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Background: Contemporary questions about treatment and outcomes of patients (pts) living with multiple myeloma (MM) demand efficient and timely evidence generation methods, where real-world/ everyday practice data can play an important role. Relevant potential applications include understanding and addressing disparities in treatment access, mitigating toxicities of novel therapies while maintaining quality of life, appropriately sequencing treatments within long-term management strategies, and disseminating and appropriately using surrogate endpoints in practice, such as minimal residual disease. However, existing real-world data (RWD) repositories are limited by an inability to implement interventions in response to issues identified through retrospective data analysis, which is pivotal for the use of newer therapies. The ASH Research Collaborative (ASH RC) MM Data Hub Program was developed to address these gaps. Methods: We developed a multicenter network of US-based tertiary academic medical centers, engaging site clinicians, patients, biostatisticians, informaticians, and data scientists. Initial activities included constructing a shared real-world MM data model comprised of consensus core data elements. Pt data from each site, dating back to at least 2019, is currently being entered through electronic case report forms, batch uploaded utilizing existing institutional data repositories, and soon direct electronic health record import in standard data acquisition formats. Data are aggregated in the Data Hub and shared in a confidential Site Portal with each site. The Portal allows sites to track their own pts, analyze outcomes, and identify ways to improve the quality of care provided to individuals living with MM. We also developed an innovative evidence generation learning community of site clinicians who meet monthly and collaborate on the “COVID-19 OutcomeS in Myeloma and the Impact of VaCcines (COSMIC)” study, a prospective, decentralized observational study that rapidly accrued pts and collects relevant practice information. The group also shares best practices in study conduct to accelerate study enrollment and execution. Results: The MM Data Hub Program now contains twelve centers: Memorial Sloan Kettering Cancer Center, Mayo Clinic, Icahn School of Medicine at Mount Sinai, University of California San Francisco, University of California Davis, Medical College of Wisconsin, Barbara Ann Karmanos Cancer Institute, University of North Carolina Medical Center at Chapel Hill, Emory University Hospital, Washington University School of Medicine in St. Louis, Dana-Farber Cancer Institute, and Atrium Health. From this Network, six centers have contributed data from 8,824 pts (2,825 with sufficiently complete data are included in this analysis). The median age at time of MM diagnosis is 63, and of the 627 deceased pts, the median age at death is 70.6 years, with median time to death from first MM diagnosis of 6 years. The proportions of pts by decade of diagnoses are 34.9% from 2020-2024; 57.6% from 2010-2019; 7.3% from 2000-2009; and 0.9% prior to 2000. 83.1% of pts had a diagnosis of plasma cell myeloma (non-light chain), and 14.4% of pts had a diagnosis of light chain myeloma. 42.3% of pts are female, and the self-reported patient races are: 85.0% white; 9.2% black or African; and 4.3% all other races (race was not documented in 1.5% of pts). 2.8% of pts are of Hispanic ethnicity. Participant data files are currently undergoing completion and cleaning procedures; the analysis will include updated results at the meeting, and a Network-wide analytic data set will be available for initial retrospective data analyses in early 2025. The COSMIC study opened for enrollment on January 22, 2024, and completed enrollment of 200 pts on May 17, 2024. Conclusions: The ASH RC Data Hub MM Program launched in 2023 and is comprised of 12 sites that collectively have contributed participant files for 8,824 pts thus far. Utilizing the structure of the Network, we successfully implemented and established the feasibility of collecting data directly from pts electronically to monitor SARS-CoV-2 vaccines and COVID-19 related outcomes. The Program serves as a successful proof-of-concept model, providing an enduring RWD resource and a prospective evidence generation platform for the myeloma community.

Introduction: Clonal hematopoiesis (CH) is a common age-related premalignant condition defined by the presence of an acquired somatic mutation in a gene frequently mutated in myeloid malignancies characterized by a variant allele frequency (VAF) of ≥2%, without fulfillment of other diagnostic criteria for myeloid neoplasm. Incidence of CH increases with age and found in 10%-30% of people > 70 years of age. CH-related mutations confer an increased risk of myeloid neoplasms, cardiovascular diseases, and are linked to inferior survival in solid tumor patients treated with chemo/radiation therapy. Such mutations can act as a driver/amplifier of inflammation, especially through myeloid cells. To distinguish true disease drivers from background genetic events related to aging or environmental factors, we need a deeper understanding of the impact of CH in different tissue microenvironments and under therapeutic pressure for better risk stratification of CH carrier patients. Recent reports suggested high prevalence of CH-related mutations in lymphoma. Current analyses aimed to investigate: i) the prevalence of CH-related mutations in two real-world lymphoma cohorts from Molecular Epidemiology Resource (MER) MER-FL and MER-DLBCL, ii) CH-related mutational landscape in DLBCL and FL, iii) the impact of CH-related mutations on clinical outcomes. Methods: Whole exome sequencing (WES) derived from blood/PBMC from lymphoma patients with paired tumor samples was analyzed to identify CH-related myeloid drivers in 42 previously reported genes. We used Sention-Tnhaplotype2 somatic pipeline with a custom panel of normals from whole blood samples. To avoid tumor contamination, we filtered variants for which VAF in the tumor was higher than that in the germline sample. Other filtering criteria included HIGH/MODERATE impact; read count > 1 in both forward and reverse reads; gnomAD_AF < 0.01. We used the R “survival” package Cox regression implementation for outcome and other statistical analysis. Results: Genomic and clinical data of 507 patients from MER-FL and 383 patients from MER-DLBCL cohorts, with median age of 60 and 64 respectively, were available for analysis. CH-related mutations were present in 17.16% (87/507) in FL and 18.28% (70/383) in DLBCL cohorts with a VAF cut off >2%. The most common CH-related mutations were DNMT3A (5%), CREBBP (2%), TET2 (1%), ASXL1 (1%) and PPM1D (1%) in MER-FL while DNMT3A (5%), TET2 (3%), TP53 (3%), ASXL1 (2%) and PPM1D (1%) in MER-DLBCL cohort. Both the prevalence of CH-related mutations and their average VAF increased with age, consistent with literature. Finally, cox regression analysis suggested that CH-related mutations were associated with significantly inferior overall survival (OS) in both FL and DLBCL cohorts (HR 1.6 p=0.028 and HR 2.3 p=<0.001 respectively); however only in DLBCL this association was significant after age correction (HR 1.8 p=0.008). When separated by individual gene mutations, genes of interest with inferior OS included TP53 (n=4, HR 3.1, p=0.057) in FL and PPM1D (n=3 HR 2.6 p=0.1), TP53 (n=8 HR 2.1 p=0.1) and DNMT3A (n=14, HR=2.0, p=0.048) in DLBCL; however, these estimates did not quite reach statistical significance. Conclusions: Taken together, our exploratory analysis indicates that CH-related mutations associate with worse OS in lymphoma patients, supporting the rationale for evaluation of CH for the risk assessment in lymphoma. Furthermore, DLBCL displays of larger size effect, which may be related to different treatment regimes. Additional studies will be needed to elucidate the interaction between high dose chemotherapy regimes and CH-associated adverse events.

Background: The COVID-19 pandemic had an outsized impact on individuals with immune compromise, such as multiple myeloma, leading to increased rates of severe COVID, hospitalization, and death in these groups. The pandemic also demonstrated the need for rapid and efficient evidence generation to address rapidly changing medical needs and accelerated the use of innovative trial designs to accomplish this goal. Methods: We designed and established a prospective, decentralized study within a site-based provider network, COVID-19 OutcomeS in Myeloma and the Impact of VaCcines (COSMIC), for patients with multiple myeloma at ASH Research Collaborative sites to monitor outcomes related to COVID-19 infection and vaccination. The direct-to-patient approach was accomplished using a study application accessed with a QR code provided to patients during usual clinical care. All study activities occurred within the patient portal at Baseline, Day 30, and Day 180, minimizing burden on site personnel and staff. Study activities included eligibility confirmation, consenting, electronic health record (EHR) data permissions, and patient-reported outcome (PRO) surveys. PRO data (EORTC QLQ-C30, EORTC QLQ MY-20) were made available to clinicians through the portal to visualize results from their patients. Patients shared if they received a COVID-19 vaccination or booster and if they had a COVID-19 infection. Patients with a history of COVID-19 infection included method of confirmation and if hospitalization was required. Patients were provided compensation for participation. Automated text and email messages were sent at three separate intervals: 24 hours, Day 8, and Day 15 for participants who initiated but did not complete study activities. A personal email reminder per participant was sent for those whose second study visit window was approaching. ASH Research Collaborative clinicians met regularly to share best practices related to enrollment and study conduct, thereby creating an innovative evidence generation learning community. We studied the feasibility of data collection in a decentralized format by focusing on the number of participants who interacted with the system, those who consented, and those who completed baseline PRO assessments. Results: The COSMIC study rapidly accrued and consented 200 patients from eight participating ASH Research Collaborative sites over four months (1/22/2024 through 5/17/2024): 69% self-reported as non-Hispanic White (NHW). Of enrolled participants, 57.5% opted to permission sharing of their EHR data, which included disease and treatment-related clinical data, laboratory results, pathology reports, and imaging reports. A total of 196 patients (98%) provided demographic and COVID-related disease and vaccine data at baseline; nearly all of these patients (n=195) provided baseline PRO data, and 150 patients provided further information at Day 30 at the time of this analysis. Those who did not provide Day 30 data were not significantly different from those who did in terms of age (median: 68 [no Day 30 data] vs. 67 [Day 30 data] years; p=0.44), sex (41% [no Day 30 data] vs. 47% [Day 30 data] Female; p=0.47), or race (65% [no Day 30 data] vs. 71% [Day 30 data] NHW; p=0.60). A higher proportion of Hispanic patients were retained at Day 30 (13/15=87%) vs. 78% of non-Hispanic patients or those who declined reporting ethnicity (2/7=29%; p=0.007). COVID-19 vaccination data were submitted by 196 patients, 186 of whom had ever received a COVID-19 vaccination. Data on number, type, brand, and dates for these vaccinations were provided. Conclusions: The COSMIC study conducted by the ASH Research Collaborative was able to rapidly accrue a diverse cohort of patients using a decentralized workflow within a site-based provider network, with high consent and compliance rates. This platform, and the innovative evidence generation learning community of ASH Research Collaborative investigators and patients, sets a precedent to address a variety of real-world questions related to disease management, infections, vaccinations, and PROs in this population of patients with multiple myeloma.

Background: Data from the ASH Research Collaborative COVID-19 Registry for Hematology demonstrated that patients with multiple myeloma and other immune compromise had elevated risk for severe complications from COVID-19 infection. To address current evidence gaps and to demonstrate proof of concept for a pandemic preparedness and response network, the ASH Research Collaborative Multiple Myeloma Program developed a prospective, decentralized study within a site-based provider network to investigate COVID-19 infections, vaccinations, and quality of life in patients with multiple myeloma. Methods: We designed and established the COVID-19 OutcomeS in Myeloma and the Impact of VacCines (COSMIC) to study COVID-19 in patients with multiple myeloma at ASH Research Collaborative network sites. A study application was accessed with a QR code and shared with patients during usual clinical care. Patients provided consent, optionally gave permission for electronic health record data collection, and completed patient-reported outcomes (EORTC QLQ-C30 and MY20) at baseline, Day 30, and Day 180 through the study portal. Clinicians at participating sites facilitated study enrollment and shared best practices monthly to accelerate study execution. Study objectives related to feasibility of data collection in a decentralized format are reported in a separate abstract. Here, we report interim results related to SARS-CoV-2 vaccination history, COVID-19 infection, and how these relate to patient reported outcomes and clinical outcomes in enrolled participants. Results: The COSMIC study rapidly accrued and consented 200 patients from eight participating ASH Research Collaborative sites over four months (1/22/2024 through 5/17/2024). Consented participants' ages ranged from 29 to 93 years, with median of 67 years; 46% were female, 69% were non-Hispanic White (NHW), 17% were non-Hispanic Black (NHB), and 8% were Hispanic/Latino. Of the 196 patients who reported COVID-19 data, 111 (57%) reported at baseline that they had a history of COVID-19 infection, with 12 having required hospitalization for this (12/111=11%). Overall, 95% (186/196) reported a history of COVID-19 vaccination, where the median number of vaccinations was 4 (range: 1 to 6); 44 patients (23%) expressed willingness to discuss getting a yearly booster vaccine with their provider. At 1-month follow-up, there were 3 additional patients who reported a COVID-19 infection and 18 patients who received an additional COVID-19 vaccination. The baseline EORTC QLQ-C30 median Global Health Status/QOL score was 66.7 (mean=64.4, range: 8.3 - 100, n=196). This overall global QOL score was not significantly different between those who did vs. did not have a history of COVID-19 infection (mean [SD]: 63.7 [19.3] vs. 65.8 [17.6]; p=0.57). In analyses adjusted for age, biological sex, and race/ethnicity group, history of COVID-19 infection was not associated with HRQOL (odds ratio=0.93, 95% CI: 0.78 - 1.10; p=0.38). Data collection is ongoing and final study results will be reported at a later date. Conclusion: COSMIC is a prospective, decentralized study within a site-based provider network conducted by the ASH Research Collaborative Multiple Myeloma Program that demonstrates the feasibility of using an innovative evidence generation strategy to drive rapid accrual of patients to address a rapidly evolving area of need. The COSMIC study also provides proof of concept that a real-world evidence generation network can play an important role in national pandemic preparedness and response. The COSMIC experience reinforces the ability to accrue diverse patient populations representing the demographic of myeloma patients in the US.

Introduction: Diffuse large B cell lymphoma (DLBCL) patients experience favorable outcomes following frontline immunochemotherapy, however, 30-40% of patients will exhibit primary refractory disease or relapse (rrDLBCL). Recent studies have expanded upon well-defined characteristics of newly diagnosed DLBCL (ndDLBCL) to elucidate genomic landscapes underlying rrDLBCL; yet, high-throughput examination of resistance and relapse mechanisms within rrDLBCL subtypes, including the newly defined dark zone signature (DZsig) addition to cell of origin (COO), have yet to be described. To expand upon the current tumor etiology and define subtype-specific driving mechanisms, we describe a multi-omic analysis leveraging clinical and biologic variables in rrDLBCL. Methods: Tumor biopsies (N=228) collected at the time of relapse were obtained from n=85 participants in the Mayo Clinic/University of Iowa Lymphoma Molecular Epidemiology Resource (MER), n=73 in the Mayo Clinic Biobank, and n=38 from CC-122-DLBCL-001 or n=32 CC-122-ST-001 trials. Tumor samples were analyzed by WES (n=158) or WGS (n=70) and by RNAseq (n=145). Comparative analysis against ndDLBCL MER samples (N=444) utilized WES (n=404) and RNAseq (n=321). Chi Square or Fisher's exact test was used for enrichment analysis of categorical variables, while Wilcoxon or Kruskal-Wallis test was used for continuous variables. Results: rrDLBCL samples were enriched for ABC (46% vs 33% in ndDLBCL, p=0.01), and fewer GCB (27% vs 40%, p=0.006). Amongst rrDLBCL patients, variance in overall survival (from time of original diagnosis; log-rank p=0.001) was observed between COO subtypes, with poor outcomes in patients with DZsig (median 15.0 mo) and GCB (36.5 mo) compared to ABC tumors (74.4 mo). Patients with progression or relapse within 6 months featured a more even COO distribution (ABC - 22%, GCB - 34%, DZsig - 28%) than patients with early (6-24 mo; 51%, 22%, 22%) or late relapses (>24 mo; 62%, 19%, 4%), which were predominantly ABC. Comparing mutation frequency within subtypes, rrDLBCL GCB tumors were enriched for B2M (41% vs 15% in ndDLBCL, p=0.002), EP300 (19% vs 7%, p=0.059), CIITA (19% vs 5%, p=0.02), PRKCB (11% vs 2%, p=0.035), CD79B (11% vs 0%, p=0.004), and CD83 (8% vs 1%, p=0.049) mutations, and CNV events including gains at 8q24.21 (MYC locus; 48% vs 14%, p<0.001) and 18q21.33 (BCL2, TCF4 locus; 36% vs 15%, p=0.021), and losses at 17p13.1 (TP53 locus; 40% vs 19%, p=0.035). rrDLBCL DZsig tumors featured enrichment for BCL6 (22% vs 3%, p=0.025), and SPEN (17% vs 3%, p=0.062) mutations and 2q22.2 losses (LRP1B locus; 20% vs 0%, p=0.019). Despite differential mutation and CNV profiles, gene expression analysis revealed minimal variance within COO subtypes in rrDLBCL and ndDLBCL, however upregulation of lymphoma driving genes including MYBPC2 (LogFC=1.68, FDR<0.001), MYOM2 (LogFC=1.33, FDR=0.007), MYC (LogFC=0.61, FDR=0.04), and CELSR2 (LogFC=0.53, FDR=0.02) were observed in ABC rrDLBCL. Increased frequency of LymphGen classifier A53 was observed in ABC (43% vs 17%, p=0.005) and GCB (40% vs 14%, p=0.009) rrDLBCL. Using CIBERSORTx to infer lymphoma microenvironment (LME) cell type abundance, an LME-depleted class was evident in rrDLBCL tumors, including reduction of CD8+ T cells (effect size (r)=-0.78, p<0.001) and T follicular helper cells (r=-0.48, p=0.012) in GCB rrDLBCL and reduction of T follicular helper cells (r=-0.43, p=0.023) and Tregs (r=-0.32, p=0.065) in DZsig rrDLBCL. Significance: We present an update to the genomic landscape of rrDLBCL, highlighting GCB and DZsig tumors with differential biology and advanced clinical course. Our data supports increased implementation of sequencing efforts in rrDLBCL to more broadly evaluate relapse mechanisms, with optimism that a more detailed understanding of r/r disease may guide trials for targeted treatment strategies. For example, rrDLBCL patients may be strong candidates for MYC pathway targeting agents (BETi), or a Lenalidomide-based regimen (R2 or Tafa-Len), as Lenalidomide has been shown to reprogram the LME via PD-L1 expression in addition to downregulation of MYC and MYC target genes. Or, due to enrichment of variants affecting anti-apoptotic proteins including BCL6 or BCL2 in DZsig and GCB rrDLBCL, a venetoclax-based therapeutic may be considered. Further targeted strategies should be considered as development of a more personalized approach remains an unmet need.

Background: Despite substantial improvements in early mortality (EM) for patients with systemic light chain amyloidosis (AL), rates remained high in the bortezomib-era, at approximately 25% (Muchtar et al. Blood. 2017). However, the therapeutic landscape in AL amyloidosis has changed with the ANDROMEDA trial, which led to the approval of daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone (Dara-VCd) in the frontline setting. The incidence and predictors of EM in the context of daratumumab-based frontline therapy have not been studied. Methods: We performed an international multicenter retrospective cohort study of all consecutive patients with newly diagnosed AL treated with frontline Dara-VCd or Dara-Vd, and followed until 12/31/2023. EM was defined as death from any cause within 6 months of treatment initiation. Our primary objective was to identify the rate and significant predictors of EM. Univariate logistic regression was used to identify significant predictors of EM, which were then included in a multivariate logistic regression model. The receiver operator characteristic (ROC) analysis was used to determine the best threshold values that discriminated EM rates for the following continuous variables: age, dFLC (involved-uninvolved), eGFR, NT-proBNP, albumin, and high-sensitivity Troponin-T (hs-TnT). Other variables tested in univariate analysis were the following: ECOG performance status, NYHA functional class, sex, race, light chain isotype, percent bone marrow plasma cells, status of the following cytogenetic abnormalities-t(11;14), +1q, hyperdiploidy, del(13q), high-risk translocations, and del(17p), and the number of organs involved (2 vs 1). To build the clinical prediction score, each variable was weighted according to the β coefficient (natural logarithm of odds ratio) obtained from the multivariable regression. The β coefficients were rounded to the nearest 0.5 and multiplied by 2 to obtain an even number. Results The study cohort included 335 AL patients treated with daratumumab-based frontline therapy (92.2% Dara-VCd, 7.8% Dara-Vd), with all surviving patients having at least 6 months of follow-up. The median age at diagnosis was 66.5 years (range, 59.4 - 71.3), and 6.7% (n = 22) were Non-Hispanic blacks. Median dFLC at diagnosis was 22.91 mg/dL (range, 0.2-1093.4), and median NT-proBNP was 2415 pg/mL (range, 13-70,000). Mayo 2004 stages IIIA/IIIB represented 44% of the total cohort, with 17% having ECOG ≥ 2 and 25.4% having NYHA Class III/IV symptoms. The cumulative incidence of EM was 10.7%, with the incidence in patients with Mayo 2004 stage I, II, IIIA, and IIIB being 0%, 8%, 12.5%, and 25% respectively. On univariate analysis with unadjusted odds ratio (OR), the following variables significantly predicted EM: Age ≥ 75 (OR=2.8, p=0.013) ECOG ≥ 2, (OR 4.9, p<0.001), NYHA Class ≥ III (OR=4.95, p<0.001), dFLC ≥9 mg/dL (OR, 10.18, p=0.023), eGFR <33 mL/min/1.73 m2 (OR=2.7, p=0.026), NT-proBNP >5276 pg/mL (OR=7.69, p <0.001), hs-TnT >70 ng/L (OR=5.88, p<0.001), and absence of t(11; 14) (OR=2.33, p=0.041). These variables were entered into multivariate regression, except for ECOG and NYHA, which were combined to create a single variable (values ranging from 0-8), and hs-TnT was dropped due to substantial missing data as centers used different troponin assays. NT-proBNP was rounded to 5300 pg/ml for ease of clinical application. Based on the multivariate analysis, the following scores were assigned to each variable: Age ≥75 (2.0), ECOG+NYHA (1.0 x combined score), NT-proBNP >5,300 pg/ml (2.0), and absence of t(11;14) (3.0). This led to a score ranging from 1-15, and two risk-groups: low-risk (score <9; 87.5%) and high-risk (score ≥9; 12.5%). The respective cumulative incidence of EM was 6.1% versus 50% (p<0.001). The c-index of the model was 0.725 (95% CI, 0.676-0.774). Conclusion: Using variables that are readily available in the clinic, we have developed a two-tiered risk-prediction model for EM in AL amyloidosis in the context of daratumumab-based frontline therapy. The model needs to be externally validated in an independent dataset.

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment with high efficacy in treating relapsed or refractory (R/R) mantle cell lymphoma (MCL). However, with CAR-T therapy, refractory disease occurs and a continuous pattern of relapse over time has been observed. Limited data exist about post-CAR-T progression of disease (POD) management and outcomes in MCL. Such data would meaningfully inform practice and set a critical benchmark for future studies in the post-CAR-T setting. We characterized treatment patterns and outcomes for pts with POD after CD19 CAR-T therapy for R/R MCL. Methods: We queried institutional databases to identify pts with R/R MCL who received CD19-directed CAR-T therapy. Treatment may have occurred as standard-of-care or in a clinical trial. We performed chart review to extract variables and categorized therapies by mechanism(s) of action. We used descriptive statistics to characterize patient/disease characteristics and treatment patterns, the reverse Kaplan-Meier method to calculate follow-up, the Kaplan-Meier method to calculate survival, and Cox proportional hazards to associate clinical and disease features with survival outcomes. Results: Across 9 sites, we identified 306 pts who received CD19 CAR-T for R/R MCL, of which 104 (34%) experienced POD and were investigated in detail: pts with POD were mostly men (73%), had a median age of 67 yrs (range 36-86) at infusion, and had received a median of 3 lines of therapy pre-leukapheresis, including a BTK inhibitor (BTKi) in 97% of patients; 36% of BTKi-exposed patients had BTKi-unresponsive disease. High-risk tumor features were common pre-CAR-T: 47/68 (69%) with a TP53 mutation, 66/93 (71%) with Ki67 ≥50%, and 47/102 (46%) with blastoid/pleomorphic MCL. Most pts (75%) received bridging therapy. Pts received brexucabtagene autoleucel (88%) or lisocabtagene maraleucel (12%). Regarding best CAR-T response for pts with POD, 71% had a complete response (CR), 13% partial response (PR), and 15% had no response. The median time from CAR-T infusion to POD was 6 months (IQR 3-12). At time of POD, high-risk MCL features were again common: 55% blastoid/pleomorphic, 42/56 (75%) Ki67 ≥50%, 51/83 (61%) MIPIb high-risk, and 21/35 (60%) TP53-mutated MCL. Among 69 pts with CD19 assessed on a post-POD biopsy, 8 (12%) had CD19-negative disease. 30% of pts had an ECOG performance status of ≥2 at time of POD. After POD occurred, 15 pts received no anti-lymphoma therapy (Tx), 11 pts underwent excision or radiation, and 78 pts received systemic therapy. The most commonly used first-line systemic Tx post-CAR-T progression included: pirtobrutinib in 13 pts [overall response rate (ORR) 31%], chemoimmunotherapy in 12 pts (ORR 25%), venetoclax in 10 patients (ORR 20%), bispecific antibodies (BsAb) in 10 pts (ORR 60%), and small molecule combinations (at least 2 of BTK inhibitor, BCL2 inhibitor, and lenalidomide) in 8 patients with ORR 50%. The ORR to all first systemic Tx post-POD was 42%. The median follow-up from POD is 15.2 months among survivors. The median progression-free and overall survival (OS) from time of POD were 2.3 (95% CI 1.9-3.4) and 5.4 months (95% CI 4.5-9.4), respectively, and 1-year OS rate was 33%. TP53 mutations predicted inferior OS (HR 2.83, 95% CI 1.08-7.43, P = 0.026) as did age ≥65 years at time of POD (HR 1.83, 95% CI 1.07-3.15, P = 0.023), MIPIb high-risk (HR 3.56, 95% CI 1.08-11.7, P = 0.042), and non-response to CAR-T (HR 3.55, 95% CI 1.93-6.53, P < 0.001). Discussion: Our data, the largest reported cohort of pts with POD post-CAR-T with R/R MCL, confirm the poor prognosis in this patient population, with a median OS of 5.4 months. BsAbs showed promise with an overall response rate of 60%. The presence of a TP53 mutation significantly predicted inferior OS, corroborating the prognostic importance of this finding in the post-CAR-T context. Data from pts treated at additional sites and updated analyses will be presented at the meeting.

Introduction: GOLCA is a potential first-in-class oral cereblon E3 ligase modulator (CELMoD™) agent for non-Hodgkin lymphoma, purposefully designed to target Ikaros/Aiolos and have favorable pharmacokinetics, resulting in apoptotic and immunomodulatory activity with preferential distribution to lymphoid organs. CC-220-DLBCL-001 (NCT04884035) is an ongoing phase 1b, open-label, multicenter, dose-escalation/expansion trial to assess safety and preliminary 1L GOLCA + R-CHOP efficacy in a-BCL. Although longer follow-up is needed to assess durability of response, MRD negativity (MRD-) is an emerging endpoint in a-BCL. Achieving MRD- on and at end of treatment (EOT) can potentially predict clinical benefit. This study aimed to analyze circulating tumor DNA (ctDNA) kinetics of GOLCA + R-CHOP across the trial population and in defined patient (pt) segments-cell of origin (COO), high baseline ctDNA, and high-risk genomics-and to correlate MRD- with imaging and clinical outcomes. Methods: Eligible pts were ≥ 18 years of age with ECOG performance status ≤2, IPI 0-5 in Part 1 and 2-5 in Part 2, and untreated a-BCL with measurable disease. Pts were treated with GOLCA + R-CHOP for 6 x 21-day (D) cycles (C) or until disease progression/unacceptable toxicity/study withdrawal. Dose escalation phase GOLCA dose levels (DLs) were 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), or 0.4 mg D1-10 (DL2). During dose expansion, pts were randomized 1:1 to R-CHOP + GOLCA DL-1 or DL1. The primary endpoint was safety of GOLCA at DL1; efficacy was a secondary endpoint, ctDNA was an exploratory endpoint. ctDNA was analyzed using the PhasED-Seq assay (<10-6 sensitivity) at baseline, C2D1, C3D1, and EOT. MRD- was defined as the absence of detectable ctDNA on-treatment. Pretreatment biopsies were sequenced by whole genome sequencing (WGS) and whole transcriptome sequencing (WTS). Results: At data cutoff (June 3, 2024), the median follow-up was 14.3 months. One-year progression-free survival (PFS) was 85.3% at 0.4 mg and 77.3% at 0.2 mg. Rates of MRD- increased over time but were consistently higher at 0.4 vs 0.2 mg, with values of 44% (14/32) vs 29% (8/28) at C2D1; 63% (17/27) vs 54% (15/28) at C3D1, and 90% (26/29) vs 73% (19/26) at EOT, respectively. Interim MRD- at C3D1 strongly predicted EOT MRD-; all 0.4 mg pts and all but two 0.2 mg pts who were MRD- at C3D1 remained MRD- at EOT. In contrast, fold-changes from baseline ctDNA were similar between 0.4 mg and 0.2 mg. The early molecular response rate (≥102-fold drop from baseline at C2D1) was 81.2% (26/32) at 0.4 mg and 82.1% (23/28) at 0.2 mg. The major molecular response rate (≥102.5-fold drop from baseline at C3D1) was 88.9% (24/27) at 0.4 mg and 85.7% (24/28) at 0.2 mg. Across genetically defined pt segments, EOT MRD- at 0.4 mg was prevalent for both COO subtypes measured by the Hans algorithm: 94% (17/18) among germinal center B-cell (GCB) and 75% (6/8) among non-GCB pts. Of the 29 pts with baseline genomics, 13 were genomically high risk: p53 mutant (VAF >0.5), DZsig and/or A7 subtype. In these pts, EOT MRD- was 80% (4/5) at 0.4 mg but only 20% (1/5) at 0.2 mg. In high baseline ctDNA (>102.5 hGE/mL) pts who were high-risk for R-CHOP failure, EOT MRD- at 0.4 mg was 86.7% (13/15) vs 57.1% (8/14) at 0.2 mg. There was an association between high baseline ctDNA and lower PFS at 0.2 mg (HR, 4.56 [95% CI, 0.53-39.12]), but interestingly the association decreased at 0.4 mg (HR, 2.10 [95% CI, 0.19-23.5]). Combining both arms, MRD- at both C3D1 and EOT trends with improved PFS (C3D1: HR, 0.73 [95% CI, 0.2114-2.523]; EOT: HR, 0.53 [95% CI, 0.1103-2.592]); longer follow-up may be required to demonstrate significance. Conclusions: Interim and EOT levels of MRD- were higher at 0.4 mg vs 0.2 mg GOLCA, with a one-year PFS of 85.3% vs 77.3%, respectively. Although pt numbers were small, the data suggest that 0.4 mg is efficacious in high-risk ctDNA and high-genomic risk pts, independent of COO, and support the 0.4 mg GOLCA + R-CHOP regimen in the randomized phase 3 trial GOLSEEK-1. Interim MRD- may play a role in future adaptive trial designs.

Introduction Poor diet quality, elevated body mass index (BMI), insulin resistance, microbiome dysbiosis, inflammation as well as immune dysfunction have all been implicated in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma (MM). Plant-based diets have been associated with reduced risk of MGUS and MM in epidemiological studies. Whether a dietary intervention can impact these modifiable risk factors and delay disease progression has not been investigated. Methods We conducted a pilot, single-arm trial providing controlled high fiber plant based dietary (HFPBD) intervention for 12 weeks and health coaching for 24 weeks in 20 patients with MGUS/SMM with BMI≥25 (NCT04920084). The primary endpoint was feasibility (adherence and BMI reduction). Secondary and exploratory endpoints included quality of life, metabolic markers (insulin, adiponectin, leptin, LDL cholesterol), microbiome (diversity and composition by 16S and shotgun sequencing) and immune profiling in peripheral blood (flow cytometry and Olink inflammation panel) and bone marrow (scRNAseq and ATACseq). We also conducted an in vivo study in transgenic Vk*MYC mice fed a high fiber or control diet at the phase of mouse(m)SMM. The mice were monitored for the progression to active mMM. Differences in microbiome and immune response profiles between high fiber- and control-treated mice were assessed via microbiome 16S sequencing and flow cytometry. Results The HFPBD intervention was safe, feasible, improved quality of life and addressed modifiable risk factors - metabolic profile (improved BMI, insulin resistance, adiponectin leptin ratio), microbiome profile (increased alpha-diversity and butyrate producers) and immune (decreased inflammation and increased anti-inflammatory classical monocyte) subsets. A reduction in long-term progression trajectory was observed in 2 patients. Consistently, the high fiber diet delayed progression from mSMM to mMM in Vk*MYC mice increasing median progression-free survival from 12 weeks in the control arm to 30 weeks in the high fiber diet intervention arm. Additionally, in the intervention arm 40% of mice did not progress to mMM during the study period whereas all mice in the control arm progressed. Both human and mouse data showed that HFPBD modulated gut microbiota composition favoring the expansion of butyrate-producing bacteria. Additionally, short-chain fatty acids were increased in the feces of mice fed a high fiber diet. Integrated analysis from human bone marrow and peripheral blood analysis indicated that the dietary intervention reduced inflammatory biomarkers and skewed the immune response towards T helper and CD14+ monocytes. Consistently, the bone marrow of Vk*MYC mice fed high fiber diet was more infiltrated by IFNg-producing T lymphocytes while displaying less exhausted T cells and immunosuppressive myeloid cells. Conclusion This is the first interventional clinical trial and in vivo study to show that a HFPBD intervention may delay progression from MGUS/SMM to MM. To our knowledge there has been no similar dietary interventional study in hematological cancers or solid tumors. Together our in vivo and clinical data support the beneficial anti-inflammatory role of a HFPBD providing a link between diet, microbiota, and immune modulation to delay disease progression in MGUS/SMM.

Background and significance: 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 the depth of hematologic and organ responses and is an approved induction therapy in newly diagnosed AL amyloid patients (DOI: 10.1056/NEJMoa2028631). However, this approach has not yet demonstrated an overall survival (OS) benefit and follow up remains short. With strict adherence to eligibility criteria, in particular severity of cardiac involvement, autologous stem cell transplantation (ASCT) as consolidative therapy is safe with transplant related mortality on par with multiple myeloma. This approach generates deep and sustained responses, but it is unclear if it offers an additional survival benefit following Dara-VCD induction. The only randomized trial evaluating the role of ASCT in AL amyloid is outdated (DOI: 10.1056/NEJMoa070484) and no randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD induction. Furthermore, multi-organ involvement in AL amyloid drives morbidity and mortality thus the impact of any consolidative therapy on cardiac and renal involvement in addition to overall survival but must be defined. Finally, the approval of Dara-VCD therapy was based on complete hematologic response rates but there is increasing data demonstrating that achieving minimal residual disease (MRD) negativity by either bone marrow next generation flow cytometry (DOI: 10.1002/ajh.26562) or peripheral blood mass spectrometry (DOI: 10.1038/s41408-020-0291-8) generates improved organ response, hematologic progression free survival, and possibly OS. Methods: This randomized phase 3 SWOG led intergroup trial (S2213; NCT06022939) is being conducted within the United States and will accrue a total of 143 participants per arm. The primary endpoint will 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 3 cycles of Dara-VCD consolidation following 3 cycles of uniform Dara-VCD induction. Following the assigned consolidation, all patients will receive 18 months of daratumumab maintenance therapy. 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, hematologic PFS, cardiac and renal responses, MRD negativity both by peripheral blood mass spectrometry and bone marrow next generation flow cytometry, delayed utilization of ASCT, and quality of life. Key inclusion criteria include non-severe cardiac AL amyloid (NT-proBNP <5000; TnT < 0.06; NYHA I or II, EF ≥ 40%), CrCl ≥30 mL/min, serum dFLC > 2 mg/dL, and supine systolic BP ≥ 90 mmHg. Importantly, patients are permitted to have up to one full cycle or 28 days of any plasma cell directed therapy prior to enrollment. This trial was activated on 12/1/2023 with the first patient enrolled 07/01/2024. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819; and in part by Janssen Pharmaceuticals Inc. of Johnson & Johnson (now J&J Innovative Medicine).