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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.

7561 Background: Pts with TCE RRMM have poor outcomes and a high unmet need, with no established SOC tx. LINKER-MM1 (NCT03761108) is a single-arm, Phase 1/2 study investigating linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody, in pts with RRMM who were previously treated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody, or were triple-class refractory (TCR) to these tx. The aim of this study was to contextualize LINKER-MM1 by comparing outcomes with linvoseltamab vs a real-world (RW) external control arm (ECA). Methods: A RW ECA was derived from 2 US electronic health record databases (COTA, Guardian Research Network) of pts who started a new line of therapy (LOT) after classification as TCE or TCR and met key eligibility criteria for LINKER-MM1. Eligibility was assessed at the initiation of each new LOT, and all eligible LOTs were included in the ECA. Data in Phase 2 pts who received linvoseltamab 200 mg in LINKER-MM1 were included (data cutoff: Sep 8, 2023). Inverse probability of tx weighting (IPTW) was used to reduce imbalances between the RW and LINKER-MM1 cohorts. Key prognostic factors were identified using a systematic review and rank ordered by an international committee of MM experts (Kumar et al., 2023). Outcomes included overall response rate (ORR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). An independent committee of epidemiology and oncology experts reviewed the comparability of the cohorts and endpoint assessments prior to conducting comparative analyses. Results: Comparative analyses were performed in 105 pts in the linvoseltamab cohort and 101 RW pts (137 LOTs). Following IPTW, the distribution of cytogenetic risk, age, TCR status, Eastern Cooperative Oncology Group Performance Status, and platelet count were balanced between the 2 cohorts (absolute standardized mean difference <0.10). After adjustment, pts receiving linvoseltamab had significantly improved ORR, PFS, TTNT, and OS vs the RW ECA (see table). Conclusions: Linvoseltamab significantly improved outcomes vs RW SOC in the US, highlighting its potential as a highly effective tx in pts with TCE RRMM. [Table: see text]

e14535 Background: Cytokine release syndrome (CRS) is the most common complication of chimeric antigen receptor T cells (CAR-T) for hematologic malignancies. We hypothesized that patients undergoing CAR-T therapy who are on metformin will experience a lower incidence or severity of CRS than patients not on this medication. Methods: We evaluated all patients treated with CAR-T at Mayo Clinic Rochester between 1/1/2018 and 1/31/2023, and abstracted relevant clinical and laboratory characteristics to determine the incidence and severity of CRS, PFS as well as OS in patients who were, or were not, on metformin before and during CAR-T therapy for Type 2 diabetes mellitus. We used the Chi-Square test, Mann-Whitney test and the Kaplan-Meier method to analyze data. Results: In the 5-year interval under consideration 237 patients received CAR-T, 168 for non-Hodgkin lymphoma (NHL), and 69 for multiple myeloma (MM). 23 patients (15 NHL and 8 MM) were on metformin at the time of CAR-T. 15 patient developed CRS while on metformin and 175 patients not on metformin (p=0.05). Grade 3 or 4 CRS incidence was 4% in both groups (p=0.41). Of the 153 patients with NHL not on metformin, 121 developed any grade of CRS, while 10 of 15 patients on metformin developed CRS (p=0.268). 4 NHL patients developed CRS Grade ≥3 or higher, while 0 of 15 on metformin developed Grade ≥3 CRS (p=0.237). For the MM patients, the incidence of CRS was 49 patients not on metformin and 5 patients on metformin (p<0.001). 3 MM patients developed CRS Grade ≥3 or higher, while 0 of 8 on metformin developed Grade ≥3 CRS (p=0.346). 12 of 15 patients on metformin with NHL achieved CR compared to 92 of 153 patients not on metformin (p=0.1305). 3 of 8 patients with MM on metformin compared to 24 of 61 patients with MM not on metformin achieved CR or better post CAR-T (p=0.92). Tocilizumab was used in 40% of patients on metformin but in 66% of patients not on metformin (p=0.0016). In NHL patients, PFS from CAR-T infusion was not reached (range: 6.3 to NR) for patients on metformin versus 9.9 months (range: 6.3–19.5) in patients not on metformin (p = 0.3332). In the MM patients, progression-free survival (PFS) from CAR-T infusion was 8.4 months (95% CI: 7.9–not reached [NR]) for patients on metformin and 22.6 months (13.7–NR) for those not on metformin (p = 0.07). Median OS for NHL patients on metformin was not reached (9.766–NR) versus 32.6 months (18.6–NR) for patients not on metformin (p = 0.7022). Median OS was 17 months (95% CI: 8.3 to NR) for patients with MM on metformin vs NR (95% CI: 9.4 to NR) for patients not on metformin (p = 0.2559). Conclusions: In this retrospective study, the co-administration of metformin during CAR-T cell therapy for NHL and MM appears to be associated with a numerically reduced incidence of CRS. The effect appears to be particularly marked in patients with multiple myeloma. Metformin therapy did not seem to affect the response to CAR-T therapy in either NHL or MM.

AbstractBackgroundPrecursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma‐derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology of MM.MethodsThis study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet‐poor peripheral blood plasma of MGUS (n = 9) and MM (n = 12) patients using the size exclusion chromatography‐based method and evaluated their proteome using a label‐free proteomics workflow.ResultsIn total, 2055 proteins were identified in SEVs, while 2794 proteins were identified in LEVs. The transferrin receptor (or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher in the LEVs derived from MM patients than in MGUS patients.ConclusionsThis study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest.

PURPOSE Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88 L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters. PATIENTS AND METHODS We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. RESULTS In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively ( P < .0001). CONCLUSION Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.

Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.

AbstractSeveral tools exist for assessing frailty in multiple myeloma (MM), but most are based on clinical trial datasets. In this study, we evaluate the prognostic impact of frailty based on the cumulative deficit frailty index (FI), and the prognostic impact of relationship and socioeconomic status (SES) in newly diagnosed MM patients. This is a retrospective study including 515 patients with MM seen at Mayo Clinic (Rochester, MN) at diagnosis between 2005–2018. The FI was calculated using patient-reported data on activities of daily living and comorbidity data. Items were scored as 0/0.5/1, with 1 indicating deficit. The FI was calculated by adding individual scores and dividing that by the number of non-missing items. Frailty was defined as FI ≥ 0.15; 61% were non-frail and 39% were frail. Frailty and non-married/relationship status were associated with higher disease stage, decreased likelihood of early transplantation, and independently associated with decreased survival. SES was not independently associated with survival. Frail patients reported worse scores for fatigue, pain, and quality of life. In conclusion, a cumulative deficit FI was associated with higher symptom burden and decreased survival in a real-world cohort of newly diagnosed MM patients. Social support has prognostic value and should be assessed in clinical practice.

AbstractSmoldering multiple myeloma (SMM) is a precursor stage that precedes multiple myeloma (MM). SMM is heterogenous with nearly 40% of patients progressing to MM in the first 5 years. The high rate of progression of SMM patients highlights the need for early intervention, which underscores the importance of identifying SMM patients with the highest risk of progression. Several risk stratification models showed utility in identifying high‐risk SMM patients; however, these systems showed limited sensitivity. To date, identifying high‐risk SMM patients remains an important clinical need. In this study, we present the 3‐dimensional telomere profiling as a structural biomarker capable of stratifying SMM patients as a function of genomic instability. Quantifying telomere dysfunction using the TeloView technology showed utility in risk stratification of cancer patients, particularly hematological malignancies. In this study, we analyzed 168 SMM patients. We report an AUC in ROC analysis of 0.8 using a subset of the patients as a training dataset. We then conducted a blind validation on a different cohort and demonstrated a positive predictive value of 85% and negative predictive value of 73%, with sensitivity and specificity of 83% and 76%, respectively. We examined the correlation between the TeloView prediction and the 20‐2‐20 scoring system, and cytogenetic abnormalities. We report a correlation of 53% with the 20‐2‐20 scores and over 60% correlation with cytogenetic abnormalities. The result of this study presents the telomere profiling as an effective biomarker able to stratify SMM patients to their respective risk groups with high sensitivity and specificity.

Abstract Three classes of BCMA-directed therapy (BDT) exist: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs), each with distinct strengths and weaknesses. To aid clinicians in selecting between BDTs, we reviewed myeloma patients treated at Mayo Clinic with commercial or investigational BDT between 2018–2023. We identified 339 individuals (1-exposure = 297, 2-exposures = 38, 3-exposures = 4) who received 385 BDTs (ADC = 59, TCE = 134, CAR-T = 192), with median follow-up of 21-months. ADC recipients were older, with more lines of therapy (LOT), and penta-refractory disease. Compared to ADCs, CAR-T (aHR = 0.29, 95%CI = 0.20–0.43) and TCEs (aHR = 0.62, 95%CI = 0.43–0.91) had better progression-free survival (PFS) on analysis adjusted for age, the presence of extramedullary (EMD), penta-refractory disease, multi-hit high-risk cytogenetics, prior BDT, and the number of LOT in the preceding 1-year. Likewise, compared to ADCs, CAR-T (aHR = 0.28, 95%CI = 0.18–0.44) and TCEs (aHR = 0.60, 95%CI = 0.39–0.93) had superior overall survival. Prior BDT exposure negatively impacted all classes but was most striking in CAR-T, ORR 86% vs. 50% and median PFS 13-months vs. 3-months. Of relapses, 54% were extramedullary in nature, and a quarter of these cases had no history of EMD. CAR-T demonstrates superior efficacy and where feasible, should be the initial BDT. However, for patients with prior BDT or rapidly progressive disease, an alternative approach may be preferable.

Abstract Multiple myeloma (MM) exhibits significant heterogeneity in its presentation, genetics, and treatment response. Despite therapeutic advances, some patients continue to relapse early (ER, <18‐months) and rapidly cycle through therapies. Myriad prognostic factors have been identified and incorporated into risk stratification models; however, these produce discordant, often three‐tiered outputs that fail to identify many patients destined for ER. Treatment strategies are increasingly focused on disease biology and trials enriched for high‐risk (HR)MM, but consensus on the minimum required testing and a succinct, specific, and clinically meaningful definition for HRMM remains elusive. We review the risk‐factors, definitions, and future directions for HRMM.