How should we choose optimal salvage treatments following BCMA-directed CAR T-cell therapy?

Introduction

Pivotal clinical trials within the last few years have led to the approval of B-cell maturation antigen (BCMA) directed chimeric antigen receptor T-cell therapy (CAR-T) for the treatment of relapsed/refractory multiple myeloma (RRMM). In the KarMMa study of idecabtagene vicleucel (ide-cel), the median progression-free survival (PFS) was 8.8 months with an overall survival of 19.4 months [ 1 ]. Ide-cel had an overall response rate (ORR) of 73%, with 33% achieving a complete response (CR). In the subsequent CARTITUDE-1 study of ciltacabtagene autoleucel (cilta-cel), the median PFS was 34.9 months and the median OS was 60.7 months, with about one-third of patients alive and progression-free after 5 years [ 2 , 3 ]. Notably, cilta-cel also led to deep responses, with an ORR of 97.9% and 82.5% of patients achieving a stringent complete response (sCR) by 28 months [ 4 ]. These studies led to the FDA approval of ide-cel and cilta-cel for patients with RRMM after four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. More recently, the KarMMa-3 and CARTITUDE-4 studies have demonstrated improved PFS when compared to standard-of-care therapies in earlier line settings, and this prompted the FDA approvals for ide-cel after two or more prior lines of therapy (including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody) and cilta-cel after one or more prior lines of therapy (including a proteasome inhibitor and an immunomodulatory agent as well as being lenalidomide refractory) [ 5 , 6 ].

Despite the high response rates, relapses are common after BCMA CAR-T and most patients are not effectively cured. In total, 81% of patients had progressive disease (PD) after 2 years in the KarMMa trial [ 7 ] and 71.6% of patients had PD after 5 years in a follow-up study of patients from the LEGEND-2 trial using cilta-cel [ 8 ]. The studies that have evaluated responses to subsequent therapy after BCMA CAR-T have reported poor outcomes, with an ORR of 43.4% to first salvage therapy and median PFS of 3.5 months in one retrospective analysis of 79 patients [ 9 ]. Another study of 68 patients receiving salvage therapy after ide-cel reported median time to second disease progression of only 13.6 months from the time of ide-cel therapy [ 7 ]. This raises the critical question of which therapies post CAR-T are most likely to benefit patients, especially with BCMA CAR-T moving to earlier lines of therapy. Optimal salvage treatment strategies remain unclear for patients with RRMM with a relapse after BCMA-directed CAR-T, with no standard of care established to date. In this review, we discuss the mechanisms of relapse after BCMA CAR-T, salvage treatment options based on prospective and retrospective studies to date, and strategies when deciding on the sequencing of available salvage therapies.

Mechanisms of relapse

Proposed mechanisms of resistance to BCMA CAR-T can guide the decisions regarding optimal salvage treatment strategies for patients who relapse. These resistance mechanisms include T-cell exhaustion and poor CAR-T persistence, antigen loss or mutation, changes in the marrow microenvironment, and overall T-cell fitness ( Figure 1 ).

T-cell exhaustion is defined as an inhibition of T-cell proliferation and effector function that can arise due to persistent antigen stimulation. Studies evaluating T-cell phenotypes after CAR-T infusion have found that the presence of CD8+ T-effector memory cells and a greater CD4:CD8 T-cell ratio led to durable responses and better clinical outcomes [ 10 , 11 ]. Additionally, exhausted T-cells express inhibitory receptors such as PD-1, LAG-3, TIM-3, and CTLA-4 that have been the target of studies to improve the efficacy of CAR-T cells [ 12 ]. The co-stimulatory domains of CAR T-cells also play a significant role in their persistence and efficacy. Compared with CD28, the 4-1BB costimulatory domain used in both ide-cel and cilta-cel is associated with greater persistence and expansion of memory CD8+ T cells [ 13 ]. Novel synthetic binding D-domains, as seen with anitocabtagene autoleucel, have been used to overcome antigen-independent tonic signaling that can lead to T-cell exhaustion [ 14 ]. Newer CAR-T constructs also have evaluated fully humanized antigen binding domains to overcome anti-CAR immunogenicity [ 15 ]. Any inhibitory effects on CAR-T cells are further amplified by regulatory T-cells and myeloid-derived suppressor cells in the bone marrow microenvironment that express immunosuppressive cytokines such as TGFβ and IL-10 [ 16 ]. Attempting to overcome T-cell exhaustion and lack of persistence may be possible with modulating these pathways, and recent strategies of overcoming the suppressive tumor microenvironment have included metabolic engineering of CAR T-cells by modulating glycolysis, mitochondrial oxidative phosphorylation, and amino acid pathways [ 17 , 18 ]. Restoring T-cell function is particularly important as T-cell exhaustion may play a role in efficacy of a second CAR-T cell therapy or post-CAR-T bispecific treatment.

Antigen escape is another potential resistance mechanism of BCMA CAR-T, whereby the downregulation of BCMA due to the selection of treatment resistant clones or subpopulations may limit its efficacy as a target. While a complete loss of BCMA is rare, several studies have reported this phenomenon. Firestone et al. demonstrated that in a series of 30 patients with prior exposure to BCMA-directed therapies, 3 patients had therapy-related loss of plasma-cell BCMA expression by immunohistochemistry and very low-to-undetectable levels of soluble BCMA, with whole-exome sequencing confirming the presence of bialleic loss of TNFRSR17, the gene encoding BCMA. Notably, none of these patients had subsequent response to BCMA-directed bispecific therapy [ 19 ]. The FCARH143 trial reported a patient having BCMA-negative plasma cell population at 60 days recurring after CAR-T infusion [ 20 ], while another study also reported biallelic loss of BCMA expression 8 months after ide-cel infusion leading to relapse as well as lack of response to second CAR-T infusion [ 21 ]. Complete antigen loss is unlikely the predominant resistance mechanism of BCMA CAR-T, as reappearance or increase of soluble BCMA levels has been shown to be a marker for disease relapse after BCMA CAR-T [ 22 ]. However, another mechanism of antigen escape in the presence of soluble BCMA levels may be through extracellular domain mutations in BCMA leading to functional loss of binding epitopes and this has been identified in patients relapsing after BCMA-directed therapies. Lee et al. found that non-truncating missense mutations as well as in-frame deletions in the extracellular domain of BCMA can influence the binding affinity and efficacy of BCMA-directed T-cell engagers [ 23 ]. In patients with antigen escape, downregulation of BCMA expression, or mutations in the BCMA extracellular domain at the time of relapse, targeting alternative myeloma markers such as GPRC5D, SLAMF7, FCRH5, or CD38 may lead to more favorable responses.

As the early trials studied BCMA CAR-T in RRMM, prior treatment regimens are also thought to have an impact on T-cell fitness and therefore the efficacy of BCMA CAR-T. RRMM patients with greater exposure to more lines of therapy had a lower frequency of an early memory T-cell phenotype and lower CD4/CD8 ratio compared to patients undergoing leukapheresis after initial induction therapy [ 24 ]. Both ide-cel and cilta-cel have since been studied in earlier lines of therapy with KarMMa-3 and CARTITUDE-4 demonstrating promising efficacy [ 5 , 6 ], and now ongoing studies are evaluating BCMA CAR-T in the newly diagnosed setting. The choice of lymphodepletion regimen is also thought to influence CAR-T cell fitness by both reducing the risk of anti-CAR immunity and creating a favorable environment for T-cell expansion, with fludarabine and cyclophosphamide being used in most patients prior to BCMA CAR-T. There is now also emerging data that the gut microbiome and prior antibiotic exposure can influence BCMA CAR-T outcomes [ 25 ]. Given the heterogeneity in host factors, most patients with disease recurrence after BCMA CAR-T have multifactorial reasons for relapse without a single driving resistance mechanism.

Chemotherapy and transplant

Traditional cytotoxic chemotherapy can provide disease control in patients as a bridge to more definitive therapy. For patients who are not candidates or able to receive investigational or T-cell redirection therapies, chemotherapy can cytoreduce disease and has been studied in several retrospective analyses after BCMA CAR-T relapse. In a cohort of 79 patients who relapsed and received a median of 5 treatment lines before salvage therapy, Van Oeklen et al. demonstrated an ORR of 56.9% for chemotherapy with or without stem cell support, but with only 23.5% achieving at least a very good partial response (VGPR) [ 9 ]. Combinations of existing drug classes including immunomodulatory drugs (IMiDs), proteasome inhibitors, and anti-CD38 monoclonal antibodies had a low ORR of 28.3% with only 7.5% with a VGPR or better response [ 9 ]. This is expected as the majority of patients were refractory to one or more drug classes prior to BCMA CAR-T, with 68.4% of patients being penta-drug exposed and 38% being penta-drug refractory. In a subsequent retrospective analysis, Reyes at al individually evaluated response rates to each drug class as salvage therapy following BCMA CAR-T relapse in patients who received a median of 7 prior lines of therapy and among whom 66% were triple-class refractory and 26% were penta-drug refractory. Notably, alkylator-containing regimens with melphalan, cyclophosphamide, or bendamustine were found to be particularly effective with an ORR of 50% but were predominantly used for rapid PD and had median duration of therapy of only 1.3 months among 62 alkylator-containing lines of therapy received [ 26 ]. Of these lines, 3 included patients who received high-dose melphalan with autologous stem cell transplantation. Bendamustine, however, must be used with caution given its lymphotoxic effects on circulating T-cells if there are future plans for repeat apheresis and CAR T-cell therapy. Additionally, a venetoclax-based combination can be considered in patients with t(11;14) [ 27 ]. While effective as a bridging approach, responses to chemotherapy are rarely durable. In patients post BCMA CAR-T who also have cytopenias and a poor marrow reserve, cytotoxic chemotherapy can lead to more toxicity and treatment-related adverse events.

Van Oeklen et al. also evaluated responses in a subgroup of patients who received autologous (auto-SCT) or allogeneic stem cell transplantation (allo-SCT) following BCMA CAR-T. Among 14 patients who received auto-SCT, the ORR was 71.4% with a VGPR or better response in 50% of patients [ 9 ]. Four patients received an allo-SCT, among whom the ORR was 100% with a VGPR or better response in 50% of patients [ 9 ]. This suggests that for patients who have stored autologous stem cells, repeating auto-SCT can be an efficacious option as long as the patient remains fit and otherwise transplant eligible. This again may be complicated by the high rate of cytopenias after BCMA CAR-T [ 1 , 6 ]. While allo-SCT had a high response rate, this was only in a small cohort of patients and the advantages of the graft-vs-myeloma effect must be weighed against the risks of graft-vs-host disease and non-relapse mortality. There is a need for more data on outcomes for auto-SCT following BCMA CAR-T, as BCMA CAR-T therapies are moving into earlier lines of therapy and potentially in the future, may be part of frontline therapy (in lieu of upfront auto-SCT) pending results of studies such as CARTITUDE-6.

Retrial of BCMA-targeted therapy

Given that antigen loss is not the primary resistance mechanism of BCMA CAR-T, a retrial of therapy targeting BCMA may be a suitable approach, with several retrospective studies supporting the use of BCMA CAR-T (ide-cel or cilta-cel), BCMA bispecific antibodies (teclistamab and elranatamab) and BCMA antibody-drug conjugates (belantamab mafodotin).

In the original KarMMA trial, 28 patients were treated with a second infusion ide-cel, of whom 5 had a partial response (PR) and 1 had a VGPR. The ORR was 21.4% and the median PFS was only 1-month (DOR 1.9–6.8 months) after retreatment with the same product [ 1 ]. All responders received a higher cell dose during their second infusion. Only 3 patients were retreated with cilta-cel in CARTITUDE-1. Despite having at least a VGPR with the first infusion, all 3 patients had stable or progressive disease after the second infusion [ 4 ]. This occurred despite only 1 of the 3 patients developing anti-drug antibodies prior to retreatment. Together, these data suggest that a retrial of the same BCMA CAR-T product has limited efficacy given the challenges associated with T-cell exhaustion and development of anti-CAR-T antibodies.

Despite this, there is promising data that a trial of a different BCMA CAR-T product may lead to better salvage outcomes, especially if the second product has a different mechanism such as a different costimulatory domain or humanized binder. In one single-center study, 9 patients who initially achieved at least a VGPR on BCMA CAR-T were then infused with a second BCMA CAR-T product, with an ORR of 89% and median PFS of 8.3 months [ 26 ]. The ORR was 100% among patients with early relapse ( < 6 months) compared with 80% in patients with later relapse. Eight of the 9 patients were infused with a different BCMA CAR-T product. In a series of 5 patients who received cilta-cel between 8 and 38 months after ide-cel therapy, the ORR was 80% with a 6-month PFS rate of 75% [ 28 ]. This was supported by another retrospective analysis, in which 10 patients receiving cilta-cel after ide-cel had an ORR of 100% with a 6-month PFS rate of 64.8% [ 29 ]. Outcomes were worse among patients with early relapse after ide-cel ( < 12 months). Several additional studies have supported this finding in trials of fully humanized BCMA CAR-T products, such as CT103A and HRC0202. Four patients receiving CT103A after murine BCMA CAR-T had an ORR of 100%, with 3 patients achieving stringent complete response (sCR) status for at least 455 days post-infusion [ 30 ]. Separately, seven RRMM patients who received HRC0202 following BCMA CAR-T had an ORR of 71.4%, with 3 patients achieving a sCR or CR and 2 patients achieving a VGPR or PR [ 31 ]. The median PFS in this study was 269 days, and all patients who achieved at least a CR had sustained responses for at least 8 months. The available data on retrial of a second BCMA CAR-T product is limited to small series, yet demonstrates that a second CAR-T, especially if fully humanized, can overcome resistance mechanisms either by better persistence, avoiding immune neutralization, enhanced T-cell memory, or maximizing BCMA targeting.

Other FDA-approved T-cell redirection therapies that target BCMA include the bispecific antibodies teclistamab, elranatamab, and linvoseltamab. These bispecific antibodies engage CD3 on T cells and BCMA on plasma cells, facilitating the targeting of myeloma cells. In MajesTEC-1 trial, teclistamab had an overall ORR of 63% in a heavily pretreated population of patients with RRMM who had received at least 3 prior lines of therapy [ 32 , 33 ] and comparable response rates were observed in MagnetisMM-3 [ 34 ] and LINKER-MM1 [ 35 ] trials for elrantamab and linvoseltamab, respectively, facilitating accelerated FDA approval for these therapies. These studies were completed predominantly in patients without prior exposure to BCMA-directed therapies. However, a small subset of these prospective studies did include patients with prior anti-BCMA exposure. Cohort C of MajesTEC-1 studied a subgroup of 25 patients who had prior exposure to anti-BCMA treatment. Among 15 patients who had received prior BCMA CAR-T, the ORR for teclistamab was 53.3% with 46.7% of patients achieving a VGPR or better [ 33 ]. Among responders, responses were durable and deepened over time, as the median duration of response was 14.4 months. However, the median PFS in this cohort was only 4.4 months and the median OS was 14.9 months, suggesting that although responders may achieve a durable response, a fair proportion of patients may not respond and have a short PFS. In a pooled analysis of the MagnetisMM trials, among 36 patients previously treated with BCMA CAR-T therapy prior to elranatamab, the ORR of elranatamb was 52.8% (compared to 61% in BCMA treatment-naive patients). The duration of response (DOR) rate at 9 months was 78.9% for patients with prior BCMA CAR-T [ 34 ]. Linvoseltamab was recently FDA-approved based on the results of LINKER-MM1 trial demonstrating an ORR of 71% with 50% of patients achieving a CR or better; prior BCMA-directed therapies were excluded from this study and thus future studies are needed to assess its efficacy after prior BCMA therapy [ 35 ].

BCMA bispecific antibodies after BCMA CAR-T have also been evaluated in several retrospective cohort studies. In Reyes et al., the ORR for patients receiving BCMA bispecific antibodies as any line of salvage therapy after BCMA CAR-T was 60% ( n = 20 lines of therapy) with a median DOR of 4.4 months and median PFS of 3.6 months [ 26 ]. Both response rates and PFS were shorter for BCMA bispecific antibodies compared to patients who received subsequent BCMA CAR-T in this cohort. Other retrospective studies have demonstrated lower response rates, ranging from ORR 33–57% with short duration of response [ 9 , 34 , 36 , 37 ].

These results suggest that BCMA bispecific antibodies can be effective in patients following BCMA CAR-T. However, the response rates and duration of remission may be lower and shorter than in BCMA-naive patients. Using a BCMA bispecific as a salvage treatment option can leverage residual BCMA-expressing tumor and the patient’s T-cells, which may still be responsive, and may explain the better ORR and longer PFS rates for bispecifics compared to traditional salvage regimens [ 38 ]. BCMA bispecifics can thus prolong disease control or deepen responses by maximizing BCMA targeting. One of the challenges is that although some patients receiving BCMA bispecifics after prior BCMA CAR-T can achieve long-term responses, it may be difficult to predict if a patient will respond. Waiting a longer interval from last anti-BCMA treatment or assessing for BCMA expression by flow cytometry may be beneficial for efficacy of subsequent BCMA bispecific therapy. In one real-word data set of 385 patients who received teclistamab after prior BCMA-directed therapy, median PFS was higher (8.1 vs 2.5 months) in patients receiving teclistamab after 8.7 months from last BCMA-directed therapy [ 39 ]. Other BCMA bispecifics, including TNB-383B/ABBV-383 [ 40 ], are also being studied in ongoing trials, which may increase the availability of these products in the future for patients who relapse after BCMA CAR-T. The risks of bispecifics after CAR-T include infections due to cytopenias and/or persistent hypogammaglobulinemia. The risk of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) are similar regardless of prior BCMA CAR-T exposure.

Compared to a retrial of BCMA CAR-T and BCMA bispecific antibodies, the antibody drug conjugate belantamab mafodotin (belamaf) has had comparatively less efficacy as salvage therapy. Belamaf targets BCMA by delivering a cytotoxic payload (MMAF) to myeloma cells. Its overall use has been limited by corneal toxicity. Among nine patients who received belamaf after CAR-T, the ORR was 11% with a median PFS of 1 month and DOR of 2.8 months ( n = 9) [ 26 ]. In a separate study, the ORR was similarly low at 25% among eight patients, especially when compared to an ORR of 75% and a median PFS of 9.1 months among all patients receiving T-cell redirection therapy with CAR-T or bispecifics as first salvage therapy [ 9 ]. The limited efficacy of belamaf in the post-CAR-T setting could be due to lower BCMA expression and belamaf also requires functional uptake of the drug conjugate, creating an opportunity for separate resistance mechanisms. Given the low overall ORR, short PFS, and the risk of corneal toxicity that can impact quality of life, single agent belamaf may not be an optimal first-line salvage treatment option, but further data on combination strategies and its use subsequently after long wash-out from BCMA-directed therapies is warranted. At the time of this publication, belamaf is not currently available in the United States following its withdrawal from market after the DREAMM-3 phase 3 study [ 41 ]. However, the FDA is reevaluating belamaf for approval in combination with bortezomib/dexamethasone and pomalidomide/dexamethasone based on the positive DREAMM-7 and DREAMM-8 studies, respectively.

Targeting GPRC5D

The G protein-coupled receptor class C group 5 member D (GPRC5D) is another antigen highly expressed on myeloma cells and has demonstrated success as a target for anti-myeloma T-cell redirection therapy. GPRC5D, as a transmembrane receptor, does not have a serum or soluble component unlike BCMA so may be more likely to ensure that T-cells are appropriately targeting myeloma cells rather than free antigen [ 42 ]. Additionally, GPRC5D expression is independent of BCMA expression [ 43 ] and is expressed at low levels in normal tissues [ 44 ]. It has thus become an effective emerging treatment strategy for BCMA-exposed patients or patients with antigen escape following anti-BCMA therapy such as BCMA CAR-T.

Two bispecific antibodies that engage CD3 and GPRC5D, talquetamab and forimtamig, have been studied as salvage therapies. Talquetamab has since been approved by the FDA for RRMM in patients who have received at least 4 lines of prior therapy and thus has been used as a highly effective salvage strategy for patients after BCMA CAR-T. The MonumenTAL-1 study enrolled 48 patients who had received prior BCMA CAR-T, in whom the ORR was 72.9% [ 45 , 46 ]. This ORR for patients who received prior BCMA CAR-T was higher than for patients who had received prior BCMA bispecifics (52.2%) and comparable to the overall MonumenTAL-1 cohort, which had an ORR of 70% and 64% at both dose levels. Notably, the median PFS for patients with prior BCMA CAR-T exposure was 13 months versus 3.9 months for patients with prior BCMA bispecific exposure [ 47 ]. Forimtamig, another GPRC5DxCD3 bispecific antibody, had an ORR of 66.7% for all groups at a median DOR of 12.2 months and similar response rates in 5 patients who received prior CAR-T cell therapy [ 48 ].

Subsequent studies have tried to augment the efficacy of GPRC5D bispecifics using combination therapies. In the TRiMM-2 study, 9 of 50 total patients receiving talquetamab 0.8 mg/kg every 2 weeks and daratumumab had prior exposure to BCMA CAR-T and had an ORR of 88.9% [ 49 ]. 86% of all responders at 12 months still had an ongoing response [ 50 ]. Among patients receiving talquetamab, daratumumab, and pomalidomide in TRiMM-2, 31.2% of patients had prior exposure of BCMA CAR-T and this group had an ORR of 83.3% with 70.8% achieving at least a CR. The 12-month DOR and PFS rate was 84.4% and 73.9%, respectively, indicating deep and sustained responses [ 51 ]. The median PFS among all patients for this combination was 20 months. The RedirecTT-1 phase 1b/2 study of talquetamab plus teclistamab had an ORR of 78% across all dose levels and an estimated PFS of 70% at 18 months [ 52 ]. Four patients in this study had prior exposure to CAR-T and all of these patients responded to the combination therapy.

In addition, several prospective phase 1 trials have investigated GPRC5D CAR-T products and included patients with RRMM who had relapsed after BCMA CAR-T. In a cohort of 17 patients who received MCARH109, 10 patients received prior anti-BCMA therapy and 8 patients had received prior BCMA CAR-T [ 53 ]. The ORR was comparable between those who did and did not receive prior BCMA CAR-T at about 70% with 40% of patients achieving a CR or better, and the median duration of response was 7.8 months. Another more recent Phase 1 study of arlocabtagene autoleucel (BMS-986393) included 25 patients who had received prior BCMA CAR-T. ORR was 75% in this subgroup of patients, compared to 86% in the overall cohort of 70 patients [ 54 ]. 75% of responses were ongoing at 5.9 months of median follow-up. Similarly, the POLARIS trial of OriCAR-017 studied 10 patients, of whom 5 had prior BCMA CAR-T [ 55 ]. The ORR in this group was 100% with 40% achieving a CR or better. Estimated PFS at 9 months was 87.5%, with only one patient with prior BCMA CAR-T having relapsed at a median of 238 days of follow-up. Risks of the GPRC5D CAR-T products are similar to other CAR-T therapies with the addition of rashes, skin lesions, dysgeusia, nail changes, and cerebellar toxicity. The most common of these GPRC5D associated toxicities were nail changes, seen in 65% of patients who received MCARH109 [ 53 ].

GPRC5D targeting therapy has also remained highly effective in comparative retrospective studies of salvage therapies after BCMA CAR-T. Van Oekelen et al’s analysis included 79 patients receiving salvage therapy, of whom 23 patients received a non BCMA-directed bispecific trial and the ORR was 65% with at least 45% achieving a VGPR. This ORR was higher than response rates for BCMA-directed bispecifics, BCMA ADC, and other chemotherapies [ 9 ]. Separately, another analysis studying sequencing of T-cell redirection therapies included of 17 patients receiving salvage after BCMA CAR-T. Six patients received GPRC5D bispecifics, 2 patients receiving FcRH5 bispecifics, and 1 patient who received a BCMA and GPRC5D targeting trispecific antibody. The ORR of this group was 87.5%, with 37.5% achieving a CR or better. Notably, these response rates were higher than any other alternative salvage regimen studied, including traditional chemotherapy and allo-SCT, as well as sequential bispecific therapy prior to CAR-T [ 38 ]. This was further validated in a recent multi-center retrospective study of bispecifics after BCMA CAR-T, where the ORR of talquetamab was highest at 79% followed by teclistamab at 64% [ 56 ]. Median OS was not reached for either talquetamab or teclistamab after 8.6 months of follow-up, and both were effective in patients with early or late relapse (>3 months) after BCMA CAR-T [ 56 ]. Despite this, talquetamab appears to be more effective when administered >6 months after prior BCMA-directed therapies based one study of 63 patients (ORR 56.8% vs 84.6%, p = 0.02) [ 57 ].

These prospective and retrospective data suggest that GPRC5D is an ideal alternate target following BCMA CAR-T, as response rates are better compared to BCMA bispecifics and ADCs and may be more sustained when combined with existing agents such as daratumumab and pomalidomide. These therapies may especially be useful for patients with low BCMA expression or antigen escape after BCMA CAR-T, given that there is no cross-resistance with anti-BCMA therapies. Risks of GPRC5D targeting include rare cerebellar toxicities, skin/nail changes, dysgeusia, dermatologic rashes that improve with emollients and corticosteroids, and rates of CRS/ICANS comparable to other T-cell redirection therapies [ 58 ]. Cerebellar toxicities are also more rare with bispecific antibodies compared with GPRC5D CAR T-cells, with only one patient developing ataxia with talquetamab in the MonumenTAL-1 cohort [ 47 ]. More data is needed to study the efficacy of combination bispecific therapy and trispecific therapies, as well as the sequencing of bispecific therapies after BCMA CAR-T relapse given the increasing availability of these agents.

Other CAR-T cell therapy approaches

Beyond solely targeting BCMA and GPRC5D, other more effective and novel CAR-T approaches and targets are being explored, which may also provide options after BCMA CAR-T relapse.

One approach includes dual-target CAR-T cells. The advantage of this approach is to reduce the likelihood of relapse due to antigen escape. The creation of a single CAR-T product against two antigens, as opposed to infusion of two different CAR-T products, also homogenizes the cell product, eliminates the issue of uneven expansion, and potentially reduces manufacturing costs. Dual-target CAR-T cells may also have less on-target, off tumor toxicities through affinity optimization.

One logical approach is through a dual-target CAR-T against BCMA and GPRC5D, two well-established targets in the RRMM population. Dual-target BCMA/GPRC5D CAR-T cells reduced risk of BCMA escape-driven relapses and were associated with improved efficacy in MM xenograft models. In the first-in-human clinical trial of BCMA/GPRC5D CAR-T cells, an overall response rate of 86% was observed for 21 patients, including 100% response rates in 4 patients with BCMA negative MM cells [ 59 ]. The estimated PFS at 10 months was 84% for patients who received therapy at dose levels 2 and 3. Ongoing studies are further evaluating this treatment strategy for RRMM.

Another approach is by utilizing a dual BCMA/CD19 CAR-T product. Although CD19 is traditionally expressed on B-cells and only a subset of myeloma cells, there is a role for CD19 targeting in MM as the marker may be expressed at low but targetable levels and potentially in less differentiated MM precursors [ 60 ]. Dual BCMA/CD19 CAR-T takes advantage of this and was studied in a phase 1/2 trial in 50 patients. The ORR of 92% in this population of RRMM patients was one of the highest seen, although only 5 patients had prior CAR-T of any type and only 4 patients had penta-refractory disease. The ORR among prior CAR-T recipients was 60% with 2 patients achieving a sCR and 1 achieving a PR. The median PFS and OS among the entire cohort was 19.7 months [ 61 ]. Ongoing studies are investigating G012F (AZD010), another dual BCMA/CD19 CAR-T, with preliminary results demonstrating an ORR of 100% with all 19 patients achieving stringent complete response and minimal residual disease negativity [ 62 ].

SLAMF7, also called CS1, is another transmembrane protein that serves as an immune checkpoint to suppress the cytotoxicity of NK and T cells and is found to be expressed as a growth factor on myeloma cells. This led to the approval of elotuzumab, a monoclonal antibody targeting SLAMF7 [ 63 , 64 ]. Subsequently, a BCMA/SLAMF7 CAR-T trial in 16 patients was found to have an ORR of 81% and sCR rate of 38%. This trial included 2 patients who relapsed after BCMA CAR-T, of whom 1 achieved a VGPR and another has progressive disease [ 65 ].

Other single target CAR-T cells are being explored against other targets such as CD38, FcRH5, and light chains. In a mouse model, disease control was superior in mice treated with CD38 CAR-T compared with mice receiving BCMA CAR-T at similar levels of expression of both antigens, though CD38 CAR-T also led to significant hematopoietic toxicity [ 66 ]. Another study of CD28ζ CAR-T cells targeting FcRH5 found that they were successful in impeding tumor growth both in vitro and in xenograft murine models even in populations with low BCMA expression [ 67 ]. A phase 1 clinical trial of kappa light chain CAR-T included 7 patients with RRMM with an ORR of 57% [ 68 ]. Allogeneic CAR-T cells, CAR-NK, and T-cell receptor-based therapies are also in development and may be an option in the future for patients as possible salvage therapies.

Novel targets

Other salvage strategies with novel and alternative targets may be useful in overcoming resistance mechanisms seen with BCMA and GPRC5D. These include selinexor, cevostamab, modakafusp alfa, cereblon E3 ligase modulator drugs, and PD-1 inhibitors.

Selinexor is an oral selective inhibitor of the nuclear export protein XPO1 that regulates gene expression and cell cycle progression. It has a unique mechanism compared to other myeloma targets in that it can restore tumor suppressor function and induce apoptosis and notably is already FDA approved for use in RRMM with dexamethasone. In the phase 3 BOSTON trial, median PFS was extended to 13.9 months by the addition of selinexor to bortezomib and dexamethasone from 9.46 months in the control arm [ 69 ]. In a cohort of 122 patients with triple-class refractory myeloma, the ORR was 26% with a median PFS of 3.7 months and median OS of 8.6 months [ 70 ]. Data for selinexor post BCMA CAR-T is limited to retrospective series. The ORR in one cohort among 13 lines of therapy was 46% with a median duration of therapy of 2 months [ 26 ], while in another cohort of 14 patients, the ORR was lower at only 21.4% [ 9 ]. In this group, 2 out of 5 patients who received selinexor as first-line salvage therapy responded to treatment [ 9 ]. An earlier study of 7 patients who received selinexor as first-line salvage therapy had a better ORR of 85.7% with 4 patients achieving a VGPR of better [ 71 ]. From the limited available data, selinexor may be an active agent after BCMA CAR-T relapse and may also improve T-cell fitness to promote efficacy of subsequent immunotherapies [ 72 ]. Selinexor appears to be most effective when given in combination with other anti-myeloma therapies rather than as single-agent, and response rates exceeding 70% have been observed with combination therapies in heavily pre-treated patients [ 73 ].

Another emerging therapy is cevostamab, a bispecific antibody targeting the FC receptor-homolog 5 (FcRH5) receptor that is expressed on myeloma cells and CD3 on T-cells. Because it is expressed on almost all myeloma cells, FcRH5 is a promising anti-myeloma target that is independent from BCMA and does not demonstrate cross-resistance. Updated data from an ongoing Phase 1 trial of 167 patients revealed an ORR of 43.1% in a population where the majority of patients (57%) had received prior anti-BCMA therapy, with a median DOR of 10.4 months. The ORR was slightly lower at 33.3% among the 20 patients who had received prior CAR-T therapy and 30.0% in patients who had received prior bispecific antibodies [ 74 ]. Many patients have shown durable responses beyond 1 year. Safety risks with cevostamab include high rates of CRS in 74.3% (1.8% Grade 3–4) of patients and transient neutropenia in 31.1% (28.2% Grade 3–4) [ 74 ]. Cevostamab is being studied in ongoing Phase 2 and 3 trials, and if approved, would be a novel off-the-shelf bispecific agent that could be sequenced after both BCMA and GPRC5D targeting therapies or combined with them since it involves a novel target with independent expression.

Modakafusp alfa is an immunocytokine designed to deliver IFNα2b to CD38+ cells, consisting of IFNα2b molecules focused to an anti-CD38 monoclonal antibody. In a phase 1/2 study of 30 patients receiving modakafusp alfa 1.5 mg/kg every 4 weeks, about 50% received anti-BCMA therapy and 26.7% received prior CAR-T. Compared to an overall ORR of 43% with a median PFS of 5.7 months, the ORR in recipients of prior anti-BCMA therapy was lower at 28%, but this group also had overall more extensive prior lines of therapy [ 75 , 76 ]. Among patients who were anti-BCMA therapy refractory, the ORR was similar at 29% [ 76 ].

Another class of drugs being studied for their utility in RRMM are cereblon E3 ligase modulator compounds (CELMoDs). These compounds, such as iberdomide and mezigdomide, co-opt cereblon, which plays a crucial role in the ubiquitination of target proteins and leads to the degradation of the lymphoid transcription factors Ikaros and Aiolos, and in addition, these agents have been found to increase activation of T and NK cells while reducing T-cell exhaustion markers [ 77 ]. In a study of mezigdomide plus dexamethasone in patients with triple-class refractory MM, the ORR was 25% but higher at 50% in patients treated with prior anti-BCMA therapy. The median PFS in patients treated after anti-BCMA therapy was 5.4 months, compared with 4.4 months in the overall cohort [ 78 ]. In a separate study of iberdomide and dexamethasone from the CC-220-MM-001 trial, the ORR was 36.8% among patients receiving prior anti-BCMA therapy, including 36.8% of patients who received anti-BCMA CAR T-cell therapy. The median duration of response was 7.5 months, but with a lower median PFS of only 2.4 months [ 79 ].

Anti-PD1 immune checkpoint inhibitors are of potential interest as PD-1 levels are increased in the setting of T-cell exhaustion and immunosuppressive tumor microenvironments, all contributors to relapse after CAR-T cell therapy. Nivolumab is a monoclonal antibody that targets PD-1 on T cells to limit immune evasion in myeloma. In a prospective trial of 11 patients who received nivolumab after any CAR-T therapy, the ORR was only 18%. However, among the two patients who responded, both achieved a VGPR by Day +28 and had sustained responses of at least 198 days [ 80 ]. More data is needed to support the efficacy of checkpoint inhibitors as salvage therapy after BCMA-CAR T relapse, including appropriate patient selection and whether combination with other T-cell re-vitalizing therapies may be more effective.

Future perspective

Patients relapsing after BCMA CAR-T have historically had a poor prognosis with a median OS of 18 months from the time of relapse [ 26 ]. Efforts to improve on this depend on developing optimal sequencing strategies to most effectively utilize available salvage therapies. A summary of all salvage therapies with their corresponding ORR and PFS is listed in Table 1 . Most of the available data evaluating the efficacy of salvage therapies is in patients who received BCMA CAR-T after at least 4 prior lines of therapy, and outcomes may be better in patients who receive BCMA CAR-T during earlier lines of therapy.

Given that relapses may be due to BCMA tumor antigen loss and the well-established nature of GPRC5D as a targetable MM antigen, a rational initial approach would be to target GPRC5D, either with the currently FDA-approved bispecific talquetamab or an alternative GPRC5D-targeted T-cell engager (e.g., on clinical trial). A retrial of BCMA-directed therapy, either via ide-cel, cilta-cel, or BCMA bispecifics can yield high ORR’s of 60–90% when a different product is used, but there is caution for reduced durability of responses, especially when BCMA bispecifics are used after prior BCMA CAR-T and there is short time interval between two BCMA-directed therapies. Other established therapies including immunomodulatory drugs and proteasome inhibitors can be tried, especially if patients are not refractory to the specific agent.

As BCMA CAR-T therapies are moving to earlier lines, many patients post-BCMA CAR-T relapse may be treatment-naïve to commonly used RRMM therapies including pomalidomide and carfilzomib, and these would be reasonable to trial in treatment sensitive patients. In patients with rapidly aggressive disease, conventional chemotherapy or retransplant can be considered, especially if previously collected autologous stem cells are available. Clinical trials exploring novel treatments, combinations, and strategies are highly encouraged, as the above options, although effective, are not able to achieve long-term remissions or cures for the majority of patients.

Given the increasing number of BCMA-directed therapies, it is likely that patients will undergo re-trial of a BCMA directed therapy after relapse from prior BCMA CAR-T. Assessing BCMA expression on myeloma cells would be a potentially attractive methods to predict subsequent response for patients. However, tools to reliably assess myeloma BCMA expression by immunohistochemistry and flow cytometry assays are still not yet standardized or widely available in clinical practice. Based on current available data, responses and duration of response are better with a longer duration elapsed between two BCMA-directed therapies, and thus in clinical practice, it is preferable that duration of time is>12 months if possible. A second BCMA CAR-T may be an option for select patients with good performance status, and in these situations, a different construct should be utilized, preferably with a dual target CAR-T or fully humanized BCMA CAR-T. If a second BCMA CAR-T is planned, it may be preferable to avoid the use of BCMA bispecifics in the interim, as the duration of anti-BCMA exposure appeared to inversely correlate with subsequent CAR-T associated responses in the CARTITUDE-2 study [ 82 ].

As many of the newest and most active myeloma therapies utilize T-cell redirection, optimizing T-cell fitness is of utmost importance. Unfortunately, sequential T-cell engaging therapies are associated with T-cell exhaustion, limiting sustained treatment responses. Strategies aimed at reinvigorating T-cells and controlling the immunosuppressive tumor microenvironment are paramount for long-term disease control. Agents such as the CELMODs (iberdomide, mezigdomide) and to a lesser-degree, the iMiDs, have been found to promote T-cell activation and improve the innate and adaptive immune response [ 83 , 84 ]. These agents are being studied post-CART administration and in combination with bispecific therapies to augment therapy responses. Regulatory T-cells, expressing CD38, also play a role in suppressing cytotoxic T-cell responses, and the utilization of anti-CD38 therapies with bispecific T-cell therapies have shown favorable response profiles and are further being investigated in clinical trials. ISB 2001 is a novel CD3xBCMAxCD38 trispecific antibody under investigation with preliminary data showing high response rates in patients with prior CD38 refractoriness and prior BCMA exposure [ 85 , 86 ]. Selinexor may also have a role in promoting T-cell fitness, as combination studies assessing XPO1 inhibitors and CAR-T cells have shown that pretreatment with XPO1 inhibitor increased CAR-T cell killing and reduced T-cell exhaustion markers. Importantly, high-dose alkylating agents and bendamustine must be used with caution as they are lymphodepleting and particularly should be avoided prior to apheresis for CAR-T. A summary of available salvage treatment options and a practical approach to sequencing them is illustrated in Figure 2 .

There are still several unanswered questions in the field. Approaches for salvage after BCMA CAR-T have not specifically been studied in frail patients for whom several lines of T-cell redirection therapies may not be feasible. The role of maintenance therapy after CAR-T, while it has been shown in some studies to enhance PFS and deepen responses [ 87 ], is still unclear. Several prospective studies examining various approaches to T-cell redirection therapy sequencing, such as a Phase 2 trial of talquetamab consolidation after ide-cel ( NCT06066346 ), are ongoing. The role of allogeneic CAR-T cell therapies are being explored in trials, such as with ALLO-715 in the Phase 1 UNIVERSAL trial [ 88 ] and P-BCMA-ALLO1 in a Phase 1/1B trial [ 89 ]. Trispecific T-cell engagers and dual-targeted CAR-T therapies will hopefully prevent antigen escape and allow for treatment of disease with variable target expressivity; whether these multi-targeted therapies are better than sequential treatment or individual products combined warrants further investigation. Future comparative trials with preplanned randomization to specific salvage regimens at the time of CAR-T infusion should also be conducted for better head-to-head comparisons of therapies post CAR-T. There may also be a role for biomarkers such as high-risk cytogenetics, genomic profiling, or soluble BCMA levels that can help risk stratify patients who need consolidation or maintenance after BCMA CAR-T.

Relapse after BCMA CAR-T, while still an emerging area of study, has several efficacious treatment options. Until consensus guidelines develop in the future, optimal salvage strategies will need to be individualized for each patient to maximize disease control and translate into better outcomes for myeloma patients after relapse from CAR-T therapy.

Funding Statement

This paper was not funded.

Article highlights

Despite high initial response rates, relapse is common after BCMA CAR-T

Optimal salvage treatment after BCMA-directed CAR-T is unknown, with no standard of care established to date.

Resistance mechanisms after BCMA CAR-T include T-cell exhaustion and poor CAR-T persistence, antigen loss, changes in the marrow microenvironment, and overall T-cell fitness. These can guide selection of salvage therapies after BCMA CAR-T.

Targeting GPRC5D, including with FDA-approved bispecific talquetamab, may be a rationale option for heavily pre-treated patients with relapsed/refractory multiple myeloma.

The use of alternative BCMA T-cell engaging therapies can yield initial high response rates, but duration of response may be lower than those who are BCMA-naïve and longer washout between BCMA targeting is preferable.

Other therapeutic targets, novel immunotherapies, and combination therapies are being explored in multiple myeloma patients with relapsed/refractory disease post-BCMA therapies.

Author contributions

Arvind Suresh: Conceptualization, Methodology, Formal analysis, Investigation, Visualization, Writing-Original Draft, Writing-Review & Editing

Darren Pan: Writing-Review & Editing

Jodi Lipof: Writing-Review & Editing

Anupama Kumar: Writing-Review & Editing

Shagun Arora: Writing-Review & Editing

Peter Sayre: Writing-Review & Editing

Jeffrey Wolf: Writing-Review & Editing

Thomas Martin: Writing-Review & Editing, Supervision

Ajai Chari: Writing-Review & Editing, Supervision

Alfred Chung: Conceptualization, Methodology, Visualization, Writing-Original Draft, Writing-Review & Editing, Supervision

Disclosure statement

D. Pan has received honoraria from Sanofi. J. Lipof has received research funding from Karyopharm and honoraria from Sanofi. A. Kumar has received research funding from Bristol Myers Squibb and Janssen and will be receiving an honorarium from Sanofi. J. Wolf reported consulting activity for Adaptive Biotech. T. Martin has received research funding from Sanofi, Janssen, and Bristol Myers Squibb, advisory board for GlaxoSmithKline and Pfizer, and reported consulting activity for GlaxoSmithKline, Pfizer, and Arcellex. A. Chari has received research funding from Janssen, and he reported consulting activity for AbbVie, Adaptive, Amgen, Antengene, Bristol Myers Squibb, Forus, Genentech/Roche, GlaxoSmithKline, Janssen, Karyopharm, Millenium/Takeda, and Sanofi/Genzyme. A. Chung has received research funding from AbbVie, Bristol Myers Squibb, Caelum, CarsGen, Cellectis, Janssen, K36 Therapeutics, and Merck Consulting, and he reported consulting activity for Janssen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

A reviewer on this manuscript has disclosed that they have consulted for BMS, Johnson and Johnson, Biolegend, Takeda and Sanofi. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

1. Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705–716. doi: 10.1056/NEJMoa2024850 •• This pivotal clinical trial established the efficacy of ide-cel, one of the main BCMA CAR T-cell therapy options for relapsed/refractory multiple myeloma in use today.

2. Berdeja JG, Madduri D, Usmani SZ, 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. doi: 10.1016/S0140-6736(21)00933-8 • This pivotal clinical trial established the efficacy of cilta-cel, one of the main BCMA CAR T-cell therapy options for relapsed/refractory multiple myeloma in use today. It also had better response rates than ide-cel.

3. Jagannath S, Martin TG, Lin Y, et al. Long-term (≥5-year) remission and survival after treatment with ciltacabtagene autoleucel in CARTITUDE-1 patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2025;43(25):2766–2771. doi: 10.1200/JCO-25-00760

4. Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene autoleucel, an anti–B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J Clin Oncol. 2023;41(6):1265–1274. doi: 10.1200/JCO.22.00842

5. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002–1014. doi: 10.1056/NEJMoa2213614

6. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335–347. doi: 10.1056/NEJMoa2303379

7. Rodriguez-Otero P, San-Miguel JF, Anderson LD, et al. Subsequent anti-myeloma therapy after Idecabtagene Vicleucel (ide-cel, bb2121) treatment in patients with relapsed/refractory multiple myeloma from the KarMMa study. Blood. 2021;138(Supplement 1):2743. doi: 10.1182/blood-2021-14799034967867

8. Xu J, Wang B-Y, Yu S-H, et al. Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial. J Hematol Oncol. 2024;17(23). doi: 10.1186/s13045-024-01530-z

9. Van Oekelen O, Nath K, Mouhieddine TH, 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. doi: 10.1182/blood.2022017848 This retrospective cohort analysis of patients receiving salvage therapy after BCMA CAR-T evaluated a wide range of subsequent therapies and demonstrated the utility of both a retrial of BCMA targeted therapy as well as targeting alternative myeloma tumor antigens.

10. Cohen AD, Garfall AL, Stadtmauer EA, et al. B cell maturation antigen–specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019. 3;129(6):2210–2221. doi: 10.1172/JCI126397

11. Ledergor G, Fan Z, Wu K, et al. Cd4+ CAR-T cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR-T cell therapy. Blood Adv. 2024;8(13):3562–3575. doi: 10.1182/bloodadvances.2023012416

12. Xia A, Zhang Y, Xu J, et al. T cell dysfunction in cancer immunity and immunotherapy. Front Immunol. 2019;10(1719). doi: 10.3389/fimmu.2019.01719

13. Labanieh L, Mackall CL.. Car immune cells: design principles, resistance and the next generation. Nature. 2023;614(7949):635–648. doi: 10.1038/s41586-023-05707-3 • This review article provides a comprehensive overview of reasons for relapse after CAR T-cell therapy and approaches to overcome resistance mechanisms.

14. Frigault MJ, Bishop MR, Rosenblatt J, et al. Phase 1 study of CART-ddBCMA for the treatment of subjects with relapsed and refractory multiple myeloma. Blood Adv. 2023;7(5):768–777. doi: 10.1182/bloodadvances.2022007210

15. Lam N, Trinklein ND, Buelow B, et al. Anti-BCMA chimeric antigen receptors with fully human heavy-chain-only antigen recognition domains. Nat Commun. 2020;11(1):283. doi: 10.1038/s41467-019-14119-9

16. Holthof LC, Mutis T. Challenges for immunotherapy in multiple myeloma: bone marrow microenvironment-mediated immune suppression and immune resistance. Cancers (Basel). 2020;12(4):988. doi: 10.3390/cancers12040988

17. Shen L, Xiao Y, Tian J, et al. Remodeling metabolic fitness: strategies for improving the efficacy of chimeric antigen receptor T cell therapy. Cancer Lett. 2022;529:139–152. doi: 10.1016/j.canlet.2022.01.006

18. McPhedran SJ, Carleton GA, Lum JJ. Metabolic engineering for optimized CAR-T cell therapy. Nat Metab. 2024;6(3):396–408. doi: 10.1038/s42255-024-00976-2

19. Firestone RS, Socci ND, Shekarkhand T, et al. Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma. Blood. 2024;144(4):402–407. doi: 10.1182/blood.2023023557

20. Green DJ, Pont M, Sather BD, et al. Fully human BCMA targeted chimeric antigen receptor T cells administered in a defined composition demonstrate potency at low doses in advanced stage high risk multiple myeloma. Blood. 2018. 29;132(Supplement 1):1011. doi: 10.1182/blood-2018-99-117729

21. Samur MK, Fulciniti M, Aktas Samur A, et al. Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat Commun. 2021. 8;12(1):868. doi: 10.1038/s41467-021-21177-5

22. Shen Y, Liu J, Wang B, et al. Serum soluble BCMA can be used to monitor relapse of multiple myeloma patients after chimeric antigen receptor T-cell immunotherapy. Curr Res Transl Med. 2023. 1;71(2):103378. doi: 10.1016/j.retram.2023.103378

23. Lee H, Ahn S, Maity R, et al. Mechanisms of antigen escape from BCMA-or GPRC5D-targeted immunotherapies in multiple myeloma. Nat Med. 2023;29(9):2295–2306. doi: 10.1038/s41591-023-02491-5

24. Dancy E, Garfall AL, Cohen AD, et al. Clinical predictors of T cell fitness for CAR T cell manufacturing and efficacy in multiple myeloma. Blood. 2018;132(Supplement 1):1886–1886. doi: 10.1182/blood-2018-99-115319

25. Hu Y, Li J, Ni F, et al. Car-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies. Nat Commun. 2022. 9;13(1):5313. doi: 10.1038/s41467-022-32960-3

26. Reyes KR, Liu YC, Huang CY, et al. Salvage therapies including retreatment with BCMA-directed approaches after BCMA CAR-T relapses for multiple myeloma. Blood Adv. 2024. 14;8(9):2207–2216. doi: 10.1182/bloodadvances.2023012066 •• This retrospective cohort analysis of patients receiving salvage therapy after BCMA CAR-T evaluated a wide range of subsequent therapies and demonstrated the utility of both a retrial of BCMA CAR-T as well as other BCMA targeted therapies, such as bispecific antibodies.

27. Chakraborty R, Bhutani D, Lentzsch S. How do we manage t (11; 14) plasma cell disorders with venetoclax? Br J Haematol. 2022. Oct;199(1):31–39. doi: 10.1111/bjh.18243

28. Attar N, Cirstea D, Branagan AR, et al. Use of cilta-cel CAR T cells following previous use of a BCMA-directed CAR T-cell product in heavily treated patients with relapsed/refractory multiple myeloma: a single institution case series. Blood. 2023;142(Supplement 1):6924–6924. doi: 10.1182/blood-2023-182212

29. Richardson T, Holtick U, Frenking JH, et al. Sequential BCMA CAR T-cell therapy in refractory multiple myeloma. Blood Adv. 2025;9(18):2025016712. doi: 10.1182/bloodadvances.2025016712

30. Wang D, Wang J, Hu G, et al. A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. Blood J Am Soc Hematol. 2021. 27;137(21):2890–2901. doi: 10.1182/blood.2020008936

31. Wang Q, Wei R, Guo S, et al. An alternative fully human anti-BCMA CAR-T shows response for relapsed or refractory multiple myeloma with anti-BCMA CAR-T exposures previously. Cancer Gene Ther. 2024. Mar;31(3):420–426. doi: 10.1038/s41417-023-00712-0

32. Moreau P, Garfall AL, Donk NW, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022. 11;387(6):495–505. doi: 10.1056/NEJMoa2203478

33. Touzeau C, Krishnan AY, Moreau P, et al. Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies. Blood. 2024. 5;144(23):2375–2388. doi: 10.1182/blood.2023023616

34. Nooka AK, Lesokhin AM, Mohty M, et al. Efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma (RRMM) and prior B-cell maturation antigen. J Clin Oncol. 2023;41(16_suppl):8008. doi: 10.1200/JCO.2023.41.16_suppl.8008

35. Bumma N, Richter J, Jagannath S, et al. Linvoseltamab for treatment of relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(22):2702–2712. doi: 10.1200/JCO.24.01008

36. Riedhammer C, Bassermann F, Besemer B, et al. Real-world analysis of teclistamab in 123 RRMM patients from Germany. Leukemia. 2024. Feb;38(2):365–371. doi: 10.1038/s41375-024-02154-5

37. Dima D, Davis JA, Ahmed N, et al. Safety and efficacy of teclistamab in patients with relapsed/refractory multiple myeloma: a real-world experience. Transpl Cell Ther. 2024. 1;30(3):308.e1–e1. doi: 10.1016/j.jtct.2023.12.016

38. Puertas B, Fernández-Sánchez A, Alejo E, et al. A research center’s experience of T-cell–redirecting therapies in triple-class refractory multiple myeloma. Blood Adv. 2024. 9;8(13):3478–3487. doi: 10.1182/bloodadvances.2024012773

39. Dima D, Vazquez-Martinez MA, Davis JA, et al. Outcomes of teclistamab (tec) in patients with relapsed/refractory multiple myeloma (RRMM) with prior exposure to BCMA-Directed therapy (BCMA-DT): a multicenter study from the U.S. Multiple Myeloma Immunother Consortium. Blood. 2024;144(Supplement 1):897. doi: 10.1182/blood-2024-203409

40. Kumar S, D’Souza A, Shah N, et al. A phase 1 first-in-human study of tnb-383B, a BCMA x CD3 bispecific T-cell redirecting antibody, in patients with relapsed/refractory multiple myeloma. Blood. 2021;138(Supplement 1):900–900. doi: 10.1182/blood-2021-150757

41. Dimopoulos MA, Hungria VTM, Radinoff A, et al. Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study. Lancet Haematol. 2023;10(10):e801–e812. doi: 10.1016/S2352-3026(23)00243-0

42. Del Giudice ML, Galimberti S, Buda G. Beyond BCMA, why GPRC5D could be the right way: treatment strategies with immunotherapy at relapse after anti-BCMA agents. Cancer Immunol, Immunother: CII. 2023;72(12):3931–3937. doi: 10.1007/s00262-023-03559-4

43. Smith EL, Harrington K, Staehr M, et al. Gprc5d is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019. 27;11(485):eaau7746. doi: 10.1126/scitranslmed.aau7746

44. Atamaniuk J, Gleiss A, Porpaczy E, et al. Overexpression of G protein‐coupled receptor 5D in the bone marrow is associated with poor prognosis in patients with multiple myeloma. Eur J Clin Invest. 2012;42(9):953–960. doi: 10.1111/j.1365-2362.2012.02679.x

45. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell–redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022. 15;387(24):2232–2244. doi: 10.1056/NEJMoa2204591

46. Jakubowiak AJ, Anguille S, Karlin L, et al. Updated results of talquetamab, a GPRC5D× CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma with prior exposure to T-cell redirecting therapies: results of the phase 1/2 MonumenTAL-1 study. Blood. 2023;142(Supplement 1):3377–3377. doi: 10.1182/blood-2023-187242 • This pivotal trial established the safety and efficacy of talquetamab, one of the main treatment options after BCMA CAR T-cell therapy, and included patients who received prior BCMA CAR-T.

47. Chari A, Touzeau C, Schinke C, et al. Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): a multicentre, open-label, phase 1–2 study. Lancet Haematol. 2025;12(4):e269–e281. doi: 10.1016/S2352-3026(24)00385-5

48. Harrison S, Riley CH, Manier S, et al. Efficacy of forimtamig, a GPRC5DxCD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): analysis of patient and disease‐related factors associated with responses. IMS. 2023;23:S3–S4. doi: 10.1016/S2152-2650(23)01572-0

49. Dholaria BR, Weisel K, Mateos M-V, et al. Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): updated TRIMM-2 results. J Clin Oncol. 2023;41(16_suppl):8003–8003. doi: 10.1200/JCO.2023.41.16_suppl.8003

50. Bahlis NJ, Weisel K, Mateos MV, et al. S192: talquetamab (TAL) + daratumumab (DARA) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): updated TRIMM-2 results. Hemasphere. 2023;7(S3):e90062ca. doi: 10.1097/01.HS9.0000967680.90062.ca

51. Bahlis N. Talquetamab + daratumumab + pomalidomide in patients with relapsed/refractory multiple myeloma: results from the phase 1b TRIMM-2 study. Clinical Lymphoma, Myeloma & Leukemia. 2024;24(S2):S1. • This prospective study evaluating combination therapy with the GPRC5D bispecific antibody talquetamab had the highest response rates for salvage therapy after BCMA CAR T-cell therapy of any of the treatments included in this review article.

52. Cohen YC, Magen H, Gatt M, et al. Talquetamab plus teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2025;392(2):138–149. doi: 10.1056/NEJMoa2406536

53. Mailankody S, Devlin SM, Landa J, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med. 2022. 29;387(13):1196–1206. doi: 10.1056/NEJMoa2209900

54. Bal S, Htut M, Nadeem O, et al. BMS-986393 (CC-95266), a G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma (RRMM): updated results from a phase 1 study. Blood. 2023;142(Supplement 1):219. doi: 10.1182/blood-2023-181857

55. Zhang M, Wei G, Zhou L, et al. GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial. Lancet Haematol. 2023. 1;10(2):e107–16. doi: 10.1016/S2352-3026(22)00372-6 • GPRC5D CAR T-cells show significant promise as a salvage treatment option after BCMA CAR T-cell therapy for patients with adequate performance status and this trial included patients who had received prior BCMA targeted therapy.

56. Merz M, Dima D, Hashmi H, et al. Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy. Blood Cancer J. 2024. 5;14(1):1–8. doi: 10.1038/s41408-024-01197-2

57. Vegel AJ, Loeffler BT, Lochner J, et al. Talquetamab in heavily pretreated multiple myeloma patients, including BCMA-refractory. Blood Immunol Cell Ther. 2025;4(1):100001. doi: 10.1016/j.bict.2025.100001

58. Chari A, Krishnan A, Rasche L, et al. Clinical management of patients with relapsed/refractory multiple myeloma treated with talquetamab. Clin Lymphoma Myeloma Leuk. 2024. 1;24(10):665–693.

59. Zhou D, Sun Q, Xia J, 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. doi: 10.1016/S2352-3026(24)00176-5

60. Nerreter T, Letschert S, Götz R, et al. Super-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T. Nat Commun. 2019. 17;10(1):3137. doi: 10.1038/s41467-019-10948-w

61. Shi M, Wang J, Huang H, et al. Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial. Nat Commun. 2024. 20;15(1):3371. doi: 10.1038/s41467-024-47801-8

62. Qiang W, Lu J, Jia Y, et al. B-cell maturation antigen/CD19 dual-targeting immunotherapy in newly diagnosed multiple myeloma. JAMA Oncol. 2024. 1;10(9):1259–1263. doi: 10.1001/jamaoncol.2024.2172

63. Ishibashi M, Soeda S, Sasaki M, et al. Clinical impact of serum soluble SLAMF7 in multiple myeloma. Oncotarget. 2018. 5;9(78):34784. doi: 10.18632/oncotarget.26196

64. Kikuchi J, Hori M, Iha H, et al. Soluble SLAMF7 promotes the growth of myeloma cells via homophilic interaction with surface SLAMF7. Leukemia. 2020. Jan;34(1):180–195. doi: 10.1038/s41375-019-0525-6

65. Li C, Xu J, Luo W, et al. Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma. Leukemia. 2024. Jan;38(1):149–159. doi: 10.1038/s41375-023-02065-x

66. Glisovic-Aplenc T, Diorio C, Chukinas JA, et al. Cd38 as a pan-hematologic target for chimeric antigen receptor T cells. Blood Adv. 2023. 22;7(16):4418–4430. doi: 10.1182/bloodadvances.2022007059

67. Yu Z, Li H, Lu Q, et al. Fc receptor-like 5 (FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma. Sig Transduct Target Ther. 2024. 12;9(1):16. doi: 10.1038/s41392-023-01702-2

68. Ramos CA, Savoldo B, Torrano V, et al. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest. 2016. 1;126(7):2588–2596. doi: 10.1172/JCI86000

69. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020. 14;396(10262):1563–1573. doi: 10.1016/S0140-6736(20)32292-3

70. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor–dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019. 22;381(8):727–738. doi: 10.1056/NEJMoa1903455

71. Chari A, Vogl DT, Jagannath S, et al. Selinexor‐based regimens for the treatment of myeloma refractory to chimeric antigen receptor T cell therapy. Br J Haematol. 2020;189(4). doi: 10.1111/bjh.16550

72. Binder AF, Walker CJ, Mark TM, et al. Impacting T-cell fitness in multiple myeloma: potential roles for selinexor and XPO1 inhibitors. Front Immunol. 2023;14(1275329). doi: 10.3389/fimmu.2023.1275329

73. Gasparetto C, Schiller GJ, Tuchman SA, et al. Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients. Br J Cancer. 2022. 23;126(5):718–725. doi: 10.1038/s41416-021-01608-2

74. Richter J, Thomas SK, Krishnan AY, et al. Cevostamab in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM): updated results from an ongoing phase I study demonstrate clinically meaningful activity and manageable safety and inform the doses and regimen for combination studies. Blood. 2024;144(1021):187–200. doi: 10.1182/blood.2023023242

75. Vogl DT, Atrash S, Holstein SA, et al. Final results from the first-in-human phase 1/2 study of modakafusp alfa, an immune-targeting attenuated cytokine, in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Blood. 2022. 15;140(Supplement 1):1357–1359. doi: 10.1182/blood-2022-162253

76. Vogl DT, Atrash S, Holstein SA, et al. Targeted interferon therapy with modakafusp alfa for relapsed or refractory multiple myeloma. Blood. 2025. 27;145(9):944–955. doi: 10.1182/blood.2024026124

77. Hartley-Brown MA, Mo CC, Nadeem O, et al. Mezigdomide—a novel cereblon E3 ligase modulator under investigation in relapsed/refractory multiple myeloma. Cancers (basel). 2024. 15;16(6):1166. doi: 10.3390/cancers16061166

78. Richardson PG, Trudel S, Popat R, et al. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N Engl J Med. 2023. 14;389(11):1009–1022. doi: 10.1056/NEJMoa2303194

79. Lonial S, Abdallah AO, Anwer F, et al. Iberdomide (IBER) in combination with dexamethasone (DEX) in relapsed/refractory multiple myeloma (RRMM): results from the anti-B-cell maturation antigen (BCMA)-exposed cohort of the CC-220-MM-001 trial. Blood. 2022. 15;140(Supplement 1):4398–4400. doi: 10.1182/blood-2022-158180

80. Banerjee R, Lynch RC, Wu Q, et al. A phase 2 study of nivolumab for relapsed/refractory multiple myeloma or non-Hodgkin lymphoma following CAR-T therapy. Blood. 2023;142(Supplement 1):3509–3509. doi: 10.1182/blood-2023-173202

81. Ferreri CJ, Hildebrandt MA, Hashmi H, et al. Idecabtagene vicleucel (ide-cel) chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory multiple myeloma (RRMM) who have received a prior BCMA-targeted therapy: real world, multi-institutional experience. Blood. 2022. 15;140(Supplement 1):1856–1858. doi: 10.1182/blood-2022-164884

82. Cohen AD, Mateos MV, Cohen YC, et al. Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents. Blood. 2023;141(3):219–230. doi: 10.1182/blood.2022015526

83. Van Oekelen O, Amatangelo M, Guo M, et al. Iberdomide increases innate and adaptive immune cell subsets in the bone marrow of patients with relapsed/refractory multiple myeloma. Cell Rep Med. 2024;5(6):101584. doi: 10.1016/j.xcrm.2024.101584

84. Chen LY, Oekelen O, Amatangelo M, et al. Mezigdomide treatment in relapsed-refractory myeloma patients shifts bone marrow nk and T cell populations from exhaustion to activation. Blood. 2023;142(Supplement 1):4686–4686. doi: 10.1182/blood-2023-187748

85. Carretero-Iglesia L, Hall OJ, Berret J, et al. Isb 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells. Nat Cancer. 2024;5(10):1494–1514. doi: 10.1038/s43018-024-00821-1

86. Quach H, Augustson B, Sia H, et al. First results of a phase 1, first-in-human, dose escalation study of ISB 2001, a BCMAxCD38xCD3 targeting trispecific antibody in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2024;144(Supplement 1):1026–1026. doi: 10.1182/blood-2024-208189

87. Yan Y, Tu Y, Wu DP, et al. Bcma CAR-T-cell therapy in combination with long-term pomalidomide is a safe and effective treatment for relapsed/refractory multiple myeloma. Blood. 2023;142(Supplement 1):2116–2116. doi: 10.1182/blood-2023-181573

88. Mailankody S, Matous JV, Chhabra S, et al. Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results. Nat Med. 2023. Feb;29(2):422–429. doi: 10.1038/s41591-022-02182-7

89. Dholaria B, Shune LO, Kocoglu MH, et al. A phase 1 study of P-BCMA-ALLO1, a non-viral, allogeneic BCMA directed CAR-T in relapsed/refractory multiple myeloma (RRMM): results from optimized lymphodepletion cohort. Blood. 2024;144(Supplement 1):4828. doi: 10.1182/blood-2024-207459