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Abstract Introduction: Achieving rapid and deep hematological responses is essential for improving organ function and reducing early mortality in AL amyloidosis. While daratumumab has transformed the management of newly diagnosed disease, many daratumumab-treated patients will not clear amyloidogenic serum free light chains or will relapse. Chimeric antigen receptor (CAR) T-cell therapy is a highly active modality in multiple myeloma, capable of inducing deep and durable remissions. Whether this strategy can be safely and effectively adopted in AL amyloidosis remains an important unanswered question. Methods: This multicenter retrospective study involved 8 US academic medical centers within the US Multiple Myeloma Immunotherapy Consortium. We included patients with systemic AL amyloidosis who received BCMA-targeted CAR T therapy to treat AL amyloidosis with concurrent myeloma to investigate the safety, and efficacy of this approach. Results: Between September 2021 and March 2025, we identified 33 patients with AL amyloidosis treated with CAR T (n=9 ide-cel, n=24 cilta-cel). The median age was 69-years (IQR: 60, 72); 48% were female. Most patients were kappa light-chain isotype (61%, n=20), 4 patients (13%) had the t(11;14) translocation. Although baseline plasma cell burden was unknown in 2 cases, all patients had a concurrent diagnosis of myeloma, and 88% of patients had ≥20% bone marrow plasma cells (BPMC) at diagnosis. The median number of prior lines was 6 (range: 3-13), all patients had previous anti-CD38 exposure, and 27 patients (82%) had received previous autologous stem cell transplant. Regarding organ involvement, 11 patients (33%) had cardiac, 9 (27%) renal, 8 (24%) gastrointestinal, 3 (9%) peripheral nerve and 1 (3%) autonomic nerve involvement. Five patients had AL amyloid deposition without known organ involvement. Prior to CAR T, cardiac staging was unavailable or unknown in 19 cases. Of the remaining 14 cases, 6 cases were European Modification of Mayo 2004 stage 3A with no stage 3B cases. Prior to lymphodepletion the median BMPC was 6% (IQR: 1, 20). The overall rate of cytokine release syndrome (CRS) was 64% (Grade 1, G1: n=15, Grade 2, G2: n=4, Grade 3, G3: n=2), and immune cell associated neurological syndrome (ICANS) was 15% (G1: n=3, G3: n=2). The rate of CRS was 56% for ide-cel (G1: 33%, G2: 22%) and 67% for cilta-cel (G1: 50%, G2: 8%, G3: 8%). The median time to CRS onset was 1 day for ide-cel and 6 days for cilta-cel. The median duration of CRS was 1 day for ide-cel and 2 days for cilta-cel. The rate of ICANS was 11% for ide-cel (G1: n=1), and 16% for cilta-cel (G1: n=2, G3: n=2). There were no cases of non-ICANS neurotoxicity. Ten patients (30%) experienced infections (≥Grade 3 = 9%). The overall response rate (ORR) by AL amyloidosis response criteria (Palladini et al. 2012) was 91%, including n=5 very good partial responses (VGPRs) and n=24 complete responses (CRs). The ORR for ide-cel was 78% (n=6 CRs, n=1 VGPR), and for cilta-cel was 96% (n=18 CRs, n=4 VGPRs). Among responders, the median time to VGPR or better was 30 days (IQR: 29, 32). One cilta-cel recipient died of infection on day 17 prior to disease reassessment. At a median follow up of 17.8 months, the 12 and 18-month overall survival rates were 88% (95%CI: 76%-100%) and 83% (95%CI: 68%-100%), respectively. There were 5 deaths; 3 were related to underlying disease, 1 related to infection, and 1 unrelated. Seven patients were eligible for cardiac response assessment (NTproBNP>650 OR BNP>150) at the time of CAR T, and of those, three obtained a cardiac response (2 Cardiac PR, 1 Cardiac VGPR). Three patients were eligible for renal response assessment (>1g proteinuria/day) at the time of CAR T; of those, two obtained a renal PR. Conclusion: We demonstrate that commercial BCMA-targeted CAR T-cell therapy induces deep and rapid hematological responses in a cohort of heavily pretreated patients with AL amyloidosis. Although all patients exhibited overlapping features with concurrent multiple myeloma (≥10% plasma cells at diagnosis), CAR T-cell therapy was feasible to administer, with modest rates of CRS and only isolated cases of severe CRS or ICANS. Nearly all patients achieved a deep hematological response, which appeared to translate into meaningful organ improvement among those who were evaluable.

Abstract Introduction: The attainment of rapid and deep hematologic responses is key to restoring organ function and reducing mortality in AL amyloidosis. Despite the introduction of anti-CD38 monoclonal antibodies, ~50% of AL patients will respond sub optimally to 1st-line therapy, and many will relapse. Bispecific T-cell engagers (TCEs) have produced unprecedented outcomes in relapsed myeloma, and whether they can be safely applied to AL amyloidosis is a key clinical question. Methods: A multicenter retrospective study involving 9 US academic medical centers within the US Multiple Myeloma Immunotherapy Consortium. We included patients with systemic AL amyloidosis who received bispecific TCE therapy targeting either BCMA or GPRC5D to investigate the safety, and efficacy of this approach. Results: Between February 2023 and March 2025, we identified 29 patients with AL amyloidosis treated with TCEs (n=19 teclistamab, n=6 elranatamab, n=4 talquetamab). The median age was 72-years (IQR: 66, 75), with a female predominance (59%, n=17). Most patients had lambda light-chain isotype (59%, n=17), 31% (n=9) had t(11;14). Diagnostic bone marrow plasma cell (BMPC) burden was unknown in 6 cases, of the remaining cases 74% had ≥10% and 65% had ≥20% BMPCs. Ten patients (34%) had either ≥60% BMPCs at diagnosis or an involved FLC ratio >100 prior to TCE. The median number of prior lines was 5 (IQR: 4, 6), all patients had previous anti-CD38 monoclonal antibody exposure, 55% (n=16) had received an autologous stem cell transplant, and 28% (n=8) had received prior BCMA-directed therapy (n=4 antibody drug conjugates [ADCs], n=3 CAR T, n=1 ADC + TCE). Immediately prior to TCE therapy, 8% (n=2) were stage 3A and 19% (n=5) were stage 3B according to the European modification of the Mayo 2004 prognostic score. Staging was unknown in n=3 cases. Regarding organ involvement, 66% (n=19) had cardiac, 59% (n=17) had renal, 24% (n=7) had gastrointestinal (biopsy-proven), 10% (n=3) had peripheral nerve and 3% (n=1) had autonomic nerve involvement. The rate of cytokine release syndrome (CRS) was 45% (Grade 1, G1: n=8, Grade 2, G2: n=5, Grade ≥3,G3+: n=0), and immune cell associated neurological syndrome (ICANS) was 14% (G1: n=3, G2: n=1, G3+: n=0). Seven patients (24%) received tocilizumab as treatment, a further one patient received prophylactic tocilizumab. One-third of the cohort experienced at least one infection (n=10), and 20 (n=6) experienced a ≥grade 3 infection. The overall response rate was 76% (n=22) by AL amyloidosis response criteria, including a 66% (n=19) complete response (CR), 7% (n=2) very good partial response (VGPR), and 3% (n=1) partial response (PR) rate. Two patients did not undergo disease reassessment; one due to an early treatment-emergent death, and one who was lost to follow-up before cycle 2. Among responders, the median time to a VGPR or better was 29 days (IQR: 18, 56). At a median follow up of 8.8 months, the 1-year overall survival rate was 77% (95%CI: 62%-95%). Of the 6 deaths which occurred, 3 occurred while on TCE therapy (VF arrest during step up not associated with CRS, cardiac failure, and infectious complication), and 3 deaths occurred off therapy (unknown, progressive disease, and as a complication of surgery). Of 14 patients eligible for cardiac response assessment at the time of TCE therapy (NTproBNP>650 OR BNP>150), 9 (64%) obtained a response (CarPR=4, CarVGPR=2, CarCR=3). Of 4 patients eligible for renal response assessment at the time of TCE initiation (>1g proteinuria/day), all 4 patients obtained a response (RenPR=1, RenVGPR=2, RenCR=1). Conclusion: This is the largest cohort of TCE therapy in AL amyloidosis. TCE therapy produced a high rate of rapid and deep haematological responses. Despite a high prevalence of cardiac and renal involvement, rates of CRS were low with no grade ≥3 events, however, infectious complications were frequent. Non-relapse mortality reflected our cohort's advanced disease and prior treatment, including 2 deaths (7%) unequivocally related to cardiac causes. Although follow-up was limited, there was a high rate of early organ responses, consistent with the deep hematological response rates observed. Although our cohort exhibited overlapping features with multiple myeloma, such as a high baseline plasma cell burden, the pattern of organ involvement was consistent with typical AL amyloid populations, supporting the broader application of this therapy in AL amyloidosis.

Abstract Background Patients (pts) with plasma cell leukemia (PCL) were excluded from key trials, so we assessed their outcomes with standard of care bispecific antibodies (BsAbs). Methods Our multicenter retrospective US Myeloma consortium study included PCL pts treated with BsAbs. PCL was defined as ≥5% circulating plasma cells, including primary PCL, secondary PCL, historical PCL, and active PCL within 30 days of BsAb initiation. Endpoints were toxicity rates, overall response (ORR), progression-free survival (PFS), and overall survival (OS). Results Our study involved 122 PCL pts from 15 US centers with: 27% primary PCL, 65% secondary PCL, 51% active PCL, 53% women, median age of 65 years (range 31-83), 77% white, 15% black, 60% high-risk cytogenetics, 45% high bone marrow burden (≥50% plasma cells), 5% CNS myelomatosis, and 20% EMD. Median prior lines of therapy (tx) were 6 (IQR 5-9), 94% triple-refractory, 57% penta-refractory, 73% prior transplant, and 57% prior BCMA tx (70% in talquetamab group, 41% in BCMA BsAb group). Treatments included 4 cohorts: 37% teclistamab, 11% elranatamab, 42% talquetamab definitive tx, and 11% talquetamab bridge to CAR-T. BsAb was used either as monotherapy (94%) or in combination (6%) with other agents. CRS grade (G) 1 was 41%, G2 14.8%, G3 2.5%, and G4 1.6%, while ICANS G1 was 8.2%, G2 7.4%, G3 3.3%, and G4 1.6%. Infections occurred in 34% and median hospitalization was 10 days (IQR 8-15). Of 110 evaluable pts, ORR was 54.5%, with 24.5% CR, 13.6% VGPR, and 16.4% PR. The ORR was 60.8% for talquetamab definitive tx (21.6% CR, 23.5% VGPR, 15.7% PR), 46.2% for elranatamab (38.5% CR, 7.7% PR), and 33.3% for teclistamab (20% CR, 4.4% VGPR, 8.9% PR). Talquetamab bridge to CAR-T in 12 evaluable pts had a pre-CAR-T day 30 ORR of 58.3% (16.7% CR, 8.3% VGPR, 33.3% PR). With a median follow-up of 8.3 months (mo), the median (m) PFS was 3.2 mo, and mOS was 9.2 mo, with similar outcomes between primary vs. secondary PCL (p=0.37 for PFS, p=0.18 for OS). Talquetamab definitive tx had better outcomes with a mPFS of 5.5 mo, mOS of 11.5 mo, 10-mo PFS of 31.2%, and 10-mo OS of 55.7%, and further improved when used as a bridge to CAR-T, with unreached mPFS, unreached mOS, 10-mo PFS of 53.8%, and 10-mo OS of 62.7%. BCMA BsAbs had inferior outcomes, with teclistamab yielding a mPFS of 1.2 mo, mOS of 8.1 mo, 10-mo PFS of 15.3%, and 10-mo OS of 44.3%, while elranatamab showed a mPFS of 1.6 mo and mOS of 3.6 mo (p=0.007 for PFS, p=0.023 for OS). In BCMA naive pts, BCMA BsAbs' outcomes remained inferior to talquetamab with a mPFS of 1.2 mo and mOS of 3.4 mo (p=0.003, 0.001). Sixty pts with active PCL had a poor mPFS (1.6 vs. 4.4 mo, p=0.036) and mOS (5.3 vs. 10.7 mo, p=0.004) compared to pts with only historical PCL. However, in active PCL, talquetamab definitive tx (n=29) showed superior outcomes with a mPFS of 6.9 mo and mOS of 12.2 mo (p=0.003, 0.012). Talquetamab bridge to CAR-T (n=3) showed a mPFS of 3.2 mo and mOS of 5.2 mo. BCMA BsAbs had inferior outcomes: teclistamab with a mPFS of 0.7 mo and mOS of 1.4 mo, while elranatamab showed a mPFS of 1.0 mo and mOS of 3.1 mo (p=0.003, 0.012). In BCMA naive pts, BCMA BsAbs' efficacy remained poor with a mPFS of 0.7 mo and mOS of 1.4 mo (p=0.006, 0.002). While in pts with only historical PCL (without active PCL), BCMA BsAbs in BCMA naive pts led to similar outcomes with a mPFS of 5.2 mo and mOS of 8.5 mo, compared to a mPFS of 3.7 mo and mOS of 10.4 mo with talquetamab (p=0.90, 0.86). Multivariable analysis (MVA) associated active PCL with worse PFS (p=0.035, HR=1.93, CI 1.05-3.55) and OS (p=0.017, HR=2.3, CI 1.16-4.60), talquetamab with improved PFS (p=0.009, HR=0.41, CI 0.21-0.81) and OS (p=0.012, HR=0.40, CI 0.19-0.82), and talquetamab bridge to CAR-T with improved PFS (p=0.042, HR 0.28, CI 0.08-0.95) without reaching statistical significance for OS (p=0.11, HR 0.29, HR 0.07-1.3). MVA results remained similar when the talquetamab bridge to CAR-T cohort was excluded. Conclusions Despite PCL's poor prognosis, talquetamab was superior to BCMA BsAbs in active PCL, with a mPFS of 6.9 mo and mOS of 12.2 mo, aligning with the broader cohort. BCMA BsAbs had poor efficacy in active PCL, even in BCMA naive pts, with a mPFS of 0.7 mo and mOS of 1.4 mo. In historical PCL without active PCL, BCMA BsAbs in BCMA-naive pts showed comparable outcomes to talquetamab. In the overall cohort, talquetamab bridge to CAR-T improved PFS without reaching significance for OS benefit in MVA.

Abstract Background: Talquetamab (Talq), a GPRC5D-targeting bispecific antibody, shows promising activity in relapsed/refractory multiple myeloma (RRMM). However, outcomes in patients (pts) with soft tissue plasmacytoma (STP) remain poorly characterized. Method: We retrospectively analyzed 463 RRMM pts treated with Talq at 15 U.S. centers by Dec 2024. Pts were grouped by presence of STP at Talq start: (1) extramedullary disease (EMD; lesions not contiguous with bone), (2) paraskeletal disease (PSK; bone-contiguous), (3) EMD + PSK, and (4) No-STP. Those receiving Talq as a bridge-to-CAR T (n=103, 22%) were censored at CAR T infusion if progression had not occurred. Time-to-event endpoints were calculated from Talq step-up, using Kaplan-Meier/Cox models. Result: Median age was 66 years (y) (35–89); 54 (11.7%) had EMD, 26 (5.6%) PSK, 60 (13%) EMD+PSK, and 320 (69%) No-STP. EMD pts were younger than No-STP (62 vs 66 y, p=.009), while PSK (66.5) and EMD+PSK (64.5) were similar to No-STP. Median prior lines were higher in PSK (7) vs EMD (5), EMD+PSK (6) and No-STP (6) (p=.035). Median time from diagnosis to Talq was shortest in EMD (3.8 y), followed by EMD+PSK (4.6 y), vs PSK (6.4 y), and No-STP (5.9 y) (p=.015). Among pts with any EMD (EMD or EMD+PSK), 81 (69%) had visceral involvement and 85 (73%) had multiple lesions. Rates of prior BCMA- or GPRC5D-directed therapy, plasma cell leukemia (≥5% circulating plasma cells at the time of Talq), and penta-refractoriness were similar across groups. ECOG ≥ 2 at Talq was more common in EMD (42%), PSK (39%), EMD+ PSK (37%) than in No-STP (23%) (p = .002). Other baseline features were similar. Cytokine release syndrome (CRS) rate/severity were similar across groups. The immune effector cell–associated neurotoxicity syndrome (ICANS) was more frequent in PSK (38%) vs EMD (11%), EMD + PSK (18%), and No-STP (11%), with the most PSK cases (60%, 6/10) being grade ≥2 (p=.006). No difference in CRS/ICANS onset or duration. Infection rates were lower in No-STP (36%) vs EMD (55%), PSK (46%), and EMD+ PSK (48%) (p=.025). Best overall response rates (ORR) were 71% in EMD, 68% in PSK, 67% in EMD+PSK, and 71% in No-STP (p=.9). Complete response (CR) rates were 14% in EMD, 20% in PSK, 13% in EMD+ PSK, and 25% in No-STP (p=.1) [CRs were not required to be confirmatory, which may not meet full IMWG criteria]. Radiographic response was evaluable in 41 EMD (86%), 16 PSK (61.5%), and 48 EMD+PSK (80%) pts, with partial response (PR) or better observed in 48%, 27%, and 38%, respectively. Among pts with any STP, 34% received radiation (XRT) (4 as bridge-to-CAR T), 24 (51%) were evaluable, and 71% (n=17) achieved ≥PR. The median follow-up from Talq initiation was 10.1 months (mo) (95% CI: 8.8–11.4) and was longest in EMD (13.9 mo) compared with PSK (10.8 mo), EMD+PSK (12.4 mo), and No-STP (9.8 mo) (p = .040). Median progression-free survival (PFS) was 4.3 mo (95% CI: 3.6–5.06) in EMD, 4.8 mo (95% CI: 2.2–7.3) in PSK, 3.8 mo (95% CI: 3.1-4.5) in EMD+ PSK, and 8.3 mo (95% CI: 7.0–9.6) in No-STP (p <.001). Among pts receiving XRT for any STP (within 4 weeks prior to or during Talq), responders had longer PFS vs non-responders (15.4 vs. 2.4 mo; p=.009). Multivariable analysis (MVA) showed inferior PFS with EMD (Hazard Ratio (HR) 1.58; 95% CI, 1.04-2.3; p=.029), EMD+PSK (HR 1.91; 95% CI, 1.2–2.8; p = .001), ECOG ≥ 2 (HR 1.4; 95% CI, 1.04–1.9; p = .024), and del(17p) at any timepoint (HR 1.99; 95% CI, 1.1–3.5; p=.017), while longer time from diagnosis to Talq was modestly protective (HR 0.95 per year; p = .016), likely reflecting less aggressive biology in those reaching 5th+ line later. PSK alone showed a non-significant trend toward inferior PFS (HR 1.5; p = .1). Median overall survival (OS) was 13.0 mo (95% CI: not reached [NR]–NR) in EMD, 12.9 mo (95% CI: 6.9–18.9) in PSK, 10.9 mo (95% CI: NR–NR) in EMD+PSK, and NR (95% CI: NR–NR) in No-STP (p = .017). The primary cause of death was disease-related across all groups (p = .6). MVA for OS showed worse outcomes with EMD+PSK (HR 1.7; p=.033), ECOG ≥ 2 (HR 1.98; p <.001), and active PCL at Talq (HR 2.1; p =.010). Conclusion: Soft tissue plasmacytoma, particularly EMD and EMD+PSK, remain strong adverse prognostic factors in Talq-treated patients, with significantly shorter PFS and OS despite similar response rates. Radiation to STP sites was associated with improved outcomes in select cases. Prospective strategies are needed to optimize management for this high-risk population.

Abstract Background Patients (pts) with multiple myeloma and CNS involvement (CNS MM) have poor outcomes, and we recently showed that CAR-T has activity and is reasonable in this population (Gaballa et al., 2025). We sought to evaluate the safety and efficacy of Bispecific T-cell engagers (BsAbs) in CNS MM pts, with specific interest in evaluating ICANS. Methods We conducted a retrospective study of CNS MM pts treated with BsAbs via the MM immunotherapy consortium. Primary endpoints were toxicity rates, with a specific focus on ICANS. Secondary endpoints were systemic responses, CNS responses, and survival outcomes. CNS MM was defined as involvement of the brain parenchyma, spinal cord tissue, leptomeningeal disease, or CSF positivity. CNS response was determined based on CSF and imaging, as complete CNS response, partial CNS response, and non-response/progression. Results The study included 24 pts from 13 US institutions treated with teclistamab (33%), talquetamab (50%), elranatamab (17%), and were used as monotherapy in 83% while 17% received them in combination with either daratumumab or IMiDs. The median age was 64.5 (range 41-82), 50% female, 79% white, and 17% black. High-risk cytogenetics were identified in 39%, 4% had prior primary PCL, and 21% had secondary PCL (2 active within 30 days of BsAb initiation). All pts were triple-refractory, 33% were penta-refractory, and 39% had non-CNS EMD. Pts received a median of 5 prior lines of therapy (IQR 4-7), 71% prior transplant, and 21% prior CAR-T. Prior BCMA therapy was received in 83% of the talquetamab group and 17% of the BCMA BsAbs group (teclistamab and elranatamab). CNS disease was determined based on both imaging and CSF findings in 58%, imaging only in 33%, and CSF only in 8%. Site of CNS disease included 42% brain/cranial nerves, 13% spinal cord, or 46% with both. CNS disease was diagnosed prior to BsAb in 19 pts, with a median interval of 46 days (IQR 7-234), and 3 pts were identified within 2 weeks after BsAb initiation. Two pts identified at days 68 and 121 were included in the safety evaluation but excluded from the efficacy assessments. One pt received teclistamab and intrathecal chemotherapy (IT chemo) as a bridge to CAR-T and achieved a complete CNS response before CAR-T. CNS-directed therapy consisted of: 30% radiotherapy (RT), 30% IT chemo, 13% RT + IT chemo, 9% RT + surgery, and 4% steroids. CRS grade (G) 1-2 occurred in 50%, with no G3-4 CRS. ICANS G 1, 2, and 3 occurred in 13%, 21%, and 4%, respectively, with no G 4 ICANS. One pt developed delayed parkinsonism, and another developed leukoencephalopathy; both had CNS MM diagnosed pre-BsAbs and achieved a CNS response (1 complete, 1 partial). Infections occurred in 67% of pts, with 42% being severe, and 1 infection-related death. The systemic ORR of 18 evaluable pts was 67%, including 22% CR, 17% VGPR, and 28% PR. The overall CNS response of 19 evaluable pts was 58%, including 37% complete CNS response and 21% partial CNS response. Of 11 pts achieving a CNS response, 82% didn't have subsequent CNS progression. In 9 pts achieving CNS response after BsAb initiation, the median time to CNS response was 0.9 months (range 0.03-2.8), with an unreached median duration of CNS response. With a median follow-up of 11 months, the median PFS was 5.0 months (95% CI 2.5-NA) and OS was 12.2 months (95% CI 7.7-NA). No significant difference in median PFS (10.6 vs 4.6 months, p=0.11) or OS (20.2 vs 9.3 months, p=0.37) was observed between BCMA BsAbs (n=11) and talquetamab (n=11). Due to small sample limitation, no significant difference was observed in the median PFS (4.6 vs 8.2 months, p=0.48) or OS (20.2 vs 9.9 months, p=0.73) between BsAb monotherapy (n=19) and BsAb combination therapy (n=3). One pt who received teclistamab as a bridge to CAR-T achieved a complete CNS response and remains progression-free to date, demonstrating the best long-term outcome with a PFS of 674 days. Conclusions Our study demonstrates that BsAb use in pts with CNS MM is safe without increased incidence of ICANS. The use of BsAbs in combination with a multimodal CNS-directed approach led to an overall CNS response rate of 58% and an unreached median duration of CNS response. Previous studies (Gaballa et al., 2025) reported a 100% CNS response rate with CAR-T. In this study, 1 pt treated with BsAb as a bridge to CAR-T had the longest PFS, warranting further research to evaluate this combination's efficacy in this very high-risk population.

Abstract Background Talquetamab (talq) is a GPRC5D-directed bispecific antibody (BsAb) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). The pivotal monumenTAL-1 clinical trial did not include patients with renal impairment (RI, creatinine clearance<40 mL/min) and therefore, data for the use of this agent in RI is lacking. Methods We examined the outcomes of patients with RRMM treated with standard of care (SOC) talq in a multicenter, retrospective cohort study. RI was defined as creatinine clearance (CrCl) <40 mL/min. For each patient we recorded demographics, disease characteristics, prior therapies, incidence and severity of adverse events of special interest, namely cytokine release syndrome (CRS) and immune-cell associated neurotoxicity syndrome (ICANS), along with response, progression-free (PFS) and overall survival (OS). We compared binary variables between different groups using Chi-squared test and assessed progression free survival (PFS) and overall survival (OS) using Kaplan Meier and Cox proportional hazards models. Patients who received talq as a bridge therapy prior to chimeric antigen receptor T-cells (CART cells) were censored for PFS analysis at the time of subsequent therapy. Results We included 417 patients who received SOC Talq and had complete datasets. 91 (22%) had RI, including 20 (5%) on dialysis. The median age was 68 and 65 years for patients with and without RI. Patients with RI were more likely to be female (64% vs. 51%), less likely to have prior CART cells (35% vs. 48%). There were no differences in performance status, race, presence of high-risk cytogenetic abnormalities [del17p, t(4;14), t(14;16), gain/amplification 1q], lines of prior therapy (median 6 vs. 6), prior ASCT (68% vs. 72%), presence of CNS disease (4% vs. 4%), prior plasma cell leukemia (8% vs 9%), prior BCMA therapy (54% vs. 61%) and triple class refractory disease (90% vs. 94%) among patients with and without RI. Rates of CRS (63% vs. 56%, P=0.21) were similar in the two groups, while severe CRS (grade ≥3: 6% vs 2%, P=0.02) was more common in patients with RI. Any grade (20% vs 14%, P=0.21) and high grade ICANS (grade ≥3: 4% vs 4%, P=0.97) were similar in patients with and without RI. There was no difference between groups on risk of infection (P=0.65) with cumulative risk at 6 months of 39% vs. 40%. With 11.1 months of median follow up, the overall response rate (60% vs 67%; P = 0.12), and progression-free survival (median 7.3 vs. 6.5 mo.; P = 0.9) were comparable between the two groups. There was no difference in outcomes according to RI in both patients previously treated with BCMA-directed therapy and BCMA-naïve. Conversely, among patients with RI, median PFS was 4.6 and 8.5 mo. for patients with and without prior BCMA therapy. Similarly, among patients without RI, median PFS was 6.5 and 6.2 mo, respectively. Among BCMA-naïve patients, there was no difference in OS between patients with and without RI (median not reached, 12 mo. OS rate 71% vs. 73%, P=0.53), while among patients with prior BCMA-directed therapy there was a trend towards better OS for patients without RI (median 8.9 vs. 13.8 mo; 12 mo. OS rate 43% vs 59%, P=0.06). Five patients (25%) became dialysis independent following talq therapy. On multivariable analysis, ECOG >1 (HR 1.62, 95% C.I. 1.25-2.10, P<0.001) and deletion of 17p (HR 1.55, 95% C.I. 1.17-2.06, P=0.003) but not RI or prior BCMA-directed therapy affected PFS. OS was affected by ECOG >1 (HR 2.37, 95% C.I 1.71-3.30, P<0.001), triple-class refractoriness (HR 3.03, 95% C.I. 1.12-8.21, P=0.03) and prior BCMA-directed therapy (HR 1.79, 95% C.I. 1.24-2.59, P=0.002) but not by RI. Conclusion Our findings support the feasibility of talq in patients with RI, including those on dialysis, with similar safety and efficacy profile to patients without RI. While neither prior BCMA-directed therapy nor RI affect PFS, refractoriness to conventional agents and prior exposure to BCMA-directed therapy adversely affects OS. This observation likely reflects better post progression survival following talq due to the availability of efficacious therapeutic options, including those directed at BCMA.