Background: Recent advancements in cellular therapies, particularly chimeric antigen receptor T-cells (CAR-T) and T-cell-engaging bispecific antibodies have significantly altered the therapeutic landscape for multiple myeloma. There are two US FDA approved CAR-T products targeting BCMA available for commercial use at this time. Though these innovative therapies have demonstrated considerable efficacy in heavily pretreated multiple myeloma patients, many challenges remain, including accessibility, potential toxicities such as cytokine release syndrome and neurotoxicity and development of resistance through targeted antigen loss and T-cell exhaustion and various other mechanisms. CRISPR edited allogeneic CAR-T cells, CAR-NK cells, and structural makeover of autologous CART with safety switches are being studied to address current limitations in cellular therapy. Additionally, newer target antigens such as GPRC5D, FcRH5, armored CAR-T cells that resist immunosuppressive cytokines such as TGF-β are being investigated. Summary: This review summarizes safety and efficacy of currently available CART, discusses challenges with these therapies, and ongoing research efforts aimed at addressing resistance, mitigate treatment-related toxicities, and refining for broader applicability and prolonged efficacy. Key Messages: CART cell therapy has shown significant benefit in treatment of multiple myeloma. Many challenges persist. Novel strategies with structural modifications are being incorporated to overcome the limitations.

Multiple myeloma (MM) is characterized by malignant proliferation of plasma cells in the bone marrow resulting in end organ damage and significant morbidity and mortality over time. Beyond immunomodulatory agents (IMiD), proteasome inhibitors (PIs), and CD38 targeting monoclonal antibodies (CD38 mAbs), in last several years, chimeric antigen receptor T-cells (CAR-T) and Bispecific antibodies targeting B-cell maturation agent (BCMA) and (G Protein-coupled Receptor, class C, group 5, member D (GPRC5D) have significantly improved outcomes in clinical trials leading to food and drug administration (FDA) approval of two CART products and two bsAbs targeting BCMA and one bsAb targeting GPRC5D as of August 2024. Many newer targets and more effective cellular therapeutic agents are currently being explored in clinical trials. In this paper, we review currently approved CART cell therapies in MM, their limitations, resistant mechanisms and novel approaches to overcome them and newer targets in MM.

CARs are fusion proteins engineered to therapeutically target-specific antigens expressed on various tumor cells. Since the development of the first chimeric receptor in 1989 [1], the technology has evolved canonically over the last 2 decades. There are three essential components of CAR structure, the extracellular, transmembrane, and intracellular domains (Fig. 1). The extracellular domain consists of a fusion protein comprising of light and heavy chain, the single chain variable fragment (scFv) facilitating antigen binding. The intracellular domain, evolved over several generations, encompasses primary and secondary costimulatory domains that help in activation of T cells [2].

Fig. 1.

Structure of CAR-T cells – evolution over five generations: this figure illustrates the evolution of CAR-T-cell designs from the first to fifth generation. The three essential components of CAR structure are, the extracellular, transmembrane, and the intracellular domains. The extracellular antigen recognition domain consists of a fusion protein comprising of light and heavy chain, the single chain variable fragment (scFv). This domain is connected to the lipidic transmembrane domain through a spacer. The extracellular scFv facilitates attachment of CART cells to specific target cells. The intracellular domain encompasses primary and secondary costimulatory domains that help in activation of T cells [2]. The intracellular domain plays an important role in signaling T lymphocytes, facilitating killing of target malignant cells independent of human leukocyte antigen (HLA) [3]. The intracellular signaling domains evolved with each generation of CART. The first-generation CAR-T cell incorporates a CD3ζ intracellular domain, responsible for initiating T-cell activation. This lacks co-stimulatory domain limiting their efficacy. In the second generation, a co-stimulatory domain (such as CD28 or 4-1BB) is added to enhance activation, proliferation, and persistence. The third-generation CART includes two co-stimulatory domains, amplifying the strength and durability of the T-cell response. Fourth generation CAR-T cells, known as T-cells Redirected for Universal Cytokine Killing (TRUCKs), can secrete cytokines such as IL-12, enhancing the immune response by improving the TME. The fifth generation CAR-T cells integrate a cytokine receptor-based signaling domain, such as IL-2Rβ, with STAT3/JAK pathways to enhance proliferation and resistance to tumor-induced immunosuppression.

Fig. 1.

Structure of CAR-T cells – evolution over five generations: this figure illustrates the evolution of CAR-T-cell designs from the first to fifth generation. The three essential components of CAR structure are, the extracellular, transmembrane, and the intracellular domains. The extracellular antigen recognition domain consists of a fusion protein comprising of light and heavy chain, the single chain variable fragment (scFv). This domain is connected to the lipidic transmembrane domain through a spacer. The extracellular scFv facilitates attachment of CART cells to specific target cells. The intracellular domain encompasses primary and secondary costimulatory domains that help in activation of T cells [2]. The intracellular domain plays an important role in signaling T lymphocytes, facilitating killing of target malignant cells independent of human leukocyte antigen (HLA) [3]. The intracellular signaling domains evolved with each generation of CART. The first-generation CAR-T cell incorporates a CD3ζ intracellular domain, responsible for initiating T-cell activation. This lacks co-stimulatory domain limiting their efficacy. In the second generation, a co-stimulatory domain (such as CD28 or 4-1BB) is added to enhance activation, proliferation, and persistence. The third-generation CART includes two co-stimulatory domains, amplifying the strength and durability of the T-cell response. Fourth generation CAR-T cells, known as T-cells Redirected for Universal Cytokine Killing (TRUCKs), can secrete cytokines such as IL-12, enhancing the immune response by improving the TME. The fifth generation CAR-T cells integrate a cytokine receptor-based signaling domain, such as IL-2Rβ, with STAT3/JAK pathways to enhance proliferation and resistance to tumor-induced immunosuppression.

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First-generation CARs carry scFv and immunomodulatory tyrosine-based activation motifs of CD3ζ. These lack costimulatory domains and were not efficient enough for clinical utility unless they have independently functioning endogenous costimulatory domain, for example, NKG2D CAR that has endogenous ligands that can function independently as co-stimulatory domain [4]. Second-generation CARs integrate 4-1BB or CD28 co-stimulatory domains. 4-1BB functions as a memory stem cell and has longer persistence whereas CD28 incorporated cells are more potent and have greater growth potential [5]. Currently approved CARTs in myeloma are 2nd generation CARs with 4-1BB and CD28 co-stimulatory domains. Third-generation CARs are more complex, incorporating two or more co-stimulatory domains that can result in better persistence and effectiveness. These are in early stages of development [6]. The fourth and fifth generation CARs in MM are being built with expression of immunomodulatory molecules like IL-7 and CCL19 in response to antigenic stimulation. BCMA-targeting fourth generation CARs expressing IL-7 and CCL19 (i.e., BCMA-7 X19 CART cells) exhibit superior expansion, differentiation, migration, and cytotoxicity in preclinical studies [7]. These CARs form an immune synapse following interaction with malignant cells subsequently leading to release of cytotoxic molecules such as perforins, granzymes, leading to cytolysis [8]. Each generation has aimed to address prior limitations, improving persistence, activation strength, and the ability to overcome immunosuppressive environments.

Over the past decade, CART has emerged as a highly potent form of immunotherapy in lymphoid malignancies, positively impacting the treatment landscape of various subtypes of aggressive lymphomas and MM. BCMA, otherwise known as CD269 or tumor necrosis factor receptor super family 17 (TNFRS17), is heavily expressed in plasma cells and plasmablasts making it a reliable target in MM. Currently, there are two FDA approved commercially available autologous CART cell products, targeting BCMA, first is idecabtagene vicleucel (Ide-cel) and second is ciltacabtagene autoleucel (Cilta-cel).

Idecabtagene Vicleucel

Ide-cel is a second-generation CART product that has bb2121 construct, comprising of a BCMA binding scFv fused to a CD8-α extracellular linker region, transmembrane CD137 (4-1BB) co-stimulatory domain and CD3-zeta T-signaling domains. In March 2021, FDA approved first BCMA directed CART cell product, Ide-cel (Abecma) for the treatment of relapsed refractory multiple myeloma (RRMM) who failed four prior lines of therapies including an IMiD, PI, and CD38 mAb based on the results from the phase II KarMMA trial [9]. In KarMMA-1, among 140 patients with RRMM, 128 received Ide-cel. At median follow-up of 13 months, 73% achieved the primary end point, overall response rate (ORR). Complete remission (CR) rates were 33%; measurable residual disease (MRD) negativity was achieved by 26%. The median duration of response (DOR) was 10.7 months and the median progression-free survival (PFS) was 8.8 months. Cytokine release syndrome (CRS) was reported in 84% of the patients, grade 3 or higher in 5%, neurotoxic effects were reported in 18%, grade 3 in 6% patients [9]. Real-world outcomes are also consistent with KarMMA-I results [10].

The open label phase III KarMMA-3 trial compared Ide-cel to one of five standard of care regiments in RRMM patients who received 2–4 prior lines of therapy including IMiD, PI, and CD38 mAb Daratumumab and refractory to last regimen. Among 386 patients who underwent randomization, 254 patients were assigned to Ide-cel arm. 66% of the total patients had triple class refractory disease, notably a significant 95% had daratumumab refractory disease. At median follow-up of 18.6 months median PFS was significantly higher with Ide-cel (13.3 months vs. 4.4 months). ORR (71% vs. 42%) and CR (39% vs. 5%) rates were significantly higher with Ide-cel. Overall survival data are still immature from this trial. Though any grade CRS was reported in 88%, only 5% had grade 3 or higher. Neurotoxic effects occurred in 15%, with 3% grade 3 or higher consistent with KarMMA-I and real-world Ide-cel outcomes [11]. In Both KarMMA-1 and KarMMA-3 trials, patients with age >65 had favorable odds ratio for ORR compared to younger patients, consistent with previously reported real-world outcomes with CD19-CART cell by German registry demonstrating superior survival outcomes in elderly patients [12]. Though favorable outcomes in elderly could be attributed to strict selection in clinical trials, and less aggressive disease than younger patients, this underlines the fact that CART therapy can be administered in elderly without age cut off and can expect superior outcomes. Ide-cel is currently approved to use in RRMM after two or more lines of therapy including IMiD, PI and anti-CD-38 mAb.

Ciltacabtagene Autoleucel

The structure of Cilta-cel, the second FDA approved CART cell therapy for MM consists of an antigen recognition domain that typically possesses dual single-domain mAB as scFv binding to two distinct BCMA epitopes, providing high avidity against BCMA, a 4-1BB costimulatory domain and a CD3ζ signaling cytoplasmic domain. In phase 1b/2 CARTITUDE-1 study, Cilta-cel was administered to adult, fit, BCMA-CART naïve patients with RRMM that have received three or more prior lines of therapy or double refractory to PI, IMid and have received a PI, IMid and anti-CD38 mAb with progression at 12 months or less after last line of therapy. At a median follow-up of 11.5 months, ORR was achieved in a significant 97% with manageable safety profile. 67% of the patients achieved stringent CR, 97% of these patients are MRD negative. Twelve-month PFS rate was 77%, median PFS and DOR were not reached. Grade 3 or 4 CRS was observed only in 4%. One patient had grade 5 CRS. Grade 3 or 4 CART cell neurotoxicity occurred in 9% of the patients. Among the 14 deaths that occurred in the study, six were treatment related [13]. The 2-year update reported 27-month PFS of 54.9% and OS of 70.4%. Greater than 80% MRD negativity rates were reported across all subgroups. International staging system III, high-risk cytogenetics, extramedullary disease or >60% bone marrow plasma cells are associated with lower PFS rates and shorter DORs [14].

Efficacy of Cilta-cel in earlier lines was studied in the open label, randomized, phase 3 CARTITUDE-4 trial. In this study, patients with lenalidomide refractory disease who received 1–3 prior lines of therapy were randomized to Cilta-cel or the physician’s choice of Pomalidomide, Velcade, Dexamethasone or Daratumumab, Pomalidomide, Dexamethasone (DPD). At a median follow-up of 15.9 months the median PFS was not reached in the Cilta-cel group, 11.8 months in the SOC group (HR: 0.26; 95% CI: 0.18–0.38; p < 0.001). PFS at 12 months was 75.9% in the Cilta-cel group and 48.6% in SOC group. More patients in the Cilta-cel group than in the SOC group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). OS data are not mature yet, but there is a trend favoring Cilta-cel (HR: 0.78, CI: 0.5–1.2). In the Cilta-cel cohort, grade 3 or 4 CRS and cranial nerve palsies were reported in 1.1%, no grade 5 events were reported. There were no grade 3 or 4 immune effector cell-associated neurotoxicity syndrome reported [15]. These results lead to Cilta-cel’s approval in April 2024, in second line in lenalidomide refractory RRMM patients.

The phase III CARTITUDE –5 trial was designed to study the efficacy of frontline consolidation with Cilta-cel in patients with newly diagnosed multiple myeloma not intended for transplant. In this international trial, 650 newly diagnosed MM patients for whom autologous stem cell transplant (ASCT) was not planned as initial therapy, were randomized to receive either bortezomib, lenalidomide and dexamethasone (VRd) followed by lenalidomide and dexamethasone (Rd) or VRd followed by Cilta-cel. This study has completed enrolling, and results are awaited [16]. Phase III CARTITUDE-6 study, now enrolling patients compare the efficacy of induction with DVRd quadruplet (daratumumab-VRD) followed by Cilta-cel or ASCT in newly diagnosed MM patients who are eligible for transplantation. Comparative outcomes of currently approved BCMA-targeted CART therapies in MM are described in Table 1.

Table 1.

Comparison of currently approved BCMA-targeted CART therapies in MM

CharacteristicsIde-CelCilta-cel
Initial approval date, label March 2021 (Phase 2 KarMMa trial) February 2022 (Phase 1b/II CARTITUDE-1 trial) 
Updated label date April 2024 April 2024 
Approval based on KarMMa-3, Phase 3 RCT CARTITUDE-4, Phase 3 RCT 
Comparator arm DPd or DVd or IRd or Kd or EPd PVd or DPd 
Prior lines of therapy per updated label, n 2 or more prior line including IMiD, PI, and anti-CD38 monoclonal antibody One prior line of therapy, including a PI and IMiD, and refractory to lenalidomide 
Efficacy 
 Median follow-up, months 18.6 (KarMMa-3) 15.9 (CARTITUDE-4) 
 Median PFS (primary end point) 13.3 months (95% CI: 11.8–16.1) with Ide-cel versus 4.4 months (95% CI: 3.4–5.9) with SOC HR: 0.49, p < 0.0001 Not reached with Cilta-cel versus 11.8 months with SOC (HR: 0.26; 95% [CI: 0.18–0.38; p < 0.001) 
 ORR 71% (66%–77%) versus 42% (95% CI: 33%–50%, HR: p < 0.0001 84.6% and 67.3%, respectively (OR: 3.0; 95% CI: 1.8–5.0) 
 sCR 39% versus 5% 58.2% versus 15.2% 
 DOR 14.8 months (95% CI: 12.0–18.6) with PR or better 20 months (95% CI: 15.8–24.3) if achieved CR or better 12 months DOR 84.7 (78.1–89.4) 63.0 (54.2–70.6) 
 MRD negative 39% 60.6% of those in the Cilta-cel arm and 15.6%, OR: 8.7; 95% CI: 5.4–13.9) 
Safety (grade 3 or 4 reported in at least 10%) 
 CRS rates 5% (1% grade 5) 1.1% 
 Median time to onset of CRS, duration 1 day, 3.5 days 8 days, 3 days 
 ICANS rates/neurotoxicity/encephalopathy 3% 2.8(No grade 3 icans) 
 Median time to onset of ICANS, duration 3 days, 2 days 9.5 days, 2 days 
 Infections 16% 26.9% 
 LD Cyclophosphamide at 300 mg/m2 daily for 3 days plus fludarabine at 30 mg/m2 daily for 3 days Cyclophosphamide at 300 mg/m2 daily for 3 days plus fludarabine at 30 mg/m2 daily for 3 days 
 Median dose of CART 445 × 106 0.71 × 106 cells per kilogram 
CharacteristicsIde-CelCilta-cel
Initial approval date, label March 2021 (Phase 2 KarMMa trial) February 2022 (Phase 1b/II CARTITUDE-1 trial) 
Updated label date April 2024 April 2024 
Approval based on KarMMa-3, Phase 3 RCT CARTITUDE-4, Phase 3 RCT 
Comparator arm DPd or DVd or IRd or Kd or EPd PVd or DPd 
Prior lines of therapy per updated label, n 2 or more prior line including IMiD, PI, and anti-CD38 monoclonal antibody One prior line of therapy, including a PI and IMiD, and refractory to lenalidomide 
Efficacy 
 Median follow-up, months 18.6 (KarMMa-3) 15.9 (CARTITUDE-4) 
 Median PFS (primary end point) 13.3 months (95% CI: 11.8–16.1) with Ide-cel versus 4.4 months (95% CI: 3.4–5.9) with SOC HR: 0.49, p < 0.0001 Not reached with Cilta-cel versus 11.8 months with SOC (HR: 0.26; 95% [CI: 0.18–0.38; p < 0.001) 
 ORR 71% (66%–77%) versus 42% (95% CI: 33%–50%, HR: p < 0.0001 84.6% and 67.3%, respectively (OR: 3.0; 95% CI: 1.8–5.0) 
 sCR 39% versus 5% 58.2% versus 15.2% 
 DOR 14.8 months (95% CI: 12.0–18.6) with PR or better 20 months (95% CI: 15.8–24.3) if achieved CR or better 12 months DOR 84.7 (78.1–89.4) 63.0 (54.2–70.6) 
 MRD negative 39% 60.6% of those in the Cilta-cel arm and 15.6%, OR: 8.7; 95% CI: 5.4–13.9) 
Safety (grade 3 or 4 reported in at least 10%) 
 CRS rates 5% (1% grade 5) 1.1% 
 Median time to onset of CRS, duration 1 day, 3.5 days 8 days, 3 days 
 ICANS rates/neurotoxicity/encephalopathy 3% 2.8(No grade 3 icans) 
 Median time to onset of ICANS, duration 3 days, 2 days 9.5 days, 2 days 
 Infections 16% 26.9% 
 LD Cyclophosphamide at 300 mg/m2 daily for 3 days plus fludarabine at 30 mg/m2 daily for 3 days Cyclophosphamide at 300 mg/m2 daily for 3 days plus fludarabine at 30 mg/m2 daily for 3 days 
 Median dose of CART 445 × 106 0.71 × 106 cells per kilogram 

Access to CART

Given the complexity of CART therapy administration and post procedural monitoring, the procedure requires highly specialized and trained medical personnel in resource intensive setting. This limits administration of CART therapies to large academic centers and certified facilities so that patients can be adequately monitored and intervened appropriately to address adverse effects. Patients are required to remain within a specified travel time from the treatment center, restricted driving for several weeks following CART administration, need for a continuous caregiver presence can be significant challenges for many patients. Travel costs to treatment centers, temporary housing costs, and costs of paid caregiver support when needed are additional financial barriers. The time from collection of T cells to infusion of engineered CART cells can take 3–5 weeks currently (vein-to-vein time). During this time, patients may experience disease progression, may need additional therapies incurring additional toxicities. CART manufacturing failure is another concern particularly in heavily pretreated patients [17].

Authorization of treatment delivery to outpatient treatment centers and aggressive awareness education of community oncologists can offer improved access to CART therapy. In a meta-analysis examining inpatient versus outpatient CAR-T administration, Hansen et al. [18] reported comparable response rates and lower costs and healthcare resource utilization with outpatient administration. Rapid, in-house/regional manufacturing of CART, innovative off-the-shelf allogeneic CARTs [19] can help decrease the vein-to-vein time. Uniform streamlined mechanisms of reimbursement across payers can help mitigate coverage of CART therapy.

Toxicities: CRS/ICANS and Beyond

BCMA-targeting CART cell therapies are associated with cytokine release syndrome of varying levels of severity that can range from low-grade fevers to life threatening cytokine storms. Many of these can be effectively managed with supportive care, steroids, tocilizumab, and other cytokine inhibitors. Though less frequent than CRS, neurotoxicity symptoms particularly ICANS were described following BCMA-targeting CART cell therapies. In both KarMMA and CARTITUDE trials, the incidence was relatively low, and symptoms were manageable with corticosteroids and cytokine inhibitors.

There is growing evidence for non-ICANS neurological symptoms such as Parkinson’s like movement and neurocognitive disorders, in patients treated with anti-BCMA CART cells. In CARTITUDE-1 trial, 5% of the patients with MM reported movement and neurocognitive treatment emergent adverse events [20]. There is at least one documented case presenting with confusion and bradykinesia with increased muscle tone following Ide-cel administration [21]. BCMA is expressed in basal ganglia, so that CART targeting BCMA might have resulted in these irreversible symptoms. In phase 2 Cilta-cel trial, 3 patients developed grade 3 or higher parkinsonism. Ide-cel package insert describes the possibility of grade 3 parkinsonism [22]. In one recent report from Germany, Leipold et al. [23] described pulmonary flare-up 90 days after Ide-cel, which was subsequently identified as pseudo-progression. Single-cell RNA-seq of the bronchioalveolar lavage cells identified CD4 positive T cells with a Th1 polarized Th17 phenotype that are pro-inflammatory and pathogenic. Authors postulated Th17.1 driven autoimmune mechanism as a possible underlying phenomenon for pulmonary findings. The post-CART pulmonary lesions had transcriptomic similarities with sarcoidosis. This patient had grade 1 CRS immediately following CART which was well managed with tocilizumab, subsequently achieved MRD negative CR. This demonstrates that late complications can occur irrespective of grade of CRS and response following CART. Though this patient improved with steroids alone, more severe complications might have been challenging. Second primary malignancies are another clinically relevant long-term AE following CART. Recent update on the CARTITUDE-4 study reported 13% incidence of second primary malignancies including a significant 3.4% hematological malignancies [24].

Modification of CART construct to enable deactivation of CART cells under certain circumstances silencing/on demand killing of circulating persistent CART is a possible therapeutic intervention to effectively address life threatening complications post-CART. On a separate note, authors described utilization of tracers binding to CXCR4 that can complement FDG PET to discriminate between immune mediated changes and true relapse following CART. This needs to be further evaluated [23].

Resistance to BCMA CAR-T

Even though the currently approved BCMA-targeting CART cell therapies achieve unprecedented deep and durable responses in heavily pretreated MM patients, relapse is frequently observed, many within 2 years following CART [9, 14]. Van Oekelen et al. [25] compared outcomes of 79 patients receiving salvage therapy following progression after receiving anti-BCMA CART therapy. These patients received a median of 2 salvage therapies (range 1–10). Median PFS for the first salvage therapy was 3.5 months after reinfusion and ORR was 43.3%. Salvage therapies included subsequent CART and/or BiSpecifics, allogeneic and ASCT, various approved agents with or without chemotherapy. Overall, T-cell engaging treatments showed the highest response rates and durable responses. Among the 35 patients that received T cell engaging therapy, 29 patients received total 32 instances of bsAbs, 9 were BCMA directed, 23 were non BCMA directed. 6 patients received salvage treatment with GPRC5D targeting CART at any point after BCMA-CART relapse. The ORR was 91.4% for the cohort receiving T cell engaging therapies after progression from anti-BCMA CART cells. ORR does not significantly decrease with following lines of therapy [25].

Though resistance mechanisms are not well defined, T-cell exhaustion and emergence of immunosuppressive microenvironment, antigen escape, BCMA shedding, development of anti-scFv antibodies is some of the pathways contributing for BCMA resistance [26]. As BCMA is essential for the survival of plasma cells, antigen escape does not appear to be frequent with anti-BCMA therapies [27]. In the KarMMa study, only one out of 16 patients with evaluable bone marrow samples at relapse had an antigen loss [28].

Antigen Loss and Escape Mutations in BCMA

Antigen loss, wherein tumor cells develop resistance by downregulating or losing the targeted antigen is a significant challenge in cellular therapy. Though this is rare with anti-BCMA therapies, it can be challenging when it occurs in MM.

BCMA antigen loss and emergence of BCMA mutant plasma cell clone are important resistance mechanisms in MM following BCMA-targeted therapies. Similar mechanism of biallelic tumor necrosis factor super family receptor super family 17 (TNFRSF17)-BCMA loss involving a large preexisting chromosome 16p loss followed by second focal hit on the remaining genomic allele was reported in multiple analysis [29‒31]. Monoallelic 16p loss is thought to be associated with risk of progression following BCMA-targeted therapies. To examine the tumor intrinsic factors that promote BCMA antigen escape in MM patients, Lee et al. [32] performed whole-genome sequencing and copy number variation analysis of 16 patients treated with anti-BCMA CART and BiTEs and relapsed. In one patient, they observed TNFRSF17 biallelic loss involving clonal focal events at both TNFSF17 loci without large-scale aberrations or monosomy of chromosome 16 [32]. This suggests large-scale structural events on chromosome 16 are not only predisposing risk factors for BCMA negative relapse and focal biallelic deletions of TNFRSF17 can occur even in the setting of diploid chromosome 16. During relapse following Ide-cel therapy, rare biallelic loss of TNSRSF17 was reported suggesting that BCMA antigen loss may not be the only main driver of resistance [30]. Lee et al. [32] also reported higher rates of mutational events involving TNFRSF17 gene locus following BiTEs than CART which may be related to longitudinal selective therapeutic pressure with BiTEs in comparison to the transient immune selection post-CART cell therapy. In this report, authors also described TNFRSF17 extracellular domain clonal hotspot missense mutations or in-frame deletions mediating loss of functional BCMA epitopes inhibiting binding of anti-BCMA drugs, though BCMA expression is still detectable. There is heterogeneity in detection and therapeutic resistance following TNFRSH17 mutations and dependent on targeted epitope specificities and on structural design on the therapeutic molecules.

Acquired resistance to one anti-BCMA therapy may not necessarily mean resistance to other BCMA-targeted therapies. No BCMA extracellular domain mutant subclones were detected prior to therapy initiation highlighting dynamic nature of clonal antigen escape and need for serial genomic analysis to detect emerging antigen escape clones and make therapeutic modifications. Avoiding prior therapy against targeted antigen with alternative mechanisms and dual antigen targeting are possible ways to overcome these secondary resistance mechanisms. Use of CART in earlier lines, preferably first line may avoid prior immunotherapy-based mode of action and prevent primary resistance [33].

Biallelic deletion on chromosome 16 that harbors BCMA locus has been described as a mechanism of BCMA loss [34]. Gamma secretase mediated shedding of plasma cells can lead to circulation of soluble BCMA (sBCMA) [35]. High levels of sBCMA could interfere with anti-BCMA therapies by coating BCMA binding target on therapeutic agent such as CART resulting in antigen masking [36]. However, no clinical evidence exists to suggest sBCMA levels negativity impacts BCMA-targeting therapies.

Currently approved BCMA-targeting CART cells incorporates nonhuman derived scFv portion, for example, bb2121 is mouse derived [37]. Cilta-cel is of Camelid (Llama) origin [38]. Utilization of nonhuman scFv can induce immunogenicity from activation of adaptive immune response following CART administration. This can ultimately result in limiting the persistence of CART. A recent study of 17 patients with RRMM treated with Cilta-cel revealed 7 of them developed high levels of anti-CAR antibodies, incidence of relapses was significantly higher in these patients than in patients without detectable humoral immunogenicity [39].

A higher CD4/CD8 ratio and an increased frequency of CD45RO−CD27+CD8+ T cells, reflective of stem memory T cells is associated with responses following T-cell-based therapies such as CART and BiSpecifics. T cells with exhausted phenotype or senescent phenotype are enriched in patients who are resistant to anti-BCMA CART or BiSpecifics [40]. These findings suggest T-cell-mediated BCMA-targeting therapies may be more efficacious early in disease course when the immunosuppression is less.

Newer Targets

Optimal strategies to treat relapses following currently approved therapies and sequencing of various approved agents are not well established at present.

CART Cells Targeting GPRC5D

GPRC5D is a transmembrane receptor protein with unclear function and signaling mechanisms within the MM cells [41]. The G protein-coupled receptor is expressed on malignant bone marrow plasma cells and normal tissue expression is limited to hair follicles [42]. High GPRC5D expression in the bone marrow is correlated with poor prognosis in MM [43]. The CD 138+ plasma cells have similar BCMA and GPRC5D expression but do not correlate with each other, making both independent therapeutic targets [44]. CART cells incorporating GPRC5D-targeted scFv clone 109 eradicated MM and enabled long-term survival in in vitro testing. Efficacy was seen in BCMA antigen escape models as well. GPRC5D (109) is specific for GPRC5D and resulted in MM cell line and primary MM cytotoxicity, cytokine release and in vivo activity comparable to anti-BCMA CART cells [44]. These findings led GPRC5D targeting CART cells into clinical trials.

POLARIS trial, first-in-human, single center, single arm phase 1 Chinese trial of GPRC5D-targeted CART cells demonstrated that GPRC5D is a promising treatment modality for RRMM. All 10 patients treated with the CART product showed a response with 60% sCR and 40% VGPR [45]. In another Chinese study, 33 patients received GPRC5D CART in phase II setting. This study reported ORR of 91%, sCR of 33%, 30% CR, 12% VGPR rates. All patients achieved PR or better, [46]. From the USA, Mailankody et al. [47] from memorial Sloan Kettering reported safety and efficacy of the GPRC5D directed CART cells MCARH109 in their open label, single center, phase I study results. 17 heavily pretreated patients received 25–450 million cells/kg. Fifteen developed CRS of grade 1 or 2, one patient who received highest dose of 450 million developed grade 4 CRS, ICANS, and macrophage activation syndrome. At 2.1 weeks following infusion of CART, two other patients developed dizziness and gait disturbances, both developed grade 3 cerebellar toxicity at 6.5 and 8.4 months, respectively. CART cells were detected in CSF (cerebrospinal fluid) by flow cytometry in one patient, but magnetic resonance imaging (MRI) and positron emission tomography (PET) completed within 6 weeks (about 1 and a half months) and 4 months did not reveal any findings. The two patients continue to exhibit ongoing grade 3 cerebellar toxicity. No other patient experience similar symptoms. Among the patients who received MCARH109 at determined dose levels, ORR was reported at 71% (44–90), median DOR was 7.8 months (5.7 months to not reached), 8 of 12 patients achieved MRD negativity. At least PR or better was noted in 70% of the patients with prior BCMA therapy [47].

FcRH5 Targeting CART

Fc receptor-homolog 5 (FcRH5), also known as CD307 is a differentiation antigen homologous to the family of Fc receptors, exclusively expressed as a surface marker in cells of B-cell lineage. Though it is detected on pre-B cells, earlier in development, its expression is retained on normal plasma cells unlike CD19, CD20 [48]. FcRH5 expression is upregulated on malignant plasma cells particularly in cells with gain or amplification of chromosome1q21, compared to normal plasma cells making it a potential target in high-risk MM [49, 50]. Furthermore, expression of FcRH5 found to be persistent on relapsed or refractory MM patients treated with PI or IMiD [51]. In treatment of RRMM, FcRH5 is being explored as potential target with various immunotherapeutic approaches. In xenograft models, anti FcRH5 T-cell dependent bispecific antibody [50], antibody drug conjugates DFRF4539A [52] and CART [53] have shown meaningful efficacy. Unfortunately, in a phase 1 study, DFRF4539A demonstrated only limited clinical benefit at the dose investigated [51]. Cevostamab, a FcRH5xCD3 bispecific antibody monotherapy demonstrated clinically meaningful activity in a large cohort of patients with heavily pretreated RRMM with a target dose dependent increase in ORR without increase in CRS rates. Reponses appear to durable and are observed in patients with prior exposure to CART, BsAbs, and ADCs [54]. FcRH5 targeting CART is currently being explored in clinical trials.

Transforming Growth Factor Beta

TGFs, specifically TGF-β exhibit pleotropic effects that facilitate plasma cell growth, modulate many immune cell types in tumor microenvironment (TME) resulting in emergence of drug resistance, tumor progression, and poor prognosis that correlates with elevated levels of TGF-β in TME [55, 56]. TGF-β secreted by malignant plasma cells triggers interleukin-6 (IL-6) and vascular endothelial growth factor in bone marrow stromal cells resulting in tumor growth. TGF-β also silences IL-2, regulates cytotoxic CD8+ T cell, regulatory T cell, natural killer [NK]) cell and macrophage activity through transcriptional downregulation of perforins, granzymes, and multiple other cytokines. TGF-β also suppresses cytotoxic activity of Th1 cells, inhibits TCR-CD28 signaling to promote hyporesponsive memory T cells. CD28 is a costimulatory receptor expressed on naïve T cells needed for activation and also part of the costimulatory component of recombinant engineered CART cells [56]. Blocking TGF-beta signaling promotes CD8+ T cells and NK cells driven antitumor responses [57].

CART Cells and TGF-Beta Pathway

As TGF-beta negatively impacts MM in its progression and tumor resistance to multiple therapeutic agents particularly CART cells, therapeutically targeting TGF-beta with antibodies or modification of T cells may help with better tumor control [58, 59]. Genetic ablation of TGF-beta receptor II (TGFBR2) in CART cells reduces T-cell exhaustion in turn resulting in improved tumor killing in in vivo models [60].

Knowledge of CART-cell repressing mechanisms of TGF-beta lead to development of armored BCMA CART cells that co-express BCMA-targeting CAR with DN-TGFbIIR armor that confer resistance to TGF-b, despite prolonged exposure [61]. CD28 ζ CART cells retain better potency against TGF-b repression and improve antitumor efficacy [62]. Engineered Chimeric switch receptors can reverse the original intended signaling pathways to overcome immune suppressive TME resulting in T-cell persistence [63]. An armored dual CAR targeting BCMA and TGF-b is being studied at Medical College of Wisconsin in a soon to open phase 1 clinical trial.

CART-Ddbcma (Anitocabtegene Autoleucel)

Traditional CART cells use antibody fragments such as humanized or murine scFv or camelid heavy chain antibody fragments as an antigen recognition motif. ScFv domains can aggregate and mis-pair causing antigen-independent tonic signaling that can result in exhausted T-cell phenotype and compromised CART function. Utilization of D domains derived from de-novo-designed single-domain protein that lack disulfide bonds may overcome this [64]. CART-ddBCMA cells incorporate a synthetic D domain engineered to specifically engage BCMA-expressing MM cells, 4-1BB costimulatory domain, and CD3-zeta T-cell activation domain. These CART cells have shown efficacy in preclinical studies [65].

In phase 1 study, at a median follow-up of 22 months, Anito-cel was able to achieve 100% overall response rates with 76% CR/sCR rates with manageable CRS and ICANS (only one grade 3 CRS and 2 grade 3 ICANS) that got resolved quickly. Responses were durable; MRD rates were 86% in the evaluable patients. There was no off-tumor tissue toxicity or delayed neurotoxicity. There were no manufacturing failures [66]. Anito-cel is currently being studied in a phase II and III trials [67]. Ongoing responses and further updates will provide insights into the durability and overall efficacy of CART-ddBCMA in RRMM.

MCARH171 Anti-BCMA CART and JCARH125 Anti-BCMA CART

Murine derived scFv containing CART can induce immune responses that can prevent repeat dosing of CART. In one clinical trial, ten-fold higher repeat dosing of anti-CD19 autologous CART could not expand or elicit anti-lymphoma activity. Host cellular immunity specific to specific to peptide from FMC63 murine scFv was postulated to be responsible for this in eighty percent of the patient who cound not expand [68]. Smith et al. [69] engineered human scFv, and generated bicistronic construct including a second-generation CAR incorporating a truncated-epithelial growth factor marker that can be silenced on demand. MCARH171, the second-generation human derived BCMA-targeted autologous 4-1BB containing CART including a truncated epithelial growth factor receptor safety system was studied in a phase 1 trial, demonstrated acceptable safety profile. Among the 11 patients treated in this trial, median lines of prior therapy was 6, overall response rates were 64% with median DOR of 106 days (range 17–235 days). Expansion, persistence, and durable clinical responses were dose dependent. Patients treated on lower dose cohorts (≤150 × 106) had a lower peripheral blood expansion (mean 14,098 copies/μL) whereas, higher dose cohorts (≥450 × 106, CART cells) had a peak expansion of 90,208 copies/μL. Response rates were 100% in the higher dose cohorts with responses lasting >6 months in 3 of 5 patients compared to only one of 6 patients in lower dose cohorts. No dose limiting toxicities were observed with MCARH171, dose-response relation with toxicity was not observed [70].

Juno therapeutics developed JCARH125 which is a BCMA-targeting CART product that contains a lentiviral CAR construct with a fully human scFv, optimized spacer, 4-1BB costimulatory domain, and CD3z activation domains. The binding domain binds to BCMA with high affinity, without off target cell membrane staining [71]. The construct has shown minimal tonic signaling and lack of inhibition by sBCMA. In multicenter, phase I/II EVOLVE (NCT03430011) trial, JCARH125 showed acceptable safety profile with no DLTs reported in RRMM patients that received 3 or more prior lines of treatment [72].

CART and Immune Check Point Inhibitors

Over last decade immune check point inhibitors have revolutionized cancer treatment particularly in solid tumors and lymphomatous disorders. In MM, ICI have not shown remarkable benefit. Several studies demonstrated synergy between CAR-T cell therapy and PD-1 blockade potentiating therapeutic effects of CART cell therapy in treatment of malignancies [73]. Wang et al. [74] reported utilization of low dose nivolumab to salvage CD19-CART in a patient with follicular lymphoma that achieved less satisfactory response following CART. Following ICI, the patient achieved remission for greater than 10 months with reduced adverse effects. Stimulation of CAR may increase the PD-1 inhibitory signaling and check point inhibition may be an effective strategy to restore intended CART function. BCMA-PD-1-CART is currently being investigated in RRMM patients [75].

Allogeneic CART Cells

Allo-715

Allo-715 is a first in class, donor derived, allogeneic off the shelf CART targeting BCMA engineered to evade graft versus host disease and minimize CAR T rejection that can be administered without the need for leukapheresis and prolonged manufacturing times. Allo-715 contains an integrated, self-inactivating, third-generation, recombinant lentiviral vector that expresses a second-generation anti-BCMA CAR containing a scFv derived from a human anti-BCMA antibody and the intracellular domains of 4-1BB and CD3ζ, The extracellular region contains rituximab susceptible mimotopes, aiding as an off-switch mechanism. T-cell receptor alpha constant and CD 52 are knocked out facilitating reduced GVHD rates.

In the phase 1 UNIVERSAL trial, safety, tolerability, and responses to ALLO-715 in MM were studied. In addition to fludarabine and cyclophosphamide, anti-CD52 drug ALLO-647 was used for lymphodepletion (LD), which provides prolonged LD with no apparent ≥ grade 3 infections compared to autologous CART. 43 patients successfully received the drug with a median time from enrollment to start of treatment of 5 days. CRS was observed in 56%, ICANS in 14% of the patients with only one grade 3 CRS and no ≥ grade 3 ICANS. Prolonged cytopenia rates (19%) were comparable to autologous CART. No GVHD was reported. 22% grade ≥ grade 3 infections (similar to Cilta-cel [20%] and Ide-cel [22%]) including 3 grade 5 events were observed. Overall, 55.8% had responses, among patients treated with 320 × 106 CART cells and a FluBu-Allo-647-based LD (24 patients), 70.8% responded, 45.8% achieved VGPR or better, 25% CR/sCR, median DOR was 8.3 months. These results are encouraging [19].

CB-011

CB-011 is another off the shelf anti-BCMA CART cell therapy derived from healthy donor T cells. Caribou sciences developed next generation clustered regularly interspaced short palindromic repeats (CRISPR)-Cas12a genome editing technology using CRISPR hybrid RNA-DNA technology to manufacture CB-011 allo CART product to reduce off target editing and to achieve an immune cloaking strategy by removing B2M protein and inserting a B2M-HLA-E fusion protein. This modification is expected to achieve enhanced persistence of antitumor response. The CRSPR-based editing takes place in 4 steps. In the first two steps, insertion of a humanized anti-BCMA CAR into the T-cell receptor alpha constant gene, which knocks out reception of the T cells to reduce the risk of graft versus host disease that is seen with allo CART cells. In the next two steps, B2M-HLA-E peptide fusion gene is inserted into the B2M gene of the CART cells to prevent rejection of patient T and NK cells, which also knocks out endogenous B2M expression and further reduces patient immune rejection [76]. CB-011 is currently being investigated in Phase 1 CaMMouflage study (NCT05722418) [77].

Allogeneic Non-T-Cell CAR Therapies

CAR-NK Cells

Despite promising results with autologous and allogeneic CAR-T cells, associated serious toxicities, delays in manufacturing pose challenges to their widespread use. A promising alternative is utilization of off the shelf NK cells, which can be transplanted without triggering alloreactivity. CAR-NK cells are emerging as an alternative to CAR-T cells, offering several advantages such as intrinsic killing capacity and minimal post-CAR side effects and reducing the incidence of CRS, neurotoxicity, and GvHD associated with allogeneic CAR-T cells [78].

NK cells, possessing innate tumor cell recognition capabilities, can evade antigen escape, wherein tumor cells develop resistance by downregulating or losing the targeted antigen. With this, Unlike CAR-T cells, which depend on single antigen targeting, NK cells exhibit a broader spectrum of tumor recognition. They express a diverse array of activating and inhibitory receptors, enabling them to recognize and attack cells with altered or downregulated antigens. This intrinsic diversity makes NK cells less susceptible to antigen escape, allowing them to adapt to changes in the tumor antigen profile [79].

However, there are many challenges with NK cell therapy that include difficulties with collection of a single-cell dose from a related donor and inconsistent export of donor apheresis-derived NK cells. Genetic editing of NK cells has been historically challenging, limiting its therapeutic potential in cancer settings. To address these concerns, a culture system for producing large quantities of induced NK (iNK) cells has been developed. This involves a manufacturing process starting with a clonal population of engineered induced pluripotent stem cells, serving as a renewable source for generating off-the-shelf iNK cell doses. These iNK cells, like PB NK cells, remain stable as frozen banks and exhibit broad cytotoxic functions through both natural and engineered receptors upon thaw, without the need for recovery or cytokine priming, common requirements for most NK cell products. Additionally, iNK cells activate T cells, enhancing their responsiveness to programmed death 1 (PD-1) blockade, thereby triggering a secondary immune response for improved tumor elimination [80].

One key advantage of iNK cells is the ability to perform precise genetic engineering at the stem cell stage, addressing difficulties faced in editing NK cells directly. iDuo-MM CAR-NK cells were designed, incorporating anti-BCMA CAR, hnCD16, IL-15RF, and CD38 knockout, aiming for enhanced MM cell targeting. These cells displayed sustained tumor control in various tests, rivaling the efficacy of primary anti-BCMA CAR-T cells without associated complications like GvHD. iDuo-MM CAR-NK cells, when combined with daratumumab, showed potent anti-MM activity through antibody-dependent cell-mediated cytotoxicity, while avoiding CD38-related issues. The addition of a BCMA antigen stabilization method further improved tumor elimination. These findings support the translation of iDuo-MM CAR-NK cells into clinical trials (FT576) for refractory and relapsed MM, offering an off-the-shelf, cost-effective, and consistent immunotherapy approach. Clinical trials are underway to evaluate the effectiveness of FT576, either alone or combined with daratumumab, in treating patients with MM (NCT05182073) [81, 82]. Table 2 describes selected clinical trials exploring CART cell therapy in multiple myeloma.

Table 2.

Selected clinical trials exploring CART cell therapy in multiple myeloma

NCT06413498  A Study Comparing Anitocabtegene Autoleucel to Standard of Care Therapy in Participants with Relapsed/Refractory Multiple Myeloma (iMMagine-3) Phase 3 randomized Kite, A Gilead Company  1 to 3 prior lines, including an anti-CD38 mAb and an IMid 
NCT06304636  Descartes-15 for Patients with Relapsed/Refractory Multiple Myeloma (DC15-MM-01) Phase 1 non-randomized Cartesian Therapeutics  Failed at least 3 prior lines of therapy, an IMid, PI, anti-CD38 mAb 
NCT06298266  To Assess Safety, Tolerability, and Efficacy of Anti-GPRC5D-CD19-CAR-T in Relapsed/Refractory Multiple Myeloma Early phase non-randomized Guangdong Second Provincial General Hospital 18–75 Failed treatment with at least 3 different mechanisms of drugs (including chemotherapy, PIs, immune modulators, etc.), or has experienced disease progression or relapse within 6 months after the last treatment 
NCT06185751  Safety and Efficacy of CS1 CAR-T (WS-CART-CS1) in Subjects with Multiple Myeloma Phase 1 Non-Randomized Washington University School of Medicine 18 years and older 3 or more prior lines of therapy, including PI (e.g., bortezomib or carfilzomib), anti-CD38 therapy (e.g., daratumumab), and anti-BCMA therapies (e.g., BCMA bispecific antibodies or BCMA CAR-T) 
NCT06153251  A Study to Assess BMS-986453 in Participants with Relapsed and/or Refractory Multiple Myeloma Phase 1 Juno Therapeutics, Inc., a Bristol-Myers Squibb Company 18 years and older Received at least 3 prior anti-myeloma treatment regimens, including a PI and immunomodulatory agent 
NCT06067581  the Safety and Efficacy of SENL103 Autologous T Cell Injection Early Phase 1 Hebei Senlang Biotechnology Inc., Ltd 18 years to 75 years At least 3 kinds of anti-plasma cell blood tumor therapy, including at least one PI and one immunomodulator 
NCT06006741  Universal CAR-T Cells Targeting Multiple Myeloma Phase 1 Shenzhen Geno-Immune Medical Institute 18 years to 80 years Failed curative treatment options, (CR) cannot be achieved after at least 2 prior therapy regimens, high-risk MM in CR1 or CR2 and not eligible for SCT because of age or comorbid diseases, most recent progression-free interval < 1 year 
NCT05979363  A Study of Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by BCMA CAR-T Therapy in Transplant-Ineligible Patients with Primary Plasma Cell Leukemia Phase 2 Institute of Hematology & Blood Diseases Hospital, China 18 years to 75 years primary plasma cell leukemia Not considered for high-dose chemotherapy with Autologous Stem Cell Transplant (ASCT) 
NCT05870917  A Study of VRD-based Regimen Combined With CART-ASCT-CART2 Treatment in Patients with Primary Plasma Cell Leukemia Phase 2 Institute of Hematology & Blood Diseases Hospital, China 18 years to 65 years primary plasma cell leukemia Not received any treatment 
NCT05860036  A Study of VRd-based Regimen Followed by BCMA CAR-T Therapy in Transplant-Ineligible Patients with New-diagnosed Multiple Myeloma Phase 2 Institute of Hematology & Blood Diseases Hospital, China 18 years to 75 years NDMM, not considered for high-dose chemotherapy with autologous stem cell transplant (ASCT) 
NCT05838131  Study of CT071 Injection in RRMM or PPCL Early Phase 1 Shanghai Changzheng Hospital 18 years and older Three lines therapy for MM (requires relapse, progression, non-response after treatment with at least 1 PI and at least 1 immunomodulator Patients with primary plasma cell leukemia progressed after treatment with at least 1 regimen 
NCT05442580  CART-38 in Adult AML and MM Patients Phase 1 University of Pennsylvania 18 years and older Cohort B: relapsed/refractory MM (MM): ≥3 lines of therapy, to ensure the patient has been exposed to ≥1 IMiD®, ≥1 PI, and daratumumab 
NCT05412329 Study of Dual Targeted CD19/BCMA FASTCART GC012F in Relapsed/Refractory Multiple Myeloma Phase 1 Shanghai Changzheng Hospital 18 years to 70 years 3 different prior lines of therapy or primary refractory and PD within 12 months of their last line of therapy 
NCT05396885 Study of Anitocabtegene autoleucel in Relapsed or Refractory Multiple Myeloma (iMMagine-1) Phase 2 Kite, A Gilead Company 18 years and older Relapsed or refractory MM treated with at least 3 prior regimens of systemic therapy including PI, immunomodulatory drugs (IMiD) and anti-CD38 antibody and are refractory to the last line of therapy 
NCT04677452 Dose Exploration Study OF JWCAR129, BCMA-Targeted CART for RRMM Phase 1 The First Affiliated Hospital of Soochow University 18 years and older At least 3 prior anti-myeloma treatment regimens 
NCT04617704 BCMA and CD19 Targeted Fast Dual CART for Chromosomal Abnormalities High-risk BCMA+ Multiple Myeloma Early Phase 1 Shanghai Changzheng Hospital 18 years and older MM with high-risk chromosomal abnormal defined as presence of del17p, and/or t(4; 14) and/or t(14; 16) 
NCT04309981 Clinical Trial Using Humanized CART Directed Against BCMA (ARI0002h) in Patients with Relapsed/Refractory Multiple Myeloma to Proteasome Inhibitors, Immunomodulators and Anti-CD38 Antibody Phase 1 Phase 2 Sara V. Latorre 18 years to 75 years Previous two or more lines of treatment. Patients must have received at least a PI (such as bortezomib or carfilzomib), an immunomodulatory drug (lenalidomide or pomalidomide) and an anti-CD38 monoclonal antibody (such as daratumumab) 
NCT03549442 Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma Phase 1 University of Pennsylvania 18 years and older High-risk MM 
NCT03196414  Study of T Cells Targeting CD138/BCMA/CD19/More Antigens (CART-138/BCMA/19/More) for Chemotherapy Refractory and Relapsed Multiple Myeloma Phase 1 Phase 2 The First Affiliated Hospital of Soochow University 18 years to 75 years CD138 or BCMA antigen positive MM. Relapsed after prior autologous or allogenic SCT 
NCT06413498  A Study Comparing Anitocabtegene Autoleucel to Standard of Care Therapy in Participants with Relapsed/Refractory Multiple Myeloma (iMMagine-3) Phase 3 randomized Kite, A Gilead Company  1 to 3 prior lines, including an anti-CD38 mAb and an IMid 
NCT06304636  Descartes-15 for Patients with Relapsed/Refractory Multiple Myeloma (DC15-MM-01) Phase 1 non-randomized Cartesian Therapeutics  Failed at least 3 prior lines of therapy, an IMid, PI, anti-CD38 mAb 
NCT06298266  To Assess Safety, Tolerability, and Efficacy of Anti-GPRC5D-CD19-CAR-T in Relapsed/Refractory Multiple Myeloma Early phase non-randomized Guangdong Second Provincial General Hospital 18–75 Failed treatment with at least 3 different mechanisms of drugs (including chemotherapy, PIs, immune modulators, etc.), or has experienced disease progression or relapse within 6 months after the last treatment 
NCT06185751  Safety and Efficacy of CS1 CAR-T (WS-CART-CS1) in Subjects with Multiple Myeloma Phase 1 Non-Randomized Washington University School of Medicine 18 years and older 3 or more prior lines of therapy, including PI (e.g., bortezomib or carfilzomib), anti-CD38 therapy (e.g., daratumumab), and anti-BCMA therapies (e.g., BCMA bispecific antibodies or BCMA CAR-T) 
NCT06153251  A Study to Assess BMS-986453 in Participants with Relapsed and/or Refractory Multiple Myeloma Phase 1 Juno Therapeutics, Inc., a Bristol-Myers Squibb Company 18 years and older Received at least 3 prior anti-myeloma treatment regimens, including a PI and immunomodulatory agent 
NCT06067581  the Safety and Efficacy of SENL103 Autologous T Cell Injection Early Phase 1 Hebei Senlang Biotechnology Inc., Ltd 18 years to 75 years At least 3 kinds of anti-plasma cell blood tumor therapy, including at least one PI and one immunomodulator 
NCT06006741  Universal CAR-T Cells Targeting Multiple Myeloma Phase 1 Shenzhen Geno-Immune Medical Institute 18 years to 80 years Failed curative treatment options, (CR) cannot be achieved after at least 2 prior therapy regimens, high-risk MM in CR1 or CR2 and not eligible for SCT because of age or comorbid diseases, most recent progression-free interval < 1 year 
NCT05979363  A Study of Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by BCMA CAR-T Therapy in Transplant-Ineligible Patients with Primary Plasma Cell Leukemia Phase 2 Institute of Hematology & Blood Diseases Hospital, China 18 years to 75 years primary plasma cell leukemia Not considered for high-dose chemotherapy with Autologous Stem Cell Transplant (ASCT) 
NCT05870917  A Study of VRD-based Regimen Combined With CART-ASCT-CART2 Treatment in Patients with Primary Plasma Cell Leukemia Phase 2 Institute of Hematology & Blood Diseases Hospital, China 18 years to 65 years primary plasma cell leukemia Not received any treatment 
NCT05860036  A Study of VRd-based Regimen Followed by BCMA CAR-T Therapy in Transplant-Ineligible Patients with New-diagnosed Multiple Myeloma Phase 2 Institute of Hematology & Blood Diseases Hospital, China 18 years to 75 years NDMM, not considered for high-dose chemotherapy with autologous stem cell transplant (ASCT) 
NCT05838131  Study of CT071 Injection in RRMM or PPCL Early Phase 1 Shanghai Changzheng Hospital 18 years and older Three lines therapy for MM (requires relapse, progression, non-response after treatment with at least 1 PI and at least 1 immunomodulator Patients with primary plasma cell leukemia progressed after treatment with at least 1 regimen 
NCT05442580  CART-38 in Adult AML and MM Patients Phase 1 University of Pennsylvania 18 years and older Cohort B: relapsed/refractory MM (MM): ≥3 lines of therapy, to ensure the patient has been exposed to ≥1 IMiD®, ≥1 PI, and daratumumab 
NCT05412329 Study of Dual Targeted CD19/BCMA FASTCART GC012F in Relapsed/Refractory Multiple Myeloma Phase 1 Shanghai Changzheng Hospital 18 years to 70 years 3 different prior lines of therapy or primary refractory and PD within 12 months of their last line of therapy 
NCT05396885 Study of Anitocabtegene autoleucel in Relapsed or Refractory Multiple Myeloma (iMMagine-1) Phase 2 Kite, A Gilead Company 18 years and older Relapsed or refractory MM treated with at least 3 prior regimens of systemic therapy including PI, immunomodulatory drugs (IMiD) and anti-CD38 antibody and are refractory to the last line of therapy 
NCT04677452 Dose Exploration Study OF JWCAR129, BCMA-Targeted CART for RRMM Phase 1 The First Affiliated Hospital of Soochow University 18 years and older At least 3 prior anti-myeloma treatment regimens 
NCT04617704 BCMA and CD19 Targeted Fast Dual CART for Chromosomal Abnormalities High-risk BCMA+ Multiple Myeloma Early Phase 1 Shanghai Changzheng Hospital 18 years and older MM with high-risk chromosomal abnormal defined as presence of del17p, and/or t(4; 14) and/or t(14; 16) 
NCT04309981 Clinical Trial Using Humanized CART Directed Against BCMA (ARI0002h) in Patients with Relapsed/Refractory Multiple Myeloma to Proteasome Inhibitors, Immunomodulators and Anti-CD38 Antibody Phase 1 Phase 2 Sara V. Latorre 18 years to 75 years Previous two or more lines of treatment. Patients must have received at least a PI (such as bortezomib or carfilzomib), an immunomodulatory drug (lenalidomide or pomalidomide) and an anti-CD38 monoclonal antibody (such as daratumumab) 
NCT03549442 Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma Phase 1 University of Pennsylvania 18 years and older High-risk MM 
NCT03196414  Study of T Cells Targeting CD138/BCMA/CD19/More Antigens (CART-138/BCMA/19/More) for Chemotherapy Refractory and Relapsed Multiple Myeloma Phase 1 Phase 2 The First Affiliated Hospital of Soochow University 18 years to 75 years CD138 or BCMA antigen positive MM. Relapsed after prior autologous or allogenic SCT 

NDMM, newly diagnosed multiple myeloma.

CAR-T has emerged as a transformative therapy in MM leading to deep and durable responses. Two BCMA-targeted CAR-T have received approval in patients with early relapse with several frontline randomized trials underway. Additionally, several novel targets are being explored beyond BCMA. Relapses, however, are inevitable despite these early responses and are mediated by several factors. Multi-targeted CAR-T approaches as well as combination approaches are underway to overcome the relapse. Allogeneic CAR that offers “off-the-shelf” approach is being developed to mitigate the access issues. Future strategies with the established and the novel approaches are likely to provide a long-lasting remission in majority of the patients.

Binod Dhaka: consultancy – Genentech, Pfizer Speakers Bureau: Karyopharm, Janssen, Pfizer research funding: Janssen, Bristol-Myers Squibb, Carsgen, Arcellx, Sanofi, C4 Therapeutics Honoraria: Janssen, Bristol-Myers Squibb, Karyopharm, Genentech, Pfizer employment: Medical College of Wisconsin. Ravi Narra: consultancy – Sanofi, AstraZeneca, Incyte employment: Medical College of Wisconsin. Supriya Peshin: none employment: residency at Norton community Hospital.

The authors declare no relevant funding.

Conceptualization and manuscript review and editing: B.D. and R.N.; data collection: B.D., R.N., and S.P.; draft manuscript preparation: R.N. and S.P.; figures: S.P.; tables: R.N. All authors reviewed and approved the final version of the manuscript.

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