Citations

Abstract Outcomes are poor in triple-class–exposed (TCE) relapsed and refractory multiple myeloma (R/RMM). In the phase 3 KarMMa-3 trial, patients with TCE R/RMM and 2 to 4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary end point; 13.3 vs 4.4 months; P < .0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median was 41.4 (95% CI, 30.9 to not reached [NR]) vs 37.9 (95% CI, 23.4 to NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI, 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE R/RMM. This trial was registered at www.ClinicalTrials.gov as #NCT03651128.

Abstract Currently, the role of DNA methylation in the immunoglobulin M (IgM) monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multiomics prospective analysis was conducted integrating DNA methylation, RNA sequencing (RNA-seq), and whole-exome sequencing data in 34 subjects (23 with Waldenström macroglobulinemia [WM], 6 with IgM monoclonal gammopathy of undetermined significance [MGUS], and 5 normal controls). Analysis was focused on defining differences between IgM gammopathies (WM/IgM-MGUS) compared with controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions that were annotated according to genomic region. Next, integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. We found that pathways involved in cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of the CXCR4 signaling pathway along with several interleukin (interleukin 6 [IL-6], IL-8, and IL-15) signaling pathways in WM compared with IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. Overall, this report defines how aberrant DNA methylation in IgM gammopathies may play a critical role in the epigenetic control of oncogenesis and key cellular functions.

TPS7575 Background: Light chain (AL) amyloidosis is a plasma cell malignancy characterized by the production of amyloidgenic clonal light chains that deposit in various tissues. The addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) has improved depth of hematologic and organ responses. However, this approach has not yet demonstrated an overall survival (OS) benefit with short follow-up. Autologous stem cell transplant (ASCT) consolidation remains safe and is associated with deep and durable hematologic responses with an 83% 2-year progression free survival (PFS) and up to 72% of patients achieving a VGPR or better, comparable to Dara-VCD (79%). In multiple myeloma, ASCT improved PFS even in patients who are MRD negative at the end of standard induction therapy. It is thus reasonable to consider that ASCT might provide similar benefits in AL patients. No randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD. Methods: This randomized phase 3 SWOG led intergroup trial will accrue a total of 143 participants per arm and compare MOD-PFS (major organ deterioration progression free survival: defined as time from randomization to death, cardiac/renal progression, or hematologic progression) between participants receiving an ASCT with those receiving Dara-VCD consolidation following uniform Dara-VCD induction. A median MOD-PFS of 31 months is anticipated in the non-ASCT arm. This study has 90% power and a two-sided significance level of 0.05 to detect a hazard ratio of 0.62 corresponding to a MOD-PFS of 50 months in the ASCT arm. Important additional endpoints include OS, hematological PFS, cardiac and renal responses and progression, MRD negativity both by peripheral blood mass spectrometry and bone marrow next generation flow cytometry, delayed utilization of ASCT, and quality of life. This trial was activated on 12/1/2023. Funding: NIH/NCI/NCTN grants and in part by Janssen Pharmaceuticals. Clinical trial information: NCT06022939 . [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]

7078 Background: Lisaftoclax is a novel, oral, highly selective, potent BCL-2 inhibitor in development. In an ibrutinib-resistant patient-derived WM xenograft/preclinical model, lisaftoclax + ibrutinib has a strong synergistic effect. This report provides updated efficacy and safety data of lisaftoclax-based therapies (including combinations with ibrutinib) in pts with WM. Methods: In this global, open-label, phase 1b/2 multicenter study, pts with WM were enrolled in 3 arms: Arm A (lisaftoclax) included BTKi-resistant/intolerant pts; Arm B (lisaftoclax + ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax + rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high risk of tumor lysis syndrome (TLS). Objectives were efficacy, safety, and pharmacokinetics (PK) assessments (responses assessed per IWWM criteria). Results: As of January 25, 2024, 46 pts were enrolled and treated at doses of up to 1,000 (Arm A), 1,200 (Arm B), and 800 mg (Arm C; Table). The median (range) treatment duration was 11 (1-28; Arm A), 23.5 (1-34; B), and 11.5 (5-33; C) months. Objective response rates (PR, VGFR, CR) were: 41.7% (Arm A), 90.9% (B), and 37.5% (C). In Arm A, pts with wild-type CXCR4 (n = 7) had better overall response to lisaftoclax than the CXCR4mut group (n = 3). No significant difference was observed between pts with/without CXCR4mut in Arms B and C. In Arm B, 1 DLT (grade 3 clinical TLS due to preexisting renal impairment) was reported at 1,200 mg; 1 grade 3 laboratory TLS, primarily attributed to dehydration and concomitant symptomatic therapies, occurred at 1,000 mg; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (15.2%), thrombocytopenia (4.3%), decreased leukocytes (4.3%), TLS (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmia was not observed. One pt required dose reduction because of neutropenia. The MTD was not reached. Lisaftoclax + ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone, indicating no potential drug-drug interactions. Conclusions: Lisaftoclax alone and combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. (CT.gov: NCT04260217; Internal ID: APG2575WU101) *Co-first authors: ML and SA. Clinical trial information: NCT04260217 . [Table: see text]

e23310 Background: Chimeric antigen receptor T-cell therapy (CAR T) is FDA-approved in pts with triple-class exposed (TCE) relapsed/refractory (RR) MM after four or more prior lines of therapy (LOTs). Real-world access to CAR T remains challenging due to manufacturing capacity, financial barriers, and pt fitness. Pts with certain pre-existing comorbidities (e.g., central nervous system disease, heart disease, secondary malignancies) are commonly excluded from clinical trials, including those investigating CAR T. The objective of this study was to identify the factors associated with the use of CAR T in pts with TCE RRMM to better understand the unmet need in this population. Methods: We conducted an observational cohort study using Medicare fee-for-service data; each pt in the CAR T intention-to-treat (ITT) population between 2021 and 2023 was matched to three non-CAR T pts, without replacement. Pts were eligible if they had an initial MM diagnosis, were continuously enrolled, were TCE, and did not receive treatment in a clinical trial. The index date was the ITT date. Baseline characteristics included age, sex, race/ethnicity, census region, three comorbidity indexes (Charlson, Elixhauser, CMS hierarchical condition categories [HCCs]), a claims-based frailty index (CFI), and dual enrollment in Medicare and Medicaid (as a proxy to social economic status [SES]). Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CIs) comparing the characteristics of CAR T vs non-CAR T pts. Results: Seventy-three ITT CAR T pts (nine underwent apheresis but did not receive CAR T) were matched to 219 non-CAR T pts by LOT and index year. Matched pts were treated with varied standard regimens (daratumumab-containing: 63%). Median prior LOTs were similar in the two cohorts (8; range 2–13). Median time from MM diagnosis to index date was 44.6 and 51.9 months for CAR T and non-CAR T pts, respectively. Compared with non-CAR T pts, pts in the CAR T population were younger (aged < 75 years: 59% CAR T vs 36% non-CAR T), less frail (mean CFI: 0.18 vs 0.20) and had higher SES (without dual enrollment in Medicare and Medicaid: 96% vs 81%), but were similar in terms of sex, region, and race/ethnicity. Variation in individual comorbidity prevalence was observed between CAR T and non-CAR T pts. In a multivariable regression analysis, factors strongly associated with lower odds of CAR T use included age ≥75 years (OR 0.29; 95% CI 0.16–0.53), comorbidities (lung/other severe cancers [OR 0.39; 95% CI 0.20–0.74] and chronic obstructive pulmonary disease [OR 0.32; 95% CI 0.10–0.99] defined by HCCs), and SES (OR 0.09; 95% CI 0.02–0.37). Conclusions: Older age, certain comorbidities, and lower SES are associated with lower odds of receiving CAR T in real-world pts with TCE RRMM, demonstrating an unmet need for more accessible and effective treatment options with acceptable safety profiles for these pts.

e23309 Background: BCMA-directed T-cell–engaging therapies have been introduced into clinical practice for the treatment of TCE RRMM. While efficacious, such treatments are associated with safety considerations such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and serious infections. These treatments also vary in reported efficacy, administration processes, and hospitalization requirements. The aim of this study is to quantify patient preferences and tradeoffs regarding these attributes. Methods: A discrete choice experiment (DCE) was designed to elicit preference weights corresponding to seven attributes related to efficacy (objective response rate [ORR], overall survival [OS]), safety (all-grade CRS, all-grade ICANS, serious infections) and treatment procedures (treatment administration, hospitalization requirements). Attribute levels were based on plausible ranges of potential values. Patients in the United States (US) with a physician-confirmed diagnosis of TCE RRMM were recruited. Pre-test interviews with patients were conducted and the final survey deployed online in 2023. A random-parameters logit model was used to estimate preference weights. Conditional relative importance (CRI) was calculated to rank the relative importance of each attribute. The minimum acceptable benefit (MAB) and maximum acceptable risk (MAR) were calculated to estimate the tradeoffs between efficacy and safety attributes. Results: The sample included 200 respondents (mean [standard deviation] age: 61 [6.4] years; 43% female; 46% White; 10% African American). A total of 197 participants reported having responded to prior treatment, of whom 195 had relapsed or become refractory. In the DCE, a 24-month increase in OS was found to be the most important attribute, with a CRI of 32.0%. Next most important were avoiding a 60% risk of serious infection (CRI 17.3%), avoiding 14-day hospitalization requirements (CRI 15.0%), and a 38% increase in ORR (CRI 13.7%). A treatment that could be started immediately and administered weekly or up to every 4 weeks was preferred over a CAR T-like procedure with a waiting period. Fewer initial hospitalization days was significantly preferred over more hospitalization days. The MABs for OS when the risk of serious infection was increased from 20% to 60%, CRS from 40% to 95%, and ICANS from 3% to 20% were 24.2, 17.1, and 18.0 months, respectively. When OS was increased from 12 to 36 months, the estimated MARs for serious infections, CRS, and ICANS were > 60%, > 95%, and > 20%, respectively. Conclusions: This study highlights US patient preferences regarding treatment attributes for TCE RRMM. Treatment benefits and risks and the mutual tradeoffs considered by patients should be evaluated when developing and selecting therapeutic approaches.

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.

Abstract There has been an increase in volume as well as an improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have affected racial/ethnic minorities equally. In this observational study from the Center for International Blood and Marrow Transplant Research of 79 904 autologous (auto) and 65 662 allogeneic (allo) HCTs, we examined the volume and rates of change of autoHCT and alloHCT over time and trends in OS in 4 racial/ethnic groups: non-Hispanic Whites (NHWs), non-Hispanic African Americans (NHAAs), and Hispanics across 5 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.04-1.22; P = .004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; P &lt; .001) had a higher risk of mortality after alloHCT than NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT. Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics than in NHWs. Survival after autoHCT and alloHCT improved over time; however, NHAAs have worse OS after alloHCT, which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT.