Paper Details

ABSTRACT

Background: Circadian rhythm biology has emerged as an important regulator of immune cell function, affecting both leukocyte activation and migration. Preclinical studies have described a “time-of-day” administration effect on post-vaccination T-cell responses. Subsequent large retrospective clinical analyses of solid tumor and B-cell lymphoma patients treated with immune checkpoint inhibitors and CAR-T cell therapies have reported a time-of-day association, describing worse clinical outcomes with later time-of-day administration of these therapies. Circadian rhythm biology may offer an opportunity to maximize therapeutic efficacy with little to no added toxicity, compelling immunotherapy researchers to consider time of treatment administration as a variable that could impact clinical outcomes. Bispecific T-cell Engager (TCE) therapy is standard-of-care in relapsed and refractory multiple myeloma (RRMM), and, to our knowledge, the association of time-of-day administration with TCE therapy in multiple myeloma has not been previously described.

Methods: We conducted a multi-center retrospective study of 355 adults with anti-BCMA TCE-naïve RRMM who received their first anti-BCMA TCE at full dose for at least one cycle. We defined time of treatment from the median treatment administration time for all doses as well as only the first cycle. Similar to prior retrospective clinical analyses, we used serial hourly cut-points from 12:00 to 17:00 to separate the cohort into “before” and “after” groups. We performed a Kaplan-Meier analysis using both duration of treatment (DOT) and progression free survival (PFS) outcomes. We also performed Cox proportional hazard modeling on time-of-day and established clinical variables.

Results: Approximately 70% of our cohort was treated at tertiary academic medical centers. Elranatamab was administered in 166 cases (66%), and teclistamab in 189. The cohort was 52% men with a median age of 71 years at data cutoff. The median time from diagnosis to treatment was 6.2 years. The median DOT was 147 days. Ninety-one progression events were recorded across the cohort. The median treatment administration time for the cohort was 13:34 for all doses, and 14:00 for the first four full doses (excluding ramp-up doses). Cytogenetic data for 302 patients were available, and 89 of those cases had “high-risk” features (i.e. at least one of the following: del(17p), t(4;14), t(14;16), t(14;20).

We found a trend towards statistical significance for shorter DOT and an increased risk of progression with each later hour. A statistically significant difference was observed at 16:00 (hazard ratio 1.94; 95% CI, 1.07 – 3.51; P = 0.028). Other time points were not statistically significant.

Neither age, sex, time from diagnosis, TCE used, serum inflammatory markers, nor the Charlson Comorbidity Index were associated with shorter DOT or an increased risk of progression. However, the presence of high-risk (HR) cytogenetics was associated with shorter DOT and PFS (HR = 1.84, 95% CI 1.17–2.90, p = 0.008). We performed a cytogenetic risk-stratified time-of-day Kaplan-Meier analysis and found that the standard-risk (SR) group receiving treatment before 15:00 (SR-before) had the longest DOT and lowest likelihood of a progression event compared to HR-before, SR-after, and HR-after groups (p = 0.001). Log-rank testing revealed that this finding was driven almost entirely by differences between the SR-Before (15:00) and HR-After (15:00) groups.