PURPOSE: We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM). METHODS: 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 then 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 end point in phase II was overall response rate (ORR). RESULTS: Among the 117 patients treated with 200 mg, the median age was 70 years, 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 (CR). In 104 patients treated with 50 mg at a median follow-up of 7.4 months, the ORR was 48%, with 21% achieving ≥CR. The median duration of response (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 (35.0% Gr1, 10.3% Gr2, 0.9% Gr3), neutropenia (0.9% Gr2, 18.8% Gr3, 23.1% Gr4), and anemia (3.4% Gr1, 4.3% Gr2, 30.8% Gr3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Gr1, Gr2, Gr3). Infections were reported in 74.4% of patients (33.3% Gr3, 2.6% Gr4); infection frequency and severity declined over time. CONCLUSION: Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.

Byun JM, et al. Korean J Intern Med. 2013 Sep;28(5):565-572. http://dx.doi.org/10.3904/kjim.2013.28.5.565

Objective. Real-world epidemiological data on tuberculosis (TB) infection in patients with inflammatory bowel disease (IBD) receiving TNF-α inhibitors are scarce. We investigated the risks for and case characteristics of TB in a large cohort of IBD patients treated with TNF-α inhibitors in Korea, where TB is endemic. Materials and methods. We performed an observational study on all TB cases identified in a cohort of 873 IBD subjects treated with TNF-α inhibitors from January 2001 to December 2013. The standardized incidence ratio (SIR) of TB was calculated using data from the matched general population. Results. A total of 25 newly developed TB cases were identified in the cohort (pulmonary TB, 84% [21/25]; extrapulmonary TB, 16% [4/25]). The adjusted SIR of TB was 41.7 (95% confidence interval, 25.3–58.0), compared with that of the matched general population. Nineteen of the 25 patients (76%) developed TB within 2–62 months of initiation of TNF-α inhibitor treatment despite screening negative for latent TB infection (LTBI), whereas three patients with LTBI (12%, 3/25) developed TB 3 months after completion of chemoprophylaxis. The outcomes of TB treatment were mostly favorable, although one death from peritoneal TB was noted. The type of TNF-α inhibitor prescribed (infliximab) was a significant predictor of TB (p = 0.033). Conclusions. TNF-α inhibitor treatment strikingly increases the risk of TB infection in an IBD population from a TB endemic area. Continuous evaluation of the development of de novo TB infection in IBD patients subjected to long-term TNF inhibitor therapy is mandatory.

BACKGROUND: Chronotherapy is a drug intervention at specific times of the day to optimize efficacy and minimize adverse effects. Its value in hematologic malignancy remains to be explored, in particular in adult patients. METHODS: We performed chronotherapeutic analysis using 2 cohorts of patients with diffuse large B cell lymphoma (DLBCL) undergoing chemotherapy with a dichotomized schedule (morning or afternoon). The effect of a morning or afternoon schedule of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on survival and drug tolerability was evaluated in a survival cohort ( n = 210) and an adverse event cohort ( n = 129), respectively. Analysis of about 14,000 healthy individuals followed to identify the circadian variation in hematologic parameters. RESULTS: Both progression-free survival (PFS) and overall survival (OS) of female, but not male, patients were significantly shorter when patients received chemotherapy mostly in the morning (PFS HR 0.357, P = 0.033; and OS HR 0.141, P = 0.032). The dose intensity was reduced in female patients treated in the morning (cyclophosphamide 10%, P = 0.002; doxorubicin 8%, P = 0.002; and rituximab 7%, P = 0.003). This was mainly attributable to infection and neutropenic fever: female patients treated in the morning had a higher incidence of infections (16.7% vs. 2.4%) and febrile neutropenia (20.8% vs. 9.8%) as compared with those treated in the afternoon. The sex-specific chronotherapeutic effects can be explained by the larger daily fluctuation of circulating leukocytes and neutrophils in female than in male patients. CONCLUSION: In female DLBCL patients, R-CHOP treatment in the afternoon can reduce toxicity while it improves efficacy and survival outcome. FUNDING: National Research Foundation of Korea (NRF) grant funded by the Korean government (grant number NRF-2021R1A4A2001553), Institute for Basic Science IBS-R029-C3, and Human Frontiers Science Program Organization Grant RGY0063/2017.

Jiyeon Ryu, Youngil Koh, Hyejoo Park, Dae Yoon Kim, Dong Chan Kim, Ja Min Byun, Hyun Jung Lee, and Sung-Soo Yoon. Mol. Cells 2016;39:898-908. https://doi.org/10.14348/molcells.2016.0210