Evaluating the Kinetics of Absolute Lymphocyte Counts Following Bispecific T-Cell Engager Therapy to Predict Clinical Outcomes in Relapsed/Refractory Multiple Myeloma

Background
Bispecific T-cell engagers (BiTEs) are effective in treating relapsed/refractory multiple myeloma (RRMM). This study examines the kinetics of absolute lymphocyte counts (ALCs) in RRMM patients (px) receiving BiTEs, hypothesizing that the stimulatory effect of BiTEs on T-cells would result in a higher ALC expansion in px with deeper and longer-lasting responses, aiding in predicting outcomes.

Methods
A retrospective study included all px with RRMM receiving a BiTE at one institution. We collected ALC data from 5 days prior to starting BiTE therapy (tx), during step-up dosing, and at every follow-up visit. Demographic data, baseline disease characteristics, previous lines of treatment (LOT), cytogenetics, staging at diagnosis, best response according to IMWG, progression (POD), and toxicities were recorded. We identified the minimum (ALCmin d1-22) and maximum ALC values (ALCmax d1-22) during the first 3 weeks after BiTE initiation. The difference between ALCmax and ALCmin during the first 3 weeks (deltaALC d1-22) was calculated to determine the expansion rate of ALCs early post-BiTE. Progression-Free Survival (PFS) was calculated from step-up dose 1 to either POD or last follow-up.

Results
As of April 2024, 48 BiTEs step-up dosing were initiated in 41 px. Clinical response was evaluated in 45 events. Anti-BCMA BiTEs were administered to 37 px, and anti-GPRC5D BiTEs to 9 px. Five px received a BiTE in more than one LOT, and two switched from a BCMA to a non-BCMA-targeted BiTE. Baseline disease characteristics and demographics were comparable across different BiTEs, except for race. Response rates were similar between anti-BCMA and non-BCMA agents, with CR/VGPR rates of 72% for elranatamab, 41% for teclistamab, and 56% for talquetamab. No significant difference was observed in the incidence of CRS, ICANS, or severe infections between anti-BCMA and non-BCMA BiTEs. However, severe cytopenias were significantly higher in subjects with elranatamab and teclistamab (65% and 53%, respectively).

ALC kinetics were similar across all BiTEs, with a decrease in ALCs appearing early after starting tx. The median ALCs from day 1 to either POD or last follow-up while receiving a BiTE was 0.58 x10⁹ cells/L [IQR 0.29, 1.07], and was significantly higher in px with CR/VGPR compared to those with ≤PR: 0.92 [0.57, 1.28] vs. 0.31x10⁹ cells/L [0.22, 0.55]; p<0.001. Higher median ALCs were observed in px with CR/VGPR within the first 3 weeks post-BiTE tx vs. those with ≤PR: 0.39 [0.25, 0.57] vs. 0.27 [0.17, 0.55] in week 1, p=0.028; 0.34 [0.24, 0.57] vs. 0.25 [0.17, 0.4] in week 2, p=0.01; and 0.6 [0.38, 0.9] vs. 0.25x10⁹ cells/L [0.12, 0.75] in week 3, p=0.005.

During the first 3 weeks, the median ALCmin (d1-22) was 0.15x10⁹ cells/L [0.07, 0.24], occurring at a median of 5 days [3, 7], while the median ALCmax (d1-22) was 0.70x10⁹ cells/L [0.32, 1.00], appearing at a median of 15 days [11, 21]. The median deltaALC (d1-22) was 0.48x10⁹ cells/L [0.26, 0.85]. The difference in deltaALC (d1-22) according to response group was not significant, but px with CR/VGPR took significantly longer to reach the max deltaALC (d1-22) vs. ≤PR: 11 [6, 15] vs. 6 days [2, 9]; p=0.011.

Px with CR/VGPR more commonly developed CRS (81% vs. 47%; p=0.019), with higher ALCmax (d1-22) and deltaALC (d1-22) associating with CRS: 0.89 [0.54, 1.06] vs. 0.31x10⁹ cells/L [0.20, 0.78]; p=0.02 and 0.61 [0.41, 0.91] vs. 0.24x10⁹ cells/L [0.13, 0.58]; p=0.022, respectively. Px with overall median ALCs ≥0.5x10⁹ cells/L had higher rates of CR/VGPR vs. those with median ALCs <0.5 (75% vs. 28%; p=0.003), but did not predict improved PFS in a multivariate analysis. Remarkably, the increased time to max deltaALC (d1-22) significantly associated with improved PFS (HR: 0.88; CI 0.78-0.9, p=0.03).

Conclusion
Higher median ALCs within the first 3 weeks following BiTE tx in RRMM associate with better clinical responses and increased incidence of CRS, but could not predict improved PFS. Px achieving CR/VGPR experienced a significant delay in ALC recovery post-BiTE initiation vs. those with ≤PR. A delayed time to maximum deltaALC (d1-22) was a protective factor for PFS, suggesting its potential as a predictive marker for treatment outcomes. The immunobiologic mechansisms underlying this protective delayed lymphocyte expansion remain to be elucidated and further research is required to optimize the use of ALC kinetics in guiding clinical decisions in px receiving BiTEs.