multiple myeloma. IV. L-Phenylalanine mustard (NSC-8806). Cancer Chemother Rep 1962;21:87–99.

41. Harandi A, Laber DA. Historical perspective and advances in the treatment of multiple myeloma. Oncol Rev 2008;2:250–258. doi: 10.1007/s12156-008-0082-0.

42. Greil C Engelhardt M Ihorst G Schoeller K Bertz H Marks R, et al. Allogeneic transplantation of multiple myeloma patients may allow long-term survival in carefully selected patients with acceptable toxicity and preserved quality of life. Haematologica 2019;104:370–379. doi: 10.3324/haematol.2018.200881.

43. Attal M Harousseau JL Stoppa AM Sotto JJ Fuzibet JG Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 1996;335:91–97. doi: 10.1056/nejm199607113350204.

44. Osserman EF, DiRe LB, DiRe J, Sherman WH, Hersman JA, Storb R. Identical twin marrow transplantation in multiple myeloma. Acta Haematol 1982;68:215–223. doi: 10.1159/000206984.

45. Zhou X Wu H Hao L Wei L Li X Yin J, et al. Treatment efficacy for relapsed/refractory multiple myeloma patients with gain/amplification of 1q21. Chin Med J 2025;138:871–873. doi: 10.1097/cm9.0000000000003435.

46. Twombly R. First proteasome inhibitor approved for multiple myeloma. J Natl Cancer Inst 2003;95:845. doi: 10.1093/jnci/95.12.845.

47. Shah UA, Mailankody S. Emerging immunotherapies in multiple myeloma. BMJ 2020;370:m3176. doi: 10.1136/bmj.m3176.

48. Yu Z Wei X Liu L Sun H Fang T Wang L, et al. Indirubin-3′-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma. EBioMedicine 2022;78:103950. doi: 10.1016/j.ebiom.2022.103950.

49. Holstein SA, McCarthy PL. Immunomodulatory drugs in multiple myeloma: Mechanisms of action and clinical experience. Drugs 2017;77:505–520. doi: 10.1007/s40265-017-0689-1.

50. Zhu YX Braggio E Shi CX Kortuem KM Bruins LA Schmidt JE, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood 2014;124:536–545. doi: 10.1182/blood-2014-02-557819.

51. Ito T Ando H Suzuki T Ogura T Hotta K Imamura Y, et al. Identification of a primary target of thalidomide teratogenicity. Science 2010;327:1345–1350. doi: 10.1126/science.1177319.

52. D’Souza C, Prince HM, Neeson PJ. Understanding the role of T-cells in the antimyeloma effect of immunomodulatory drugs. Front Immunol 2021;12:632399. doi: 10.3389/fimmu.2021.632399.

53. Hideshima T Ogiya D Liu J Harada T Kurata K Bae J, et al. Immunomodulatory drugs activate NK cells via both Zap-70 and cereblon-dependent pathways. Leukemia 2021;35:177–188. doi: 10.1038/s41375-020-0809-x.

54. Wu W Nelson GM Koch R Donovan KA Nowak RP Heavican-Foral TB, et al. Overcoming IMiD resistance in T-cell lymphomas through potent degradation of ZFP91 and IKZF1. Blood 2022;139:2024–2037. doi: 10.1182/blood.2021014701.

55. Lonial S Popat R Hulin C Jagannath S Oriol A Richardson PG, et al. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): A multicentre, multicohort, open-label, phase 1/2 trial. Lancet Haematol 2022;9:e822–e832. doi: 10.1016/s2352-3026(22)00290-3.

56. Amatangelo M Flynt E Stong N Ray P Van Oekelen O Wang M, et al. Pharmacodynamic changes in tumor and immune cells drive iberdomide’s clinical mechanisms of activity in relapsed and refractory multiple myeloma. Cell Rep Med 2024;5:101571. doi: 10.1016/j.xcrm.2024.101571.

57. Richardson PG Ocio E Raje NS Gregory T White D Oriol A, et al. CC-92480, a potent, novel cereblon E3 ligase modulator (CELMoD) agent, in combination with dexamethasone (DEX) and bortezomib (BORT) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Preliminary results from the phase 1/2 study CC-92480-MM-002. Blood 2021;138:2731. doi: 10.1182/blood-2021-147812.34499707

58. Lonial S Weiss BM Usmani SZ Singhal S Chari A Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial. Lancet 2016;387:1551–1560. doi: 10.1016/s0140-6736(15)01120-4.

59. Sonneveld P Chanan-Khan A Weisel K Nooka AK Masszi T Beksac M, et al. Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): A randomized, open-label, phase III trial. J Clin Oncol 2023;41:1600–1609. doi: 10.1200/jco.21.02734.

60. Usmani SZ Quach H Mateos MV Landgren O Leleu X Siegel D, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): Updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol 2022;23:65–76. doi: 10.1016/s1470-2045(21)00579-9.

61. Dimopoulos MA Oriol A Nahi H San-Miguel J Bahlis NJ Usmani SZ, et al. Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): A randomized, open-label, phase III trial. J Clin Oncol 2023;41:1590–1599. doi: 10.1200/jco.22.00940.

62. Dimopoulos MA Terpos E Boccadoro M Delimpasi S Beksac M Katodritou E, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): An open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:801–812. doi: 10.1016/s1470-2045(21)00128-5.

63. Moreau P Attal M Hulin C Arnulf B Belhadj K Benboubker L, 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: 10.1016/s0140-6736(19)31240-1.

64. Moreau P Hulin C Perrot A Arnulf B Belhadj K Benboubker L, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: Long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol 2024;25:1003–1014. doi: 10.1016/s1470-2045(24)00282-1.

65. Mateos MV Nahi H Legiec W Grosicki S Vorobyev V Spicka I, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): A multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol 2020;7:e370–e380. doi: 10.1016/s2352-3026(20)30070-3.

66. Moreau P Dimopoulos MA Mikhael J Yong K Capra M Facon T, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): A multicentre, open-label, randomised phase 3 trial. Lancet 2021;397:2361–2371. doi: 10.1016/s0140-6736(21)00592-4.

67. Attal M Richardson PG Rajkumar SV San-Miguel J Beksac M Spicka I, 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;394:2096–2107. doi: 10.1016/s0140-6736(19)32556-5.

68. Goldschmidt H Mai EK Bertsch U Fenk R Nievergall E Tichy D, 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–e821. doi: 10.1016/s2352-3026(22)00263-0.

69. Facon T Dimopoulos MA Leleu XP Beksac M Pour L Hájek R, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2024;391:1597–1609. doi: 10.1056/NEJMoa2400712.

70. Mikhael J Belhadj-Merzoug K Hulin C Vincent L Moreau P Gasparetto C, et al. A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab. Blood Cancer J 2021;11:89. doi: 10.1038/s41408-021-00478-4.

71. Hsi ED Steinle R Balasa B Szmania S Draksharapu A Shum BP, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res 2008;14:2775–2784. doi: 10.1158/1078-0432.Ccr-07-4246.

72. Collins SM Bakan CE Swartzel GD Hofmeister CC Efebera YA Kwon H, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother 2013;62:1841–1849. doi: 10.1007/s00262-013-1493-8.

73. Kurdi AT Glavey SV Bezman NA Jhatakia A Guerriero JL Manier S, et al. Antibody-dependent cellular phagocytosis by macrophages is a novel mechanism of action of elotuzumab. Mol Cancer Ther 2018;17:1454–1463. doi: 10.1158/1535-7163.Mct-17-0998.

74. Dimopoulos MA Dytfeld D Grosicki S Moreau P Takezako N Hori M, et al. Elotuzumab plus pomalidomide and dexamethasone for relapsed/refractory multiple myeloma: Final overall survival analysis from the randomized phase II ELOQUENT-3 trial. J Clin Oncol 2023;41:568–578. doi: 10.1200/jco.21.02815.

75. Isoda A Kaira K Iwashina M Oriuchi N Tominaga H Nagamori S, et al. Expression of L-type amino acid transporter 1 (LAT1) as a prognostic and therapeutic indicator in multiple myeloma. Cancer Sci 2014;105:1496–1502. doi: 10.1111/cas.12529.

76. Hasegawa K Ikeda S Yaga M Watanabe K Urakawa R Iehara A, et al. Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain. Sci Transl Med 2022;14:eaax7706. doi: 10.1126/scitranslmed.aax7706.

77. Brighton TA Khot A Harrison SJ Ghez D Weiss BM Kirsch A, et al. Randomized, double-blind, placebo-controlled, multicenter study of siltuximab in high-risk smoldering multiple myeloma. Clin Cancer Res 2019;25:3772–3775. doi: 10.1158/1078-0432.Ccr-18-3470.

78. Zanwar S, Nandakumar B, Kumar S. Immune-based therapies in the management of multiple myeloma. Blood Cancer J 2020;10:84. doi: 10.1038/s41408-020-00350-x.

79. Nadeem O, Tai YT, Anderson KC. Immunotherapeutic and targeted approaches in multiple myeloma. Immunotargets Ther 2020;9:201–215. doi: 10.2147/itt.S240886.

80. Sperling AS, Anderson KC. Facts and hopes in multiple myeloma immunotherapy. Clin Cancer Res 2021;27:4468–4477. doi: 10.1158/1078-0432.Ccr-20-3600.

81. Moreau P, Ghori R, Farooqui M, Marinello P, San Miguel J. Pembrolizumab combined with carfilzomib and low-dose dexamethasone for relapsed or refractory multiple myeloma: Cohort 2 of the phase I KEYNOTE-023 study. Br J Haematol 2021;194:e48–e51. doi: 10.1111/bjh.17448.

82. Lesokhin A LeBlanc R Dimopoulos MA Capra M Carlo-Stella C Karlin L, et al. Isatuximab in combination with cemiplimab in patients with relapsed/refractory multiple myeloma: A phase 1/2 study. Cancer Med 2023;12:10254–10266. doi: 10.1002/cam4.5753.

83. Kazandjian D Dew A Hill E Ramirez EG Morrison C Mena E, et al. Avelumab, a PD-L1 inhibitor, in combination with hypofractionated radiotherapy and the abscopal effect in relapsed refractory multiple myeloma. Oncologist 2021;26:288–e541. doi: 10.1002/onco.13712.

84. Oriol A Hájek R Spicka I Sandhu I Cohen YC Gatt ME, et al. Nivolumab, pomalidomide, and elotuzumab combination regimens for treatment of relapsed and refractory multiple myeloma: Results from the phase 3 CheckMate 602 Study. Clin Lymphoma Myeloma Leuk 2024;24:703–714. doi: 10.1016/j.clml.2024.05.014.

85. Wong S Hamidi H Costa LJ Bekri S Neparidze N Vij R, et al. Multi-omic analysis of the tumor microenvironment shows clinical correlations in Ph1 study of atezolizumab +/- SoC in MM. Front Immunol 2023;14:1085893. doi: 10.3389/fimmu.2023.1085893.

86. Richard S Lesokhin AM Paul B Kaufman JL Pianko M Biran N, et al. Clinical response and pathway-specific correlates following TIGIT-LAG3 blockade in myeloma: The MyCheckpoint randomized clinical trial. Nat Cancer 2024;5:1459–1464. doi: 10.1038/s43018-024-00818-w.

87. Suvannasankha A Bahlis N Trudel S Weisel K Koenecke C Oriol A, et al. Safety and efficacy of belantamab mafodotin with pembrolizumab in patients with relapsed or refractory multiple myeloma. Cancer 2024;130:2629–2641. doi: 10.1002/cncr.35319.

88. Schjesvold F Paiva B Ribrag V Rodriguez-Otero P San-Miguel JF Robak P, et al. Cobimetinib alone and plus venetoclax with/without atezolizumab in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk 2023;23:e59–e70. doi: 10.1016/j.clml.2022.10.006.

89. Ma F Liu X Zhang Y Tao Y Zhao L Abusalamah H, et al. Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming. Sci Transl Med 2025;17:eadm7269. doi: 10.1126/scitranslmed.adm7269.

90. Ray U, Orlowski RZ. Antibody-drug conjugates for multiple myeloma: Just the beginning, or the beginning of the end? Pharmaceuticals (Basel) 2023;16:590. doi: 10.3390/ph16040590.

91. Morè S, Offidani M, Corvatta L, Petrucci MT, Fazio F. Belantamab mafodotin: From clinical trials data to real-life experiences. Cancers (Basel) 2023;15:2948. doi: 10.3390/cancers15112948.

92. Leong S, Lam HPJ, Kirkham Z, Popat R. Antibody drug conjugates for the treatment of multiple myeloma. Am J Hematol 2023;98(Suppl 2):S22–S34. doi: 10.1002/ajh.26750.

93. Lonial S Lee HC Badros A Trudel S Nooka AK Chari A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): A two-arm, randomised, open-label, phase 2 study. Lancet Oncol 2020;21:207–221. doi: 10.1016/s1470-2045(19)30788-0.

94. Nooka AK Cohen AD Lee HC Badros A Suvannasankha A Callander N, et al. Single-agent belantamab mafodotin in patients with relapsed/refractory multiple myeloma: Final analysis of the DREAMM-2 trial. Cancer 2023;129:3746–3760. doi: 10.1002/cncr.34987.

95. Dimopoulos MA Hungria VTM Radinoff A Delimpasi S Mikala G Masszi T, et al. Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): A phase 3, open-label, randomised study. Lancet Haematol 2023;10:e801–e812. doi: 10.1016/s2352-3026(23)00243-0.

96. Hungria V Robak P Hus M Zherebtsova V Ward C Ho PJ, et al. Belantamab mafodotin, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 2024;391:393–407. doi: 10.1056/NEJMoa2405090.

97. Dimopoulos MA Beksac M Pour L Delimpasi S Vorobyev V Quach H, et al. Belantamab mafodotin, pomalidomide, and dexamethasone in multiple myeloma. N Engl J Med 2024;391:408–421. doi: 10.1056/NEJMoa2403407.

98. Lee HC Raje NS Landgren O Upreti VV Wang J Avilion AA, et al. Phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma. Leukemia 2021;35:255–258. doi: 10.1038/s41375-020-0834-9.

99. Dimopoulos MA Migkou M Bhutani M Ailawadhi S Kalff A Walcott FL, et al. Phase 1 first-in-human study of MEDI2228, a BCMA-targeted ADC, in patients with relapsed refractory multiple myeloma. Leuk Lymphoma 2024;65:1789–1800. doi: 10.1080/10428194.2024.2373331.

100. Vij R Nath R Afar DEH Mateos MV Berdeja JG Raab MS, et al. First-in-human phase I study of ABBV-838, an antibody-drug conjugate targeting SLAMF7/CS1 in patients with relapsed and refractory multiple myeloma. Clin Cancer Res 2020;26:2308–2317. doi: 10.1158/1078-0432.Ccr-19-1431.

101. Stewart AK Krishnan AY Singhal S Boccia RV Patel MR Niesvizky R, et al. Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma. Blood Cancer J 2019;9:17. doi: 10.1038/s41408-019-0178-8.

102. Figueroa-Vazquez V Ko J Breunig C Baumann A Giesen N Pálfi A, et al. HDP-101, an anti-BCMA antibody-drug conjugate, safely delivers amanitin to induce cell death in proliferating and resting multiple myeloma cells. Mol Cancer Ther 2021;20:367–378. doi: 10.1158/1535-7163.Mct-20-0287.

103. Kaufman J Raab M Richard S Grosicki S Takács I Strassz A, et al. Abstract CT067: The anti-BCMA antibody-drug conjugate HDP-101 with a novel amanitin payload shows promising initial first in human results in relapsed multiple myeloma. Cancer Research 2024;84:CT067–CT067. doi: 10.1158/1538-7445.Am2024-ct067.

104. Zhou D, Wang Y, Chen C, Li Z, Xu K, Zhao K. Targeting GPRC5D for multiple myeloma therapy. J Hematol Oncol 2024;17:88. doi: 10.1186/s13045-024-01611-z.

105. Lim S-L Augustson B Mian HS Stadtmauer EA Iida S Slade M, et al. A Phase I/II study of AZD0305, a novel antibody-drug conjugate (ADC) targeting GPRC5D, in patients with relapsed/refractory multiple myeloma (RRMM). Blood 2024;144:2000.2002–2000.2002. doi: 10.1182/blood-2024-207816.

106. Huang W, Luo J, Li Y, Fei D, Qin X, Li R. Abstract 6020: Preclinical activity of LM-305 targeting G-protein-coupled receptor class 5 member D (GPRC5D) antibody drug conjugate for the treatment of multiple myeloma. Cancer Res 2022;82:6020–6020. doi: 10.1158/1538-7445.Am2022-6020.

107. Chakraborty R, Yan Y, Royal M. A Phase 1, open-label, dose-escalation study of the safety and efficacy of anti-CD38 antibody drug conjugate (STI-6129) in patients with relapsed or refractory multiple myeloma. Blood 2021;138:4763–4763. doi: 10.1182/blood-2021-150783.

108. Bruins WSC Rentenaar R Newcomb J Zheng W Ruiter RWJ Baardemans T, et al. Preclinical evaluation of the CD38-targeting engineered toxin body MT-0169 against multiple myeloma. Hemasphere 2024;8:e70039. doi: 10.1002/hem3.70039.

109. Dholaria B Mamuye A Yurewicz D Dabovic K Yuet A Abonour R, et al. A Phase 1, open-label, dose-escalation and expansion, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of MT-0169 in patients with relapsed or refractory multiple myeloma or non-hodgkin lymphoma. Blood 2022;140:12621–12622. doi: 10.1182/blood-2022-168960.

110. Kumar S Mamuye A Dabovic K Wang J Anand B Yuet A, et al. 447 Interim results of a phase 1 study of the novel engineered toxin body TAK-169 in patients with relapsed or refractory multiple myeloma. J ImmunoTher Cancer 2021;9:A475–A475. doi: 10.1136/jitc-2021-SITC2021.447.

111. Wong S Imus P Mark T Kaufman J Imus A Zonder JA, et al. P-225: A first-in-human study of FOR46 in patients with triple refractory multiple myeloma. Clinical Lymphoma Myeloma and Leukemia 2021;21:S164. doi: 10.1016/S2152-2650(21)02352-1.

112. McMillan A, Warcel D, Popat R. Antibody-drug conjugates for multiple myeloma. Expert Opin Biol Ther 2021;21:889–901. doi: 10.1080/14712598.2020.1802422.

113. Lewis TS Olson D Gordon K Sandall S Quick M Finn M, et al. SGN-CD48A: A novel humanized anti-CD48 antibody-drug conjugate for the treatment of multiple myeloma. Blood 2016;128:4470. doi: 10.1182/blood.V128.22.4470.4470.

114. Till BG Jensen MC Wang J Chen EY Wood BL Greisman HA, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 2008;112:2261–2271. doi: 10.1182/blood-2007-12-128843.

115. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood 2017;130:2594–2602. doi: 10.1182/blood-2017-06-793869.

116. Xu J Wang BY Yu SH Chen SJ Yang SS Liu R, 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: 10.1186/s13045-024-01530-z.

117. Oliver-Caldés A González-Calle V Cabañas V Español-Rego M Rodríguez-Otero P Reguera JL, et al. Fractionated initial infusion and booster dose of ARI0002h, a humanised, BCMA-directed CAR T-cell therapy, for patients with relapsed or refractory multiple myeloma (CARTBCMA-HCB-01): A single-arm, multicentre, academic pilot study. Lancet Oncol 2023;24:913–924. doi: 10.1016/s1470-2045(23)00222-x.

118. Yu Z, Li H, Lu Q, Zhang Z, Tong A, Niu T. Fc receptor-like 5 (FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma. Signal Transduct Target Ther 2024;9:16. doi: 10.1038/s41392-023-01702-2.

119. Smith EL Harrington K Staehr M Masakayan R Jones J Long TJ, 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: 10.1126/scitranslmed.aau7746.

120. Baumeister SH Murad J Werner L Daley H Trebeden-Negre H Gicobi JK, 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;7:100–112. doi: 10.1158/2326-6066.CIR-18-0307.

121. Amatya C Pegues MA Lam N Vanasse D Geldres C Choi S, et al. Development of CAR T cells expressing a suicide gene plus a chimeric antigen receptor targeting signaling lymphocytic-activation molecule F7. Mol Ther 2021;29:702–717. doi: 10.1016/j.ymthe.2020.10.008.

122. Lin Y Raje NS Berdeja JG Siegel DS Jagannath S Madduri D, et al. Idecabtagene vicleucel for relapsed and refractory multiple myeloma: Post hoc 18-month follow-up of a phase 1 trial. Nat Med 2023;29:2286–2294. doi: 10.1038/s41591-023-02496-0.

123. San-Miguel J Dhakal B Yong K Spencer A Anguille S Mateos MV, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med 2023;389:335–347. doi: 10.1056/NEJMoa2303379.

124. Qu X An G Sui W Wang T Zhang X Yang J, et al. Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma. J Immunother Cancer 2022;10:e005145. doi: 10.1136/jitc-2022-005145.

125. Wang D Wang J Hu G Wang W Xiao Y Cai H, et al. A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. Blood 2021;137:2890–2901. doi: 10.1182/blood.2020008936.

126. Mailankody S Matous JV Chhabra S Liedtke M Sidana S Oluwole OO, et al. Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: Phase 1 UNIVERSAL trial interim results. Nat Med 2023;29:422–429. doi: 10.1038/s41591-022-02182-7.

127. Frigault MJ Bishop MR Rosenblatt J O’Donnell EK Raje N Cook D, et al. Phase 1 study of CART-ddBCMA for the treatment of subjects with relapsed and refractory multiple myeloma. Blood Adv 2023;7:768–777. doi: 10.1182/bloodadvances.2022007210.

128. Wang T Yang Y Ma L Feng R Li J Zhang C, et al. BCMA-BBZ-OX40 CAR-T therapy using an instant manufacturing platform in multiple myeloma. J Immunother Cancer 2024;12:e009476. doi: 10.1136/jitc-2024-009476.

129. Zhang M Wei G Zhou L Zhou J Chen S Zhang W, 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–e116. doi: 10.1016/S2352-3026(22)00372-6.

130. Mailankody S Devlin SM Landa J Nath K Diamonte C Carstens EJ, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med 2022;387:1196–1206. doi: 10.1056/NEJMoa2209900.

131. Xia J Li H Yan Z Zhou D Wang Y Qi Y, et al. Anti-G protein-coupled receptor, class C group 5 member D chimeric antigen receptor T cells in patients with relapsed or refractory multiple myeloma: A single-arm, phase Ⅱ trial. J Clin Oncol 2023;41:2583–2593. doi: 10.1200/jco.22.01824.

132. Zhou D Sun Q Xia J Gu W Qian J Zhuang W, et al. Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial. Lancet Haematol 2024;11:e751–e760. doi: 10.1016/s2352-3026(24)00176-5.

133. Mei H Li C Jiang H Zhao X Huang Z Jin D, 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: 10.1186/s13045-021-01170-7.

134. Tang Y Yin H Zhao X Jin D Liang Y Xiong T, 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: 10.1186/s13046-021-02214-z.

135. Shi M Wang J Huang H Liu D Cheng H Wang X, 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: 10.1038/s41467-024-47801-8.

136. Li C Xu J Luo W Liao D Xie W Wei Q, et al. Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma. Leukemia 2024;38:149–159. doi: 10.1038/s41375-023-02065-x.

137. Carpenter RO Evbuomwan MO Pittaluga S Rose JJ Raffeld M Yang S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res 2013;19:2048–2060. doi: 10.1158/1078-0432.CCR-12-2422.

138. Avery DT Kalled SL Ellyard JI Ambrose C Bixler SA Thien M, et al. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J Clin Invest 2003;112:286–297. doi: 10.1172/jci18025.

139. Novak AJ Darce JR Arendt BK Harder B Henderson K Kindsvogel W, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: A mechanism for growth and survival. Blood 2004;103:689–694. doi: 10.1182/blood-2003-06-2043.

140. Ali SA Shi V Maric I Wang M Stroncek DF Rose JJ, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016;128:1688–1700. doi: 10.1182/blood-2016-04-711903.

141. Brudno JN Maric I Hartman SD Rose JJ Wang M Lam N, et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J Clin Oncol 2018;36:2267–2280. doi: 10.1200/jco.2018.77.8084.

142. Raje N Berdeja J Lin Y Siegel D Jagannath S Madduri D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med 2019;380:1726–1737. doi: 10.1056/NEJMoa1817226.

143. Munshi NC Anderson LD, Jr. Shah N Madduri D Berdeja J Lonial S, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 2021;384:705–716. doi: 10.1056/NEJMoa2024850.

144. Rodriguez-Otero P Ailawadhi S Arnulf B Patel K Cavo M Nooka AK, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med 2023;388:1002–1014. doi: 10.1056/NEJMoa2213614.

145. Ailawadhi S Arnulf B Patel K Cavo M Nooka AK Manier S, et al. Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: Updated KarMMa-3 analyses. Blood 2024;144:2389–2401. doi: 10.1182/blood.2024024582.

146. Natrajan K, Kaushal M, George B, Kanapuru B, Theoret MR. FDA approval summary: Ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. Clin Cancer Res 2024;30:2865–2871. doi: 10.1158/1078-0432.Ccr-24-0378.

147. Strassl I, Podar K. The preclinical discovery and clinical development of ciltacabtagene autoleucel (Cilta-cel) for the treatment of multiple myeloma. Expert Opin Drug Discov 2024;19:377–391. doi: 10.1080/17460441.2024.2319672.

148. Berdeja JG Madduri D Usmani SZ Jakubowiak A Agha M Cohen AD, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study. Lancet 2021;398:314–324. doi: 10.1016/s0140-6736(21)00933-8.

149. Cohen AD Mateos MV Cohen YC Rodriguez-Otero P Paiva B van de Donk N, et al. Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents. Blood 2023;141:219–230. doi: 10.1182/blood.2022015526.

150. Mi JQ Zhao W Jing H Fu W Hu J Chen L, et al. Phase II, Open-label study of ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor-T-cell therapy, in Chinese patients with relapsed/refractory multiple myeloma (CARTIFAN-1). J Clin Oncol 2023;41:1275–1284. doi: 10.1200/jco.22.00690.

151. Martin T Lin Y Agha M Cohen AD Htut M Stewart AK, et al. Health-related quality of life in patients given ciltacabtagene autoleucel for relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b-2, open-label study. Lancet Haematol 2022;9:e897–e905. doi: 10.1016/s2352-3026(22)00284-8.

152. Martin T Usmani SZ Berdeja JG Agha M Cohen AD Hari P, 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;41:1265–1274. doi: 10.1200/jco.22.00842.

153. 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: 10.1016/j.canlet.2022.215949.

154. Lin Y Qiu L Usmani S Joo CW Costa L Derman B, et al. Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T-cell therapy in clinical practice for relapsed and refractory multiple myeloma: A report from the International Myeloma Working Group Immunotherapy Committee. Lancet Oncol 2024;25:e374–e387. doi: 10.1016/s1470-2045(24)00094-9.

155. Anderson LD, Jr. Dhakal B Jain T Oluwole OO Shah GL Sidana S, et al. Chimeric antigen receptor T cell therapy for myeloma: Where are we now and what is needed to move chimeric antigen receptor T cells forward to earlier lines of therapy? Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Transplant Cell Ther 2024;30:17–37. doi: 10.1016/j.jtct.2023.10.022.

156. Van Oekelen O Aleman A Upadhyaya B Schnakenberg S Madduri D Gavane S, et al. Neurocognitive and hypokinetic movement disorder with features of Parkinsonism after BCMA-targeting CAR-T cell therapy. Nat Med 2021;27:2099–2103. doi: 10.1038/s41591-021-01564-7.

157. Ge C, Yin C, Chen X. International approvals of cilta-cel: A lens on CAR T cell regulation. Nat Rev Clin Oncol 2025;22:233–234. doi: 10.1038/s41571-025-00996-1.

158. Manier S Ingegnere T Escure G Prodhomme C Nudel M Mitra S, et al. Current state and next-generation CAR-T cells in multiple myeloma. Blood Rev 2022;54:100929. doi: 10.1016/j.blre.2022.100929.

159. Chen R Jin C Liu K Zhao M Yang T Zhang M, et al. Predictive value of pre-treatment circulating tumor DNA genomic landscape in patients with relapsed/refractory multiple myeloma undergoing anti-BCMA CAR-T therapy: Insights from tumor cells and T cells. Chin Med J 2024. doi: 10.1097/cm9.0000000000003306.

160. Li C Zhou K Hu Y Zou D Chen L Chen B, et al. Equecabtagene autoleucel in patients with relapsed or refractory multiple myeloma: The FUMANBA-1 nonrandomized clinical trial. JAMA Oncol 2024;10:1681–1688. doi: 10.1001/jamaoncol.2024.4879.

161. Keam SJ. Equecabtagene autoleucel: First approval. Mol Diagn Ther 2023;27:781–787. doi: 10.1007/s40291-023-00673-y.

162. Mailankody S Devlin SM Landa J Nath K Diamonte C Carstens EJ, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med 2022;387:1196–1206. doi: 10.1056/NEJMoa2209900.

163. Mi X, Penson A, Abdel-Wahab O, Mailankody S. Genetic basis of relapse after GPRC5D-targeted CAR T cells. N Engl J Med 2023;389:1435–1437. doi: 10.1056/NEJMc2308544.

164. Dimopoulos MA Dytfeld D Grosicki S Moreau P Takezako N Hori M, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med 2018;379:1811–1822. doi: 10.1056/NEJMoa1805762.

165. Zah E Nam E Bhuvan V Tran U Ji BY Gosliner SB, et al. Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma. Nat Commun 2020;11:2283. doi: 10.1038/s41467-020-16160-5.

166. Gogishvili T Danhof S Prommersberger S Rydzek J Schreder M Brede C, et al. SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7(+) normal lymphocytes. Blood 2017;130:2838–2847. doi: 10.1182/blood-2017-04-778423.

167. Globerson Levin A Rawet Slobodkin M Waks T Horn G Ninio-Many L Deshet Unger N, et al. Treatment of multiple myeloma using chimeric antigen receptor T cells with dual specificity. Cancer Immunol Res 2020;8:1485–1495. doi: 10.1158/2326-6066.Cir-20-0118.

168. van der Schans JJ Wang Z van Arkel J van Schaik T Katsarou A Ruiter R, et al. Specific targeting of multiple myeloma by dual split-signaling chimeric antigen receptor T cells directed against CD38 and CD138. Clin Cancer Res 2023;29:4219–4229. doi: 10.1158/1078-0432.Ccr-23-0132.

169. Polson AG Zheng B Elkins K Chang W Du C Dowd P, et al. Expression pattern of the human FcRH/IRTA receptors in normal tissue and in B-chronic lymphocytic leukemia. Int Immunol 2006;18:1363–1373. doi: 10.1093/intimm/dxl069.

170. Inoue J Otsuki T Hirasawa A Imoto I Matsuo Y Shimizu S, et al. Overexpression of PDZK1 within the 1q12-q22 amplicon is likely to be associated with drug-resistance phenotype in multiple myeloma. Am J Pathol 2004;165:71–81. doi: 10.1016/s0002-9440(10)63276-2.

171. Jiang D Huang H Qin H Tang K Shi X Zhu T, 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: 10.1038/s41467-023-39395-4.

172. Lee L Draper B Chaplin N Philip B Chin M Galas-Filipowicz D, et al. An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma. Blood 2018;131:746–758. doi: 10.1182/blood-2017-05-781351.

173. Lee L Lim WC Galas-Filipowicz D Fung K Taylor J Patel D, et al. Limited efficacy of APRIL CAR in patients with multiple myeloma indicate challenges in the use of natural ligands for CAR T-cell therapy. J Immunother Cancer 2023;11:e006699. doi: 10.1136/jitc-2023-006699.

174. Schmidts A Ormhøj M Choi BD Taylor AO Bouffard AA Scarfò I, et al. Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma. Blood Adv 2019;3:3248–3260. doi: 10.1182/bloodadvances.2019000703.

175. Larson RC Kann MC Graham C Mount CW Castano AP Lee WH, et al. Anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma. Nat Commun 2023;14:7509. doi: 10.1038/s41467-023-43416-7.

176. Atanackovic D Panse J Hildebrandt Y Jadczak A Kobold S Cao Y, et al. Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma. Haematologica 2011;96:1512–1520. doi: 10.3324/haematol.2010.036814.

177. Radhakrishnan SV Luetkens T Scherer SD Davis P Vander Mause ER Olson ML, et al. CD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide. Nat Commun 2020;11:798. doi: 10.1038/s41467-020-14619-z.

178. Vander Mause ER Baker JM Dietze KA Radhakrishnan SV Iraguha T Omili D, et al. Systematic single amino acid affinity tuning of CD229 CAR T cells retains efficacy against multiple myeloma and eliminates on-target off-tumor toxicity. Sci Transl Med 2023;15:eadd7900. doi: 10.1126/scitranslmed.add7900.

179. Singh L Muise ES Bhattacharya A Grein J Javaid S Stivers P, et al. ILT3 (LILRB4) Promotes the immunosuppressive function of tumor-educated human monocytic myeloid-derived suppressor cells. Mol Cancer Res 2021;19:702–716. doi: 10.1158/1541-7786.Mcr-20-0622.

180. Deng M Gui X Kim J Xie L Chen W Li Z, et al. LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature 2018;562:605–609. doi: 10.1038/s41586-018-0615-z.

181. John S Chen H Deng M Gui X Wu G Chen W, et al. A novel anti-LILRB4 CAR-T cell for the treatment of monocytic AML. Mol Ther 2018;26:2487–2495. doi: 10.1016/j.ymthe.2018.08.001.

182. Wang H Wang L Luan H Xiao J Zhao Z Yu P, et al. LILRB4 on multiple myeloma cells promotes bone lesion by p-SHP2/NF-κB/RELT signal pathway. J Exp Clin Cancer Res 2024;43:183. doi: 10.1186/s13046-024-03110-y.

183. Xie L Chen C Zhang T Yang W Zheng D Cao L, et al. LILRB4 regulates multiple myeloma development through STAT3-PFKFB1 pathway. Cell Death Dis 2024;15:515. doi: 10.1038/s41419-024-06883-4.

184. Wang Y Sun Y Deng S Liu J Yu J Chi H, et al. Discovery of galectin-8 as an LILRB4 ligand driving M-MDSCs defines a class of antibodies to fight solid tumors. Cell Rep Med 2024;5:101374. doi: 10.1016/j.xcrm.2023.101374.

185. Garfall AL. New biological therapies for multiple myeloma. Annu Rev Med 2024;75:13–29. doi: 10.1146/annurev-med-050522-033815.

186. Cohen AD. Myeloma: next generation immunotherapy. Hematology Am Soc Hematol Educ Program 2019;2019:266–272. doi: 10.1182/hematology.2019000068.

187. Cohen AD, Raje N, Fowler JA, Mezzi K, Scott EC, Dhodapkar MV. How to train your T cells: Overcoming immune dysfunction in multiple myeloma. Clin Cancer Res 2020;26:1541–1554. doi: 10.1158/1078-0432.Ccr-19-2111.

188. Moreau P Garfall AL van de Donk N Nahi H San-Miguel JF Oriol A, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med 2022;387:495–505. doi: 10.1056/NEJMoa2203478.

189. Donk NWCJvd Moreau P Garfall AL Bhutani M Oriol A Nooka AK, et al. Long-term follow-up from MajesTEC-1 of teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol 2023;41:8011–8011. doi: 10.1200/JCO.2023.41.16_suppl.8011.

190. Bahlis NJ Costello CL Raje NS Levy MY Dholaria B Solh M, et al. Elranatamab in relapsed or refractory multiple myeloma: The MagnetisMM-1 phase 1 trial. Nat Med 2023;29:2570–2576. doi: 10.1038/s41591-023-02589-w.

191. Lesokhin AM Tomasson MH Arnulf B Bahlis NJ Miles Prince H Niesvizky R, et al. Elranatamab in relapsed or refractory multiple myeloma: Phase 2 MagnetisMM-3 trial results. Nat Med 2023;29:2259–2267. doi: 10.1038/s41591-023-02528-9.

192. Chari A Touzeau C Schinke C Minnema MC Berdeja JG Oriol A, et al. Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): A multicentre, open-label, phase 1–2 study. Lancet Haematol 2025;12:e269–e281. doi: 10.1016/S2352-3026(24)00385-5.

193. Chari A Minnema MC Berdeja JG Oriol A van de Donk N Rodríguez-Otero P, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med 2022;387:2232–2244. doi: 10.1056/NEJMoa2204591.

194. Schinke CD Touzeau C Minnema MC Donk NWCJvd Rodríguez-Otero P Mateos M-V, et al. Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM). J Clin Oncol 2023;41:8036–8036. doi: 10.1200/JCO.2023.41.16_suppl.8036.

195. Eckmann J Fauti T Biehl M Zabaleta A Blanco L Lelios I, et al. Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma. Blood 2025;145:202–219. doi: 10.1182/blood.2024025987.

196. Carlo-Stella C Mazza R Manier S Facon T Yoon S-S Koh Y, et al. RG6234, a GPRC5DxCD3 T-cell engaging bispecific antibody, is highly active in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Updated intravenous (IV) and first subcutaneous (SC) results from a phase I dose-escalation study. Blood 2022;140:397–399. doi: 10.1182/blood-2022-157988.

197. Jagannath S Richter J Dhodapkar MV Hoffman JE Lee HC Suvannasankha A, et al. Patterns of response to 200 mg linvoseltamab in patients with relapsed/refractory multiple myeloma: Longer follow-up of the linker-MM1 study. Blood 2023;142:4746–4746. doi: 10.1182/blood-2023-177968.

198. Shah MR Richter J Lee HC Suvannasankha A Hoffman JE Lentzsch S, et al. Linvoseltamab in patients with relapsed/refractory multiple myeloma: Longer follow-up and selected high-risk subgroup analyses of the linker-MM1 study. Blood 2024;144:3369–3369. doi: 10.1182/blood-2024-199733.

199. Vij R Kumar SK D’Souza A Mckay JT Voorhees PM Chung A, et al. Updated safety and efficacy results of Abbv-383, a BCMA x CD3 bispecific T-cell redirecting antibody, in a first-in-human phase 1 study in patients with relapsed/refractory multiple myeloma. Blood 2023;142:3378–3378. doi: 10.1182/blood-2023-182388.

200. Topp MS Duell J Zugmaier G Attal M Moreau P Langer C, et al. Anti-B-cell maturation antigen BiTE molecule AMG 420 induces responses in multiple myeloma. J Clin Oncol 2020;38:775–783. doi: 10.1200/jco.19.02657.

201. Usmani SZ Garfall AL van de Donk N Nahi H San-Miguel JF Oriol A, et al. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): A multicentre, open-label, single-arm, phase 1 study. Lancet 2021;398:665–674. doi: 10.1016/s0140-6736(21)01338-6.

202. Touzeau C Krishnan AY Moreau P Perrot A Usmani SZ Manier S, et al. Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies. Blood 2024;144:2375–2388. doi: 10.1182/blood.2023023616.

203. Eckmann J Fauti T Biehl M Zabaleta A Blanco L Lelios I, et al. Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma. Blood 2024;145:202–219. doi: 10.1182/blood.2024025987.

204. Neri P, Leblay N, Lee H, Gulla A, Bahlis NJ, Anderson KC. Just scratching the surface: Novel treatment approaches for multiple myeloma targeting cell membrane proteins. Nat Rev Clin Oncol 2024;21:590–609. doi: 10.1038/s41571-024-00913-y.

205. 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: 10.1186/s13045-023-01489-3.