OAB-022: Monoallelic deletion of BCMA locus is a frequent feature in MM and is associated with increased genomic loss

Abstract

<h3>Background</h3> Immunotherapies in MM targeting BCMA, have shown remarkable clinical benefits. However, two recent reports highlighted that biallelic loss of BCMA cause resistance to anti-BCMA therapy. In both studies BCMA locus was deleted bringing in focus importance of del16p. We have evaluated 2883 MM patients at diagnosis and relapse to understand frequency of BCMA targeting events and characteristics of MM patients with BCMA deletion. <h3>Methods</h3> We observed del16p in 8.58% (7.6% to14.6% in individual studies) of newly-diagnosed patients (n=2458).Frequency of 16p loss in both HMM and NHMM were similar, suggesting its independence from MM subtypes. Overall CN loss was significantly higher in patients with BCMA loss compared to rest of the MM patients. High risk deletion events such as del1p and del17p were more likely to be observed in patients with loss of BCMA locus (OR [95% CI] 19.3(13.1-25.8), FDR=1.5e-65; and 8.8(6.3-12.1), FDR=5.5E-39, respectively)]. MM patients with loss of BCMA locus have increased mutational load (8202 with 95% HDI 6921 and 9535) compared to those without BCMA locus loss (6975 with 95% HDI 6626 – 7343); probability of difference greater than 0 was 96.8% and difference of the means were 1222 [95% CI 112-2589]. To understand the risk profile of patients with loss of BCMA locus, we next focused on the observation that BCMA loss frequently co-occurs with other deletions. <h3>Results</h3> We observed that when BCMA and TP53 or BCMA and del1p loss are present in the same patient, they are likely to have same clonality. These data suggested a possibility of co-occurrence of these events in same cell. To further investigate this observation, we used single cell DNA sequencing data from patients with sub clonal and clonal BCMA locus loss. Interestingly, almost all cells with BCMA loss also had p53 loss, while not all p53 loss cells had BCMA loss suggesting that the chronology of this copy number alternation may suggest first p53 loss followed by BCMA loss. Our data from a patient with BCMA targeting therapy also indicated that BCMA loss tend to co-occur with TP53 deletions (OR=5.67 [95% CI 4.12-7.84], p value < 0.0001).Moreover, we found that TP53 mutations were more frequent for patients with del16p and del17p, compared to patients who only had del16p. <h3>Conclusions</h3> Our data from large scale copy number profiles showed that even without treatment pressure, monoallelic BCMA deletions are frequent events. Moreover, patients with these events show increased genomic loss. Such behavior potentially make these cells vulnerable for biallelic loss of other genes. Our results highlight that by looking at mRNA or protein expressions at bulk sample would not directly indicate the presence or absence of cells with target loss and therefore evaluating single cell level data are necessary. These results suggest the need to study del16p in patients being targeted for BCMA-directed therapy and its association with del17p raises question about the role of BCMA targeted therapy in high-risk myeloma.