Usmani, Saad Z.

Background: Despite recent major advances, multiple myeloma (MM) remains incurable using therapies that are currently available to patients. There are no available/approved targeted therapies for MM that allow for individualized therapeutic approaches to the disease. Fifteen to 20% of newly diagnosed MM patients have a translocation of chromosomes 4 and 14 [t(4;14)]. This translocation puts transcription of the gene encoding Multiple Myeloma SET domain-containing protein (MMSET or NSD2), a histone 3 lysine 36 methyltransferase, under the control of the IgH super enhancer. The super enhancer drives the overexpression of MMSET resulting in an abnormal histone code that promotes myelomagenesis. Presence of t(4;14) is associated with poor clinical prognosis (Caro Am Soc Clin Oncol Educ Book 2021). KTX-1001 is a first-in-class, selective and potent small molecule inhibitor of MMSET, and is the first investigational drug that targets the t(4;14) MM patient population. Methods: This Phase 1, first-in-human open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001 in relapsed/refractory MM (RRMM) and has two parts: dose escalation (Part A) and dose expansion (Part B). In Part B, only t(4;14)+ MM patients will be evaluated in single agent and combination expansion cohorts. Patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody are eligible for the dose escalation part. The primary objective of the study is to determine a recommended phase 2 dose (RP2D) and schedule of KTX-1001. Secondary and exploratory objectives include pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of KTX-1001, and assessment of preliminary efficacy. KTX-1001 is administered orally until disease progression, unacceptable toxicity, or patient withdrawal from the study. A Safety Review Committee (SRC) reviews all data prior to each dose escalation decision and on a regular basis. Results: As of June 14, 2024, 17 patients (pts) have been treated with KTX-1001 in Part A across 6 dose levels (SRC reviewed). Dose Level 7 has been reached with no dose limiting toxicities (DLTs). Ten of these patients are t(4;14) positive. Patients have received a median of 5 prior lines of therapy (range: 3-17), including 7 pts with prior BCMA CAR-T, 6 pts with prior BCMA bispecific and/or ADC, 5 pts with prior non-BCMA bispecific, and 12 pts with prior transplant. Patient demographics include a median age of 68 years (range: 50-83), 10 male/ 7 female, 13 white, 2 black or African American, 2 as other identified race, and 3 Hispanic or Latino pts. Six pts remain on treatment. KTX-1001 shows excellent tolerability to date, with treatment emergent AEs (TEAEs) (CTCAEv5.0) predominantly of grade 1 and 2 severity. Most frequently observed TEAEs suspected to be related to KTX-1001 include fatigue (35%), diarrhea (24%), and constipation (24%), for which no grade 3 or 4 events have been observed. Frequency and/or severity of TEAEs have not increased with escalating doses nor treatment duration, and no patients have discontinued due to an AE. Two heavily pre-treated patients [one known to be t(4;14)+] have demonstrated long-lasting stable disease and clinical benefit at 10 and 7 months respectively. Both patients have been intra-patient dose escalated. For PK and PD data collected to date, drug exposure and steady-state concentration of KTX-1001 (at C1D15, when steady state concentration has been reached) appear to be dose-proportional. PD data indicate a dose-dependent decrease in the H3K36me2 mark on treatment versus baseline across dose levels 1 through 6, suggesting that the RP2D may be reached by year end. Updated results will be presented at the congress. Conclusions: Dose escalation of KTX-1001 is ongoing with an excellent tolerability profile to date and demonstration of on-target pharmacodynamics that will inform the determination of the RP2D(s). These PD data support the targeted mechanism of action of KTX-1001 to selectively inhibit MMSET and break the t(4;14) histone code. Given KTX-1001's promising safety profile, single-agent and combination expansion cohorts with standard-of-care MM agents/classes will begin in 2025 to further optimize doses and provide proof of concept in Part B of the Phase 1 study.

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: Understanding patient preferences and decision-making processes is crucial in managing relapsed multiple myeloma (RRMM). Shared decision-making has become a key element of patient-centered care, allowing patients to collaborate with healthcare providers in choosing treatments that align with their health and quality of life goals. This study examines how the perceived severity of treatment side effects influences patient decision-making autonomy and communication patterns, providing insights into decision-making practices in hematology. Methods: A survey was conducted with 784 RRMM patients as of January 1, 2024, using HealthTree Cure Hub (PMID: 35271305). Among the participants, 333 experienced a relapse and responded to the question about how side effect severity affected their treatment choices. Of these, 54% (n=181) considered side effects to be very or extremely influential (VE), whereas 46% (n=152) regarded them as somewhat, slightly, or not influential at all (SSN). Participants evaluated these factors on 5-point Likert scales: 1 (very poor) to 5 (very good); 0 (not at all influential) to 4 (extremely influential). The survey assessed patient involvement in final treatment decisions, discussions with fellow patients, family or caregivers, and the time allocated and used for decision-making. Results: Patients in the VE group reported a better understanding of the likely side effects of treatment options compared to the SSN group (VE: 3.9±1.0; SSN: 3.6±1.0, p<0.05), with a higher proportion reporting a very good understanding (VE: 31%, n=45; SSN: 18%, n=29, p=0.036). A weak relationship confirmed VE patients engaged in additional side effect education before making a change in treatment decisions (r=0.164, p=0.004). VE patients also reported a better understanding of the balance between effectiveness and potential side effects of treatments than SSN patients (VE: 3.8±1.0; SSN: 3.5±1.1, p<0.05), with more VE patients reporting a very good understanding (29%, n=41 vs. 15%, n=24, p=0.006). A weak relationship confirmed that VE patients more closely evaluated the trade-offs of treatment options when choosing a new treatment regimen (r=0.197, p<0.001). Likely to achieve a better understanding, more VE patients talked with fellow patients (VE: 19%, n=24; SSN: 7%, n=11, p = 0.003) and rated these conversations as more influential than SSN (VE: 1.5±1.5; SSN: 1.1±1.4, p<0.05). Additionally, VE patients were more likely to discuss treatment options with family or caregivers before making a final decision (VE: 49%, n=61; SSN: 29%, n=43, p<0.05). Moreover, VE patients reported greater involvement in their doctor-patient communication approach (VE: 3.2±0.8; SSN: 2.8±0.8, p<0.05), with scores ranging from 1 (“...follow the doctor's suggestions”) to 4 (“...we discuss my preferences... and I make the final decision”). Furthermore, VE patients reported more self-determination in the treatment decision-making process than SSN patients, with more VE patients making the final treatment decision themselves rather than having their doctor decide (“I made the final decision” - VE: 66%, n=93; SSN: 52%, n=81; “My doctor made the final decision” - VE: 34%, n=47; SSN: 46%, n=72, p=0.013). VE patients reported being provided 1.5 more weeks of time to make a treatment decision than the SSN (4.8±8.9 v. 3.3±6.0 wks, p<0.05). Subsequently, VE patients reported using 79% more time than SSN patients to arrive at a final decision (VE: 2.5±6.0; SSN: 1.4±1.9 wks, p<0.05), likely attributed to time spent gaining a better understanding, having more conversations with patients and family, more shared decision making and self-determination in their treatment decision. Conclusion: The study highlights that RRMM patients who consider side effects to be very or extremely influential in their treatment decisions report being more proactive in understanding and discussing their treatment options. These patients engage more with healthcare providers, peers, and family members and are granted more time to make informed decisions. This emphasis on understanding and communication underscores the importance of personalized patient education and shared decision-making in the treatment of RRMM, especially for patients who are highly influenced by potential side effects. Together, these findings underscore the ongoing need for patient-centered care and education to optimize treatment choices.

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.

Multiple myeloma (MM) is an incurable cancer of plasma cells with nearly 70% of all new diagnoses occurring in adults aged ≥ 65 years. For older adults, medical comorbidities and functional deficits become increasingly more prevalent with increased age and can impact disease outcomes and survival. There are unmet medical needs in this vulnerable patient population who are not eligible for autologous stem cell transplantation to optimize the frontline therapy for better survival and less toxicity. This randomized phase 3 clinical trial is designed to focus on real world patient population to identify an optimal frontline three drug regimen in frail or a subset of intermediate fit newly diagnosed MM patients. Diagnostic criteria and response criteria will be based on IMWG guidelines. Participants must have a calculated myeloma frailty index (Myeloma Frailty Score Calculator (http://www.myelomafrailtyscorecalculator.net/) categorized as frail or intermediate fit (regardless of age) within 28 days prior to registration (NCT05561387). The two most commonly used induction/maintenance regimens in this patient population will be compared, including RVd-Lite (lenalidomide (R), bortezomib (V), and dexamethasone (dex) followed by R maintenance) and DRd (Daratumumab, lenalidomide, and dex followed by R or R-daratumumab maintenance). The study will include three cohorts: (1) RVd-Lite induction followed by Rev maintenance (2) DRd induction followed by Rev maintenance (3) DRd induction followed by D-R maintenance. Induction phases will be 9 cycles in total of 28 days each, followed by maintenance for cycle 10 and beyond in all cohorts until disease progression: V 1.3 mg/m2 on days 1, 8, 15, 22, R 15 mg days 1-21, dex 20 mg days 1, 8, 15, 22 for induction phase and R 10 mg days 1-21 for maintenance phase in cohort 1 (VRd-Lite); SubQ Dara 1800 mg (on days 1, 8, 15, 22 for C1-2, on days 1, 15 for C3-6, on day 1 for C7-9), R 15 mg day 1-21, dex 20 mg days 1, 8, 15, 22 for induction phase and R 10 mg days 1-21 for maintenance in cohort 2 (DRd-R); SubQ Dara 1800 mg (on days 1, 8, 15, 22 for C1-2, on days 1, 15 for C3-6, on day 1 for C7-9), R 15 mg day 1-21, dex 20 mg days 1, 8, 15, 22 for induction phase and Dara 1800mg on day 1 and R 10mg days 1-21 for maintenance in cohort 3 (DRd-DR). The dual primary objectives are (A) to compare progression free survival (PFS) between cohorts 1 (VRd-Lite) and 2 (DRd-R); (B) to compare overall survival (OS) between cohorts 1 (VRd-Lite) and 3 (DRd-DR). Quality of life objectives are to compare patient reported global health status between treatment arms at the end of induction therapy using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire. A total of 459 eligible patients will be enrolled in this randomized three cohort trial. It is hypothesized that Cohort 1 will have a median PFS of 2.667 years and a median OS of 5 years. With 153 eligible participants per cohort accrued over 5 years, and an additional follow-up period of 3 years, this trial has 80% power to detect an increase in the median PFS in Cohort 2 from 2.667 years to 4 years, and 83.4% power to detect an increase in the median OS in Cohort 3 from 5 years to 8.5 years, each with a one-sided type I error rate of 2%. This trial will be conducted among the NCI cooperative groups SWOG, ALLIANCE, and ECOG/ACRIN and incorporate substantial involvement from NCORP and VA member sites. This study is anticipated to provide practice changing data for this transplant-ineligible real world population to achieve deeper and longer remissions with less side effects and better quality of life.

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.

Abstract Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM), despite common toxicities, including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 mg once weekly was associated with lower mortality than higher doses. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM has not been fully characterized. We conducted a secondary pooled analysis of the SWOG 0777 and SWOG 1211 studies of NDMM, which used lenalidomide and dexamethasone (Rd) alone, with or without bortezomib, and with or without elotuzumab. The planned dexamethasone intensity was 40 to 60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for grade 3+ toxicities per both study protocols). Of the 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There were no differences in PFS or OS between the FD-DEX and LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in the multivariate models were treatment arm, age ≥70 years, and thrombocytopenia. FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given the many toxicities and unclear benefits of dexamethasone in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective studies. These trials were registered at www.clinicaltrials.gov as #NCT00644228 and NCT01668719.

Abstract Artificial intelligence (AI)–enabled interpretation of electrocardiogram (ECG) images (AI-ECGs) can identify patterns predictive of future adverse cardiac events. We hypothesized that such an approach would provide prognostic information for the risk of cardiac complications and mortality in patients undergoing hematopoietic cell transplantation (HCT). We retrospectively subjected ECGs obtained before HCT to an externally trained, deep-learning model designed to predict the risk of atrial fibrillation (AF). Included were 1377 patients (849 autologous [auto] HCT and 528 allogeneic [allo] HCT recipients). The median follow-up was 2.9 years. The 3-year cumulative incidence of AF was 9% (95% confidence interval [CI], 7-12) in patients who underwent auto HCT and 13% (10%-16%) in patients who underwent allo HCT. In the entire cohort, pre-HCT AI-ECG estimate of AF risk correlated highly with the development of clinical AF (hazard ratio [HR], 7.37; 95% CI, 3.53-15.4; P < .001), inferior survival (HR, 2.4; 95% CI, 1.3-4.5; P = .004), and greater risk of nonrelapse mortality (NRM; HR, 95% CI, 3.36; 1.39-8.13; P = .007), without increased risk of relapse. Association with mortality was only noted in allo HCT recipients, where the risk of NRM was greater. The use of cyclophosphamide after transplantation resulted in greater 90-day incidence of AF (13% vs 5%; P = .01) compared to calcineurin inhibitor–based graft-versus-host disease prophylaxis, corresponding to temporal changes in AI-ECG AF prediction after HCT. In summary, AI-ECG can inform risk of posttransplant cardiac outcomes and survival in HCT patients and represents a novel strategy for personalized risk assessment.