RE-MIND2: comparative effectiveness of tafasitamab plus lenalidomide versus polatuzumab vedotin/bendamustine/rituximab (pola-BR), CAR-T therapies, and lenalidomide/rituximab (R2) based on real-world data in patients with relapsed/refractory diffuse large B-cell lymphoma.

RE-MIND2 (NCT04697160) compared patient outcomes from the L-MIND (NCT02399085) trial of tafasitamab+lenalidomide with those of patients treated with other therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are autologous stem cell transplant ineligible. We present outcomes data for three pre-specified treatments not assessed in the primary analysis. Data were retrospectively collected from sites in North America, Europe, and the Asia Pacific region. Patients were aged ≥18 years with histologically confirmed DLBCL and received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients enrolled in the observational and L-MIND cohorts were matched using propensity score-based 1:1 nearest-neighbor matching, balanced for six covariates. Tafasitamab+lenalidomide was compared with polatuzumab vedotin+bendamustine+rituximab (pola-BR), rituximab+lenalidomide (R2), and CD19-chimeric antigen receptor T-cell (CAR-T) therapies. The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and progression-free survival. From 200 sites, 3,454 patients were enrolled in the observational cohort. Strictly matched patient pairs consisted of tafasitamab+lenalidomide versus pola-BR (n = 24 pairs), versus R2 (n = 33 pairs), and versus CAR-T therapies (n = 37 pairs). A significant OS benefit was observed with tafasitamab+lenalidomide versus pola-BR (HR: 0.441; p = 0.034) and R2 (HR: 0.435; p = 0.012). Comparable OS was observed in tafasitamab+lenalidomide and CAR-T cohorts (HR: 0.953, p = 0.892). Tafasitamab+lenalidomide appeared to improve survival outcomes versus pola-BR and R2, and comparable outcomes were observed versus CAR-T. Although based on limited patient numbers, these data may help to contextualize emerging therapies for R/R DLBCL. CLINICAL TRIAL REGISTRATION: NCT04697160 (January 6, 2021).

Improved Efficacy of Tafasitamab plus Lenalidomide versus Systemic Therapies for Relapsed/Refractory DLBCL: RE-MIND2, an Observational Retrospective Matched Cohort Study.

PURPOSE: In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes. RESULTS: In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R-GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P < 0.0001), and R-GemOx (HR: 0.47; P = 0.0003). CONCLUSIONS: RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx. See related commentary by Cherng and Westin, p. 3908.

RE-MIND: Comparing Tafasitamab + Lenalidomide (L-MIND) with a Real-world Lenalidomide Monotherapy Cohort in Relapsed or Refractory Diffuse Large B-cell Lymphoma.

PURPOSE: Tafasitamab, an Fc-modified, humanized, anti-CD19 monoclonal antibody, in combination with lenalidomide, demonstrated efficacy in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), in the single-arm, phase II L-MIND study (NCT02399085). RE-MIND, a retrospective observational study, generated a historic control for L-MIND to delineate the contribution of tafasitamab to the efficacy of the combination. PATIENTS AND METHODS: Data were retrospectively collected from patients with R/R DLBCL treated with lenalidomide monotherapy for comparison with tafasitamab + lenalidomide-treated patients (L-MIND). Key eligibility criteria were aligned with L-MIND. Estimated propensity score-based Nearest Neighbor 1:1 Matching methodology balanced the cohorts for nine prespecified prognostic baseline covariates. The primary endpoint was investigator-assessed best overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). RESULTS: Data from 490 patients going through lenalidomide monotherapy were collected; 140 qualified for matching with the L-MIND cohort. The primary analysis included 76 patients from each cohort who received a lenalidomide starting dose of 25 mg/day. Cohort baseline covariates were comparable. A significantly better ORR of 67.1% (95% confidence interval, 55.4-77.5) was observed for the combination therapy versus 34.2% (23.7-46.0) for lenalidomide monotherapy [odds ratio, 3.89 (1.90-8.14); P < 0.0001]. Higher CR rates were achieved with combination therapy compared with lenalidomide monotherapy [39.5% (28.4-51.4) vs. 13.2% (6.5-22.9)]. Survival endpoints favored combination therapy. Lenalidomide monotherapy outcomes were similar to previously published data. CONCLUSIONS: RE-MIND enabled the estimation of the additional treatment effect achieved by combining tafasitamab with lenalidomide in patients with R/R DLBCL.

Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study.

BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit-risk profile for patients with relapsing-remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. OBJECTIVE: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). METHODS: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. RESULTS: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1-5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia. CONCLUSION: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.

Effect of Aspirin Pretreatment or Slow Dose Titration on Flushing and Gastrointestinal Events in Healthy Volunteers Receiving Delayed-release Dimethyl Fumarate.

PURPOSE: In Phase III trials, delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated significant efficacy and an acceptable safety profile in patients with relapsing-remitting multiple sclerosis. The purpose of the present study was to examine 2 potential mitigation strategies for flushing and gastrointestinal (GI) events associated with DMF treatment: aspirin (ASA) 325 mg pretreatment for flushing, and slow dose titration of DMF for flushing and GI events. METHODS: The 8-week study included 173 healthy volunteers randomized to 4 groups; 172 underwent dosing. The placebo group (n = 44) received placebo ASA 30 minutes before placebo DMF (weeks 1-4), then placebo DMF alone (weeks 5-8). The DMF without ASA group (n = 43) and the DMF with ASA group (n = 43) received placebo ASA or ASA, respectively, 30 minutes before DMF (weeks 1-4), then DMF alone (weeks 5-8); in both groups, DMF was dosed at 120 mg BID (week 1) and 240 mg BID (weeks 2-8). The slow dose titration DMF group (n = 42) received DMF 120 mg once daily (week 1), 120 mg BID (week 2), 240 mg in the morning/120 mg in the evening (week 3), and 240 mg BID (weeks 4-8). Subjects recorded information about flushing and GI-related events by using an eDiary and numerical rating scales. FINDINGS: Flushing and GI-related events were reported in all groups and were mostly rated as mild or moderate in severity. Flushing events were generally ~1 hour in duration and, for most subjects with flushing, initially occurred the first day of study treatment. The duration of GI-related events and time to first GI-related event varied by event type. ASA reduced the incidence, severity, and number of flushing events without affecting duration or time to first flushing event, and had no adverse effect on GI-related events. Dose titration of DMF had no significant effect on flushing or GI events. No subjects discontinued the study due to flushing events. One subject (2%) in the placebo group, 3 subjects (7%) in the DMF without ASA group, 6 subjects (14%) in the DMF with ASA group, and 2 subjects (5%) in the slow dose titration DMF group discontinued treatment because of GI events. IMPLICATIONS: ASA pretreatment may mitigate flushing associated with DMF, with no adverse effect on GI events. Dose titration of DMF did not have a significant effect on flushing or GI events and is being evaluated further in ongoing clinical trials. ClinicalTrials.gov identifier: NCT01568112.

Efficacy and safety of delayed-release dimethyl fumarate in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS).

BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials. OBJECTIVE: To evaluate delayed-release DMF in newly diagnosed relapsing-remitting multiple sclerosis (RRMS) patients, in a post-hoc analysis of integrated data from DEFINE and CONFIRM. METHODS: Patients included in the analysis were diagnosed with RRMS within 1 year prior to study entry and naive to MS disease-modifying therapy. RESULTS: The newly diagnosed population comprised 678 patients treated with placebo (n = 223) or delayed-release DMF 240 mg BID (n = 221) or TID (n = 234). At 2 years, delayed-release DMF BID and TID reduced the annualized relapse rate by 56% and 60% (both p < 0.0001), risk of relapse by 54% and 57% (both p < 0.0001), and risk of 12-week confirmed disability progression by 71% (p < 0.0001) and 47% (p = 0.0085) versus placebo. In a subset of patients (MRI cohort), delayed-release DMF BID and TID reduced the mean number of new or enlarging T2-hyperintense lesions by 80% and 81%, gadolinium-enhancing lesion activity by 92% and 92%, and mean number of new non-enhancing T1-hypointense lesions by 68% and 70% (all p < 0.0001 versus placebo). Flushing and gastrointestinal events were associated with delayed-release DMF. CONCLUSION: Delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients.

Efficacy and safety of BG-12 (dimethyl fumarate) and other disease-modifying therapies for the treatment of relapsing-remitting multiple sclerosis: a systematic review and mixed treatment comparison.

OBJECTIVE: Currently, direct comparative evidence or head-to-head data between BG-12 (dimethyl fumarate) and other disease-modifying treatments (DMTs) is limited. This study is a systematic review and data synthesis of published randomized clinical trials comparing the efficacy and safety of existing DMTs to BG-12 for relapsing-remitting multiple sclerosis (RRMS). METHODS: A systematic review was conducted by searching MEDLINE, EMBASE, and the Cochrane Library for English-language publications from 1 January 1960 to 15 November 2012. Clinicaltrials.gov, metaRegister of Controlled Trials, and conference proceedings from relevant annual symposia were also hand searched. Two independent reviewers collected and extracted data, with discrepancies reconciled by a third reviewer. Included studies were randomized controlled trials (RCTs) of DMTs (interferon [IFN] beta-1a, IFN beta-1b, glatiramer acetate [GA], BG-12, fingolimod, natalizumab, and teriflunomide) in adults with RRMS. Mixed treatment comparisons were conducted to derive the relative effect size for the included treatments. Annualized relapse rate (ARR), disability progression, and safety outcomes were assessed. RESULTS: BG-12 240 mg twice a day (BID) significantly reduces ARR compared to placebo (rate ratio: 0.529 [95% CI: 0.451-0.620]), IFNs (0.76 [95% CI: 0.639-0.904]), GA (0.795 [95% CI: 0.668-0.947]), and teriflunomide 7 mg and 14 mg (0.769 [95% CI: 0.610-0.970] and 0.775 [95% CI: 0.614-0.979]), and does not show a significant difference when compared to fingolimod. Only natalizumab was significantly superior to BG-12 in reducing ARR. BG-12 also demonstrated favorable results for disability and safety outcomes. CONCLUSION: Based on indirect comparison, BG-12 offers an effective oral treatment option for patients with RRMS with an overall promising efficacy and safety profile compared to currently approved DMTs. Key limitations of the systematic review were the large heterogeneity in patients enrolled and the variability in the definition of outcomes in included trials.

Oral BG-12 (dimethyl fumarate) for relapsing-remitting multiple sclerosis: a review of DEFINE and CONFIRM. Evaluation of: Gold R, Kappos L, Arnold D, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107; and Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087-97.

INTRODUCTION: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system involving inflammation, chronic demyelination and axonal loss. MS affects more than 2 million people worldwide. AREAS COVERED: This article aims to summarize the findings from two pivotal 2-year, randomized, double-blind, placebo-controlled, Phase III studies of BG-12 (dimethyl fumarate) for relapsing-remitting MS (RRMS): DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in RRMS) and CONFIRM (Comparator and an Oral Fumarate in RRMS). Results from both studies demonstrated that BG-12 provides clinical and radiological efficacy over 2 years across a range of outcomes. These results were apparent as early as 12 weeks and sustained over the course of both studies. BG-12 was found to have an acceptable safety profile, with a similar overall incidence of adverse events across all treatment groups. EXPERT OPINION: The combination of robust efficacy, ease of administration and established safety profile is unique to a new therapy in MS. Findings from the pivotal Phase III studies support BG-12 as a potential initial oral treatment for patients with RRMS or as an alternative to other currently available therapies.

Cladribine tablets for the treatment of relapsing-remitting multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system leading to progressive neurodegeneration and disability. Until 2010, all approved disease-modifying drugs for MS required parenteral administration, which is associated with suboptimal adherence. It was anticipated that new approaches to treatment, including oral agents such as cladribine tablets, may improve adherence. In 2011, the development of cladribine tablets was stopped following negative feedback from the EMA and FDA. AREAS COVERED: This article provides an overview of the chemistry, mechanism of action and pharmacological properties of cladribine tablets therapy, and highlights the rationale for its development as an oral treatment for MS. Key efficacy and safety data from the pivotal Phase III CLARITY study are presented, providing context for the opinion received from the regulatory agencies. EXPERT OPINION: Despite the promising efficacy data observed in the cladribine tablets clinical trial program, regulatory agencies identified a potential risk of increased malignancies, and raised concerns about the implications of sustained lymphocyte depletion. Following the feedback received from the regulatory agencies, Merck Serono made the decision to withdraw the agent from the regulatory approval process. The experience gained will benefit other research efforts to address the outstanding unmet treatment needs of patients with relapsing MS.

Ethanol influences on native T-type calcium current in thalamic sleep circuitry.

Ethanol is known to disrupt normal sleep rhythms; however, the cellular basis for this influence is unknown. This study uses an in vitro slice preparation coupled with electrophysiological recordings to probe neuronal responses to acute ethanol exposure. Recordings were conducted in ferret and rat thalamic slices, since thalamic circuitry is an integral component of sleep/wake cycles and sleep spindles. A key mediator of spindle wave activity is the low-threshold calcium current (T-type current). The T-type current underlies burst responses in the lateral geniculate and thalamic reticular nuclei that are important in spindle propagation. Whole cell patch recordings in thalamic brain slices revealed that ethanol has a differential, dose-dependent effect on the native T-type current in thalamic relay cells. Low concentrations of ethanol (2.5, 5, and 10 mM) enhance T-type current (n = 35), whereas higher concentrations of ethanol (20 and 50 mM) decrease T-type current (n = 27). To address whether this dose-dependent effect was due to variation between cells, in a subset we verified the differential effect within the same cell (n = 7). In an effort to examine whether the biphasic effects on the current were due to the order of ethanol exposures, we varied the order of high and low ethanol concentrations within the same cell. The ability of ethanol to perturb calcium currents in thalamic relay cells may provide a mechanistic framework for the well documented disruptions in sleep/wake behavior in subjects with ethanol exposure.