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Background: Despite effective front-line therapies, DLBCL & MM have high relapse rates. Novel therapies like CAR-T & bispecific antibodies (BsAb) offer deep & durable remission compared to salvage therapies, but have a unique toxicity profile (TP) that requires monitoring. With no head-to-head trials, the rationale for therapy selection may vary. This study explores provider choices, sequencing preferences, & access barriers. Methods: Two anonymous surveys (MM and DLBCL) of US-based Hematologists were conducted from 2/2024 to 6/2024, on practice settings, CAR-T & BsAb availability, treatment preferences & barriers. Responses were analyzed to assess preferences across clinical scenarios. Results: Surveys were completed by 37 MM & 45 DLBCL providers. Most were at centers offering both CAR-T & BsAb. Most gave CAR-T inpatient, & BsAb outpatient. CAR-T was given by 73% MM providers & 66% DLBCL (92% used Cilta-cel, 96% used Ide-cel; 100% used Axi-cel, 90% used Liso-cel & 73% Tisa-cel). In MM, 78% used Teclistamab, 60% Talquetamab & 24% Elranatamab. In DLBCL, 62% used Epcoritamab & 40% Glofitamab. Providers preferred CAR-T over BsAb in MM after 4+ prior lines of therapy (LOT) (89%), & in DLBCL after 2+ prior LOT (93%). CAR-T was favored more among academic providers & those at CAR-T centers. Practice volume did not impact selection. Among providers at centers with BsAb-only, CAR-T was preferred by 60% (MM) and 50% (DLBCL). Providers at centers without both favored CAR-T (MM: 75%, DLBCL: 86%). CAR-T was chosen for better outcomes, short treatment, center choice, & prior experience. Other factors that influenced decisions were lower incidence of cytopenia/infection & “BsAb effective post-CAR-T, less so vice versa” (MM), & “curative potential of CAR-T” (DLBCL). Logistical barriers & institutional constraints influenced BsAb selection: CAR-T unavailability, access to specialized centers, referral complexity, insurance delay, manufacturing delay & hospitalization needs. In MM, 78% providers preferred Cilta-cel over Ide-cel, especially academic providers & those with CAR-T experience. CAR-T volume did not impact selection. Cilta-cel was preferred due to perceived better response rate (RR), more experience, “progression-free survival (PFS) benefit”, center choice, & logistical issues with Ide-cel. Ide-cel was selected due to center choice, favorable TP & insurance preference. Teclistamab was preferred by 78% due to more experience, better RR, TP & center choice, Elranatamab by 11% (better TP, RR, & “PFS”), & Talquetamab by 11% due to having a non-BCMA target. Academic providers preferred Teclistamab (89% vs 50%), & nonacademic providers preferred Talquetamab (38% vs 4%) and Elranatamab (13% vs 8%). In DLBCL after 2+ LOT, 69% favored Axi-cel due to prior experience, RR, center choice, & logistical issues with other products. Liso-cel & Tisa-cel were chosen by 27% & 2%, respectively, due to favorable TP. Axi-cel was also preferred 2nd line by 73% for similar reasons, while 24% favored Liso-cel for its favorable TP. Epcoritamab was preferred by 56% (subcutaneous injection, more experience & center choice) & Glofitamab by 42% (shorter treatment duration, easy administration, more experience, & center choice). Practice setting & volume did not impact selection between products in DLBCL. InBCMA-naïve MM pts, majority (97%) chose an anti-BCMA agent over GPRC5D due to better RR, TP, prior experience, & center choice. InBCMA-exposed pts, most (92%) favored an anti-GPRC5D agent. In contrast in DLBCL, 80% chose CD19 CAR-T after prior CD19-directed therapy, & 18% chose CD20 BsAb. Therefore, antigen escape was less of a concern in DLBCL vs MM. For relapse after 2nd line CAR-T in DLBCL, 78% preferred BsAb over other salvage options due to better RR, TP, & more experience. Providers prioritized RR, survival, & TP in decision making. Treatment logistics, duration, frequency, & cost were less crucial. MM providers also prioritized quality of life, which was less so in DLBCL. There were no differences in priority based on practice setting & experience with CAR-T. Conclusion: The study highlights factors influencing therapy choices in MM & DLBCL. Despite CAR-T's potential for better outcomes, significant access barriers exist. Efforts to streamline referral pathways, logistics, & expanding availability are crucial to improve outcomes. Understanding these preferences & barriers can guide future management strategies.

Abstract Patient-reported outcomes (PROs) are associated with treatment outcomes in multiple myeloma (MM) in the clinical trial setting. However, most PRO tools are time consuming, which hinders use in routine practice. Our institution incorporated a “Hematology Patient-Reported Symptom Screen” (HPRSS), a 3-item questionnaire for fatigue, pain, and quality of life (QOL). The main objective of this study was to evaluate the impact of these symptoms on progression-free survival (PFS) and overall survival (OS) in a real-world cohort of patients with newly diagnosed MM. This retrospective study included patients with MM diagnosed between April 2011 and December 2017, seen at Mayo Clinic (Rochester, MN), who completed the HPRSS. Patients rated their symptoms on a scale from 0 to 10. Clinically relevant symptoms were defined as scores ≥5 for pain and fatigue, and ≤5 for QOL. At diagnosis, 735 patients had scores for all domains. The median follow-up was 8.1 years. Age was associated with increased odds of fatigue and decreased QOL. Female sex and comorbidities were associated with fatigue and pain. Higher disease stage, anemia, lytic lesions, and increased plasma cell burden were associated with fatigue, pain, and decreased QOL. Clinically relevant fatigue, pain, and decreased QOL were associated with decreased PFS and OS. On multivariate analysis including age, International Staging System III, high-risk cytogenetics, and postinduction transplantation, fatigue and decreased QOL were independently associated with decreased OS. A composite HPRSS score stratified patients into 3 groups with distinct OS. Patient-reported symptoms are prognostic in patients with newly diagnosed MM. The prognostic values of fatigue and decreased QOL are independent of age, disease stage, and transplant status.

Summary In 2014, the International Myeloma Working Group (IMWG) updated the criteria for diagnosing myeloma and added three additional criteria to the traditional Calcium elevation, Renal impairment, Anemia, Bone disease (CRAB) criteria, called the Sixty % marrow plama cells, Light chain ratio >60, Mri demonstates lytic lesions (SLiM) criteria (clonal bone marrow plasma cells ≥60%, involved to uninvolved free light chain ratio (FLCr) ≥100 and >1 focal lesion on magnetic resonance imaging (MRI)). We report on the outcomes of 30 patients who underwent autologous stem cell transplantation (ASCT) where therapy was initiated solely based on SLiM criteria and compared them to a matched cohort of 60 patients whose myeloma‐defining event was CRAB. The SLiM cohort had a shorter median time to neutrophil (15 vs. 16 days, p = 0.049) and platelet (15 vs. 17 days, p = 0.0004) engraftment. The 36‐month overall survival (OS) was 100% in the SLiM group and 93.27% in the control group (95% CI 83.06%–97.42%), with a trend towards longer OS in the SLiM cohort ( p = 0.065). The 36‐month progression‐free survival (PFS) was 91.61% in the SLiM (95% CI 69.93%–97.87%) and 65.95% in the control group (95% CI 52.31%–76.53%). There was no difference in the PFS between the cohorts ( p = 0.414). ASCT is efficacious and safe in MM patients transplanted only due to SLIM criteria. Early intervention in this asymptomatic cohort did not appear to result in deeper responses or better PFS compared to outcomes in symptomatic patients.

Abstract As patients with relapsed/refractory multiple myeloma (RRMM) continue to live longer, they might get exposed to most available drugs and drug classes during the disease course. For such late line RRMM or among patients without access to novel therapies, retreatment with a drug that the disease had previously been refractory to might be one option. In this retrospective study, we describe 315 patients with RRMM at our institution who were retreated with a drug that the disease had been previously refractory to. We found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (>28.4 months) had a superior PFS with retreatment (median PFS, 16.9 vs 8.1 months; P < .001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (>46.1 months) had better PFS with retreatment (28.2 vs 8.9 months; P = .016). In conclusion, retreatment with a previously refractory drug is a viable therapeutic option for RRMM, with the most significant benefit derived in disease demonstrating sensitivity to initial drug exposure and among those with a longer gap between initial drug exposure and retreatment.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease characterized by complement-mediated hemolysis. OPERA is the first US longitudinal real-world study on C3 inhibitor therapy, known as pegcetacoplan. Methods: OPERA enrolled US patients with PNH, age ≥18, who were prescribed pegcetacoplan, and data were collected from routine care. Hemoglobin was reported by patients during regular follow-up (censored from transfusions). The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (0–52 score) and Patient-Reported Outcomes Measurement Information System scale for Cognitive Function Abilities (PROMIS-CF; 23.27–67.09 t-score) were completed electronically (low score = negative outcome). Patients self-reported incidence of healthcare resource utilization (HCRU). Results: By January 2024, 70 patients (mean age 44.6 years; 57.1% female) reported up to 9 months of pegcetacoplan treatment, with a median [IQR] follow-up of 6.6 [3.8] months. The latest reported hemoglobin levels improved by a mean (SD) of 2.6 (1.9) g/dL from baseline. At 3, 6 and 9 months, patients reported clinically meaningful improvements (≥5 points) in FACIT-F (53.3–69.0%) and (≥2 points) PROMIS-CF (46.7–55.2%). Patients reported a <10% incidence rate per person month of all HCRU events. Conclusions: This first longitudinal real-world US study indicates a positive trend in Hb, fatigue, and cognition with limited HCRU during pegcetacoplan treatment in adults with PNH.

AbstractRenal AL amyloidosis can be complicated by end‐stage renal disease (ESRD) requiring renal replacement therapy (RRT). In this study, we describe the long‐term outcomes of renal AL amyloidosis patients undergoing autologous stem cell transplantation (ASCT) and assess the utility of the renal staging system. Retrospective study of renal AL patients (n = 697; Mayo Clinic, Boston University) who underwent ASCT between 2003 and 2020. Renal stage was assigned based on 24‐h proteinuria and estimated glomerular filtration rate measurements. Renal survival was defined as the time from ASCT until initiation of RRT, while patients who were not placed on RRT were censored at their last follow‐up. With a median follow‐up of 10.4 years, RRT was required in 149 patients (21%). The median time from ASCT to ESRD was 3.4 years, with late events of progression to ESRD seen >10 years from ASCT. Pre‐ASCT renal stage was significantly associated with the cumulative incidence of RRT: 3‐year RRT rate was 3%, 10%, and 37% for renal stages I, II, and III, respectively. However, in the 2012–2020 period subset, a significant decrease in ESRD risk was noted across all renal stages (3‐year RRT 0%, 5%, and 24%, respectively). In multivariate analysis, renal survival was independently associated with the pre‐ASCT renal stage, lambda isotype, bone marrow plasmacytosis ≥20%, post‐ASCT hematologic response, and year of ASCT. Long‐term outcomes of renal AL amyloidosis treated with ASCT are presented. Renal stage reliably predicts renal outcomes in patients with AL undergoing ASCT, despite a reduction in the proportion of patients progressing to RRT in recent years.

7558 Background: Survival in patients with multiple myeloma (MM) continues to improve with the newer therapies, but there is no clear evidence of a cure and patients continue to relapse. However, most patients have the most extended period without progression with their first-line therapy, and subsequent therapies often provide a shorter duration of response due to the use of drugs with overlapping mechanisms of action and, more importantly, a shorter first remission, pointing toward more aggressive disease biology. With newer immunotherapies being used at 1st relapse, this may change. We designed this study to explore the natural history of MM after the 1st relapse and define the predictors of outcome after the initial relapse. Methods: We identified all patients in the Mayo Clinic database diagnosed between Jan 2004-June 2019 who had had initial disease progression. The study cohort included 2005 patients. We explored the overall survival (OS) from the time of documented disease progression or the start of second-line treatment in patients who had not met IMWG criteria before second-line therapy. Front-line therapy was grouped into those with either an IMiD or PI, both IMiD and PI, daratumumab with IMiD and PI, and none of these agents. The IMiD and PI were always used with dexamethasone with or without an alkylator. Results: The median age was 63 (range 24-95) years and 60% were male. The median estimated follow-up from diagnosis for all patients was 86 mos. (95% CI; 82, 88) and the median time to progression from the start of therapy was 25 mos. (95% CI; 24, 26). The median OS from the first progression was 45 mos. (95% CI; 42, 50), 36 mos. for those diagnosed before 2009, and 52-53 mos. for those diagnosed later. On univariate analysis, age <70 at 1st relapse, RISS I, novel agents in initial therapy, CR in the first line, diagnosis after 2009, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse (Table). On multivariate analysis, age <70, RISS I, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse. Conclusions: The study provides an estimate of the outcomes and significant predictors of outcomes after 1st relapse in patients with MM. These factors should be taken into consideration when designing clinical trials in this patient population. In particular, these factors identify a high-risk group of patients not always identified by baseline characteristics and should be the focus of future trials. [Table: see text]

7520 Background: There are 2 CAR-T products and 3 bispecific antibodies (BsAbs) that are FDA-approved for patients (pts) with relapsed, refractory multiple myeloma (MM). Clinical trials experience to date suggests that clinical response of BsAb is less impacted after CAR-T therapy. We examined the outcome of pts who received BsAb in standard-of-care (SOC) practice at Mayo Clinic Rochester. Methods: Retrospective analysis of MM patients who received FDA-approved BsAb at Mayo Clinic, Rochester between 12/2022- 1/2024. IMWG criteria was used for clinical response. Results: Sixty-two patients received BsAbs: 77% (48/62) received teclistamab, and 23% (14/62) received talquetamab. Median age was 62 years (range: 33-81), 60% (37/62) were males, and 45% (28/62) received prior CAR-T. Patients who had prior CAR-T therapy had more prior lines of therapy compared to those who did not. Overall, ORR to teclistamab was 61%, which is comparable to previous studies and other real-world reports. ORR and ≥CR rates were comparable between patients with and without prior CAR-T (Table). Of the 28 pts who received CAR-T before BsAbs, 61% (17/28) received idecabtagene vicleucel, 10% (3/28) were ciltacabtagene autoleucel, and 29% (8/28) on clinical trial. We then compared outcome of BsAb between pts who had relapsed from CAR-T within 1 year (n=21, median PFS: 8.84 months (range, 1.12, 10.84)) or after 1 year (n=7, median PFS: 16.62 months (range, 13.30, 36.20)). At the time of BsAb infusion, pts with who relapsed < 1 year vs ≥1 year post CAR-T had comparable blood counts, ALC, M-protein and involved FLC levels, CRP, ferritin and LDH. BsAb CR/sCR rate was significantly higher in pts with disease relapse ≥1 year compared to <1 year post CAR-T (57% vs 14%, p=0.02). Conclusions: Irrespective of prior CAR-T exposure, BsAb have clinical activity in SOC practice in pts with MM. Our preliminary data suggest that responses to BsAbs are better in pts with late compared to early relapse post CAR-T. Longer follow-up is needed to understand the duration of response. Larger, multi-center studies with longer follow-up will help identify factors that impact BsAb response post CAR-T.[Table: see text]

7515 Background: BCMA directed CAR T cells, antibody drug conjugates (ADCs), and T cell engagers (TCEs) each have distinct strengths and weaknesses. While these agents have shown unprecedented response rates and survival outcomes, no head-head comparisons exist. We assessed the relative efficacy of different BCMA-therapies in relapsed myeloma, with a focus on high-risk subgroups. Methods: Retrospective study of MM patients treated at Mayo Clinic with commercial or investigational BCMA targeted therapies between April 2018-June 2023. Results: 385 patients (ADC=59, TCE=134, CAR T=192) with a median follow up of 20-months. The median time from diagnosis was 6.1 years. The table shows disease, and treatment characteristics. Amongst ADCs and TCEs recipients, the median treatment duration was 1.9 and 3.5 months respectively, disease progression (64% and 79%) and intolerance (22% and 10%) were the most common reasons for discontinuation. The overall response rates were 27, 50, and 86% for ADCs, TCEs and CAR T, respectively. Compared to ADCs, CAR T was associated with improved PFS (adjusted HRPFS=0.29, 95%CI=0.20-0.43) and OS (aHROS=0.28, 95%CI=0.18-0.44) when adjusting for age, R-ISS, double hit high risk cytogenetic abnormalities (HRCAs), extramedullary disease (EMD, excluding paraskeletal plasmacytomas), triple class refractoriness, and the number of lines of therapy (LOTs) received in the preceding 1 year. Likewise compared to ADCs, TCEs were associated with superior PFS (aHRPFS=0.59, 95%CI=0.40-0.86) and OS (aHROS=0.60, 95%CI=0.39-0.93). Amongst patients with plasma cell leukemia (PCL) or EMD at the time of BCMA therapy (n=123), median PFS was poor irrespective of the therapeutic class at 1.3, 1.7 and 6.1 months for ADCs, TCEs and CAR T, respectively. Equally, for patients previously treated with BCMA therapy (n=58), median PFS was poor regardless of class at 1.9, 2.4 and 3 months for ADCs, TCEs and CAR T, respectively. Of 229 relapses the mode of relapse was known in 192 cases (84%), with 101 (52%) having EMD at relapse. Conclusions: While contingent on myriad other factors, patients able to receive BCMA-directed CAR T therapy experience superior survival compared to ADC and TCEs. EMD, PCL and BCMA-exposed populations are recalcitrant to BCMA-directed immunotherapy, and EMD is a common means of relapse. [Table: see text]

7038 Background: While chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment for hematological malignancies, severe (≥ grade 3,Gr 3, CTCAE) cytopenias post CAR-T and therapy related myeloid neoplasms (t-MN) are particularly difficult to manage. Survival after diagnosis of t-MN is dismal. Management of ≥Gr 3 cytopenias that do not recover by month 3 after CAR-T require frequent monitoring and transfusion support. Growth factor and thrombopoietin mimetics have variable success, with stem cell boost emerging as having more consistent success. Evaluation for CAR-T eligibility, prior to leukapheresis, is the critical timepoint where factors identified at this time could inform risks and benefits of CAR-T versus alternative treatment and for consideration of stem cell collection in patients who may benefit from stem cell boost to treat severe cytopenia post CAR-T. Methods: We conducted a retrospective analysis comparing clinical data of patients (pts) with lymphoma (NHL) and multiple myeloma (MM) treated with FDA-approved and investigational CAR-T between 01/2016 – 06/2022 at Mayo Clinic. Prolonged cytopenias were defined as hemoglobin (Hg)<8 g/dL, absolute neutrophil count (ANC)<0.5 x 109/L, and/or platelet count (PLT)<50 x 109/L at 3 months after CAR-T. Pts with progressive disease were excluded from cytopenia analysis. Logistic regression to identify factors correlated with cytopenia and t-MN. Results: Among the 186 pts who received CAR-T, 42 (22%) patients developed severe cytopenia (26/102, 25%, in NHL; 16/84, 19% in MM); 15/186 (8%) had more than 1 concurrent cytopenia. Univariate analysis identified that baseline ferritin and CAR-HEMATOTOX score correlated with cytopenia. Multivariate analysis showed that advanced age (≥ 65 years) (HR 2.69, 95%CI 1.17 – 6.40, P = 0.02) and thrombocytopenia (HR 4.01, 95%CI 1.77 – 9.34, P = 0.001) were associated with severe cytopenia. Twenty (10.7%) patients [8 (40%) males] developed t-MN at a median of 9.5 months (IQR 4.8 – 19.3 months) after CAR-T (14/102, 13% in NHL; 6/84, 7% in MM). Univariate analysis identified ferritin and CAR-HEMATOTOX score correlated with t-NM. Multivariate logistic regression showed advanced age (HR 5.03; 95%CI 1.59-18.7, P= 0.009), hemoglobin ≤ 10 g/dl (HR 3.63, 95%CI 1.04-13.30, P = 0.04), and thrombocytopenia (HR 4.06, 95%CI 1.32-14.2, P 0.02) are significantly associated with development of post-CART t-MN. Conclusions: Advanced age, anemia and thrombocytopenia at the time of evaluation for CAR-T eligibility, prior to leukapheresis, are associated with the development of post-treatment severe cytopenia and t-MN. Larger, multi-center studies are needed to validate these findings.