Pederson, Levi D

Abstract Patients with multiple myeloma have an elevated risk of severe complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) infection. To demonstrate proof of concept for a pandemic preparedness and response network, the American Society of Hematology Research Collaborative Multiple Myeloma Program developed a prospective, decentralized study within a site-based provider network. In the COVID-19 outcomes in myeloma and the impact of vaccines (COSMIC) study, patients provided consent, permitted electronic health record data collection, completed patient-reported outcomes at baseline, day 30, and day 180 through an electronic study portal, and were compensated for participation. Clinicians at participating sites facilitated study recruitment and shared best practices monthly to accelerate study execution. The COSMIC study rapidly consented 201 patients from 8 participating sites over 4 months (22 January 2024 through 17 May 2024). Consented participants were 30 to 93 years old, with a median age of 67; 46% were female, 69% were non-Hispanic White, 17% were non-Hispanic Black, and 8% were Hispanic/Latino. Patient-reported data completion was 97% at baseline, 81% at 1 month, and 79% at 6 months. At baseline, 55% of patients reported a history of COVID-19 infection and had received a median of 4 SARS-CoV-2 vaccines. For all patients, there were an additional 18 COVID-19 infections and 57 vaccines received during the 6-month observation period. There were no significant differences in health-related quality of life over time or by history of COVID-19 infection. COSMIC demonstrates the feasibility of an innovative evidence generation strategy to drive rapid accrual of patients to address an evolving area of need. This trial was registered at www.clinicaltrials.gov as #NCT05831787.

Abstract Combination therapy incorporating programmed cell death protein 1 (PD-1) blockade results in unprecedented response rates in both frontline and relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). Previous retrospective studies have suggested benefit for PD-1 blockade before autologous stem cell transplant (ASCT) but included few patients receiving PD-1 blockade with cytotoxic chemotherapy. To explore the impact of anti–PD-1 based salvage on outcomes for patients with R/R cHL, we retrospectively reviewed 1280 patients with R/R cHL who underwent ASCT from 2010 to 2022 at 6 transplant centers, none of whom received PD-1 blockade as part of frontline therapy. Overall, 25% received a PD-1 inhibitor at any point before ASCT (10% in conjunction with chemotherapy), 28% received salvage brentuximab vedotin (BV) without PD-1 blockade, and the rest received salvage chemotherapy alone. Patients who received PD-1 inhibitors at any point before ASCT had a significantly higher 2-year progression-free survival than those who received BV without PD-1 inhibitors or patients receiving chemotherapy alone (88.2%, 70.2%, and 67.4%, respectively; P< .0001). When restricted to patients in complete response before ASCT, the benefit of PD-1 blockade remained significant. PD-1 blockade before ASCT is independently associated with superior post-ASCT outcomes and patients proceeding to ASCT should be treated with PD-1–based salvage.

ABSTRACT As the treatment paradigm for Waldenström macroglobulinemia (WM) continues to evolve, the debate surrounding the prioritization of depth of response versus disease control as therapeutic goals gains significant relevance. However, the impact of depth of response from fixed‐duration therapy on overall survival (OS) was unclear. This multicenter study evaluated the prognostic impact of depth of response using a landmark survival analysis. A total of 440 patients with WM treated with frontline fixed‐duration regimens were included. Attaining a major response (MaR) was associated with superior outcomes, including significantly longer OS. The estimated 5‐year PFS rates for patients with MaR at 6 months versus not were 50% versus 32%, respectively, p < 0.001, and the estimated 5‐year OS rates for patients with MaR at 6 months versus not were 89% versus 70%, respectively, p < 0.001. In a multivariable analysis, MaR at 6 months was independently associated with superior PFS (HR 0.66, p = 0.007) and OS (HR 0.28, p < 0.001). Similar results were seen when considering deeper responses (CR + VGPR vs. PR). Depth of response at 6 months is an important prognostic marker in WM and an independent predictor of PFS and OS. These results support its utilization as a suitable endpoint in clinical studies in WM.

PURPOSE Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease–negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM. PATIENTS AND METHODS Individual patient data from 20 randomized multicenter trials were collected. Eleven studies (4,773 patients) with sufficient data were analyzed to evaluate whether 9- or 12-month MRD-CR classified at a 10 –5 threshold could be reasonably likely to predict the clinical benefit of new agents regarding PFS and OS. Global odds ratio (OR) was estimated using the bivariate Plackett Copula model. Supportive evaluation included correlations of the treatment effects on MRD-CR end points and PFS/OS, evaluated by both linear regression ( R 2 weighted least squared ) and Copula ( R 2 Copula ) models. RESULTS The analysis demonstrated that both 9- and 12-month MRD-CR strongly correlated with PFS at patient level in NDTE patients, NDTinE patients, and patients with RRMM. Global ORs ranged from 3.06 to 16.24, all with 95% CIs excluding 1.0. Encouraging trial-level correlations ( R 2 , 0.61-0.70) were observed by pooling three populations and were stronger ( R 2 , 0.67-0.78) in the ND population. Similar results were observed for OS. CONCLUSION Our findings provided the support for use of MRD-CR classified at a 10 –5 threshold at either 9 or 12 months after starting of the treatment, as an intermediate end point to support accelerated approvals, in future trials in NDTE patients, NDTinE patients, and patients with RRMM.

PURPOSE A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

AbstractBackgroundQuantitative methods of Fluorodeoxyglucose Positron Emission Tomography (FDG‐PET) interpretation, including the percent change in FDG uptake from baseline (ΔSUV), are under investigation in lymphoma to overcome challenges associated with visual scoring systems (VSS) such as the Deauville 5‐point scale (5‐PS).MethodsIn CALGB 50303, patients with DLBCL received frontline R‐CHOP or DA‐EPOCH‐R, and although there were no significant associations between interim PET responses assessed centrally after cycle 2 (iPET) using 5‐PS with progression‐free survival (PFS) or overall survival (OS), there were significant associations between central determinations of iPET ∆SUV with PFS/OS. In this patient cohort, we retrospectively compared local vs central iPET readings and evaluated associations between local imaging data and survival outcomes.ResultsAgreement between local and central review was moderate (kappa = 0.53) for VSS and high (kappa = 0.81) for ∆SUV categories (<66% vs. ≥66%). ∆SUV ≥66% at iPET was significantly associated with PFS (p = 0.03) and OS (p = 0.002), but VSS was not. Associations with PFS/OS when applying local review vs central review were comparable.ConclusionsThese data suggest that local PET interpretation for response determination may be acceptable in clinical trials. Our findings also highlight limitations of VSS and call for incorporation of more objective measures of response assessment in clinical trials.

AbstractThe combination of pomalidomide (POM) and dexamethasone (DEX) was evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) to determine the maximal tolerated dose (MTD) of POM as the primary objective, and overall response rate (ORR), progression-free survival (PFS), and safety profile as secondary objectives. A cohorts-of-3 study design was used with a dose-escalation schedule consisting of POM (3, 5, 7, or 10 mg) orally daily for 21 days every 28 days and DEX 40 mg orally every week. After 2 cycles, POM was continued alone until disease progression, intolerance, or subject withdrawal. Following MTD determination, the MTD cohort was expanded. Twenty-five of 29 patients with the median of 3 prior treatments were eligible for assessment as per international PCNSL collaborative group criteria. The MTD of POM was 5 mg daily for 21 days every 28 days. Whole-study ORR was 48% (12 of 25; 95% confidence interval [CI], 27.8%, 68.7%) with 6 complete response (CR), 2 complete response, unconfirmed (CRu), and 4 partial response (PR). MTD cohort ORR was 50% (8 of 16; 95% CI, 24.7%, 75.4%) with 5 CR, 1 CRu, and 2 PR. Median PFS was 5.3 months (whole study) and 9 months (for responders). One patient had pseudoprogression. Grade 3/4 hematologic toxicities included neutropenia (21%), anemia (8%), and thrombocytopenia (8%). Grade 3/4 nonhematologic toxicities included lung infection (12%), sepsis (4%), fatigue (8%), syncope (4%), dyspnea (4%), hypoxia (4%), respiratory failure (8%), and rash (4%). POM/DEX treatment is feasible with significant therapeutic activity against relapsed/refractory PCNSL and PVRL. This trial was registered at www.clinicaltrials.gov as #NCT01722305.

AbstractPatients with relapsed aggressive non‐Hodgkin lymphoma (NHL) are often treated with platinum‐based chemoimmunotherapy regimens in preparation for autologous stem cell transplant. We sought to reduce toxicity and maintain efficacy by using oxaliplatin with rituximab, cytarabine and dexamethasone (ROAD) in a phase II clinical trial in patients who had relapsed after one prior regimen. ROAD was delivered q21 days and consisted of rituximab 375 mg/m2 IV weekly x 4 doses (cycle 1 only); dexamethasone 40 mg PO/IV d2 – 5; oxaliplatin 130 mg/m2 IV day 2; cytarabine 2000 mg/m2 IV × two doses on days 2 to 3; and pegfilgrastim 6 mg SC on day 4. Forty‐five eligible patients were accrued between 2006 and 2008. Patient characteristics were a median age of 69 years; 96% had received prior rituximab; 53% were within one year of diagnosis. The median number of cycles received was 2 (range, 1‐6). Forty‐four % received ROAD as an outpatient. The overall response rate was 71% with 27% (12/45) CR and 44% (20/45) PR. Forty‐four % (20/45) of all patients and 69% (18/26) of patients whom responded after 2 cycles proceeded to transplant. Median overall survival was 26 mos (95% CI: 7.3 mos—not reached) and median progression‐free survival was 11 mos (95% CI: 6—104 mos). There was no grade 3/4 nephrotoxicity; the rate of grade 3/4 neuropathy was 4%. Forty‐two percent of all patients and 69% of patients transplanted remain alive at 5 years. ROAD represents an acceptable salvage therapeutic option for patients with relapsed aggressive NHL.