Dynamics of B Cell Maturation Antigen (BCMA) Expression Pre-Treatment and at Relapse in Patients with Relapsed/Refractory Multiple Myeloma Receiving BCMA Directed CAR-T Cell Therapy

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Introduction BCMA directed CAR-T therapy is effective in treating relapsed/refractory multiple myeloma (RRMM). The impact of BCMA expression on outcomes with standard of care (SOC) CAR-T is unclear. We assessed BCMA status before and after SOC CAR-T therapy to evaluate its prognostic and decision-making utility in RRMM. Methods This was a single center, retrospective analysis of RRMM patients who received SOC BCMA directed CAR-T between 2021-2024. BCMA was tested in real time by immunohistochemistry (IHC), flow cytometry (FC), or both prior to CAR-T and at relapse on plasma cells (PC) in bone marrow (BM) or extramedullary disease (EMD). Patients were stratified as having positive or negative BCMA status and then further into 4 groups: BCMA– (0% expression), low+ (<50% expression), high+ (³ 50% expression), or NOS+ (unspecified BCMA expression). If there were discrepancies between IHC and FC, the higher BCMA level was used. Analysis is based on clinical data and is being validated by central review by one pathologist . Continuous variables were compared using Mann-Whitney U-test, categorical using Fisher's exact tests , and time-to-event variables using log-rank statistics. Results BCMA was tested at pre-CAR-T baseline in 66 patients (BM, n=65, EMD, n=1) (Figure 1A). Median age was 65.5 years, 33% had high-risk cytogenetics, and 47% had EMD. Median prior therapy lines were 5 (range: 4–8), 64% were penta-refractory, and 14% had prior BCMA-directed therapy. Among them, 56% received cilta-cel and 44% ide-cel with similar characteristics. BCMA status was determined by FC only in 47%, IHC only in 24%, and both in 29%. Median PCs were 14%. Baseline BCMA was expressed in 98% (n=65). BCMA– patient (n=1) was excluded from inferential analyses due to low number. Median time to progression (TTP) was 15.3 months (IQR: 1.41–NR) for low+ and not achieved for high+, p=0.40. Complete response (CR) rates were similar for high/low groups (64%/55%; p=0.73), as was overall response rate (ORR) (89%/91%; p >0.99). Due to low numbers in the ide-cel low+ group (n=2), we focused on cilta-cel: CR (41%/56%; p=0.48) and ORR (96%/89%; p=0.43) were similar for high/low. TTP was similar as well (p=0.30). After a median follow-up of 9.4 months, 41 patients (62%) relapsed. BCMA was evaluable for 24 patients (FC: 33%, IHC: 29%, Both: 38%, all done on BM) (Figure 1B). BCMA loss was seen in 6% (n=1) by FC and 19% (n=3) by IHC. More were low+ by FC at relapse than baseline. Median PCs were 6%. In patients with FC and IHC at relapse, 2 had discordant BCMA. In both, FC was low+ (6%/1%) and IHC was BCMA–, with PC burden of 60%/87%, respectively. Conclusion BCMA is detected in most patients pre-CAR-T therapy via FC and IHC. BCMA loss at relapse was uncommon (FC: 6%, IHC: 19%) but decrease in expression was more common. Future work should focus on using sensitive methods to quantitate BCMA expression and measure epitope mutations linked with resistance.

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