The use of 99mTc-MIBI scanning in multiple myeloma.

Tc-99m 2 methoxy-isobutyl-isonitrile (99mTc-MIBI), also called Sestamibi, is a safe and effective scanning agent in solid tumours. Its use in imaging lesions in multiple myeloma has been studied in 21 patients with either multiple myeloma (19/21) or monoclonal gammopathy of undetermined significance (MGUS) (2/ 21). 99mTc-MIBI scanning was positive in 14 patients, 13 with active myeloma and one patient with MGUS showing possible transformation to a more accelerated phase. In seven patients 99mTc-MIBI scanning was negative. In four of them, the result was unexpected, as they had the features of active myeloma. All four were either primarily or secondarily resistant to chemotherapy, with high total cumulative doses of doxorubicin. Overexpression of P-glycoprotein associated with multidrug resistance could be a factor, as it has been shown that 99mTc-MIBI is actively eliminated from the cell by P-glycoprotein. With this assumption, sensitivity of the scanning technique in this series is 100%, and the specificity 88%. No toxicity was experienced by any patient. 99mTc-MIBI scanning is a useful adjunct to the investigation of multiple myeloma, and may have potential as an in vivo test for multidrug resistance.     

Intensive chemotherapy with hematopoietic cell transplantation after ESHAP therapy for relapsed or refractory non-Hodgkin's lymphoma. Results of a single-centre study of 65 patients.

This study was designed to assess the results of protracted courses of ESHAP (etoposide, cytarabine, cisplatin, methylprednisolone) therapy followed by intensive chemotherapy and hematopoietic cell transplantation (IC+HCT) for relapsed or refractory non-Hodgkin's lymphoma (NHL). Treatment consisted of 3 cycles of ESHAP; responsive patients (pts) then received 3 more cycles, and IC+HCT was used for pts in maintained partial (PR) or complete (CR) remission after the sixth ESHAP. Sixty-five pts entered the study. At enrollment, 27 pts had bone marrow (BM) and/or central nervous system (CNS) lymphomatous infiltration. Disease status was primary refractory lymphoma in 41 pts (63 %), and relapse in 24 pts (37 %). Results showed that two pts were not evaluable for the therapeutic response because of early treatment-related death. Thirty-nine (62 %) pts entered PR or CR after 3 cycles of ESHAP. Eleven pts subsequently had disease progression. Twenty-eight pts were in persistent CR or PR after 6 cycles of ESHAP. Refractory pts did not show a different response rate to relapsing pts (chi2= 1.73). Five pts were excluded from IC+HCT because of an inadequate graft or treatment-related toxicity. Twenty-three (35 %) pts completed the procedure. Five pts (22 %) relapsed after IC+HCT. The overall survival rate of the 39 responsive pts is 45 % at 60 months, with a median survival time of 30 months. Median survival among the 35 pts in whom second-line chemotherapy failed is 7.1 months, with a 4-year survival rate of 3 %. Despite the poor prognostic features of this group, 45% of pts responding to the first 3 cycles of chemotherapy are in prolonged remission, suggesting that rather than to transplant after just 2 cycles of salvage therapy, pursuing second-line chemotherapy may better discriminate between patients more likely to benefit from a subsequent transplant.     

雷利度胺为主方案治疗多发性骨髓瘤25例疗效分析

 目的　观察雷利度胺为主方案治疗多发性骨髓瘤（MM）患者的疗效及不良反应。方法　MM患者25例,其中5例为初治患者,13例为含沙利度胺方案治疗后难治、复发患者,7例为治疗后达平台期维持治疗患者。初治MM患者均采用R-PAD方案,难治、复发患者选用R-MD方案,维持治疗MM患者由于出现Ⅱ级伴疼痛以上的周围神经炎（PN）,采用雷利度胺单药治疗。结果　初治组5例,经过2个疗程的治疗均达到完全缓解（CR）（100 %）;难治、复发组13例,CR率为23.08 %（3／13）,非常好的部分缓解（VGPR）率为15.38 %（2／13）,部分缓解（PR）率为38.46 %（5／13）,总反应率（ORR）为76.92 %（10／13）;其余3例无反应患者中,2例疾病稳定（SD）,1例疾病进展（PD）。维持治疗组7例在平均38周的随访期内均维持缓解;改用雷利度胺后,PN获得不同程度的缓解。结论　对于初治MM患者,R-PAD方案缓解率高,起效快;对于难治、复发患者,特别是伴严重PN的MM患者,R-MD是值得选择的方案;雷利度胺还可用于伴PN的MM患者的维持治疗。     

Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality therapy

This study reports the results of cisplatin (CDDP)-based chemotherapy (CT) as sole therapy and as neoadjuvant (NA) therapy in 28 consecutive patients (pts) with advanced basal cell (BC) and squamous cell (SC) cancers of the skin. CT in 24 pts consisted of CDDP 75 mgm/m2 and doxorubicin (Dox) 50 mg/m2 intravenously (IV) every 3 weeks with Dox being omitted in four pts due to severe preexisting cardiac disease. Thirteen of the 28 pts received CT in the NA setting, five before surgery and eight before radiation therapy (RT). Response rates to CT were complete remission (CR) in eight of 28 (28%) pts, partial remission (PR) in 11 of 28 (40%) for an overall response rate of 68%. Thirteen pts received a second treatment modality with five of 13 pts having a CR to CT alone before the second modality and seven converting to CR postsecond modality for a total CR rate of 12 of 13 (92%) in the multimodality group. Duration of responses in the CT-only group ranged from 4 to 82 months; however, only two patients remain in remission in this group. Of the twelve CRs from the multimodality therapy group, 11 of 12 (91%) pts remain in CR with duration of response ranging from 3 to 81 months. Toxicities were manageable, with no toxic deaths and only five pts stopped CT secondary to side effects. This study suggests the combination of CDDP and Dox is highly effective in BC and SC cancers of the skin and by itself can produce long unmaintained remissions, but when combined with a second modality of therapy, it is capable of producing not only long unmaintained CRs but probable cures in the majority of pts.     

硼替佐米联合异环磷酰胺、甲泼尼龙、沙利度胺方案治疗多发性骨髓瘤

 目的　观察硼替佐米联合异环磷酰胺、甲泼尼龙、沙利度胺（V-CMPT方案）治疗多发性骨髓瘤（MM）的临床疗效和患者不良反应。方法　回顾性分析应用V-CMPT方案进行治疗的24例初治和复发难治MM患者资料,3周为1个周期,治疗2个周期。应用骨髓细胞学检查、M蛋白鉴定以及其他血液学指标评价病情及疗效。结果　初治的9例患者中,完全缓解（CR）3例、部分缓解（PR）5例、轻微缓解（MR）1例;复发难治的15例患者中,CR2例、接近完全缓解（nCR）2例、PR 3例、MR 6例、无变化（NC）2例;两组间总缓解率（ORR）（P＝0.511）及CR／nCR率（P＝1.000）差异无统计学意义。总的CR／nCR率29.2 %（7／24）,ORR达到91.7%（22／24）。2个周期V-CMPT化疗后,患者的血红蛋白、血清清蛋白及血清β2微球蛋白得到明显改善。不良反应包括胃肠道反应、血小板减少、周围神经病变等,经对症处理或间歇期停药多好转,不影响化疗的继续进行。结论　V-CMPT方案对初治和复发难治性MM临床疗效明显,能够明显改善血液学指标,药物耐受性良好。     

Low efficacy of thalidomide in improving response after induction in multiple myeloma patients who are candidates for high-dose therapy

Giving the impact of complete response (CR) on outcome of multiple myeloma patients addressed to high-dose melphalan, we explored the role of a pre-transplant intensification with 3 months thalidome plus dexamethasone therapy (Thal-Dex), after pulse-VAD induction. Seventy-four multiple myeloma patients (MM pts) uniformly treated, were retrospectively studied. The response rate after pulse-VAD were: CR 6%, VGPR 40%, PR 23%, MR 23%, and progression 8%. The response rate after Thal-Dex were similar: CR 11%, VGPR 39%, PR 17%, MR 9%, and progression 24%. Giving no advantage in terms of response rate with an additive toxicity, Thal-Dex does not seem useful for intensification before transplant.     

PCD方案与VAD方案治疗多发性骨髓瘤的临床观察

  目的  探讨硼替佐米+环磷酰胺+地塞米松（PCD方案）和长春新碱+表阿霉素+地塞米松（VAD方案）治疗多发性骨髓瘤的临床疗效及不良反应。  方法  回顾天津市第一中心医院血液科2011年1月至2013年1月收治的多发性骨髓瘤患者41例,依治疗方案不同分为PCD组及VAD组,分析两组患者的疗效及不良反应。  结果  PCD组治疗后部分缓解及以上的有效率达42.9%,而VAD组仅15.0%,差异有统计学意义（P < 0.05）,在初治患者中反应良好的患者（CR和VGPR）PCD组为50.0%,VAD组7.7%,差异有统计学意义（P < 0.05）,两组患者在疱疹感染、血细胞减少及乏力腹胀等方面的不良反应无明显差异,但PCD组的神经毒性的发生率较VAD组高,差异有统计学意义（P < 0.05）。  结论  PCD方案治疗多发性骨髓瘤疗效优于VAD方案,特别是对于初治患者PCD方案能明显提高缓解率,但治疗过程中应注意硼替佐米的神经毒性,必要时应减量应用。      

Survivin在多发性骨髓瘤患者骨髓细胞中的表达及其临床意义

背景与目的:Survivin是凋亡抑制蛋白家族成员之一,在多种恶性肿瘤中高表达,但在正常成人分化组织无表达。其表达与多种肿瘤的预后及肿瘤对放、化疗的耐受有关。本研究旨在通过检测Survivin在正常人、初治及复发/难治多发性骨髓瘤(multiplemyeloma,MM)患者骨髓细胞及骨髓瘤细胞系KM3中的表达,以揭示Survivin在骨髓瘤中的表达与耐药及疗效的关系。方法:RT-PCR和Westernblot法检测29例MM患者(其中初治17例,复发/难治12例)、9例正常人骨髓标本及KM3细胞系中SurvivinmRNA和蛋白质水平表达。结果:骨髓瘤细胞系KM3高表达Survivin。SurvivinmRNA在正常人、初治和难治/复发MM患者骨髓细胞中阳性率分别为22.2%、70.5%和83.3%,表达水平(Survivin/β-actin比值)分别为0.06±0.04、0.31±0.14和0.69±0.24,骨髓瘤患者表达率和表达水平显著高于正常人(P<0.01),而难治/复发MM组表达水平高于初治组(P<0.05)。所有的正常人标本中均未检测到Survivin蛋白,在初治和难治/复发MM组Survivin蛋白阳性率分别为41.1%和58.3%(P>0.05),表达水平(Survivin/α-tubulin半定量比值)分别为0.11±0.07和0.21±0.12,难治/复发MM组明显为高(P<0.05)。17例初治患者中,7例Survivin阳性者4例部分缓解(partialresponse,PR),1例微小反应(minorresponse,MR),2例无变化(nochange,NC),有效率[完全缓解(completeresponse,CR) PR MR]71.4%;10例Survivin阴性者中2例CR,4例PR,2例MR,2例NC,有效率80%,略高于阳性组。但统计学分析未发现两组有效率存在显著性差异。结论:Survivin在骨髓瘤患者中的高表达可能是部分患者对化疗不敏感的原因之一,由于Survivin仅特异性表达于骨髓瘤细胞,Survivin可作为逆转骨髓瘤细胞耐药治疗中的潜在靶点。     

Functional imaging of multidrug resistant phenotype by 99mTc-MIBI scan in patients with multiple myeloma

Overexpression of P-glycoprotein (Pgp) is one of the primary mechanisms of multidrug resistance (MDR) in several diseases, including multiple myeloma. The aim of this study was to investigate whether the washout of 99mTc-MIBI, a transport substrate of Pgp, is enhanced in the bone marrow of patients with multiple myeloma overexpressing Pgp. Seventeen (17) patients were i.v. injected with 555 MBq of 99mTc-MIBI, and whole-body scans were performed at 10 and 60 minutes. A region of interest (ROI) was drawn over the thoracic spine of each scan, and the washout of 99mTc-MIBI was calculated, after decay correction, as: (10-minute counts/pixel minus 60-minute counts/pixel) divided by 10-minute counts/pixel. Pgp expression was determined in 17 bone marrow samples obtained from the same patients immediately before the 99mTc-MIBI scan. Following centrifugation over the Ficoll-Hypaque gradient, cytospins were obtained and immunostained with C219 monoclonal antibody. The immunostaining of Pgp was graded as 1, 2, or 3 when a faint, moderate, or intense reaction, respectively, was observed in infiltrating plasma cells. Washout of 99mTc-MIBI ranged between 5% and 26%. A statistically significant direct correlation was found between the washout of the tracer and Pgp expression (Spearman rank correlation coefficient r = 0.74, p < 0.001). A partial overlap of washout values was observed in different classes of Pgp expression, thus preventing the discrimination of individual patients. Washout of 99mTc-MIBI, expressed as the percentage of radioactivity cleared from the bone marrow over a 1-hour period, may be used as a noninvasive tool for in vivo whole-body imaging of Pgp expression and function in multiple myeloma patients.     

Multiple myeloma. An update on diagnosis and management

Patients with multiple myeloma must be differentiated from those with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). The plasma cell labeling index is helpful in differentiating MGUS or SMM from multiple myeloma (MM). No difference in survival was noted between patients given a single alkylating agent and those given a combination of alkylating agents. Alternating cycles of interferon alpha 2 and VBMCP (vincristine, BCNU, melphalan, cyclophosphamide, prednisone) produced a complete or near-complete response in 41% of patients. Allogeneic or syngeneic bone marrow transplantation has produced some benefit. Autologous bone marrow transplantation is potentially applicable to treat more patients. Major problems are eradication of myeloma cells from the bone marrow and removal of myeloma cells from autologous bone marrow. Purging of myeloma cells with monoclonal antibodies and chemotherapy may be helpful. Stem cells from autologous peripheral blood are being used for rescue after high-dose chemotherapy and total-body irradiation.     

BDT方案治疗多发性骨髓瘤的临床疗效

目的:探讨应用BDT(硼替佐米+地塞米松+沙利度胺)方案治疗多发性骨髓瘤(MM)临床疗效及安全性。方法:硼替佐米每周注射2次,每次注射1.3mg/m2,连续2周(即第 1、4、8、11 天),地塞米松20mg,第1～4d静脉滴注,28d为1个疗程。同时早晚口服沙利度胺100mg,连续服用28d(1个疗程)。结果:31例MM患者,经过3个疗程联合化疗,完全缓解(CR)8例,非常好的部分缓解(VGPR)13例,部分缓解(PR)5例,疾病稳定(SD)3例,总有效率(OR)83.87％,其中,初治组21例患者有效率85.71％,复发或难治组10例患者有效率80.00％,两组疗效比较差异无统计学意义(P＞0.05),与治疗前比较,治疗后M-蛋白、β2－微球蛋白及骨髓浆细胞数均有明显下降,而血红蛋白(HGB)有显著上升,治疗前后各项观察指标的变化差异具有显著性,有统计学意义(P＜0.05）。结论:BDT联合化疗方案治疗多发性骨髓瘤(MM)完全缓解(CR)率高,起效快,毒副反应小,耐受性好,对于初治、复发或难治MM患者均可获得较为满意的临床疗效,值得临床推广应用。     

腔内注射国产香菇多糖治疗恶性胸腹腔积液（附38例报告）

目的:进一步评价国产香菇多糖(天地欣)治疗恶性胸腹腔积液的效果。方法:采用国产香菇多糖4mg～6mg/次胸腹腔内注射,每周1～2次,连续2周。结果:全组共38例,显效8例(21.1％),有效18例(47.4％),总有效率为68.4％。其中胸水24例,有效率为70.8％;腹水14例,有效率为64.3％。未见明显毒副反应。结论:国产香菇多糖是治疗恶性胸腹腔积液的良好药物,尤其适宜年老体弱和其他不能耐受强烈化疗的患者。     

Importance of quantitative histology of bone changes in monoclonal gammopathy

Quantitative histology of bone changes, using undecalcified transiliac bone biopsies (UTBB), was performed blindly in 46 individuals with monoclonal gammopathy (MG), including 17 with MG of undetermined significance (MGUS) and 29 with overt multiple myeloma (MM). Three MGUS presented an excess of osteoclastic resorption (OR) in the vicinity of clusters of tumour cells and developed overt B cell malignancies, chronic lymphocytic leukaemia, Waldenström''s disease and MM respectively. On the other hand, MGUS with normal OR remained stable (median follow-up = 28 months), with one exception who developed a systemic amyloidosis. In MM, excessive OR was only observed in areas invaded by myeloma cells. OR was frequently normal in active MM lacking myeloma cells in UTBB. Active MM without lesions on radiography had excessive OR. IgA and pure Bence Jones MM appeared more osteoclastic than IgG cases (P less than 0.05). Of major interest was the finding that one third of MM presented histological bone changes similar to osteoporosis, osteosclerosis or osteoblastic metastasis. Two major findings must be emphasized from the current data: UTBB could be of major interest for the early detection of a B cell malignancy; heterogeneity of myeloma bone condition is unexpected. If some changes appear directly related to the tumour (i.e. excessive OR or osteoblastic dysfunction), some others are probably accidentally associated with it (i.e. osteoporosis), both needing treatment other than chemotherapy.     

Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis.

PURPOSE: To determine whether bone marrow (BM) angiogenesis progressively increases along the spectrum of plasma cell disorders ranging from monoclonal gammopathy of undetermined significance (MGUS) to advanced myeloma. EXPERIMENTAL DESIGN: Four hundred patients with the following disorders were studied: MGUS (76 patients); smoldering (indolent; early-stage) multiple myeloma (SMM; 112 patients); newly diagnosed, active multiple myeloma (MM; 99 patients); relapsed (advanced) multiple myeloma (RMM; 26 patients); and primary amyloidosis (AL; 87 patients). Forty-two normal control BM samples were studied for comparison. BM angiogenesis was studied in a blinded manner by immunohistochemical staining for CD34 to identify microvessels. RESULTS: The median (range) microvessel density (MVD) per x400 high power field was 1.3 (0-11) in the controls, 1.7 (0-10) in AL, 3 (0-23) in MGUS, 4 (1-30) in SMM, 11 (1-48) in newly diagnosed MM, and 20 (6-47) in RMM; P < 0.001. MVD was significantly higher in MGUS, SMM, newly diagnosed MM, and RMM compared with controls and AL; P < 0.001. MVD was not significantly different between controls and AL. By grading, high-grade angiogenesis was present in 0% of controls and AL, 1% of MGUS, 3% of SMM, 29% of newly diagnosed MM, and 42% of RMM; P < 0.001. MVD correlated with the BM plasma cell labeling index (rho = 0.46, P < 0.001) and BM plasma cell percentage (rho 0.5, P < 0.001). Survival was 28 months in SMM and newly diagnosed MM with high-grade angiogenesis, compared with 53 months for those with low- and intermediate-grade angiogenesis; P = 0.02. CONCLUSIONS: BM angiogenesis progressively increases along the spectrum of plasma cell disorders, from the more benign MGUS stage to advanced myeloma, indicating that angiogenesis may be related to disease progression.     

30例自体外周造血干细胞移植治疗多发性骨髓瘤的疗效及预后因素评价

目的:对30例多发性骨髓瘤（multiple myeloma,MM）患者经自体外周造血干细胞移植（autologous hematopoietic stem cell transplantation ,APBSCT）治疗后的临床疗效进行评估,并分析可能影响预后的因素。方法:30例MM患者有2 例复发行2 次APBSCT,因此共计移植32例次。移植前予常规联合化疗（11例含万珂）,化疗联合G-CSF 动员APBSC ,选择以马法兰为基础的预处理方案,d0 天回输。结果:动员后患者采集的单个核细胞（MNC）中位数为6.41× 108/kg,CD34+细胞4.75× 106/kg。APBSCT后中位中性粒细胞和血小板重建时间分别为9.5 天和11天。APBSCT后CR和VGPR 率分别为37.5% 和34.4% ,中位生存期（overallsurvival ,OS）为67.27个月,中位无进展生存期（progression-freesurvival ,PFS）为29.77个月,其中CR组、PR组中位PFS 分别为29个月、20个月,VGPR 组中位PFS 未达到,CR+VGPR组与PR组PFS 比较P=0.025。万珂组和非万珂组CR率分别为63.6% 和23.8%（P=0.034）,万珂组中位OS及PFS 均未达到,非万珂组中位PFS 为22个月（P=0.045）。 结论:硼替佐米诱导序贯APBSCT可获得更长的无病生存。APBSCT作为MM诱导缓解后的强化治疗,缓解率高,且移植后获得VGPR 以上反应的患者PFS 获益。      

硼替佐米联合化疗治疗多发性骨髓瘤28例疗效分析

 【摘要】　目的　观察以蛋白酶体抑制剂硼替佐米为主的化疗方案治疗多发性骨髓瘤（MM）的疗效和患者不良反应。方法　28例MM患者接受以硼替佐米为主的联合方案化疗。疗效评定按照EBMT 标准进行。结果　28 例MM患者中,初治20例,复发难治8 例。25例可评估疗效,总反应率达100 %（25／25）,其中完全缓解（CR）5 例,接近完全缓解（nCR）10 例,部分缓解（PR）10 例。主要不良反应包括周围神经病变、血小板减少、消化道反应及病毒感染,经对症处理后好转,一般不影响治疗。结论　以硼替佐米为主的联合化疗治疗初治和复发难治MM 起效较快,治疗反应率高,不良反应可耐受。     

Impact of metaiodobenzylguanidine scintigraphy on assessing response of high-risk neuroblastoma to dose-intensive induction chemotherapy.

PURPOSE: The International Neuroblastoma Response Criteria (INRC) recommend, but do not make mandatory, metaiodobenzylguanidine (MIBG) scans. We present the first report on the effect of MIBG scans on the classification of response to dose-intensive induction therapy. PATIENTS AND METHODS: After dose-intensive induction and before consolidative therapy, 162 Memorial Sloan-Kettering Cancer Center (MSKCC) patients with high-risk neuroblastoma (NB) had MIBG scans (99 with (131)I, 63 with (123)I), computed tomography, (99m)Tc-bone scan, bone marrow (BM) tests, and urine catecholamine measurements. Induction included high-dose cyclophosphamide (140 mg/kg) plus other agents and high-dose cisplatin (200 mg/m(2))/etoposide (600 mg/m(2)). RESULTS: In 90 patients treated with dose-intensive therapy from diagnosis at MSKCC, the use of MIBG scintigraphy increased the incomplete response numbers from 14 (15.5%) to 20 (22%), giving a complete remission/very good partial remission (CR/VGPR) rate of 78%. In 72 patients treated before referral to MSKCC for intensified therapy, MIBG findings changed the response classification of one patient; the CR/VGPR rate was 43%. MIBG scans showed no BM disease in 15 of 38 patients with histologically evident NB in BM but did show uptake consistent with BM involvement in five patients who had no NB observed in BM tests. CONCLUSION: With the less effective therapy consequent to the intensification of induction only after initial exposure to standard-dose chemotherapy, MIBG scintigraphy merely confirms the findings of other staging modalities for detection of relatively widespread residual NB. However, when dose-intensive therapy is initiated at diagnosis, the reliable achievement of major disease responses makes extensive BM testing and MIBG scintigraphy prerequisites for accurate determination of disease status.     

硼替佐米治疗多发性骨髓瘤的初步临床研究

  目的 初步观察硼替佐米（商品名：万珂）联合化疗对多发性骨髓瘤（MM）的疗效和毒副作用。方法 5例MM患者采用万珂联合地塞米松或DVD方案治疗4个疗程,评价疗效和毒副作用。结果 3例完全缓解（CR）,1例部分缓解（PR）,1例达到微小反应（MR）;总缓解（CR+PR）率为80 %;最常见的毒副反应为指趾麻木感、轻度白细胞和血小板减少以及肝功能异常改变。结论 万珂联合化疗治疗MM疗效好,毒副作用轻微,患者易于耐受。     

The Value of the Bone Marrow Plasma Cell Cytoplasmic Light Chain Ratio in Differentiating Between Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance

We compared the plasma cell light chain ratios in the bone marrows of 13 patients with multiple myeloma (MM), with those of 13 patients with monoclonal gammopathy of undetermined significance (MGUS). The mean light chain ratio in favour of the paraprotein isotype in the myeloma group was 51.83 (95% confidence limits (CL) 29.52-74.14) while in the MGUS group it was 5.30 (CL 2.07-8.52). The difference between the MGUS and MM groups was significant (p = 0.0005). Neither the bone marrow plasma cell count nor the paraprotein level were significantly correlated with the light chain ratio in either of these two groups. We found a cut-off ratio of 8 to be the most useful in differentiating between myeloma and MGUS. Only one patient with myeloma had a ratio below 8, and one MGUS patient had a ratio above this cut-off point. We conclude that determination of the bone marrow plasma cell light chain ratio is a simple and useful test in differentiating between myeloma and MGUS in difficult cases.     

Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post-bortezomib monotherapy

Sclerostin is a Wingless and Int-1 inhibitor, which is produced by osteocytes and inhibits osteoblast-driven bone formation. Sclerostin is implicated in the pathogenesis of bone loss in metabolic bone disorders but there is no information for its effect on multiple myeloma (MM)-related osteolytic disease. We evaluated circulating sclerostin in 157 newly diagnosed patients with symptomatic myeloma, in 25 with relapsed myeloma who received bortezomib monotherapy, in 21 patients with monoclonal gammopathy of undetermined significance (MGUS), and in 21 healthy controls. Patients with active myeloma had elevated circulating sclerostin compared to MGUS patients and controls (p < 0.01). MM patients who presented with fractures at diagnosis (n = 34) had very high levels of circulating sclerostin compared with all others (p < 0.01), whereas sclerostin correlated negatively with bone specific alkaline phosphatase (a bone formation marker; r = -0.541, p < 0.0001) and positively with C-telopeptide of collagen type-1 (a bone resorption marker; r = 0.524, p < 0.0001). Patients with International Staging System (ISS)-3 disease had higher circulating sclerostin compared to ISS-1 and ISS-2 MM (p = 0.001). Furthermore, patients with high sclerostin (upper quartile, n = 40) had a median survival of 27 months versus 98 months of all others (p = 0.031). Relapsed MM patients had higher levels of circulating sclerostin even compared to newly diagnosed patients (p < 0.01). Bortezomib monotherapy resulted in a reduction of sclerostin by almost 50% in both responders and non-responders. These results suggest that patients with active myeloma have elevated circulating sclerostin, which correlated with advanced disease features including severe bone disease. Our study indicates sclerostin as a possible target for the development of novel therapies to enhance osteoblast function in myeloma.