复发、难治性多发性骨髓瘤的治疗策略

 【摘要】　多发性骨髓瘤（MM）是一种不可治愈的恶性浆细胞疾病。虽然靶向治疗和干细胞移植的广泛应用,显著提高了MM的缓解率及延长了生存期,但治疗的疗效仍难以长期维持,几乎所有的患者最终都会出现复发及耐药。在复发时,如何为每例患者选择合理的治疗方案仍然是一个挑战,疾病和患者双方特点都需要加以考虑。     

Treatment of relapsed and refractory multiple myeloma

Opinion statement The definition of relapsed and refractory myeloma was straightforward when melphalanprednisone constituted the mainstay of treatment and high-dose therapy with transplantation was rarely used in myeloma. However, several advances have occurred in the treatment of myeloma over the past decade. Most notably, high-dose therapy and transplantation have become broadly applicable, thalidomide has become available as effective salvage therapy, and several investigational agents with novel mechanisms of action appear to be very promising. Because of the differing properties of some of these agents, it is often possible to control the disease with an alternative treatment approach after the failure of one therapy. Some data indicate that combinations of these agents work when the drugs have failed individually. Therefore, refractory myeloma indicates disease unresponsive to the most recent therapy administered. Broadly, the salvage approaches that are used in patients with refractory or relapsed disease include high-dose dexamethasone, high-dose chemotherapy with autotransplantation, allogeneic hematopoietic stem cell transplantation, thalidomide-based therapies, and novel/ investigational agents. The appropriate therapy for a given situation depends on the nature of the disease, age, organ function, bone marrow function, prior treatment, the availability of stem cell donors, and access to novel agents. A therapeutic trial of thalidomide is essential at some stage of the disease in all patients. High-dose therapy with autotransplantation is needed at some stage of the disease in most patients younger than 65 to 70 years.     

复发、难治性多发性骨髓瘤治疗进展

目前,复发、难治性多发性骨髓瘤的治疗仍是临床比较棘手的问题。随着多发性骨髓瘤发病机制研究的深入,新药不断涌现,其疗效和毒副作用也逐渐被认识。近年来,针对复发、难治性多发性骨髓瘤的治疗涌现出许多新药和新的治疗方案。文章就复发、难治性多发性骨髓瘤的治疗进展作一介绍。     

Management of relapsed and relapsed/refractory multiple myeloma

Despite significant progress in the treatment of multiple myeloma (MM) over the past decade, this disease remains incurable and almost all patients ultimately experience relapse and become refractory to treatment over time. However, the outlook for patients with relapsed MM has improved markedly with the use of the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib. Moreover, the development of new drug classes based on preclinical rationale and the introduction of next-generation agents is likely to further expand treatment options and improve outcomes for relapsed MM.     

伊沙佐米为基础的化疗方案治疗复发难治多发性骨髓瘤临床研究

目的:探讨以伊沙佐米为基础的化疗方案治疗复发难治多发性骨髓瘤（RRMM）的临床效果及相关不良反应。方法:收集2018年10月至2020年2月山东省菏泽市立医院、邹城市人民医院接受≥2个疗程以伊沙佐米为基础化疗方案治疗的RRMM患者21例,其中既往接受过含硼替佐米方案治疗患者15例,接受过含来那度胺方案治疗患者10例,接受过含以上两种药物方案治疗患者6例。采用伊沙佐米（4 mg,口服,第1、8、15天）联合其他药物（地塞米松、环磷酰胺或来那度胺）的两药或三药方案治疗。治疗第2、4个周期后评估其治疗效果及安全性。结果:21例RRMM患者治疗2个周期后评估总反应率（ORR）为38.09%（8/21）,其中部分缓解（PR）6例、非常好的部分缓解（VGPR）2例;4个周期后ORR为57.14%（12/21）,其中PR 7例、VGPR 4例、完全缓解（CR）1例。以伊沙佐米为基础的化疗方案3~4级不良反应发生率为23.81%（5/21）,血液学不良反应包括中性粒细胞减少、血小板降低及贫血,其他常见不良反应包括消化道反应、乏力、低钾血症等,周围神经不良反应均为2级及以下。结论:以伊沙佐米为基础的化疗方案对RRMM治疗有效,安全性较好。     

复发难治性多发性骨髓瘤的治疗新进展

多发性骨髓瘤(MM)是一种不可治愈的恶性浆细胞疾病,且几乎所有的患者最终都会出现复发及耐药。目前尚无针对复发难治性MM的标准治疗方案。近年来,关于药物治疗、造血干细胞移植治疗有了新的进展,本文就近年来新的治疗进展综述如下。     

复发、难治多发性骨髓瘤的新药治疗

 【摘要】　新型药物如免疫调节剂（IMiD）沙利度胺和雷利度胺及蛋白酶体抑制剂（PI）硼替佐米的应用极大地改善了复发、难治多发性骨髓瘤（MM）的临床预后。但是,也有患者对这些新型药物耐药或不能耐受。多种药物包括新一代IMiD（泊马度胺）、新一代PI（如卡非佐米、MLN9708及marizomib）、组蛋白去乙酰化酶抑制剂（如帕比司他及伏林司他）、信号转导调节剂（如哌立福新）等正在进行临床试验,它们表现出良好的抗MM活性,尤其在那些对现有新型药物耐药的患者中也有效。文章介绍现有的及处于临床研究中新型抗骨髓瘤药物在复发、难治MM患者中的应用。     

Choosing treatment options for patients with relapsed/refractory multiple myeloma

Multiple myeloma (MM) is a clonal plasma cell disorder that is still incurable using conventional treatments. Over the last decade, advances in front-line therapy have led to an increase in survival, but there are still some doubts in the case of relapsed/refractory disease. We searched the PubMed database for articles on treatment options for patients with relapsed/refractory MM published between 1996 and 2013. These treatments included hematopoietic cell transplantation (HCT), rechallenges using previous chemotherapy regimens, and trials of new regimens. The introduction of new agents such as the immunomodulatory drugs (IMIDs) thalidomide and lenalidomide, and the first-in-its-class proteasome inhibitor bortezomib, has greatly improved clinical outcomes in patients with relapsed/refractory MM, but not all patients respond and those that do may eventually relapse or become refractory to treatment. The challenge is therefore to select the optimal treatment for each patient by balancing efficacy and toxicity. To do this, it is necessary to consider disease-related factors, such as the quality and duration of responses to previous therapies, and the aggressiveness of the relapse, and patient-related factors such as age, comorbidities, performance status, pre-existing toxicities and cytogenetic patterns. The message from the trials reviewed in this article is that the new agents may be used to re-treat relapsed/refractory disease, and that the sequencing of their administration should be modulated on the basis of the various disease and patient-related factors. Moreover, our understanding of the pharmacology and molecular action of the new drugs will contribute to the possibility of developing tailored treatment.     

Treatment of relapsed and refractory myeloma

Treatment options for patients with relapsed and refractory myeloma have dramatically changed as a result of the approval of bortezomib, thalidomide, lenalidomide, and bortezomib/liposomal doxorubicin by the US Food and Drug Administration. These changes have resulted in improved responses to salvage therapy and, in many cases, improved overall survival. The challenge for clinicians is choosing which agent to use and deciding whether a single agent or combination therapy is the optimal treatment option for each patient. This article outlines some of the data underpinning the use of bortezomib, thalidomide, lenalidomide, or combinations of these agents in the setting of relapsed myeloma, as well as a number of potential future agents or combinations that may improve outcomes for patients with relapsed and refractory disease.     

苯达莫司汀治疗复发/难治性多发性骨髓瘤的研究进展

多发性骨髓瘤（multiple myeloma,MM）是一种浆细胞恶性克隆性疾病。随着自体造血干细胞移植（autologous stem cell transplantation,ASCT）、免疫调节剂(immunomodulatory drugs,IMiDs)和蛋白酶抑制剂(proteasome inhibitors,PIs）等药物的应用,患者的整体生存期显著延长。但患者常因疾病复发、耐药及进展而死亡,MM至今仍无法治愈。苯达莫司汀（bendamustine,Ben）是一种古老的双功能氮芥衍生物,具有独特的作用机制,与其他烷化剂无交叉耐药性。在东欧地区,该药已广泛应用于慢性淋巴细胞白血病、恶性淋巴瘤、MM等淋巴系统肿瘤及乳腺癌的治疗。近年来,国外开展了一系列Ben单药或联合化疗治疗复发/难治性多发性骨髓瘤（relapsed/refractory multiple myeloma,RRMM）的临床研究,并显示出良好的疗效。本文就Ben单药或联合化疗治疗RRMM的疗效进行综述。     

Carfilzomib and pomalidomide in patients with relapsed and/or refractory multiple myeloma with baseline risk factors

While survival times have increased over the last decade, most patients with multiple myeloma (MM) eventually relapse and become refractory to therapy. The treatment of patients with relapsed and/or refractory MM is frequently further complicated by the presence of pre-existing comorbidities that arise from an advanced disease state and of toxicities stemming from prior antimyeloma treatment. Carfilzomib and pomalidomide have recently been approved for the treatment of patients with relapsed and refractory MM. While these agents represent important additions to the available treatment options, the identification of patients who may best benefit from the use of each of therapy is still being investigated. A number of patient-related and disease-related factors may impact treatment efficacy and/or tolerability, and the clinical presentation and medical history of each patient must be carefully considered to optimize treatment. Here, we review results from carfilzomib and pomalidomide clinical trials in patients with relapsed and/or refractory MM who also have baseline comorbidities or treatment-induced or disease-induced complications (including the presence of renal impairment, cardiac risk factors, peripheral neuropathy, or high-risk chromosomal abnormalities) to evaluate the safety and efficacy of the two agents in these difficult-to-treat patients and to provide treatment recommendations specific to each scenario.     

Single-institute phase 2 study of thalidomide treatment for refractory or relapsed multiple myeloma: prognostic factors and unique toxicity profile

We previously reported a pilot study of thalidomide monotherapy for Japanese patients with refractory or relapsed multiple myeloma. In the present work, we have extended this clinical trial to a single-institute phase 2 study with a larger number of patients and longer follow-up time. New information on the optimal dose and prognostic factors as well as the correlation of toxicities with treatment schedule was obtained. Fifteen of 56 (27%) patients achieved a partial response, including three cases with near-complete remission. Most patients suffered toxicities at a dose of 400 mg per day, but there was no clear dose–response relationship. Thus, a lower dose such as 200 mg per day or less is considered optimal. Multivariate analyses identified only lack of response to therapy as an adverse prognostic factor for progression-free survival. Chromosomal abnormality, C-reactive protein >10 mg/L, and more than six previous courses of chemotherapy were significantly associated with shorter overall survival. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 23 and 11% of patients, respectively. Grade 4 interstitial pneumonia and grade 5 pulmonary hypertension were observed; however, no patient suffered deep vein thrombosis, which has frequently been observed in other studies. Duration of therapy was closely related to the development of peripheral neuropathy. The efficacy and prognostic factors of this treatment were confirmed in long-term observation. However, special attention should be paid to toxicities such as hematological and pulmonary complications as well as peripheral neuropathy in long-term users. ( Cancer Sci 2008; 99: 1243–1250)     

Treatment of elderly patients with refractory/relapsed multiple myeloma: oral drugs adherence and the COVID-19 outbreak

Once the treatment of refractory/relapsed multiple myeloma in the elderly is greatly influenced by the adherence of patients and family members, clinicians should be aware of patients’ behavior and lifestyle, as it may influence the individual treatment plan for each patient. Furthermore, treatment with oral chemotherapy is of special value during the COVID-19 outbreak. Multidisciplinary healthcare involvement is crucial in the management of polypharmacy, adverse events and dose adjustment due to comorbidities and natural loss of renal function with age. Oral drugs simplify intake, reduce hospital visits, and improve autonomy and quality of life. However, although oral drugs have advantages, they also transfer control and responsibility from the healthcare professional to the patient, who must be able to understand and follow the directions given. Therefore, patient education and communication with healthcare professionals are critical for adherence.     

复发多发性骨髓瘤的治疗策略

随着新药的不断问世,多发性骨髓瘤(MM)的疗效有了极大提高,但是所有患者都要面临复发的难题.对于复发患者,首先要判断何时开始治疗并明确治疗目的 .在重新判定其分期后,需综合考虑患者体能状态、既往治疗方案的疗效及药物的耐受性、是否接受维持治疗、首次复发还是二次或多次复发、是否接受过移植等因素制定治疗策略.联合一种以上新药为主的三药方案是复发患者的主要治疗方案,若能入组新药临床试验则为最优选择.异基因造血干细胞移植也许能真正改善年轻、高危、髓外或浆细胞白血病患者的预后.     

含脂质体阿霉素方案治疗复发难治性多发性骨髓瘤伴继发髓外病变患者的临床研究

  目的  探讨复发/难治性多发性骨髓瘤（relapsed/refractory multiple myeloma,RRMM）患者伴继发髓外病变（secondary extramedullary disease,sEMD）后应用脂质体阿霉素（liposomal doxorubicin,LPD）治疗的疗效、无进展生存期（progression-free survival,PFS）与安全性,以及RRMM患者出现sEMD的总生存期（overall survival,OS）及预后因素。  方法  回顾性分析2015年1月至2020年1月就诊于首都医科大学附属北京朝阳医院西院的40例RRMM伴sEMD、接受LPD治疗患者的临床资料。记录患者初诊基线特征,继发sEMD的临床表现。观察其应用LPD的疗效、不良反应与PFS;并根据sEMD临床特点对其进行亚组分析,多因素分析得出sEMD-OS预后因素。  结果  多因素分析显示国际分期系统（international stage system,ISS）Ⅲ期为继发EMD的危险因素。所有患者完成中位5（3～9）个疗程的LPD治疗,2个疗程总体反应率（overall response rate,ORR）为60.0%,13例完成6个疗程及以上化疗,ORR为100%;3级以上不良反应率为5%;预计中位PFS（median PFS,mPFS）为8.0个月（95%CI:7.5～8.5）,界标分析示LPD≥6个疗程组相比于<6个疗程组PFS延长（P=0.093）。预计sEMD中位OS（median OS,mOS）为22.0个月（95%CI:18.2～25.8）,1年OS率为73.6%,2年OS率为38.2%。多因素回归分析显示,非骨旁sEMD与乳酸脱氢酶（lactate dehydrogenase,LDH）>250 U/L为sEMD-OS的独立预后因素。  结论  含LPD方案治疗RRMM继发EMD短期疗效好,安全性高。非骨旁sEMD及LDH>250 U/L预后不良,此类患者需寻求其他治疗策略。