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Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) has shown high efficacy in relapsed MM, but further efforts are needed to mitigate non-ICANS delayed neurotoxicity (DNT) and non-relapse mortality (NRM). Identifying risk factors associated with DNT and NRM may help with risk mitigation by aiding the development of interventions for potentially modifiable risk factors and also help with clinical decision making. Methods: In this multi-center retrospective study from the US MM Immunotherapy Consortium, we evaluated 761 patients treated at 15 centers receiving standard of care cilta-cel for relapsed MM between May 2022 to December 2024. Risk factors for DNT, particularly Parkinsonism and NRM were evaluated in by univariable and multivariable analysis. Any NRM events occurring after disease progression were censored for NRM evaluation. Results: The median age of the cohort was 65 years old (range: 30-88), median prior lines of therapy (pLoT) were 5 (range: 1-23). Cilta-cel was used in earlier relapse (1-3 pLOT) in 16% (n=120) patients. High-risk cytogenetics [del 17p, t(14;16) or t(4;14)] were present in 39%, with extramedullary disease (EMD) in 27% and R-ISS stage III in 18% of patients, respectively. Majority of patients (86%) received bridging therapy with response to bridging (≥ partial response, PR) seen in 33% of patients, respectively. Median follow up was 10.1 months, with response rate of 92% and CR rate of 70%. DNT was seen in 10% (n=75) of patients, with distribution as follows: Parkinsonism in 2.9% (n=22), cranial nerve palsy in 4.6% (n=35) and other DNT in 2.4% (n=18), with some patients manifesting more than one type of DNT. Risk of DNT was higher in patients who did not respond to bridging therapy (Any DNT: 12% vs 6%; Parkinsonism: 5% vs 0.5%, both p<0.05) Of the 22 cases of Parkinsonism, 21 patients (95%) did not respond to bridging, even though they achieved a post CAR-T response with ORR of 91% and ≥ CR in 68%. Absolute lymphocyte count (ALC), a surrogate measure of CAR expansion was higher in patients who developed DNT, particularly Parkinsonism, including ALC at days 7,14,21,28 and as peak ALC in the first month post cilta-cel (p<0.05 for all). Median peak ALC for patients with vs without Parkinsonism was: 5.88 vs 1.17/uL (p<0.001). We evaluated risk of Parkinsonism with various thresholds of peak ALC expansion. Amongst patients who developed Parkinsonism vs. not, peak ALC was as follows, > 1000/uL: 100% vs 57%, > 2500/uL: 73% vs 19% and > 3000/uL: 68% vs 14% (all p<0.001). The absolute risk of Parkinsonism with ALC > 3000 vs ≤ 3000/uL was 12% vs 1%, p<0.001; for ALC 2500 vs ≤ 2500uL was 9% vs 1%, p<0.001. On multivariable analysis, peak ALC > 3000/uL (OR: 12.7, p<0.001) and non-response to bridging therapy (OR: 9.9, p=0.03) were independent risk factors for developing Parkinsonism after cilta-cel. After cilta-cel, 1 and 2 year NRM estimates were 9% and 10%, respectively. Amongst 63 (8%) patients experiencing NRM events, the most common cause of NRM was infectious complications (35, 56%), followed by acute immune-mediated adverse events (AEs) like CRS, ICANS, IEC-HS in 14 (22%), delayed immune mediated AEs like DNT and colitis in 6 (9.5%), second cancers in 5 (8%) and other causes in 3 (5%) patients, respectively. When evaluating the timing of NRM events, the risk of infection related mortality remained relatively stable in the first year, though immune mediated toxicty deaths were uncommon after 6 months, while SPMs were uncommon within the first 6 months. On multivariable analysis, non-response to bridging (HR 2.41, p=0.046), poor performance status ≥ 2, high-risk cytogenetics and age ≥ 70 years were independent predictors for NRM. Conclusion: In a large cohort of over 750 patients receiving cilta-cel, we identified potentially modifiable risk factors for Parkinsonism and NRM. Non-response to bridging therapy and peak ALC > 3000/uL were independent predictors of developing Parkinsonism. Peak ALC of > 2500/uL and > 3000/uL were associated with 9% and 12% absolute risk of Parkinsonism. This indicates that peak ALC of 2500/uL or 3000/uL in the first month after cilta-cel may be a potential biomarker to identify patients for pre-emptive interventions such as steroids that can suppress rapid CAR expansion and perhaps decrease the risk of Parkinsonism. In addition, we need to focus on effective bridging strategies to further decrease the risk of Parkinsonism, as well as NRM with cilta-cel.

Abstract Introduction Ciltacabtagene autoleucel (cilta-cel) has demonstrated unprecedented response rates and progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM), but a proportion of patients experience early relapse. Identifying these patients is essential to guide future therapeutic strategies, such as enhanced bridging therapy or consolidation, while avoiding overtreatment in those likely to achieve durable disease control. Methods We conducted a multi-center study of patients treated with cilta-cel at 15 U.S. academic centers. Outcomes were evaluated based on high-risk (HR) features, including functional HR disease (FHR; relapse within 18 months of first-line therapy initiation), true extramedullary disease (EMD), traditional HR cytogenetics as defined in CARTITUDE-1 [deletion 17p, t(4;14), t(14;16)], and a 2024 IMS-IMWG-adapted HR definition (deletion 17p; t(4;14) or t(14;16) with gain 1q or deletion 1p; and gain 1q with deletion 1p). Multivariable Cox regression was used to examine the association of HR features (FHR, adapted IMS-IMWG HR, and EMD, individually and collectively) with PFS while adjusting for baseline ferritin, prior BCMA, and ECOG performance status (PS ≥2). Among patients with ≥18 months of follow-up, we evaluated predictors of early relapse (≤18 months post infusion) using logistic regression. Results Our cohort included 598 patients treated with cilta-cel between 5/2022 and 12/2024 who had available data on all HR features. The median age was 65 years (range 33-83), and the median prior lines of therapy (pLOT) was 5 (range: 1-18, 84% with >3 pLOT); 8% had received prior BCMA-directed therapy, and 27% were penta-refractory. Most patients (88%) received bridging therapy and 30% achieved ≥ partial response. In our cohort, 33% (n=195) had FHR, 43% (n=258) had traditional HR cytogenetics, 42% (n=253) had adapted IMS-IMWG HR disease, and 11% (n=64) had EMD. Median follow up was 10.6 months (range 0.4-34.1). Overall response rate (ORR) and complete response (CR) rates were lower in patients with vs without HR features: FHR (ORR: 89% vs 94%, CR: 61% vs 75%), traditional HR (ORR: 90% vs 94%, CR: 65% vs 74%), adapted IMS-IMWG HR (ORR: 91% vs 94%, CR: 64% vs 75%) and EMD (ORR: 77% vs 94%, CR: 61% vs 71%). Corresponding 12-month PFS was also lower in patients with vs without HR features: FHR (55% vs 79%), traditional HR (63% vs 78%), adapted IMS-IMWG HR (61% vs 80%) and EMD (59% vs 73%). ORR, CR rate, and 12-month PFS in patients without any HR features compared to those with ≥1 HR feature were 96% vs 90%, 81% vs 64%, and 83% vs 65%, respectively. In multivariable models, each HR feature (FHR, adapted IMS-IMWG HR, and EMD) was independently associated with inferior PFS after adjusting for baseline ferritin, prior BCMA, and ECOG PS ≥ 2. However, because early relapse cannot always be identified a priori based on traditional risk factors, we sought to identify predictors of relapse within 18 months of cilta-cel in a subset of patients with ≥18 months of follow-up (N=247; infused by 12/2023). Notably, while FHR (OR=3.04, 95% CI=1.59-5.89) and adapted IMS-IMWG HR (OR=2.07, 95% CI=1.10-3.89) were independently associated with odds of relapse within 18 months, EMD was not (OR=0.90, 95% CI=0.32, 2.40) when accounting for prior BCMA, ECOG PS ≥ 2, and baseline ferritin. We also used a time-varying Cox model to examine each HR feature associated with PFS at two time periods, <18 and ≥18 months, while adjusting for baseline ferritin, ECOG PS, and prior BCMA. We confirmed that FHR and adapted IMS-IMWG HR were both associated with relapse <18 months (HR=2.05, 95% CI=1.48-2.83 and HR=1.56, 95% CI=1.11-2.19) but not in the ≥18-month time period (HR=0.70, 95% CI=0.19-2.59 and HR=0.76, 95% CI=0.24-2.40). The magnitude of the association for EMD with PFS was similar across both time periods (<18 months HR=1.67, 95% CI=1.09-2.57 and ≥18 months HR=2.17, 95% CI=0.45-10.40). Conclusion While cilta-cel leads to high response rates and durable PFS in RRMM, a subset of patients with FHR and adapted IMS-IMWG HR remains at increased risk for early relapse. In this large multi-center cohort, we describe PFS outcomes across high-risk subgroups and identify key predictors of relapse within 18 months of cilta-cel. These findings inform risk-adapted therapeutic strategies and interventional trials, including bridging, consolidation, or maintenance approaches, to improve outcomes in the highest-risk RRMM patients.

Abstract Introduction: The CAR-T therapies ide-cel and cilta-cel are approved for patients (pts) with relapsed/refractory multiple myeloma (RRMM). The aim of this study was to determine the incidence, subtypes, and associated risk factors for subsequent primary malignancies (SPMs) in MM pts treated with CAR-T therapy in the real-world setting. Methods: A retrospective, multicenter observational cohort study was conducted of pts who received CAR-T therapy between May 2021 and Dec 2024 at 15 centers within the US Multiple Myeloma Immunotherapy Consortium. Logistic models were used for univariable analyses of invasive SPMs (excluding non-melanoma skin cancers). Variables significant at p < 0.10 were included as candidate variables in the multivariable analysis. Time to event endpoints were analyzed using Kaplan-Meier curves. Results: Of n=1460 CAR-T recipients, median follow-up from the time of CAR-T infusion for the entire cohort, ide-cel, and cilta-cel pts was 13.1, 16.9, and 10 months, respectively. A total of 55 invasive SPMs were noted in 53 pts (SPM incidence 3.6%). The incidence rate of SPMs was 4.55 per 1,000 person-years, based on 53 SPMs occurring over 11,646.14 person-years (calculated from CAR-T to the SPM diagnosis, death, or last follow-up). Baseline characteristics were similar for pts with no SPM versus SPM including: age at CAR-T (median 67 vs 65), female (36% vs 43%), Black (13% vs 16%), prior autologous transplant (87% vs 80%), lenalidomide for ≥2 years (31% vs 27%), high risk cytogenetics (23% vs 29%), and known clonal hematopoiesis (7.5% vs 9.9%). Differences were observed in baseline characteristics among pts with SPM versus no SPM for ≥2 prior alkylator lines of therapy (LOT) (82% vs 60%, p=0.002) and median prior LOT (6 vs 5, p=0.008). There was a trend for more patients with SPMs being age ≥70 (35% vs 37%, p=0.074). Of the 53 SPMs, 26 (49%) were myeloid (MDS or AML), 19 (35.8%) were solid, 7 (13.2%) were of T-cell origin, and 1 was a B-cell lymphoma. Of the T-cell SPMs, three were of T-LGL, though one of the T-LGL pts later developed an invasive CNS T-cell lymphoma (CAR-negative). There were four cases of confirmed CAR-positive T-cell SPMs (all pts treated with cilta-cel), of which two were indolent T-cell lymphoma of the GI tract and two were cutaneous PTCL. There was no difference in total incidence of SPMs among pts who received ide-cel (total=4.4%; myeloid=2.2%, T-cell=0.04%) versus cilta-cel (total=3%; myeloid=1.4%; T-cell=0.5%) (p=0.21). Median OS from the time of CAR-T therapy was 40.8 months for pts without SPM compared to 27.6 months for pts with SPM (p=0.4). Median OS did not differ by myeloid, solid, and T-cell subgroup: 26.4, 37.2, and 24 months, respectively (p=0.21). Median time from CAR-T cell to SPM was 12 months overall, and by subtypes of myeloid, solid, and T-cell was 13.2, 9.6, and 9.6 months, respectively (p=0.74). There was no difference in time to any SPM among pts receiving ide-cel versus cilta-cel (p=0.61). An earlier time to diagnosis of myeloid SPM was observed for cilta-cel versus ide-cel (4.8 vs 20.4 months; p=0.003). Median OS from the time of diagnosis of any SPM, myeloid, solid, or T-cell SPM was 9.6, 7.2, 15.6, and not reached in months, respectively (p=0.006), demonstrating that pts diagnosed with myeloid subtype SPM had inferior OS from the time of their SPM diagnosis compared to other subtypes. The cause of death of 4/11 myeloid SPM pts was the myeloid SPM itself. In univariable analysis for the entire cohort, age ≥70 (p=0.079), ≥5 prior LOT (p=0.012), and ≥2 prior alkylator LOT (p<0.001) were associated with higher risk for SPM. In multivariable analysis, ≥2 LOT containing alkylators was associated with higher risk of SPM (p=0.005). For the univariable analysis of the myeloid subgroup, ≥2 prior alkylator LOT (p=0.016) and ≥2 years of lenalidomide maintenance (p=0.063) were associated with higher risk of SPM. In multivariable analysis, ≥2 years of lenalidomide (p=0.065) was associated with a trend toward increased risk of myeloid SPM. Conclusions: With a median follow up of 13.1 months, the incidence of developing a SPM following CAR-T in pts with RRMM was 3.6%, of which approximately half were myeloid malignancies. There was no difference in SPM incidence when comparing the two CAR-T products. Pts treated with ≥2 alkylator LOT had a higher risk of SPM in multivariable analysis and may warrant additional monitoring for SPM development.

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 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.

Abstract Introduction The monoclonal gammopathies of renal significance (MGRS) are defined by the presence of a nephrotoxic monoclonal protein in the absence of a well-defined malignant entity. Mechanistically it has been postulated that, across the varied subtypes of MGRS, abnormal plasma cell or B-cell clones in the marrow produce nephrotoxic proteins; however, in many cases, no paraprotein is detected by conventional laboratory methods and the bone marrow can be morphologically normal. The genomic underpinnings of MGRS are unexplored and, due to the rarity of this disease, clinicians are often left to unable to determine the exact nature of the clonal cell populations. We carried out a pilot study to characterize ctDNA in MGRS patients (pts). The first phase of the protocol sought to collect peripheral blood samples and, when possible, matched bone marrow aspirates, from MGRS pts to evaluate the feasibility of ultra-low pass whole genome sequencing (ULP-WGS) from peripheral blood to identify and characterize ctDNA. Methods We report ULP-WGS results from peripheral blood samples in the initial phase of the study. Peripheral blood samples were collected from renal biopsy proven non-amyloidosis MGRS pts prior to the initiation of treatment. Cell free DNA (cfDNA) was extracted and quantified. A total of 5-20 ng of cfDNA input was used for ULP-WGS. Libraries were pooled and sequenced using 100-bp paired-end runs to an average genome-wide coverage of 0.5x. After deconvolution and alignment, fragments with size 90-150bp were extracted using samtools. IchorCNA was utilized to calculate tumor fraction based on a panel of normals derived from three plasma samples from healthy controls. Model parameters were optimized for low tumor fraction and a threshold of 3% ctDNA was used to identify positive samples. Renal responses were assessed based on International Kidney and Monoclonal Gammopathy (IKMG) group criteria. Results Nine pts and were consented and gave samples for the study along with 3 healthy controls. Seven pts were sequenced, 4 of which were females and 3 were males. Median age was 58 years. Among sequenced pts, 5 presented with proliferative glomerulonephritis with monoclonal immune deposition (PGNMID) and 2 with light chain deposition disease (LCDD). Both patients with LCDD were kappa predominant and showed detectable plasma clones (8% and 3%). One of these pts displayed t(11:14) on bone marrow FISH testing. Among the 5 pts with PGNMID, 3 had IgG kappa deposition and only one had a detectable plasma clone (5%), which harbored trisomy 9 by FISH. Bone marrow flow cytometry was positive in 2 pts. Median 24-hour urine protein content was 7.11g (0.92 – 10.58), median serum albumin 3.20 g/dL (2.90 – 4.90) and median serum creatinine at the time of diagnosis was 2.15 mg/dL (1.30-6.40). CKD was present in 6 of 7 pts at the time of diagnosis. Four pts had known hypertension. One exhibited a history of malignancy and one had a history of autoimmune disease. ctDNA was detectable at a threshold of > 3.0% of cfDNA in 5 of 7 pts. Median ctDNA content was 4.0% (3.18% - 14.97%) of cfDNA. Four of the 5 samples containing ctDNA were hyperdiploid. Chromosome 19 was the most common site of copy number increase whereas chromosomes 6, 10, and 18 exhibited the most frequent decreases in copy number. Two pts with PGNMID had detectable ctDNA without evidence of a serological or marrow-based clone. All pts received daratumumab, cyclophosphamide, bortezomib and dexamethasone as initial treatment. Five pts responded to therapy. Two patients ultimately underwent autologous stem cell transplant and a single patient received venetoclax as second line therapy. Of the patients exhibiting detectable ctDNA, three did not exhibit renal response to initial treatment. Both pts without ctDNA had PGNMID and responded to frontline treatment. Mass spectrometry analysis and deep targeted sequencing of bone marrow aspirates and peripheral blood will be presented. Conclusions To our knowledge, this is the first study to detect ctDNA in MGRS. ULP-WGS, when combined with targeted sequencing and diagnostic modalities such as mass spectrometry, has the potential to not only to aid in diagnosis and treatment selection on a practical basis, but also to begin to unravel the underlying genomics of this rare disease. This approach has potential to serve as a platform for further genomic exploration and biomarker development in MGRS.

ABSTRACT Thogotoviruses are arthropod-borne viruses belonging to the genus Thogotovirus within the family Orthomyxoviridae . Like other orthomyxoviruses, such as the influenza A viruses (IAV), thogotoviruses replicate in the nucleus. As a result, progeny viral ribonucleoprotein complexes (vRNPs) must be exported to the cytoplasm prior to virion assembly and budding at the plasma membrane. In IAV, this export depends on binding of the viral nuclear export protein (NEP) to the cellular exportin chromosomal maintenance 1 (CRM1). In contrast, the mechanism of vRNP nuclear export, including identification of a protein with NEP functionality, has not been characterized for any thogotoviruses. Here, we characterized vRNP nuclear export in Dhori virus (DHOV), a prototypic member of the Thogotovirus genus. DHOV replication and nuclear export of the viral nucleoprotein were inhibited by the canonical CRM1 inhibitor leptomycin B (LMB), suggesting that DHOV vRNP export also utilizes CRM1. Interestingly, LMB treatment led to nuclear retention of the DHOV matrix (M) protein in both infected and transfected cells. Using a mammalian two-hybrid system, we found that DHOV M interacts with CRM1 through a nuclear export sequence (NES) located between amino acids 111 and 128. Mutation of hydrophobic residues within this NES reduced M-CRM1 interaction, abolished the NES phenotype when fused to a fluorescent protein, and impaired rescue of recombinant DHOV by reverse genetics. Together, our results reveal that DHOV vRNP nuclear export is CRM1-dependent and mediated by the M protein rather than a dedicated NEP-like protein, providing the first mechanistic insight into vRNP egress in the genus Thogotovirus . IMPORTANCE Dhori virus (DHOV) is a pathogenic tick-borne virus in the genus Thogotovirus , in the family Orthomyxoviridae. Despite evidence of DHOV exposure in various mammals, including humans, its basic biology is not well understood. We investigated how DHOV’s progeny genome and protein complexes—viral ribonucleoprotein complexes (vRNPs)—are transported out of the nucleus. Our findings show that DHOV, like the influenza viruses, uses the cellular protein chromosomal maintenance protein 1 (CRM1) for vRNP export. We found that chemically inhibiting CRM1 completely blocked DHOV vRNP export, preventing the production of progeny viruses from infected cells. Screening of all known DHOV proteins revealed that the matrix protein, which forms the virus’ scaffold, interacted with CRM1, suggesting it may link CRM1 to the vRNPs. These results advance our understanding of DHOV replication and suggest that chemically inhibiting vRNP export could be a way to treat thogotovirus infections.