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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 The only randomized trial evaluating the role of ASCT in AL amyloid is outdated (DOI: 10.1056/NEJMoa070484) and no randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD induction.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).

Background: Approximately20% of patients with follicular lymphoma (FL) will experience disease progression or death within two years of years (POD24) of immunochemotherapy (IC) (Casulo et al, JCO 2015). A proportion of patients with POD24 have histologic transformation (HT), which heightens the risk of lymphoma-related death (Freeman et al, Blood 2019). To clarify the impact of HT on prognosis in POD24, we analyzed data from the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real-World Evidence (CReWE) to compare differences in outcomes among patients with POD24 with retained FL histology versus POD24 with HT. Methods: This was a multicenter study among 8 academic cancer centers. Eligible patients hadgrade 1-3a FL at diagnosis between 2003 and 2022, with POD24 following first line IC treatment with BR, R-CHOP, or R-CVP. POD24 was defined as disease recurrence within 24 months of IC. Patients with prior lines of treatment for FL were excluded. Patients with HT at first line IC were excluded. Biopsy at POD24 was obtained at the discretion of the treating physician. Three groups of POD24 were defined: POD24 with biopsy-proven retained FL histology (POD24_FL), POD24 with biopsy-proven HT to aggressive lymphoma (POD24_HT), and POD24 either without a biopsy or indeterminate histology on biopsy (POD24_I). We evaluated second-line treatments at time of POD24. Survival probabilities from second-line treatment initiation were estimated by the Kaplan-Meier method. Results A total of1,122 patients with FL were screened and308 patients with POD24 were identified.Median age at POD24 was 58 years (IQR 50-65).Among available data, race and ethnicity was reported as 76% non-Hispanic White, 3% non-Hispanic Black/African American, 9% Hispanic/Latino (any race), and 1% other minorities. First line therapy was R-CHOP in45% (140/308), BR in 33% (102/308) and R-CVP in 21% (66/308). Most patients (52%) had biopsy-proven retained FL at POD24 (162/308); 30% had no biopsy or indeterminate histology at POD24 (94/308), and 17% had biopsy-proven HT at POD24 (52/308). In the POD24_HT group, 52% received R-CHOP and 21% received intensive salvage chemotherapy as second line therapy. Patients with POD24_FL and POD24_I had similar rates of salvage chemotherapy (21% and 18%), BR (13% and 18%), R-CHOP (19% and 24%), and targeted therapies (8% and 5%), respectively, at second line. Consolidative autologous stem cell transplant was more common in POD24_HT patients at 21% versus 16% in POD24_FL and 6% in POD24_I. Patients with POD24_HT had significantly worse overall survival (OS) compared to POD24_FL (ref), with a hazard ratio of 3.79 (95% confidence interval [CI] 2.46-5.84), even after adjusting for age, FLIPI score, and first-line IC treatment. At 5 years, patients with POD24_HT had OS of 31% compared with an OS of 71% for patients with POD24_FL. Patients with POD24_I had similar outcomes to those with POD24_FL (5-year OS 75% versus 71%, respectively). Event-free survival (EFS) was also significantly lower in POD24_HT compared to POD24_FL: At 2 years, EFS was 27% for POD24_FL (21-35%) and 10% for POD24 _HT (4-23%). At 5 years, lymphoma remained the leading cause of death among patients with POD24, with 20% probability of lymphoma-related death in those with POD24_FL (95% CI 14.2-27.8) compared to 53% probability of lymphoma-related death in patients with POD24_HT (95% CI 40.6-70.7). Conclusions: In our multicenter cohort, we identified remarkable differences between the two biopsy-demonstrated entities of POD24 (i.e., with and without HT). Patients without a biopsy or indeterminate histology had similar outcomes as those with POD24_FL. Patients withearlyrelapse of FL after first-line IC remain a heterogeneous group with poor outcomes and a heightened risk of lymphoma-related mortality particularly compared with nonPOD24 groups. Even with retained FL histology, patients with POD24 had 20% probability of lymphoma-related death within 5 years of second-line treatment initiation. We demonstrate that poor survival is driven in part, but not entirely, by HT. Despite most patients receiving appropriate aggressive treatment, those with POD24_HT represent a distinctly vulnerable population warranting further study in directed prospective studies of both FL biology and clinical trials.

Introduction: Pembrolizumab Gemcitabine Vinorelbine and Liposomal Doxorubicin (P-GVD) has become a commonly employed regimen for the treatment of relapsed or refractory classical Hodgkin lymphoma (CHL), often preceding autologous stem cell transplant in patients with good response. The utilization of P-GVD is based on a 38-evaluable patient prospective trial (Moskowitz et al. JCO 2021). There remains minimal data regarding the efficacy of this regimen in a larger, real-world cohort. Methods:Patients with CHL who received P-GVD at 9 United States centers were retrospectively evaluated to estimate efficacy and safety, with a focus on the second line use of this regimen. Demographic and clinical data were extracted from medical records. Responses reflected Lugano criteria per local investigator assessment. Study objectives were overall response rates (ORR), complete response rates (CRR), progression free survival (PFS), overall survival (OS), and safety. PFS and OS were estimated by Kaplan-Meier. Results: Patients and Treatment: We identified 65 CHL patients who received P-GVD between July 2019 and June 2024, including 43 who were treated in the second line. Enrolled patients included a median age of 31 years (range 17-69 years), 36.9% (24) females, 75.4% (49) nodular sclerosing subtype, and 60% (39) stage III-IV at diagnosis. Patients included 64.6% (42) White and non-Hispanic, 15.4% (10) Hispanic or White and Hispanic, 10.8% (7) Black, 3.1% (2) Asian/Pacific Islander, 3.1% (2) other, and 3.1% (2) unknown. The median number of prior regimens was 1 (range 0-12); these included 3.1% (2) who had prior checkpoint inhibitor (CPI), 50.8% (33) who had prior brentuximab vedotin (BV), and 3.1% (2) who had prior transplant. Patients with primary refractory disease [no initial complete response (CR)] comprised 58.5% (38), and 35.4% (23) had relapse within 1 year of completing initial therapy. The median number of cycles received was 3 (range 1-5). Treatment in a community practice setting was noted for 21.5% (14) patients. Efficacy: At a median follow up of 17.7 months, ORR and CRR after P-GVD were 95% (62/65) and 74% (48/65), respectively. This increased to 95% ORR and 81% CRR when limited to 43 patients who were treated 2nd line. Responses by line included: 1st [n=1; 100% ORR and CRR]; 3rd [n=15; 100% ORR, 73.3% CRR], 4th [n=3; 100% ORR, 33.3% CRR], 5th [n=2; 100% ORR, 0% CRR], and 13th [n=1; SD]. CRR in BV- and CPI-exposed patients were 60.6% and 50%, respectively. Ninety one percent (39) of 2nd line treated patients proceeded to autologous transplant, as well as all 3 patients > age 60. Among 41 response-evaluable second-line patients, CR was achieved in 94% (30/32) who received 2 or 3 cycles of P-GVD, and 56% (5/9) who received 4 cycles of P-GVD. For the entire cohort at 12 and 24 months after starting P-GVD, PFS was 95% (95% CI: 89-100%), 91% (95% CI: 83-100%) and OS was 98% (95% CI: 94-100%), 94% (95% CI: 86-100%), respectively. Ninety five percent (41) of 2nd line transplanted patients remain alive and in remission at a median of 18.5 months (range 3.5-38.7 months). In the primary refractory subset, PFS and OS at 24 months were 91% and 97%, respectively. For the cohort with 2 or more prior lines of therapy, PFS and OS at 24 months were 91% and 94%, respectively. Safety: Immune-related adverse events (IRAEs) were reported in 20% (13) of patients, of which grade 3 IRAEs per NCCN criteria version 1.2024 comprised 38.5%; all others were grades 1-2. Non-IRAE grade 3-4 toxicities per CTCAE version 5.0 were reported in 22% (14) patients. Of 29 patients evaluable for treatment-related interruptions, 7% (2) had therapy discontinued, and 34% (10) had holds, dose reductions, and/or delays. No deaths were attributed to P-GVD treatment. Conclusions:This retrospective study confirms the utility of P-GVD in treating relapsed/refractory CHL in a real-world population. Though fewer CRs and higher rates of grade 3 adverse events were observed, the vast majority of patients were able to proceed to transplant, and outcomes to date are highly encouraging.

Background: Chromosomal rearrangements involving the KMT2A gene and mutations involving the nucleophosmin (NPM1) gene have been associated with response to menin inhibitors in multiple studies of acute myeloid leukemia (AML) patients characterized by these genetic alterations. Both alterations are more common in younger AML patients and those with NPM1 mutations historically perform better. However, the prevalence and outcomes of older (≥60 years) AML patients with these alterations who are treated with current therapies is less well understood. We present results from the Beat AML Master Trial (BAMT) that analyze the outcomes of this large, but less common subset of patients in an older AML population. Methods: Patients were consented and enrolled on this precision medicine-based Beat AML Master Trial (NCT03013998) from November 2016 to June 2024. Patients were included in this analysis if they harbor either the classic NPM1 mutation or a KMT2A rearrangement (over 10 different gene partners). Additionally, 2 patients with a NUP98 rearrangement were included with the KMT2A cohort as they are known to have similar biology in terms of menin dependence. These patients were treated with the following therapies: a sub-study specific targeted therapy for the dominant clone, venetoclax + hypomethylating agent (Ven/HMA), intensive chemotherapy (IC), alternative non-intensive therapy (NIT), or no therapy. Clinical/genetic characteristics and median overall survival (OS) were analyzed in each group separately. Overall survival (OS) was calculated from master consent and estimated using the Kaplan-Meier method. Results: Of 1096 AML patients enrolled on the BAMT, 246 patients had either an NPM1 (N=207, 18.9%) or KMT2A (N=39, 3.6%) genetic alteration. The baseline characteristics for the NPM1 cohort were median age 72 years (range: 60-92), 50% female, and ECOG performance status: 0-16%, 1-58%, 2-25% and 3-1%. Additional disease characteristics include treatment related AML at 11% and complex karyotype (≥3 abnormalities) at 3%. Median OS for the entire NPM1 cohort was 18.4 months (95% CI: 14.2-24.7). Patients were treated on a sub-study (35%), Ven/HMA (19%), IC (26%), NIT (8%) or no treatment (9%). Between treatment groups, median OS was 21 months (95% CI: 12.8-31.7) for those treated on a sub-study, 22 months (95% CI: 12.6-not reached (NR)) for Ven/HMA, 41.6 months (95% CI: 18.2-NR) for IC, and 6.3 months (95% CI: 1.3-23) for NIT, which was significantly different (p<0.0001). The baseline characteristics for the KMT2A cohort were median age 69 years (range: 60-88), 44% female, and ECOG performance status: 0-19%, 1-45%, 2-35% and 3-0%. Treatment related AML occurred in 23% of patients and complex karyotype in 31%. Median OS for the KMT2A cohort was 6.5 months (95% CI: 3.6-31.6). Patients were treated on a sub-study (38%), Ven/HMA (15%), IC (15%), NIT (15%), or no treatment (5%). Between treatment groups, median OS was 31.6 months (95% CI: 3.2-NR) for sub-study, 5.0 months (95% CI: 3.0-NR) for Ven/HMA, 12.7 months (95% CI: 4.9-NR) for IC, and 2.9 months (95% CI: 1.5-NR) for NIT, which was also significantly different (p<0.0001). Conclusions: In this cohort of older AML patients who possess NPM1 or KMT2A mutations, initial demographics and clinical characteristics upon presentation are as expected. Within each cohort and depending on the type of therapy received, there were interesting differences in survival. Median OS was the highest for the NPM1 cohort that received IC while the KMT2A cohort had the highest median OS when enrolled on a KMT2A targeted sub-study; a finding that supports precision-based medicine for this high-risk KMT2A group characterized by poor outcomes. As menin inhibitor combinations with induction chemotherapy or Ven/HMA move to the frontline setting, we anticipate seeing significant improvement in outcomes for AML patients in both of these genomic subsets. Further multivariable analysis will be performed to validate treatment effect on OS. Our analyses for these two cohorts also provide valuable outcome benchmarks for the design of future precision oncology studies that seek to improve survival in these subsets of older AML patients.

Background: Immunosuppressive therapy (IST) is considered the standard front-line treatment for acquired severe aplastic anemia (SAA) for pts >40 years. For pts aged <40 years who have a suitable human leukocyte antigen (HLA)-matched sibling donor (MSD), hematopoietic stem cell transplantation (HSCT) is recommended. This recommendation is based on the toxicity associated with alternative donors; haploidentical (HAPLO) and unrelated donor (URD) HSCT for patients who lack a MSD. However, the hematopoietic response after IST is ~ 70-80%, even after augmentation with eltrombopag in the front-line setting, and failure-free survival (FFS, defined as patients alive and in remission without clonal disease more than 10 years after IST) remains < 40%. HSCT is often employed as a second line salvage therapy for those who do not respond to IST or have disease recurrence. However, outcomes after HSCT are often compromised because of IST-related complications such as clonal evolution, development of donor specific antibodies, infectious adverse events and organ dysfunction. In contrast, a successful allogeneic HSCT leads to relatively prompt hematopoietic and immune reconstitution and mitigates the risk of secondary clonal disease. Innovations in recent decades, such as improved graft versus host disease (GVHD) prophylaxis and supportive care, have steadily reduced the morbidity and mortality of adults undergoing HSCT from unrelated or mismatched donors and expanded the donor pool such that almost all pts with SAA have a potential donor available. The use of post-transplant cyclophosphamide (PTCy) is now a well-established approach to facilitate engraftment and mitigate the risk of GVHD. It was successfully used in relapsed/refractory SAA pts using HAPLO donors in the multi-center BMT CTN #1502 trial (NCT02918292). Similar PTCy based approaches have been effective in the upfront setting with HAPLO and URD in small single center studies. Opened in July 2024, the CureAA trial (NCT06517641), seeks to increase donor options for SAA pts who have not yet received IST by using PTCy based GVHD prophylaxis for HSCT using HAPLO or URD. Study Design and Methods: This BMT CTN study (#2207) is a prospective multi-center phase II trial to assess efficacy of HSCT using HAPLO or URD bone marrow with a reduced intensity, thymoglobulin (ATG)-containing preparative regimen and PTCy GVHD prophylaxis in previously untreated SAA pts. This trial has two parallel cohorts for each donor type, HAPLO and URD, with an accrual goal of 30 participants in each cohort. All will receive ATG (0.5mg/kg on day -9 and 2mg/kg on days -8 and -7), cyclophosphamide (14.5mg/kg on days -6 and -5), fludarabine (30mg/m2 on days -6 to -2), 400 cGy total body irradiation (day -1 in a single fraction), a marrow graft (goal >2.5 x 108 nucleated cells per kg of recipient) on day 0 and PTCy (50mg/kg on days +3 and +4). Additionally, participants receive tacrolimus (until day +180) and mycophenolate mofetil days +5-35. The primary objective of the trial is to estimate the GVHD-free failure-free survival (GFFS) rate at 1 year after initiation of conditioning. GFFS is a composite endpoint of survival without grade III-IV acute GVHD, chronic GVHD requiring immunosuppression, or primary or secondary graft failure requiring second definitive therapy within 1 year after initiation of conditioning. Secondary objectives will evaluate patient survival, engraftment, transfusion dependence, cumulative incidence of GVHD and hematologic response. Health related quality of life, healthcare utilization and financial toxicity data will also be collected. These endpoints will allow clinical comparison with current results achieved with upfront IST in other studies. We hypothesize that this HSCT approach will improve survival without significant transplant-associated morbidity by using a low toxicity regimen that reduces rates of GVHD and provides rapid hematologic recovery without graft failure, thereby making HAPLO and URD HSCT a viable option for initial upfront treatment of SAA. The ability to use mismatched donors will also ensure that a HSCT option is more widely available to all racial/ethnic groups. This collaborative study was funded by grants U10HL069294, U24HL138660 to the BMT CTN from the NHLBI/ NCI, along with funding from Sanofi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Introduction The pathogenic role of somatic non-coding (nc) single nucleotide variants (SNVs) is underexplored in multiple myeloma (MM) and additional characterization of these regions has the potential to provide significant new insights into disease progression. To investigate the role of ncSNVs and their relationship with MM pathogenesis, we have characterized a novel series of WGS from 294 cases of MGUS, SMM, and MM using computational tools optimized to identify functional driver SNVs in these regions. We hypothesize the ncSNVs that co-localize to sites of super-enhancers (SEs) active in plasma cells (PC) are sites of high functional impact SNVs and these mutations lead to the dysregulated expression of genes that should be silent at the terminally differentiated stage of PCs, providing a selective advantage that shapes the fitness of the MM genomic landscape. Methods We analyzed 294 high-coverage matched tumor/normal pairs (80x tumor and 40x normal) derived from 21 MGUS, 86 SMM, 167 NDMM and 40 RRMM. In addition to previously sequenced samples, newly sequenced patients were obtained from NYU Langone Health, Memorial Sloan Kettering Cancer Center, University of Alabama at Birmingham and University of Miami following IRB-approved informed consent. DNA was extracted from CD138+ purified bone marrow plasma cells using standard approaches. We used the MGP1000 (https://github.com/pblaney/mgp1000) to process sequencing data which employs a union-consensus mechanism for determining the final set of variants. We collected enhancer elements (E/SEs) active in GC B-cells, ABC-DLBCL and GBC-DLBCL (Bal, et al. Nature, 2022) and PC specific E/SEs (Loven, et al. Cell 2013). FunSeq2 was used to score ncSNVs. GRAM was used to predict how variants alter TF binding and gene expression in a subset of 6 cases with paired WGS in our series and will expand this analysis on a validation set of 263 NDMM and 93 RRMM cases from University-Hospital Heidelberg enrolled in the GMMG-HD6 clinical trial. Results We identified 1,952,232 high-quality SNVs with 18,199 (0.93%) accumulating in 280 focal sites we termed “mutationally enriched regions” or MERs. To discern SNVs in MERs with the highest potential for imparting a selective advantage, we clustered mutations based on the density of FunSeq2 impact scores which uses reference data contexts on sequence conservation, modification of transcription factor (TF) binding, and gene linkage to regulatory elements and network hubs from pan-cancer studies. We show that MERs are enriched for ncSNVs with high impact scores (mean=2.57) compared to random similarly-sized regions of the genome (Fisher's exact test P<9.7e-12, OR=10.10 [3.88-37.40]). The high impact ncSNVs (hi-ncSNVs) in MERs (n=220) account for 8.09% of all hi-ncSNVs and are present in 46.3% of cases (136/294) with some patients having up to 7. The proportion of cases carrying a MER hi-ncSNVs was similar across disease stages (MGUS=42.9%, SMM=46.5%, MM=40.7%, and RR=47.5%). Analysis of the VAF of MER hi-ncSNVs shows a minor shift towards more clonal versus subclonal mutations (53.6% vs 46.4% VAF>=0.25) suggesting some high impact mutations are acquired in the GC but additional hi-ncSNV are acquired later in PC development, providing evidence that hi-ncSNVs accumulate in MERs throughout disease progression. We mapped these hi-ncSNVs to associated genes then intersected the loci with E/SEs active in GCBs and PCs to determine their functional context. This approach identified 12 genes affected by hi-ncSNVs including the previously identified nc-drivers NEAT1, MIR142, ZCCHC7, and IGLL5 as well as the PC differentiation genes IRF8, BACH2, proliferation genes RHOH, SPRED2, known coding MM drivers CCND1, ZFP36L1, and chr1q genes BTG2 and CROCC. We predicted the effect of ncSNVs on expression through modulation of TF binding at this set of putative nc drivers in MM and identified a trend towards increase in expression of SPRED2, CCND1, NEAT1, and IGLL5 compared to non-mutated cases (P=0.089). We will present data on the validation of this set of genes on a larger set of data derived from the Heidelberg group. Conclusions We identified a set of 12 putative nc driver genes in MM that modify expression and have the potential to significantly alter the pathogenesis of MM by providing a selective survival advantage. We will present the impact of these by clinical stage and on outcome.

Background Clonal hematopoiesis (CH) is defined by somatic mutations in hematopoietic stem cells, often conferring a selection advantage based on clonal selection pressures. CH in DNA Damage Response and Repair (DDR, e.g. TP53, PPM1D) genes are frequent in individuals exposed to chemotherapy and radiation (chemo/XRT). In metastatic prostate cancer (mPC) patients, the prevalence of CH is estimated at 57% and is increased among those with prior exposure to chemo or XRT. In these patients, the use of radiotheranostics is becoming more prevalent and are now being tested in earlier lines of therapy. We have identified an increase in DDR-somatic variants post lutetium-177-PSMA, raising concern for long term hematologic safety. Here, we evaluate the spectrum of CH and CCUS (clonal cytopenias of undetermined significance) in mPC patients, prior to receiving radioisotope therapies. Methods We performed error corrected next-generation sequencing (NGS) on peripheral blood samples from 67 mPC patients enrolled in the Prostate Cancer Medically Optimized Genome Enhanced Therapy Study (PROMOTE) study (NCT #01953640). All patients enrolled also had whole exome sequencing (WES) performed on initial metastatic biopsies and on whole blood for germline genotyping. Somatic variants with a variant allele fraction (VAF) ≥0.5% were considered as CH, using standard bioinformatic variant calling algorithms. Results The median age at NGS was 74.4 years (range, 58.4-92.3). While all patients received androgen deprivation therapy (ADT) +/- androgen receptor pathway inhibitor (ARPI), 67.2% (n=45, pelvic XRT- 35, palliative XRT- 10) received prior XRT and 3% (n=2) received prior docetaxel. No patients in this cohort received prior platinum or PARP inhibitor. Of those treated with XRT or chemo, the median time from first exposure to CH sample collection was 4.1yrs (range, 0.12-29.6) and 2.3yrs (range, 0.6-4.0), respectively. Of the 67 patients, we identified a total of 111 pathogenic variants in 59 (88.1%) patients. We compared our NGS data to the germline data and tumor for each patient (All samples obtained at the same time point; Wang et al 2018). Our analysis excluded 2 ATM variants likely to be germline, and 1 TP53 variant likely to be tumor-derived. Each patient had at least one somatic variant, with a median of 2 variants (range, 1-6The median CH VAF was 1.8% (range, 0.5-50.2) with 91.0% of alterations detected at a VAF of <10%. Specific somatic variants, presence/absence of CH, number of variants, nor VAF was associated with age, prior chemo, or XRT exposures. At time of NGS, 54% of patients were anemic (hgb <13g/dL), 7% were thrombocytopenic (platelets <135 x109), 6% were leukopenic (WBC <3 x 109), and no patients were neutropenic (ANC <1 x109). Persistent cytopenias, lasting >3months, were present in 25% (n=17) of patients; however, bone marrow biopsies (BMB) were performed only in 6% (n=4). Three (75%) of these 4 patients had mPC infiltration in the BM, and 1 (25%) had mild dysplasia not meeting criteria for MDS but meeting criteria for CCUS (CHEK2 somatic variant). At last follow-up, there were no patients formally diagnosed to have myeloid neoplasm (MN). Median overall survival (OS) from prostate cancer diagnosis was 8.6yrs (range, 1.4-28.4). With a median follow up of 2.2yrs (range 0.1-10.8) after CH testing, 3.0% (n=2) were alive, with most deaths occurring due to mPC. The presence of CH did not impact overall survival (OS), however, presence of cytopenias at the time of NGS testing was associated with worse outcomes (median OS 2.5yrs vs 1.2 yrs., p=0.025). Conclusions We define the landscape of CH mutations in mPC patients predominantly treated with ADT/ARPI and XRT, demonstrating that DNMT3A, TET2, PPM1D and ASXL1 are frequently mutated (88%) and largely subclonal (91% with VAF ≤10%). While 25% of these patients had cytopenias, with cytopenias negatively impacting survival, due to inadequate BM biopsy work up, the true prevalence of CCUS and MN could not be estimated. Given the advancement of genotoxic therapies and the high prevalence of subclonal CH in mPC, future studies investigating CH as a predictive biomarker of hematological dysfunction are much needed.

Background: Due to recent advances, patients with follicular lymphoma (FL) have multiple treatment options with high response rates and durability. However, there is a gap in understanding how patient preferences influence treatment selection. To close this gap, we conducted a qualitative study using focus groups of adults with FL to understand their knowledge of treatment options, priorities, and decision-making process. We designed this study to inform the content of a planned discrete choice experiment in a larger population of patients with FL to better understand patient preferences and trade-offs around treatment delivery, side effects, outcomes, and quality of life. Methods: We conducted focus groups lasting 60-90 minutes, each with 3-5 participants recruited from the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study. The LEO Cohort Study is a multi-institutional prospective cohort study of newly diagnosed adults with non-Hodgkin lymphoma from July 2015 to present. Each focus group was co-led by two investigators (U.D. and M.T.) and conducted using Zoom video technology. Participants were asked to comment on their understanding about FL and available treatments, their ideal treatment, their decision-making process about prior therapies, and quality of life and side effects associated with treatment. We performed exploratory content analysis of participant understanding of FL and their treatment preferences. We will continue to conduct focus groups until we reach thematic saturation, which we anticipate will occur with one additional focus group. Themes from all focus groups were identified and agreed upon by both investigators (U.D. and M.T.) and were verified by additional investigators (J.D., M.L, M.H., B.K.L, C.C., M.M.). Results: To date, we conducted five focus groups with a total of N=21 participants (median age 60 [range 41-88], 66.7% female, 71.4% non-Hispanic White, 14.3% Hispanic, 9.5% Asian, 4.8% Black/Hispanic). We identified the following themes and representative quotes: 1) Holistic approach:Participants wanted their oncologists to view their care from a holistic perspective, discussing their individual priorities and options that would accommodate their fitness routine and ability to work. “[I wish] if doctors can consider not just the physical choices, but also the mental and emotional choices as well, the holistic person.” - Participant 13 “There's zero chance I can go back to working in the type of career where other people rely on me for things. I can't keep things straight.” - Participant 16 2) Ideal treatment:An ideal treatment would limit impact on fatigue, cognitive function, and have minimal toxicity to preserve quality of life and an active lifestyle. “I would say something that has minimal impact on daily life would be ideal and something that would make you feel better.” - Participant 6 3) Shared decision-making: Participants wanted to be better informed about available treatment options and often utilized second opinions to inform their decisions. “It helped to get the second opinion versus not. It would've been a completely different set of events.” - Participant 17 4) Treatment burden:Financial impact and effort required by patients to receive care (e.g., travel, number of office visits, and duration of therapy) were key factors in patient decision-making. “Part of my quality of life went down because I had to fight with my insurance company consistently, and we pay a lot of money.” - Participant 11 “Really explain the time options and calendarize the treatment and be more specific about the amount of time that you're going to spend at the hospital and the process.” - Participant 20 5) Representation: Minority participants raised concerns about not knowing if the available treatment data pertained to them. “[My end-goal would be] having an understanding of how the treatment is going to be for minority people. Many times the treatments are tested, they are not tested for minorities.” - Participant 21 Conclusions: The patient perspective is critical for treatment decision-making and education. People living with FL expressed a desire for a holistic and individualized approach to treatment decision-making that incorporated their lifestyle, minimized side effects, and limited overall treatment burden. These focus groups identified emerging themes that warrant further investigation for survivors with FL.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and severe hematologic disorder caused by somatic mutation(s) in hematopoietic stem cells, which results in dysregulation of complement activation and complement-mediated hemolysis. Several complement inhibitors are approved for PNH, including the intravenous or subcutaneous C5 inhibitors (C5is) eculizumab, ravulizumab, and crovalimab; the subcutaneous self-administered C3 inhibitor pegcetacoplan; and the oral factor B inhibitor iptacopan and factor D inhibitor danicopan (as add-on therapy to a C5i). Although oral self-administered medications would be expected to lighten treatment burden over injectable medications in patients with PNH, adherence to anticomplement therapies is essential to maintain stable hematologic response while avoiding adverse events of breakthrough hemolysis and thrombosis. Real-world adherence to pegcetacoplan in patients with PNH was evaluated and compared with reported real-world adherence to long-term oral therapies for chronic conditions. Methods: A descriptive review of recent literature was conducted to summarize real-word oral medication adherence rates in chronic conditions. The Medical Subject Headings “compliance, medication” and “administration, oral” were applied in PubMed, and yielded reports on oral antidiabetic medications (OADs) in type 2 diabetes, oral anticoagulants (OACs) in atrial fibrillation (AF), and oral oncolytics in hematologic cancers; observational, real-world studies reporting medication adherence rates were reviewed and summarized. Adherence to pegcetacoplan therapy among patients with PNH in the US postmarketing setting was calculated as the percentage of patients who take pegcetacoplan as prescribed (adherence definition) based on the number of days patients had pegcetacoplan vials in their possession (dispensed) divided by the total number of days in a dispensing period (proportion of days covered) using central pharmacy prescription refill data. Results: In general, patients who take ≥80% of prescribed doses are considered adherent; using this definition, adherence rates among patients receiving long-term therapies for chronic conditions are typically 50% to 60% but vary greatly [Kleinsinger F. Perm J. 2018;22:18-033]. For example, reported OAD adherence rates in type 2 diabetes vary across countries (42% in Switzerland [Huber CA et al. Medicine (Baltimore). 2016;95:e3994] to 67% in Canada [Simard P et al. Acta Diabetol. 2015;52:547]) and by medication types (36.7% with thiazolidinediones to 47.3% with dipeptidyl peptidase 4-inhibitors [Farr AM et al. Adv Ther. 2014;31:1287]). OAC adherence rates in AF range widely (~40% to ~90%), differing across countries, patient populations (incident AF vs. post cardiovascular event), OAC types (warfarin, direct OACs), and follow-up period lengths. OAC adherence is also influenced by patient demographic and clinical characteristics and regional determinants in US Medicare beneficiaries [Hernandez I et al. J Am Heart Assoc. 2019;8:e011427]. Interestingly, an inverse relationship between oral medication adherence and dosing frequency is observed in chronic diseases in general (progressively decreasing adherence rates from once-daily to twice, 3-times, and 4-times daily dosing regimens [Coleman CI et al. J Manag Care Pharm. 2012;18:527]), and with OACs in AF [Vrijens B, Heidbuchel H. Europace. 2015;17:514]. As with other chronic conditions, nonadherence to oral oncolytics in hematologic cancers is more prevalent than suspected (32.7%) and associated with poorer clinical response [Noens L et al. Blood. 2009;113:5401], which can further increase the economic burden on patients [Dashputre AA et al. J Manag Care Spec Pharm. 2020;26:186]. Pegcetacoplan adherence for PNH in the US postmarketing setting from launch (2021) to date (2024) was estimated at 97%, well above the 80% threshold defining medication adherence in the literature. Conclusions: Real-world patients with PNH who self-administer pegcetacoplan subcutaneously have adherence rates exceeding the reported real-world adherence rates for oral medications in chronic conditions, especially those with high dosing frequencies. Retaining a stable hematologic response and preventing potentially life-threatening complications in PNH relies on continuous patient adherence to lifelong anticomplement therapies.

Introduction Multiple myeloma (MM) is considered incurable. Despite improved outcomes with novel agents, including BCMA-targeted chimeric antigen receptor (CAR) T-cell therapies, antibody-drug conjugates (ADCs), and bispecific antibodies, patients with relapsed/refractory MM (RRMM) often have poor prognoses. LINKER-MM1 (NCT03761108) is a global, single-arm, Phase 1/2 study of linvoseltamab, a BCMA×CD3 bispecific antibody, in patients with RRMM who were either triple-class exposed (TCE; previously treated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody) during ≥3 prior lines of therapy (LOTs), or triple-class refractory to these therapies. Here, we present comparisons of clinical outcomes from LINKER-MM1 with those of a current, international, real-world (RW) external control arm (ECA; NCT05673967). Methods The ECA was derived from 16 academic sites of the International Myeloma Foundation International Myeloma Working Group (IMWG) (N=203; 309 eligible LOTs) and compared with linvoseltamab (N=105; Phase 2 200 mg cohort). Patients in the ECA initiated ≥1 anti-MM therapy after meeting key LINKER-MM1 eligibility criteria. Weighted random sampling and inverse probability of treatment weighting were used to select 1 LOT per patient and balance the ECA and trial populations on prespecified prognostic factors (Kumar S, et al. IMS 2023). The primary endpoint was objective response rate (ORR; IMWG criteria) determined by an independent central review committee (ICRC) based on myeloma laboratories. An independent data review committee reviewed comparability of cohorts and endpoint assessments prior to conducting comparative analyses. Results Median follow-up was 14.3 months for the linvoseltamab cohort (data cutoff: Jan 6, 2024) and 13.4 months for the ECA. After weighting, 15 prognostic factors were balanced between cohorts. Patients in the ECA received 68 distinct regimens, most commonly CAR T-cell therapies (11.3%) and ADCs (10.3%). After balancing the cohorts, patients in the ECA evaluable for response had ICRC-assessed ORR of 46.3% (40.8% by treating physician assessment), among whom 24.0% had very good partial response or better (≥VGPR). When including patients who died without evaluable response, ECA ICRC-assessed ORR was 44.2%. Linvoseltamab induced significantly higher ICRC-assessed ORR (69.5% vs 46.3%, odds ratio [OR] 2.65 [95% confidence interval (CI) 1.66-3.69]) and rate of ≥VGPR (62.9% vs 24.0%, OR 5.37 [95% CI 3.61-8.49]) compared with ECA regimens. Conclusion Despite current use of novel therapies, there is no well-established RW standard of care (SOC) for patients with TCE RRMM treated at IMWG sites. To our knowledge, this is the first RW ECA study in MM with a high percentage of anti-BCMA therapies and response ascertainment for all patients by ICRC. Linvoseltamab induced significantly higher response rates, including rate of ≥VGPR, compared with current RW SOC therapies, highlighting its potential as a highly effective treatment in patients with TCE RRMM.