Are we there yet? CAR-T therapy in multiple myeloma.

INTRODUCTION

Multiple myeloma (MM) is a clonal plasma cell (PC) neoplasm characterised by features of end‐organ damage including hypercalcaemia, renal insufficiency, anaemia and lytic bone lesions. 1 Median overall survival (OS) ranges from 7 to 10 years in standard‐risk patients to 3 years in patients with high‐risk cytogenetic abnormalities such as t(4;14), t(14;16), t(14;20) and del(17/17p). 2 In the MAMMOTH study, median OS was only 9.2 months in patients triple refractory to a proteasome inhibitor (PI), immunomodulatory drug (IMiD) and anti‐cluster of differentiation (CD)38 monoclonal antibody (CD38 mAb). 3 Second autologous stem cell transplant (ASCT) has limited efficacy; 975 patients salvaged with second ASCT had cumulative incidence of relapse/progression of 49% at 1 year and 84% at 3 years. 4 Outcomes of allogeneic SCT in MM are generally poor, with 1‐year transplant‐related mortality at 23.5% and 5‐year OS at 22.2%. 5 There is, therefore, an urgent need for treatment with long‐term curative potential for relapsed/refractory MM (RRMM).

Novel therapeutic strategies include bispecific T‐cell engagers (BiTEs) and chimeric antigen receptor T‐cell (CAR‐T) therapy. BiTEs consist of two antigen recognition domains connected via a linker. They create an indirect immunological synapse between MM cells and T‐cells, resulting in T‐cell activation and MM cell death. 6 BiTEs targeting B‐cell maturation antigen (BCMA), G protein‐coupled receptor, class C, group 5, member D (GPRC5D) and Fc receptor homologue 5 (FcRH5) have been developed and are reviewed elsewhere. 7 , 8 , 9

CAR‐T therapy involves reprogramming T cells with a CAR construct targeting a tumour‐associated antigen. Antigen binding triggers CAR‐T activation, proliferation and cytotoxic effector functions. First approved in 2017, CD19 CAR‐T now plays a transformative role in relapsed/refractory B‐cell acute lymphoblastic leukaemia, large B‐cell lymphomas and mantle cell lymphoma. 10 More recently, CARs have been manufactured against MM tumour antigens, including BCMA, GPRC5D and several others.

In addition to an intracellular CD3ζ signal transduction domain, second‐generation CARs are equipped with a costimulatory domain, for example, CD28 or 4‐1BB, which improves proliferation, cytokine secretion, resistance to apoptosis and persistence. 11 All currently licensed CARs are second generation. Third‐generation CARs have two costimulatory domains, usually CD28 combined with 4‐1BB. Fourth‐/next‐generation CARs have further modifications, including armoured CAR‐T cells, which overpower the inhibitory tumour microenvironment (TME), and T cells redirected for universal cytokine‐mediated killing (TRUCKs), which express cytokines to promote CAR‐T function and survival. 12

CAR‐T manufacture begins with leukapheresis; T cells are subsequently activated and transduced with a viral vector encoding the CAR, resulting in CAR expression on the T‐cell surface. Following CAR‐T expansion, the product is concentrated and cryopreserved. 13 Prior to CAR‐T infusion, the recipient requires lymphodepletion, usually with fludarabine and cyclophosphamide. 14

The most common CAR‐T toxicity is cytokine release syndrome (CRS), a state of immune over‐activation associated with CAR‐T expansion. Grade 1 CRS involves fever; however, symptoms can rapidly progress to multiorgan failure. In addition to supportive care, severe CRS is treated with tocilizumab (anti‐IL‐6 mAb) and if refractory, corticosteroids. Immune effector cell‐associated neurotoxicity syndrome (ICANS) can range from mild confusion to seizures to fatal cerebral oedema. The mechanism is poorly understood. 15 Other common toxicities include cytopaenias and infection.

This review will discuss the novel cellular immunotherapy targets being explored in RRMM, with an emphasis on strategies to overcome resistance and improve depth and duration of response.

NOVEL IMMUNOTHERAPY TARGETS

BCMA

BCMA (CD269) is a pro‐survival non‐tyrosine kinase receptor surface glycoprotein and a member of the tumour necrosis factor receptor (TNFR) superfamily (Figure 1 ). Expression is restricted to late memory B cells and PCs and is highest in MM cells. BCMA transmits downstream signals which are important for PC survival. 16

BCMA CAR‐T has shown impressive results in heavily pretreated MM. A meta‐analysis of 21 trials including total of 761 RRMM patients showed overall response rate (ORR) of 87%, complete response rate (CRR) of 44%, median progression‐free surviv (PFS) of 8.77 months and median OS of 18.87 months. 17 Idecabtagene vicleucel (Ide‐cel) contains a murine anti‐BCMA single‐chain variable fragment (scFv) with 4‐1BB as the costimulatory domain delivered via a lentiviral vector. In the phase II KarMMa study, 128 patients who progressed after median of six lines of treatment (LOT) attained ORR of 73% and median PFS of 8.8 months (Table 1 ). 19 There was correlation between depth and duration of response, with duration of 4.5, 10.4 and 19 months for patients attaining partial response (PR), very good PR (VGPR) and CR/stringent CR (sCR) respectively. In phase III KarMMa‐3, which enrolled patients treated with two to four prior LOT, Ide‐cel achieved ORR of 71% compared with 42% in the standard chemotherapy treatment arm; median PFS was 13.3 months versus 4.4 months. Grades 3–4 CRS occurred in 5% and grades 3–4 ICANS in 3% (Table 2 ). 21 A retrospective study of real‐world data included 196 patients, 75% of whom would have been ineligible for KarMMa due to comorbidities. ORR was 84%, median PFS 8.5 months and median OS 12.5 months. 47 The largest real‐world study of Ide‐cel outcomes includes 603 patients with median of seven prior LOT. ORR was 71%, again comparable with KarMMa and KarMMa‐3. With median follow‐up of 6.6 months, estimated 6‐month PFS was 62% and OS of 82%. 48 Multivariate analysis has identified prior BMCA‐directed therapy, high‐risk cytogenetics and elevated baseline ferritin level as potential predictors of early progression/refractory disease following Ide‐cel. 49 KarMMa‐2 ( NCT03601078 ) is investigating Ide‐cel in clinical high‐risk MM patients at an earlier stage of the disease. Interim results demonstrate ORR of 83.8% and median PFS of 11.4 months in patients who progressed within 18 months of initial ASCT. 20

Ciltacabtagene autoleucel (Cilta‐cel) has an scFv consisting of two llama heavy chains which bind to two distinct BCMA epitopes, resulting in high avidity against human BCMA. 50 In CARTITUDE‐1 (median of six prior LOT), ORR was 97%, with 67% achieving sCR. 22 Responses were durable, with an impressive median PFS of 34.9 months and median OS not reached. 51 While study populations differ in patient and disease characteristics, these responses are remarkably superior to results seen with Ide‐cel and other products. In the phase III CARTITUDE‐4, where patients with one to three prior lines were enrolled, Cilta‐cel achieved CR/sCR in 73.1% of lenalidomide‐refractory patients, compared with 21.8% in the standard care group receiving chemotherapy alone. 24 In Cohort B of the ongoing CARTITUDE‐2 ( NCT04133636 ), patients received Cilta‐cel second line following early clinical relapse. ORR was 88.9% and median time to first response was only 0.9 months. 23 A recently published real‐world study of Cilta‐cel included 236 RRMM patients, with median of six prior LOT, and a higher proportion of extra‐medullary disease and high‐risk cytogenetics than in CARTITUDE‐1. Fifty‐six per cent would not have CARTITUDE‐1 eligibility criteria. ORR was 89% and ≥CRR was 70%. Median PFS was not reached after median follow‐up of 13 months. 52

The FDA approved Ide‐cel in 2021 and Cilta‐cel in 2022, for RRMM following ≥4 prior LOT; the EMA authorised both CARs soon thereafter (after ≥3 prior LOT). 53 , 54 , 55 In 2024, in light of CARTITUDE‐4, the FDA and EMA approved Cilta‐cel for lenalidomide‐refractory RRMM following ≥1 prior LOT including a PI and IMiD. 56 , 57 In 2024, the FDA also approved Ide‐cel for triple‐class exposed RRMM following ≥2 prior LOT. 58

FHVH‐T is a CAR with a fully human anti‐BMCA heavy‐chain variable domain, designed to reduce immunogenicity. In 25 RRMM patients, ORR was 92% and median PFS was 65 weeks. Surprisingly, humoral anti‐CAR responses were detected in 4/12 evaluated patients. 26 Equecabtagene autoleucel (CT103A), another fully human BCMA CAR, was granted conditional approval in China in 2023 as a fourth‐line treatment. In the phase Ib/II FUMANBA‐1 trial, 11.4% had received previous BCMA CAR‐T. Impressively, ORR was 96% with CR/sCR at 74.3%; 12‐month PFS was 78.8%. 27 In the ongoing CARTBCMA‐HCB‐01 study in RRMM, patients received ARI0002h, a humanised BCMA CAR‐T, in three fractions, followed by a booster dose after ≥100 days. Interim analysis showed 100% ORR. 28

Frigault et al engineered CART‐ddBCMA, which has a unique, synthetic small stable protein (D‐Domain) as its binding domain, to reduce immunogenicity and improve cell surface stability. In a phase I study, 33 RRMM patients were treated with CART‐ddBCMA and achieved an ORR of 100% with 71% CR/sCR, and at median follow‐up of 12.1 months, 86% of evaluable patients had minimal residual disease (MRD) negativity. 30 The pivotal phase II iMMagine‐1 study ( NCT05396885 ) with this CAR (anitocabtagene autoleucel) is underway.

GPRC5D

GPRC5D is an orphan G protein‐coupled receptor which is highly expressed by MM cells. Its signalling mechanism and function have not yet been identified. 59 Expression is restricted to PCs, skin (hair follicles and eccrine glands), filiform papillae of the tongue and seminiferous tubules of the testis. 60 Expression was also found to be specifically enriched in the inferior olivary nucleus of the brainstem. 32

MCARH109 is a humanised, lentivirally transduced GPRC5D CAR‐T employing 4‐1BB costimulation. In a first‐in‐human dose escalation study, ORR was 12/17 (71%), reduced to 58% in patients not exceeding the maximum tolerated dose of 150 × 10 6 CAR‐T cells. Importantly, 7/10 patients who relapsed following prior BCMA therapy responded. Of the 12 responses, 6 relapsed after 3–9 months. Grade 4 toxicities included CRS (one patient), ICANS (one patient) and macrophage activation syndrome (one patient); two patients had a grade 3 cerebellar disorder of unclear aetiology. 32 In a phase II trial of another humanised GPRC5D CAR‐T, ORR was 91% and response was achieved in 9/9 patients who previously received BCMA CAR‐T therapy. 35

Zhou et al conducted a phase I trial of the first bispecific BCMA‐GPRC5D CAR‐T cells. ORR for 21 RRMM patients was 86%, ≥CRR 62% and 81% had MRD negativity. There was no grade ≥ 3 ICANS or CRS. Median PFS and OS were not reached after median follow‐up of 5.8 months. 36

FcRH5

FcRH5 (CD307) belongs to a family of six genes of the immunoglobulin superfamily. Function is unknown. 61 FcRH5 is expressed in all B cells with peak expression in mature B cells. Expression in MM cells is more than threefold higher than in non‐malignant PCs. 62

Jiang et al generated FcRH5‐BCMA bispecific CAR‐T cells which showed cytotoxicity against MM cells expressing FcRH5 and BCMA alone and in combination. Most significantly, FcRH5‐BCMA CAR‐T demonstrated improved tumour infiltration and longer survival than FcRH5 or BCMA monospecific CAR‐T cells in a subcutaneous NCI‐H929 xenograft model. 63

CD19

CD19, a co‐receptor of the B‐cell receptor, is typically absent in terminally differentiated PCs and MM cells. Nevertheless, low‐level expression is seen in a minor subset of less mature MM cells and is associated with drug resistance, relapse and poor survival. 64 CD19 may therefore be a desirable target.

Safety and efficacy of co‐administered BCMA and CD19 CAR‐T have been demonstrated in late‐relapsed MM and in high‐risk newly diagnosed (NDMM) post‐ASCT. 37 , 38 GC012F is a BCMA‐CD19 bispecific CAR‐T developed with the FastCAR‐T platform. In a phase I study, response rate and durability were excellent: 29 patients (median of five prior LOT) had ORR 93.1% and sCRR 82.8%. Median PFS was 38 months. 39 Lee et al are currently evaluating a dual BCMA/persistent CD19 CAR strategy. 65

Roex et al developed bispecific BCMA‐CD19 allo‐CAR NK, by co‐electroporating cells from the NK‐92 cell line with BCMA and CD19 CAR mRNA. Dual‐ and single‐CAR NK‐92 cells showed equivalent cytotoxicity in vitro . 66

CS1/signalling lymphocyte activation molecule family member 7 (SLAMF7)

CS1 (also known as SLAMF7) is involved in immune regulation. It is expressed by dendritic cells, monocytes and lymphocytes, and upregulated in MM cells, in which it promotes cell proliferation and growth. 67

Li et al constructed bispecific CS1‐BCMA CAR‐T cells, incorporating novel murine anti‐CS1 scFv and anti‐BCMA scFv in tandem, with 4‐1BB costimulation. In a phase I/IIa trial, ORR was 13/16 (81%). 40

CD229

CD229 is another member of the signalling lymphocyte activation molecule (SLAM) family. Expression is restricted to B and T cells and it is universally and strongly expressed by MM cells. Silencing of CD229 causes spontaneous MM cell apoptosis. 68 Efficacy of CD229 CAR‐T has been demonstrated in preclinical models, both as a single‐targeted therapy and with a CD229‐BCMA bicistronic CAR‐T. 69 , 70

Semaphorin‐4A (SEMA4A)

SEMA4A is a cell surface protein involved in embryonic and pathological angiogenesis, fine‐tuning of the immune response and retinal function. 71 It is expressed by MM cells at a higher level than BCMA and SLAMF7. Loss of SEMA4A leads to MM cell apoptosis. 72 A humanised SEMA4A CAR‐T demonstrated potent and specific anti‐MM activity in vitro. 73

Transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI)

TACI, like BCMA, is a member of the TNFR superfamily that is almost exclusively expressed by PCs, and upregulated by most MM cells. 74 BCMA and TACI have two primary natural ligands: B‐cell activating factor (BAFF) and a proliferation‐inducing ligand (APRIL). 6 APRIL ligand as a CAR was evaluated in the phase I AUTO2 trial but showed limited efficacy with ORR of 45.5%, median PFS of 5 months and median OS of 375 days. The APRIL CAR demonstrated in vitro functional deficiencies including reduced target binding, reduced IL‐2 secretion and impaired interferon signalling compared with other BCMA CARs. 75 A trimeric APRIL‐based (TRIPRIL) CAR has been developed to enhance binding to both BCMA and TACI and is currently being evaluated in a clinical study ( NCT05020444 ). 76

CD38

CD38 has high, uniform expression on MM cells. Three trials involving dual targeting of CD38 and BCMA have been conducted in China. BM38 CAR is a humanised bispecific BCMA‐CD38 CAR. In a phase I study, 23 RRMM patients had ORR of 87% including 52% sCR. Responses were durable with median PFS of 17.2 months. 42 A second bispecific BCMA‐CD38 CAR‐T product showed ORR of 87.5% with 81% sCR. 43 In both trials, grade ≥ 3 CRS was common (22% and 31% including one death respectively). In a third trial, 22 RRMM patients with median of eight prior LOTs received humanised BCMA CAR‐T cells in combination with murine anti‐CD38 CAR‐T cells, and achieved an ORR of 90.9%, 24‐month PFS rate of 48.7% and OS rate of 56.6%. Grade 3 CRS occurred in 27.3%. 44

In dual‐split CD38‐CD138 CAR‐T cells, the stimulatory and costimulatory signals were split into two separate stimulatory and costimulatory CARs (sCAR and cCAR) to increase specificity for MM cells. The most optimal combination in vitro was a low‐affinity CD138sCAR combined with a high‐affinity CD38cCAR. This combination also demonstrated efficacy against MM cells with reduced CD38 expression following daratumumab pretreatment. 77

CAR ‐T TOXICITIES

In addition to CRS and ICANS (discussed in the Introduction), other toxicities to CAR‐T therapy include prolonged cytopaenias, with median time to recovery of grade 3–4 cytopaenias of 2 months following BCMA CAR‐T therapy. 22 Age and cumulative treatment‐related toxicity appear to be significant contributing factors. 78 Infection is also very common. In 55 patients treated with BCMA CAR‐T, 47 infections were diagnosed in 29 patients (53%); 6% were severe and 2% fatal. 79 Infection risk is compounded by treatment‐associated lymphopaenia and hypogammaglobulinaemia. Lancman et al observed 90% reduction in grade 3–5 infections during periods of treatment with IV immunoglobulin (IVIG) following BCMA‐targeted BiTE therapy; IVIG is likely to provide valuable prophylaxis following BCMA CAR‐T as well. 80 IVIG is therefore administered monthly until resolution of hypogammaglobulinaemia.

Movement and neurocognitive toxicities (MNTs) occurred in 5% of patients in CARTITUDE‐1. 53 MNTs manifest after a period of recovery from CRS and/or ICANS. MNTs are associated with high tumour burden, grade ≥ 2 CRS, any ICANS and high CAR‐T cell expansion/persistence. 81 In CARTITUDE‐4, following strategies to reduce baseline tumour burden with bridging therapy, together with more aggressive, early management of CRS and ICANS, incidence of MNTs decreased to one grade 1 case (0.2%). 24 Management approaches include corticosteroids, plasmapheresis and IVIG; Graham et al also reported a case of rapid improvement following cyclophosphamide. 81 , 82

In view of GPRC5D expression in the skin and tongue, GPRC5D CAR‐T therapy can cause time‐limited on‐target, off‐tumour toxicities which include nail changes (12%–65%), skin changes/rash (3%–18%) and dysgeusia/dry mouth (12%). These were all grade 1 apart from one patient who developed grade 2 desquamation of palms and soles. 32 , 33 , 35 The exact cause of the grade 3 persistent cerebellar disorders seen in two recipients of MCARH109 is unclear but could relate to expression of GPRC5D in the inferior olivary nucleus. 32

It is important to consider whether dual‐antigen targeting confers additional toxicity. With the dual BCMA‐CD19 targeting approaches discussed above, grade 3–4 CRS was identified in total of 2/69 patients (3%) and there were no grade 3–4 ICANS. 37 , 38 , 39 No grade 3–4 CRS or ICANS were observed in 21 patients who received bispecific BCMA‐GPRC5D CAR‐T cells. 36 In contrast, grade ≥ 3 CRS was more prevalent with dual BCMA‐CD38 targeting at 22%–27.3% in the three trials discussed, including one death. 42 , 43 , 44

OVERCOMING CAR ‐T RESISTANCE

Despite impressive response rates seen with CAR‐T in MM, including high rates of CR/sCR, the majority still relapse. The disease kinetics that mediate resistance to CAR‐T are poorly understood. Work to identify and circumvent mechanisms of resistance has predominantly focused on BCMA. Mechanisms can be categorised into tumour‐intrinsic factors, host factors and CAR‐T factors. Tumour‐intrinsic factors : These include higher disease burden, high‐risk cytogenetics and extra‐medullary disease. 83 BCMA is important for PC function and unlike CD19, where loss or downregulation is seen in up to one‐third of patients who relapse following CD19 CAR‐T, BCMA loss is rare. 84 In KarMMa, BCMA expression was lost in 3/71 (4%) of patients who progressed following Ide‐cel. 19 In one of the cases, homozygous deletion of TNFRSF17 (BCMA) on chromosome 16 was subsequently confirmed. 85 In another case report, Samur et al describe biallelic BCMA loss involving deletion of one allele and a mutation that engendered an early stop codon on the other allele. 86 Mutational events appear a more common mechanism of resistance following BCMA‐directed BiTE therapy. Lee et al analysed 14 cases of relapse following teclistamab or elranatamab, and identified biallelic TNFRSF17 deletion in one case, as well as functional epitope loss secondary to non‐truncating, missense mutations or in‐frame deletions in five cases, despite evidence of surface BCMA expression. They postulated that the repeated administration of BiTEs exerts a longitudinal selective pressure that is avoided by the single administration of BCMA CAR‐T. 87 Perica et al observed that while BCMA loss is uncommon following BCMA CAR‐T, resistance/relapse is associated with reduction in BCMA expression below the threshold necessary for optimal CAR‐T cell functioning. 88 Dual‐antigen targeting approaches, discussed above, are intended to thwart the risk posed by BCMA loss in order to improve depth and duration of response. BCMA is cleaved from the MM cell surface by the γ‐secretase complex, releasing soluble BCMA and reducing target density (Figure 1 ). Concurrent use of a γ‐secretase inhibitor (GSI) enhanced anti‐tumour efficacy of BCMA CAR‐T in an MM murine model. 89 In a first‐in‐human trial, an oral GSI (JSMD194) was co‐administered with BCMA CAR‐T. Following JSMD194, BCMA antigen binding capacity increased by 20‐fold in seven heavily pretreated patients. ORR was 100% among the six assessable patients (one patient died on day +33 in context of CRS and fungal infection). 90 In contrast to BCMA CAR‐T, antigenic escape appears to be a key mechanism of resistance to GPRC5D CAR‐T, with loss/decrease of GPRC5D observed in all six patients who relapsed following MCARH109. 35 Derrien et al used a single‐nucleus multiomic strategy to analyse three cases of relapse following GPRC5D‐targeted BiTE therapy and identified two resistance mechanisms: biallelic GPRC5D inactivation and long‐range epigenetic silencing of its promoter and enhancer regions. 91 MM cells express the inhibitory ligands PD‐L1 and PD‐L2 (ligands for PD‐1), MHC class II (ligand for LAG‐3) and galectin‐9 (ligand for TIM‐3), which enable immune escape. 83 PD‐1 knock‐out significantly enhanced anti‐MM activity of cytotoxic T cells in vitro and in a murine xenograft model. 92 Trials of PD‐1 blockade with nivolumab or pembrolizumab following BCMA CAR‐T are ongoing ( NCT04205409 and NCT05191472 ). Yuti et al generated anti‐BCMA‐CAR5‐T cells, which secrete anti‐PD‐L1 scFv blockade molecules. They demonstrated superior anti‐tumour efficacy in vitro, compared with non‐PD‐L1‐blocking CAR‐T cells. 93 Wang et al registered a phase II trial investigating BCMA‐PD1‐CART, a TRUCK which secretes a PD‐1 Fc fusion protein ( NCT04162119 ). Melnekoff et al observed significantly upregulated expression of the anti‐apoptotic genes MCL‐1, FOSB and JUND following relapse after Ide‐cel. 94 Targeting of the MCL‐1/BCL‐2 axis may therefore be appropriate to treat selected relapsed patients. ORR for patients who relapsed following BCMA CAR‐T and received first‐line salvage with venetoclax was 66.7%. 95 Interferon‐γ (IFN‐γ) plays a vital role in orchestrating anti‐tumour immune responses. Larson et al generated IFN‐γ receptor 1 knock‐out (IFNγR1‐KO) tumours in a variety of cancer cell lines. They found that disrupted IFN‐γ receptor signalling promoted resistance to CAR‐T cell cytotoxicity in vitro and in vivo in glioblastoma and other solid tumours, but not in MM or lymphoma. 96 Host factors : These include the TME and T‐cell fitness. Stromal cells in the TME produce extra‐cellular matrix proteins that limit trafficking of tumour‐infiltrating T cells, via activation of TGF‐β. 97 The TME also recruits Treg cells, myeloid‐derived suppressor cells and tumour‐associated macrophages, which express immunosuppressive cytokines including TGF‐β and IL‐4. 98 Armoured B2ARM CAR‐T cells co‐express a BCMA CAR and TGF‐β dominant‐negative receptor II, endowing resistance to TGF‐β. In preclinical models, B2ARM CAR‐T cells demonstrated superior persistence and anti‐tumour function compared with non‐armoured CAR‐T cells. 99 Anti‐MM treatment impairs baseline T‐cell fitness. Heavy pretreatment decreases the CD4/CD8 T cell ratio and the frequency of early memory T cells in the leukapheresis product, hindering CAR‐T expansion and persistence. 100 T cells from resistant patients expressed higher levels of the inhibitory receptors PD‐1, LAG‐3 and TIGIT; blockade of TIGIT enhanced MM cell death in vitro. 101 It is therefore possible that earlier leukapheresis will improve CAR‐T efficacy. Dubnikov Sharon et al evaluated clinical outcome of CD19 CAR‐T cells manufactured from earlier leukapheresis (at first relapse) compared with standard leukapheresis (at second relapse or beyond) in diffuse large B‐cell lymphoma (DLBCL). The early group demonstrated increased percentage of naive T cells, increased T‐cell functionality in vitro and lower exhaustion profile. This did not translate into significantly improved clinical outcome, although a trend towards better PFS and OS was seen. 102 CAR‐T cell fitness may also be improved by use of healthy donor (HD)‐derived allogeneic CAR‐T cells (see ‘Allogeneic CAR‐T’ below). CAR‐T factors : Efficacy of CAR‐T therapy in MM is influenced by several aspects of CAR‐T manufacture. CARs with fully humanised or synthetic binding domains are engineered to reduce immunogenicity. Compared with CD28 costimulation, CD19 CARs employing 4‐1BB had slower activation but superior persistence with better maintenance of memory phenotype. 103 The BCMA CAR‐T product bb21217 incorporates the same CAR construct as Ide‐cel, with the addition of a PI3K inhibitor (bb007) during ex vivo culture, to enrich memory‐like T cells. 104 The bespoke manufacture of autologous CAR‐T cells is costly and takes up to 6 weeks, during which time there is risk of disease progression. Manufacturing time can be reduced to 22–36 h with the use of FastCAR‐T platforms such as the CliniMACS Prodigy® (Miltenyi Biotec) and the Cocoon® (Lonza). 25 , 39 Melnekoff et al observed significant expansion of non‐CAR CD8 + T cells with effector memory immunophenotype 4 weeks after Ide‐cel, suggesting that IMiDs, which provide a costimulatory signal to T cells, may augment CAR‐T efficacy. 94 Indeed, lenalidomide potentiated BCMA CAR‐T activity in vitro and significantly prolonged survival in a murine MM model. 105 In a case report, a patient with IgD‐λ MM who progressed after multiple LOT including ASCT and two prior BCMA CAR‐T products was treated with humanised BCMA CAR‐T combined with 25 mg lenalidomide once daily. He achieved VGPR which was maintained for more than 8 months. 106 Prospective studies are required to evaluate safety and efficacy of co‐administration of IMiDs. Wachsmann et al recently proposed combining BCMA CAR‐T with T‐cell receptor (TCR)‐engineered T cells to prevent immune escape. Unlike CARs, TCRs recognise peptides presented in the context of human leukocyte antigens (HLA). They transduced T cells to express a TCR targeting a peptide derived from BOB1, a transcription factor (TF) cofactor essential for MM cell survival. Single‐antigen targeting resulted in immune escape and proliferation of tumour cells in vitro and in vivo, whereas dual‐antigen targeting completely cleared MM cell populations. 107 Simultaneous targeting using HLA‐dependent and HLA‐independent recognition modes may therefore be complementary. CD38 is weakly expressed by T cells and therefore CD38 CAR‐T cells are fraught with the potential for fratricide. To overcome this, BM38 CAR‐T cells were manufactured with a high affinity of anti‐CD38 scFv and reduced affinity of anti‐CD38 scFv, to selectively eliminate CD38 ++ MM cells but spare CD38 + T cells. 42

ALLOGENEIC CAR ‐T

In addition to the risk of disease progression during the 6‐week manufacture of auto‐CAR‐T, manufacturing failure occurred in 18% of patients in CARTITUDE‐1. 22 Allo‐CAR‐T can be manufactured from young HDs, produced in large batches and cryopreserved, allowing immediate ‘off‐the‐shelf’ availability with decreased cost. 108 Metelo et al compared efficacy of HD‐derived and MM‐derived BCMA CAR‐T cells in vitro. The HDs had higher T‐cell counts, CD4/CD8 ratio, naive T‐cell phenotype and increased proportion of central memory cells. HD‐derived T cells had superior transduction rate, superior cytotoxicity and greater expansion compared with late‐relapsed MM‐derived CAR‐T cells. 109

αβ T cells constitute 95% of peripheral blood T cells. 110 Allo‐CAR‐αβ T cells require gene editing to inactivate the endogenous TCRα/β, to prevent alloreactivity in the form of graft‐versus‐host disease (GvHD). To date, allo‐CAR‐αβ T‐cell therapies targeting BCMA and CS1 have been trialled in humans and are reviewed here.

Sommer et al manufactured an allo‐BCMA CAR which reduced tumour burden in a murine model. 111 In the first‐in‐human phase I UNIVERSAL trial, RRMM patients received the allo‐BCMA CAR‐T ALLO‐715 +/− the GSI nirogacestat ( NCT04093596 ). ALLO‐715 contains an integrated, recombinant lentiviral vector encoding a humanised BCMA CAR with a CD20 off‐switch and 4‐1BB costimulation. TRAC (TCRα constant) and CD52 were knocked out by transcription activator‐like effector nucleases (TALENs) to obviate GvHD and confer resistance to alemtuzumab respectively. Interim results demonstrated 55.8% ORR and median duration of response (mDOR) of only 8.3 months. Toxicities were significant: 23.3% had grade ≥ 3 infection including 7% grade 5. Twenty‐eight per cent had grade 1–2 CMV reactivation and 5% had grade ≥ 3. No GvHD was observed. 31 Other allo‐BCMA CAR‐T trials include ALLO‐605 (IGNITE study, NCT05000450 —terminated prematurely, data not yet published) and the ongoing P‐BCMA‐ALLO1 ( NCT04960579 ).

UCARTCS1 is a CS1 allo‐CAR‐T, in which TALENS were used to disrupt the genes encoding TCRα and CS1, to obviate GvHD and CS1‐mediated fratricide respectively. UCARTCS1 showed specific and dose‐dependent anti‐MM activity in preclinical models. 112 In preliminary results for MELANI‐01 ( NCT04142619 ), a first‐in‐human phase I dose escalation trial, 2/5 patients responded; however, both subsequently died (one from organising pneumonia and the second from haemorrhagic pancreatitis in the context of grade 4 CRS, HLH, disseminated mucormycosis and pseudomonal pneumonia). After a clinical hold by the FDA, the study resumed with protocol updates to mitigate the risks from prolonged lymphopaenia and CRS. 113

Kinder et al validated an allogeneic hypoimmune (HIP) GPRC5D CAR‐T. Manufacture involved disruption of the TCR , B2M and CIITA genes to prevent GvHD, and lentiviral transduction to express a humanised GPRC5D CAR and CD47, which promotes CAR‐T persistence by protecting from innate immune system killing. The HIP GPRC5D CAR‐T cells showed in vitro and in vivo efficacy in line with a clinically validated GPRC5D CAR‐T. 114

γδ T cells, natural killer (NK) cells and invariant natural killer T cells (iNKT) cells recognise antigens in an HLA‐independent fashion and do not require TCR gene editing. 115 γδ T cells are a small group of effector T cells, comprising 1%–5% of circulating CD3+ T cells. Zhang et al electroporated Vγ9Vδ2 T cells (a subset of γδ T cells) with BCMA CAR‐encoding mRNA. The resultant CAR‐Vγ9Vδ2 T cells reduced tumour burden and significantly prolonged survival in murine MM models. 116

NK cells play an important role in immune surveillance of cancer and viral infections. 117 CARs arm NK cells with cancer‐specific cytotoxicity; however, NK cell manipulation can downregulate homing receptors required for trafficking, and CAR‐NK cells need modification to overcome this. 115 Ng et al electroporated NK cells with mRNA encoding a BCMA CAR and CXCR4. The CAR‐NK cells significantly reduced tumour burden and extended survival in xenograft murine MM models. Furthermore, transgenic CXCR4 expression promoted CAR‐NK cell migration to the bone marrow, compared with non‐CXCR4‐transfected CAR‐NK cells. 118 FT576 is an iPSC‐derived BCMA CAR‐NK product which demonstrated durable antitumour activity in an MM murine model. 119 A phase I trial of FT576 +/− daratumumab is in progress ( NCT05182073 ).

CAR NK cells have also been developed to target CS1, GPRC5D and CD38. CS1 CAR NK was generated from NK‐92 cells. In a murine model, the product suppressed growth of human IM9 MM cells and significantly prolonged survival. 120 Bicistronic BCMA‐GPRC5D allo‐CAR NK cells reduced relapse and improved survival compared with single‐targeting CAR NK cells in a xenograft murine model. 121 Stikvoort et al manufactured CD38 CAR NK from KHYG‐1 cells, an immortal NK cell line. It showed excellent expansion and effective CD38‐dependent cytotoxicity in vitro and in a xenograft murine model. Importantly, it was also effective against primary MM cells from daratumumab‐refractory patients. 122

iNKT cells have an invariant TCR that interacts with altered glycolipids presented by CD1d, a non‐polymorphic MHC‐I‐like molecule. Poels et al demonstrated CAR‐dependent cytotoxicity of both BCMA and CD38 CAR iNKT cells against the UM9 MM cell line, without compromising their inherent cytotoxic functioning. 123 O'Neal et al recently demonstrated significant anti‐MM activity of human BCMA CAR iNKT cells in a xenograft murine model. CAR iNKT cells induced less IL‐6 than CAR‐T cells, suggesting reduced potential for CRS. 124

CONCLUSION AND FUTURE DIRECTIONS

BCMA CAR‐T has achieved hitherto unseen outcomes in heavily pretreated RRMM patients and in early relapse. Nevertheless, the prospect of long‐term cure remains elusive. Strategies to overcome resistance include γ‐secretase inhibition and arming the CAR‐T to inhibit PD‐L1 or TGF‐β. Antigen escape can be mitigated by multiantigen targeting; the most impressive results to date are for bispecific BCMA‐CD19 CAR‐T; however, many other potential target combinations require evaluation. 39

BCMA CAR‐T is the most expensive MM treatment to date. Ide‐cel and Cilta‐cel currently cost ~0.5 million USD per infusion. 125 Cost‐effectiveness will improve with prolonged PFS. As discussed, manufacturing time can be expedited to 22–36 h with FastCAR‐T platforms.

CAR‐T cell fitness, cost and availability can be improved with the use of allogeneic products. The early trial results for ALLO‐715 and UCARTCS1 reveal no GvHD but limited duration of response and significant risk of infection. 31 , 113 Further research is needed to optimise the safety and efficacy of allo‐CAR treatments.

The role of BCMA CAR‐T as a front‐line treatment in NDMM is yet to be elucidated. Ongoing trials include phase I KarMMa‐4, a single‐arm study of Ide‐cel following four cycles of induction therapy in patients with high‐risk NDMM ( NCT04196491 ). EM agine/CARTITUDE‐6 is a phase III randomised study comparing Cilta‐cel with ASCT in transplant‐eligible patients with NDMM, following induction with daratumumab, velcade, lenalidomide and dexamethasone (DVRd) ( NCT05257083 ). Meanwhile, CARTITUDE‐5 is a phase III randomised study comparing Cilta‐cel with Rd in patients with NDMM not intended for ASCT, following induction with VRd ( NCT04923893 ). CAR‐PRISM is a phase II trial investigating Cilta‐cel at an even earlier stage, in the setting of high‐risk smouldering MM ( NCT05767359 ).

Teclistamab is a BiTE targeting BCMA and CD3 and was NICE approved as fourth‐line treatment for RRMM in October 2024. 126 Talquetamab, a GPRC5DxCD3 BiTE, is FDA approved as fifth‐line treatment and has received a conditional marketing authorisation from the EMA. 127 , 128 Other BiTEs include elranatamab and linvoseltamab (targeting BCMAxCD3) and cevostamab (FcRH5xCD3). 7 With the simultaneous emergence of CAR‐T therapy and BiTEs, it is important to consider the ideal sequencing of these immunotherapies. BiTEs are cheaper, readily available ‘off‐the‐shelf’ and require less resources to manufacture and deliver than CAR‐T. Lymphodepletion is not required and toxicity is typically less severe, with lower frequency and grade of CRS and ICANS. These factors make BiTEs a promising option for frailer patients. However, clinical outcomes of BiTEs are inferior to CAR‐T. In the phase I–II MAJESTEC‐1 study of 165 RRMM patients, teclistamab achieved ORR of 63% and median PFS of 11.3 months after median of five previous LOT, comparing unfavourably with the majority of CAR‐T outcomes reviewed here. 129 While CAR‐T cells are transduced and expanded in vitro, BiTE efficacy is more reliant on underlying T‐cell fitness. BiTEs have a shorter half‐life and require ongoing treatment, prolonging the risks of cytopaenias and hypogammaglobulinaemia and necessitating long‐term monthly IVIG. For these reasons, it appears that CAR‐T should preferentially be delivered earlier than BiTEs in the treatment journey of fit patients. In the MagnestisMM studies, patients previously exposed to BCMA CAR‐T (28% of whom were refractory) who were treated with elranatamab had ORR of 52.8%, compared with 61% in CAR‐T naive patients. 130 , 131 There is, therefore, a role for BCMA x CD3 BiTEs in the setting of BCMA CAR‐T relapse; however, it is not clear how this approach would compare with targeting a different MM antigen with CAR‐T, BiTE or other therapy. Further studies are required to establish the optimal sequence of ASCT, CAR‐T, BiTEs and other treatments in MM. Notwithstanding, treatment decisions will ultimately be based on accessibility, with NICE approval awaited for BCMA CAR‐T.

Following approval of novel cellular immunotherapies, patient access presents significant new challenges. More Good Manufacturing Practice (GMP)‐approved facilities are required, together with increased resources to manage patients throughout the treatment journey. Training is required in supportive care and prompt diagnosis and management of CRS, ICANS and other toxicities. CAR‐T therapy is a rapidly developing field with potential to transform outcomes in RRMM, and healthcare centres need to rise to these challenges.

AUTHOR CONTRIBUTIONS

EM undertook literature review and wrote the manuscript; RB reviewed and edited the manuscript.

CONFLICT OF INTEREST STATEMENT

EM: None declared; RB: Received research funding from Servier and Allogene.

REFERENCES

1 Rajkumar SV , Dimopoulos MA , Palumbo A , Blade J , Merlini G , Mateos MV , et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma . Lancet Oncol . 2014 ; 15 ( 12 ): e538 – e548 . 25439696 10.1016/S1470-2045(14)70442-5

2 Rajkumar SV . Multiple myeloma: 2022 update on diagnosis, risk stratification, and management . Am J Hematol . 2022 ; 97 ( 8 ): 1086 – 1107 . 35560063 10.1002/ajh.26590 PMC9387011

3 Gandhi UH , Cornell RF , Lakshman A , Gahvari ZJ , McGehee E , Jagosky MH , et al. Outcomes of patients with multiple myeloma refractory to CD38‐targeted monoclonal antibody therapy . Leukemia . 2019 ; 33 ( 9 ): 2266 . 30858549 10.1038/s41375-019-0435-7 PMC6820050

4 Dhakal B , D'Souza A , Kleman A , Chhabra S , Mohan M , Hari P . Salvage second transplantation in relapsed multiple myeloma . Leukemia . 2021 ; 35 ( 4 ): 1214 . 32747684 10.1038/s41375-020-1005-8 PMC8020391

5 Schmidt WM , Perera ND , Buadi FK , Hayman SR , Kumar SK , Dispenzieri A , et al. Long‐term outcomes of allogeneic stem cell transplant in multiple myeloma . Blood Cancer J . 2023 ; 13 ( 1 ): 1 – 8 . 37591876 10.1038/s41408-023-00900-z PMC10435482

6 Kegyes D , Constantinescu C , Vrancken L , Rasche L , Gregoire C , Tigu B , et al. Patient selection for CAR T or BiTE therapy in multiple myeloma: which treatment for each patient? J Hematol Oncol . 2022 ; 15 ( 1 ): 1 – 27 . 10.1186/s13045-022-01296-2 35672793 PMC9171942

7 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 ( 1 ): 92 . 37537597 10.1186/s13045-023-01489-3 PMC10401827

8 Ravi G , Costa LJ . Bispecific T‐cell engagers for treatment of multiple myeloma . Am J Hematol . 2023 ; 98 ( S2 ): S13 – S21 . 10.1002/ajh.26628 35702871

9 van de Donk NWCJ , O'Neill C , de Ruijter MEM , Verkleij CPM , Zweegman S . T‐cell redirecting bispecific and trispecific antibodies in multiple myeloma beyond BCMA . Curr Opin Oncol . 2023 ; 35 ( 6 ): 601 . 37501530 10.1097/CCO.0000000000000983 PMC10566598

10 Haslauer T , Greil R , Zaborsky N , Geisberger R . CAR T‐cell therapy in hematological malignancies . Int J Mol Sci . 2021 ; 22 ( 16 ): 8996 . 34445701 10.3390/ijms22168996 PMC8396650

11 Hartmann J , Schüßler‐Lenz M , Bondanza A , Buchholz CJ . Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts . EMBO Mol Med . 2017 ; 9 ( 9 ): 1183 – 1197 . 10.15252/emmm.201607485 28765140 PMC5582407

12 Tomasik J , Jasiński M , Basak GW . Next generations of CAR‐T cells—new therapeutic opportunities in hematology? Front Immunol . 2022 ; 13 : 1034707 . 36389658 10.3389/fimmu.2022.1034707 PMC9650233

13 Blache U , Popp G , Dünkel A , Koehl U , Fricke S . Potential solutions for manufacture of CAR T cells in cancer immunotherapy . Nat Commun . 2022 ; 13 ( 1 ): 5225 . 36064867 10.1038/s41467-022-32866-0 PMC9445013

14 Sidana S , Hosoya H , Jensen A , Liu L , Goyal A , Hovanky V , et al. Bendamustine vs. fludarabine/cyclophosphamide lymphodepletion prior to BCMA CAR‐T cell therapy in multiple myeloma . Blood Cancer J . 2023 ; 13 ( 1 ): 158 . 37833271 10.1038/s41408-023-00929-0 PMC10576036

15 Graham C , Hewitson R , Pagliuca A , Benjamin R . Cancer immunotherapy with CAR‐T cells—behold the future . Clin Med . 2018 ; 18 ( 4 ): 324 . 10.7861/clinmedicine.18-4-324 PMC6334043 30072559

16 O'Connor BP , Raman VS , Erickson LD , Cook WJ , Weaver LK , Ahonen C , et al. BCMA is essential for the survival of long‐lived bone marrow plasma cells . J Exp Med . 2004 ; 199 ( 1 ): 91 – 97 . 10.1084/jem.20031330 14707116 PMC1887725

17 Hu D , Chen L , Yan D , Dong W , Chen M , Niu S , et al. Effectiveness and safety of anti‐BCMA chimeric antigen receptor T‐cell treatment in relapsed/refractory multiple myeloma: a comprehensive review and meta‐analysis of prospective clinical trials . Front Pharmacol . 2023 ; 14 : 1149138 . 37408760 10.3389/fphar.2023.1149138 PMC10318167

18 Raje N , Berdeja J , Lin Y , Siegel D , Jagannath S , Madduri D , et al. Anti‐BCMA CAR T‐cell therapy bb 2121 in relapsed or refractory multiple myeloma . N Engl J Med . 2019 ; 380 ( 18 ): 1726 . 31042825 10.1056/NEJMoa1817226 PMC8202968

19 Munshi NC , Anderson LD , Shah N , Madduri D , Berdeja J , Lonial S , et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma . N Engl J Med . 2021 ; 384 ( 8 ): 705 – 716 . 33626253 10.1056/NEJMoa2024850

20 Usmani S , Patel K , Hari P , Berdeja J , Alsina M , Vij R , et al. Kar MMa‐2 cohort 2a: efficacy and safety of idecabtagene vicleucel in clinical high‐risk multiple myeloma patients with early relapse after frontline autologous stem cell transplantation . Blood . 2022 ; 140 ( Supplement 1 ): 875 – 877 . 10.1182/blood-2022-162469 35709354

21 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 ( 11 ): 1002 – 1014 . 10.1056/NEJMoa2213614 36762851

22 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 ( 10297 ): 314 – 324 . 34175021 10.1016/S0140-6736(21)00933-8

23 Van de Donk NWCJ , Delforge M , Agha M , Cohen AD , Cohen YC , Hillengass J , et al. CARTITUDE‐2: efficacy and safety of ciltacabtagene autoleucel, a B‐cell maturation antigen (BCMA)‐directed chimeric antigen receptor T‐cell therapy, in patients with multiple myeloma and early relapse after initial therapy . Blood . 2021 ; 138 ( Supplement 1 ): 2910 . 10.1182/blood-2021-146074

24 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 ( 4 ): 335 – 347 . 10.1056/NEJMoa2303379 37272512

25 Magen H , Fried S , Itzhaki O , Shem‐Tov N , Danylesko I , Yerushalmi R , et al. P 889: point‐of‐care anti‐BCMA CAR T‐cell therapy induces encouraging response rates in high‐risk relapse/refractory multiple myeloma . Hemasphere . 2023 ; 7 ( S3 ): e94543ab .

26 Mikkilineni L , Manasanch EE , Natrakul D , Weissler K , Brudno JN , Mann J , et al. T cells expressing a fully‐human anti‐BCMA chimeric antigen receptor with a heavy‐chain‐only antigen‐recognition domain exhibit rapid and durable activity against multiple myeloma . Blood . 2022 ; 140 ( Supplement 1 ): 7433 – 7434 . 10.1182/blood-2022-159156

27 Li C , Wang D , Song Y , Huang H , Li J , Chen B , et al. CT103A, a novel fully human BCMA‐targeting CAR‐T cells, in patients with relapsed/refractory multiple myeloma: updated results of phase 1b/2 study (FUMANBA‐1) . J Clin Oncol . 2023 ; 41 ( 16_suppl ): 8025 .

28 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 ARI 0002h, 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 ( 8 ): 913 – 924 . 37414060 10.1016/S1470-2045(23)00222-X

29 Chen W , Fu C , Fang B , Liang A , Xia Z , He Y , et al. Phase II study of fully human BCMA‐targeting CAR‐T cells (Zevorcabtagene autoleucel) in patients with relapsed/refractory multiple myeloma . Blood . 2022 ; 140 ( Supplement 1 ): 4564 – 4565 . 10.1182/blood-2022-168610 PMC12482220 41029877

30 Frigault M , Rosenblatt J , Dhakal B , Raje N , Cook D , Gaballa MR , et al. Phase 1 study of CART‐Ddbcma for the treatment of subjects with relapsed and/or refractory multiple myeloma . Blood . 2022 ; 140 ( Supplement 1 ): 7439 – 7440 . 10.1182/blood-2022-163827 PMC9989524 35468618

31 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 ( 2 ): 422 – 429 . 36690811 10.1038/s41591-022-02182-7

32 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 ( 13 ): 1196 . 36170501 10.1056/NEJMoa2209900 PMC10309537

33 Bal S , Kocoglu MH , Nadeem O , Htut M , Gregory T , Anderson LD , et al. Clinical activity of BMS‐986393 (CC‐95266), a G protein‐coupled receptor class C group 5 member D (GPRC5D)‐targeted chimeric antigen receptor (CAR) T cell therapy, in patients with relapsed and/or refractory (R/R) multiple myeloma (MM): first results from a phase 1, multicenter, open‐label study . Blood . 2022 ; 140 ( Supplement 1 ): 883 – 885 . 10.1182/blood-2022-162395

34 Zhang M , Wei G , Zhou L , Zhou J , Chen S , Zhang W , et al. GPRC5D CAR T cells (Ori CAR‐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 ( 2 ): e107 – e116 . 36725117 10.1016/S2352-3026(22)00372-6

35 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 ( 14 ): 2583 . 36881785 10.1200/JCO.22.01824 PMC10414745

36 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 ( 10 ): e751 – e760 . 39059405 10.1016/S2352-3026(24)00176-5

37 Shi X , Yan L , Shang J , Kang L , Yan Z , Jin S , et al. Anti‐CD19 and anti‐BCMA CAR T cell therapy followed by lenalidomide maintenance after autologous stem‐cell transplantation for high‐risk newly diagnosed multiple myeloma . Am J Hematol . 2022 ; 97 ( 5 ): 537 – 547 . 10.1002/ajh.26486 35114022

38 Garfall AL , Cohen AD , Susanibar‐Adaniya SP , Hwang WT , Vogl DT , Waxman AJ , et al. Anti‐BCMA/CD19 CAR T cells with early immunomodulatory maintenance for multiple myeloma responding to initial or later‐line therapy . Blood Cancer Discov . 2023 ; 4 ( 2 ): 118 – 133 . 10.1158/2643-3230.BCD-22-0074 36413381 PMC9975770

39 Du J , Fu WJ , Jiang H , Dong B , Gao L , Liu L , et al. Updated results of a phase I, open‐label study of BCMA/CD19 dual‐targeting fast CAR‐T GC012F for patients with relapsed/refractory multiple myeloma (RRMM) . J Clin Oncol . 2023 ; 41 ( 16_suppl ): 8005 .

40 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 . 37848634 10.1038/s41375-023-02065-x PMC10776387

41 Lee L , Lim WC , Galas‐Filipowicz D , Fung K , Taylor J , Patel D , et al. Original research: 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 ( 6 ): 6699 . 10.1136/jitc-2023-006699 PMC10314698 37399355

42 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 ( 1 ): 1 – 17 . 10.1186/s13045-021-01170-7 34627333 PMC8501733

43 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 ( 1 ): 2 . 34980210 10.1186/s13046-021-02214-z PMC8722124

44 Zhang H , Liu M , Xiao X , Lv H , Jiang Y , Li X , et al. A combination of humanized anti‐BCMA and murine anti‐CD38 CAR‐T cell therapy in patients with relapsed or refractory multiple myeloma . Leuk Lymphoma . 2022 ; 63 ( 6 ): 1418 – 1427 . 10.1080/10428194.2022.2030476 35105265

45 U.S. Department of Health and Human Services . Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 . 2017 .

46 Lee DW , Santomasso BD , Locke FL , Ghobadi A , Turtle CJ , Brudno JN , et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells . Biol Blood Marrow Transplant . 2019 ; 25 ( 4 ): 625 – 638 . 30592986 10.1016/j.bbmt.2018.12.758 PMC12180426

47 Hansen DK , Sidana S , Peres LC , Colin Leitzinger C , Shune L , Shrewsbury A , et al. Idecabtagene vicleucel for relapsed/refractory multiple myeloma: real‐world experience from the myeloma CAR T consortium . J Clin Oncol . 2023 ; 41 ( 11 ): 2087 – 2097 . 36623248 10.1200/JCO.22.01365 PMC10082273

48 Surbhi Sidana M , Ahmed N , Akhtar OS , Heim M , Brazauskas R , Hansen DK , et al. Real world outcomes with idecabtagene vicleucel (Ide‐Cel) CAR‐T cell therapy for relapsed/refractory multiple myeloma . Blood . 2023 ; 142 ( Supplement 1 ): 1027 . 10.1182/blood-2023-181762

49 Hashmi H , Hansen DK , Peres LC , Castaneda Puglianini OA , Freeman CL , De Avila G , et al. Factors associated with refractoriness or early progression after idecabtagene vicleucel (Ide‐cel) in patients with relapsed/refractory multiple myeloma (RRMM): U.S. myeloma CAR T consortium real world experience . Blood . 2022 ; 140 ( Supplement 1 ): 4642 – 4645 . 10.1182/blood-2022-164828

50 Chekol Abebe E , Yibeltal Shiferaw M , Tadele Admasu F , Asmamaw DT . Ciltacabtagene autoleucel: the second anti‐BCMA CAR T‐cell therapeutic armamentarium of relapsed or refractory multiple myeloma . Front Immunol . 2022 ; 13 : 991092 . 36119032 10.3389/fimmu.2022.991092 PMC9479060

51 Lin Y , Martin TG , Usmani SZ , Berdeja JG , Jakubowiak AJ , Agha ME , et al. CARTITUDE‐1 final results: phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma . J Clin Oncol . 2023 ; 41 ( 16_suppl ): 8009 . 10.1200/JCO20234116_suppl8009

52 Sidana S , Patel KK , Peres LC , Bansal R , Kocoglu MH , Shune L , et al. Safety and efficacy of standard of care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma . Blood . 2024 . 10.1182/blood.2024025945 39365257

53 Martin T , Usmani SZ , Schecter JM , Roccia T , Jackson CC , Deraedt W , et al. Updated results from a matching‐adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE‐1 versus idecabtagene vicleucel in Kar MMa for the treatment of patients with relapsed or refractory multiple myeloma . Curr Med Res Opin . 2023 ; 39 ( 1 ): 81 – 89 . 36271807 10.1080/03007995.2022.2139052

54 First cell‐based gene therapy to treat adult patients with multiple myeloma|European Medicines Agency [Internet] . 2024 . Available from: https://www.ema.europa.eu/en/news/first‐cell‐based‐gene‐therapy‐treat‐adult‐patients‐multiple‐myeloma

55 New gene therapy to treat adult patients with multiple myeloma|European Medicines Agency [Internet] . 2024 . Available from: https://www.ema.europa.eu/en/news/new‐gene‐therapy‐treat‐adult‐patients‐multiple‐myeloma

56 Johnson & Johnson . U.S. FDA Oncologic Drugs Advisory Committee recommends CARVYKTI® (ciltacabtagene autoleucel) for the earlier treatment of patients with relapsed or refractory multiple myeloma . 2024 . Available from: https://www.jnj.com/media‐center/press‐releases/u‐s‐fda‐oncologic‐drugs‐advisory‐committee‐recommends‐carvykti‐ciltacabtagene‐autoleucel‐for‐the‐earlier‐treatment‐of‐patients‐with‐relapsed‐or‐refractory‐multiple‐myeloma

57 CARVYKTI®▼ . (ciltacabtagene autoleucel; cilta‐cel) is the first BCMA‐targeted treatment approved by the European Commission for patients with relapsed and refractory multiple myeloma who have received at least one prior line of therapy [Internet] . 2024 . Available from: https://www.jnj.com/media‐center/press‐releases/carvykti‐ciltacabtagene‐autoleucel‐cilta‐cel‐is‐the‐first‐bcma‐targeted‐treatment‐approved‐by‐the‐european‐commission‐for‐patients‐with‐relapsed‐and‐refractory‐multiple‐myeloma‐who‐have‐received‐at‐least‐one‐prior‐line‐of‐therapy

58 Bristol Myers Squibb . U.S. FDA Approves Bristol Myers Squibb and 2seventy bio's Abecma for Triple‐Class Exposed Relapsed or Refractory Multiple Myeloma After Two Prior Lines of Therapy . 2024 . Available from: https://news.bms.com/news/corporate‐financial/2024/U.S.‐FDA‐Approves‐Bristol‐Myers‐Squibb‐and‐2seventy‐bios‐Abecma‐for‐Triple‐Class‐Exposed‐Relapsed‐or‐Refractory‐Multiple‐Myeloma‐After‐Two‐Prior‐Lines‐of‐Therapy/default.aspx

59 Rodriguez‐Otero P , van de Donk NWCJ , Pillarisetti K , Cornax I , Vishwamitra D , Gray K , et al. GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review . Blood Cancer J . 2024 ; 14 ( 1 ): 1 – 13 . 38307865 10.1038/s41408-023-00966-9 PMC10837198

60 Bhutani M , Usmani SZ . GPRC5D: the next frontier for immunotherapy in multiple myeloma . The Hematologist . 2023 ; 20 ( 1 ). 10.1182/hem.V20.1.202314

61 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 . 10.1038/s41408-019-0178-8 30718503 PMC6362066

62 Elkins K , Zheng B , Go M , Slaga D , Du C , Scales SJ , et al. FcRL5 as a target of antibody‐drug conjugates for the treatment of multiple myeloma . Mol Cancer Ther . 2023 ; 11 ( 10 ): 2222 – 2232 . 10.1158/1535-7163.MCT-12-0087 22807577

63 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 ( 1 ): 3642 . 37339964 10.1038/s41467-023-39395-4 PMC10282100

64 Paiva B , Puig N , Cedena MT , De Jong BG , Ruiz Y , Rapado I , et al. Differentiation stage of myeloma plasma cells: biological and clinical significance . Leukemia . 2017 ; 31 ( 2 ): 382 . 27479184 10.1038/leu.2016.211 PMC5439510

65 Lee LSH , Lim WC , Mactier C , Dias Alves Pinto J , Pereira V , Vaughan M , et al. Development of a phase 1 study evaluating the activity of modular CAR T for multiple myeloma (MCARTY) targeting BCMA and CD19 for improved persistence . Blood . 2023 ; 142 ( Suppl 1 ): 350 . 10.1182/BLOOD-2023-185085

66 Roex G , Campillo‐Davo D , Flumens D , Shaw PAG , Krekelbergh L , De Reu H , et al. Two for one: targeting BCMA and CD19 in B‐cell malignancies with off‐the‐shelf dual‐CAR NK‐92 cells . J Transl Med . 2022 ; 20 ( 1 ): 124 . 35287669 10.1186/s12967-022-03326-6 PMC8919645

67 Chu E , Wu J , Kang SS , Kang Y . SLAMF7 as a promising immunotherapeutic target in multiple myeloma treatments . Curr Oncol . 2023 ; 30 ( 9 ): 7891 . 37754488 10.3390/curroncol30090573 PMC10529721

68 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 ( 10 ): 1512 – 1520 . 21606160 10.3324/haematol.2010.036814 PMC3186313

69 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 ( 1 ): 798 . 32034142 10.1038/s41467-020-14619-z PMC7005855

70 Rodríguez‐Lobato LG , Cardus O , Mañe‐Pujol J , Battram AM , Pérez‐Amill L , Calderón H , et al. Bicistronic CAR T cell against CD229 and BCMA effectively controls multiple myeloma . Blood . 2022 ; 140 ( Supplement 1 ): 10281 – 10282 . 10.1182/blood-2022-166764

71 Ito D , Kumanogoh A . The role of Sema 4A in angiogenesis, immune responses, carcinogenesis, and retinal systems . Cell Adhes Migr . 2016 ; 10 ( 6 ): 692 – 699 . 10.1080/19336918.2016.1215785 PMC5160039 27736304

72 Anderson GSF , Ballester‐Beltran J , Giotopoulos G , Guerrero JA , Surget S , Williamson JC , et al. Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma . Blood . 2022 ; 139 ( 16 ): 2471 – 2482 . 10.1182/blood.2021015161 35134130 PMC11022854

73 Roy JP , Anderson GSF , Walker I , Chapman MA . Development of the first SEMA4A CAR‐T cell targeting multiple myeloma . Blood . 2022 ; 140 ( Supplement 1 ): 9961 – 9962 . 10.1182/blood-2022-168968

74 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 ( 2 ): 689 – 694 . 10.1182/blood-2003-06-2043 14512299

75 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 ( 6 ): 6699 . 10.1136/jitc-2023-006699 PMC10314698 37399355

76 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 ( 21 ): 3248 – 3260 . 10.1182/bloodadvances.2019000703 31698455 PMC6855119

77 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 ( 20 ): 4219 – 4229 . 10.1158/1078-0432.CCR-23-0132 37527004

78 Thibaud S , Mia MB , Van Oekelen O , Mouhieddine TH , Schaniel C , Ghodke‐Puranik Y , et al. Comprehensive characterization of prolonged unexplained cytopenias in relapsed/refractory multiple myeloma patients following BCMA‐directed CAR‐T cell therapy . Blood . 2022 ; 140 ( Supplement 1 ): 614 – 616 . 10.1182/blood-2022-165646

79 Kambhampati S , Sheng Y , Huang CY , Bylsma S , Lo M , Kennedy V , et al. Infectious complications in patients with relapsed refractory multiple myeloma after BCMA CAR T‐cell therapy . Blood Adv . 2022 ; 6 ( 7 ): 2045 . 34543400 10.1182/bloodadvances.2020004079 PMC9006279

80 Lancman G , Parsa K , Kotlarz K , Avery L , Lurie A , Lieberman‐Cribbin A , et al. IVIg use associated with ten‐fold reduction of serious infections in multiple myeloma patients treated with anti‐BCMA bispecific antibodies . Blood Cancer Discov . 2023 ; 4 : 450 – 451 . 10.1158/2643-3230.BCD-23-0049 PMC10618720 37769148

81 Cohen AD , Parekh S , Santomasso BD , Pérez‐Larraya JG , van de Donk NWCJ , Arnulf B , et al. Incidence and management of CAR‐T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies . Blood Cancer J . 2022 ; 12 ( 2 ): 32 . 35210399 10.1038/s41408-022-00629-1 PMC8873238

82 Graham CE , Lee WH , Wiggin HR , Supper VM , Leick MB , Birocchi F , et al. Chemotherapy‐induced reversal of ciltacabtagene autoleucel‐associated movement and neurocognitive toxicity . Blood . 2023 ; 142 ( 14 ): 1248 – 1252 . 37467494 10.1182/blood.2023021429 PMC10579042

83 van de Donk NWCJ , Themeli M , Usmani SZ . Determinants of response and mechanisms of resistance of CAR T‐cell therapy in multiple myeloma . Blood Cancer Discov . 2021 ; 2 : 302 – 320 . 34386775 10.1158/2643-3230.BCD-20-0227 PMC8357299

84 Lemoine J , Ruella M , Houot R . Born to survive: how cancer cells resist CAR T cell therapy . J Hematol Oncol . 2021 ; 14 ( 1 ): 199 . 34809678 10.1186/s13045-021-01209-9 PMC8609883

85 Da Vià MC , Dietrich O , Truger M , Arampatzi P , Duell J , Heidemeier A , et al. Homozygous BCMA gene deletion in response to anti‐BCMA CAR T cells in a patient with multiple myeloma . Nat Med . 2021 ; 27 ( 4 ): 616 – 619 . 33619368 10.1038/s41591-021-01245-5

86 Samur MK , Fulciniti M , Aktas Samur A , Bazarbachi AH , Tai YT , Prabhala R , et al. Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma . Nat Commun . 2021 ; 12 ( 1 ): 868 . 33558511 10.1038/s41467-021-21177-5 PMC7870932

87 Lee H , Ahn S , Maity R , Leblay N , Ziccheddu B , Truger M , et al. Mechanisms of antigen escape from BCMA‐ or GPRC5D‐targeted immunotherapies in multiple myeloma . Nat Med . 2023 ; 29 ( 9 ): 2295 – 2306 . 37653344 10.1038/s41591-023-02491-5 PMC10504087

88 Perica K , Nataraj S , Sjojstrand ML , Nagel K , Pavkovic E , Payson E , et al. Low target antigen expression mediates resistance to BCMA CAR T cell therapy . Blood . 2023 ; 142 ( Supplement 1 ): 2124 . 10.1182/blood-2023-178954 38095919

89 Pont MJ , Hill T , Cole GO , Abbott JJ , Kelliher J , Salter AI , et al. γ‐Secretase inhibition increases efficacy of BCMA‐specific chimeric antigen receptor T cells in multiple myeloma . Blood . 2019 ; 134 ( 19 ): 1585 . 31558469 10.1182/blood.2019000050 PMC6871311

90 Cowan AJ , Pont M , Sather BD , Turtle CJ , Till BG , Nagengast AM , et al. Efficacy and safety of fully human BCMA CAR T cells in combination with a gamma secretase inhibitor to increase bcma surface expression in patients with relapsed or refractory multiple myeloma . Blood . 2019 ; 134 ( Supplement_1 ): 204 . 10.1182/blood-2019-129405

91 Derrien J , Gastineau S , Frigout A , Giordano N , Cherkaoui M , Gaborit V , et al. Acquired resistance to a GPRC5D‐directed T‐cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation . Nat Can . 2023 ; 4 ( 11 ): 1536 – 1543 . 10.1038/s43018-023-00625-9 37653140

92 Zhao Z , Shi L , Zhang W , Han J , Zhang S , Fu Z , et al. CRISPR knock out of programmed cell death protein 1 enhances anti‐tumor activity of cytotoxic T lymphocytes . Oncotarget . 2018 ; 9 ( 4 ): 5208 . 29435173 10.18632/oncotarget.23730 PMC5797044

93 Yuti P , Sawasdee N , Natungnuy K , Rujirachaivej P , Luangwattananun P , Sujjitjoon J , et al. Enhanced antitumor efficacy, proliferative capacity, and alleviation of T cell exhaustion by fifth‐generation chimeric antigen receptor T cells targeting B cell maturation antigen in multiple myeloma . Biomed Pharmacother . 2023 ; 1 ( 168 ): 115691 . 10.1016/j.biopha.2023.115691 37844355

94 Melnekoff DT , Ghodke‐Puranik Y , Van Oekelen O , Aleman A , Upadhyaya B , Sebra R , et al. Single‐cell profiling reveals contribution of tumor extrinsic and intrinsic factors to BCMA‐targeted CAR‐T cell efficacy in multiple myeloma . Blood . 2021 ; 138 ( Supplement 1 ): 326 . 10.1182/blood-2021-150923

95 Van Oekelen O , Nath K , Mouhieddine TH , Farzana T , Aleman A , Melnekoff DT , et al. Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA‐directed CAR T therapy . Blood . 2023 ; 141 ( 7 ): 756 – 765 . 10.1182/blood.2022017848 36327160 PMC10082354

96 Larson RC , Kann MC , Bailey SR , Haradhvala NJ , Llopis PM , Bouffard AA , et al. CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours . Nature . 2022 ; 604 ( 7906 ): 563 – 570 . 35418687 10.1038/s41586-022-04585-5

97 Valkenburg KC , De Groot AE , Pienta KJ . Targeting the tumour stroma to improve cancer therapy . Nat Rev Clin Oncol . 2018 ; 15 ( 6 ): 366 . 29651130 10.1038/s41571-018-0007-1 PMC5960434

98 Kankeu Fonkoua LA , Sirpilla O , Sakemura R , Siegler EL . Kenderian SS. CAR T cell therapy and the tumor microenvironment: current challenges and opportunities . Mol Ther Oncolytics . 2022 ; 25 : 69 . 35434273 10.1016/j.omto.2022.03.009 PMC8980704

99 Alabanza LM , Xiong Y , Vu B , Webster B , Wu D , Hu P , et al. Armored BCMA CAR T cells eliminate multiple myeloma and are resistant to the suppressive effects of TGF‐β . Front Immunol . 2022 ; 13 : 832645 . 35222421 10.3389/fimmu.2022.832645 PMC8863610

100 Garfall AL , Dancy EK , Cohen AD , Hwang WT , Fraietta JA , Davis MM , et al. T‐cell phenotypes associated with effective CAR T‐cell therapy in postinduction vs relapsed multiple myeloma . Blood Adv . 2019 ; 3 ( 19 ): 2812 . 31575532 10.1182/bloodadvances.2019000600 PMC6784521

101 Leblay N , Maity R , Barakat E , McCulloch S , Duggan P , Jimenez‐Zepeda V , et al. Cite‐Seq profiling of T cells in multiple myeloma patients undergoing BCMA targeting CAR‐T or bites immunotherapy . Blood . 2020 ; 136 ( Supplement 1 ): 11 – 12 . 10.1182/blood-2020-137650 32276273

102 Dubnikov Sharon T , Assayag M , Avni B , Kfir‐Erenfeld S , Lebel E , Gatt ME , et al. Early lymphocyte collection for anti‐CD19 CART production improves T‐cell fitness in patients with relapsed/refractory diffuse large B‐cell lymphoma . Br J Haematol . 2023 ; 202 ( 1 ): 74 – 85 . 10.1111/bjh.18816 37070396

103 Long AH , Haso WM , Shern JF , Wanhainen KM , Murgai M , Ingaramo M , et al. 4‐1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors . Nat Med . 2015 ; 21 ( 6 ): 581 . 25939063 10.1038/nm.3838 PMC4458184

104 Raje NS , Shah N , Jagannath S , Kaufman JL , Siegel DS , Munshi NC , et al. Updated clinical and correlative results from the phase I CRB‐402 study of the BCMA‐targeted CAR T cell therapy bb 21217 in patients with relapsed and refractory multiple myeloma . Blood . 2021 ; 138 ( Supplement 1 ): 548 .

105 Works M , Soni N , Hauskins C , Sierra C , Baturevych A , Jones JC , et al. Anti–B‐cell maturation antigen chimeric antigen receptor T cell function against multiple myeloma is enhanced in the presence of lenalidomide . Mol Cancer Ther . 2019 ; 18 ( 12 ): 2246 – 2257 . 10.1158/1535-7163.MCT-18-1146 31395689

106 Zhao G , Wei R , Feng L , Wu Y , He F , Xiao M , et al. Lenalidomide enhances the efficacy of anti‐BCMA CAR‐T treatment in relapsed/refractory multiple myeloma: a case report and revies of the literature . Cancer Immunol Immunother . 2022 ; 71 ( 1 ): 39 . 34003300 10.1007/s00262-021-02959-8 PMC8738460

107 Wachsmann TLA , Meeuwsen MH , Remst DFG , Buchner K , Wouters AK , Hagedoorn RS , et al. Combining BCMA‐targeting CAR T cells with TCR‐engineered T‐cell therapy to prevent immune escape of multiple myeloma . Blood Adv . 2023 ; 7 ( 20 ): 6178 . 37567150 10.1182/bloodadvances.2023010410 PMC10582830

108 Depil S , Duchateau P , Grupp SA , Mufti G , Poirot L . ‘Off‐the‐shelf’ allogeneic CAR T cells: development and challenges . Nat Rev Drug Discov . 2020 ; 19 ( 3 ): 185 – 199 . 31900462 10.1038/s41573-019-0051-2

109 Metelo AM , Jozwik A , Luong LA , Dominey‐Foy D , Graham C , Attwood C , et al. Allogeneic anti‐BCMA CAR T cells are superior to multiple myeloma‐derived CAR T cells in preclinical studies and may be combined with gamma secretase inhibitors . Cancer Res Commun . 2022 ; 2 ( 3 ): 158 . 36874402 10.1158/2767-9764.CRC-21-0157 PMC9980918

110 Rådestad E , Sundin M , Törlén J , Thunberg S , Önfelt B , Ljungman P , et al. Individualization of hematopoietic stem cell transplantation using alpha/beta T‐cell depletion . Front Immunol . 2019 ; 10 ( February ): 189 . 30804948 10.3389/fimmu.2019.00189 PMC6378311

111 Sommer C , Boldajipour B , Kuo TC , Bentley T , Sutton J , Chen A , et al. Preclinical evaluation of allogeneic CAR T cells targeting BCMA for the treatment of multiple myeloma . Mol Ther . 2019 ; 27 ( 6 ): 1126 . 31005597 10.1016/j.ymthe.2019.04.001 PMC6554542

112 Korst CLBM , Bruins WSC , Cosovic M , Verkleij CPM , Twickler I , Le Clerre D , et al. Preclinical Activity of allogeneic CS1‐specific CAR T‐cells (UCARTCS1) in multiple myeloma . Blood . 2022 ; 140 : 4215 – 4216 . 10.1182/blood-2022-157950 PMC11284884 39060023

113 Patel K , Bharathan M , Esteva FJ , Siegel D , Rossi A , Frattini MG , et al. UCARTCS1A, an allogeneic CAR T‐cell therapy targeting CS1 in patients with relapsed/refractory multiple myeloma (RRMM): preliminary translational results from a first‐in‐human phase I trial (MELANI‐01) . Mol Ther . 2021 ; 29 ( 4S1 ): 59 – 60 .

114 Kinder J , Estrada CA , Granger B , O'Rourke A , Liang O , Lampano A , et al. Development of a novel, allogeneic GPRC5D‐directed CAR for treatment of multiple myeloma patients . Blood . 2023 ; 142 ( Supplement 1 ): 3290 . 10.1182/blood-2023-189665

115 Du Z , Zhu S , Zhang X , Gong Z , Wang S . Non‐conventional allogeneic anti‐BCMA chimeric antigen receptor‐based immune cell therapies for multiple myeloma treatment . Cancers (Basel) . 2023 ; 15 ( 3 ): 567 . 36765526 10.3390/cancers15030567 PMC9913487

116 Zhang X , Ng YY , Du Z , Li Z , Chen C , Xiao L , et al. Vγ9Vδ2 T cells expressing a BCMA—Specific chimeric antigen receptor inhibit multiple myeloma xenograft growth . PLoS One . 2022 ; 17 ( 6 ): e0267475 . 35709135 10.1371/journal.pone.0267475 PMC9202950

117 Clara JA , Childs RW . Harnessing natural killer cells for the treatment of multiple myeloma . Semin Oncol . 2022 ; 49 ( 1 ): 69 – 85 . 35125241 10.1053/j.seminoncol.2022.01.004

118 Ng YY , Du Z , Zhang X , Chng WJ , Wang S . CXCR4 and anti‐BCMA CAR co‐modified natural killer cells suppress multiple myeloma progression in a xenograft mouse model . Cancer Gene Ther . 2021 ; 29 ( 5 ): 475 – 483 . 34471234 10.1038/s41417-021-00365-x

119 Cichocki F , Bjordahl R , Goodridge JP , Mahmood S , Gaidarova S , Abujarour R , et al. Quadruple gene‐engineered natural killer cells enable multi‐antigen targeting for durable antitumor activity against multiple myeloma . Nat Commun . 2022 ; 13 ( 1 ): 1 – 15 . 36446823 10.1038/s41467-022-35127-2 PMC9709157

120 Chu J , Deng Y , Benson DM , He S , Hughes T , Zhang J , et al. CS1‐specific chimeric antigen receptor (CAR)‐engineered natural killer cells enhance in vitro and in vivo anti‐tumor activity against human multiple myeloma . Leukemia . 2014 ; 28 ( 4 ): 917 . 24067492 10.1038/leu.2013.279 PMC3967004

121 Cao Z , Yang C , Wang Y , Wang C , Wang Q , Ye G , et al. Allogeneic CAR‐NK cell therapy targeting both BCMA and GPRC5D for the treatment of multiple myeloma . Blood . 2022 ; 140 ( Supplement 1 ): 7378 . 10.1182/blood-2022-159289

122 Stikvoort A , Van Der Schans J , Sarkar S , Poels R , Ruiter R , Naik J , et al. CD38‐specific chimeric antigen receptor expressing natural killer KHYG‐1 cells: a proof of concept for an “off the shelf” therapy for multiple myeloma . Hemasphere . 2021 ; 5 ( 7 ): E596 . 34131635 10.1097/HS9.0000000000000596 PMC8196092

123 Poels R , Drent E , Lameris R , Katsarou A , Themeli M , van der Vliet HJ , et al. Preclinical evaluation of invariant natural killer T cells modified with CD38 or BCMA chimeric antigen receptors for multiple myeloma . Int J Mol Sci . 2021 ; 22 ( 3 ): 1 – 16 . 10.3390/ijms22031096 PMC7865760 33499253

124 O'Neal J , Cooper ML , Ritchey JK , Gladney SW , Niswonger J , Gonzalez LS , et al. Anti‐myeloma efficacy of CAR‐iNKT is enhanced with a long‐acting IL‐7, rh IL‐7‐hy Fc . Blood Adv . 2023 ; 7 ( 20 ): 6009 – 6022 . 10.1182/bloodadvances.2023010032 37399471 PMC10582278

125 Drug Price Information [Internet] . 2023 . Available from: https://www.drugs.com/price‐guide/

126 Final draft guidance | Project documents | Teclistamab for treating relapsed and refractory multiple myeloma after 3 or more treatments (Review of TA869) [ID6333] | Guidance | NICE .

127 Mullard A . FDA approves first GPRC5D × CD3‐targeted bispecific for multiple myeloma . Nat Rev Drug Discov . 2023 ; 22 ( 10 ): 775 . 10.1038/d41573-023-00150-5 37673980

128 EMA Recommends Granting a Conditional Marketing Authorisation… [Internet] . 2024 . Available from: https://www.esmo.org/oncology‐news/ema‐recommends‐granting‐a‐conditional‐marketing‐authorisation‐for‐talquetamab

129 Moreau P , Garfall AL , van de Donk NWCJ , Nahi H , San‐Miguel JF , Oriol A , et al. Teclistamab in relapsed or refractory multiple myeloma . N Engl J Med . 2022 ; 387 ( 6 ): 495 – 505 . 10.1056/NEJMoa2203478 35661166 PMC10587778

130 Nooka AK , Lesokhin AM , Mohty M , Niesvizky R , Maisel C , Arnulf B , et al. Efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma (RRMM) and prior B‐cell maturation antigen (BCMA)‐directed therapies: a pooled analysis from Magnetis MM studies . J Clin Oncol . 2023 ; 41 ( 16_suppl ): 8008 . 10.1200/JCO.2023.41

131 Lesokhin AM , Tomasson MH , Arnulf B , Bahlis NJ , Miles Prince H , Niesvizky R , et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 Magnetis MM‐3 trial results . Nat Med . 2023 ; 29 ( 9 ): 2259 – 2267 . 37582952 10.1038/s41591-023-02528-9 PMC10504075