Mutations landscape of relapsed refractory multiple myeloma patients prior to anti-BCMA treatment

Abstract Introduction: The approval of anti-BCMA therapies has significantly expanded the treatment arsenal and has prolonged survival in relapsed-refractory multiple myeloma (RRMM). However, like all other therapies, patients develop resistance to these agents. Multiple resistance mechanisms have been proposed, including tumor-intrinsic, humoral immune evasion, and T cell-specific dysfunction. Although mutation or deletion in the TNFRSF17 locus on chromosome 16 has been described as a resistance mechanism after anti-BCMA therapy, the role of pre-treatment mutations has not been explored. Here, we report the spectrum of mutational aberrancies present prior to treatment with BCMA-directed therapies to determine predictive markers of response, resistance, and long-term hematologic toxicities. Methods: We performed genomic sequencing, focusing on 144 genes via next-generation sequencing on the DNA extracted from the cryopreserved bone marrow specimens of the patients within 1-3 months prior to starting anti-BCMA treatment (CAR-T or bispecific antibody or antibody drug conjugate therapy). The clinical characteristics of the patients were derived from a review of the medical records and a prospectively maintained database. Patients were excluded if they didn't have enough sample for genetic mutation analysis. Multivariable analysis was performed evaluating for progression-free survival (PFS) and overall survival (OS). Results: Overall, 47 BCMA-naïve patients were included in the final mutation analysis and were divided in responders (R) (n=37, 79%%) and non-responders (NR)(n=10, 21%). Patients with partial response or better were categorized as R, and minimal response, stable disease or progressive disease as NR. The median age of the whole group was 60 years (56-71). R group included mostly white patients (33/37) while NR group consisted of 6 white, and 3 African American patients (p=0.017). The median prior lines of therapy were 6 in the R group and 9 in the NR group (p=0.014). Total median mutational burden in the R group was 5 (4-8) while in the NR group it was 9.5 (5-14)(p=0.039). There were no patients who had mutation in TNFRSF17 locus prior to starting anti-BCMA therapy. The most common mutations seen were DNMT3A (n=5, R=2, NR=3 p=0.05) FANCD2 (n=11; R=5, NR=6 p=0.006), MALT1 (n=8; R=4, NR=4 p=0.051), PMS2 (n=6; R=4, NR=2 p=0.6) STAG2 (n=6, R=3, NR=3 p=0.1) and TP53 (n=5; R=2, NR=3 p=0.051). JAK2, MSH2, MED 12 and PIK3CA were seen in the R group only, while APC, DIS3, FANCI and SF1 were seen exclusively in the NR group (n=2 each). In multivariable analysis, FANCD2, P53, MALT1 and STAG2 mutations were associated with inferior PFS and OS. Conclusions:Patients who are treated with multiple lines of therapy prior to getting anti-BCMA therapy harbor multiple mutations in various oncogenes. In our analysis, FANCD2, TP53, MALT1 and STAG mutations prior to infusion of BCMA-based treatment were associated with inferior PFS and OS.