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MiRNAs located at chromosome fragile sites play important roles in regulating critical genes associated with myeloma pathogenesis, disease progression and drug resistance. Our previous results have identified miR-33b (located in chromosome 17p) was one of the dysregulated miRNAs in the sera of newly diagnosed MM patients. However, little is known about its expression pattern in myeloma tumor cells and its prognostic value in MM patients. In the present study, we investigated the expression pattern of miR-33b in 58 newly diagnosed, 11 relapsed, 12 remission MM patients and 18 health donors by quantitative real-time PCR. Our results showed the expression of miR-33b was obviously down-regulated in newly diagnosed and relapsed MM patients compared to remission patients and health donors ( p < 0.001). Moreover, patients with del(13q), del(17p), t(4;14) and high-risk genetic abnormalities have lower expression levels of miR-33b compared to patients without those of abnormalities ( p = 0.032, 0.018, 0.034, 0.005). Survival analysis showed patients with miR-33b low expression had significantly shortened PFS ( p = 0.016) and OS ( p = 0.033) and might be associated with drug resistance to bortezomib-based treatment. Our data suggest that down-regulated miR-33b might be a novel predictor associated with disease progression and poor prognosis in MM. [ABSTRACT FROM AUTHOR]

Abstract: Normal plasma cells (PCs) are either undetectable or outnumbered by the myelomatous PC compartment in bone marrow of multiple myeloma (MM). However, residual normal PCs have been detected in a minority of symptomatic MM patients with superior survival. The number of normal PCs is also an important factor to identify monoclonal gammopathy of undetermined significance (MGUS)-like MM. We speculate that the polyclonal serum IgM level in non-IgM myelomas may reflect the number of residual normal PCs. Here we investigated the prognostic relevance of polyclonal serum IgM level in a series of 485 newly diagnosed symptomatic MM (NDMM) patients. Our results showed that symptomatic MM patients with polyclonal IgM more than 0.5g/L displayed a favorable baseline clinical feature, together with a significantly lower frequency of high-risk cytogenetic abnormalities. This group of patients had a significantly prolonged progression-free survival (PFS) and overall survival (OS) regardless of thalidomide or bortezomib therapy. Furthermore, the superior outcome was independent of the depth of response. Our findings suggest that polyclonal IgM level is capable of identifying a group of symptomatic MM patients with distinct clinicobiological characteristics and favorable survival, similar with MGUS-like MM. [Copyright &y& Elsevier]

Abstract: Secondary monoclonal gammopathy of undetermined significance (MGUS) is a special phenomenon that occurs during the treatment of multiple myeloma (MM). The incidence, biological characteristics, and prognostic value of secondary MGUS in patients with MM remain undefined. We proceed with a retrospective systematic review of serum immunofixation electrophoresis studies performed in 438 cases of patients with plasma cell dyscrasias, including 409 cases of newly diagnosed MM and 29 cases of primary plasma cell leukemia. Secondary MGUS was more common in patients with myeloma who had undergone stem cell transplantation than in those who had not (17 [29.8%] of 57 versus 5 [1.4%] of 352, P < .001). The clinical parameters and cytogenetic characteristics in patients with or without secondary MGUS were comparable. The complete response rates in patients with or without secondary MGUS were 81.8% and 21.8% respectively (P < .01). For the cohort as a whole, secondary MGUS was associated with significantly prolonged progression-free survival (median, 52.0 months versus 22.5 months; P = .002) and overall survival (median, not reached versus 35.0 months; P < .001). The presence of secondary MGUS retained independent prognostic value with a moderate impact on overall survival (hazard ratio .128 [95% confidence interval .018 to .922]; P = .041) in the multivariate Cox regression model. However, when analysis was restricted to patients undergoing stem cell transplantation, no statistical differences in progression-free survival and overall survival were found. In conclusion, we observe that secondary MGUS was frequently observed in MM patients after transplantation and conferred a survival prolongation. The favorable survival in patients with secondary MGUS may be explained by beneficial effect from myeloablative therapy. [Copyright &y& Elsevier]

Abstract: t(11;14)(q13;q32) is the most common chromosome translocation in multiple myeloma (MM), but a consensus of clinicopathological features and impact on survival is yet to be reached. We analyzed a cohort of 350 patients with various plasma cell malignancies, including newly diagnosed MM (NDMM, n =253), relapsed/refractory MM (RRMM, n =77), as well as primary and secondary plasma cell leukemia (PCL, n =10 and n =10, respectively). Results: A remarkably higher frequency of t(11;14) was observed in the PCL than in the NDMM. A high incidence of t(11;14) was detected in the IgD, IgM, and nonsecretory MM. The t(11;14) MM group was associated with a significantly higher positive rate of B-lineage associated antigens CD20 and CD79a as well as the lack of CD56 expression. t(11;14) was less likely to be accompanied by 13q14 deletion than 13q14 deletion frequency in non-t(11;14) population (p =0.026), and fewer patients displaying t(11;14) were identified as belonging to the high-risk cytogenetic group due to the extremely low incidence of t(4;14) and t(14;16). As a whole, patients exhibiting t(11;14) had a comparable outcome with the control cohort in NDMM, but CD20 was able to identify two subsets of the disease with dissimilar outcomes. Among patients receiving bortezomib-based treatment, patients harboring t(11;14) without CD20 expression had a significantly shortened PFS (11.0 versus 43.0 months, p =0.005) and OS (16.5 versus 54.0 months, p =0.016) compared with patients displaying t(11;14) with CD20. Our findings suggest that although the t(11;14) plasma cell disorder displayed distinct biological, clinical and laboratory features, it was a heterogeneous disease with divergent outcome. [Copyright &y& Elsevier]

Multiple myeloma (MM) is a heterogeneous disease, and the benefit from bortezomib treatment is not uniform among all patients subgroups. Currently, little information is available to predict patients response to bortezomib treatment. In this study, we aimed to identify patients benefiting minimally from bortezomib as part of first-line therapy and to define high-risk MM in the context of bortezomib treatment. We compared the effect of a bortezomib-based treatment (arm B) with that of a treatment without bortezomib (arm A) on different genetic patient subgroups in a series of 273 cases of newly diagnosed MM. These patients were enrolled in a prospective, non-randomized clinical trial (BDH 2008/02). A subgroup of patients exhibiting little benefit from bortezomib treatment was identified. These patients had at least one of the following characteristics: del(17p13), 1q21 gain, or high lactate dehydrogenase levels. In this subgroup, survival of patients treated with bortezomib was comparable (progression-free survival: 14.0 vs. 15.0 months, p = 0.992; overall survival: 21.0 vs. 14.0 months, p = 0.472) to that of patients undergoing thalidomide-based treatment. We propose that all patients with newly diagnosed MM should be evaluated for these three markers before bortezomib treatment. Other novel drugs and alternative therapeutic strategies are needed for patients with such markers. [ABSTRACT FROM AUTHOR]