多发性骨髓瘤 患者管理浙江大学医学院附属第二医院张晓红多发性骨髓瘤主要表现和并发症疾病相关：骨病、高钙血症、肾功能不全、反复感染、浆细胞瘤治疗相关：心、肝、肾脏器毒性、深静脉血栓形成、周围神经病变、胃肠道反应、血细胞减少、周围性水肿、呼吸困难、潜在致畸性、第二肿瘤。疼痛—骨病常见骨受累部位：头颅、腰椎/胸椎椎体、骨盆、长骨、可发生脊柱压缩多发性溶骨病变支持治疗理疗, 双膦酸盐, 放疗, 卧床, 药物止痛, 后凸成形术或脊柱成形术反复感染WBC 减少，浆细胞正常免疫功能丧失发生率增加15 倍支持治疗抗生素, Ig 治疗考虑应用肺炎和流感疫苗, 并预防卡氏肺囊虫，带状疱疹和真菌感染肾功能不全M 蛋白聚集导致肾小管损伤高钙血症加重肾脏损害支持治疗水化避免应用非甾体类抗炎药(NSAIDs) 避免静脉注射(IV) 造影剂慎用肾毒性药物万珂对肾功能不全患者的疗效肾功能不全万珂药代动力学不受肾功能不全影响无需改变计量由于透析降低万珂浓度，药物应在透析之后应用高钙血症骨病恶化时发生，血/ 尿中钙浓度升高症状食欲减退，乏力，呕吐，肌无力，昏迷，便秘，口渴，多尿支持治疗充分水化, 呋塞米, 双膦酸盐, 皮质激素浆细胞瘤浆细胞聚集并粘附于骨或软组织可发生神经，脊柱或脑组织压缩/ 错位压缩需要紧急处理支持治疗皮质激素，放疗，手术万珂副作用管理万珂潜在不良反应外周神经病变低血压乏力胃肠道血小板减少中性粒细胞减少神经病- 评价方法评估疼痛评估方法: 数字评分量表周围神经病变管理基础评估，神经病问卷调查每次随访时监测有助于早期发现早期监测和适当调整剂量能够缓解或改善神经病变用药控制症状周围神经病管理中推荐的万珂剂量调整方案任何神经病变应用的治疗药物- 引自医学杂志以下是任何神经病患者可以应用的治疗方法FDA 批准糖尿病周围神经病相关性神经性疼痛可应用以下药物治疗Cymbalta ( 度洛西汀) Lyrica ( 普加巴林) 非FDA 批准用于神经病或神经性疼痛的药物抗惊厥药1-3 抗抑郁药4 万珂胃肠道(GI) 不良反应通常易于处理处理治疗相关性低血压处理应包括: 调整降压药患者可能需要抗恶心药物水化锻炼监测血钠水平应用盐皮质激素水化注射万珂前后不需要水化乏力恶心/ 呕吐便秘/ 腹泻发热电解质失衡肾功能不全轻链病可预测的血小板和中性粒细胞变化谢谢! Peripheral neuropathy is characterized by numbness, tingling, burning in feet 	or hands, and may start as discomfort and progress to severe, shooting pain 	and cramps Peripheral neuropathy is associated with myeloma and therapies used to 	treat the disease (vincristine, thalidomide, Velcade) In a study designed to determine the frequency and characteristics of 	neuropathy with Velcade, over 80% of patients had preexisting 	neuropathy 	from prior treatment or from the disease process Patients with prior neuropathy may be at higher risk of worsening symptoms Routine monitoring and assessment are critical Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with Velcade. J Clin Oncol. 2006;24:3113-3120. Patients with myeloma have greatly increased risk for infection—as high as 	15-fold Immune dysfunction is an integral part of the disease process and cytotoxic 	and steroid therapy further reduce neutrophils and the immune response Because infection is the greatest, most dangerous complication for patients 	with myeloma, aggressive antibiotic treatment and prophylaxis is advised Herpes zoster prophylaxis should be considered for patients treated with 	single-agent Velcade Durie BG, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation [erratum Hematol J. 2004;5:285]. Hematol J. 2003;4:379-398. Multiple Myeloma Research Foundation. Intro to Myeloma. Available at: www.multiplemyeloma.org/about_myeloma/index.html. Accessed 2/12/07. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in OncologyTM. Multiple Myeloma. www.book118.com. Available at: www.book118.com. Accessed 2/14/07. Although not all patients with multiple myeloma develop nephropathy, it is a 	significant concern The greatest contributor to kidney dysfunction is monoclonal light chain 	excretion (Bence Jones proteinuria) Other features of myeloma that increase the risk of kidney involvement 	include hypercalcemia, dehydration, hyperuricemia, hyperviscosity, and 	infection Close monitoring is warranted, and hydration, avoidance of NSAIDs and IV 	contrast dyes, and caution with bisphosphonates are required measures Durie BG, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation [erratum Hematol J. 2004;5:285]. Hematol J. 2003;4:379-398. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in OncologyTM. Multiple Myeloma. www.book118.com. Available at: www.book118.com. Accessed 2/14/07. As myeloma cells grow unchecked, bone destruction occurs, producing 	lesions, fractures, and pain Pain, particularly in the back and associated with movement, is often present 	at diagnosis Patients’height may be reduced by several inches because of vertebral 	collapse The majority of patients with myeloma (80%) develop lytic bone lesions 	and/or diffuse osteopenia The accumulation of myeloma cells in the bone produces an imbalance 	between osteoblast activity (formation) and osteoclast activity (resorption) Bone formation is inhibited and osteoclast activity is activated Supportive therapy centers on bisphosphonates, pain control, low-dose 	radiation, and kyphoplasty Barlogie B, Shaughnessy J, Epstein J, et al. Plasma cell myeloma. In: Lichtman MA, Beutler E, Kipps TJ, et al, eds. Williams Hematology. 7th ed. New York, NY: McGraw-Hill; 2006:chap 100. Durie BG, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation [erratum Hematol J. 2004;5:285]. Hematol J. 2003;4:379-398. Kyle RA, Rajkumar SV. Plasma cell disorders. In: Goldman L, Ausiello D, eds. Cecil Textbook of Medicine, 22nd ed. Philadelphia, PA: Saunders; 2004:1184-1195. 	 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in OncologyTM. Multiple Myeloma. www.book118.com. Available at: www.book118.com. Accessed 2/14/07. VELCADE: Efficacy in Patients With Renal Impairment To assess the impact of impaired renal function on the efficacy and tolerability of VELCADE, data from the SUMMIT and CREST studies were analyzed according to baseline creatinine clearance values. The subset analysis demonstrated a response rate of 30% in patients with severe renal impairment (creatinine clearance <30 mL/min) and 25% in those with moderate renal impairment. The overall frequency of discontinuation was similar regardless of renal function at baseline. Minor differences in the incidence of grade 3/4 adverse events were observed, with a trend toward a higher incidence of weakness, diarrhea, pyrexia, and constipation. The only grade 3/4 event with a significantly higher incidence in patients with creatinine clearance ≤50 mL/min vs >80 mL/min was dyspnea. Reference Data on file. Millennium Pharmaceuticals, Inc. *  SUMMIT 和CREST 试验患者亚组分析显示万珂使肾功能不全患者获益30 38 22 万珂停药率(%) 30 25 33 反应率(CR+PR+MR, %) 13.8-30 (n = 10) 30–50 (n = 42) 51–80 (n = 99) CrCl (mL/min) 参加试验患者最低肌酐清除率为13.8 mL/min 药物安全性在肾功能正常或异常患者中类似气短是肌酐清除率≤50 mL/min 患者唯一显著升高的不良反应CrCl = creatinine clearance. Data on file, Millennium Pharmaceuticals, Inc. Durie BG, et al. Hematol J. 2003;4:379-398. NCCN Clinical Practice Guidelines. www.book118.com. Barlogie B, et al. In: Williams Hematology. 7th ed. 2006:chap 100. Durie BGM. International Myeloma Foundation. 2006. www.book118.com. NCCN Clinical Practice Guidelines. www.book118.com. MM 疾病与PN MM 与周围神经病变相关是不争的事实。新诊断MM 11-20% ，60% 异常NCS （神经传导检测）进展期MM 39- 50% 异常NCS 难治复发MM 83% （临床神经学检查）1. Chaudhry V, et al. J Peripheral Nervous System. 2008;13(4)2 6 7- 74 2. Richardson PG, et al. J Clin Oncol. Epub ahead of print. 2009. 3. Richardson PG, et al. J Clin Oncol. 2006;19:3113–3120. 4. Mileshkin L, et al. J Clin Oncol. 2006;20;24(27):4507–4514. 化疗药物相关PN 沙利度胺也会造成剂量相关性周围神经病长春新碱的副作用是严重的周围神经病，胃肠道反应，脱发。周围神经病的首发症状是足下垂（腓神经），鞘注是绝对禁忌，致残率100% 其它化疗药物：顺铂、紫杉醇、甲氨蝶呤、阿糖胞苷、异环磷酰胺化疗药物的应用和减停