Case Discussion [Brief History] The 63 year-old male was a case of general health before and denied any systemic disease. This time, the patient suffered from petechiae over four limbs, easy bruising, dizziness, easy fatigue and exertion dyspnea in recent 2~3 months. No tarry stool or bloody stool, no orthopnea, no fever, no chills, no cough, no sputum was noted. There was also no family history of bleeding tendency. Due to the symptoms and signs described above, the patient visited medical help and initial CBC revealed anemia and thrombocytopenia (WBC 3510/ul, Hb 7.2 g/dl, PLT 120000/ul) and then transferred to our hospital for further evaluation treatment. [Laboratory Date] After admitted to our ward, a serial survey were performed a listed as below: Peripheral blood smear: Thrombocytopenia and Rouleaux formation was noted. Biochemistry: TP/Alb: 9.48/3.93 g/dl, A/G ratio: 0.7 Beta-2 Microglobulin : 598 ug/dl, LDH 517 u/L BUN/Cr: 25/1.6 mg/dl  Immunoglobulin:IgG/A/M: 6880/11.5/9.54 mg/dl Electrolyte: Na/K/Cl: 141/4.1/103 mEq/L, Total calcium: 10.3 mg/dl Protein Electrophoresis: monoclonal gammopathy. Immunoelectrophoresis: IgG l monoclonal gammopathy, Bence-Jones proteinuria. BMA: Increased cellularity (70%), plasma cell increased (80%) with bizarre formation. Abdominal echo: splenomegaly. Hepatitis marker: HBsAg (-), Anti-HCV (-) [Treatment and Course]  According to the above survey, the patient was diagnosed as multiple myeloma (IgG, ltype). Besides, the stage IIIA was also diagnosed because of hemoglobin level < 8.5 g/dl and serum creatinine level < 2 mg/dl. Due to advance stage, the patient received systemic chemotherapy with melphalan (8 mg/m2) and prednisolone (25~60 mg/m2) administered for 7 days every 4~6 weeks. After several courses of treatment, the IgG level may reduce to around 2 mg/dl. [Discussion]  多發性骨髓瘤是一種plasma cells惡性增生的疾病，其確切發病原因仍未確定。多發性骨髓瘤的發生率隨著年紀的增加而增加，診斷的median age是68 歲，很少有患者在40歲之前被診斷出來。 骨頭疼痛是多發性骨髓瘤最常見的症狀，影響大約70%的患者。這種疼痛常會因為活動而加重。其原因通常是因為proliferation of tumor cells以及activation of osteoclasts that destroy the bone所造成。骨頭病灶大多是蝕骨性的 (osteolytic)，少有new bone formation的情形。第二常見的問題是容易遭受細菌感染。多發性骨髓瘤患者最常發生的感染是pneumonia以及pyelonephritis。在肺炎最常見的菌種包括：Streptococcus pneumoniae、Staphylococcus aureus、Klebsiella pneumoniae，在泌尿道最常見的菌種則包括：Escherichia coli以及其他gram-negative organisms。大約有25%的患者是以反覆性感染來表現的。此外，有25%的患者會有腎臟衰竭的情形。造成腎臟衰竭的原因包括：高血鈣、Amyloid沈積在glomerulus、泌尿道反覆感染、或是腎臟被myeloma cells所浸潤。其他的臨床表現包括：貧血、高血鈣、黏滯係數過高…等。 診斷方面，多發性骨髓瘤的triad包括：(1) marrow plasmacytosis > 10%,(2) lytic bone lesions, (3) Serum and/or urine M component。但即使患者沒有osteolytic bone lesion，若是患者有marrow plasmacytosis以及逐漸上升的M component仍然可以診斷為多發性骨髓瘤。但是，測不到M component的多發性骨髓瘤患者則是不到1%。Staging System主要根據hemoglobin、serum calcium、lytic bone lesion、M-component production而分為Stage I, II, III；並根據serum creatinine level再細分為A or B。b2-microglobulin是單一變項中與預後關係最密切的。 大多數的多發性骨髓瘤患者是必須受治療的，包括所有的stage II、stage III、以及部分的stage I患者必須接受systemic combination chemotherapy；治療可以改善survival以及生活品質。傳統standard treatment是間歇性的給予一種Alkylating agent加上prednisolone，每次給予4~7天，每4~6星期給予一次。在Alkylating agent中最常用的Melphalan，其常用劑量為8 mg/m2/day；至於prednisolone的常用劑量為25~60 mg/m2/day。至於治療最適當的duration目前仍未確定，大部分的醫師會每4~6 weeks一個療程持續1~2年。停藥之後疾病常常會再復發，而且大都在一年之內復發。再次給予治療，2nd response rate仍然可以達到80%。其他的治療方式有自體或是異體造血幹細胞移植，thalidomide等。預後方面，有15%的患者 在診斷後的三個月內會死亡，其後每年增加15%的死亡率。病患在發生acute terminal phase (通常以pancytopenia表現且對治療沒有反應)之前，通常會有2~5年的chronic course。 繼續教育考題 1. (A) Multiple myeloma represents a malignant proliferation of which cells? A Plasma cell. B  Neutrophil C  Monocyte D  Macrophage E Lymphoblast 2. (B) Which is the most common symptom in myeloma, affecting nearly 70% of patients? A Abdominal pain B Bone pain. C Burning urination D Consciousness disturbance E Cough 3. (C) The two most common infections in myeloma patients are: 1. pneumonia, 2. perianal abscess, 3. liver abscess, 4. pyelonephritis A 1+2 B 1+3 C 1+4 D 1+2+3 E 1+2+3+4 4. (D) Renal failure occurs in nearly 25% of myeloma patients. Many factors may contribute to renal failure except: A Hypercalcemia. B Glomerular deposits of amyloid. C Hyperuricemia. D Hypoalbuminemia E Infiltration of the kidney by myeloma cells. 5. (E) M components may be detected in which of following conditions: A Lymphoid neoplasms such as CLL, Lymphoma. B Non-lymphoid neoplasms such as CML, breast cancer and colon cancer. C Non-neoplastic conditions such as cirrhosis, sarcoidosis, parasitic diseases, Gaucher’s disease. D A number of autoimmune conditions, including rheumatoid arthritis, myasthenia gravis, and cold agglutinin disease. E All of above. 6. (A) Anemia occurs in a about 80% of myeloma patients. Which of the following descriptions about this condition is “wrong”? A Schistocytes usually seen on peripheral blood smear. B It is usually normocytic and normochromic C Related to replacement of normal marrow by expanding tumor cells. D Related to inhibition of hematopoiesis by factors made by the tumor. E Mild hemolysis may also contribute to anemia. 7. (B) Which of the description is “not” classic triad of myeloma? A Marrow plasmacytosis (> 10%). B Recurrent infection. C Lytic bone lesions. D  Serum and/or urine M component. E None of above. 8. (C) Which is the single most powerful predictor of survival and can substitute for staging. A Hemoglobin. B Serum Calcium. C b2-microglobulin D Advanced lytic bone lesions. E High M-component production. 9. (D) The most frequent pneumonia pathogens in myeloma patients are: 1. Streptococcus pneumoniae, 2. Staphylococcus aureus, 3. Klebsiella pneumoniae, 4. Pseudomonas aeruginosa A 1+4 B 2+4 C 3+4 D 1+2+3 E 1+2+3+4 10. (E) Which of the clinical finding and underlying cause in myeloma patient is “not” correct? A Hypercalcemia — Skeletal destruction.  B Infection — Hypogammaglobulinemia, decreased neutrophil migration. C Neurologic symptoms — Hyperviscosity, cryoglobulins, amyloid deposits. D Bleeding — Interference with clotting factors, amyloid damage of endothelium, platelet dysfunction. E None of above.

答案解說 (A)  Multiple myeloma是plasma cell惡性增生所導致的疾病。 (B  Multiple myeloma患者最常見的symptom是bone pain。 (C ) Multiple myeloma患者最常見的感染是pneumonia以及pyelonephritis。 (D) 造成myeloma患者renal failure原因包括hypercalcemia、glomerular deposits of amyloid、hyperuricemia、infiltration of the kidney by myeloma cells等，但不包括hypoalbuminemia。  (E) 造成monoclonal gammopathy的原因不是只有multiple myeloma而已，其他一些malignant甚至non-malignant diseases如autoimmune conditions都有可能。 (A ) Schistocytes可能在TTP、HUS、DIC見到。 (B) Multiple myeloma的triad包括marrow plasmacytosis、lytic bone lesions、serum and/or urine M component。 (C ) Multiple myeloma患者與survival最有關的單一預後因子是β2-microglobulin。 (D) Multiple myeloma患者罹患肺炎最常見的致病菌是Streptococcus pneumoniae、Staphylococcus aureus、Klebsiella pneumoniae。 (E ) Ａ、Ｂ、Ｃ、Ｄ都正確。