Citation for published version (APA): Hovenga, S. (2007). Clinical and biological aspects of Multiple Myeloma s.n.

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1 University of Groningen Clinical and biological aspects of Multiple Myeloma Hovenga, Sjoerd IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2007 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Hovenga, S. (2007). Clinical and biological aspects of Multiple Myeloma s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Prognostic value of CD27 expression on malignant plasma cells from multiple myeloma patients upfront treatment S. Hovenga 1, J.E.J. Guikema 1,2, N.A. Bos 2, R. Bekkema 3 and E. Vellenga 1 1 Department of Hematology, University Hospital Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands. 2 Department of Cell Biology, section Histology and Immunology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. 3 Department of Immunochemistry & Clinical Biochemistry, University Hospital Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands. Submitted 111

3 Multiple Myeloma (MM) is characterized by a clonal accumulation of malignant plasma cells in the bone marrow. Phenotypically plasma cells strongly express CD38 and CD138 (syndecan-1) 18, but can also display an aberrant phenotype compared to the normal counterpart. The importance of these phenotypic changes is not well defined, but might be related to an unfavorable prognosis. For example lack of CD56 in MM defines an unique patient subset with poorer prognosis. 22 Recently, we showed that CD27 is expressed on malignant plasma cells in MM. The expression pattern on malignant plasma cells is highly variable in contrast to normal plasma cells, which demonstrate a homogenous high CD27 expression pattern. 31 Recent analysis of gene expression profiles in CD138-enriched plasma cells from untreated myeloma patients revealed that newly diagnosed myeloma could be classified into four subgroups with variable prognosis. The two extremes being similar to either MGUS or myeloma cell lines. The MM cells with a myeloma cell line expression pattern also tended to have poor-risk features at presentation, including elevated serum β2 microglobulin (>4 mg/ml) and cytogenetic abnormalities. According to a consensus report of a recent workshop in Paris on myeloma genetics, hyperdiploid and t(11;14)(q13,q32)-positive myeloma are associated with a good prognosis, whereas non-hyperdiploidy, often associated with translocations other than t(11;14) and chromosome 13 deletion, imparts a strikingly dismal prognosis. 253 Micro-array analysis of the malignant plasma cells also revealed that the prognosis of the high-risk group coincided with a low CD27 mrna expression. However the low CD27 expression was not the single parameter but additional genes were part of this cluster including FGFR3 and CCND1. CCND1 expression, either low-level expression associated with chromosome 11 trisomy and hyperdiploid karyotypes or spiked expression linked to the t(11;14)(p13;q32) translocation and presence of normal karyotypes, defined two distinct subgroups with relatively low risk for relapse. Elevated expression of proliferation-associated genes, whether in a hyperdiploid or hypodiploid karyotype or MMSET/MAF/MAFB, defined two poor-prognosis subgroups. 254 Based on these findings we questioned whether the expression level of CD27 alone on the malignant plasma cells might be of prognostic value for Event Free Survival (EFS) or Overall Survival (OS). 112

4 Prognostic value of cd27 expression on malignant plasma cells from multiple myeloma Subsequently CD27 expression was studied on CD38 + /CD138 + plasma cells from multiple myeloma (MM) patients upfront treatment (n=67) by flowcytometry. CD27 expression was determined within the CD138 + CD38 ++ plasma cell gate. The percentage of positive cells was calculated by subtracting isotype-control histograms from the CD27 histograms using the Enhanced Normalisation Subtraction (ENS) protocol from the Winlist software-package. Mean fluorescence intensities (MFI) were calculated for CD27 and CD19. The study population consisted of 33 patients treated with high dose chemotherapy, including autologous stem cell transplantation (ASCT) (group A) and 34 MM patients not eligible for high dose chemotherapy (group B). Group A demonstrated a median age of 58 (range 41 67), where group B demonstrated a median age of 68 (range 39 86). According to the Durie Salmon staging system 83% of the patients belong to stage III A and 17% stage III B. Increased β2-microglobulin (β2 M) levels were observed in 75% of the patients. The median β2 M level measured at presentation was 4.6 mg/l with a range of A median CD27 expression of 31.5 (range ) and 55.1 (range ) was found for group A and group B respectively. A median CD27 value of 455 (range ) was demonstrated for normal plasma cells. Multiple variant analysis with Cox-regression was performed in order to find a prognostic value of the CD27 measurements upfront treatment. The MFI value of the CD27 expression was included in the model with age, β2 M, percentage plasma cells in the bone marrow, response after induction chemotherapy, response after ASCT and with EFS and OS. No prognostic value of CD27 expression level could be found. Looking at the survival of both groups, lower expression of the CD27 value was not correlated with shorter EFS and OS. A hazard ratio (HR) of (95% CI ) was found for the EFS (P=0.461) and a HR of 0.95 (95% CI ) was found for the OS (P=0.816). However a significant difference in EFS and OS could be demonstrated between the ASCT group versus conventional chemotherapy group. A hazard ratio of (95% CI ) for EFS (P=0.001) and a HR of (95% CI ) for OS (P=0.002). The superiority of high dose over conventional chemotherapy confirms previously published studies. 105,

5 In conclusion, the present study demonstrates that CD27 expression is not an independent negative prognostic factor in 67 MM patients upfront treatment, despite the fact that micro-array analysis of the malignant plasma cells revealed that the prognosis of the high-risk group coincided with a low CD27 mrna expression. Based on these results it appears that other members of the gene profile identified by the microarray analysis, have more impact, including FGFR3 and CCND1. References See page