Meirong Zang

The Impact of Clone Size on the Prognostic Value of Chromosome Aberrations by Fluorescence In Situ Hybridization in Multiple Myeloma

Purpose: Accumulating evidence indicates that intratumor heterogeneity is prevalent in multiple myeloma and that a collection of multiple, genetically distinct subclones are present within the myeloma cell population. It is not clear whether the size of clonal myeloma populations harboring unique cytogenetic abnormalities carry any additional prognostic value. Experimental Design: We analyzed the prognostic impact of cytogenetic aberrations by fluorescence in situ hybridization at different cutoff values in a cohort of 333 patients with newly diagnosed myeloma and 92 patients with relapsed myeloma. Results: We found that nearly all IgH-related arrangements were observed in a large majority of the purified plasma cells; however, 13q deletion, 17p deletion, and 1q21 amplification appeared in different percentages within the malignant plasma cell population. Based on the size of subclones carrying these cytogenetic aberrations, the patients were divided into four groups: 0%–10%, 10.5%–20%, 20.5%–50%, and >50%. Receiver-operating characteristics analysis was applied to determine the optimal cutoff value with the greatest differential survival and showed that the most powerful clone sizes were 10% for 13q deletion, 50% for 17p deletion, and 20% for 1q21 gains, which provided the best possible cutoffs for predicting poor outcomes. Conclusions: Our study indicated that the impact of clone size on prognostic value varies between specific genetic abnormalities. Prognostic value was observed for even a subgroup of plasma cells harboring the cytogenetic aberration of 13q deletion and 1q21 gains; however, 17p deletion displayed the most powerful cutoff for predicting survival only if the predominant clones harbored the abnormality. Clin Cancer Res; 21(9); 2148–56. ©2015 AACR.

Low serum miR-19a expression as a novel poor prognostic indicator in multiple myeloma.

Multiple myeloma (MM) is the second most common hematologic malignancy characterized by the clonal expansion of plasma cells. Despite continuing advances, novel biomarkers are needed for diagnosis and prognosis of MM. In our study, we characterized the diagnostic and prognostic potential of circulating microRNAs (miRNAs) in MM. Serum miRNA levels were analyzed in 108 newly diagnosed symptomatic MM patients and 56 healthy donors (HDs). Our analysis identified 95 dysregulated miRNAs in newly diagnosed MM patients. Of the 95 dysregulated miRNAs, dysregulation of miR‐19a, miR‐92a, miR‐214‐3p, miR‐135b‐5p, miR‐4254, miR‐3658 and miR‐33b was confirmed by quantitative reverse transcription PCR (RT‐qPCR). Receiver operating characteristic analysis revealed that a combination of miR‐19a and miR‐4254 can distinguish MM from HD with a sensitivity of 91.7% and specificity of 90.5%. Decreased expression of miR‐19a was positively correlated with international staging system advancement, del(13q14) and 1q21 amplification. Furthermore, downregulation of miR‐19a resulted in significantly decreased progression‐free survival (PFS) and overall survival (OS). Our analysis indicated that the poor prognostic correlation of miR‐19a expression was independent of genetic abnormalities in MM. Multivariate analysis revealed that miR‐19a was a significant predictor of shortened PFS and OS. Interestingly, although miR‐19a levels portend a poor prognosis, patients with low miR‐19a levels had an improved response to bortezomib compared to those with high miR‐19a profile. Patients with downregulated miR‐19a experienced a significantly extended survival upon bortezomib‐based therapy. These data demonstrate that the expression patterns of serum microRNAs are altered in MM, and miR‐19a levels are a valuable prognostic marker to identify high‐risk MM.

Serum high expression of miR-214 and miR-135b as novel predictor for myeloma bone disease development and prognosis.

Multiple myeloma (MM) originates from malignant plasma cells, leading to multiple destructive lytic bone lesions that occur in more than 80% of MM patients. MicroRNAs have been reported to be involved in development of bone lesions in MM. However, the circulating microRNA as diagnostic and prognostic biomarkers for bone lesions has not been elucidated yet. In this study, we identified differentially expressed miRNAs that are potentially involved in myeloma-related bone disease in serum of MM patients. MiR-214 and miR-135b was shown to be increased in serum of MM patients with bone lesions. Serum level of miR-214 and miR-135b was highly correlated with the severity of lytic bone lesions and demonstrated as a diagnostic tool for identifying bone diseases based on results of a receiver operating characteristic analysis (ROC). In addition, patients with high levels of serum miR-214 had a dismal survival with significantly shortened progression free survival (PFS) and overall survival (OS). Interestingly, bisphosphonates treatment significantly extended PFS and OS in patients with higher level of miR-214 comparing to patients without bisphosphonates treatment. Taken together, our findings revealed the significance of circulating miR-214 and miR-135b levels in detection of bone disease and in prediction of prognosis of patients with multiple myeloma, suggesting its potential clinical applications. The result of this study also set the foundation for searching more circulating miRNA as biomarker for tumor bone lesions.

Downregulated miR-33b is a novel predictor associated with disease progression and poor prognosis in multiple myeloma

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.

Cytogenetic and clinical marks for defining high-risk myeloma in the context of bortezomib treatment.

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.