Outcomes of lenalidomide-based treatment for 57 patients of relapsed or refractory multiple myeloma

正Objective To investigate the clinical efficacy and safety of lenalidomide(Revlimid,R)-based chemotherapy in the treatment of relapsed/refractory multiple myeloma(MM)patients.Methods 57 consecutively relapsed/refractory MM patients were retrospectively analyzed from June 2013 to February 2016.All the patients received lenalidomide-based chemotherapy.Results(1)60.4%patients had international staging system(ISS)stageⅢ,     

Novel biological therapies for the treatment of multiple myeloma

The therapeutic management of multiple myeloma (MM) for the last several decades has mainly involved regimens based on use of glucocorticoids and cytotoxic chemotherapeutics. Despite progress in delineating the activity of such regimens, at either conventional or high doses, MM has remained an incurable disease, without substantial improvement in the median overall survival. This has sparked major interest in the development of novel therapies that in part capitalize on recent advances in our understanding of the biology of MM, including the molecular mechanisms by which MM cell-host bone marrow (BM) interactions regulate tumor-cell growth, survival, and drug resistance in the BM milieu. The development of in vitro and in vivo models of MM-stromal interactions has allowed not only for better characterization of these molecular phenomena but also for identification of specific therapeutic strategies to overcome these interactions and achieve an enhanced anti-MM effect, even against MM resistant to conventional therapies. Herein, we review the latest progress in the development of these novel anti-MM therapies, with major focus on therapies which have translated from preclinical evaluation to clinical application, including thalidomide and its more potent immunomodulatory (IMiD) derivatives, the first-in-class proteasome inhibitor bortezomib (formerly known as PS-341), and arsenic trioxide (As2O3).     

Novel therapies for multiple myeloma

Multiple myeloma (MM) continues to evade cure by conventional therapies, increasing the urgency for new, biologically based treatments. Reviewed in this discussion are novel chemotherapies under clinical trial that capitalize upon greater comprehension of tumor pathophysiology. In targeting tumor biology, these therapies serve as a model of treatment with great potential for improving outcomes in patients with MM.     

Future drug developments in multiple myeloma: an overview of novel lenalidomide-based combination therapies

The introduction of thalidomide, lenalidomide, and bortezomib has changed the way that multiple myeloma (MM) is treated and has greatly improved survival outcomes. These novel agents are often used in combination with conventional drugs, such as dexamethasone, to optimize clinical responses; however, they are also being evaluated as part of novel treatment combinations to build upon the success of available treatment regimens. Lenalidomide-based combinations are a focus of clinical research due to the high efficacy, good tolerability, and lack of cumulative toxicity associated with lenalidomide. Lenalidomide is an IMiDs? immunomodulatory compound with a dual mechanism of action - tumoricidal effects rapidly reduce MM burden while long-term immunomodulatory actions maintain tumor suppression. Several new agents with antimyeloma effects have been identified including: epigenetic agents (e.g. histone deacetylase inhibitors); novel proteasome inhibitors; novel immunomodulatory compounds; cyclin-dependent kinase inhibitors; interleukin-6 inhibitors; and other experimental agents such as heat-shock protein 90 inhibitors and monoclonal antibodies targeting MM cell surface receptors (e.g. anti-CS1 and anti-CD40). Many of these new agents, in combination with lenalidomide, are in early phases of clinical evaluation. Early clinical results are promising, indicating that the novel lenalidomide-based drug combinations are effective and generally well tolerated in patients with MM; future research will continue to evaluate these novel combinations and help to identify the optimal setting (e.g. induction, salvage, or maintenance) in which they may provide the greatest impact on the disease course.     

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多发性骨髓瘤(multiple myeloma,MM)为浆细胞恶性肿瘤,以骨髓中异常浆细胞恶性增殖,血清或尿液中出现单克隆免疫球蛋白,正常免疫球蛋白受到抑制及溶骨病变为特征。发病率占恶性肿瘤1%,血液系统肿瘤10%。目前,多发性骨髓瘤的治疗主要包括常规化疗、干细胞移植以及新型治疗药物如     

Novel therapeutics in multiple myeloma

Most myeloma patients still experience recurrent relapse and eventually become resistant and/or intolerant of effective agents such as corticosteroids, alkylating agents, immune modulators (lenalidomide and thalidomide) or proteasome inhibitors such as bortezomib. Once this happens average survivals are less than one year. Progress has been made for such patients, however, with the demonstration of clinical benefit of novel proteasome inhibitors (carfilzomib) and immune modulators (pomalidomide). Pomalidomide when used with dexamethasone has activity in 30-60% of patients depending on disease stage. Carfilzomib is an irreversible proteasome inhibitor with favorable toxicity profile (minimal neuropathy) and response rates of 17-54% depending on the disease stage treated. Novel targets are also being explored. Histone deacetylase inhibitors such as vorinostat and panobinostat are in phase II testing although results from a randomized trial combining vorinostat with bortezomib were disappointing. Other small molecules or monoclonal antibodies with novel targets such as kinase inhibitors(AKT, CDK5) and cell surface receptors (e.g. elotuzumab) are undergoing active investigation.     

Current treatment strategies for multiple myeloma

Until 1990, the melphalan-prednisone regimen was the standard treatment for multiple myeloma (MM). The role of alpha-interferon still remains controversial, both in induction therapy and in maintenance therapy. Over the last 10 years, there has been considerable improvement in the treatment of MM. In patients under 65 years of age, high-dose therapy with autografting has clearly demonstrated an advantage over conventional treatment. Bisphosphonates have proved very useful in reducing skeletal events. More recently, an old drug, thalidomide, has shown surprising efficacy in patients with advanced MM. Future trends include the extension of high-dose therapy to older patients and the use of immunotherapy in induction and/or maintenance therapy.     

New treatment strategies for multiple myeloma

During the past 5 years, several new treatments and strategies have been developed for patients with multiple myeloma. For patients with disease resistant to standard therapies, these include the VAD regimen, dexamethasone alone, high-dose melphalan, and intensive chemoradiotherapy with bone marrow transplantation. Alpha interferon appears to have its greatest potential as part of early induction therapy or during remission maintenance. The role of hemopoietic growth factors or blood stem cells in support of high-dose therapy and drugs that may overcome multiple drug resistance continues under study. A sequence of non-cross-resistant therapies early in the disease course seems worthy of investigation, especially in patients at high risk for early relapse.     

Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment,but not bortezomib-based treatment,in patients with multiple myeloma

Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0–8) and a score ≥4.5 was used for CRBN positivity (CRBN⁺) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN⁺ NDMM patients, CRBN^? NDMM patients had more international staging system (ISS) III (26 vs. 61 %, respectively; P?=?0.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN⁺ patients than CRBN^? patients (LD 79 vs. 33 %, respectively; P?=?0.005) (TD 75 vs. 29 %, respectively; P?=?0.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN⁺ for treatment response was 79 and 67 % and 75 and 71 %, respectively. Multivariate analysis showed that CRBN⁺ was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.     

多发性骨髓瘤治疗新药及新的治疗策略

从1962年以来,多发性骨髓瘤（Multiple Myeloma,MM）常规化疗方案多采用口服马法兰联用泼尼松（MP）,其后也应用VAD,M2等改良方案,但完全缓解率不到5%,中位生存期不超过3年,MM病人从治疗中获益有限.近10年来,随着临床认识的深入,新的治疗药物不断涌现,由此衍生出一些新的治疗策略大大提高了治疗缓解率,使MM患者的生存期不断延长,甚至有治愈可能。     

Novel therapeutic targets in multiple myeloma

Multiple myeloma remains an incurable disease, and a new perspective on the approach to therapy is required. The aim of this review is to focus on a number of key areas where recent advances in the biology of the disease have not only yielded an understanding of the disease pathogenesis but have also suggested novel treatment approaches. Factors mediating myeloma cell growth, survival and the complex interaction of myeloma cells with the bone marrow microenvironment have provided a framework for the rational design of therapeutic agents. The development of such biologically based treatments which target both the tumour cell and the microenvironment, in order to achieve more complete and selective eradication of myeloma cells and the maintenance of minimal residual disease states, may ultimately lead to improved disease-free survival and potentially a cure.     

Frontline treatment of multiple myeloma

The treatment of myeloma has been revolutionized by the availability of new drugs. Combination therapy followed by stem cell transplant holds the promise of ultimately curing a fraction of patients. Objective responses are the norm for induction therapy and up to 50% of patients achieve a complete remission. Ongoing clinical trials continue to address the role of long term maintenance therapy. Understanding the proper management of these agents is paramount to providing patients disease control and yet minimizing side effects from treatment.     

New treatment of multiple myeloma

PURPOSE: After decades of minimal progress, two new classes of drugs with novels mechanisms of action: immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) have shown great activity for the treatment of multiple myeloma. CURRENT KNOWLEDGE AND KEY POINTS: Thalidomide acts by a variety of mechanisms; its efficacy is well known in disease relapse especially associated with dexamethasone. Recent results prove that combination of thalidomide with melphalan and prednisone should be considered as the first line standard of care in elderly patient. The main side effects are peripheral neuropathy and deep-vein thrombosis. Bortezomib is the first proteasome inhibitor. It is approved for the treatment in first disease relapse. The combination with glucocorticoids is synergistic. This combination in induction treatment before autologous stem cell transplantation is promising, as well as the combination with melphalan and prednisone in elderly patient. The main toxicities are fatigue and peripheral neuropathy. Lenalidomide is a structural analogue of thalidomide. Its efficacy in combination with dexamethasone has been proved in relapsing patients. The main toxicity is hematologic. Utilisation as first line treatment is also promising. FUTURE PROSPECTS AND PROJECTS: These three drugs have toxicities predictable and manageable and can be used successively or in combination for greater effectiveness. They have an impact on the multiple myeloma treatment strategies and on the disease course itself.     

雄黄在多发性骨髓瘤治疗中的作用

目的 :研究雄黄治疗多发性骨髓瘤 (MM )的作用机制 ,并对其临床效果进行观察。方法 :采用MTT法、双抗体夹心ELISA法检测 15例MM患者应用雄黄治疗前后血清中白细胞介素 6 (IL 6 )活性及其受体 (sIL 6R)水平。结果 :MM患者血清中IL 6活性及sIL 6R水平明显高于健康对照组 (P <0 .0 1) ;应用雄黄治疗 5 0天后 ,MM患者血清中IL 6活性及sIL 6R水平无明显降低 (P >0 .0 5 ) ,Ⅲ期MM患者的IL 6活性显著高于Ⅰ、Ⅱ期 (P <0 .0 5 ) ,但sIL 6R水平两者差异无显著性意义 (P >0 .0 5 )。用雄黄治疗 15例患者 ,3例完全缓解 ,5例有效 ,7例无效。结论 :雄黄可能不是通过降低IL 6活性及sIL 6R水平来抑制肿瘤细胞生长的。     

Current approaches for the treatment of multiple myeloma

The development of novel therapeutic agents over the past decade, including the proteasome inhibitor, bortezomib, and the immunomodulatory drugs, lenalidomide and thalidomide, has resulted in improved outcomes for patients with multiple myeloma. However, there is still considerable controversy as to which regimen should be used as first-line therapy, which patients should be considered for autologous or allogeneic transplantation, and how consolidation or maintenance therapy is used in patients that have a good response to first-line therapy. The present paper will review clinical evidence from previous and ongoing studies to explore issues related to these questions.