IgL Translocations for Risk Stratification in Multiple Myeloma

Multiple myeloma (MM) is a rare hematologic malignancy characterized by the clonal expansion of aberrant plasma cells within the bone marrow. MM is characterized by widespread intratumor heterogeneity and clonal evolution, which is believed to be the main confounder of durable clinical responses (CRs). This is especially so in the high-risk subset of patients with MM, who are defined by an overall survival (OS) of two years or less despite the use of novel treatments.¹ 

Next-generation sequencing (NGS) analyses of MM and its precursor stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), have led to a profound understanding of the underlying disease biology and clonal evolution patterns in MM.^2-9  Currently, the consensus for the classification of newly diagnosed MM (NDMM) includes molecular cytogenetics to risk stratify patients into high-risk (deletion of chromosome 17p, t[14;16], and t[14;20]), intermediate-risk (t[4;14], deletion of chromosome 13, and hypodiploidy), and standard-risk (t[11;14], t[6;14], and hyperdiploidy) groups.^10,11  Notably, due to the nature of clonal evolution, in which subclonal populations continually evolve under selective pressures, a patient may acquire abnormalities in a subclonal branch during the continuum of disease that was not initially present at diagnosis. Therefore, current classification methods at diagnosis may not identify true risk status with the same degree of accuracy as genetic-based biomarkers. Indeed, large cohorts of patients with NDMM are important for the statistical power needed to identify both frequent and rare genomic abnormalities. This recognition underlies the Multiple Myeloma Research Foundation’s (MMRF’s) Clinical Outcomes in Multiple Myeloma to Personal Assessment (CoMMpass) study (ClinicalTrials.gov identifier: NCT01454297), which aims to collect samples from more than 1,000 patients with NDMM (currently 1,154 patients from 90 sites worldwide) and track their clinical and genomic characteristics to establish molecular-based subgroups of MM to improve clinical outcomes for the patient population.

As part of the MMRF CoMMpass study, a recent investigation by Dr. Benjamin G. Barwick and colleagues revealed novel insight into a previously unrecognized genomic biomarker of high-risk MM, in which patients are characterized by translocation of the immunoglobulin λ (t[IgL]) light chain locus. Dr. Barwick’s team performed long-insert whole-genome sequencing analyses on a large cohort of patients with NDMM (n = 795). While they observed common translocations of the immunoglobulin heavy chain region with partner oncogenes, such as t(4;14), t(11;14), and t(14;16), they were not predictive of patient prognosis. Notably however, patients harboring t(IgL) accounted for approximately 10 percent of NDMM patients (n = 78/795) and were associated with poor progression-free survival (PFS), OS, and CR. While most IgL translocations occurred throughout the genome and were rare, IgL-MYC translocation was the most prevalent, accounting for 41 percent of patients (n= 32 of 78). Interestingly, IgL translocations were found to be subclonal and were associated with hyperdiploidy, which is remarkable as hyperdiploidy is a prognostic marker associated with standard risk. However, patients harboring t(IgL) were found to have significantly worse PFS and OS rates, independent of hyperdiploidy. Moreover, RNA sequencing was performed on a subset of patients (n = 629) to determine if t(IgL) patients show an underlying gene expression signature or associated with MM subtypes; however, no specific relationship was found. Patients with an IgL translocation were observed to have poor CR to immunomodulatory drug (IMiDs) treatment. To investigate the underlying mechanism, chromatin immunoprecipitation sequencing of Ikaros family zinc finger 1 (IKZF1), a lymphoid transcription factor in MM known to be degraded by the action of IMiDs, was performed on three MM cell lines: ARP-1 (expressing IgK), MM.1S (expressing IgL), and RPMI-8226 (expressing IgL and harboring t[IgL]). Indeed, IKZF1 was bound at high levels to enhancers in the IgL locus and not targeted for depletion by IMiD treatment, consequently conferring the poor CR reported. These data exemplify that infrequent genetic characteristics of MM can also be prognostic of patient survival and treatment outcomes.