Containing Myeloma Cells in Patients with Newly
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Cancer Medicine Open Access ORIGINAL RESEARCH Clinical significance of granule-containing myeloma cells in patients with newly diagnosed multiple myeloma Kazuhito Suzuki1, Shingo Yano1, Kaichi Nishiwaki1, Koji Sano1, Takaki Shimada1, Yuichi Yahagi1, Yoji Ogasawara1, Katsuki Sugiyama1, Shinobu Takahara1, Takeshi Saito1, Kinuyo Kasama1, Jiro Minami1, Hiroki Yokoyama1, Yutaro Kamiyama1, Atsushi Katsube1, Hidekazu Masuoka1, Mitsuji Katori1, Tomohito Machishima1, Aya Ouchi1, Nobuaki Dobashi1, Ken Kaito2, Noriko Usui1,3 & Keisuke Aiba1 1Division of Clinical Oncology/Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan 2Central Clinical Laboratory, The Jikei University Hospital, Tokyo, Japan 3Division of Transfusion Medicine, The Jikei University School of Medicine, Tokyo, Japan Keywords Abstract CD49e, CD56, granules, morphology, myeloma, prognosis The clinical features and prognostic significance of myeloma cells containing granules remain unclear. The purpose of this retrospective study was to inves- Correspondence tigate the clinical significance of granule-containing myeloma cells in patients Kazuhito Suzuki, Division of Clinical with newly diagnosed multiple myeloma (NDMM). We retrospectively analyzed Oncology/Hematology, The Jikei University the records of 122 patients diagnosed with NDMM between January 2007 and School of Medicine, 3-25-8 Nishi-Shinbashi, December 2013. Granule-containing myeloma cells were defined as myeloma Minato-ku, Tokyo 105-8461, Japan. Tel: +81-3-3433-1111; cells that exhibited three or more granules in their cytoplasm by May-Giemsa Fax: +81-3-3436-3233; staining. The patients were classified into two groups, the granule-containing E-mail: [email protected] myeloma (GM) and nongranule-containing myeloma (non-GM) groups, depend- ing on the proportion of myeloma cells that contained granules (cut-off value: Funding Information 10%). There were 25 (20.5%) patients in the GM group. Patients in the GM No funding information provided. group displayed significantly higher CD56 and CD49e expression than those in the non-GM group (t-test, P = 0.027 and 0.042). None of the patient charac- Received: 18 April 2016; Revised: 26 July 2016; Accepted: 28 July 2016 teristics differed significantly between the two groups. There was no significant difference in the chemotherapy profiles of the two groups, and the overall Cancer Medicine 2016; 5(11):3051–3058 response rates of the two groups were similar. During the median follow-up period of 33.9 months, the overall survival (OS) in the GM group was similar doi: 10.1002/cam4.875 to that in the non-GM group; 4-year OS of the GM and non-GM groups were 78.5% and 51.9%, respectively (P = 0.126). We concluded that cases of NDMM involving granule-containing myeloma cells are not infrequent. Moreover, CD56 and CD49e expression was significantly higher in the presence of myeloma cell populations, and the presence of granules did not affect survival. Introduction which include staging the disease according to the inter- national staging system (ISS) [1] and/or Durie-Salmon Multiple myeloma comprises a heterogeneous group of staging system [2], detection of high-risk cytogenetic plasma cell neoplasms, which vary in terms of their mor- abnormalities using fluorescence in situ hybridization phology, phenotype, molecular biology, and clinical behav- (FISH) [3–7], plasma cell labeling index [8], presence of ior. Even though the development of novel agents, such circulating plasma cells [9], and the patient’s gene expres- as bortezomib, thalidomide, and lenalidomide, has sion profile [10–12]. Morphological findings also help in improved the prognosis of the condition over the last predicting the prognosis of multiple myeloma as in the decade, multiple myeloma remains incurable because of case of other hematological malignancies. Greipp et al. its heterogeneity. Studies on multiple myeloma have iden- [13] developed a morphological classification of myeloma tified a large number of prognostic factors for survival, cells. The plasmablastic group demonstrated significantly © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. 3051 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Granule Myeloma K. Suzuki et al. shorter survival rates than those with mature, intermedi- two hematologists and one laboratory technician, identi- ate, and immature cells. fied the granule- containing myeloma cells in each hospital. Granules are detected in the cytoplasm of myeloma Each individual counted 200 cells of each of the patients cells by May- Giemsa staining in some cases. Since the in the hospital in which they worked. Based on the per- first identification of granule- containing myeloma cells by centage of the myeloma cells that contained granules Steinmann, several case reports about granule- containing (cut- off value: 10%), the patients were classified into two myeloma have been published [14–16]. However, the clini- groups; the granule- containing myeloma group (GM) and cal features of granule- containing myeloma cells have not the nongranule- containing myeloma group (non- GM). yet been elucidated. The purpose of this retrospective The patients’ morphological findings were evaluated using study was to investigate the clinical significance of granule- the Greipp criteria, such as mature subtype, intermediate containing myeloma cells, in terms of patient characteristics, subtype, immature subtype, and plasmablastic subtype laboratory results, morphological findings, and prognosis, [13]. in patients with newly diagnosed multiple myeloma (NDMM). Treatment and response assessment Materials and Methods Of the 122 patients, 112 patients received standard induc- tion therapy regimens, such as bortezomib plus dexa- We reviewed the medical records of NDMM patients at methasone (BD); melphalan, bortezomib, and prednisolone Jikei University Hospital or Jikei Kashiwa Hospital diag- (MBP); vincristine, adriamycin, and dexamethasone (VAD); nosed between January 2007 and October 2013 and were melphalan plus prednisolone (MP); or high- dose dexa- followed up until December 2014. This study was approved methasone (HDD). Seventeen patients received high-dose by the independent ethics committee/institutional review melphalan followed by autologous peripheral blood stem board of our institution. cell transplantation after induction therapy. Patients who relapsed or had refractory disease received salvage therapy involving BD and MBP; cyclophosphamide, bortezomib, Patients and dexamethasone (CVD); bortezomib, thalidomide, and Patients were included if they had symptomatic multiple dexamethasone (BTD); bortezomib, lenalidomide, and myeloma and were older than 20 years. Symptomatic dexamethasone (BLD); lenalidomide plus low- dose dexa- multiple myeloma was defined as serum monoclonal pro- methasone (Ld); thalidomide plus dexamethasone (TD); tein level of 3 g/dL or more and when 10% or more of ranimustine, vincristine, melphalan, and dexamethasone the bone marrow plasma indicated any of the following (ROAD) [20]; MP; HDD; or VAD. Disease response was conditions: calcium elevation, renal insufficiency, anemia, assessed according to the International Myeloma Working or bone disease (CRAB) [17, 18]. The CRAB components Group criteria [21]. were defined as follows; calcium elevation: serum calcium level >11.0 mg/dL, renal insufficiency: serum creatinine Prognostic factors level >2 mg/dL, anemia: hemoglobin concentration <10 or 2 g/dL less than the lower limit of the normal range, The following parameters were recorded and evaluated and bone disease: lytic or osteopenic bone disease [19]. in each myeloma group: age, gender, hemoglobin con- Patients with monoclonal gammopathy of undetermined centration, estimated glomerular filtration rate (eGFR), significance (MGUS), smoldering multiple myeloma, or serum C- reactive protein (CRP) level, serum lactate dehy- primary plasma cell leukemia were excluded from the drogenase (LDH) level, serum beta- 2 microglobulin (β2m) analysis. level, disease stage according to the ISS, morphological subtype according to Greipp’s criteria, surface antigen expression patterns analyzed by flow cytometry (FCM), Analysis of morphological findings and cytogenetic abnormalities. FCM analysis was performed Granule- containing myeloma cells were defined as mye- in a single laboratory at Special Reference Laboratories, loma cells in which three or more granules were detected Inc. (SRL, Tokyo Japan) using antibodies against CD19, in the cytoplasm by May-Giemsa staining. The ultras- CD33, CD45, CD49e, and CD56. The expression levels tructure of typical granule-containing myeloma cells was of CD19, CD33, CD45, CD49e, and CD56 in CD38-positive analyzed by electron microscopy. Granule- containing cells were evaluated using a two-color panel of antibodies. myeloma cells were identified after differential counts of Cytogenetic analyses were performed using Q banding 200 cells had been performed by three hematologists and karyotyping at Jikei University Hospital and G banding two laboratory technicians. Three individuals, including karyotyping at Jikei Kashiwa Hospital. 3052 © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. K. Suzuki et al. Granule Myeloma Table 1. Patient characteristics. Table 1. (Continued). Granule Nongranule Granule Nongranule All