Final analysis of a phase II trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma without transplant.

We evaluated the efficacy and safety of 24 cycles of Dara in combination with carfilzomib (K), lenalidomide (R), and dexamethasone (d) without autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma (NDMM) irrespective of ASCT eligibility in a single-arm, phase II study. The primary endpoint was the rate of stringent complete response (sCR) and/or measurable residual disease (MRD) < 10-5 by next-generation sequencing (NGS) at the end of cycle 8 (C8). MRD was also assessed on peripheral blood samples using both the EXENT® system and liquid chromatography-mass spectrometry (LC-MS). Forty-two patients entered the treatment phase; forty were evaluable for the primary endpoint. The rate of sCR and/or MRD < 10-5 following C8 was 30/40 (75%), meeting the statistical threshold for efficacy. The 10-6 MRD negative rate improved with treatment beyond C8. Agreement between EXENT® and NGS was high and increased over time; agreement between LC-MS and NGS was lower. The estimated 3-year progression-free survival progression-free survival was 85%, and 3-year overall survival was 95%. Upper respiratory infections occurred in 67% (7% grade 3-4). There were no treatment-related deaths. Extended frontline Dara-KRd induced a high rate of sCR and/or MRD negativity; the rate and depth of MRD negativity improved beyond C8.

The CNS relapse in T-cell lymphoma index predicts CNS relapse in patients with T- and NK-cell lymphomas.

ABSTRACT: Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Mixed-Methods Study of End-of-Life Experiences of Patients With Hematologic Malignancies in Social Hospice Residential Home Care Settings.

PURPOSE: Hospice is underutilized by patients with hematologic malignancies (HM), and when patients are referred, they are typically more ill, hospitalized, and with shorter length of stay (LOS) than patients with solid tumors (ST), limiting research about home hospice care experiences of patients with HM. In this mixed-methods study, we examined the hospice experiences of patients with HM who died at residential care homes (RCHs), home-based settings in which volunteer caregivers and hospice staff provide end-of-life (EOL) care under the social hospice model. METHODS: We queried a registry of 535 hospice patients who died at RCHs between 2005 and 2020 that included quantitative medication administration data as well as qualitative data from hospice intake forms and written volunteer caregiver narratives. Qualitative data were analyzed by collective case study methodology. Quantitative comparisons of LOS and liquid morphine use were performed with matched patients with ST. RESULTS: The registry yielded 29 patients with HM, of whom qualitative data were available for 18 patients. Patients with HM exhibited common EOL symptoms (pain, dyspnea, and agitation). Instances of bleeding were low (22%), and notable HM-specific care concerns were described regarding bone fractures, skin integrity, and delirium. Most (78%) experienced good symptom management and peaceful or comfortable deaths. In only one case were symptoms described as severe and poorly managed. Patients with HM had comparable LOS on hospice and at the RCHs to patients with ST, with no group differences in liquid morphine use. CONCLUSION: In this registry cohort, most patients with HM achieved good symptom management in home care settings with volunteer caregivers and hospice support. Caregivers may require additional counseling and palliative medications for HM-specific EOL symptoms.

Multi-gene measurable residual disease assessed by digital polymerase chain reaction has clinical and biological utility in acute myeloid leukemia patients receiving venetoclax/azacitidine.

Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broadscale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital polymerase chain reaction (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.

Selection of bispecific antibody therapies or CAR-T cell therapy in relapsed lymphomas.

Patients with relapsed and refractory (R/R) aggressive B-cell non-Hodgkin lymphomas have historically poor survival outcomes, with chimeric antigen receptor T-cell (CAR-T) therapy now presenting a curative option for a subset of those patients. However, with the approval of several novel bispecific monoclonal antibody (BsAb) therapies with considerable activity in R/R aggressive large B-cell lymphomas (LBCL), patients and oncologists will be faced with decisions regarding how to sequence CAR-T and BsAb therapies based on patient- and disease-related factors. In this review, we compare CAR-T and BsAb therapies for R/R LBCL, highlighting data on the efficacy and toxicity of each treatment paradigm, and provide a roadmap for sequencing these highly effective therapies.

Dynamic frailty risk assessment among older adults with multiple myeloma: A population-based cohort study.

Multiple myeloma (MM) is a cancer of older adults and those who are more frail are at high risk of poor outcomes. Current tools for identifying and categorizing frail patients are often static and measured only at the time of diagnosis. The concept of dynamic frailty (i.e. frailty changing over time) is largely unexplored in MM. In our study, adults with newly-diagnosed MM who received novel drugs between the years 2007-2014 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Using a previously published cumulative deficit approach, a frailty index score was calculated at diagnosis and each landmark interval (1-yr, 2-yr, 3-yr post diagnosis). The association of frailty with overall survival (OS) both at baseline and at each landmark interval as well as factors associated with worsening frailty status over time were evaluated. Overall, 4617 patients were included. At baseline, 39% of the patients were categorized as moderately frail or severely frail. Among those who had 3 years of follow-up, frailty categorization changed post diagnosis in 93% of the cohort (78% improved and 72% deteriorated at least at one time point during the follow up period). In a landmark analysis, the predictive ability of frailty at the time of diagnosis decreased over time for OS (Harrell's C Statistic 0.65 at diagnosis, 0.63 at 1-yr, 0.62 at 2-yr, and 0.60 at 3-yr) and was inferior compared to current frailty status at each landmark interval. Our study is one of the first to demonstrate the dynamic nature of frailty among older adults with MM. Frailty may improve or deteriorate over time. Current frailty status is a better predictor of outcomes than frailty status at time of diagnosis, indicating the need for re-measurement in this high-risk patient population.

Efficacy of checkpoint inhibition after CAR-T failure in aggressive B-cell lymphomas: outcomes from 15 US institutions.

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes.

EBV-positive PCNSL in older patients: incidence, characteristics, tumor pathology, and outcomes across a large multicenter cohort.

The objective of this multicenter retrospective study was to examine the incidence, patient characteristics, pathology, and outcomes associated with Epstein-Barr virus (EBV)-related CNS lymphoma (CNSL) in older patients. Among 309 CNSL patients aged ≥60, 11.7% had EBV + tumors of which 72.2% were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD). Younger age, SOT or autoimmune disease, and immunosuppressive treatment correlated highly with EBV-positivity. EBV + tumors were associated with absent C-MYC and BCL6 expression. EBV + PTLD was more likely to be associated with the absence of CD5 expression. EBV + non-PTLD had better median OS (not reached) compared to EBV + PTLD (10.8 months) and EBV-negative patients (43 months). Multivariable Cox regression analysis showed that age, performance status, and PTLD were negative predictors of OS. EBV status and immunosuppressive treatment were not correlated with OS. Our findings merit further investigation of EBV + PCNSL tumors and EBV-directed therapies.

Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 U.S. cancer centers.

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.

Rational Targets of Therapy in Extranodal NK/T-Cell Lymphoma.

Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) with poor outcomes, particularly in advanced-stage and relapsed/refractory disease. Emerging research on molecular drivers of ENKTL lymphomagenesis by next-generation and whole genome sequencing has revealed diverse genomic mutations in multiple signaling pathways, with the identification of multiple putative targets for novel therapeutic agents. In this review, we summarize the biological underpinnings of newly-understood therapeutic targets in ENKTL with a focus on translational implications, including epigenetic and histone regulatory aberrations, activation of cell proliferation signaling pathways, suppression of apoptosis and tumor suppressor genes, changes in the tumor microenvironment, and EBV-mediated oncogenesis. In addition, we highlight prognostic and predictive biomarkers which may enable a personalized medicine approach toward ENKTL therapy.

A phase I study of selinexor combined with weekly carfilzomib and dexamethasone in relapsed/refractory multiple myeloma.

We performed a phase I study of weekly selinexor, carfilzomib, and dexamethasone (wSKd) in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to identify the maximum tolerated dose (MTD) of wSKd. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Prior exposure/refractoriness to carfilzomib was permitted. Thirty patients were enrolled; 26 (87%) had triple-class exposed disease and 6 (20%) received chimeric antigen receptor (CAR) T-cell therapy. Dose level 2 (carfilzomib 70 mg/m2 Intravenous [IV] on Days 1, 8, and 15; selinexor 100 mg PO on Days 1, 8, 15, 22; dexamethasone 40 mg on Days 1, 8, 15, 22 of 28-day cycles) was chosen as the MTD, with no DLTs having occurred. The most common hematologic adverse events (AE) were thrombocytopenia (83%), anemia (70%), lymphopenia (50%), and neutropenia (50%). The most common nonhematologic AE were fatigue (70%), nausea (70%), diarrhea (53%), and anorexia (47%). The ORR was 21/30 (70%) overall and 18/23 (78%) at the MTD. At a median follow-up of 12.3 months, the median PFS was 5.3 months and median OS 23.3 months. Responses were similar in carfilzomib naïve and exposed patients. Long-term efficacy of wSKd is modest; wSKd could be employed as a bridging strategy to immunotherapies.

Phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone with and without daratumumab in relapsed multiple myeloma.

We conducted a phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone (KPd) and KPd with daratumumab (Dara-KPd) in relapsed/refractory multiple myeloma. The primary end points were identification of a maximum tolerated dose (MTD) of KPd for phase 1, and rates of overall response (ORR) and near complete response (nCR) after 4 cycles of KPd and Dara-KPd, respectively, for phase 2. The MTD for KPd was carfilzomib 20/27 mg/m2 on days 1, 2, 8, 9, 15, and 16 (cycles 1-8) and days 1, 2, 15, and 16 for cycles 9 and beyond; oral pomalidomide 4 mg on days 1 to 21; and oral dexamethasone 40 mg weekly in 28-day cycles. Sixty-six patients received KPd, including 34 at the MTD. The ORR after 4 cycles of KPd at the MTD was 27/34 (79%; 95% confidence interval [CI], 62%-91%), meeting the statistical threshold for efficacy. At a median follow-up of 44 months, the median progression-free survival (PFS) was 13 months and overall survival (OS) 44 months. Twenty-eight patients received Dara-KPd. The rate of nCR or better after 4 cycles was 11/28 (39%; 95% CI, 22%-59%), meeting the statistical threshold for efficacy. As the best response to Dara-KPd, the ORR was 25/28 (89%) and the rate of measurable residual disease negativity by flow cytometry (10-5) was 17/26 (65%). At a median follow-up of 26 months, the median PFS and OS for Dara-KPd were not reached. Dara-KPd induced deeper and more durable responses than KPd without compromising safety in a predominantly high-risk, lenalidomide-refractory population, warranting further evaluation of this quadruplet. This trial is registered at www.clinicaltrials.gov as #NCT01665794.

Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial.

BACKGROUND: Lenalidomide is a cornerstone of maintenance therapy in patients with newly diagnosed multiple myeloma after autologous stem-cell transplantation. We aimed to compare the efficacy and safety of maintenance therapy with carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone in this patient population. METHODS: This study is an interim analysis of ATLAS, which is an investigator-initiated, multicentre, open-label, randomised, phase 3 trial in 12 academic and clinical centres in the USA and Poland. Participants were aged 18 years or older with newly diagnosed multiple myeloma, completed any type of induction and had stable disease or better, autologous stem-cell transplantation within 100 days, initiated induction 12 months before enrolment, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) using permuted blocks of sizes 4 and 6 and a web-based system to receive up to 36 cycles of carfilzomib, lenalidomide, and dexamethasone (28-day cycles of carfilzomib 20 mg/m2 administered intravenously in cycle one on days 1 and 2 then 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles one to four and 36 mg/m2 on days 1, 2, 15, and 16 from cycle five up to 36 [per protocol]; lenalidomide 25 mg administered orally on days 1-21; and dexamethasone 20 mg administered orally on days 1, 8, 15, and 22) or lenalidomide alone (10 mg administered orally for the first three cycles and then at the best tolerated dose [≤15 mg for 28 days in 28-day cycles]) until disease progression or unacceptable toxicity as maintenance therapy. After 36 cycles, patients in both treatment groups received lenalidomide maintenance. Randomisation was stratified by response to previous treatment, cytogenetic risk factors, and country. Investigators and patients were not masked to treatment allocation. Patients in the carfilzomib, lenalidomide, and dexamethasone group with no detectable minimal residual disease after cycle six (as per International Myeloma Working Group criteria) and standard-risk cytogenetics were switched to lenalidomide maintenance as of cycle nine. The primary endpoint was progression-free survival in the intention-to-treat population (defined as all randomly assigned patients). Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. This unplanned interim analysis was triggered by the occurrence of 59 (61%) of the expected 96 events for the primary analysis and the results are considered preliminary. This trial is registered with ClinicalTrials.gov, NCT02659293 (active, not recruiting) and EudraCT, 2015-002380-42. FINDINGS: Between June 10, 2016, and Oct 21, 2020, 180 patients were randomly assigned to receive either carfilzomib, lenalidomide, and dexamethasone (n=93) or lenalidomide alone (n=87; intention-to-treat population). The median age of patients was 59·0 years (IQR 49·0-63·0); 84 (47%) patients were female and 96 (53%) were male. With a median follow-up of 33·8 months (IQR 20·9-42·9), median progression-free survival was 59·1 months (95% CI 54·8-not estimable) in the carfilzomib, lenalidomide, and dexamethasone group versus 41·4 months (33·2-65·4) in the lenalidomide group (hazard ratio 0·51 [95% CI 0·31-0·86]; p=0·012). The most common grade 3 and 4 adverse events were neutropenia (44 [48%] in the carfilzomib, lenalidomide, and dexamethasone group vs 52 [60%] in the lenalidomide group), thrombocytopenia (12 [13%] vs six [7%]), and lower respiratory tract infections (seven [8%] vs one [1%]). Serious adverse events were reported in 28 (30%) patients in the carfilzomib, lenalidomide, and dexamethasone group and 19 (22%) in the lenalidomide group. One treatment-related adverse event led to death (respiratory failure due to severe pneumonia) in the carfilzomib, lenalidomide, and dexamethasone group. INTERPRETATION: This interim analysis provides support for considering carfilzomib, lenalidomide, and dexamethasone therapy in patients with newly diagnosed multiple myeloma who completed any induction regimen followed by autologous stem-cell transplantation, which requires confirmation after longer follow-up of this ongoing phase 3 trial. FUNDING: Amgen and Celgene (Bristol Myers Squibb).

Frontline polatuzumab vedotin for diffuse large B-cell lymphoma: A survey of clinician impressions.

In the POLARIX trial, pola-R-CHP demonstrated improved progression-free survival (PFS) compared to R-CHOP in untreated intermediate- to high-risk DLBCL. We surveyed practicing clinicians regarding their interpretation of POLARIX, including impressions of efficacy, safety, and cost. Of 174 respondents, most from academic centers (82%) in the United States (57%), 70% stated they would not replace R-CHOP with pola-R-CHP due to insufficient PFS difference, lack of overall survival benefit, and excessive cost. Respondents not recommending pola-R-CHP expressed concerns about financial implications for both society and patients. We observed considerable heterogeneity in both study interpretation and plans for real-world implementation of pola-R-CHP.