經 多 線 新 藥 治 療 後 多 發 性 骨 髓 瘤 產 生 之 " 輕 鍊 脫 逃 " 現 象 及 災 難 性
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1 台 灣 癌 症 醫 誌 (J. Cancer Res. Pract.) 1(1), 39-45, 2014 Case Report journal homepage: Light Chain Escape Multiple Myeloma Complicated with Catastrophic Extramedullary Plasmacytoma Following Novel Agent Treatment Yi-Ping Hung 1,2, Ching-Fen Yang 2,3, Liang-Tsai Hsiao 1,2 * 1 Division of Haematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 2 National Yang-Ming University School of Medicine, Taipei, Taiwan 3 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Abstract. The treatment of multiple myeloma (MM) has made greatly advances over the last decade, nearly doubling the overall survival time after the use of novel agents such as thalidomide, lenalidomide and bortezomib. However, the improvement of overall survival has occasionally led to clinical scenarios that were rarely recognized before, for example, light chain escape and extramedullary plasmacytoma (EMP). Here we report an MM patient who relapsed and manifested simultaneously with both a light chain escape and a disseminated pattern of EMP after several different modes of treatment, including conventional chemotherapy, autologous peripheral blood stem cell (PBSC) transplantation, and novel agents. The result was disappointing in this case, which taught us several important things: First, intact immunoglobulin may not be a reliable marker in the surveillance of pretreated multiple myeloma. Various tests for renal function, skeletal condition, and serum free light chain should also be carried out for a comprehensive evaluation. Second, EMP remains a tremendous challenge to the clinician, especially when refractory to current novel agents. Further researches are required to clarify the optimal treatment of such a condition in order to help more patients. 病 例 報 告 Keywords : multiple myeloma, light chain escape, extramedullary plasmacytoma, novel agents, serum free light chain 經 多 線 新 藥 治 療 後 多 發 性 骨 髓 瘤 產 生 之 " 輕 鍊 脫 逃 " 現 象 及 災 難 性 髓 外 漿 細 胞 瘤 洪 逸 平 1,2 楊 靜 芬 2,3 蕭 樑 材 1,2 * 1 台 北 榮 民 總 醫 院 內 科 部 血 液 腫 瘤 科 2 國 立 陽 明 大 學 醫 學 院 3 台 北 榮 民 總 醫 院 病 理 檢 驗 部 中 文 摘 要 多 發 性 骨 髓 瘤 的 治 療 在 近 幾 年 來 蓬 勃 的 發 展, 使 得 病 患 的 存 活 時 間 幾 乎 延 長 至 兩 倍, 不 過, 存 活 時 間 的 進 步 也 導 致 一 些 原 本 不 常 見 的 臨 床 情 況 出 現, 輕 鏈 脫 逃 和 髓 外 漿 細 胞 瘤 就 是 其 中 的 代 表 在 這 裡 我 們 提 出 了 一 個 多 發 性 骨 髓 瘤 的 臨 床 案 例, 就 是 在 接
2 40 Y. P. Hung et al./jcrp 1(2014) 受 了 包 含 傳 統 化 療 自 體 幹 細 胞 移 植 以 及 標 靶 藥 物 後 同 時 發 生 了 這 兩 種 現 象, 這 個 病 患 的 治 療 結 果 是 令 人 失 望 的 但 是 我 們 從 這 個 案 例 學 到 了 一 些 經 驗 : 第 一 免 疫 球 蛋 白 的 檢 查 在 多 發 性 骨 髓 瘤 的 監 控 上 可 能 不 是 一 個 可 靠 的 工 具, 需 要 合 併 腎 功 能 檢 查 骨 骼 檢 查 以 及 血 漿 游 離 輕 鍊 檢 查, 才 能 得 到 最 好 的 監 測 效 果 ; 第 二, 髓 外 漿 細 胞 瘤 仍 是 一 個 非 常 難 治 療 的 病 症, 仍 有 賴 後 續 的 研 究 來 發 展 出 真 正 有 效 的 治 療 藥 物, 以 幫 助 更 多 的 病 患 關 鍵 字 : 多 發 性 骨 髓 瘤 輕 鏈 脫 逃 髓 外 漿 細 胞 瘤 新 藥 血 漿 游 離 輕 鏈 檢 查 INTRODUCTION The treatment of multiple myeloma (MM) has made great advances over the last decade and has nearly doubled the overall survival time as compared to that of patients treated before 2000, primarily awing to the novel agents, including thalidomide, lenalidomide and bortezomib [1,2]. However, the improvement of overall survival has occasionally led to clinical scenarios that were rarely recognized before. One of these most difficult is the disease manifested or relapsed as extramedullary plasmacytoma (EMP) in visceral organs, lymph nodes, and the central nervous system[3-10]. The presentations of such EMPs vary in different locations and most studies report a very disappointing prognosis in this group of patients [3,4,11]. On the other hand, free light chain (FLC) concentration (in the serum) is a new assay method that used polyclonal antibodies against FLC to determine the serum concentration of free lambda and kappa light chains [12]. It has not only improved the diagnosis of myeloma, non-secretory MM [13], but also became a powerful tool to detect early relapse. Recently, light chain escape has been observed in some patients with former secretory MM after administration of chemotherapy [14], and in these patients the MM appeared stable as indicated by decreasing intact Ig levels, but *Corresponding author: Liang-Tsai Hsiao M.D. * 通 訊 作 者 : 蕭 樑 材 醫 師 Tel: Fax: lthsiao@vghtpe.gov.tw they developed notable organ dysfunctions as a consequence of unexpected light-chain MM progression. Here we report a MM patient who relapsed and manifested simultaneously with both light chain escape and a disseminated pattern of EMP after several different modes of treatment, including conventional chemotherapy, autologous peripheral blood stem cell (PBSC) transplantation, and novel agents. CASE REPORT A 70-year-old Chinese female presented with left hip pain in February, She had a history of essential hypertension under medical control for 20 years. The X-ray of the left hip showed an osteolytic bone lesion, and subsequent studies. Investigating monoclonal gammopathy confirmed the diagnosis of IgA/lambda multiple myeloma, International Staging System stage 1, and Durie-Salmon stage II. At the time of diagnosis, the level of serum IgA was 2390 mg/dl (normal range, ), but serum FLC assay was not available at that time, as shown in Figure 1. She received induction chemotherapy with the VAD regimen (vincristine, doxorubicin and dexamethasone) for 6 cycles between March 2010 and September During the period, she also received zoledronic acid monthly and the harvest of PBSC. Autologous PBSC transplantation was performed on November 11, After transplantation, she received regular out-patient follow up, with laboratory monitoring including serum IgA, FLC assay and renal function tests (including creatinine [Cr]). A complete response was achieved one month after the transplantation, with the serum IgA level of 156 mg/dl (normal range, ) and
3 Y. P. Hung et al./jcrp 1(2014) Figure 1. The changes of serum IgA, free kappa/lambda ratio, creatinine and free lambda and treatments through the whole course of multiple myeloma. Two episodes of light chain escapes were noted in August 2011 and October 2012 serum FLC (Kappa/Lambda) ratio of 0.95 (normal range, ), as shown in Figure 1. Maintenance therapy with thalidomide was asministrated, starting on day 71 post-transplantation, but stopping on June 15, 2011 (day 201) because of the intolerance. The serum levels of Cr and IgA, and FLC ratio remained normal till August 2, 2011, when serum Cr (1.1 mg/dl) and IgA (124 mg/dl) levels were within the normal range, but an increased lambda light chain level with an FLC ratio of 0.01 was found. Two weeks later, when she re-visited the out-patient department on August 16, 2011, acute renal failure with serum Cr increasing to 5.07 mg/dl, and the level of serum IgA surging to 900 mg/dl (reference range mg/dl), and the bone marrow study confirmed the relapse of disease. According to the criteria described before [14], myeloma relapse with light chain escapes and resulting acute renal failure was diagnosed. Bortezomib was promptly started on August 20, 2011 and the serum Cr level returned to normal 2 months later. However, bortezomib therapy was discontinued in February 2012 because of peripheral neuropathy. Conventional chemotherapy with different combinations including melphalan and dexamethasone, and cyclophosphamide and prednisolone was carried out thereafter to control the disease till October The second episode of light chain escapes was noted in October 2012, when the serum IgA level was normal (140 mg/dl), but the serum FLC ratio declined to 0.03 on October 23, As was seen in the first event,
4 42 Y. P. Hung et al./jcrp 1(2014) A B Figure 2. Extramedullary plasmacytoma manifested as two huge pedunculated polypoid masses, located in the high body (a) and fundus (b) of the stomach, both measuring 4 cm in diameter A B Figure 3. Histology of polypoid masses in the stomach. The sections showed an inflammatory exudate and an aggregate of atypical plasma cells with H&E stain (a), which were immunocytochemically positive for CD138 (b) and Lambda light chain (c) C
5 Y. P. Hung et al./jcrp 1(2014) Figure 4. Sagittal views of abdominal CT showed variable-sized polypoid masses noted in gastric fundus and pars angularis of lesser sac of stomach; small soft tissue nodules in right renal fossa, right para-renal space and left posterior para-renal space; Ill-definted lobulated soft tissue nodules noted beside both common iliac arteries, right internal iliac artery, left external, internal iliac artery, uterus and bladder; and plasmacytoma encasing left ureter, resulting in proximal hydroureter and hydronephrosis acute renal failure was noted with serum Cr increasing from 1.07 mg/dl on September 25, 2012 to 4.83 mg/dl on November 20, Although bortezomib was given again to control the disease, the renal failure was not improved, and hemodialysis was soon initiated. The serum IgA level remained within the normal range and did not elevate, with the level at 518 mg/dl (normal range, ) till January Furthermore, progressive ileus and gastrointestinal (GI) bleeding were noted in late December 2012, with fresh-blood vomitus. Panendoscopy of the upper GI tract was performed and revealed two huge pedunculated polyp-like masses in the high body and fundus of the stomach, each 4 cm in size (Figure 2A and 2B). The pathological examination of the biopsy confirmed plasmacytoma, which was immune-histochemically positive to lambda and CD138 (Figure 3). As the patient further suffered from the symptoms of progressive abdominal distention and hematuria, a computed tomogram of the abdomen was taken in February 2013 and showed disseminated plasmacytoma involving the stomach, kidney, urinary bladder, uterus and retroperitoneum (Figure 4). Left hydronephrosis and hydroureter due to plasmacytoma encasing the left ureter was found. Although lenalidomide was given, pancytopenia and intermittent bleeding including vomiting of fresh blood, passage of bloody stools and hematuria were not well controlled. The renal failure
6 44 Y. P. Hung et al./jcrp 1(2014) did not recover. On April 26, 2013, the patient died of pneumonia. DISCUSSION Novel agents have improved the treatment outcome of patients with multiple myeloma. However, prolonged survival has resulted in changes in the biological behavior of MM and unusual types of relapse, such as EMP or a shift in secretion from intact immunoglobulin (Ig) to free-light chains (FLCs) only [14]. Both of these phenomena simultaneously occurred in our patient. In the two episodes of acute renal failure, the serum FLC ratio had changed when the IgA still remained in the normal range. Acute renal failure rapidly developed later. The IgA level seemed to lose the power to predict the disease activity of the myeloma. Former researchers noticed such changes and denominated the phenomenon as the escape of myeloma or light chain escape [15,16]. The findings in our patient further provide clues supporting the importance of simultaneous serum FLC monitoring of myeloma progression, instead of IgA detection alone. If not, we may overlook the early signs of disease relapse and miss the chance to save the patient s life. One of the previous case series showed an aggressive disease course in such a group of patients [16], but another did not [14]. Aggressive EMP is another critical issue in the era of novel anti-myeloma agents. In our case, the patient received conventional chemotherapy with VAD and melphalan, autologous peripheral blood stem cell transplant, and novel agents including thalidomide and bortezomib before the occurrence of EMP. Although lenalidomide was administrated, the efficacy was limited. Papanikolaou et al. reported the incidence of extramedullary relapse of 9% in 303 Greek patients with MM [11], and these patients had a poor outcome. Another study in the US which enrolled 936 EMP patients demonstrated shorter progression-free survival and overall survival [3], when novel agents had been administered. On the other hand, previous case reports have demonstrated the efficacy of lenalidomide in refractory EMP [17], or administration of thalidomide and bortezomib as induction and reinforced by autologous stem cell transplantation [5,18-20]. In addition, there was another case of primary EMP in the stomach that achieved a durable complete pathological response after radical radiotherapy with minimal toxicity [21]. Recently, the analysis of cytogenetic aberration of EMP using fluorescence in situ hybridization suggested the relevance of del(17p13) and del(13q14) to the metastatic feature of myeloma cells [22]. CONCLUSIONS To the best of our knowledge, this is the first report to the record a case that had extramedullary plasmacytoma after light chain escape. The treatment result of this patient was disappointing; however we have learned something from this case: First, intact immunoglobulin may not be a reliable marker in the surveillance of pretreated multiple myeloma. Renal function, skeletal condition, and serum free light chains should also be examined for a comprehensive evaluation. Second, EMP remains a tremendous challenge to the clinician, especially when refractory to current novel agents. Further researches are necessary to clarify the optimal treatment of such a condition in order to help more patients. REFERENCES 1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 111: , Yang SH, Teng HW, Hong YC, et al. International Staging System predicts prognosis of Chinese patients with multiple myeloma across different calendar periods with application of novel agents. Ann Hematol 91: , Usmani SZ, Heuck C, Mitchell A, et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in
7 Y. P. Hung et al./jcrp 1(2014) high-risk disease even in the era of novel agents. Haematologica 97: , Moreau P, Polliack A. Extramedullary multiple myeloma: extraosseous relapse is extra "bad news," but why? Leuk Lymphoma 54: , Lopes da Silva R. Extramedullary plasmacytoma of the small intestine: clinical features, diagnosis and treatment. J Dig Dis 13: 10-18, Gozzetti A, Marchini E, Banchi B, et al. Extramedullary multifocal plasmacytoma relapse in multiple myeloma. Leuk Res 36: e34-36, Park BJ, Kalish RJ, Vercillo AP. Disseminated plasmacytoma of the thyroid. Ear Nose Throat J 89: , Gupta P, Rice GD, Abraham K, et al. Extramedullary plasmacytoma of the pancreas and jejunum. Clin Imaging 33: , Straetmans J, Stokroos R. Extramedullary plasmacytomas in the head and neck region. Eur Arch Otorhinolaryngol 265: , Lopez A, Mendez F, Puras-Baez A. Extramedullary plasmacytoma invading the bladder: case report and review of the literature. Urol Oncol 21: , Papanikolaou X, Repousis P, Tzenou T, et al. Incidence, clinical features, laboratory findings and outcome of patients with multiple myeloma presenting with extramedullary relapse. Leuk Lymphoma 54: , Bradwell AR, Carr-Smith HD, Mead GP, et al. Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine. Clin Chem 47: , Mayo MM, Johns GS. Serum free light chains in the diagnosis and monitoring of patients with plasma cell dyscrasias. Contrib Nephrol 153: 44-65, Kuhnemund A, Liebisch P, Bauchmuller K, et al. 'Light-chain escape-multiple myeloma'-an escape phenomenon from plateau phase: report of the largest patient series using LC-monitoring. J Cancer Res Clin Oncol 135: , Joshua DE, Gibson J, Brown RD. Mechanisms of the escape phase of myeloma. Blood Rev 8: 13-20, Dawson MA, Patil S, Spencer A. Extramedullary relapse of multiple myeloma associated with a shift in secretion from intact immunoglobulin to light chains. Haematologica 92: , Nakazato T, Mihara A, Ito C, et al. Lenalidomide is active for extramedullary disease in refractory multiple myeloma. Ann Hematol 91: , Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348: , Laura R, Cibeira MT, Uriburu C, et al. Bortezomib: an effective agent in extramedullary disease in multiple myeloma. Eur J Haematol 76: , Kumar S, Rajkumar SV. Thalidomide and dexamethasone: therapy for multiple myeloma. Expert Rev Anticancer Ther 5: , Tan J, Lade S, Harrison S, et al. Complete remission of localised gastric plasmacytomas following definitive radiotherapy. J Med Imaging Radiat Oncol 56: , Billecke L, Murga Penas EM, May AM, et al. Cytogenetics of extramedullary manifestations in multiple myeloma. Br J Haematol 161: 87-94, 2013.
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