Duek et al. [1] describe their institution’s experience of multiple myeloma (MM) in patients <50 years of age. In the absence of a comparator group of patients who are ≥50 years from the same institution, this descriptive report suggests that younger patients with MM tend to present at diagnosis with a lower ISS stage (1 and 2) as well as a lower incidence of severe renal insufficiency (13%) and hypercalcemia (4%) [1]. However, they have a higher incidence of extramedullary plasmacytomas (26%) and light chain myeloma (45%) at diagnosis. However, most interesting and novel was the finding that 68% of these younger patients had a t(11;14) primary cytogenetic abnormality in contrast to ∼20%, which is expected based on prior large studies of all patients with MM [1]. Furthermore, despite the absence of other co-existing high-risk cytogenetic abnormalities and all patients in this cohort receiving novel agent therapies such as proteasome inhibitors and/or immunomodulators, the hematological response was relatively low in patients with t(11;14), with most achieving only partial response rather than a very good partial response or complete response. Among those patients who underwent an autologous stem cell transplant (ASCT) as part of consolidation therapy, there was a lower very good partial response/complete response rate (56%) in patients with t(11;14) compared to those who did not have this cytogenetic abnormality (71%). However, only 2 patients received maintenance therapy after ASCT in this series. Finally, these poor hematologic responses in the subgroup of patients with t(11;14) translated to a relatively low median progression-free survival (PFS) of 18 months. These adverse outcomes reported in young patients with t(11;14) support previous findings described by Lakshman et al.[2] in MM patients with a t(11;14) cytogenetic abnormality seen at the Mayo Clinic. They demonstrated that after an upfront ASCT, MM patients with t(11;14) experience a worse overall survival compared to those with standard-risk MM. In addition, clinical outcomes including progression-free survival and time to next therapy in the t(11;14) group were better than those of patients with high-risk cytogenetics, but worse than MM patients with trisomies or a normal fluorescence in situ hybridization cytogenetics.
It has been well known that translocations involving the immunoglobulin heavy chain region constitute half of all primary cytogenetic abnormalities in MM [3]. Of these various translocations involving the immunoglobulin heavy chain, t(11;14) is the most frequent and it structurally involves the cyclin D1 oncogene being placed under the transcriptional control of the enhancer of the immunoglobulin heavy chain. This results in the dysregulation of cyclin D1, which then goes on to accelerate the transition of the cell cycle of clonal plasma cells from the G1 to the S phase. Key characteristics of clonal plasma cells possessing the t(11;14) abnormality have been its lymphoid-like biology, such as the higher surface expression of CD20, and its lymphoplasmacytic-like morphology under the light microscope [2]. It has also been associated with contrasting clinical features, such as a higher production of free light chains on one end and non-secretory MM on the other end [2, 4]. However, it is critical to appreciate the association of t(11;14) with other plasma cell disorders, such as primary plasma cell leukemia (∼50%) as well as light chain amyloidosis (∼40–50%). The higher incidence of extramedullary plasmacytomas at diagnosis and significantly higher proteinuria found in this small cohort of young MM patients with a t(11;14) cytogenetic abnormality is intriguing, as it could raise the possibility of these patients having a missed diagnosis of primary plasma cell leukemia and light chain amyloidosis, respectively [1]. However, this information was not readily available. Given that the study by Duek et al. [1] is relatively small and from a single institution, data on the biological race of this patient cohort will be hard to analyze. Nevertheless, it is critical to note that a recent study leveraged ancestry informative single-nucleotide polymorphisms to quantify one’s genetic ancestry and found that the probability of having either t(11;14), t(14;16), or t(14;20) was significantly higher in MM patients with the highest level of African ancestry [5]. This has major implications when evaluating the racial disparities in MM.
In conclusion, the study by Duek et al. [1] supports several previously reported laboratory findings and clinical outcomes associated with t(11;14) MM patients. However, it also adds a novel twist to the already colorful story of t(11;14) in MM with its preponderance for patients of younger age. This finding will need to be evaluated and confirmed in larger studies. Given that t(11;14) is associated with a higher level of Bcl-2 expression and has been found to be clinically susceptible to the oral small molecule Bcl-2 inhibitor, venetoclax [6], this has major implications on future personalization of therapy for younger patients with MM.
Disclosure Statement
The authors have no conflicts of interest to declare.
Funding Sources
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award No. K23CA218742. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research is also supported in part by the Fraternal Order of the Eagles Grant of the Mayo Clinic Cancer Center and the Marion Schwartz Foundation for Multiple Myeloma.
Author Contributions
W.I.G. and H.P. wrote and reviewed the manuscript.
