Predictive Markers for Outcomes after Disease Progression Post BCMA-Directed CAR T-Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma

BACKGROUND Idecabtagene vicleucel (I) and Ciltacabtagene autoleucel (C) are two commercially available BCMA-directed CAR-T cell products initially FDA approved after > 4 lines of therapy in patients with triple class exposed relapsed or refractory multiple myeloma patients (RRMM). Despite a high overall response rate, patients develop progressive disease. Little is known regarding factors associated with outcomes after progression post BCMA-directed CAR T-cell therapy and the optimal management strategy for post progression remains to be elusive. METHODS We conducted a single-center retrospective analysis of all patients with RRMM treated at Moffitt Cancer Center between 05/2021 to 12/2023 who developed progressive disease (early progression (EP): < 60 days and late progression (LP): > 60 days) after receiving either Ide-cel or Cilta-cel. Patient and disease characteristics were collected at the time of progression. Treatment at progression was categorized as follows: combination therapy (CT including alkylating agents, proteasome inhibitors, immunomodulatory agents, BCL2 inhibitors, XPO1 inhibitors, monoclonal antibodies), BCMA bispecific antibody (teclistamab, elranatamab), GPRC5D bispecific antibody (talquetamab), BCMA antibody-drug conjugate (ADC) (belantamab) and clinical trial. RESULTS Of 251 RRMM patients who received commercial BCMA-directed CAR T-cell therapy,106 patients (I= 92; C=14) had progressive disease: 92 LP (I=79; C=13) and 14 EP (I=13; C=1). The median time from CAR T to progression in these patients was 7.6 months (95% CI: 5.9- 9.5) for all patients (I= 6.6 months (95% CI: 5.4- 9.1) and C= 9.9 months (95% CI: 5.9- 9)). The median age at progression was 66 years with majority patients being male (56%) and white (66%) with high-risk cytogenetics (64%) and received prior autologous stem cell transplant (75%). Out of 106 patients with progression, 89 (83.9%) received 1st line treatment, 10 (9.4%) had unknown status and 7 (7.3%) opted for hospice. The remainder analysis focuses on these 89 patients who received subsequent treatment. The 1st line treatment included: CT (n=46; 48%), BCMA bispecific (n=29; 30%), GPRC5D bispecific (n=8; 8.3%), BCMA ADC (n= 4, 4.2%), clinical trial (n=2, 2.1%). Subsequently, 39 patients received 2nd line treatment, 14 patients received 3rd line treatment and 4 patients received 4th line treatment. The median PFS (mPFS) and OS (mOS) for all patients post BCMA CAR-T cell therapy was 5.8 months (95% CI: 4.7-NA) and 12.5 months (95% CI: 8.6- NA). On comparison, mPFS and mOS for patients with EP and LP was 5.2 vs 5.6 months (p=0.19) and 10.2 vs 21.2 months (p=0.40), respectively. Median PFS was lower in patients with high-risk disease as compared to standard-risk disease (4.8 vs 8.5 months, p= 0.034) bu (13.6 vs 12.5 months, p= 0.7). The mPFS for patients who received first line treatment with BCMA bispecific was 22.4 months (95% CI: 12.5-NA), GPRC5D bispecific was 8.5 months (95% CI: 8.5 -NA), BCMA ADC therapy was 15.1 months (95% CI: 1.21- NA), CT was 4.8 months (95% CI: 3.6-6.7) and clinical trial was 7.4 months (95% CI: 7.4-NA). Univariate analyses for PFS and OS identified the following factors associated with increased risk: Gain or amplification 1q (HR 2, 95% CI: 1.1-3.7); t(14;16) (HR 3.8, 95% CI: 1.5-9.9); LDH > 250 U/L (HR 2.8, 95% CI: 1.5-5.6); hemoglobin < 10 g/dl (HR 1.96, 95% CI: 1.2-3.2), albumin < 3.5g/dl (HR 2.48, 95% CI: 1.4- 4.3), bone marrow plasma cells > 60 % (HR 3.2, 95% CI: 1.7-6.2); serum M-spike > 3 g/dl (HR 3.7, 95% CI: 1.8-7.6); UPEP > 500 mg/24 hours (HR 5.0: 95% CI: 1.2-18.3); extramedullary disease (HR 1.7, 95%CI: 1.1-2.9). Univariate analysis showed that PFS and OS from the time of progression was significantly better in patients who received 1st line treatment with BCMA bispecific antibody (HR 0.3: 95% CI: 0.1-0.6), GPRC5D bispecific antibody (HR 0.2, 95% CI: 0.05-0.95) or BCMA ADC (HR 0.3, 95% CI: 0.07 -1.4) as compared to the CT. However, there was no significant difference in PFS (p=0.83) and OS (p=0.91) between the two bispecific antibodies as1st line treatment. CONCLUSIONS The prognosis of RRMM who develop progressive disease post-BCMA CAR T-cell therapy is poor. High-risk cytogenetics and high tumor burden at the time of progression are associated with worse outcomes in these patients. The post progression use of either BCMA or GPRC5D bispecific antibody is associated with improved outcomes as compared to combination chemotherapy