Disease burden at the time of BCMA-directed chimeric antigen receptor (CAR) T-cell infusion is a key determinant of outcome in relapsed or refractory multiple myeloma (RRMM). Bridging therapy is frequently administered between leukapheresis and infusion to prevent disease progression, yet its clinical impact remains unclear. We conducted a multicenter real-world cohort study of 399 patients with RRMM treated with BCMA-directed CAR T-cell therapy, including 348 (87%) who received bridging therapy. Bridging therapy recipients had more advanced and biologically adverse disease, including higher rates of high-risk cytogenetics and penta-class refractoriness. Bridging efficacy varied substantially by regimen (P.

We explored single or consecutive chimeric antigen receptor (CAR) T and bispecific antibody (BsAb) treatment modalities as correlates of clinical outcomes, by complementary bias-correction analysis of a retrospective multicenter study of 640 patients with relapsed/refractory multiple myeloma. The sequential use of both modalities seemed to yield the most favorable survival trajectories. Initiating treatment with CAR T [idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), cesnicabtagene autoleucel (cesni-cel)] was associated with longer remission. However, mortality from early progression was similar regardless of initial modality, suggesting that resistance may negate initial efficacy difference. On the product level, the benefit of CAR T seemed to be driven by cilta-cel and cesni-cel, whereas BsAbs showed at least comparable outcomes with ide-cel. These exploratory findings highlight the critical importance of treatment sequencing in optimizing long-term outcomes and underscore the need for equitable and timely access to both modalities across healthcare systems. SIGNIFICANCE:In this real-world cohort, initiating treatment with CAR T was associated with longer remission, and sequential immunotherapy incorporating both modalities yielded the most favorable outcomes. However, early treatment failure negated initial efficacy differences between modalities. These findings provide a rationale for prospective sequencing trials and equitable access to both treatments. See related commentary by Banerjee, p. 650.

Background: BCMA-targeted Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of Relapsed/Refractory Multiple Myeloma (RRMM). However, the disease is not curable and progression after CAR T-cell treatment remains a challenge. Clonal hematopoiesis, specifically mutations in the DNA damage response gene PPM1D, has been linked to therapy resistance and inferior survival in lymphoma patients undergoing cellular therapy. The impact of PPM1D mutations on MM patient outcome after CAR T-cell therapy remains undefined. Methods: We conducted a retrospective single-center study of 83 patients with RRMM patients treated with idecabtagene vicleucel or ciltacabtagene autoleucel between 2022 and 2025. Next-generation sequencing was performed on peripheral blood mononuclear cells collected prior to CAR T-cell infusion to identify PPM1D exon 6 mutations (variant allele frequency > 0.01). We analyzed associations between mutational status, clinical characteristics, toxicity, and survival. Results: PPM1D mutations were detected in 14.5% (12/83) of patients. PPM1D-mutated patients had fewer prior autologous stem cell transplantation compared to wild-type patients (50% vs. 82%, p = 0.02) and presented more advanced disease burden and adverse prognostic features (R-ISS stage III 58% vs. 20%, p = 0.05). Notably, PPM1D status did not impact initial efficacy; complete remission rates were comparable between groups (67% vs. 69%). However, PPM1D mutations were significantly associated with inferior progression-free survival (PFS) (median PFS: 6 months vs. 16 months, p = 0.04). Regarding toxicity, the mutated subgroup exhibited significantly higher rates of grade ≥2 cytokine release syndrome and a trend toward increased neurotoxicity (25% vs. 7%). Conclusions: PPM1D clonal hematopoiesis is frequent in RRMM and despite deep initial responses, patients harboring PPM1D mutations face a significantly higher risk of early relapse. PPM1D mutations may serve as a biomarker for poor durability of response and should be further evaluated in larger, prospective trials.

Background/Objectives: Previous studies suggested superior outcomes for AL amyloidosis patients eligible for consolidation with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) compared to patients who did not receive these therapies. However, data are limited due to disease rarity, differing patient selection, and evolving treatment algorithms. Following the introduction of daratumumab, which improved outcomes in AL amyloidosis patients, it remains unclear whether HDCT/ASCT still confers additional benefit. Methods: Our retrospective, single-center study aimed to compare patients diagnosed between January 2003-December 2024 and consolidated in first remission with HDCT/ASCT vs. without HDCT/ASCT, both before and within the era of CD38-targeting daratumumab. Results: In our cohort of 106 AL systemic amyloidosis patients, 57 patients underwent HDCT/ASCT after induction therapy, while 49 had chemoimmunotherapy regimens alone. The two groups differed at initial diagnosis by age (p = 0.0028), renal function (eGFR, p = 0.0054), Troponin T levels (p < 0.0001) and NT-proBNP (p = 0.038). Patients treated with HDCT/ASCT had considerably better outcomes than patients without HDCT/ASCT. The median overall survival (OS) was 157 vs. 36 months (p < 0.0001), and median progression-free survival (PFS) was 81 vs. 24 months (p < 0.0001). Daratumumab was given to 45 patients (41.7%) during first line treatment, and patients were divided into additional subgroups: HDCT/ASCT ± daratumumab and chemotherapy ± daratumumab. OS and PFS were longer in patients treated with HDCT/ASCT, regardless of whether daratumumab was added to induction. The 5-year OS was 88%/86% in patients treated with HDCT with/without daratumumab and 37%/47% in the chemoimmunotherapy group with/without daratumumab (n.s.). The 5-year PFS in patients receiving HDCT was 63%/78% and in the group without HDCT/ASCT 38%/22% each with/without daratumumab. Conclusions: Thus, regardless of daratumumab use during induction treatment, our results strongly suggest that patients with AL amyloidosis undergoing HDCT/ASCT consolidation achieve superior PFS and OS compared with those treated with chemoimmunotherapy alone.

Background/Objectives: Therapeutic options for patients with relapsed and refractory multiple myeloma (RRMM) have advanced substantially in recent years. In particular, T-cell-engaging therapies, including chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (bsAbs), have emerged as highly effective treatment modalities. However, data on predictive biomarkers for response to these therapies remain limited. Patients currently receiving T-cell-engaging therapies are typically heavily pretreated and frequently exhibit clonal hematopoiesis. Clonal hematopoiesis, especially involving PPM1D mutations, may adversely affect the efficacy of T-cell-engaging therapies. Methods: We conducted a retrospective, single-center study including 27 patients with RRMM who were treated with bsAbs (teclistamab, elranatamab, or talquetamab) between June 2022 and September 2025 and for whom genetic material was available before bsAB treatment. We evaluated the impact of PPM1D mutations on treatment response, progression-free survival (PFS), and overall survival (OS). Results: The prevalence of PPM1D mutations in our cohort was 27%. Compared with patients without PPM1D mutations, mutation carriers showed a trend toward less deep remissions and demonstrated significantly inferior 6-month PFS (43% vs. 85%, p = 0.0272) and 6-month OS (57% vs. 90%, p = 0.0473). Conclusions: These findings suggest that PPM1D mutations may represent a promising biomarker in patients with RRMM treated with bsAbs. Larger, prospective studies are warranted to validate and further elucidate these observations.

(1) Background: The combination of venetoclax and hypomethylating agents (HMAs) is a standard first-line regimen for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Since venetoclax-HMAs are usually administered until progression and delayed hematologic recovery is one of the limiting toxicities, cyclic administration including 7-14-day breaks is recommended. However, whether longer venetoclax schedules lead to higher response rates and how venetoclax pharmacokinetics correlate with toxicity and efficacy remains unclarified. In this single-center retrospective study, we analyzed how venetoclax plasma levels and treatment duration impact hematologic toxicity and treatment responses. (2) Methods: We analyzed the safety and efficacy of venetoclax-HMA combination regimens in a cohort of AML patients unfit for intensive chemotherapy treated at our institution between June 2020 and September 2023. The primary endpoint was the correlation between venetoclax plasma levels or administration schedule with hematologic recovery after the first cycle. Secondary endpoints included the following clinical outcomes: correlation with complete response (CR) status, progression-free survival, and overall survival. (3) Results: Within our cohort of 75 AML patients, we found no correlation between venetoclax plasma peak and trough levels, or venetoclax treatment duration (≤ or >14 days), and hematologic toxicity. Patients receiving shorter venetoclax schedules (≤14 days) had similar CR rates compared to patients treated with longer schedules. (4) Conclusions: Our results suggest that shorter (≤14 days) venetoclax schedules may have no negative impact on tumor responses in AML patients receiving venetoclax and HMA combinations. However, prospective validation studies would be required to confirm these findings.

Background: Cytogenetic abnormalities and the persistence of minimal residual disease (MRD) following autologous stem cell transplantation (ASCT) are two established prognostically unfavorable biomarkers in multiple myeloma (MM). Previous studies have shown that post-transplant MRD status is a powerful predictor of progression-free survival (PFS) and overall survival (OS). However, the impact of MRD remains poorly characterized in MM patients with high- or ultra-high-risk cytogenetics. Objectives: This study investigated the prognostic value of post-transplant MRD in standard- versus high- and ultra-high-risk MM. To this aim, we performed a retrospective analysis of 137 MM patients who underwent high-dose chemotherapy (HDCT) and ASCT at our institution between January 2019 and December 2021. Cytogenetics were assessed by fluorescence in situ hybridization. High-risk genomic alterations included del(17p), t(4;14), t(14;16), t(14;20), gain(1q), and TP53 mutations, with two or more alterations defining the ultra-high-risk category. MRD was assessed in bone marrow aspirates post-ASCT using flow cytometry. Results: Eighty-two (60%) patients were categorized as being at standard risk, forty (29%) as high risk, and fifteen (11%) as ultra-high risk. Median follow-up was 47 months. MRD negativity was achieved in 76 (55%) patients. At 48 months, the overall PFS rate was 61% (72%, 50%, and 32% for the standard-, high-, and ultra-high-risk subgroups, respectively; p = 0.0004), while the OS rate was 85% (89%, 79%, and 80% in standard-, high-, and ultra-high-risk MM patients, respectively; p = 0.1494). Within the standard-risk subgroup, longer PFS was observed for patients achieving MRD negativity (p = 0.0172). High- and ultra-high-risk patients showed no significant differences in PFS when stratified by MRD status, possibly due to prompt progression to MRD positivity. Conclusions: Our results suggest that high- and ultra-high-risk MM patients might benefit from closer response monitoring, including dynamic MRD assessment. Further, high- and ultra-high-risk patients might require a more intensive peri-transplant treatment.

Glycosphingolipids (GSLs) are promising cancer biomarkers. Using multiplexed capillary gel-electrophoresis with laser-induced fluorescence detection (xCGE-LIF), we profile GSLs in bladder cancer (BC) tissues and find a significant increase in neolactotetraosylceramide (nLc4) compared to matched normal tissue (n = 30). Immunofluorescence confirms tumor-specific nLc4 expression in both non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC), colocalizing with luminal and basal urothelial markers. Analysis of paired tissue/urine samples, along with BC cell lines, reveals secretion of nLc4 associated with extracellular vesicles in MIBC. Urine profiling shows elevated nLc4 levels in BC patients (n = 16) versus controls (n = 50; area under the curve [AUC] 0.75; accuracy 82%). To support clinical translation, we apply an anti-nLc4 ELISA in a discovery cohort (n = 18) and a multi-center validation cohort (n = 123). In the validation set, urinary nLc4 levels are significantly elevated in MIBC (AUC 0.78; accuracy 64%) and increase with disease severity. These findings support the potential of urinary nLc4 as a non-invasive biomarker for BC detection.

Autologous stem cell transplantation (ASCT) after high-dose chemo-therapy (HDCT) is an option of consolidation therapy in patients with AML, lymphoma, or myeloma. Clonal hematopoiesis (CH) is a premalignant state, associated with an increased risk of hematological cancer. The incidence of CH in patients with AML, myeloma, and lymphoma and its effect on the outcome after HDCT/ASCT remain poorly studied. Here we screened 142 patients treated with HDCT/ASCT between 2002 and 2021 at Bern University Hospital for somatic gene mutations in ASXL1, DNMT3A, JAK2, TET2, and TP53. CH-associated somatic gene mutations were detected in 14/31 AML patients (45%), 13/64 myeloma patients (20%), and 9/47 lymphoma patients (19%). Clinical characteristics, treatment modalities, and responses to treatment were similar in patients with and without CH. Patients with CH-associated gene mutations had higher relapse rates and reduced progression free survival, most evident in lymphoma patients (p = 0.007). Overall survival tended to be shorter in lymphoma patients with CH-associated mutations (p = 0.078), whereas this was not observed in AML and myeloma patients. Survival in lymphoma patients with CH was inferior, which may have an impact on post-transplant surveillance strategies in the future. In contrast, survival outcomes were not associated significantly with CH in AML and myeloma patients in our study. Longer follow-ups and larger cohorts will be needed to validate our observations.

Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), but direct comparisons are lacking. Leveraging an international multicenter RRMM cohort, we compared the outcome of ide-cel (n = 162) versus cilta-cel (n = 42). Co-primary efficacy endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). Co-primary safety endpoints were the incidence of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS). Median turnaround time between apheresis and infusion was 47 days for ide-cel versus 68 days for cilta-cel (p < 0.001). Cilta-cel showed significantly higher ORR (93% vs. 79%; p < 0.001), with complete response at Day 30 of 48% versus 26% (p < 0.001). The 10-month PFS and overall survival (OS) was 82% and 90% for cilta-cel versus 47% and 77% ide-cel (p < 0.001 and p = 0.06), and improved outcome for cilta-cel was confirmed after multivariable adjustment. Incidence of CRS and ICANS appeared similar (81% and 19% for cilta-cel versus 85% and 19% for ide-cel), while 10% and 7% in the cilta-cel group versus 4% and 2% in the ide-cel group showed severe CRS and ICANS grade 3-4, with CRS occurring significantly earlier for ide-cel (median, 2 days vs. 4 days; p < 0.001). Nonrelapse mortality was 5% for cilta-cel versus 3% for ide-cel (p = 0.51). Cilta-cel showed later peak of CAR-T expansion at Day 14 versus Day 7 for ide-cel, while cilta-cel expansion was associated with ICANS. Our study provides real-world evidence that cilta-cel was associated with superior outcomes and distinct cellular dynamics versus ide-cel in triple-class exposed RRMM.

Background: The benefit of adjunctive aminoglycosides in the treatment of patients with febrile neutropenia (FN) is controversial. We investigated the incidence of acute kidney injury (AKI) in patients with FN or suspected infection according to empirical amikacin treatment. Methods: This two-centre, retrospective cohort study was conducted at the University Hospitals of Basel (amikacin group) and Bern (non-amikacin group), Switzerland, between 2016 and 2022. Adult patients requiring antibiotic treatment after autologous hematopoietic stem cell transplantation (HSCT) were included. All patients received empiric beta-lactam treatment combined with amikacin in the amikacin group (only University Hospital Basel). The primary endpoint was the incidence of AKI within seven days after the initiation of antibiotic treatment. Results: Overall, 250 patients were included. The majority was male (n = 163, 65.2%) and had a median age of 61 years (interquartile range (IQR) 55 to 67). The median baseline eGFR was similar in both groups (>90 mL/min/1.7 m2). There was no statistically significant difference in the incidence of AKI (4/125 vs. 5/125, p = 1.0). The maximum decline in eGFR from baseline within 7 days was significantly higher in the amikacin group (-4 mL/min/1.7 m2 (IQR 8 to -12) vs. -2 mL/min/1.7 m2 (IQR -7 to -1), p = 0.001). Two patients suffered from an infection with an extended spectrum beta-lactamase producing (ESBL) pathogen. Conclusions: Amikacin treatment did not significantly impact the incidence of AKI in patients undergoing autologous HSCT. The short-term administration of amikacin in patients with normal to high baseline eGFR is safe regarding renal function. However, in a low-resistance setting, the omission of empirical amikacin treatment should be considered.

Background: Patient management following a multidisciplinary tumor board (MTB) recommendation has become standard of care in oncology and aims to ensure optimization and personalization of patient care. To assess the impact of MTB recommendations in clinical practice, adherence to the recommended procedures needs to be evaluated. Within this retrospective case series, we examined adherence rates to recommendations formulated at multidisciplinary myeloma tumor boards (MMTB) held at our institution. Specifically, we analyzed how often recommendations involving diagnostic procedures, therapies, and enrollment into clinical trials recommended by the MMTB were implemented. In addition, factors leading to non-adherence were evaluated. Methods: We reviewed all consecutive patient cases discussed at MMTBs held at the University Hospital of Bern, Switzerland, between 1 January and 31 December 2023. Adherence was assessed by systematically comparing all available clinical records with the recommendations formulated at the MMTBs. Results: In total, 218 patients were included in the study. Of all MMTB recommendations, 86% (n = 251) of all MMTB recommendations were followed. Of these, 84% (n = 244) were followed with complete adherence and 2% (n = 7) incompletely. All cases of non-implementation of MMTB recommendations concerning diagnostics or therapy were clinically justified. The main reason for non-adherence was patient decision. Other reasons included lack of cost coverage and relevant changes in the clinical scenario, including patient’s death. In total, 36% (n = 104) of MMTB recommendations included clinical trial enrollment. However, study enrollment occurred only in 32% (n = 33) of the 104 cases. In 41% (n = 29) of the cases, justification for non-enrollment was documented in the clinical records. The most frequent reasons were patient decision, unmet inclusion criteria, delays in recruitment, lack of reimbursement, and changes in the clinical scenario. Conclusions: Our study showed an overall high level of adherence to MMTB recommendations for diagnostic procedures and therapy. However, only one third of recommendations for clinical trial enrollment were implemented, frequently due to patient decisions. Our results highlight the relevance of regular assessments of adherence rates to MTB recommendations and suggest that considering patient preferences in MTB discussions might minimize deviations.

Mesenchymal stromal cells (MSCs), such as bone marrow-derived cells (BMSCs) and adipose-derived cells (ASCs), are key candidates for bone regeneration therapies but have not yet been integrated into standard clinical practice due to heterogeneity in their osteogenic capacities. This study investigated the osteogenic differentiation of porcine BMSCs and ASCs by analyzing BMP-2-induced receptor expression and the effects of inhibiting BMP, TGF-β, and FGF signaling pathways. While pBMSCs underwent osteogenesis in standard differentiation medium, pASCs required BMP-2 stimulation to initiate this process. BMP signaling inhibition via dorsomorphin suppressed osteogenic differentiation, but this effect was reversed by co-inhibition of TGF-β or FGF signaling. Notably, simultaneous inhibition of TGF-β and FGF in the presence of BMP-2 optimized osteogenic differentiation in both pMSC types. In pASCs, successful differentiation correlated with early activation of p38 MAPK and Wnt signaling pathways, with BMP-2 serving as a primary driver, while TGF-β and FGF pathways acted as modulators. These findings highlight the importance of signaling context and MSC tissue origin in bone formation and suggest that tailored modulation of BMP, TGF-β, and FGF signaling will be necessary in future in vivo applications to maximize the regenerative potential of MSC-based therapies.

Relapsed/refractory multiple myeloma (RRMM) patients with dialysis-dependent renal impairment face limited therapeutic options due to exclusion from clinical trials, a lack of evidence-based guidelines, and inferior outcomes. Bispecific antibodies targeting B-cell maturation antigen (BCMA) have shown promise in RRMM treatment but remain understudied in this vulnerable population. To illustrate this issue, we introduce the case of a 68-year-old female with triple-class RRMM and end-stage renal disease requiring hemodialysis, treated with elranatamab as a second line treatment following progression after therapy with daratumumab, bortezomib, lenalidomide, and dexamethasone. Despite experiencing grade I cytokine release syndrome during the initial administrations, symptoms were managed effectively with tocilizumab and dexamethasone, allowing treatment continuation. The patient achieved a very good partial remission within 7 weeks. Although hemodialysis dependence persisted, the therapy was well-tolerated with manageable adverse events. According to the literature, BCMA-directed immunotherapies, including teclistamab, belantamab mafodotin, and idecabtagene vicleucel, have shown efficacy in dialysis-dependent RRMM patients, though data remain limited. Pharmacokinetic analyses indicate that mild or moderate renal impairment does not have a significant impact on the pharmacokinetics of elranatamab. Although no retrospective studies or case series have investigated the use of elranatamab in dialysis-dependent patients, a single case report suggests that its administration is both feasible and well-tolerated in this population despite the absence of comprehensive pharmacokinetic data. This review highlights feasibility, safety, and encouraging efficacy of elranatamab in managing RRMM in a dialysis-dependent patient, representing the second case report in the literature. By providing real-world evidence for the use of bispecific antibodies in end stage renal disease patients, this review emphasizes the potential for expanding therapeutic options to this vulnerable population while highlighting the need for vigilant monitoring of infection prevention and management. Prospective studies are warranted to validate these findings and optimize therapeutic strategies for patients with RRMM and severe renal impairment.

The incidence of multiple myeloma is higher in males. The underlying mechanisms may be related to differences in immune system orchestration in males and females. LAG3 and CTLA4 are immune checkpoint proteins and inhibitory regulators of T cells. Here, we analyzed the prevalence of the common LAG3 gene variant rs870849 and the common CTLA4 gene variant rs231775 in myeloma patients eligible for autologous stem cell transplantation. CTLA4 rs231775 was prevalent at normal allele frequencies. In contrast, LAG3 rs870849 was prevalent at elevated allele frequencies in myeloma patients, with allele frequency 0.61 in male and 0.53 in female patients compared to 0.39 in the European population. The gene risk analysis of rs870849 indicated an odds ratio 6.8 in male and 3.6 in female patients. Moreover, treatment outcomes differed in the three genetic LAG3 subgroups with median progression-free survival of 2.6, 3.3 and 3.4 and median overall survival of 7, 15 and 18 years in the I455hom, I455Thet and T455hom subgroups, respectively. LAG3 rs870849 may affect survival and treatment outcome after autologous stem cell transplantation in myeloma patients with favorable outcomes in rs870849 carriers.

Background: BCMA-directed CAR-T therapies and bispecific antibodies (BsAbs) have transformed the treatment landscape for relapsed/refractory multiple myeloma (RRMM), yet the optimal sequencing of these therapies remains unclear. Limited access to CAR-T – especially across Europe – and the lack of direct comparative data hinder clinical decision-making. To address this, we conducted a large, real-world, multicenter European study using propensity-weighted analysis to compare the efficacy, safety, and accessibility of CAR-T versus BsAb therapy in RRMM. Methods: We retrospectively analyzed 640 patients with RRMM treated with either a BCMA-directed CAR-T product (n=399; including idecabtagene vicleucel [ide-cel], ciltacabtagene autoleucel [cilta-cel], and academic CAR-T construct [ARI]) or a BsAb (n=241; including teclistamab, talquetamab, and elranatamab). Among BsAb-treated patients, 200 had no access to CAR-T due to regulatory, logistical, or economic barriers. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences in key prognostic covariates: extramedullary disease (EMD), high-risk cytogenetics, International Staging System (ISS), ECOG performance status, penta-refractoriness, and age. The co-primary endpoints were overall response rate (ORR) and progression-free survival (PFS), assessed by Kaplan-Meier analysis and IPTW-adjusted Cox proportional hazards regression. Safety endpoints were immune effector cell associated neurotoxicity (ICANS), cytokine release syndrome (CRS), and non-relapse mortality (NRM). Results: Patients treated with BsAb were generally older (median age 66 vs. 64 years) and exhibited a higher burden of adverse clinical features compared to those receiving CAR-T therapy. Specifically, high-risk cytogenetics (74% vs. 55%), extramedullary disease (EMD, 32% vs. 25%), and ECOG performance status ≥2 (35% vs. 17%) were more prevalent in the BsAb cohort. The ORR was significantly higher among CAR-T recipients (p<0.001), with complete response rates reaching 58% in the CAR-T group versus 15% in BsAb-treated patients. Among CAR-T products, cilta-cel achieved the highest complete response rate (69%), followed by academic CAR-T (ARI, 60%) and ide-cel (48%). In contrast, BsAbs showed markedly lower CR rates: elranatamab (22%), teclistamab (17%), and talquetamab (9%). At a median follow-up of 12 months, PFS consistently favored CAR-T over BsAb treatment. Unadjusted 12-month PFS was 66% in the CAR-T group compared to 47% for BsAbs. This benefit was maintained across subgroups stratified by EMD status: among EMD-negative patients, 12-month PFS was 70% (CAR-T) vs. 54% (BsAb), and for EMD-positive patients, 52% vs. 32%, respectively. Product-level analysis highlighted cilta-cel with the highest PFS at 86%, followed by ARI (69%) and ide-cel (52%). Among BsAbs, teclistamab and elranatamab showed comparable PFS rates of 44% and 46%. In IPTW-adjusted Cox regression, BsAb therapy remained significantly associated with shorter PFS (HR 1.54; 95% CI: 1.13-2.10; p=0.006). EMD (HR 2.03; 95% CI: 1.43-2.87; p<0.001) and ECOG ≥2 (HR range: 2.08-2.66; p<0.02) were identified as strong independent predictors of inferior PFS, while age and high-risk cytogenetics showed attenuated effects after adjustment. Safety profiles differed notably between modalities. BsAbs were generally better tolerated, with lower incidences of CRS and ICANS compared to cilta-cel and ide-cel. ARI showed similarly low toxicity to BsAbs. However, NRM varied significantly across agents (p=0.005): NRM was 5% for ide-cel, 6% for both cilta-cel and ARI, but higher in BsAb recipients – 12% for teclistamab, 11% for talquetamab, and notably 20% for elranatamab Conclusion: This is the first large-scale, real-world comparative analysis of BCMA-targeted CAR-T versus BsAb therapies in RRMM across European countries, adjusted for both access disparities and baseline prognostic factors. Cilta-cel and ARI demonstrated superior PFS compared to BsAbs, while ide-cel performed comparably to BsAb therapies. In settings where access to commercial CAR-Ts is limited or absent, academic CAR-T approaches must match the efficacy of cilta-cel to offer a meaningful advantage over readily available off-the-shelf BsAbs. These data underscore the importance of both innovation and equitable access in determining treatment sequencing strategies in RRMM.