Abstract
Multiple myeloma (MM) patients with t(4;14) is a heterogeneous group. Prognostic tools capable of predicting the outcome of patients are currently lacking. The MM SET domain (MMSET) protein is universally overexpressed and has been suggested to have an important tumorigenic role. This study analyzed whether the overexpression of full-length (MB4-1) or truncated forms (MB4-2 and MB4-3) of MMSET influence the prognosis of t(4;14)pos MM patients. A total of 53 symptomatic t(4;14)pos MM patients were retrospectively analyzed. RT-PCR was performed using cDNA from purified CD138+ bone marrow plasma cells to analyze expression and clinical significance of the IGH-MMSET fusion transcripts corresponding to MB4-1, MB4-2 and MB4-3 breakpoints. Among the patients, 25 (47.2%), 12 (22.6%) and 16 (30.2%) had the MB4-1, MB4-2 and MB4-3 breakpoints, respectively. When adjusted to the established prognostic variables including del(17p), ISS stage, serum LDH and serum calcium levels, the pooled MB4-2/MB4-3 subgroup remained a powerful independent adverse factor for PFS (P=0.013) and OS (P=0.029). Bortezomib-based therapy significantly improved the survival of the MB4-1 subgroup but could not overcome the negative effect of the MB4-2/MB4-3 breakpoints. Our results indicate that MB4-2/MB4-3 breakpoints with truncated forms of MMSET define a subset of t(4;14)posMM with poor prognosis.
Highlights
IntroductionPrevious molecular studies have demonstrated that the disease is associated with several chromosomal translocations [1]
Multiple myeloma (MM) is an incurable clonal plasma cell disorder
Due to the imbalance in the numbers of the three subgroups, we grouped them into two groups, MB4-1 subgroup (n=25) and the pooled MB4-2/MB4-3 subgroup(n=28), according to their ability to encode a full-length or a truncated MM SET domain (MMSET) protein
Summary
Previous molecular studies have demonstrated that the disease is associated with several chromosomal translocations [1]. The t(4;14) translocation is the second most common type of these translocations, affecting approximately 15% of MM patients with symptomatic disease [2]. Clinical studies showed that MM patients carrying the t(4;14) translocation were resistant to traditional chemotherapy, resulting in short median overall survival [3,4,5,6,7]. An Intergroupe Francophone du Myélome (IFM) 99 study reported that t(4;14) translocation was an independent prognostic factor for survival along with 17p deletion and high β2-microglobulin (β2-MG) [7]. Studies suggested that MM patients with t(4;14) may be a heterogeneous group with both “high risk” and “good risk” patients [10]
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