Roy, Vivek

Introduction: Myeloma therapeutics have tremendously improved in recent times, leading to unprecedented outcomes. Timely initiation of effective treatment is vital to improving survival and quality of life. Patient refusal to receive treatment is infrequent but certainly leads to increased morbidity/mortality. We studied factors associated with treatment refusal. Methods: The National Cancer Database (NCDB) was queried for adult patients diagnosed with MM between 2004-2021. Those who refused treatment for initial management despite physician's recommendation were identified. Patients with multiple primary malignancies or unknown treatment status were excluded. Patients' demographics and socioeconomic factors were collected. Kaplan-Meier and multivariate Cox regression were used to evaluate the likelihood of treatment refusal in the whole cohort and in each racial/ethnic group. Results: Out of 86,350 eligible patients with MM who were recommended to initiate therapy, 2,508 (2.9%) did not receive any treatment due to refusal. Of these, 52.6% were females, 64% were non-Hispanic White (NHW), 21.3% were non-Hispanic African American (NHAA), and 5.2% were Hispanic. On multivariate analysis, patients who were treated at comprehensive and integrated facilities were more likely to refuse treatment as compared to those at academic facilities (OR=1.36; 95% CI: 1.22-1.52, p<0.001 and OR=1.22; 95% CI: 1.07-1.4, p=0.004, respectively). Patients on Medicare (OR=1.42; 95% CI: 1.16-1.73, p<0.001), and presence of higher Charlson Comorbidity Index (CCI) also had a higher likelihood of refusing treatment. Lower refusal rates were seen for male gender (OR=0.83; 95% CI: 0.76-0.91, p<0.001), NHW racial/ethnic group (as against NHAA; OR=0.34; 95% CI: 0.16-0.71, p=0.004), being insured (OR=0.69; 95% CI: 0.52-0.93, p=0.015), having private insurance (compared to Medicaid; OR=0.47; 95% CI: 0.38-0.59, p<0.001) and having a higher income level (OR=0.82; 95% CI: 0.70-0.96, p=0.013). Among NHAA patients, 2.8% refused treatment and were more likely to have Medicare (OR=1.4; 95% CI: 1.03-1.9, p=0.032). Having private insurance (compared to Medicaid; OR=0.61; 95% CI: 0.43-0.88, p=0.008) had a lower likelihood of refusing treatment. Among NHW, 2.9% refused treatment and they were more likely to be treated at community, comprehensive and integrated facilities compared to academic facilities (OR=1.39; 95% CI: 1.12-1.73, p=0.003, OR=1.54; 95% CI: 1.33-1.77, p<0.001 and OR=1.38; 95% CI: 1.16-1.64, p<0.001, respectively), be from rural areas (OR=1.43; 95% CI: 1.05-1.96, p=0.025), and have a higher CCI. On the other hand, male gender (OR=0.79; 95% CI: 0.72-0.89, p<0.001), private insurance (compared to Medicaid; OR=0.42; 95% CI: 0.30-0.59, p<0.001) and higher income level (OR=0.80; 95% CI: 0.66-0.98, p=0.029) had a lower likelihood of refusing treatment. Among Hispanic patients, 2.3% refused treatment and were more likely to have Medicare (OR=1.96; 95% CI: 1.13-3.4, p=0.016), while those with private insurance (compared to Medicaid; OR=0.32; 95% CI: 0.14-0.73, p=0.007) had a lower likelihood of refusing treatment. Conclusions: This large real-world analysis highlights the intricate sociodemographic and economic factors that affect the decision of a MM to not proceed with the recommendation for treatment. (1) NHW are less likely to refuse treatment as compared to NHAA. (2) Insurance status is an important driver of refusal and transcends race/ethnicity. Furthermore, in this study, we highlight characteristics that are specific to different racial/ethnic groups like CCI which affect only certain racial/ethnic groups. This provides an opportunity to develop targeted interventions such that the benefit of therapeutic advancements can be realized by all.

Background: Venetoclax (Ven), a BCL2 inhibitor, has shown promising responses in multiple myeloma (MM) patients with t(11;14) and/or BCL2 expression. However, consistent benefit in clinical trials remain elusive. This report evaluates the efficacy and safety of Ven combination therapies, including in the non-t(11;14) subgroup, and examines the impact of secondary cytogenetic abnormalities (SGA) on outcomes. Methods: This retrospective study included multiple myeloma (MM) patients without concurrent AL amyloidosis treated with Ven-based combinations at Mayo Clinic sites from January 2015 to December 2023. FISH data was collected at diagnosis and before venetoclax initiation to assess SGAs. Refractoriness was defined by progression on or within 60 days of stopping treatment. Patients refractory to at least one proteasome inhibitor (PI), immunomodulatory drug (ImiD), and anti-CD38 antibody were considered triple-class refractory (TCR). Ven combinations were grouped as: Daratumumab/CD38 antibody (Dara)-Ven based if received Dara ± other drugs, PI-Ven-based without Dara, Ven-dexamethasone (Ven-d), and other combinations (Ven-Misc). BCL2 expression in patients without t(11;14) was determined by immunohistochemistry (IHC). Progression-free survival (PFS) was calculated from treatment initiation to disease progression or last follow-up. Results: We included 232 patients in this study. The median age at diagnosis of MM was 62 years (range 32-87), and the median age at initiation was 68 years (range 35-89). The median time from diagnosis of MM to initiation of Ven was 55 months (95% CI 28, 89 months), and the median follow-up from initiation of Ven-based treatment was 17.2 months (95% CI: 14, 22). Patients had received a median of 3 lines (IQR 4-6); 65% (n=152) of patients were TCR, 71% (n=163) had received autologous stem cell transplant and 7% (n=16) patients had received prior immune effector therapy prior to initiation of Ven-based therapy. The majority (83%, n=190) of the patients harbored a t(11;14); in the patients without t(11;14), a BCL2 expression by IHC was tested in 18 patients and positive in 17 patients. The most common Ven-based combinations included: Dara-Ven-d (19%, n=44), PI-Ven-d (30.2%, n=70), Ven-d (48.3%, n=112), Ven-misc (2.6%, n=6). The overall response rate for the entire cohort was 57% [64% for t(11;14) and 26% for non t(11;14), p<0.0001]. The median PFS for the entire cohort was 9.5 months (95% CI 8.5,13), and the duration of response was 18 months (95% CI 15.2-23.3). The median PFS was 11.8 months (95% CI 9.5-16.7) for patients harboring a t(11;14) compared to 2.9 months (95% CI 1.8, 8.4) for patients without a t(11;14), p<0.0001. Among the non-t(11;14) cohort with BCL2 expression, the median PFS was 1.8 months (95% CI: 1.2-4.2). Among the 190 patients with t(11;14), 18% (34/190) harbored deletion 17p and 32% (60/193) harbored a 1q gain/amplification (referred hereforth as 1q21+) at initiation of Ven-based therapy. In the cohort of patients with t(11;14), the presence of either del17p or 1q21+ (n=85/190) was associated with a significantly inferior PFS [median PFS 8.2 months (95% CI: 5.5,13)] vs. 15.1 months (95% CI: 11.6, 22), p=0.03. At the last follow-up,42 patients had ongoing treatment with ven-based combination. Most common reasons for discontinuation were progression (77% N=140), adverse effect (12%, n=22), patient/provider preference(9%, n=17); 2% (n=4) patients died without progression (3 infection, 1 unclear). The most commonly utilized maximum dose of venetoclax was 400 mg (42%); 15% (n=35) of patients required a dose reduction, and 23% (n=54) received a ramp-up. Tumor lysis syndrome was not noted in any patient. Infectious complications were noted in 23% (n=52). The estimated median OS from initiation of ven-based Rx was 34 months (95%CI 25-47). The estimated median OS for patients without a t(11;14) was 6.2 months (95% CI: 3.3-11.3) compared to 46 months (31.4-54.1), p<0.0001. In the t(11;14) subgroup, the 18-month OS rate was 79% for patients without 1q21+/del17p vs. 50% for patients with a 1q21+/del17p (p=0.002). Conclusion: Venetoclax-based regimens represent an important treatment option for patients harboring a t(11;14). The PFS in patients with BCL2 expression without t(11;14) was poor suggesting lack of efficacy of venetoclax-based regimens for that subgroup. Presence of concurrent del17p and/or 1q21+ with t(11;14) portends an inferior PFS.

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.

Introduction: Ven is a BCL2 inhibitor that has shown clinical efficacy in RRMM patients (pts) particularly those that harbor t(11;14). Ven has been evaluated in clinical trials as a single agent, in combination with dexamethasone (dex), immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and anti-CD38 monoclonal antibodies (MAb) yet its place in the therapeutic landscape remains in question. In this retrospective analysis, we aim to evaluate the real-world efficacy of Ven-based regimens in RRMM pts treated outside of a clinical trial across the 3-site MCCC. Methods: We retrospectively analyzed the medical records of pts with RRMM treated with Ven-based regimens between January 2015 and October 2023 at the MCCC. Refractoriness was defined by progression on or within 60 days of stopping treatment. Categorical variables were compared with Chi-square tests and continuous variables were compared with t-tests. Outcomes were estimated using the Kaplan-Meier method and curves were compared between the groups using log-rank tests. Results: 83 pts were included in the analysis. The median age was 71 (39-93), 63% were male, 93% were white, 27% had ISS III, 18% had high risk cytogenetics (HRCyto), 76% had t(11;14), the median prior lines of therapy (LOT) was 4 (1-15), 68% received ≥ 4 prior LOT, 87% received prior autologous transplant, 58% were triple-class refractory (TCR), 64%/23% were penta-drug exposed/refractory (PDE/R), 8% received prior BCMA-directed therapies (BDT), 58% received Ven+dex, 25% received Ven+PI +/-dex, 6 % received Ven+anti-CD38 MAb+/-dex and 11% received Ven+other. The median follow-up time from start of a Ven-based regimen was 29 months (mo). The median Ven dose was 800mg (20-1600) with 25% of pts receiving Ven ramp-up dosing. The overall response rate (ORR) to a Ven-based regimen was 58% and was 64% for pts with t(11;14) and 40% for pts without t(11;14); p=0.06. Ven-treated pts with HRCyto had inferior PFS (3mo) and OS (8mo) compared to patients who did not have HRCyto who had a PFS of 9mo (p=0.020) and OS of 80mo (p<0.001). The ORR for TCR and PDR pts were 52% and 42%, respectively. No significant ORR differences were noted across the different Ven-based regimens (p=0.32). The median PFS for pts with t(11;14) was 10mo compared to 2mo for pts w/o t(11;14); p=<0.001. The median OS for pts with t(11;14) was 80mo compared to 10mo for pts without t(11;14); p=0.001. Ven-treated pts who received 1-3 prior LOT has superior ORR, median PFS, and median OS; 89%, 25mo, and 99mo, respectively, compared to pts who received ≥4 prior LOT who achieved an ORR of 43% (p<0.001), median PFS of 5mo (p<0.001) and median OS of 25mo (p<0.001). Ven-treated pts that were TCR had inferior PFS (5mo) and OS (26mo) compared to pts who were not TCR who achieved a PFS of 12mo (p<0.001) and a median OS of 80mo (p=0.02).Ven-treated pts that were PDR had inferior PFS (4mo) and OS (22mo) compared to pts who were not PDR who achieved a PFS of 9mo (p<0.001) and a median OS of 80mo (p=0.02).Ven-treated pts who received prior BDT (n=7) achieved an ORR of 29% and had a median PFS and OS of 2mo and 6mo, respectively on a Ven-based therapy. 59 pts received additional therapy in the post Ven-progression setting. The ORR to post-Ven progression therapies was 53% (n=31/59), the median PFS was 9mo and median OS was 35mo. The most common post-Ven progression regimens used were PI-based (n=16; ORR=56%), anti-CD38 MAb-based (n=14; ORR=50%), BDT (n=12; ORR=83%), selinexor-based (n=3; ORR=0%) with BDT resulting in highest ORR (p=0.048) and PFS (p=0.005). Conclusions: Ven-based regimens are effective in heavily pre-treated pts with RRMM however they are more effective when used within 1-3 prior LOT, in pts with t(11;14), and in pts without HRCyto, TCR or PDR MM. BDT appear to be the most efficacious therapies in the post-Ven progression setting.

Background: Mature T-cell lymphomas (MTL) are a heterogenous group of diseases representing about 10-20% of non-Hodgkin lymphomas (NHL). Standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy yields poor long-term outcomes. Allogeneic hematopoietic cell transplantation (allo-HCT) is often considered as consolidation to improve outcomes, especially in younger patients. Methods: The study included adult patients (pts) with MTL who received an allo-HCT at Mayo Clinic (Rochester, Arizona and Florida) and the City of Hope Cancer Center between 2007 and 2023. Patients with cutaneous T-cell lymphomas (mycosis fungoides/Sezary syndrome) were excluded. The primary aim of the study was to evaluate long-term outcomes of allo-HCT in patients with MTL. Primary endpoints included progression-free (PFS), overall survival (OS), relapse rates, non-relapse mortality (NRM), and cumulative incidence of acute and chronic graft vs host disease (aGVHD and cGVHD). Our second aim was to assess the impact of specific disease and transplant related factors on outcomes of allo-HCT in MTL. These included a) disease status prior to allo-HCT, b) the intensity of the conditioning regimen, c) inclusion of total body irradiation (TBI) in conditioning regimens and the use of posttransplant cyclophosphamide (PTCy) based GVHD prophylaxis Results: A total of 75 pts, median age 48 (22-72) years, with MTL underwent allo-HCT between 2007 and 2023 and were included in the study population. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS; n=42, 56%) was the most common histology followed by angioimmunoblastic T cell lymphoma (AITL; n=13, 17%). Patients had a median of 3 (range 1-8) prior therapies and 26 (35%) pts had undergone a prior autologous HCT (auto-HCT). At the time of allo-HCT, 45 (63%) pts were in complete remission (CR) and 26 (36%) pts were in partial remission (PR). The most common donor source was HLA-matched unrelated donor (MUD; n=34, 45%) and matched related (MRD; n=24, 32%) followed by haploidentical donors (haplo; n=8, 10.7%), mistmatched unrelated donors (MMUD; n=7, 9.3%) and umbilical cord blood (UCB; n=2, 2.6%). Fifty-four pts (72%) received reduced intensity conditioning (RIC) and 20 (26.7%) received total body irradiation as part of their conditioning regimen. The median radiation dose was 1200cGy. Ten pts (13%) received PTCy-based GVHD prophylaxis. Median follow-up of was 3 yrs (0.05-11.34). The 5-yr PFS and OS were 64.2% (53.5%-77%) and 71.3% (61.3%-82.9%), respectively; cumulative incidence of relapse and NRM were 14.5% (5.2 - 23%) and 23.5% (12.2%-33.4%), respectively. Cumulative incidence of grade II-IV and grade III-IV aGVHD at 100 days was 45.3% (32.3%-55.9%) and 9.8% (2.6%-16.5%), respectively. One-year rate of all grade cGVHD was 50.7% (36.5%-61.8%). Patients who underwent allo-HCT while in complete remission compared to those in partial remission were noted to have superior survival with OS of 77.4% vs. 60.7% (p=0.022); no difference was noted between the two groups regarding PFS and incidence of relapse. No difference in long-term outcomes was observed based on the intensity of conditioning regimens but patients who received conditioning regimens containing TBI vs those who did not were noted to have inferior PFS of 44.9% vs 70.5% (p=0.019), with no difference in OS (58.4% vs 75.6% [p=0.059]), relapse rates (30.4% vs 10.7% [p=0.086]) and NRM (30.5% vs 20.3% [p=0.18]). Patients who received PTCy based vs. non-PTCy based GVHD prophylaxis had lower rates of chronic GVHD at 1 yrs (22% vs 56% [p=0.038]) with no difference in other outcomes. Conclusion: Results of our analysis show that allo-HCT represents a curative option for patients with MTL with excellent long-term outcomes. These outcomes were further improved for patients who achieved a complete remission prior to allo-HCT. The intensity of the conditioning regimen did not affect outcomes but TBI containing conditioning regimens were associated with adverse PFS. Within the limitations of a retrospective analysis and a relatively small sample, these data suggest that, a non-TBI RIC regimen, especially when combined with PTCy based GVHD prophylaxis can lead to long term disease control with limited morbidity.

Introduction: Overall outcomes have improved significantly for MM with a 5-year relative survival rate currently of >60%. With effective treatments, patients from all clinical strata and age groups are expected to have meaningful benefit, but despite excellent therapeutic advancements, some patients continue to have early mortality. We conducted this study to investigate factors associated with early mortality. Methods: The National Cancer Database (NCDB) was queried for adult patients with NDMM between 2004 and 2021. We excluded patients with multiple primary malignancies or lost to follow-up (unknown vital status or last contact). Early mortality was defined as death within 6 months from MM diagnosis. Patient demographics and socioeconomic factors available in NCDB were collected. Kaplan-Meier and multivariate Cox regression were used to evaluate the likelihood of early mortality in this large cohort of MM patients using multi-variate analysis. Results: Out of 255,579 eligible patients with MM, 35,302 (13.8%) died within the first 6 months of diagnosis and 108,534 (42.5%) died after the first 6 months of MM diagnosis. The early mortality cohort had significantly higher mean age at MM diagnosis (73.9 vs. 68.5 years, p<0.001) but no significant differences were noted for gender distribution. There was a statistically significant difference for racial/ethnic distribution (p=0.019), but the percentages were very similar among non-Hispanic White (69% vs 68.1%), non-Hispanic African American (18% vs 18.7%) and Hispanic patients (4.7% vs 4.8%). Patients in the early mortality cohort were less likely to be treated at academic institutions (28.4% vs 37.8%, p<0.001) and have significantly different distribution by insurance type (less likely to have private insurance; 17.3% vs. 30%, more likely to have Medicare; 72.1% vs. 58.7%, p<0.001) although overall insurance access was similar between the two groups (95.3% vs 95.2%, p=0.283). Early mortality was associated with higher morbidity scores as per the Charlson-Comorbidity Index (CCI) (p<0.001) and were more likely to have not received any treatment for MM (53.2% in early mortality group vs. 28.4% in late mortality, p<0.001). Early mortality was also associated with a lower literacy rate (high school graduation rate 21.2% vs. 19.7%, p<0.001) and lower household income (<$46,277; 19.1% vs. 17.7%, p<0.001). Conclusion: This large real-world analysis shows that despite therapeutic advances in recent years, there is a significant percentage of patients with NDMM in the U.S. who suffer from early mortality. There are several sociodemographic and economic factors that were found to be associated with early mortality, with some showing clear trends (older age, treatment facility type, insurance type, income, education, CCI), while others like racial differences were significant but somewhat ambiguous. Identifying and addressing these factors at diagnosis will help provide personalized care plans and minimize early mortality.

SummaryThis phase II study evaluated time‐limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow‐up time of 25.7 months, the median progression‐free survival (PFS) was 22.9 months. While the primary end‐point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton's tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM.

AbstractAimThe aim of study was to investigate whether depression and anxiety symptoms and illness perception prior to hematopoietic stem cell transplantation (HSCT) predict health related quality of life (HRQOL) at Day 100 and 1 year following HSCT.MethodsA total of 205 patients who underwent HSCT (N = 127 autologous transplants, N = 78 allogeneic transplants) were included in this prospective study. Baseline assessment was assessed prior to transplantation and post HSCT data were collected at Day 100 and 1 year. At baseline we assessed depressive symptoms (Patient Health Questionnaire‐9), anxiety symptoms (Generalized Anxiety Disorder‐7), illness perception (Brief Illness Perception Questionnaire), and HRQOL (Functional Assessment of Cancer Therapy‐BMT).ResultsPatients who expressed a greater level of concern about the severity, course, and ability to exert control over one's illness (i.e., illness perception) and who reported a greater level of depression and anxiety symptoms prior to HSCT reported lower HRQOL at both Day 100 and 1 year posttransplant, with a similar degree of association observed at the two follow‐up time points.ConclusionsOur findings suggest that pretransplant perceptions about their illness and negative mood are significant predictors of HRQOL following HSCT. Illness perception, depression, and anxiety are potentially modifiable risk factors for less than optimal outcome after HCSCT and intervention strategies should be explored.

Abstract Rationale Pulmonary complications contribute significantly to nonrelapse mortality following hematopoietic stem cell transplantation (HCT). Identifying patients at high risk can help enroll such patients into clinical studies to better understand, prevent, and treat posttransplantation respiratory failure syndromes. Objectives To develop and validate a prediction model to identify those at increased risk of acute respiratory failure after HCT. Methods Patients underwent HCT between January 1, 2019, and December 31, 2021, at one of three institutions. Those treated in Rochester, MN, formed the derivation cohort, and those treated in Scottsdale, AZ, or Jacksonville, FL, formed the validation cohort. The primary outcome was the development of acute respiratory distress syndrome (ARDS), with secondary outcomes including the need for invasive mechanical ventilation (IMV) and/or noninvasive ventilation (NIV). Predictors were based on prior case-control studies. Measurements and Main Results Of 2,450 patients undergoing stem cell transplantation, there were 1,718 hospitalizations (888 patients) in the training cohort and 1,005 hospitalizations (470 patients) in the test cohort. A 22-point model was developed, with 11 points from prehospital predictors and 11 points from posttransplantation or early (<24-h) in-hospital predictors. The model performed well in predicting ARDS (C-statistic, 0.905; 95% confidence interval [CI], 0.870–0.941) and the need for IMV and/or NIV (C-statistic, 0.863; 95% CI, 0.828–0.898). The test cohort differed markedly in demographic, medical, and hematologic characteristics. The model also performed well in this setting in predicting ARDS (C-statistic, 0.841; 95% CI, 0.782–0.900) and the need for IMV and/or NIV (C-statistic, 0.872; 95% CI, 0.831–0.914). Conclusions A novel prediction model incorporating data elements from the pretransplantation, posttransplantation, and early in-hospital domains can reliably predict the development of post-HCT acute respiratory failure.