2025 Update of Cellular Immunotherapy for Plasma Cell Disorders.

Introduction
The lifespan of patients with multiple myeloma (MM) has improved dramatically both among newly diagnosed and relapsed/refractory MM (RRMM) patients. The introduction of quadruplet regimens to induction treatment has increased the estimated progression-free survival (PFS) of these patients to 17.1 years [1, 2, 3]. For RRMM patients, antibody-drug conjugates, bispecific-trispecific T-cell engagers (BITEs), and chimeric antigen receptor T (CAR-T) cells are novel treatments achieving very successful outcomes even among patients who are refractory to proteasome inhibitors (PIs), immunomodulating drugs (IMIDs), or anti-CD38 monoclonal antibodies [4]. While overall response rates (ORRs) of up to 30% were previously considered successful, RRMM patients are now able to obtain minimum ORRs of 60% with these novel agents following at least four lines of therapy (LoTs) [5].
CAR-T cells have been genetically modified to recognize myeloma-specific targets such as B-cell maturation antigen (BCMA), CD38, CD138, CD44v6, CD19, kappa light chain, FcRH5, SLAMF7, integrin β 7, NKG2D, semaphorin-4A, and G protein-coupled receptor, class C, group 5, member D (GPRC5D). These receptors contain CD3ζ-activating transmembrane intracellular costimulatory domains, a hinge region, and an extracellular single-chain variable fragment (scFv). There are currently five generations of CAR-T cells [6]. All currently approved CAR-T cells belong to the second generation of CAR-T products. There are also emerging new CAR-T cells from the third generation, also known as T-cells redirected for universal cytokine-mediated killing, which differ in their capacity to generate cytokines.
CAR-T cell-mediated cellular immunotherapy consists of three steps. First, T-cells are collected from the patient following lymphopheresis. These cells are transfected with a specific vector to expand for 1-3 weeks under ex vivo good manufacturing practice conditions. After quality checks, the CAR-T products are infused into the patient following bridging and then lymphodepletion therapy [4].The first successful CAR-T product reported in MM targets BCMA, and GPRC5D-targeting or dual-targeting CAR-T products were subsequently developed. The historical evolution of CAR-T trials is summarized in Figure 1.

Current CAR-T Therapies in Multiple Myeloma

Anti-BCMA CAR-T Products

Idecabtagene Vicleucel (Ide-Cel) (Abecma)
The first anti-MM CAR-T cell targeting BCMA contained a murine scFv plus a 4-1BB costimulatory domain. Among 24 RRMM patients following a median of 7.5 LoTs, the ORR and the complete response (CR) rate were respectively 81% and 13% [7]. Subsequently, another CAR-T product named ide-cel, which includes a murine scFv with a 4-1BB costimulatory domain, was developed. The first phase 1 study with ide-cel was conducted with 33 RRMM patients with an ORR of 85% [8]. The subsequent phase 2 study, KarMMa, resulted in an ORR of 73%, leading to U.S. Food and Drug Administration (FDA) approval on March 26, 2021 [9]. The KarMMa-2 study, conducted with 128 RRMM patients, resulted in an ORR of 81% and a CR rate of 39%. The median PFS and overall survival (OS) rates were 12.1 and 19.4 months, respectively. Cytokine release syndrome (CRS) and neurotoxicity were observed among 84% and 18% of these patients, respectively [10]. To address high-risk patients, those relapsing within 18 months after induction therapy (KarMMa-2a study) or not achieving very good partial response (VGPR) after autologous stem cell transplant (ASCT) (KarMMa-2c) were included in subsequent studies, resulting in an ORR of 83.8% and PFS of 11.4 months (KarMMa-2a) and ORR of 87.1% and 36-month PFS of 76.8% (KarMMa-2c) [11]. Following the approval of ide-cel, open-label phase 3 global studies were initiated, including the KarMMa-3 study. This study was conducted with 386 RRMM patients after 2-4 LoTs. Ide-cel demonstrated a significant PFS advantage compared to the standard of care (SOC). Rates of disease progression and death were also 51% lower compared to the SOC. The ORR was 42% with 39% of patients achieving CR [12]. Subsequently, the phase 1 KarMMa-4 study was designed for high-risk newly diagnosed MM (NDMM) patients; the results are not yet published yet [11]. The KarMMa-7 study is ongoing to investigate the efficacy and tolerability of ide-cel in combination with other agents [13]. The phase 3 KarMMa-9 trial (NCT06045806) is a maintenance trial investigating the efficacy and safety of ide-cel plus lenalidomide versus lenalidomide as maintenance therapy among NDMM patients achieving only VGPR or partial response (PR) following ASCT. When these studies are completed, CAR-T therapies may find their place among previously established treatment approaches.

Ciltacabtagene Autoleucel (Cilta-Cel) (Carvykti)
The second available CAR-T product was originally manufactured in China and sold to Janssen to be named ciltacabtagene autoleucel (cilta-cel). The first relevant study was the phase 1b CARTITUDE-1 study in which 97 RRMM patients following a median of 6 LoTs achieved an ORR of 97.9%, stringent CR (sCR) of 82.5%, and median 36-month PFS and OS of 34.9 months and 63%, respectively [14]. Based on this study, cilta-cel was approved by the FDA on February 28, 2022 [15]. Approval was expanded in 2024 to RRMM patients following one or more prior line with a PI plus IMID and lenalidomide refractoriness. Subsequently, the CARTITUDE-2 study involving patients after 1-3 LoTs was reported to result in an ORR of 88.9% following a median of 0.9 months [16]. Similarly to the KarMMa-3 study, a comparison against the SOC was planned in the CARTITUDE-4 study. Among 419 RRMM patients after 1-3 LoTs, an ORR of 85% versus 67% and 12-month PFS of 75.9% versus 48.6% were obtained, reflecting significantly better outcomes in the cilta-cel arm [17]. More recently, the phase 3 CARTITUDE-5 study was planned among NDMM transplant-ineligible patients to investigate the role of cilta-cel after frontline bortezomib, lenalidomide, and dexamethasone (VRD) therapy, comparing it against VRD and lenalidomide maintenance. The results have not yet been published (NCT04923893). CARTITUDE-6, another phase 3 trial, is comparing the efficacy of induction treatment with daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) followed by ASCT, DVRd consolidation, and maintenance treatment with lenalidomide against induction treatment with DVRd followed by a single infusion of cilta-cel and subsequent maintenance treatment with lenalidomide. This study has not yet reached its endpoint and does not yet have published results (NCT05257083).
Efficacy and adverse events reported by the KarMMa-3 and CARTITUDE-4 studies are illustrated in Figure 2. To compare the specificities of these two major commercially available anti-BCMA CAR-T products, Table 1 was prepared. In addition, early and advanced phase studies, either completed or ongoing and designed to target myeloma, are summarized in Tables 2, 3, and 4.

Other Anti-BCMA Agents
LCAR-B38M is another anti-BCMA CAR-T cell produced in China. In the LEGEND-2 study, its efficacy was investigated in 57 RRMM patients and highly successful results of 88% ORR and 74% CR were reported. The median PFS and OS rates were 18 and 55.8 months, respectively [18]. The 5-year follow-up results included 5-year unmaintained PFS of 21.0% and OS of 49.1%, suggesting the possibility of a cure in MM [18].
Fully humanized (FH) CAR-T products are also now being developed to mitigate immunogenicity. As an example, FHVH-T, administered to 25 RRMM patients, resulted in a median PFS of 65 weeks and ORR of 92% [19]. Another FH CAR-T product is equecabtagene autoleucel (CT103A), approved in China and used after 4 LoTs. The FUMANBA-1 study of eque-cel and the LUMMICAR-1 study of zevor-cel have presented academic products that will be discussed in the following sections [20].
PHE885 is a novel FH CAR-T product that uses the T charge platform to enable in vivo CAR-T expansion following the in vitro phase. The production time is less than 2 days and the ORR was found to be 98% in a trial including 46 RRMM patients (NCT04318327).
Another novel anti-BCMA technology developed to increase cell surface stability and reduce immunogenicity is the ddBCMA CAR-T product anitocabtagene autoleucel, with the synthetic D-domain increasing the stability and cytotoxicity of the product, resulting in an ORR of 100% and CR/sCR rate of 71% in 33 RRMM patients [21, 22].
Finally, to reduce immunogenicity and T-cell exhaustion, allogeneic CAR-T and CAR-NK cells acting against BCMA have been investigated. There are multiple advantages to such products, including off-the-shelf availability, younger donors, and lower costs. In Arm A of the UNIVERSAL study, the ALLO-715 CAR-T product was administered to 43 RRMM patients and an ORR of 55.8% was observed [22]. In the phase 1 P-BCMA-ALLO1 study, the piggyBac system, which has a non-viral transposon, was designed for RRMM patients (NCT04960579).
Following another innovative approach, anti-BCMA CAR-NK (FT576) derived from induced pluripotent stem cells has shown sustainable antitumor activity in mouse models [22]. A phase 1 clinical trial investigating its combination with daratumumab is ongoing (NCT05182073). Early-phase anti-BCMA studies are presented in Table 2 [23].

CAR-T Products for Alternative Myeloma Targets

G Protein Receptor Coupled 5 D (GPRC5D)
GPRC5D is another highly specific MM target molecule with proven efficacy with bispecific monoclonal antibodies targeting GPRC5D. Approaches targeting this antigen are still under development. MCARH109 is the first CAR-T product to be developed against GPRC5D, humanized, and modified with a lentiviral vector containing the 4-1BB costimulatory domain. Among 17 RRMM patients following 4 or more LoTs, the ORR was 71% [24]. In a series of 10 patients, another anti-GPRC5D molecule, OriCAR-017, achieved 100% ORR [25]. In addition, dual-affinity CAR-T cells recognizing both GPRC5D and BCMA have been developed to obtain an ORR of 86% among 21 RRMM patients [26].
One of the ongoing phase 3 studies is exploring arlo-cel, developed against GPRC5D. The QUINTESSENTIAL-2 (NCT06615479) study is comparing arlo-cel versus the relevant SOC and the primary endpoints are PFS and minimal residual disease (MRD) negativity. The results have not yet been published [27].

Fc Receptor-Homolog 5 (FcRH5)
FcRH5 is a member of the immunoglobulin superfamily expressed on malignant plasma cells three times more frequently than normal plasma cells. Discussions about the use of CAR-T products against this target are still premature. However, dual-target CAR-T studies are being conducted in murine xenograft models targeting both BCMA and FcRH5, obtaining stronger cytotoxicity, better cytokine-secreting capacity, and longer median survival compared to monospecific CAR-T products [28].

Other Targets
The expression of CD19 on mature MM cells is associated with poor prognosis [29]. GC012F is a BCMA-CD19 bispecific CAR-T product developed with FastCAR-T technology. Among 29 RRMM patients, the ORR/sCR rates were very high, as expected, reported as 93.1% and 82.8%, respectively [30].
Another target is CS1 (SLAMF7), which is also expressed predominantly on plasma cells. In a study investigating the efficacy of murine-derived CS1-BCMA bispecific CAR-T cell therapy, the ORR was found to be 81% among 16 RRMM patients [31].
TACI is a receptor belonging to the TNFR superfamily. It is also overexpressed on plasma cells. These two receptors have two ligands called B-cell activating factor and a proliferation-inducing ligand (APRIL). The AUTO2 study, conducted with APRIL, resulted in an ORR of 45.5%, lower than that obtained with major CAR-T products [32]. Trimeric APRIL-targeting CAR-T (TRIPRIL) cells are currently being investigated (NCT05020444).
Finally, CD38 and CD138 are worthy of note. The CD38-BCMA bispecific CAR-T cell named BM38 was administered to 23 RRMM patients to obtain an ORR of 87% [33]. In in vitro experiments, the combination of CAR-T cells with low affinity for CD138 and high affinity for CD38 was shown to be highly effective [34]. The use of non-viral vectors such as the Sleeping Beauty transposon vector has also facilitated stable gene integration [35].

Academic CAR-T Products
The numbers of CAR-T treatments are increasing gradually, but the manufacturing capacity of the pharmaceutical industry does not meet the current need. To increase access to CAR-T products, academic CAR-T manufacturing has been attempted as a solution. ARI0002h (cesnicabtagene autoleucel) is one of the first academic point-of-care BCMA-directed CAR-T cells. This construct is an autologous CAR-T cell with costimulatory domain 4-1BB and a humanized scFv that targets BCMA, manufactured at the University of Barcelona. In a study including 60 RRMM patients, the ORR was 95% (CR: 58%) in the first 3 months. Median PFS was 15.8 months, while median OS was not reached after a median follow-up period of 23.1 months. The CRS rate was 90%, but only 5% of these cases were of grade 3-4. Mild immune effector cell-associated neurotoxicity (ICAN) was reported for only 2 patients [36]. This product is currently approved and reimbursed in Spain.
HBI0101, another academic BCMA-targeting CAR-T therapy for MM, was produced in Israel. According to phase 1b/2 clinical trial results, the ORR was 90% (CR: 56%) with MRD negativity of 70% within a median follow-up period of 12.3 months. CRS of any grade was reported in 96% of patients (grade 3: 14%) and the neurotoxicity rate was 6% [37].
China has two academic CAR-T products: zevor-cel and eque-cel. Zevor-cel is a FH anti-BCMA CAR-T cell product currently being evaluated with phase I/II data in the LUMMICAR-1 study (NCT03975907). The outcomes to date are quite successful, including an ORR of 100%. Eque-cel is also a FH anti-BCMA CAR-T cell product. Its efficacy was examined in the FUMANBA-2 study (NCT05181501), demonstrating an ORR of 100%.
Anito-cel, initially an academic CAR-T product and previously known as CART-ddBCMA, is an anti-BCMA CAR-T product developed using an alternative method incorporating a novel synthetic D-domain. This approach enhances the efficacy of CAR-T cells. The iMMagine-1 study reported an ORR of 100% (NCT05396885). The results of these studies are summarized in Table 2.
At the Würzburg University Clinic, a highly effective and economical CAR-T product known as SLAMF7 has been produced using non-viral Sleeping Beauty transposon-based mRNA/minicircle DNA technology, and its efficacy is being evaluated in the CARAMBA study (phase I/IIA; EudraCT: 2019-001264-30). At Case Western Reserve University, a novel academic CAR-T product that bypasses in vitro expansion is being developed. This novel technology alleviates the need for and costs of good manufacturing practice facilities while reducing the manufacturing time to a week and reducing the costs to highly affordable levels [38].

Real-World Data
Clinical trial design mandates eligibility and exclusion criteria to harmonize efficacy and toxicity. The meticulous selection of patients increases the probability of a favorable outcome, underscoring the need for real-world data. For example, real-world data on ide-cel indicate that 75% of patients were not eligible to participate in the KarMMa study. Even among such patients, however, the 84% ORR (≥CR: 42%) and median PFS and OS of 8.5 and 12.5 months are highly acceptable. High-risk cytogenetics, younger age, hyperferritinemia, and BCMA-based bispecific administration before CAR-T therapy were found to impair the outcome. Severe CRS and neurotoxicity were observed at rates of 82.3% and 18.6%, respectively, demonstrating safety similar to that of the clinical trial [39]. Since cilta-cel studies started later, real-world data have not yet been finalized. However, early analyses show that 57% of real-world patients were not eligible for the CARTITUDE-1 study. The ORR was 84% with a ≥CR rate of 53%, and median PFS and OR have not been reached yet. The percentages of severe CRS and neurotoxicity were 80.5% and 18.6%, respectively, in line with previous safety results [40]. In a study presenting a single center’s experience with 87 RRMM patients after a median of 5 LoTs with CAR-T cells (both ide-cel and cilta-cel), the median PFS was found to be 17.5 months. No information about side effects was provided in this report [41]. In another study of a single-center, real-world experience with ide-cel, 16 triple-class-refractory patients were evaluated. After a median of 6 LoTs, the ORR was found to be 69% (>CR 50%), the CRS rate was 94%, and the ICAN rate was 6%; the ORR was lower than previously reported values [41]. In another study involving real-world data comparing ide-cel (n=162) and cilta-cel (n=42), cilta-cel was found to be superior in terms of ORR (93% vs. 79%; p<0.001). The 10-month PFS and OS rates for these products were 82% versus 47% (p<0.001) and 90% versus 77% (p=0.06), respectively. CRS and ICAN rates were similar [42]. Real-world data from the Myeloma CAR-T Consortium, CIBMTR, and Hansen et al. [40, 45] are presented in Figure 3 [43], where they are compared with pivotal data on ide-cel and cilta-cel [44].Cilta-cel is generally accepted as a more effective product while ide-cel is less toxic. Table 1 summarizes the features of these two commercially available CAR-T products.
Despite the demonstrated efficacy of approved CAR-T treatments, survival rates remain inferior among patients presenting with extramedullary disease (EMD) compared to patients without EMD. In a study presenting international multicenter real-world CAR-T data, 29% of patients in the ide-cel group and 48% in the cilta-cel group had EMD. The presence of EMD significantly shortened PFS in this study (p=0.01), without a significant effect on OS (p=0.11) [42].

CAR-T Therapies for Smoldering Myeloma
Smoldering MM (SMM) is an asymptomatic plasma cell disorder. The risk of progression from SMM to MM increases up to 70% in the presence of the 2/20/20 criteria [42, 46]. Whether these high-risk SMM patients should be treated is still a topic of debate [47]. Daratumumab monotherapy was recently approved for the treatment of high-risk SMM. To improve efficacy, the CAR-PRISMM study was designed. The main goal is to test the safety and effectiveness of cilta-cel in high-risk SMM. In the 6-month median follow-up period, an ORR of 100% with 50% CR was achieved among 6 patients. While CRS was observed in all patients, they were all low-grade cases without any neurological abnormalities excluding Bell’s palsy [48].
Another ongoing study of high-risk SMM is CAR-HiRiSMM (NCT06574126). This study is administering cilta-cel to high-risk SMM patients following DVRd. It is planned to monitor MRD for up to 5 years. While traditional treatments in SMM are still a topic of debate, more research is needed for CAR-T therapies to come to the forefront.

CAR-T Therapies for Amyloid Light-Chain Amyloidosis
Amyloid light-chain (AL) amyloidosis is a clonal plasma cell disorder and approximately only 20% of patients are suitable for transplantation. Treatment with daratumumab and bortezomib has become the SOC. Nevertheless, in patients not responding to treatment, poor tolerance of IMIDs, the cardiotoxicity of carfilzomib, and the limitation of venetoclax to t(11;14) reduce the treatment options, increasing the demand for CAR-T therapy [49]. NEXICART-2 (NCT06097832) is a single-arm, multi-phase 1b/2 dose escalation and expansion trial of the BCMA-targeting CAR-T NXC-201 in relapsed/refractory AL amyloidosis. Although 40 patients with relapsed/refractory AL amyloidosis were screened for this study, only 7 were able to enroll. The median follow-up period was 97 days, with treatment resulting in the normalization of all hematological parameters of AL amyloidosis. The ORR was 100% without any relapses. CRS was observed in 5 patients with no neurotoxicity. Renal organ response with a decrease in albuminuria was observed in 1 of 7 patients, and the New York Heart Association heart failure score regressed from class II to I in another patient.

Challenges and Strategies for Overcoming Them
The efficacy of CAR-T treatments is impressive but long-term success is not always possible. Loss of CAR-T cell persistency, immune system exhaustion, target antigen loss, shedding of BCMA into the circulation, and immunosuppressive factors constitute the mechanisms of resistance. In addition, challenges involving tumor penetrance, high tumor burden, and CAR-T product-related factors may develop [50, 51].
The MyCARe model is able to predict the risk of early relapse following CAR-T treatment. This score includes the presence of EMD or plasma cell leukemia, IMID refractoriness, and ferritin level at the time of lymphodepletion. The model calculates the 5-month relapse rate as 7% in the absence of all four risk factors and 53% in the presence of all four [52].
Antigen loss was also found to be an important parameter. In the KarMMa study, BCMA loss was observed in only 4% of patients, and subsequent studies have identified biallelic deletions and other mutations as causative factors [53]. For CAR-T cells to function, a certain threshold level of BCMA expression is required. To address this problem, BCMA-independent targets and dual-target products have been developed. The cleavage of BCMA by gamma-secretases, detaching it from the cell surface, increases the amount of soluble BCMA. In a study in which the oral gamma-secretase inhibitor JSMD194 was used concurrently with CAR-T therapy, antigen binding capacity increased by approximately 20 times and the ORR was 100% [54]. Gamma-secretase inhibitors are approved for the treatment of Alzheimer’s disease [55].
T-cell fitness and the tumor microenvironment are two examples of relevant host factors. The CD4/CD8T cell ratio decreases following several LoTs, which has an adverse effect on cells’ ability to proliferate and survive [56]. Having a high tumor burden and receiving multiple LoTs negatively affect T-cell performance [14]. The immunomodulatory effects of BITEs and radiotherapy positively influence CAR-T treatment outcomes [57, 58]. Tumor microenvironment-related factors include less CAR-T cells trafficking to tumor sites, such as in cases of EMD, resulting in a shorter duration of response. The enhancement of CAR-T cells in immunosuppressive environments may be possible with the production of CAR-NK cells expressing NKG2D, adding the granulocyte-macrophage colony stimulating factor inhibitor lenzilumab or other similar products [59, 60, 61].
FH or synthetic binding domains aim to reduce immunogenicity. The CD28 costimulatory region activates more slowly compared to 4-1BB, but its persistence is longer [62]. The addition of a PI3K inhibitor to ide-cel can increase memory-like T-cells in an ex vivo environment [8]. The development of CAR-T enhancers is among the most recent advancements in this area. CAR-T cells can selectively activate the interleukin (IL)-2 signaling pathway in the presence of an immunomodulatory ligand. Thus, IL-2-related toxicities decrease while T cell activation and antitumor activities are enhanced [63]. Faster production may also increase the effectiveness of CAR-T cells. For example, FasT-CAR was developed based on this need. The vein-to-vein time, which can reach up to 6 weeks, has been reduced to less than 2 days with this new technology [64]. Allogeneic CAR-T and CAR-NK technologies are alternative options to serve this purpose as they are off-the-shelf products. In addition, recent studies have shown that adding selinexor to CAR-NK therapies with downregulation of HLA-E positively contributed to the outcomes [65].
Finally, a breakthrough has occurred in China in the form of early results showing the feasibility of in vivo CAR-T transduction and expansion, allowing for the bypassing of ex vivo apheresis and expansion procedures and speeding up access. ESO-T01 (NCT06691685) is a CAR-T cell produced in a similar manner, featuring a nanobody target, lentiviral vector, BCMA targeting, and humanized in vivo proliferation capability. It has been administered to 4 patients with published results. Especially due to its in vivo tumor homing capability and success in infiltration, it appears promising, particularly for EMD patients [66]. A phase 1 study (inMMyCAR) recently presented at the American Society of Hematology’s 2025 session as publication number LBA-1 offers another in vivo CAR-T approach demonstrating MRD negativity within 3 months among 3 patients (NCT07075185) [67].

Conclusion and Future Perspectives
Following the highly successful results for RRMM, CAR-T cells are now moving to the frontline of MM treatment. However, investigations are still needed to improve the efficacy, shorten the vein-to-vein time, and decrease toxicity and costs while increasing access. Recent developments have begun to highlight ionizable lipid nanoparticle technology (L829-tLNP) and in vivo T cell engineering [68, 69]. Finally, the possibility of editing normal T-cells with the CRISPR-Cas9 gene editing system and in vivo CAR-T production may enhance access to and the success of CAR-T therapies in the near future [70].