Impact of Absolute Lymphocyte Counts (ALC) on Outcomes Following Bispecific Antibody Therapy in Patients with Relapsed/Refractory Multiple Myeloma Patients: A Single Center Real-World Experience
Authors: Shah Yash , Fiala Mark , Stockerl-Goldstein Keith , Schroeder Mark A. , Vij Ravi , Crees Zachary D. , Slade Michael 
Published: December 2024

Background:
Bispecific antibodies (BsAb) have emerged as an effective therapy in patients with relapsed/refractory multiple myeloma (RRMM), leading to an overall response rate (ORR) of 60-70% and prolonged progression-free survival (PFS) in responding patients. However, these agents require functional lymphocytes to exert their anti-tumor activity and determining immune effector cell fitness prior to BsAb therapy is complex in heavily pre-treated patients. As advanced methods of cell classification (extended flow cytometry and single-cell sequencing) are not available in clinical practice, widely available biomarkers associated with treatment efficacy are needed to improve selection of patients for BsAb therapy. Consequently, we investigated if absolute lymphocyte count (ALC) by a standard complete blood count (CBC) with differential is associated with BsAb therapy efficacy and could be used as a surrogate measure of immune fitness.
Methods:
We retrospectively identified patients at a single referral center with RRMM undergoing monotherapy with a BsAb between May 2018 and March 2024 using administrative records. Both commercial and experimental BsAb were included. Clinical characteristics and lab values were collected from the electronic health record. High-risk (HR) cytogenetics was defined as del(17p), t(4;14), t(14;16), amp(1q) and double hit (DH) cytogenetics was defined as two HR changes or one HR change with gain(1q) or del(1p). The primary endpoint was response by International Myeloma Working Group (IMWG) criteria. To delineate response kinetics, we analyzed both best response and response after 2 cycles of therapy. Due to the use of BsAb for bridging therapy, we excluded patients who received less than two complete cycles of therapy and discontinued treatment for reasons other than disease progression. For PFS analysis, patients who discontinued therapy for reasons other than disease progression were censored at time of next therapy.
Results:
We identified 113 patients receiving BsAb, following exclusions 92 patients were available for analysis, including 71% receiving BCMA-directed BsAb and 29% receiving BsAb directed at other targets. 63% received BsAb on study. The median age was 68 years, 54% of patients were male and 78% of patients were White. 47% and 14% of patients had HR and DH cytogenetics. 24% were ISS Stage 1, 24% were Stage 2, 29% were Stage 3 and 23% were unknown. The median duration of therapy was 128 days (range: 21-1302) and 26% remained on BsAb at last follow up, with reasons for discontinuing therapy including disease progression (41%), toxicity (14%) and completion of therapy (5%). By best response, ORR in this cohort was 65%, with 51% achieving a very good partial response (≥VGPR) or better and a complete response rate (CRR) of 44%. On landmark analysis following two cycles of BsAb, the ORR was 55%, ≥VGPR of 34% and CRR of 20%. Median PFS in the cohort was 204 days (95% C.I. 124-284 days).
At the initiation of BsAb therapy, the median ALC was 800 cells/mcL (range: 0 - 4800). 49% and 22% of patients had grade 2 (ALC &lt; 800) and grade ≥3 (ALC &lt; 500) lymphopenia at baseline. Using best response to BsAb, baseline ALC was higher in responders (1000 vs. 700, p = 0.04) but ALC &lt; 500 was not associated with a difference in ORR (55% vs. 68%, p = 0.28) or CRR (40% vs. 44%, p = 0.72).
On landmark analysis after 2 cycles, median ALC was higher in responders (1000 vs. 700, p = 0.01). ALC &lt; 500 was associated with lower ORR (35% vs. 61%, p = 0.04) and a trend towards lower CRR (5% vs. 24%, p = 0.06). ALC &lt; 800 was not associated with a statistically significant difference in ORR or CRR on best response or landmark analysis. On univariate analysis, ALC as a continuous variable was associated with prolonged PFS; each increase in ALC by 1000 cells/mcL was associated with a 34% decrease in hazard (HR: 0.66, p = 0.04). However, ALC &lt; 500 was not associated with a difference in PFS (median 204 vs. 200 days, p = 0.87).
Conclusion:
On our analysis, we found that low ALC at baseline was associated with lower ORR and shortened PFS. Moreover, severe (grade ≥3) lymphopenia was associated with lower rates of disease response after two cycles of therapy, though best response during therapy was similar regardless of ALC. Consequently, low ALC may represent a widely available biomarker for impaired responses to BsAb therapy suggesting BsAb in lymphopenic patients may not represent optimal therapy for those in need of rapid disease response.