泊马度胺治疗复发难治多发性骨髓瘤的研究进展

多发性骨髓瘤（MM）是以产生免疫球蛋白的浆细胞克隆增殖为特征的异质性疾病,在血液系统的恶性肿瘤中占第2位。由于新型药物的广泛使用,包括蛋白酶体抑制剂（PI）、免疫调节剂（IMiD）以及单克隆抗体,MM的治疗取得了很大的进展,但几乎所有的患者最终都会出现耐药。泊马度胺为第3代IMiD,对复发难治多发性骨髓瘤（RRMM）具...     

泊马度胺联合环磷酰胺、地塞米松治疗复发难治多发性骨髓瘤的效果及安全性

目的探讨泊马度胺联合环磷酰胺、地塞米松(PCD)方案治疗复发难治多发性骨髓瘤(MM)的效果及安全性。方法回顾性分析2021年3月至2022年6月蚌埠医学院附属连云港市第二人民医院采用PCD方案治疗的20例复发难治MM患者临床资料, 并选取同期29例采用其他方案(包括DECP方案13例、VCD方案16例)治疗的复发难治MM患者作为对照组。比较两组治疗4个周期的疗效及不良反应。结果治疗4个周期后, 20例PCD组患者的总缓解率(ORR)和临床获益率(CBR)分别为70.0%(14/20)和85.0%(17/20), 其中完全缓解(CR)5例, 非常好的部分缓解(VGPR)4例, 部分缓解(PR)5例, 微小缓解(MR)3例, 疾病稳定(SD)2例, 疾病进展(PD)1例;29例对照组患者的ORR和CBR分别为41.4%(12/29)和65.5%(19/29), 其中CR 2例, VGPR 3例, PR 7例, MR 7例, SD 5例, PD 5例;两组ORR比较差异有统计学意义(χ2=3.89, P=0.048), CBR比较差异无统计学意义(χ2=2.30, P=0.129)。两组肾功...     

泊马度胺临床用药中国专家共识(2022年版)

泊马度胺是第3代免疫调节剂, 多项临床研究显示含泊马度胺的联合方案治疗复发难治多发性骨髓瘤具有良好的效果, 可改善患者预后。2013年美国食品药品管理局(FDA)批准泊马度胺用于治疗复发难治多发性骨髓瘤, 2020年5月又批准其用于治疗艾滋病相关卡波西肉瘤。泊马度胺于2020年11月在我国获批上市。鉴于目前我国多数临床医师对于泊马度胺用药经验尚少, 共识专家组成员参考国内外相关研究进展及临床实践, 制定了泊马度胺临床用药中国专家共识, 旨在为我国临床医师用药提供参考。     

天然来源的新型抗肿瘤生化调节剂

在肿瘤治疗研究领域,生化调节剂或生化调节药物受到广泛关注,近年得到迅速发展。生化调节剂（biochemicalmodulator）作用于生化代谢的特定环节或分子靶点,可提高药物的抗肿瘤效果或降低其毒性。生化调节剂可能逆转肿瘤细胞对药物的抗药性,而且生化调节剂本身亦可能具有一定的抗肿瘤活性。因此,研究抗肿瘤生化调节剂,特别是从中药和其他天然产物中研究发现新型的生化调节剂成为新药研究的重要课题,具有广阔的应用前景。十多年来,我们对于抗肿瘤生化调节剂进行了系列研究,提出了以核青转运作为研制药物靶点的策略,并筛选与研究中药…     

小剂量沙利度胺治疗多发性骨髓瘤的临床观察

 目的 观察小剂量沙利度胺联合地塞米松和化疗治疗多发性骨髓瘤（MM）的疗效和毒副作用。方法 7例MM患者予沙利度胺口服,起始剂量50 mg／d ,至最大剂量50 ~ 300 mg,联合地塞米松或VAD方案化疗。结果 4例患者部分缓解（PR）,2例患者进步,1例患者无效,总有效率达85 %。毒副作用有嗜睡、乏力、便秘、皮疹、手足麻木,毒副反应轻。结论 小剂量沙利度胺联合地塞米松和化疗治疗MM是安全有效的。     

强大的免疫调节剂——来那度胺

沙利度胺——跌宕起伏的＂人生＂提到沙利度胺（Thalidomide,商品名：反应停）很多医生甚至普通民众对其并不陌生,这个药物可以说颇具传奇色彩。早在1954年,联邦德国合成了沙利度胺,人们最初认为它是一种安全有效的止吐药物,广泛用于孕妇的止吐治疗。但是此后不断有短指畸形（海豹胎）婴儿出生,人们才开始意识到似乎与该药物的使用有关。直到1961年该药物被禁用时,已经有超过1万名＂海豹胎＂婴儿出生。这个悲剧成为新药研究领域的一个典型案例,促使世界各国非常重视新药研究的安全性,相继建立形成了较为完整的临床研究管理规范。     

Pomalidomide: the new immunomodulatory agent for the treatment of multiple myeloma

In this report, we provide a comprehensive review on the preclinical and clinical investigations conducted in development of the next-generation immunomodulatory drug (IMiD) pomalidomide for the treatment of relapsed/refractory multiple myeloma (MM). We consulted PubMed, MEDLINE, ASH, ASCO annual symposium abstracts and http://clinicaltrials.gov/ for the purpose of this literature review. Twenty-six preclinical and 11 clinical studies were examined. These studies delineate the mechanisms of action of pomalidomide and attest to the robust clinical activity in relapsed/refractory MM. MM is the second most common hematological malignancy in the US. Despite availability of several therapeutic agents, MM remains incurable. Thus, the development of new therapies remains a priority. Pomalidomide is the newest member of the IMiDs class of drugs, and in preclinical and clinical investigations, it has demonstrated an improved efficacy and toxicity profile in comparison to its sister compounds, lenalidomide and thalidomide. Importantly, recent clinical studies have demonstrated its activity in relapsed or refractory myeloma, particularly in lenalidomide and bortezomib-refractory patients. Thus, the addition of pomalidomide to the anti-myeloma armamentarium is widely anticipated to have a significant impact on the overall clinical outcome of advanced stage relapsed and refractory MM patients.     

Management of adverse events induced by next-generation immunomodulatory drug and proteasome inhibitors in multiple myeloma

Introduction: In the last decade the introduction of novel agents has strongly improved multiple myeloma prognosis by doubling median overall survival. Unfortunately disease relapse is very common and patients may become refractory to previous drugs. Therefore, new therapeutic strategies are urgently needed.

Areas covered: We have reviewed the available data on next generation novel agents, particularly immunomodulatory drug pomalidomide and proteasome inhibitors carfilzomib and ixazomib, the latter being the first-in-class orally available. We focused on adverse events associated with such agents and described how they should be managed. The main grade ≥3 adverse events correlated with these drugs are hematologic, myelosuppression-related and reversible; non-hematologic grade ≥3 toxicities are less frequent, with an incidence of <10%.

Expert commentary: These agents showed to have a good tolerability. The great majority of adverse events are easily manageable with dose-adjustment and appropriate treatment, and drug discontinuation is not frequent. Favorable safety profile and high efficacy, especially in combination, confer to these drugs a central role in development of new lines of therapy against multiple myeloma. Further investigation is certainly needed to determine the best combinations including these agents.     

Pooled analysis of the reports of pomalidomide after failure of lenalidomide and (or) bortezomib for multiple myeloma

The use of pomalidomide after lenalidomide and (or) bortezomib failure in patients with multiple myeloma is not clearly clarified in clinical practice. We sought to compile the available clinical reports to better understand the effectiveness of pomalidomide after failure of lenalidomide and (or) bortezomib. We searched published reports including pomalidomide, lenalidomide and (or) bortezomib. Seven reports were identified. Pomalidomide‐based regimen was pomalidomide plus low‐dose dexamethasone (POM + LoDEX). Six randomized controlled trials enrolling a total of 641 patients that evaluated the treatment effects of pomalidomide after lenalidomide and (or) bortezomib failure in patients with multiple myeloma were included. Pooled results showed that the overall response rate (ORR) was 31% in the POM + LoDEX group. Analysis of heterogeneity showed very little (p = 0.997, I² = 0%), suggesting that response rates of POM + LoDEX therapy were consistent across those included trials. Stable disease was achieved in 40% of 603 patients (heterogeneity: p = 0.980, I² = 0%). In those >65 years, overall response was achieved in 32% of 71 patients (heterogeneity: p = 0.77, I² = 0%). POM + LoDEX showed promising activity in the 95 patients with high‐risk cytogenetic abnormalities: ORR was 27% (heterogeneity: p = 0.97, I² = 0%). In the pooled analysis, toxicity consisted primarily of myelosuppression: Grade 3 or 4 neutropenia was seen in 53% (heterogeneity: p = 0.857, I² = 0%). Pomalidomide may produce clinical benefits in patients who had shown refractory on prior lenalidomide and (or) bortezomib therapy. Moreover, elder patients and high‐risk cytogenetic abnormalities were not negative predictors for pomalidomide response after lenalidomide and (or) bortezomib failure. Copyright © 2015 John Wiley & Sons, Ltd.     

Recent clinical studies of the immunomodulatory drug (IMiD) lenalidomide

Thalidomide is effective in the treatment of multiple myeloma. The immunomodulatory drug and thalidomide analogue lenalidomide is currently in late stage clinical development for MDS and multiple myeloma. This minireview highlights the course of initial and ongoing lenalidomide clinical development in oncology with reference to earlier thalidomide studies.     

已被证实用于多药耐药性研究的一种新的多发性骨髓瘤细胞系

Objective:To find out how to overcome resistance during multiple myeloma (MM) treatment through establishing a multidrug resistant human multiple myeloma cell line and investigating its biological features. Methods:The parent cell line MOLP-2 was exposed to different concentrations of melphalan and a melphalan-resistant cell line MOLP-2/R was identified by continuous stepwise selection. The cell morphology and growth curves were examined. Protein levels of P-gp, MRP and FANCD2 monoubiquitination were checked by Western blotting. The IC50 of melphalan and resistance index (RI) were de-tected by MTT assay. Results:A melphalan-resistant cell line MOLP-2/R was finally identified. The RI of MOLP-2/R cells to melphalan was 6.03. Besides melphalan it was cross resistant to other chemotherapeutic agents, including ADM, CTX, DDP and VP-16. The multiplication time was postponed (P<0.05). Studies showed that FANCD2 protein monoubiquitination was enhanced, but the levels of P-gp and MRP expressions in the MOLP-2/R cells were similar with the parent calls. Conclusion:MOLP-2/R cell line may serve as an ideal model for exploring the mechanism of MDR. Over-expression of FANCD2 protein monoubiquitination might contribute to acquired drug resistance in MOLP-2/R celt line.     

Therapeutic use of immunomodulatory drugs in the treatment of multiple myeloma

Immunomodulatory drugs, such as thalidomide, lenalidomide (Revlimid^®, CC-5013) and actimid (CC-4047), have a broad spectrum of activity and have shown remarkable responses in patients with multiple myeloma and related hematological diseases, such as myelodysplastic syndrome. They are currently being tested in other cancer types. This review will focus on the preclinical and clinical activity of thalidomide and its more potent immunomodulatory derivatives that are used to treat multiple myeloma. They represent a new class of antitumor agents that not only target the tumor cell directly, but also have significant activity within the bone marrow milieu. These agents have shown high responses in all phases of multiple myeloma, including the upfront setting, relapsed refractory stage and also as maintenance therapy for the disease. They have been used in combination with dexamethasone, chemotherapy and, more recently, with other novel agents, such as proteasome inhibitors. Thalidomide and lenalidomide in combination with dexamethasone have recently been approved by the US FDA for the treatment of multiple myeloma.     

Preclinical and clinical results with pomalidomide in the treatment of relapsed/refractory multiple myeloma

Despite the evolution of effective frontline treatment strategies, many patients with myeloma inevitably relapse. Treatment can be complicated by the interplay of disease-, treatment-, and patient-related factors. Unfortunately, many patients eventually develop disease that is refractory to lenalidomide and bortezomib and have few treatment options. Pomalidomide is a distinct IMiD^® agent recently approved in the US and Europe. We review the pomalidomide mechanism of action, summarizing its direct antimyeloma, immunomodulatory, and stromal-support inhibitory activities. We also detail its clinical development, including establishment of the approved dose/schedule, phase 2 and 3 trials in relapsed and refractory patients, and novel pomalidomide-based combinations.     

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。     

Benefit Versus Risk Assessment of Melflufen and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Analyses From Longer Follow-up of the OCEAN and HORIZON Studies

IntroductionMelphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but directionally different overall survival (OS) favoring pomalidomide (hazard ratio [HR], 1.10) in OCEAN.MethodsThese analyses further investigated prognostic subgroups impacting survival in updated data from the randomized, phase 3 OCEAN study (NCT03151811; date: February 3, 2022) and the phase 2 HORIZON study (NCT02963493; date: February 2, 2022).ResultsIn OCEAN, subgroups prognostic for OS were age (P = .011; <65 years favored pomalidomide) and no previous autologous stem cell transplant (ASCT) or progression >36 months after ASCT (P = .001; favored melflufen). Overall, 245 of 495 (49%) patients randomized had received a previous ASCT, of which 202 (82%) had progressed within 36 months following their ASCT. When excluding patients who had progressed <36 months post-ASCT (melflufen group, n = 145; pomalidomide group, n = 148), median OS was 23.6 months with melflufen and 19.8 months with pomalidomide (HR, 0.83 [95% CI, 0.62-1.12]; P = .22). Among patients with triple-class refractory disease in HORIZON, patients who had progressed <36 months post-ASCT (n = 58) had a lower response rate and shorter duration of response and PFS than the remaining patients (n = 52). Safety was consistent with previous reports.ConclusionThese analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811).