Costa, Luciano J.

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

Abstract Recent therapeutic advances, including bispecific antibodies (bsAbs), have improved outcomes for patients with relapsed/refractory multiple myeloma (RRMM). However, early mortality (EM) remains a significant challenge, even in the era of novel immunotherapies. We conducted a multicenter, retrospective analysis of real-world patients with RRMM treated with commercial bsAbs to evaluate the incidence and causes of EM. Between May 2022 and June 2025, a total of 441 patients were treated across 7 countries. EM, defined as death within 12 months of therapy initiation, occurred in 148 patients (34%), with a median time from bsAb initiation to death of 2.87 months (interquartile range, 1.38-6.85). The leading cause of EM was progressive disease (72%), followed by infection (13%); regardless of the cause of death, 82% had active disease at the time of death. Our findings highlight that despite encouraging efficacy, EM remains high among real-world bsAb recipients, emphasizing the need for improved disease control strategies and supportive care interventions.

Abstract Introduction: Elranatamab (Elra) is a bispecific antibody (BsAb) targeting BCMA that is approved for patients with triple class exposed relapsed refractory myeloma (RRMM) on the basis of the MagnetisMM-3 phase 2 trial. For BCMA naïve patients, an overall response rate (ORR) of 61.0% and median progression free survival (PFS) of 17.2m was observed with a median overall survival (OS) of 24.6m. However, efficacy and safety information in the real world is lacking. Methods: This was an international retrospective study of patients with RRMM treated with Elra monotherapy outside of clinical trials. Data was collected through the International Myeloma Foundation Immunotherapy Database from 7 countries (UK, USA, Canada, Greece, Spain, Czech Republic and Singapore). High-risk cytogenetic abnormalities (HRCA) were defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (range). PFS, OS were evaluated using the Kaplan-Meier method and reported with 95% confidence intervals. Results: 79 patients were included. Median age was 67 years (range: 41-95y) with 20% ≥75 years. Racial distribution was: 75% White, 16% Black/African American, 8% Asian/Pacific. 55% were ECOG performance status (PS) 1-2. Patients received a median of 5 prior lines (range 1-11), and 35% were BCMA exposed (9% CAR-T, 5% ADC, 7% BsAb, 8% BsAb plus CAR-T, 4% ADC plus BsAb). Of those with available data, 45% had HRCA,13% had extramedullary disease (EMD) and 32% had penta-drug refractory RRMM. Overall, 48% would not have been eligible for the MagnetisMM-3 trial. Median follow-up was 6.3m (range 0.5-35.0). ORR was 53% (PR 11%, VGPR 33%, CR 8%, sCR 1%) and 67% for BCMA naïve patients. Responses were significantly lower for BCMA exposed patients (ORR 31%) but did not differ by age (51% &lt;75yrs vs 60% ≥75yrs). On univariate analysis, prior BCMA exposure, platelets &lt;50, presence of HRCA and penta-refractoriness were significantly associated with a lower response rate. PFS for the whole cohort at 6 and 12m was 64% (95%CI, 54-77%) and 52% (40-67%); for BCMA naïve patients, it was 77% (65-90%) and 67% (54-84%), respectively. Within the whole cohort, PFS was shorter for: BCMA exposed (median 4.0m vs not reached (NR)), platelets &lt;50 (2.0 vs 21.7m), HRCA (7.2m vs NR), penta-refractory (4.3m vs NR). PFS did not differ significantly by EMD, PS, age, or creatinine clearance. OS for the whole cohort at 6 and12m was 74% (64-85%) and 58% (45-74%); for BCMA-naïve patients, it was 80% (43-85%) and 70% (57-87%), respectively. Within the whole cohort, OS was shorter for: BCMA exposed (median 10.3m vs NR), platelets &lt;50 (4.3m vs NR), HRCA (10.7m vs NR) and penta-refractory (10.3m vs NR). Univariate regression analysis demonstrated that prior BCMA exposure, platelets &lt;50 and penta-refractoriness were significantly associated with a worse PFS and OS, and HRCA predicted poorer survival CRS was observed in 41% of patients (grade(G)1: 35%, G2: 5%, ≥G3: 0%) with most occurring with the first step up dose (SUD): SUD1: 29%, SUD2: 15%, full dose: 4%. Tocilizumab was used in 20% and steroids in 3%. ICANS was observed in 4 cases (5%): G1: 2, G2: 1, G4: 1. Treatment was with steroids (n=3) and tocilizumab (n=2). G3-4 thrombocytopenia was observed in 19% and 14% required platelet transfusions. G3-4 neutropenia occurred in 25% with overall 31% requiring GCSF. Infections were reported in 33 (42%) patients with median time to infection of 41 days. A total of 94 infection episodes were observed over 581 personal months. There were 2 infection-related deaths reported (1 had IVIG, 1 did not). 64% had hypogammaglobulinemia (IgG &lt; 400mg/dl) and IVIG was given in 65% of patients. Conclusions: In this first international real world analysis, Elranatamab achieved a response rate of 67% and a 12m PFS of 67% in BCMA naïve patients, similar to the MagnetisMM-3 trial despite almost half not meeting trial eligibility. However, prior BCMA exposure, platelets &lt;50, high risk cytogenetics and penta refractory status were predictors of poorer outcomes. Acknowledgements: The International Myeloma Foundation, International Myeloma Working Group (IMWG)

Abstract Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), 2 B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma; however, the 6 to 8 weeks manufacturing time risks disease progression or death in up to 10% of patients. Talquetamab, a G-protein–coupled receptor, family C, group 5, member D (GPRC5D)–targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 United States, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n = 98 cilta-cel, n = 21 ide-cel). Reasons for not proceeding (n = 15) included progression (n = 7), manufacturing failure (n = 6), or patient decision (n = 2). Median age was 65 years and had median 5 prior lines of therapy. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days. Toxicity was manageable: no grade ≥3 cytokine release syndrome (CRS), 2% grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) and grade 1 to 2 talquetamab unique toxicities (70% oral, 38% skin, and 17% nail; 60% resolved). Talquetamab achieved 71% response rate. After CAR-T, 88% responded (54% complete response), with low-grade toxicities (2 grade ≥3 CRS, 1 grade 3 ICANS, and 5% grade ≥3 infections). Two cases of facial palsy and 1 acute myeloid leukemia occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe, enabling the majority of difficult-to-treat patients to successfully proceed to BCMA CAR-T therapy.

Background Emerging evidence has demonstrated rare subacute to late neurological toxicities (NTs) after BCMA CAR T-cell therapy (CAR-T) in multiple myeloma (MM). These adverse events can be categorized as: 1) Parkinsonism (PD), 2) cranial nerve (CN) palsies, and 3) peripheral neuropathies/Guillan Barré syndrome (GBS). These toxicities can cause significant morbidity, but given their relative rarity in clinical trials, there is limited data regarding evaluation and treatment. To our knowledge, this is the largest and only global registry of delayed NTs after BCMA CAR-T. Methods We retrospectively established a registry of NTs via the Immune Therapy Working Committee of the International Myeloma Working Group (IMWG). We gathered data pertaining to demographics, MM characteristics, MM response, NT signs/symptoms, diagnostic workup, and treatment. Result A total of 52 patients with delayed neurotoxicity were included from 14 institutions and 6 countries; 92% received ciltacel, 4% idecel, and 4% investigational CAR-T. Median age at CAR-T infusion was 65 years; 69% were male and 88% were Caucasian. Median bone marrow plasma cell (PC) burden was 15% prior to CAR-T (range 0-95%). Patients received a median of 4 prior lines of therapy (LOT), with 67% progressing on last LOT. Seventeen percent had pre-existing neurological diagnoses (including stroke, epilepsy, migraines). We identified sixteen cases of PD (94% with movement disorder, 69% with cognitive impairment, 75% with personality changes), occurring at a median of 26 days (range: 15-87) after CAR-T. Ninety four percent had CRS (grade (G)1 50%, G2 38%, G3 6%, G4 0%), while 19% had ICANS (G1 13%, G2 6%, G3-G4 0%). Median peak absolute lymphocyte count (ALC) was 9.5 x 109/L, peak C-reactive protein (CRP) 60.9 mg/L, and peak ferritin 1893.5 ug/L within the first 30 days. Concurrently, 3 upper respiratory infections (URIs) and 2 low-level HHV7 in the cerebrospinal fluid (CSF) were detected. A median of 73% of T-cells in the CSF were CAR-T, based on a flow cytometry assay. Ten patients received steroids (median 19 days after symptoms, 70% partial response, 20% no response, 10% unknown), 2 received intrathecal (IT) methotrexate-based therapy (median 32 days after symptoms, 1 with no response, 1 unknown), 5 received intravenous (IV) cyclophosphamide (median 31 days after symptoms, 40% full response, 20% partial response, 40% no response), 4 received high-dose IVIG ≥1g/kg for one or more dose (50% partial response, 50% no response), and 6 received dopamine agonists. There were 37 CN palsies (76% CN7, 15% CN6, 7% CN5, 2% CN3), occurring at a median of 37.5 days (range: 7-482) after CAR-T. Eighty one percent had CRS (G1 68%, G2 14%, G3-G4 0%); 11% had G1 ICANS (G2-G4 0%). Median peak ALC was 4.1 x 109/L, CRP 25.4 mg/L, and ferritin 543 ug/L within the first 30 days. We identified 2 concurrent URIs, 4 CMV viremia (50% with viral load &gt;1500 IU/mL), 1 HHV6 viremia, and 1 HSV in the CSF. Thirty-two (86%) received steroids for a median duration of 12 days, 50% with full response, 3% with no response, and 47% with partial response (of which 43% had later full recovery without further intervention). One received IT methotrexate and another received IV cyclophosphamide without response. Thirteen (41%) received IVIG, of which 38% was high-dose IVIG. Four patients with CN palsies developed peripheral neuropathy/GBS. Eight patients (15%) in this cohort were not heavily pre-treated (≤1 prior LOT); 7 developed CN palsies (6 after ciltacel, 1 after investigational CAR-T) and 1 PD (after idecel). These patients had median &lt;5% PC; none had extramedullary disease. Median ALC was 4.14 x 109/L, CRP 33 mg/L, and ferritin 448.5 ug/L within the first 30 days. Conclusions Delayed NT requires prompt recognition, evaluation for alternative causes, and treatment. In our cohort, the majority of patients were male and Caucasian, suggesting that sex and race may impact the likelihood of developing NT. Individuals with PDs had greater inflammatory response (CRS, ALC, CRP, ferritin) compared to those with CN palsies. CN palsies responded to steroids and/or IVIG, whereas PD had at best partial response to steroids, prompting additional therapy. These toxicities notably did occur in less heavily pre-treated patients, perhaps driven by immune fitness and greater circulating T-cells rather than MM burden. At the time of the annual meeting, data will be updated with additional NTs from less heavily pre-treated patients.

Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on multiple myeloma (MM) cells than on normal B cells. Cevostamab is a FcRH5xCD3 bispecific antibody that facilitates T cell-mediated killing of MM cells. In an ongoing Phase I dose-escalation and dose-expansion study (GO39775; NCT03275103), cevostamab monotherapy demonstrated target dose (TD)-dependent activity and manageable safety in patients (pts) with heavily pretreated RRMM (Trudel et al. ASH 2021). We report updated efficacy and safety data from pts who received cevostamab once every 3 weeks (Q3W) at the 160mg TD level. Methods: Eligible pts were those with RRMM for which no established therapy was available or appropriate. Cevostamab was initiated with Cycle (C) 1 single-step (SS) dosing, double-step (DS) dosing (Trudel et al. ASH 2021), or triple-step (TS) dosing (step doses on D1, D2 [or D3 or D4 depending on the emergence and resolution of cytokine release syndrome [CRS] with the previous administration], and D8, TD on D9 [or D10 or D11]). Cevostamab was then continued at the TD on D1 of each subsequent 21-day cycle. Cevostamab was continued for 17 cycles, unless disease progression or unacceptable toxicity occurred. Results: As of February 23, 2024, 167 pts (median age: 66 years, range: 40-90; ECOG PS: 0, 35% or 1, 65%; median time from first MM therapy: 6.3 years, range: 0.3-21.8) had received cevostamab at the 160mg TD level (SS: n=10; DS: n=97; TS: n=60); 28% of pts had extramedullary disease and 38% of pts with a conclusive assay result (38/100) had high-risk cytogenetics (t(4;14), t(14;16), or del(17p)). The median number of prior lines of therapy was 6 (range: 2-18). Almost all pts (95.8%) were triple-class refractory and 73.7% were penta-drug refractory; 85.0% were refractory to their last prior therapy. A majority (57%) of pts had received ≥1 prior B-cell maturation antigen (BCMA)-targeted therapy. Twenty four percent of pts had received ≥1 prior bispecific antibody. Median observation time was 11.3 months (range: 0.5-42.8). The overall response rate (ORR) in all pts who received cevostamab at the 160mg TD level was 43.1% (72/167 pts); 6.6% achieved a stringent complete response (CR), 6.6% a CR, 12.6% a very good partial response (VGPR), and 17.4% a partial response (PR). The VGPR or better rate was 25.7%. Median time to first response (PR or better) was 1.4 months (range: 0.6-4.6) and to best response was 2.4 months (range: 0.7-13.4). Median duration of response was 10.4 months (95% CI: 6.8, 10.5). ORR was 30.2% (29/96) in pts with ≥1 prior BCMA-targeted therapy and 60.6% (43/71) in those without. ORR was 30.0% (12/40) in pts with ≥1 prior bispecific antibody, 33.3% (20/60) with ≥1 prior chimeric antigen receptor (CAR) T-cell, and 41.2% (14/34) with ≥1 prior antibody-drug conjugate. Common (≥20%) adverse events (AEs) included CRS (74.3%; Grade [Gr] 1: 52.7%; Gr 2: 19.8%; Gr 3: 1.2%; Gr 4: 0.6%), neutropenia (31.1%; Gr 1-2: 3.0%; Gr 3: 12.0%; Gr 4: 16.2%), cough (30.5%; Gr 1-2: 29.9%; Gr 3: 0.6%), nausea (28.1%; Gr 1-2: 27.5%; Gr 3: 0.6%), diarrhea (24.0%; all Gr 1-2), anemia (23.4%; Gr 1-2: 5.4%; Gr 3: 17.4%; Gr 4: 0.6%), and fatigue (21.0%; Gr 1-2: 19.8%; Gr 3: 1.2%). Possible immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 13.2% of pts (Gr 1: 6.0%; Gr 2: 5.4%; Gr 3: 1.8%). Infections occurred in 53.9% of pts, with serious events and Gr ≥3 events in 22.2% and 19.2%, respectively. Treatment-related AEs leading to cevostamab discontinuation occurred in 11 pts (6.6%) and treatment-related Gr 5 (fatal) AEs in 3 pts (1.8%; hemophagocytic lymphohistiocytosis, n=2; disseminated intravascular coagulation and pseudomonal sepsis, n=1). In the 0.3/1.2/3.6/160mg TS cohort, CRS occurred in 19/30 pts (63.3%) and was all Gr 1 (46.7%) or Gr 2 (16.7%). Pts with CRS were managed with tocilizumab (47.4%), steroids (21.1%), or both agents (10.5%). No pts discontinued cevostamab due to CRS and all events were resolved at cut-off. Conclusions: Cevostamab demonstrates clinically meaningful activity and manageable safety at the 160mg TD level in pts with heavily pretreated RRMM. C1 TS dosing provides effective CRS mitigation. Cevostamab combination studies may use the 0.3/1.2/3.6mg TS regimen and the Q3W 160mg TD (or similar TD exposure).

Background The International Myeloma Working Group (IMWG) defines progression of disease (PD) in multiple myeloma by the increase in serum or urine paraprotein beyond a certain threshold. With more common use of serial bone marrow-based measurable residual disease (MRD) assessment, some patients will evolve with increase in MRD burden without meeting IMWG criteria for PD and no consensus exist on the best approach for this circumstance. Understanding the implication of increasing MRD burden is particularly relevant in patients with NDMM treated with quadruplet therapy (QUAD, consisting of a PI, an IMiD, an anti-CD38 mAb and dexamethasone) and autologous stem cell transplantation (ASCT), since most will reach MRD negativity. Methods We analyzed a large dataset of patients with NDMM patients treated with QUADs + ASCT +/- QUAD consolidation +/- single or dual-agent maintenance and monitored with serial MRD assessment by next-generation sequencing (clonoSEQ®) at end of induction, post ASCT, post consolidation and at least yearly thereafter. The dataset was built from clinical trial participants and from patients receiving standard care under an institutional guideline. MRD progression (MRD-P) was arbitrarily defined as quantitative increase in MRD burden by at least 1 log10 above the nadir. Treatment modification in the event of MRD-P without IMWG-defined PD was at discretion of treating physician. For patients with MRD-P without concomitant PD we describe cumulative incidence of PD after MRD-P. To contextualize the clinical implications of MRD-P, we describe survival free of failure of second line therapy (SFF2T), defined as time from progression event (MRD-P or PD not preceded by MRD-P) until occurrence of IMWG-defined PD or death on second line therapy, regardless of whether second line was initiated due to MRD-P or subsequent IMWG-defined PD. Results Among the 216 patients, 113 (52%) were clinical trial participants, median age was 61 years (IQR 56-68), 21% age 70 or older, 32% were non-White, 57% male, 38% had MM with 1 high risk chromosome abnormality [HRCA, gain/amp 1q, t(4;14), t(14:16), del(17p)], 15% had 2+HRCA. Median duration of follow up is 39.5 months, and 966 MRD datapoints were assessed. Overall, 83% of patients achieved sCR, 78% achieved MRD negativity at 10-5, 68% at the 10-6 threshold, and 56% ceased therapy after confirmed MRD negativity. Forty-nine patients had MRD-P(N=19) or PD not preceded by MRD-P (N=30). Patients with MRD-P or PD not preceded by MRD-P often had 1 or more HRCA (73.7% and 82.8%), International staging system III (36.8% and 30.0%), and high LDH at diagnosis (31.6% and 23.3%). Median time from onset of therapy to MRD-P was 24.4 mo (IQR 12.6-35.8) and to PD not preceded by MRD-P was 23.2 mo (IQR 18.4-29.4). Among the 19 patients with MRD-P, 12 (63%) were on observation at time of MRD-P, 2 were receiving single agent lenalidomide, 5 were receiving a QUAD, 17 (89%) had previously obtained MRD negativity at &lt;10-5 including 10 (53%) who had also achieved MRD negativity at 10-6. Upon detection of MRD-P, 12 (63%) pts changed therapy, all to a monoclonal antibody-containing triplet or quadruplet regimen. Yet, median time from MRD-P to PD was 10.1 months. Patients with MRD-P had 1-year SFF2T of 55.6%, in contrast to 35.0% for patients with PD not preceded by MRD-P. OS 2-year from progression event was 78.0% for MRD-P and 53.9% for PD not preceded by MRD-P. Conclusions In the context of NDMM treated with QUAD + ASCT, MRD-P indicates imminent IMWG-defined PD, and is driven by a thriving plasma cell population unlikely to be controlled by reinstitution of anti-CD38 mAb-based combinations. Outcomes of patients with MRD-P are similar to those of patients with IMWG-defined PD. These findings challenge the paradigm of IMWG-defined PD and paraprotein measurability as minimal parameters for change in therapy and introduction of agents with new mechanisms of action.

Introduction QUADs with an anti-CD38 mAb, an IMiD, a proteasome inhibitor and dexamethasone followed by autologous stem cell transplantation (ASCT) in the treatment of newly diagnosed multiple myeloma (NDMM) led to substantial improvements in depth of response, including minimal residual disease (MRD) negativity, and progression-free survival. The therapeutic success of QUAD + ASCT has reinvigorated an interest in fixed-duration therapy, yet optimal short term efficacy endpoint for treatment cessation is unknown. We used a large dataset of patients (pts) treated with QUAD + ASCT, monitored with serial MRD assessment and managed with MRD-adapted treatment duration to determine the best short term efficacy endpoint to identify pts at low risk of treatment failure. Methods We analyzed 221 pts with NDMM treated with QUAD + ASCT and monitored with serial marrow-based MRD by next-generation sequencing. Based on trial design (N=116) and institutional practice (N=105) most pts received post ASCT QUAD consolidation followed by treatment cessation if MRD&lt;10-5 in two consecutive datapoints. Pts were monitored with MRD post induction, ASCT and consolidation, and at least yearly thereafter. We utilized Cox regression to build parallel models of predictors of disease progression or MRD resurgence utilizing the same patient and disease features and one distinct short term efficacy endpoint per model, inputted as time-varying covariate. Efficacy endpoints tested were IMWG-defined stringent complete response (sCR), MRD&lt;10-5 (single datapoint), MRD&lt;10-6, sustained MRD (S-MRD, two consecutive assessments at least 1 year apart) &lt;10-5and S-MRD&lt;10-6. Best fitting models were determined using Akaike's information criterion (AIC, lower value indicates better fitting model), an information theory approach, and Heagerty & Zheng C index. Results Median age of the 221 pts. was 61 years (IQR 55-68), 21% age 70 or older, 37% had MM with 1 high risk chromosome abnormality [HRCA, gain/amp 1q, t(4;14), t(14:16), del(17p)], 16% had 2+HRCA, 30% were non-White and 58% male. We followed pts for a median of 40.6 mo. and performed 979 MRD assessments. One hundred and eighty-three pts (83%) achieved sCR, 170(77%) MRD&lt;10-5, 146 (66%) MRD&lt;10-6 , 110 (50%) S-MRD&lt;10-5 and 90 (41%) S-MRD&lt;10-6. Average time to achieve the endpoint was 7.8 mo for sCR, 7.1 mo. for MRD &lt;10-5, 9.4 mo. for MRD&lt;10-6, 19.3 mo. for S-MRD&lt;10-5 and 20.5 mo. for S-MRD&lt;10-6. We first tested models to predict PFS among all 221 pts. Predictive models included same covariates (ISS, high LDH and number of HRCA) other than the efficacy endpoint. The best fitting model (AIC 417.2, C-stat 0.757) was based on S-MRD&lt;10-5 (HR=0.23, 95% C.I. 0.11-0.47) and included presence of 1 HRCA (HR=2.93, 95% C.I. 1.31-6.52), 2+ HRCA (HR=7.60, 95% C.I. 3.31-17.43), high LDH (HR=1.64, 95% C.I. 0.81-3.33), ISS2 (HR 1.31, 95% C.I. 0.62-2.77) and ISS3 (HR 1.96, 95% C.I. 0.90-4.28). The model with S-MRD&lt;10-6 had similar, but not better performance (AIC 419.4, C-stats 0.752). We subsequently analyzed the 121 (55%) pts who reached MRD-guided treatment cessation for the best fitting model to predict progression or MRD resurgence in absence of continuous therapy. Among these pts, 117(97%) achieved sCR, all (by definition) MRD&lt;10-5, 116 (96%) MRD&lt;10-6 , 95 (79%) S-MRD&lt;10-5 and 81 (67%) S-MRD&lt;10-6. The best fitting model (AIC 197.2, C-stat 0.766) was based on S-MRD&lt;10-5 (HR 0.01, 95% C.I. 0.002-0.05) and included presence of 1 HRCA (HR=1.41, 95% C.I. 0.49-4.07), 2+ HRCA (HR=5.43, 95% C.I. 1.75-16.84), high LDH (HR=3.19, 95% C.I. 0.98-10.40), ISS2 (HR 1.25, 95% C.I. 0.53-2.96) and ISS3 (HR 0.73, 95% C.I. 0.23-2.37). The model with S-MRD&lt;10-6 did not perform better (AIC 232.4, C-stat 0.727). Among the 94 pts who achieved S-MRD&lt;10-5 and were monitored off therapy, the risk of MRD resurgence or progression 2.5 years after cessation of therapy was 6.1%, 15.0% and 22.2% and risk of progression was 3.0 %, 12.0% and 11.1% for patients with 0, 1 and 2+ HRCA, respectively Conclusion In the setting of QUAD therapy + ASCT, no short term conventional or MRD-based efficacy parameter negates the cumulative impact of HRCA on prognosis. S-MRD&lt;10-5 is the best predictor of PFS and yields the best predictive models for risk of MRD resurgence or progression in the setting of fixed duration therapy. This analysis validates S-MRD&lt;10-5 as efficacy parameter for treatment cessation in trials exploring fixed duration therapy in NDMM.

Introduction: Anti-BCMA CAR-T therapies like idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized RRMM treatment. However, the 6-8-week manufacturing period often leads to disease progression and/or death in up to 25% of patients (pts), necessitating effective bridging strategies. Talquetamab (talq), a bispecific antibody targeting GPRC5D, is approved for RRMM pts with four prior lines of therapy and offers rapid disease debulking without impacting BCMA. This study assesses the safety and efficacy of a short course of talq as a bridging therapy for pts receiving cilta-cel or ide-cel. Methods: This multicenter retrospective study involved 14 US academic medical centers within the US Multiple Myeloma Immunotherapy Consortium. We included pts with RRMM who underwent leukapheresis and received talq bridging therapy with the intent to proceed to commercial cilta-cel or ide-cel. We assessed the safety, feasibility, and efficacy of talq bridging therapy. Safety outcomes included cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), talq-related unique toxicities, and delayed neurotoxicity (NT). Efficacy outcomes included response rates to talq and CAR-T therapies. Results: Between June 2023 and May 2024, 77 pts received talq bridging therapy after apheresis with the intention to proceed to CAR-T. The median age was 66 years (range, 58-73); 14% were Black and 10% Hispanic. Poor prognostic features, including high-risk cytogenetics, were present in 45%, extramedullary disease (EMD) in 43%, and 72.7% were triple-class refractory. The median number of prior lines of therapy was 5 (range 3-11) and 10 pts (13%) had prior BCMA targeted therapy. Out of 77 pts, 10 pts were pending CAR-T infusion at the time of last follow up; 6 pts could not receive CAR-T infusion due to manufacturing failures. Of the remaining 61 patients who underwent successful CAR-T manufacturing, 58 (95%) pts were successfully infused with CAR-T therapy following talq bridging. Three (5%) pts died due to disease progression prior to CAR-T infusion. Talq was given 0.8 mg/kg biweekly in 59 (76%) pts and the median time on talq was 22 days (IQR: 10-41 days). Following talq bridging, none of the pts had grade &gt;=3 CRS and 2 (2.5%) had grade 3 ICANS. Skin toxicities occurred in 32 (41%), nail toxicities in 19 (25%), and oral toxicities in 43 (56%) pts mainly grade 1. Most oral, skin, and taste changes resolved at the last follow-up (60%). Response to talq was evaluable in 72 out of 77 patients. An overall response was noted in 45/72 (62%) pts including unconfirmed CR in 14, VGPR in 10 and PR in 21 pts. There was no association of AEs and response to talq with high-risk cytogenetics, EMD and high baseline ferritin levels. Out of the 58 patients who went on to receive CAR-T therapy following talq bridging (45 cilta-cel and 13 ide-cel), 38 (65%) experienced CRS, with grade 3 CRS noted in 2 (3%) pts. ICANS occurred in 5 (8.6%) pts, with 1 (1.7%) grade 3 ICANS. Only 1 pt had delayed NT (facial nerve palsy) at the last follow up. No treatment related deaths were observed. Of these 58 pts, response was evaluable in 40 pts and a response at day +30 was noted in 39/40 (97.5%) pts (14 in CR, 10 in VGPR, 15 in PR). The median follow-up from CAR-T was 61 days (28-113). For the 58 pts who received CAR-T, the median time from the last talq dose to CAR-T infusion was 25 days (IQR: 19-36), and to lymphodepletion was 24 days (IQR: 18-33). There was no difference in the CAR-T related AEs by the duration of Talq washout (&gt;4 weeks vs. =&lt; 4 weeks). Conclusions: Talquetamab is an excellent bridging option before BCMA-targeted CAR-T therapy, showing high response rates even with short-term use and enabling most pts to receive CAR-T. Most oral, skin, and taste changes resolved post CAR-T. These findings underscore the effectiveness of a short course of talq bridging to maintain disease control and improve outcomes post CAR-T. Updated data with longer follow-up will be presented at the meeting.