Evaluation of Teclistamab in BCMA-Directed Therapy Exposed Versus Naïve in Relapsed/Refractory Multiple Myeloma

Introduction: Teclistamab is a T-cell engager (TCE) designed to target B-cell maturation antigen (BCMA), which is highly expressed on plasma cells in multiple myeloma. Various drug classes, such as chimeric antigen receptor T-cell therapy (CAR-T) and antibody-drug conjugates (ADC), are available to target BCMA as well as others currently in development. Despite the availability of multiple options for targeting BCMA, there is limited guidance on the effectiveness of administering teclistamab after prior BCMA-directed therapy (BDT). Methods: A multicenter, retrospective review of 164 patients who received teclistamab between January 2022 and May 2024, in collaboration with the U.S. Myeloma Innovations Research Collaborative (USMIRC) was conducted. Prior BCMA therapies included commercial or investigational CAR-T, antibody drug conjugates (ADC), or monoclonal antibodies (mAb). Overall response rate (ORR), complete response (CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. Descriptive statistics were used to summarize patient and disease characteristics, along with efficacy outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier methods. Results: Of the 164 patients that received teclistamab, 60 patients (37%) had prior BDT. Median age was 66 (range: 37-84 years) in the BDT-exposed cohort versus 69 years (range: 46-87 years, p=0.092) in the BDT-naïve cohort. Most patients were Caucasian (75% vs. 79%) and there were similar rates of Revised International Staging System (R-ISS) stage III disease (28% vs. 28%) in BDT-exposed versus BDT-naïve cohort, respectively. There were significantly higher rates of autologous hematopoietic stem cell transplant in the patients who had prior BDT exposure (75% vs. 59%, p=0.035). Eighty-eight percent of patients were triple-refractory in the BDT-exposed cohort versus 73% in the BDT-naïve cohort (p=0.022). The median prior lines of therapy prior to teclistamab were 7 (range: 6-9) in the BDT-exposed cohort versus 4 (range: 4-6, p<0.001) in the BDT-naïve cohort. The most common prior BDT class was CAR-T (68%) followed by ADC (37%); 5 patients (8.3%) had prior TCE. Twenty percent of patients had received at least 2 prior BDTs. The median lines of therapy between prior BCMA agent and teclistamab was 1 (0-2). The ORR to prior BDT was 70% while 22% had progressive disease (PD). Most patients had received a prior BDT greater than 6 months prior to initiation of teclistamab (67%). ORR occurred in 53% of patients in the BDT-exposed cohort versus 68% in BDT-naïve cohort (p=0.02). Stringent CR and CR occurred in 16 patients (27%) in the BDT-exposed cohort versus 27 patients (26%) in the BDT-naïve cohort. Both groups had a median time to first response of 28 days (p=0.4). Median PFS was 2.5 months (95% CI 1.4-8.9) in the BDT-exposed cohort versus 9.7 months (95% CI 4.5-NR) in the BDT-naïve cohort (p=0.01). Median OS was 9.1 months (95% CI 6.1-NR) for the BDT-exposed cohort, and it was not reached for the BDT-naïve cohort (p=0.08).Univariate analysis found that amplification 1q (hazard ratio [HR] 1.62, 95% CI 1.06-2.47), double refractory (HR 2.15, 95% CI 1.06-4.46), prior BDT exposure (HR 1.7, 95% CI 1.12-2.59), and teclistamab less than 6 months from prior BCMA agent (HR 2.5, 95% CI 1.29-4.84) had a significant impact on PFS. OS was significantly impacted by teclistamab less than 6 months from prior BDT (HR 2.91, 95% CI 1.43-5.91). Conclusion: ORR rate was significantly lower in the BDT-exposed group versus the BDT-naive group; this correlates with a PFS that was significantly shorter in BDT-exposed group compared to BDT-naive group. This could be attributed to a greater number of prior lines of therapy and a higher proportion of patients with triple-refractory myeloma in the BDT-exposed group. It is currently unclear which specific type of BDT should be used in these patients and whether it should be administered more than 6 months after the last exposure to BDT. Further prospective studies are warranted to assess the impact of prior BDT on treatment efficacy.