Immunoglobulin lambda (IgL) translocation may signal poor prognosis in patients with multiple myeloma (MM), possibly due to conferred resistance of immunomodulatory drugs (IMiDs), according to results from a study recently published in Nature Communications.

In this analysis, researchers assessed samples from 795 patients with newly diagnosed MM enrolled in the Clinical Outcomes in Multiple Myeloma to Personal Assessment (CoMMpass) study (ClinicalTrials.gov Identifier: NCT01454297) using long insert whole genome sequencing.

A median of 21 structural variants, including deletions, duplications, inversions, and translocations, were found in patients with newly diagnosed MM. Deletions, duplications, and translocations were associated with inferior progression-free survival and overall survival.

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Translocations frequently occurred proximal to IgH (41%), MYC (23%), CCND1 (17%), WHSC1 (11%), IgL (9.8%), TXNDC5 (4.9%), IgK (4.3%), and MAF (4.1%). A total of 20 regions were translocated at least 2% of the time, and 66% of patients had translocations. A total of 42% of patients with these common translocations also exhibited hyperdiploidy, typically in non-IgH-translocated MM.

Most IgL translocations occurred with focal amplifications and frequently to MYC. IgL translocations were found to associate with inferior clinical outcomes. Of note, 78% of IgLMYC translocations were present simultaneously with hyperdiploid disease. Because hyperdiploidy is a marker of standard risk, and IgL-MYC translocations correlated with worse clinical outcomes, the researchers noted that patients with hyperdiploid disease and IgL-MYC translocations may be misclassified as lower risk than they actually are.

The researchers estimated the variant allele frequency (VAF) of each translocation to assess tumor clonality. A value of 50% indicated cellular clonality of a heterozygous translocation in diploid genomic regions. The mean VAF for IgH translocations was 48%. The VAF for MYC translocations was 26%, and for other non-IgH translocations, the VAF was 28%.

Additionally, results suggested patients with IgL translocations did not benefit from IMiDs. IMiDs target the transcription factor IKZF1, which binds the IgL enhancer in MM. The authors noted, however, that they cannot rule out other potential contributors to poor prognosis in IgL-translocated MM.

Reference

1.     Barwick BG, Neri P, Bahlis NJ, et al. Multiple myeloma immunoglobulin lambda translocations portend poor prognosis [published online April 23, 2019]. Nat Commun. doi:10.1038/s41467-019-09555-6