Editorial theme | How multiple myeloma cells develop resistance to/escape from BCMA-directed novel agents

This article is the first in the series of our newest editorial theme of mechanisms of escape/resistance to new therapies in multiple myeloma (MM). This piece focuses on mechanisms of resistance to anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells.

Two recent articles have been published that examine this topic. The first article was published in Nature Communications, by Mehmet Kemal Samur and colleagues, and describes an investigation of the mechanism of resistance exhibited in a patient treated with anti-BCMA CAR T cells who experienced a relapse that could not be rescued by a second infusion.¹

First case study

The patient of interest was diagnosed with IgG lambda MM and exhibited a complex karyotype with t(8;12), (q24;q14), clonal t(11;14) (q13;q32), and clonal deletion 13. The patient was treated with idecabtagene vicleucel and was given an infusion of 150 × 10⁶ CAR T cells. After 9 months, the patient relapsed and was given a second, higher dose of 450 × 10⁶ CAR T cells, however, the patient did not respond.

Measurement of serum BCMA indicated high levels prior to the first infusion, but at the time of relapse, levels were low despite increased MM cell levels. Therefore, the genomic changes were investigated. Prior to the first infusion, only 4% of MM cells exhibited a 17p deletion compared with after the second infusion, when del17p and del16p were found throughout the clone. A nonsense mutation that causes a premature stop codon in the BCMA gene was found in 70% of the population. Together, this deletion on one allele and a loss of function mutation on the second allele could explain the lack of expression in the MM cells at the time of relapse and could indicate a potential method for resistance to anti-BCMA CAR T-cell therapy.

Second case study

Matteo C. Da Vià and colleagues published an article in Nature Medicine that documented another case of BCMA loss leading to relapse following anti-BCMA CAR T-cell therapy.²

The patient in question was a 71-year-old man with IgG kappa MM, who was enrolled in the KarMMa-2 trial and was treated with an infusion of idecabtagene vicleucel at a dose of 450 × 10⁶ cells. After 1 month, minimal residual disease at the level of 10⁻⁵ was undetectable. However, early relapse was detected in one lymph node at 3 months from infusion, and overt relapse was seen by 5 months. As was the case in the study by Samur et al., serum BCMA levels were undetectable despite 90% plasma cell bone marrow infiltration.

Paired bone marrow samples at baseline and progression showed strong expression of TNFRSF17 (BCMA) in MM cells that became undetectable at progression (p < 6.2×10⁻⁹⁴). CD38 and SLAMF7 were measured as plasma cell markers and found to be unaffected. Whole-genome sequencing was carried out at progression, and a number of genomic changes were identified, including:

• amplification of 1q
• deletion of 1p
• biallelic inactivation of TP53
• a complex IGH-MYC rearrangement

In addition, a large heterozygous deletion of chromosome 16 was found, along with a homozygous deletion that caused biallelic loss of the TNFRSF17 gene.

The patient was then evaluated to see if there was a pre-existing heterozygous deletion in that region. No such change was found; however, evidence of genomic instability was identified in that region. Due to the branching evolution of clones, the team could not exclude the presence of 16p deletion in a subclone in this case.

Further investigation

Whole-genome sequencing was performed for a further 50 patients with relapsed/refractory (R/R) MM to determine the prevalence of 16p deletions at baseline. Out of this group, three patients were heterozygous for deletions encompassing the TNFRSF17 locus and therefore may be at greater risk of loss of BCMA expression following targeted therapy against this antigen.

To examine whether the heterozygous deletions impacted the expression of BCMA, a subgroup of 28 patients with R/R MM who had RNA sequencing data was identified, including two patients with the 16p deletion. The expression level was similar across all patients and demonstrated that the heterozygous deletion did not affect expression in this cohort. However, this study only looked at gene expression and not protein expression or effects on downstream signaling.

Three publicly available datasets were also analyzed to assess the impact of heterozygous TNFRSF17 gene deletions or monosomy 16 in newly diagnosed and R/R patients with MM.

Both genetic alterations were detected in all groups in the following numbers:

• 4 out of 41 with newly diagnosed MM
• 2 out of 44 with relapsed MM
• 28 out of 33 with hyperhaploid MM

As hyperhaploid MM is rare (5% of all MM cases), the prevalence of these mutations without the hyperhaploid group was 6.7%.

Conclusion

While the studies listed only include a small number of patients, they do demonstrate a clear mechanism for MM cells to escape from anti-BCMA therapies. While further investigation in larger groups needs to be done, these articles indicate that combining different treatments to target multiple antigens may overcome the problem of clonal selection. Therefore, this may allow for a greater duration of response following CAR T-cell therapy without BCMA escape in the future.