| Background and aims:Multiple myeloma (MM) is a heterogeneous disease with variable disease courses, response to therapy, and survival outcome. Evaluation of prognostic factors and risk stratification is important to define treatment strategies, compare outcome of therapeutic trials, and predict survival from diagnosis. There has been general consensus that cytogenetics was the most important prognostic factors.The purpose was to summarize the molecular cytogenetic aberrations and clinical significance of Chinese Multiple myeloma patients detected by interphase fluorescence in situ hybridization(FISH).Majority of clinical cancer studies have shown that the presence of a high number of tumor-associated macrophage(TAM) is related to poor prognosis, the prognostic role of TAM in patients with MM, however, is so far unknown.Peripheral blood absolute lymphocyte count (ALC) is a survival prognostic factor in hematological malignancies. Few reports have addressed whether ALC predicts survival in myeloma. Another important factor that has been associated with prolonged progression-free and overall survival is the quality of response to treatment, there is extensive evidence from clinical studies demonstrating that maximal response is significantly associated with prolonged progression-free and overall survival.Prognostic significance of clinical parameters, cytogenetics, TAM, ALC and quality of response were studied.Method:Specimens of bone marrow were collected from 217 patients with MM who visited the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences in Tianjin, China. FISH analysis combined with magnatic-activited cell sorting(MACS) were performed on four specific probes for the regions containing 13q14 (RB-1/D13S319),14q32 (IGH),17p13 (P53) and 1q21. And the FISH studies with LSI IGH/CCND1, LSI IGH/FGFR3, LSI IGH/MAF probes were used to detect t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23) in patients with 14q32 rearrangement.TAMs were immunohistochemically stained with a CD68 antibody in a retrospective study including 63 MM patients.Results:1.Beta-2-microglobulin?5.5mg/L, D-S stage III, CD28+, Osteolytic lesions were associated with shorter OSin newly diagnosed MM.Beta-2-microglobulin?5.5mg/L, D-S stage III and more than 65 years oldwere risk factors of unfavorableprognosis for PFS in newly diagnosed MM. OS and PFS were significantly shorter in relapsed MM with high LDH(?300u/L). 2.Of the 184 newly diagnosed patients investigate by FISH, more than one molecular cytogenetic aberrations were found in 83.6%(154/184)patients.l3q deletions,17p deletions, illegitimate IGH rearrangement, chromosome 1q amplification, t(11;14),t(4;14), t(14;16)were detected in 83 (48%).25 (14.4%),94 (55.3%).83 (49.4%).43 (25.1%).37 (22%).7 (4.2%)cases.Of the 33 relapsed patients investigate by FISH, more than one molecular cytogenetic aberrations were found in 96.9% (32/33)patients.13q deletions,17p deletions, illegitimate IGH rearrangement, chromosome 1q amplification, t(11;14), t(4;14), t(14;16) were detected in 21 (63.6%). 14(42.4%).23(71.9%).26(78.8%).3(9.4%).15(45.5%).1 (3.1%)cases. When treated with conventional medicine, the OS of cases with 17p-was significantly short (p=0.004), patients presenting with either t(4;14) or del(17p) were shown to have a short PFS(p< 0.001, p< 0.001).Butin the context of bortezomib treatment, OS(p=0.889) and PFS(p=0.510) were no statisticaldifference betweenl7p deletion or not.No significant correlation was found between t(4;14) and progression-free survival (P=0.191) or overall survival (P=0.368).13q14 deletion,14q32, rearrangement,1q amplification, t(11;14) and t(14;16) had no prognostic value.3.In patientswith MM, CD68+Macrophages were heavily infiltrated in the bone marrow, The median CD68+cell content among 63 cases of MM was 12/high-power field (hpf) (X400) (range,1-52/hpf). No significant correlation was found between the number of CD68+cells and progression-free survival (P= 0.855) or overall survival (P=0.07).4. The median among 150 cases of MM was 1.50 X 109/L(rang,0.21-5.66).No significant correlation was found between the number of CD68+cells and progression-free survival (P=0.778) or overall survival (P=0.941).5.When treated with conventional medicine,no statisticaldifference was found between VGPR and PR subgroups(P=0.089), but both of OS were longer than cases who achieved of less than PR (p?O.O1, p=0.045 respectively). Patients who achieved at least VGPR had a longer PFS than those who achieved PR (p=0.02).ln the context of bortezomib treatment,no statisticaldifference was found between VGPR and PR subgroups(P=0.288), but both were longer than cases who achieved of less than PR(p=0.020, p=0.022respectively). Patients who achieved at least VGPR had a longer PFS than those who achieved PR (p=0.034). 6. When treated with conventional medicine, In multivariate analysis,17p-[p=0.007, RR=3.751, RR 95%CI (1.430?9.843)] and achievement of less than VGPR [p=0.01, RR=2.074, RR 95%CI (1.194?3.600)] were independent factors predicting shorter OS. 17p-[p=0.015, RR=4.250, RR 95%CI (1.321?13.677)] and t(4;14)[p=0.011, RR=3.640, RR 95%CI (1.350?9.815)] were independent factors predicting shorterPFS. In the context of bortezomib treatment, In multivariate analysis,only achievement of less than VGPRwere independent factors predicting shorter OS[p=0.02, RR=2.591, RR 95%CI (1.433?4.687)] and PFS[p=0.011, RR=3.640, RR 95%CI (1.350?9.815)].Conclusion:1. The genome of MM was of highly instability, many kinds of cytogenetic aberrations were found.2. Detection of t(4;14), or 17p-by FISH suggests higher-risk disease; del13 or 13q detectedonly by FISH independently in the absence of other abnormalitydoes not carry significant higher risk, whereas t(11;14) does notpredict superior outcome; and the data are not yet adequate tosuggest routine use of 1q21 FISH markers to predict prognosis.3. When treated with conventional medicine,patients presenting with either t(4;14) or del(17p) were shown to have a short PFS.Bortezomib improves outcome of patients with t(4;14) or 17p deletion.3. No significant correlation was found between the number of CD68+cells or ALC and progression-free survival or overall survival4. Maximal response is significantly associated with prolonged progression-free and overall survival.Achievement at least VGPRshould be an achievable and important goal ofMMtherapy. |
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