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bioRxiv · 10.1101/340877

Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

Barwick, B. G.·Neri, P.·Bahlis, N. J.·Nooka, A. K.·Kaufman, J. L.·Gupta, V. A.·Auclair, D.·Keats, J. J.·Lonial, S.·Vertino, P. M.·Boise, L. H.
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Abstract

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high-risk. To better understand and identify high-risk myeloma, we analyzed the translocation landscape of 826 newly-diagnosed patients by whole genome sequencing as part of the CoMMpass study. Translocations at the IgL locus were present in 10% of myeloma patients, and corresponded with poor prognosis. Importantly, 70% of IgL translocations co-occurred with hyperdiploid disease, a marker of standard risk, which is routinely diagnosed clinically whereas IgL-translocations are not. Thus, it is likely that the majority of IgL-translocated myeloma is being misclassified. The IgL enhancer is among the strongest in myeloma cells, indicating it can robustly drive oncogene expression when translocated. Consistent with this, IgL-translocated patients failed to benefit from immunomodulatory imide drugs (IMiDs), which target the lymphocyte-specific transcription factor Ikaros. These data implicate the IgL enhancer as resistant to IMiD-inhibition, and when translocated, as a driver of poor prognosis.

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Barwick, B. G., Neri, P., Bahlis, N. J., Nooka, A. K., Kaufman, J. L., Gupta, V. A., Auclair, D., Keats, J. J., Lonial, S., Vertino, P. M., Boise, L. H.. 2018-06-07. Multiple myeloma immunoglobulin lambda translocations portend poor prognosis. https://doi.org/10.1101/340877

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