Therapeutic Effects of Lenalidomide on Hemorrhagic Intestinal Myeloma-associated AL Amyloidosis

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1 CASE REPORT Therapeutic Effects of Lenalidomide on Hemorrhagic Intestinal Myeloma-associated AL Amyloidosis Seiji Nagano 1,MinakoMori 1,AikoKato 1, Yuichiro Ono 1, Kazunari Aoki 1, Hiroshi Arima 1, Yoko Takiuchi 1, Sumie Tabata 1, Soshi Yanagita 1, Akiko Matsushita 1, Takayuki Ishikawa 1, Hiroyuki Imai 2 and Takayuki Takahashi 3 Abstract A 74-year-old woman with refractory IgG-κ multiple myeloma developed massive melena caused by hemorrhagic submucosal tumors in the duodenum and middle jejunum. A biopsy revealed the tumor to be marked AL amyloid deposition. Treatment with bortezomib did not improve the melena or the underlying disease. The patient also developed multiple amyloidomas in the bilateral femoral heads, which caused a fracture in the left femoral head. Treatment with lenalidomide, as the final therapeutic option, resolved the intractable melena and improved both the intestinal lesions and myeloma. This case shows that successful treatment of multiple myeloma leads to marked improvement of accompanying AL amyloidosis. Key words: multiple myeloma, AL amyloidosis, intestinal amyloidosis, bone amyloidosis, lenalidomide (Intern Med 52: , 2013) () Introduction Myeloma-associated amyloidosis is found in approximately 10% of myeloma patients (1). The amyloid substance, which originates from immunoglobulin light chains produced by myeloma cells, consists of misfolded proteins with a β-pleated sheet structure (AL amyloid). AL amyloid deposits and accumulates in various tissues and organs, leading to organ dysfunctions such as heart failure, renal insufficiency and peripheral neuropathy. Controlling the supply of amyloidogenic light chains, namely, successfully treating multiple myeloma, may reduce the burden of amyloidosis and lead to recovery of the damaged organ function. Under this rationale, the administration of intensive chemotherapy, including high-dose intravenous melphalan, supported by autologous hematopoietic stem cell transplantation has shown some efficacy in treating AL amyloidosis (2). In recent years, novel agents that are highly active against multiple myeloma, including bortezomib and lenalidomide, have been investigated as potential therapeutic options for AL amyloidosis. In this article, we report the excellent therapeutic effects of lenalidomide on both hemorrhagic intestinal amyloidosis and underlying multiple myeloma. Case Report A 74-year-old woman was diagnosed in 2008 with multiple myeloma (IgG-κ) accompanied by bilateral carpal tunnel syndrome, wrist pain and peripheral neuropathy in her hands. A blood test revealed a hemoglobin level of 10.6 g/ dl, an IgG serum concentration of 2,690 mg/dl, a creatinine level of 0.9 mg/dl and a β2 microglobulin level of 4.2 mg/l. Serum immunoelectrophoresis revealed the presence of IgG-κ type M-protein. Plasma cells in the bone marrow comprised 37% of nucleated cells. No osteolytic lesions were found on an X-ray examination. Although the patient did not complain of abdominal distress, an endoscopic examination performed in 2009 revealed moderate amyloid deposition in the duodenal mucosa (Fig. 1A). She subsequently received several chemotherapies, including melphalan and prednisolone (MP), vincristine, adriamycin and dex- Departments of Hematology and Clinical Immunology, Kobe City Medical Center General Hospital, Japan, Department of Clinical Pathology, Kobe City Medical Center General Hospital, Japan and Department of Hematology, Shinko Hospital, Japan Received for publication July 16, 2012; Accepted for publication December 27, 2012 Correspondence to Dr. Takayuki Takahashi, takahashi.takayuki@shinkohp.or.jp 1101

2 A B C Figure 1. Endoscopic examination of the duodenum. A: Duodenal endoscopy performed in The mucosal folds are slightly hypertrophic. B: Endoscopy of the same portion as A performed in February The mucosal folds are markedly hypertrophic and tumor-like. Hemorrhage from erosive mucosa is seen in certain areas. C: Endoscopy performed in March The hypertrophy of the mucosal folds is improved, and no mucosal bleeding is observed. Figure 2. Barium-contrasted gastrointestinography. Many tumoral lesions extending from the duodenum to the middle jejunum are noted. amethasone (VAD) and thalidomide, showing a modest decrease in the amount of M-protein. In February 2010, the patient was urgently admitted to the hospital due to massive melena. She had numbness and tingling in the distal portions of the fingers, although no skin lesions or macroglossia were physically observed. Plasma cells in the bone marrow comprised 10% of nucleated cells, while the serum IgG concentration was 1,360 mg/dl, which did not fulfill the criteria of a partial response of multiple myeloma (3). At that time, an endoscopic examination revealed many hemorrhagic submucosal tumoral lesions in the duodenum (Fig. 1B). Barium-contrasted gastrointestinography also showed many tumoral lesions extending from the duodenum to the middle jejunum (Fig. 2). A histopathological examination of the biopsy specimens obtained from the tumoral lesion revealed massive amyloid deposition (Fig. 3A, B). Treatment with permanganic acid did not affect Congo-red positivity, indicating the AL nature of the amyloid (data not shown). Skin and rectal mucosa biopsies were negative for amyloid deposition. Echocardiography also showed no signs of cardiac amyloidosis. However, CT scans revealed large osteolytic lesions in the bilateral femoral heads (Fig. 4A), suggesting bone destruction caused by myeloma invasion. The patient required large amounts of red blood cell transfusions because achieving endoscopic hemostasis was impossible due to the extensive hemorrhagic lesions. Combination treatment with bortezomib and dexamethasone (BD) did not reduce the frequency of melena or the amount of M- protein (IgG: 1,250 mg/dl) despite the administration of sufficient BD treatment (four courses for four months). The patient underwent simultaneous irradiation of the osteolytic lesions in the bilateral femoral heads. However, she developed a fracture in the left femoral neck in March 2010 (Fig. 4B). MRI demonstrated that the femoral neck was replaced by a substance exhibiting a low signal on both T1- (Fig. 5A, B) and T2-weighted imaging. Surgical replacement of the femoral head was performed (Fig. 4C), and the replaced tissue was histologically revealed to be extensive AL amyloid deposition (Fig. 3C, D). The massive melena intermittently continued, and transfusions of large amounts of red blood cells were required at each episode despite the administration of treatment with bortezomib and dexamethasone. In September 2010, lenalidomide, as the final therapeutic option in this patient, terminated the intestinal bleeding. The melena came to a stop approximately two weeks after the initiation of lenalidomide therapy, and the patient no longer required frequent blood transfusions thereafter. In February 2011, the agent also markedly reduced the size of the intestinal mass lesions (Fig. 1C) and the amount of M-protein (1,170 mg/ dl); however, the tumoral lesion in the right femoral head did not improve, as shown on MRI (Fig. 5C, D). In addition, the serum free light chain (FLC) levels were measured in September 2010 and again in March 2011 (Dept. of Lab Med & Pathology, Mayo Clinic, Rochester, USA), showing kappa/lambda FLC levels of 74.5/2.78 mg/dl and 66.3/2.3 mg/dl, respectively, indicating a modest decrease in FLC regardless of the very good partial response observed when evaluated in association with the amount of M-protein. 1102

3 A B C D Figure 3. Histopathologic examination of the biopsy specimens obtained from the duodenum (A, B) and the resected left femoral head (C, D). A: The submucosal space of the duodenum is occupied by amyloid substance (Hematoxylin and Eosin staining, 100). B: The amyloid substance shows diffuse eosinophilic stainability to Congo-red staining ( 100). C: The resected femoral head is occupied by the same amyloid substance as that observed in the duodenum (Hematoxylin and Eosin staining, 100). D: Similar to that present in the duodenum, this substance is positive for Congo-red staining ( 100). Discussion In the present patient, bilateral carpal tunnel syndrome occurred before the diagnosis of multiple myeloma, suggesting the existence of AL amyloidosis at that time. Therefore, the patient s myeloma may have progressed from AL amyloidosis-associated monoclonal gammopathy with undetermined significance (MGUS), formerly called primary AL amyloidosis (4). The current patient present with two characteristic amyloid-related clinical pictures: hemorrhagic intestinal tumor-like and bony space-occupying lesions. Symptoms of intestinal amyloidosis include nausea, diarrhea, malabsorption and less frequently hemorrhage (4). When the amount of amyloid deposition in the intestinal wall is large, endoscopy shows mucosal fold thickening, erosions and/or ulcers. Furthermore, AL amyloid has a tendency to involve intestinal smooth muscle, and muscle tissue is replaced by the amyloid substance when its deposition is massive (5). This pattern of amyloid deposition may have formed tumor-like mucosal folds or protruding polypoid lesions in the present patient. Several cases of macroscopic gastrointestinal bleeding due to amyloidosis have been reported, all of which indicate that the severe bleeding is extremely difficult to control (6-8). Various factors are responsible for massive intestinal hemorrhage in patients with amyloidosis, including amyloid deposition in the subendothelial space (9) or the muscularis mucosae (10). Two forms of amyloidosis of the skeletal system are commonly reported (11). The first is amyloid deposition in the synovia and periarticular tissues, and the second is replacement of the bone marrow of large joints with amyloid deposition. However, massive tumor-like amyloid deposition (termed amyloidoma) in the bone without plasmacytoma is rare (12). It is usually difficult to distinguish bone amylodoma from osteolytic lesions caused by myeloma invasion on bone X-ray (13). In the present patient, radiotherapy of the amyloidoma in both femoral heads was ineffective, and lenalidomide also did not improve the amylodoma on the right femoral head, as shown on MRI. Therefore, AL amyloid accumulation in the bone marrow may be metabolized more slowly than that present in other organs such as the intestines. It was believed a decade ago that deposited amyloid is hardly or very slowly metabolized; therefore, the prognosis of myeloma-related amyloidosis is poor (4). Indeed, the functional recovery of amyloid-affected organs achieved with chemotherapy has been shown to be modest or exceptional. It is also difficult to administer high-dose chemotherapy in patients with myeloma-related amyloidosis because these patients generally have organs impaired by amyloid deposition and may therefore not tolerate high doses of therapy (2). However, with the recent development of novel 1103

4 Intern Med 52: , 2013 A B C Figure 4. Transverse CT scanning (A) and X-ray imaging (B, C) of the bilateral femoral heads. A: Large osteolytic lesions in the bilateral femoral heads are seen, being more conspicuous in the left head. B: A fracture in the left femoral neck is seen (arrow). C: Consequently, surgical replacement of the left femoral head was performed. Figure 5. MRI imaging of the bilateral femoral heads with T1-weighted transverse (A, C) and coronal (B, D) planes. Large space-occupying lesions (arrows) are seen in the bilateral femoral heads, which exhibit a low signal. The left femoral head is surgically replaced (C, D). The size of the spaceoccupying lesions in the right femoral head before (A, B) and after (C, D) the operation is unchanged regardless of treatment with lenalidomide (arrows). agents highly active against multiple myeloma, effective control of multiple myeloma is expected to improve AL amyloidosis. In the present patient, lenalidomide exerted excellent therapeutic effects on the multidrug-resistant multiple myeloma and hemorrhagic intestinal lesions within six months. These data strongly suggest that sufficient control of M-protein, but not FLC, results in a marked reduction of amyloid deposition in a relatively short time, except in cases of bony amyloidosis. Apparent persistent bony amyloid deposition might be caused by large mass formation with a 1104

5 presumably poor blood supply, which leads to slower amyloid metabolism. Changes in serum FLC values, however, have been reported to be a better predictor of clinical outcomes than serum M-spike responses in patients with AL amyloidosis (14). In the present patient, the improvements in the intestinal lesions and myeloma themselves were associated with a reduction in M-protein but not an improvement in the kappa/lambda FLC ratio. This discrepancy seems to be caused by differences in the underlying diseases. That is, FLC more efficiently forms the substrate for amyloid fibril than intact immunoglobulin does in patients with MGUS-associated AL amyloidosis; in other words, FLC may not play a significant role in substrate formation when compared with monoclonal immunoglobulin in myeloma patients. In the present patient, lenalidomide therapy terminated the melena in as little as two weeks after the initiation of therapy. Therefore, we should take into consideration the suppressive effects of this agent on angiogenesis. Indeed, there are several reports of successful treatment of angiodysplasiacaused intestinal bleeding using thalidomide or lenalidomide (15, 16). Our clinical experience with the present patient also suggests that deposited amyloid can be relatively quickly metabolized if the supply of amyloid precursor is eliminated. In fact, we previously observed rapid disappearance of intestinal AA amyloid following the administration of tocilizumab in a patient with severe rheumatoid arthritis (17). Although we did not histologically confirmed a reduction in intestinal amyloidosis in the present case, marked endoscopic improvement in the submucosal tumoral lesions strongly suggests decreased intestinal amyloid deposition. Similarly, the ability to achieve significant control of AL amyloidosis with novel agents has been described in several previous reports (18-23). Therefore, therapeutic modalities for AL amyloidosis as well as multiple myeloma using novel agents should be established in the future. The authors state that they have no Conflict of Interest(COI). References 1. The International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121: , Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood 99: , Durie B, Harousseau J, Miguel J, et al. International uniform response criteria for multiple myeloma. Leukemia 20: , Bird J. Guidelines on the diagnosis and management of AL amyloidosis. Br J Haematol 125: , Tada S, Iida M, Yao T, Kitamoto T, Fujishima M. Intestinal pseudo-obstruction in patients with amyloidosis: clinicopathologic differences between chemical types of amyloid protein. Gut 34: , Chang SS, Lu CL, Tsay SH. 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