Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma (RRMM). 

Highlight(s): A phase I/II trial evaluating the safety and efficacy of linvoseltamab (a B-cell maturation antigen x CD3 bispecific antibody [BsAb]) in RRMM demonstrated induced deep and durable responses, with a median duration of response (DOR) of 29.4 months with an acceptable safety profile.

Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody, or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and once every 2 weeks. Phase II 200 mg patients who achieved a ≥very good partial response by week 24 received linvoseltamab once every 4 weeks. The primary endpoint in phase II was the overall response rate (ORR).  Among the 117 patients treated with 200 mg, 39% had high-risk cytogenetics, and 28% had penta-refractory disease. At a median follow-up of 14.3 months, the ORR was 71%, with 50% achieving ≥complete response. The median DOR for 200 mg patients (n=83) was 29.4 months (95% CI, 19.2 to not evaluable). Among 200 mg patients, the most common adverse events included cytokine release syndrome (0.9% grade 3), neutropenia (23.1% grade 4), and anemia (30.8% grade 3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Grade 1 to 3). The rate of grade 3-4 infections was 34%, and we observed a decline in this rate over time that appeared most significant in patients achieving a deep response. The LINKER-MM1 study (NCT03761108) was published in the Journal of Clinical Oncology.

Brigatinib in Anaplastic lymphoma kinase (ALK)–positive anaplastic large-cell lymphoma (ALCL) after Failure of Brentuximab Vedotin.

Highlight(s): Unfortunately, in patients in whom brentuximab vedotin (a monoclonal antibody that targets CD30) therapy has failed, the outcome is poor (median overall survival [OS] duration, 2.9 months). Off-label treatment with brigatinib in ALK-positive ALCL patients demonstrated a complete response (CR) of 73%. 

A recent correspondence in the New England Journal of Medicine describes the French experience of off-label treatment with brigatinib in 15 adults with ALK-positive ALCL in whom brentuximab vedotin had failed. Patients received brigatinib at a dose of 180 mg once daily (after receiving a dose of 90 mg daily during a 7-day lead-in period). Of the 4 patients who had received crizotinib, 3 had disease resistance to the drug and 1 had disease sensitivity; relapse of ALK-positive ALCL occurred in the latter patient after crizotinib was discontinued.  A best objective response occurred in 93% of the patients (14 of 15), and a CR occurred in 73% (11 of 15). The time to a CR ranged from 8 to 325 days. Brigatinib therapy was a bridge to allogeneic stem-cell transplantation in 7 patients with a response. Disease progression or relapse occurred in 4 patients. After a median follow-up of 26 months, progression-free survival and OS at two years were 73% and 87%, respectively. No patients permanently discontinued brigatinib because of adverse events, and the dose was reduced in 3 patients because of an adverse event that was moderate in severity (dyspnea in 1 patient and cramps in 2 patients), with complete resolution.

Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1). 

Highlight(s): Epcoritamab monotherapy (a novel CD3 x CD20 bispecific antibody) showed clinically meaningful activity,  including in patients with high-risk disease features, with an overall response rate (ORR) of 82%, in patients with multiple relapsed or refractory follicular lymphoma (R/R FL), and had a manageable safety profile.

EPCORE NHL-1 (NCT03625037) is an ongoing multicohort, single-arm, phase 1–2 trial. Primary analysis results were recently published in The Lancet Haematology included the pivotal (dose expansion) cohort and the cycle 1 optimization cohort. Eligible patients had relapsed or refractory CD20+ R/R FL and had received at least two previous lines of therapy (including an anti-CD20 monoclonal antibody and an alkylating agent or lenalidomide). Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles until disease progression or unacceptable toxicity. 128 patients (median age 65 years [interquartile range, IQR: 55–72]) were enrolled and treated in the pivotal cohort (median follow-up 17.4 months [IQR 9.1–20.9]). The ORR was 82.0% (105 of 128 patients; 95% confidence interval [CI] 74.3–88.3), with a complete response rate of 62.5% (80 of 128; 95% CI 53.5–70.9). The most common grade 3–4 treatment-emergent adverse event was neutropenia in 32 (25%) of 128 patients. Grade 1–2 cytokine release syndrome (CRS) was reported in 83 (65%) of 128 patients; grade 3 CRS was reported in two (2%). Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in eight (6%) of 128 patients (five [4%] grade 1; three [2%] grade 2).  The optimized (n=86), three-stage step-up dosing regimen, and simple measures of prophylactic dexamethasone and hydration yielded lower rates of CRS, with no ICANS, and preliminary response rates suggest no loss of activity. The optimal strategy for treatment duration, whether fixed dose or treatment to progression, is not yet determined.

Risk of second tumors and T-cell lymphoma after chimeric antigen receptor (CAR) T-cell therapy.

Highlight(s): In addition to highlighting the rarity of second malignancies, this retrospective analysis offers a framework for identifying clonal connections and viral vector surveillance.

The risk of second tumors after CAR T-cell therapy is an emerging concern. A total of 724 patients who had received T-cell therapies were analyzed. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein–Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques. 

In addition to the dangers of the cytotoxic and immunosuppressive regimens that come with CAR T-cell therapy, there are at least three additional potential ways that the treatment could result in T-cell cancer: 1) as a consequence of CAR vector integration into a cancer gene; 2) as a result of genetic or epigenetic changes occurring during ex vivo T-cell expansion; and 3) from excessive antigen-driven proliferation of T cells.

Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia (ET). 

Highlight(s): A phase 2 trial showed that twice-daily aspirin dosing was persistently superior to once-daily low-dose aspirin in suppressing thromboxane (TX) biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort. 

The ARES trial was a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial, involving 242 patients with ET who were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2 a surrogate biomarker of antithrombotic efficacy. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p <0.001; 80% median reduction; 95% confidence interval 74%–85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses were lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain (secondary endpoints). 

Serum mass spectrometry for treatment monitoring in patients with relapsed/refractory multiple myeloma (RRMM) receiving chimeric antigen receptor (CAR) T-cells.

Highlight(s): Quantitative immunoprecipitation mass spectrometry (QIP-MS) could be particularly useful as a non-invasive technique when evaluating response after CAR T-cell treatment in RRMM especially when considering the potential therapeutic monoclonal antibody interference or the identification of glycosylated or minor additional peaks. 

The outcome of QIP-MS in 33 patients treated with the academic B-cell maturation antigen (BCMA)-directed CAR T-cell ARI0002h (Cesnicabtagene autoleucel) was recently published. QIP-MS offered more detailed insights than serum immunofixation electrophoresis (sIFE), identifying glycosylated M-proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analyzing different assay platforms during patient monitoring after ARI0002h administration,  it was observed that QIP-MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow-based next-generation flow cytometry. Furthermore, QIP-MS consistently demonstrated the lowest negativity rate across the different time points (27.3% vs. 60.0% in months 1 and 12, respectively).