Frailty and Outcomes after Bispecific T-Cell Engager Therapy for Patients with Relapsed/Refractory Multiple Myeloma

Introduction: Multiple myeloma (MM) is a disease of the elderly with a median age of 69 years at diagnosis. In addition to advanced age, many of these patients are frail with pre-existing comorbidities and have been historically excluded from clinical trials evaluating cellular immunotherapy including bispecific antibodies (BsAb) for relapsed refractory (RR) settings. It has been shown that chronologic age alone should not be a barrier towards effective treatment modalities, including autologous stem cell transplant and CAR-T. Rather, frailty scores should be incorporated into screening and eligibility assessments. With limited literature on safety and efficacy of BsAb in frail patients, we conducted a single center retrospective study to evaluate clinical characteristics and outcomes of frail patients with RRMM who received BsAb. Methods: Analysis included patients with RRMM who had received teclistamab, talquetamab, and/or elranatamab between December 2017 and March 2024. Frailty was defined using the simplified frailty index as established and utilized Facon et al. (score based on age + ECOG performance status [PS] + charlson comorbidity index [CCI]; non-frail = score 0-1, frail = score ≥2) (Leukemia. 2020; 34(1): 224-233). Descriptive statistics were used to analyze clinical characteristics such as age, PS, and comorbidities. Response outcomes were evaluated using the International Myeloma Working Group (IMWG) criteria. Adverse events were graded based on the American Society for Transplantation and Cellular Therapy (ASTCT) and Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. Key datapoints included incidence and severity of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), treatment-related mortality (TRM), response rates, progression-free survival (PFS), and overall survival (OS). Kaplan-Meier analysis was used for PFS and OS assessments. Cox hazard model was used to determine predictors of PFS and OS in the frail and non-frail patient populations. Results: Of 112 patients analyzed (age range 40 - 88), 83 (74%) were considered frail at the time of BsAb treatment. As expected, the frail group had a higher proportion of patients with age>70 years (45% vs 7%, p<0.001), renal insufficiency (38% vs 7%, p= 0.005), PS ≥2 (35% vs 0%, p < 0.001), and worse median CCI (4 vs 1, CCI 3+ 75% vs 17%, p<0.001). However, the frail group had lower rates of extramedullary disease (25% vs 56%, p=0.009). Median number of prior of lines of therapy (6 vs 7, p=0.48), high-risk cytogenetics (35% vs 31%, p=0.88), and triple class refractory disease rates (84% vs 68%, p=0.17) were similar between the frail and non-frail groups, respectively. Patients in the frail group experienced similar rates of all grade CRS (62% vs 62%, p= 1) and ICANS (14% vs 3%, p= 0.21) when compared to the non-frail group. Incidence of grade 3+ CRS (frail 2% vs non-frail 3%, p= 1.0) and grade 3+ ICANS (frail 2% vs non-frail 0%, p= 0.98) were also similar between the two groups. TRM was observed in 12 (14%) patients in the frail group compared to 2 (7%) patients in the non-frail group (p= 0.46). Best overall response rate (ORR) was 72% (13% sCR/CR, 43% VGPR, 16% PR) in the frail group vs 62% (24% sCR/CR, 17% VGPR, 21% PR) in the non-frail group (p= 0.43). With a median follow up of 7.3 months (range 3.7-12.2), median PFS and OS for the entire patient population was 5.6 (2.7-10.4) and 7.4 (3.9-12.6) months, respectively. Median PFS was 6.5 (2.8-11.4) months in the frail group vs 4.6 (2.5-8.0) months in non-frail group (HR 0.82, 95% CI 0.5-1.40; p= 0.45). Similarly, median OS was 7.5 (3.6-12.1) months in the frail group vs 7.3 (4.6-13.6) months in the non-frail group (HR 1.50, 95% CI .9-2.51; p= 0.16). Conclusion: A majority of patients treated with BsAb for RRMM in this study were frail based on the simplified frailty index and would have most likely been excluded from clinical trials. While these patients had worse PS and higher comorbidity burden at time of BsAb treatment, they did not experience any excessive high-grade toxicities including TRM. When compared to the non-frail group, frail patients had similar efficacy outcomes. This study highlights the tolerable safety and reasonable efficacy of BsAb for frail MM patients in a real-world practice, highlighting that frailty should not be a barrier towards the use of BsAb in this patient population.