The treatment of multiple myeloma has changed significantly in the last decade. Antibody-drug conjugates, T-cell immunotherapies including bispecific T-cell engaging antibodies and chimeric antigen receptor T-cell therapies, have shown remarkable results in pivotal clinical trials. This has resulted in European Medicines Agency and US Food and Drug Administration approval of agents targeting the B-cell maturation antigen: antibody-drug conjugate belantamab mafodotin (belantamab), bispecific T-cell engaging antibodies teclistamab, elranatamab and linvoseltamab, and chimeric antigen receptor T-cell products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Talquetamab, a bispecific T-cell engaging antibodytargeting G protein coupled receptor family C group 5 member D has also been approved by the European Medicines Agency and Food and Drug Administration. With increasing availability of these agents, knowledge on the efficacy and safety of these novel treatments will be essential for future multiple myeloma care. In this narrative review, we discuss the pivotal trials, current real-world evidence and recent insights in the mechanisms of resistance of antibody-drug conjugates, bispecific T-cell engaging antibodies and chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen and G protein coupled receptor family C group 5 member D for multiple myeloma.

B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of multiple myeloma but can cause unique toxicities, including cranial nerve palsy, parkinsonism and enterocolitis, which we refer to collectively as CAR T cell therapy-associated immune-related adverse events (CirAEs). Among 198 patients treated with ciltacabtagene autoleucel or idecabtagene vicleucel (June 2021-December 2024), 27 (13.6%) developed CirAEs. This included one remarkable case with three distinct CirAEs in association with an extreme CD4+ CAR T cell expansion (peak lymphocytes: 197 × 103 per microliter), which was abrogated in vitro by CCR5 inhibition. CirAEs were associated with significantly higher non-relapse mortality (hazard ratio = 5.2, P = 0.006), and independent risk factors included ciltacabtagene autoleucel (odds ratio = 4.5, P = 0.058), peak absolute lymphocyte count ≥ 2.4 × 103 per microliter in the first 14 days post-infusion (odds ratio = 4.3, P < 0.001) and apheresis CD4:CD8 ratio > 1 (odds ratio = 2.6, P = 0.048). We identified marked CD4+ CAR T cell infiltration in all available CirAE tissues, including cerebrospinal fluid during neurologic CirAEs, implicating CD4+ CAR T cell therapy as a key mediator of these toxicities.

BackgroundIn patients with autoimmune hemolytic anemia (AIHA), the risk of relapse is high owing to persistent autoreactive B-cell activity. Multirefractory AIHA is a more advanced stage of disease that is defined by a lack of response to at least three lines of therapy. CD19-directed chimeric antigen receptor (CAR) T-cell therapy results in profound B-cell depletion and may be a useful approach to achieving drug-free remission in multirefractory AIHA.MethodsWe enrolled patients from a compassionate-use program and those from a phase 1 study who had primary multirefractory AIHA. Each patient received a single infusion of autologous CD19 CAR T cells. The primary objective was to assess the safety profile — the incidence, characteristics, and severity of adverse events, including cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome. Secondary objectives included efficacy and pharmacokinetic features. A complete response was defined by resolution of symptoms, an increased hemoglobin level, and normalization of hemolysis markers. B-cell reconstitution and the origin of relapse were analyzed with flow cytometry, single-cell RNA sequencing, and paired B-cell receptor sequencing.ResultsCD19 CAR T cells were administered to 11 patients — 5 in the compassionate-use program and 6 in the phase 1 study. The median follow-up was 12.2 months (range, 7.3 to 21.9). All patients had a complete response; the median time to a complete response was 45 days (range, 21 to 153). The median duration of drug-free remission was 11.5 months (range, 6.8 to 21.0). Cytokine-release syndrome of grade 1 or 2 in severity occurred in 9 patients, and immune effector cell–associated neurotoxicity syndrome of grade 1 occurred in 1 patient. A total of 15 infections occurred among 7 patients, with no infections of grade 4 or higher. One patient had immune effector cell–associated hematotoxicity of grade 3. In multi-omics assessments of sequential samples, naive B cells were predominant in the reconstituted B-cell population in patients with drug-free remission, and crosstalk between HLA-DRB5+ B cells, CD4+ T cells, and B-cell maturation antigen–expressing long-lived plasma cells contributed to a relapse-specific B-cell niche.ConclusionsCD19 CAR T-cell therapy had expected toxic effects and resulted in sustained remission in patients with multirefractory AIHA. (Funded by the National Key Research and Development Program of China and others; ClinicalTrials.gov number, NCT06231368.)

B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.

Myasthenia gravis (MG) is an autoimmune disorder characterized by B cell dysfunction. Here, we designed B cell maturation antigen (BCMA)/CD19 chimeric antigen receptor T cell (CAR T cell) therapy for six refractory MGs, demonstrating favorable safety with grade 1 cytokine release syndrome observed. CAR T cell expansion induced profound B cell depletion, a sustained reduction in acetylcholine receptor (AChR) antibody titers, and symptom improvement. Five patients achieved drug-free remission with minimal manifestations by month 6, persisting through the 12-month follow-up despite B cell reconstitution. Reconstituted B cells showed naïve predominance with diminished AChR specificity and functional capacities. Olink proteomics revealed up-regulation of anti-inflammatory factors, along with down-regulation of proinflammatory molecules. Single-cell sequencing revealed that age-associated B cells (ABCs) were up-regulated in a relapsed patient, and differential gene analysis indicated that Fc receptor-like 5 (FCRL5) expression was elevated in ABCs, whereas CAR T cell responders exhibited a down-regulated trend. Notably, similar ABC expansion and FCRL5 up-regulation occurred in rituximab-relapsed patients. Our findings support BCMA/CD19 CAR T cell therapy as feasible, tolerable, and effective in MG, identifying FCRL5 as a previously unidentified target in relapse.

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy with limited disease-specific imaging options. Current diagnostic methods often fail to detect early disease states and minimal residual disease, highlighting the need for more precise molecular imaging and targeted therapeutic approaches. We developed a radiolabeled nanobody targeting B-cell maturation antigen (BCMA) to enable both high-contrast molecular imaging and targeted radioligand therapy in human MM models.Methods: A high-affinity anti-BCMA nanobody was labeled with [18F]FPy-pyridine prosthetic group for PET imaging and [131I]I for radioligand therapy. Target expression and in vitro binding affinity and specificity were assessed using biolayer interferometry, flow cytometry, and cell-based assays. PET imaging studies were performed in subcutaneous MC38-human BCMA xenografts and systemic human MM models (H929 and RPMI8226 cell lines) administered intravenously in NSG mice. Therapeutic efficacy was evaluated using a fractionated treatment regimen with [131I]I-BCMA-Nb (four weekly injections of 7.4 or 18.5 MBq), monitoring tumor burden via bioluminescence imaging and [18F]FDG-PET. Toxicity assessment included body weight monitoring, complete blood counts, biochemical analyses, and histopathological examination.Results: [18F]FPy-BCMA-Nb demonstrated high binding affinity and excellent tumor specificity with rapid systemic clearance. PET imaging showed significantly higher uptake in BCMA-positive lesions (6-8% ID/g) compared to controls (1% ID/g), with minimal kidney retention (<1% ID/g by 3 h). In systemic MM models, the tracer specifically targeted bone marrow lesions with high tumor-to-background ratios. Therapeutic studies revealed dose-dependent tumor regression, with the 18.5 MBq [131I]I-BCMA-Nb regimen achieving 100% complete remission in treated mice. Biochemical and histopathological analyses confirmed minimal systemic toxicity, restoration of normal hematopoiesis, and significant reduction in BCMA expression and proliferation markers post-treatment.Conclusion: This BCMA-targeted nanobody platform offers a promising theranostic approach for precise detection and treatment of disseminated multiple myeloma. The combination of exceptional tumor specificity, minimal off-target accumulation, rapid clearance, and potent therapeutic efficacy, along with a favorable safety profile, supports its potential for clinical translation in MM diagnosis and therapy.

Waldenström macroglobulinemia (WM) is an uncommon indolent B-cell lymphoma driven by MYD88 and CXCR4 mutations. Although serum B-cell maturation antigen (sBCMA) has been shown to be a prognostic and monitoring tool for multiple myeloma patients, it has not been evaluated among those with WM. We assessed sBCMA levels among 50 WM patients: 16 had received prior therapy, while 34 were treatment-naïve (TN), 19 of whom never went on to require therapy (smoldering [S]WM). Levels were higher among WM patients (median, 63.76 ng/mL) than healthy subjects (median, 35.24 ng/mL; p < 0.0001). TNWM patients who required therapy showed higher initial levels (median, 137.71 ng/mL) than those with SWM (median, 50.19 ng/mL; p = 0.0002). sBCMA also correlated with disease status: levels decreased at best response (≥ minimal response; median, 38.36 ng/mL) compared to baseline (median, 117.00 ng/mL; p = 0.0078) and increased among patients who developed progressive disease (median, 79.42 ng/mL; p = 0.0625). Baseline sBCMA levels positively correlated with β2 microglobulin (p = 0.0193) and M-protein (p = 0.0450), and negatively with hemoglobin (p = 0.0090) and albumin (p = 0.0016). Overall, these findings suggest sBCMA may serve as a biomarker for prognosis and monitoring for WM patients.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has achieved notable efficacy in relapsed/refractory multiple myeloma (RRMM), yet most patients eventually relapse, highlighting the need to elucidate mechanisms of resistance. In this study, we investigated the role of TIGIT in resistance to BCMA-CAR-T therapy. Tumor-infiltrating T cells from RRMM patients receiving BCMA-CAR-T therapy were analyzed by single-cell RNA sequencing, and immune checkpoint expression was further assessed by flow cytometry. Functional assays, including luciferase-based cytotoxicity, CD107a degranulation, CFSE proliferation, and CD45RO/CD62L phenotyping, were performed to investigate the effects of TIGIT inhibition through knockout or anti-TIGIT monoclonal antibodies (mAbs). In a humanized immune cell-reconstituted mouse model, TIGIT blockade was further evaluated for its effects on tumor growth and T cell exhaustion. T cells from patients with early relapse exhibited higher TIGIT expression than those from patients with durable responses, and elevated TIGIT levels were correlated with increased tumor burden and poor prognosis. While TIGIT blockade exerted limited effects on CAR-T function in vitro, it markedly enhanced CAR-T proliferation, mitigated T cell exhaustion, and improved antitumor efficacy in vivo, particularly when mediated by anti-TIGIT mAbs. Transcriptomic profiling further revealed that TIGIT modulates CAR-T activity by regulating cytokines and chemokines pathways and T cell activation, findings that were preliminarily validated by functional assays. Collectively, these findings identify TIGIT as a critical regulator of resistance to BCMA-CAR-T therapy and highlight TIGIT blockade as a promising strategy to enhance CAR-T efficacy and overcome relapse in multiple myeloma.

Patients with relapsed/refractory multiple myeloma (R/R MM) receiving chimeric antigen receptor (CAR) T-cell therapy are at high risk of toxicities, including cytokine release syndrome (CRS). The roles of positron emission-tomography computed tomography (PET/CT) in predicting these toxicities remain unclear. We retrospectively studied 62 patients with R/R MM who received B-cell maturation antigen (BCMA) CAR T-cell therapy at our center. Baseline metabolic tumor volume (MTV) of more than 107.2 cm3 and total lesion glycolysis (TLG) exceeding 406.5 were classified as high MTV and high TLG, respectively. Both high MTV (P = 0.008) and high TLG (P = 0.011) were identified as independent risk factors for the development of severe CRS classified as grade 3 to 4. Moreover, the administration of tocilizumab for the treatment of CRS was associated with high MTV (P = 0.005) or high TLG (P = 0.010). Notably, our multivariate Cox models that incorporated either MTV (P = 0.029) or TLG (P = 0.009) along with plasmacytoma types, high-risk cytogenetics, and high bone marrow plasma cell frequencies demonstrated strong predictive capabilities for the 5.3-year long-term OS. Therefore, baseline high MTV or TLG measured by PET/CT are recognized as adverse prognostic indicators for the incidence of severe CRS and poor outcomes in patients with R/R MM undergoing BCMA CAR T-cell therapy.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting for B-cell maturation antigen (BCMA) is used to treat patients with multiple myeloma (MM). To investigate gastrointestinal changes associated with CAR-T therapy, we performed a retrospective study. A total of 10 patients with 26 gastrointestinal biopsy specimens who underwent CAR-T therapy for MM were identified. Except for one patient with residual multiple myeloma, all specimens demonstrated markedly reduced or absent plasma cells. The most prominent biopsy findings occurred in the small intestine, primarily the duodenum, and included lamina propria lymphocytic infiltration, villous atrophy, foveolar metaplasia, an absence of plasma cells, and an increase in intraepithelial lymphocytes. There was an average of 7 apoptotic bodies per 10 high-power fields (hpf). The terminal ileum was also notable for increase in apoptotic bodies (average of 9.5 apoptotic bodies/10 hpf), villous atrophy, and lamina propria lymphocytic infiltration. The stomach biopsies overall typically showed mild inflammation with no increase in apoptotic bodies. A few colonic specimens demonstrated active colitis and prominent apoptotic bodies, while the majority of the colonic biopsies did not have significant findings other than melanosis coli, and an absence or reduction of plasma cells. The disproportionately greater injury in the duodenum versus the colon highlights the importance of upper endoscopic evaluation in symptomatic patients after CAR-T therapy. The mechanisms for these patterns of injury and differential anatomic findings are unknown; however, an immune-mediated injury associated with CAR-T therapy is suspected. Our study identifies a unique pattern of intestinal injury in patients with MM who received BCMA-targeted CAR-T therapy; this encompasses histologic findings more profound in the small intestine, which include absence of plasma cells, an increase in apoptotic bodies, lymphocytic infiltration, and villous atrophy.

Chimeric antigen receptor T-cell (CART) and T-cell engager (TCE) therapies targeting B-cell maturation antigen (BCMA) are transforming the treatment landscape for relapsed multiple myeloma (MM). However, despite impressive initial response rates, most patients eventually relapse. To investigate this unmet medical need, we applied whole-genome sequencing (WGS) to MM cells from cohorts of 102 relapsed patients treated with anti-BCMA CART and TCE therapies. Several genomic alterations were associated with clinical outcomes, particularly primary refractoriness, including high genomic complexity and mutations in genes regulating plasma cell identity, which predicted resistance to therapy. Single-cell RNA sequencing further revealed that MM cells from refractory patients exhibited high proliferation signatures and reduced expression of TNFRSF17 (encoding BCMA), while were less enriched for plasma cell–associated transcriptional programs, a phenomenon we term “plasma cell identity escape.” This profile was strongly associated with immune dysregulation of CD8 T cells including increased activation and exhaustion. This evolution of MM toward a more proliferative and lineage-divergent state, refractory to the anti-BCMA T-cell redirecting therapies, was functionally validated in preclinical MM mouse models. Collectively, our results comprehensively define the cellular and molecular mechanisms underlying primary resistance to anti-BCMA therapies.

In a phase 1-2 trial, teclistamab, a bispecific antibody targeting CD3 on T-cell surfaces and B-cell maturation antigen on myeloma cells, showed durable responses in heavily pretreated patients with relapsed or refractory multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38 protein, has shown survival benefit in patients with multiple myeloma. In this phase 3 trial, we randomly assigned patients with one to three previous lines of therapy to receive combination therapy with teclistamab-daratumumab or daratumumab combined with dexamethasone plus the investigator's choice of pomalidomide (DPd) or bortezomib (DVd) - the DPd or DVd group. The primary end point was progression-free survival, as assessed by an independent review committee. A total of 587 patients underwent randomization (291 to receive teclistamab-daratumumab and 296 to receive DPd or DVd). At a median of 34.5 months, progression-free survival was significantly longer with teclistamab-daratumumab than with DPd or DVd. The estimated 36-month progression-free survival was 83.4% in the teclistamab-daratumumab group and 29.7% in the DPd or DVd group (hazard ratio, 0.17; 95% confidence interval, 0.12 to 0.23; P<0.001). Morepatients in the teclistamab-daratumumab group than in the DPd or DVd group had acomplete response or better (81.8% vs. 32.1%), an overall response (89.0% vs. 75.3%), and minimal residual disease negativity (10-5; 58.4% vs. 17.1%) (P<0.001 for all comparisons). Serious adverse events occurred in 70.7% of the patients in the teclistamab-daratumumab group and in 62.4% of those in the DPd or DVd group; death from adverse events occurred in 7.1% and 5.9%, respectively. In patients with multiple myeloma who had received one to three previous lines of therapy, those in the teclistamab-daratumumab group had significantly longer progression-free survival than those in the DPd or DVd group. (Funded by Johnson & Johnson; ClinicalTrials.gov number, NCT05083169.).

Developing SEMA4A-directed CAR T cells to overcome low BCMA antigen density in multiple myeloma.

HighlightsWhat are the main findings?A novel Nb17-based BCMA nanoCAR-T was successfully engineered and displayed in vitro cytotoxicity, cytokine release, and transcriptomic profiles comparable to the clinically validated scFv-CAR CT103a.Nb17-nanoCAR-T showed potent antitumor activity in vivo, fully eradicating myeloma tumors similarly to CT103a.What are the implications of the main findings?Single-domain antibody-based CARs can achieve efficacy equivalent to conventional scFv-CAR-T, supporting their use as viable therapeutic alternatives in multiple myeloma.The Nb17-nanoCAR-T design highlights the potential of VHH-based CARs for future development of more stable, compact, and potentially less immunogenic cell therapies.Multiple myeloma (MM) is an incurable hematologic malignancy arising from clonal plasma cells, with poor long-term outcomes due to inevitable relapse after conventional therapies. Chimeric antigen receptor (CAR) T-cell immunotherapy targeting B-cell maturation antigen (BCMA) has shown remarkable efficacy in relapsed patients. Conventional CARs employ single-chain variable fragments (scFvs), whereas single-domain antibodies (sdAb or VHHs) offer advantages such as small size, high stability, and potentially reduced immunogenicity. We designed and evaluated a novel anti-BCMA nanoCAR-T based on the VHH Nb17, compared with the conventional scFv-based CAR-T CT103a. Nb17 demonstrated strong BCMA binding and was incorporated into a CAR construct. Both nanoCAR-T and CT103a were generated via lentiviral transduction of primary T cells. Their cytotoxicity, cytokine secretion, degranulation, memory phenotype, and gene expression were assessed in vitro, along with antitumor activity in vivo. Nb17-nanoCAR-T demonstrated specific cytotoxicity, cytokine release (IL-2, TFNa, IFNg), and CD107a degranulation comparable to CT103a. Transcriptomic analysis revealed overlapping pathways between both CARs. Upon rechallenge, both CARs showed enhanced proliferation compared with untransduced T cells. In vivo, Nb17-nanoCAR-T and CT103a eradicated tumors in NSG mice. These findings demonstrate Nb17-nanoCAR-T exhibits potent anti-myeloma efficacy comparable to scFv-based CAR-T, supporting its potential as a promising therapeutic alternative.

BackgroundPatients with plasmacytomas that are noncontiguous with bone marrow (true extramedullary myeloma) are at high risk for disease progression or relapse. Phase 1 of the RedirecTT-1 study showed promising efficacy with dual-antigen targeting of myeloma with talquetamab (anti–G protein–coupled receptor family C group 5 member D) plus teclistamab (anti–B-cell maturation antigen) in patients with triple-class–exposed relapsed or refractory multiple myeloma, including those with true extramedullary myeloma.MethodsIn this phase 2 study, we investigated talquetamab plus teclistamab exclusively in patients with drug-resistant, true extramedullary myeloma. The primary end point was overall response, evaluated with the use of functional imaging. Secondary end points included the duration of response, progression-free survival, overall survival, and safety.ResultsA total of 90 patients were enrolled in the study and received treatment (median follow-up, 12.6 months). A response occurred in 79% of the patients (95% confidence interval [CI], 69 to 87). Among the patients with a response, the percentage with a response duration of at least 12 months was 64% (95% CI, 48 to 76). At 12 months, progression-free survival was 61% (95% CI, 50 to 71), and overall survival was 74% (95% CI, 63 to 83). Common adverse events of any grade included oral symptoms, such as dysgeusia, dry mouth, and dysphagia (in 87% of the patients); cytokine release syndrome (in 78%); and nonrash skin effects (in 69%). Grade 3 or 4 adverse events (most commonly hematologic events) occurred in 76% of the patients; 31% had grade 3 or 4 infection. A nonfatal adverse event led to discontinuation of one or both agents in 6% of the patients. Among 10 deaths that occurred during follow-up, 5 were due to infection and 5 were considered to be related to the study treatment.ConclusionsMost patients with drug-resistant, true extramedullary myeloma had a response with talquetamab plus teclistamab. The incidence of adverse events of grade 3 or above was high and was consistent with previous observations for each agent as monotherapy. (Funded by Johnson & Johnson; RedirecTT-1 ClinicalTrials.gov number, NCT04586426.)

The therapeutic landscape of multiple myeloma has undergone a profound transformation with the incorporation of anti-CD38 monoclonal antibody (mAb)-based quadruplet regimens in the frontline setting and T-cell redirecting immunotherapies in the relapsed setting. In this article, we synthesize evidence from pivotal trials to guide treatment decisions and sequencing across the disease trajectory. For transplant-eligible, transplant-deferred, and fit transplant-ineligible patients who are younger than 80 years old, we use anti-CD38 mAb-, lenalidomide-, and bortezomib/carfilzomib-based quadruplets as an induction regimen. For early relapse (1-3 prior lines), chimeric antigen receptor T-cell therapies targeting B-cell maturation antigen (BCMA) have demonstrated superiority over standard regimens, with ciltacabtagene autoleucel (cilta-cel) being the most efficacious product currently, albeit with some unique toxicities such as parkinsomism. Belantamab mafadotin-based triplets have shown impressive efficacy in lenalidomide and anti-CD38 mAb-refractory patients, although ocular toxicity remains a concern. Anti-CD38 mAb and carfilzomib-based triplets remain an essential therapeutic option in patients not refractory to anti-CD38 mAb. In late relapse (≥4 prior lines), bispecific antibodies (BsAbs) targeting BCMA (teclistamab, elranatamab, and linvoseltamab) and GPRC5D (talquetamab) have demonstrated impressive single-agent activity with distinct toxicity profiles. Emerging evidence supports prioritizing chimeric antigen receptor T-cell therapy before BsAbs when clinically feasible, as sequential efficacy appears compromised in the reverse sequence. For patients with BCMA- and GPRC5D-refractory disease, FcRH5-targeting BsAb (cevostamab), BCL2 inhibitors for t(11;14)-positive disease, and novel trispecific antibodies (BCMAXCD38; BCMAXGPRC5D) offer promising options. Strategic sequencing trials represent a critical unmet need, with PFS (progression-free survival)-2 potentially serving as a valuable intermediate end point to guide clinical decision-making while waiting for mature survival data.

The introduction of CAR (chimeric antigen receptor) T-cell therapy and bispecific antibodies into clinical practice has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM). Both modalities have shown impressive clinical efficacy with slightly different but overall manageable toxicity profiles. At present, two B-cell maturation antigen (BCMA)-targeted CAR T-cell therapies, idecabtagene vicleucel and ciltacabtagene autoleucel, are approved for standard use in the United States. There are currently 4 commercially approved bispecific antibodies: teclistamab, elranatamab, and linvoseltamab, which target BCMA, as well as talquetamab, which targets the GPRC5D antigen on the surface of plasma cells. In this review, we explore (a) the advantages and challenges of integrating CAR T-cell therapy earlier in the RRMM treatment course; (b) the safety and efficacy of bispecific antibodies and their evolving role in the current RRMM treatment paradigm; (c) practical considerations for both modalities, focusing on patient selection and supportive care strategies; and (d) recommendations for sequencing of T-cell redirecting therapies to maximize long-term outcomes.

Elranatamab, a bispecific antibody targeting B-cell maturation antigen and CD3, has demonstrated efficacy in relapsed/refractory multiple myeloma (RRMM). However, real-world evidence is limited, and prognostic factors have not been sufficiently evaluated. We retrospectively analyzed patients with RRMM receiving elranatamab between June 2024 and July 2025. Responses were assessed using the International Myeloma Working Group criteria. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Prognostic factors were evaluated using univariate log-rank analysis, including R2-ISS at elranatamab initiation (dynamic R2-ISS) and modified MyCARe risk, with positivity defined as any detectable plasma cells in peripheral blood. Thirty-seven patients were evaluated (median age, 67years; prior lines, 5). Median follow-up was 7.5 (median PFS, 9.7) months. One-year OS was 66.3%. The overall response rate was 67.6%, and 45.9% achieved at least a very good partial response. Extramedullary disease, plasma cells in the peripheral blood, and high-risk cytogenetics were adverse features. A baseline monocyte count < 300/µL, high-risk classification by modified MyCARe, and dynamic R2-ISS stage IV were significantly associated with shorter PFS and OS. Elranatamab was effective in real-world settings. Baseline monocyte count, modified MyCARe risk, and dynamic R2-ISS may serve as practical prognostic tools.

Multiple myeloma (MM) arises from abnormal plasma cells (PCs) progressing from precursor states, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Understanding this transition and progression to overt MM requires improved non-invasive strategies. We employed a liquid biopsy approach to detect and characterize circulating PCs across disease states in 68 patients (MGUS = 11, SMM = 21, NDMM = 19, RRMM = 17) using multi-channel immunofluorescence staining and machine learning-assisted rare event detection. PCs were identified by CD138 and B-cell maturation antigen (BCMA) expressions, with distinct phenotypic subpopulations stratifying disease states. The D | CD138 | BCMA-Memb phenotype was the most predictive, with incidence increasing from MGUS to SMM and overt MM (p < 0.005). Multivariate modeling distinguished precursors from overt disease with 86% accuracy. Shifts in BCMA and CD45 expression suggested immune cell profile alterations with progression and treatment. These findings underscore PB-based liquid biopsy as a promising tool for MM detection and monitoring, revealing circulating PC heterogeneity.

Dual targeting of BCMA and B7-H3 with CAR T cells and bispecific protein engagers enhances anti-myeloma activity.