Emerging biological insights and novel treatment strategies in multiple myeloma

Introduction: Survival in multiple myeloma (MM) has improved significantly in the past 10 years due to new treatments, such as thalidomide and lenalidomide (immunomodulatory drugs or IMiDs) bortezomib and advances in supportive care. Nevertheless, almost all MM patients show disease relapse and develop drug resistance. Areas covered: The authors review the therapeutic approach for untreated MM patients. Furthermore, the prognostic stratification of patients and the proposed risk-adapted strategy are discussed. Finally, preclinical and clinical data regarding newer antimyeloma agents, currently undergoing examination such as proteasome inhibitors (PIs, carfilzomib), IMiDs (pomalidomide), epigenetic agents (histone deacetylase inhibitors vorinostat and panobinostat), humanized monoclonal antibodies (elotuzumab and MOR03087) and targeted therapies (inhibitors of NF-κB, MAPK, HSP90 and AKT) are reported. Expert opinion: MM patient outcome has remarkably improved due to the use of three to four drug combination therapies including PIs and IMiDs, which target the tumor in its bone marrow microenvironment, however MM treatment remains challenging. The use of high-throughput techniques has allowed to discover new insights into MM biology. The identification of candidate therapeutic targets and availability of respective investigative agents will allow for a substantial progress in the development and implementation of personalized medicine in MM.     

Role of new drugs incorporated into consolidation and maintenance therapy in transplant-eligible multiple myeloma patients

Introduction: Since in multiple myeloma (MM) patients the depth of response achieved with autologous stem-cell transplantation (ASCT) seems to correlate with the time to progression, various strategies have been undertaken to control disease and improve prognosis. Novel agents thalidomide, bortezomib and lenalidomide that have allowed deeper responses to be achieved in the induction phase have been tested following the ASCT as consolidation and maintenance treatments.

Areas covered: Consolidation is generally a short-term treatment and aims to increase the depth of the response achieved with high-dose melphalan, whereas maintenance therapy consists of protracted therapy of either a fixed duration or until response and has the goal of prolonging duration of the first response. The goals of both treatments are the extension of progression-free survival and, hopefully, overall survival. This editorial will focus on the consolidation and maintenance strategies after ASCT for the treatment of MM.

Expert opinion: The incorporation of new drugs into the continuum of MM care resulted in improved outcomes and long-term disease control. However, optimal consolidation and maintenance strategies are still to be defined in the light of newer drugs to be utilized for induction strategies.     

Update on immunomodulatory drugs (IMiDs) in hematologic and solid malignancies

INTRODUCTION: Thalidomide and its analogs [small molecule immunomodulatory drugs (IMiDs?)] are among the most successful new therapeutic agents of recent years. Thalidomide is now an integral part of multiple myeloma (MM) therapy. Lenalidomide has been approved for the treatment of patients with relapsed MM and 5q-myelodysplastic syndromes (MDS). Currently, more than 400 clinical trials are evaluating the activity of lenalidomide, alone or in combination with other conventional or novel therapies, in newly diagnosed MM and 5q-MDS. Based on their broad range of actions within the tumor microenvironment, IMiDs are currently also evaluated in a wide variety of additional hematologic and solid malignancies. AREAS COVERED: This paper reviews the historic development of thalidomide and its derivatives and presents novel insights into their mode of action. Moreover, it discusses up-to-date clinical trials investigating IMiDs and potential future research and therapeutic perspectives in MM and other malignancies. EXPERT OPINION: Although IMiDs have emerged as powerful agents for the treatment of hematologic and solid tumors, more preclinical and clinical studies are urgently needed both to increase our knowledge of their mechanisms of action, and to optimize their clinical use, in order to further improve the patient's quality of life and survival.     

New pharmacotherapy options for multiple myeloma

Introduction: Novel agents and the availability of autologous stem-cell transplantation have revolutionized the treatment of patients with multiple myeloma. First-generation novel agents namely thalidomide, lenalidomide, and bortezomib have significantly improved response and survival of patients. Second-generation novel agents such as pomalidomide, carfilzomib, and monoclonal antibodies are being tested both in the newly diagnosed and relapse settings, and results are promising.

Areas covered: In this review article, the main results derived from Phase III trials with thalidomide, lenalidomide, and bortezomib for the treatment of myeloma patients, both at diagnosis and at relapse, are summarized. Data about second-generation novel agents such as pomalidomide and carfilzomib are also reported. Newer effective drugs currently under investigation and the promising results with monoclonal antibodies are described.

Expert opinion: The availability of new effective drugs has considerably increased the treatment options for myeloma patients. A sequential approach including induction, transplantation (when possible), consolidation, and maintenance is an optimal strategy to achieve disease control and prolong survival. Despite these improvements, the best combination, the optimal sequence, and the proper target of newer drugs need to be defined.     

Recent advances in the treatment of Multiple Myeloma

Multiple Myeloma (MM) remains an incurable plasma cell malignancy in the bone marrow (BM) despite conventional therapies as well as high-dose therapies with stem cell support. Therefore novel biologically-based therapeutic approaches are required. Recently, intensive laboratory and preclinical studies have identified and validated therapeutic molecular targets in MM. In particular, recognition of the biologic significance of the BM microenvironment in MM pathogenesis and as a potential target for novel therapeutics has derived several promising approaches. Novel FDA approved agents including thalidomide/thalomid, its immunomodulatory derivatives lenalidomide/Revlimid, and proteasome inhibitor bortezomib/Velcade are directed at molecular targets not only in MM cells but also in its BM milieu, and have already achieved promising results in clinical studies. Here we discuss the mechanisms of action of these novel drugs and their clinical application, alone or combined with conventional or novel drugs.     

Analysis of the efficacy and safety of carfilzomib and its combination in multiple myeloma

Carfilzomib has become a new choice for patients with multiple myeloma (MM). However, the use of carfilzomib single-agent or in combination with other agents in MM patients is not explicitly clarified in clinical practice. Therefore, we analyzed the effects of carfilzomib and its safety and effectiveness using available clinical trial reports in order to find out the best therapy of carfilzomib. We searched MEDLINE, Embase, PubMed and Cochrane databases as well as Chinese databases of carfilzomib trials (Jan. 2012 to Sep. 2016) for the MM treatment. Clinical characteristics and outcomes were extracted. Meta-analysis results were expressed as the overall response rate (ORR) and performed by R software. A fixed-effects model or random-effects model was applied based on the heterogeneity among studies. Based on our research standard, we identified 17 prospective studies enrolling 1960 patients. A total of 594 MM patients were enrolled in carfilzomib single-agent clinical trials, and the ORR was 32% (I² = 84.9%, P<0.0001). A total of 1366 MM patients were enrolled in clinical trials of 10 groups of carfilzomib combination regimens, 1081 patients had a therapeutic effect, and the ORR was 79% (I² = 91.0%, P<0.0001). The most frequent adverse events were fever, nausea, vomiting and other non-hematologic events. Carfilzomib was better tolerated than bortezomib, with a lower incidence of peripheral neuropathy and better therapeutic effects compared with other drugs. In this analysis, the highest ORR was achieved from combination of carfilzomib, lenalidomide and dexamethasone, which had a lower incidence of adverse events and a greater ORR compared with carfilzomib single-agent. Therefore, the combination of carfilzomib, lenalidomide and dexamethasone could be a good therapeutic agent with strong clinical effect. However, this conclusion needs to be validated in future study.     

Treatment strategies in elderly patients with multiple myeloma: current status

Multiple myeloma (MM), a plasma cell malignancy, is a disorder of the elderly with an increasing prevalence as the average life expectancy increases. Survival remains unacceptably low in elderly patients with MM, in whom the gold standard of treatment has been, until recently, oral melphalan and prednisolone, which induces a response rate of approximately 50% and overall survival of <3 years. In the last 15 years, traditional treatment paradigms for elderly patients with MM have been challenged not only as a result of the change in what we define as 'elderly' but also as a result of the reduced morbidity and treatment-related mortality associated with high-dose chemoradiotherapy (HDT) and autologous stem cell transplantation (ASCT), and the emergence of novel therapies including thalidomide, its immunomodulator drug derivative lenalidomide and the first-in-class proteasome inhibitor, bortezomib. In this review, we examine currently available data regarding the treatment of MM in the elderly population. Recent years have seen a paradigm shift in the standard of care of elderly patients with MM from oral melphalan and prednisolone to approaches including HDT with ASCT using intermediate-dose melphalan in selected elderly patients, and the evaluation of and incorporation of drugs such as thalidomide, bortezomib and lenalidomide. Importantly, we now have been able to change the traditional goal of palliation in the elderly group of patients to a more ambitious objective of achieving a complete response or a near complete response, in the hope that this will translate into improved progression-free survival, overall survival and quality of life.     

Update on immunomodulatory drugs (IMiDs) in hematologic and solid malignancies

Introduction: Thalidomide and its analogs [small molecule immunomodulatory drugs (IMiDs®)] are among the most successful new therapeutic agents of recent years. Thalidomide is now an integral part of multiple myeloma (MM) therapy. Lenalidomide has been approved for the treatment of patients with relapsed MM and 5q-myelodysplastic syndromes (MDS). Currently, more than 400 clinical trials are evaluating the activity of lenalidomide, alone or in combination with other conventional or novel therapies, in newly diagnosed MM and 5q-MDS. Based on their broad range of actions within the tumor microenvironment, IMiDs are currently also evaluated in a wide variety of additional hematologic and solid malignancies.

Areas covered: This paper reviews the historic development of thalidomide and its derivatives and presents novel insights into their mode of action. Moreover, it discusses up-to-date clinical trials investigating IMiDs and potential future research and therapeutic perspectives in MM and other malignancies.

Expert opinion: Although IMiDs have emerged as powerful agents for the treatment of hematologic and solid tumors, more preclinical and clinical studies are urgently needed both to increase our knowledge of their mechanisms of action, and to optimize their clinical use, in order to further improve the patient's quality of life and survival.     

Lenalidomide in myelodysplastic syndrome and multiple myeloma

The use of thalidomide is limited by adverse effects of sedation, constipation, neuropathy and thromboembolism. In order to discover more potent and less toxic immunomodulators than thalidomide, its chemical structure was modified and lenalidomide was formed. Lenalidomide is approved by the US FDA for the treatment of patients with low-risk myelodysplastic syndrome (MDS) with deletion 5q cytogenetic abnormality. Two studies and a case report have evaluated lenalidomide in these MDS patients and showed significantly higher cytogenetic responses and durable red blood cell transfusion independence. Lenalidomide should be the drug of choice for patients with low and intermediate-1 risk MDS (based on the International Prognostic Scoring System) with chromosome 5q31 deletion with or without other karyotype abnormalities. Lenalidomide, in combination with dexamethasone, has been compared with dexamethasone alone in patients with relapsed or refractory multiple myeloma (MM) in two studies (MM-009 in North America and MM-010 in Europe, Israel and Australia). In these two phase III trials, lenalidomide demonstrated impressive (58-59%) response rates with dexamethasone. Lenalidomide has also been shown to overcome thalidomide resistance in MM patients. Therefore, the lenalidomide plus dexamethasone regimen provides another treatment option, in addition to first line MM treatment regimens of bortezomib, thalidomide or high-dose dexamethasone, for the treatment of relapsed or refractory MM.Lenalidomide does not produce significant sedation, constipation or neuropathy, but does lead to significant myelosuppression, unlike thalidomide. The prescribing information has a black box warning for risk of myelosuppression, deep vein thrombosis/pulmonary embolism and teratogenicity. Administration of lenalidomide is recommended at a starting dose of 10 mg/day orally for deletion 5q in MDS patients. Significant risk of myelosuppression may lead to dose reduction in the majority of these patients. Clinical trials of relapsed and refractory MM have shown that lenalidomide is clinically efficacious at a dosage of 25 mg/day when administered in combination with dexamethasone. Lenalidomide should be continued until disease progression in both MDS and MM patients.     

多发性骨髓瘤的诊治进展

多发性骨髓瘤(MM)是好发于中老年的恶性浆细胞病,由于新药的应用,近年来其生存期明显延长,可以视为慢性病。但仍不可治愈,终将复发进展。国际MM工作组在2003年按有无器官损害将MM重新定义为有症状性、无症状性MM,制定了诊断标准,同时对临床上无症状性MM可暂观察,发展至症状性MM时需要化疗,规范了MM的诊断和治疗。目前,MM的治疗主要为靶向药物沙利度胺、硼替佐米(万珂)及来那度胺(lenalidomide)与如环磷酰胺、阿霉素等传统化疗药物组成的联合化疗方案化疗,其中以硼替佐米、环磷酰胺及地塞米松组成的化疗方案最为推崇。年轻的符合条件的MM患者,可考虑行自体外周血干细胞移植治疗。对上述药物均耐药的难治复发的患者可考虑新药临床试验。基于MM慢性病特点,其整体治疗策略及全程慢病管理模式非常重要,即对于适合化疗的MM患者,一线诱导化疗4⁶或更多周期治疗有效后,采取巩固26或更多周期治疗有效后,采取巩固2⁴个疗程(或干细胞移植治疗)后,转入有效维持治疗,延缓复发及复发后再诱导治疗。     

Novel investigational drugs active as single agents in multiple myeloma

Introduction: Multiple myeloma (MM) is a hematologic malignancy characterized by proliferation of malignant plasma cells. patient outcome has improved markedly over the last decades due to the introduction of novel therapeutic agents such as bortezomib, thalidomide and lenalidomide. However, MM still remains largely incurable and patients eventually become refractory to available treatments. To address this unmet medical need, a variety of new molecules are currently being developed in preclinical models and/or are being investigated in clinical studies.

Areas covered: We summarized available data on new investigational drugs showing anti-myeloma single-agent activity and that might have a role in the future therapeutic armamentarium against MM. Besides their single-agent activity, the synergic potential of these new agents with the currently approved drugs will be pivotal in their integration into consolidated MM backbone therapies. The drugs discussed include alkylators, new proteasome inhibitors, novel anti-CD38 monoclonal antibodies, Bcl-2 inhibitors, Cyclin-Dependent-Kinase inhibitor, Kinesin-spindle protein inhibitors, MEK1/2 inhibitors, AKT inhibitors and PIM-Kinase inhibitors.

Expert opinion: Isatuximab, oprozomib, melflufen, venetoclax and filanesib seem to be the most promising agents with single agent activity. Nevertheless, lack of clinical activity as single agent does not imply clinical inefficacy in combination treatments.     

Novel immunomodulatory compounds in multiple myeloma

Introduction: The treatment options for patients with multiple myeloma (MM) remain limited. Immunomodulatory agents (IMiDs), such as thalidomide and lenalidomide, have changed the landscape in the treatment of patients with MM while newer IMiDs such as pomalidomide are showing promise in early clinical trials.

Areas covered: This review focuses on the biologic rationales of IMiDs and the clinical results supporting their use in MM. It includes data on the new IMiD, pomalidomide and also explores the possible utility of combining IMiDs with other agents. A PubMed search and abstracts from oncology scientific meetings (ASCO and ASH) of articles related to IMiDs and MM was conducted.

Expert opinion: IMiDs have shown clinical activity as single agents and in combination. Thalidomide was the first in class drug. Lenalidomide has a better toxicity profile than thalidomide. Pomalidomide may overcome resistance to lenalidomide indicating differences in their mechanisms of action and resistance. Molecular biomarkers may allow us to identify patients who will respond to IMiDs.     

多发性骨髓瘤药物治疗新进展

多发性骨髓瘤(MM)是一种常见的血液系统恶性肿瘤,主要集中在老年人,40 a以下者少见。尽管传统化学治疗(化疗)MP、M2、VAD仍是初治Ⅰ、Ⅱ期MM的首选方法,但有效率不高且不能治愈。新的化疗组合和老药沙利度胺的新用已使MM缓解率和无病生存期明显提高,来那度胺、硼替佐米、三氧化二砷、二膦酸盐类等用于复发、难治性MM取得了更高的缓解率,同时也相信尚在实验室研究中的新药会给MM的治疗带来新的希望。     

Emerging drugs in multiple myeloma

The treatment of multiple myeloma has seen significant changes from the time of the initial use of cytotoxic agents such as melphalan, to the introduction of high-dose chemotherapy and stem cell transplantation, and most recently the era of novel targeted agents. These new drugs have rapidly become the mainstay of therapy of this disease and transformed the treatment paradigm, leading to improvements in survival and quality of life. Existing therapeutic options include agents such as thalidomide, bortezomib and lenalidomide, either used alone or in combination with standard agents, including glucocorticoids, and in conjunction with high-dose chemotherapy supported with stem cell transplantation. Several other targeted agents have demonstrated exciting preclinical activity, and are presently being tested in early Phase I and II clinical trials. This review summarizes the role of novel therapeutic agents in multiple myeloma, and the promising effect of multiple new agents in development.     

Emerging drugs in multiple myeloma

The treatment of multiple myeloma has seen significant changes from the time of the initial use of cytotoxic agents such as melphalan, to the introduction of high-dose chemotherapy and stem cell transplantation, and most recently the era of novel targeted agents. These new drugs have rapidly become the mainstay of therapy of this disease and transformed the treatment paradigm, leading to improvements in survival and quality of life. Existing therapeutic options include agents such as thalidomide, bortezomib and lenalidomide, either used alone or in combination with standard agents, including glucocorticoids, and in conjunction with high-dose chemotherapy supported with stem cell transplantation. Several other targeted agents have demonstrated exciting preclinical activity, and are presently being tested in early Phase I and II clinical trials. This review summarizes the role of novel therapeutic agents in multiple myeloma, and the promising effect of multiple new agents in development.     

Evaluation of the pharmacokinetics, preclinical, and clinical efficacy of lenalidomide for the treatment of multiple myeloma

Introduction: Lenalidomide is an oral immunomodulatory drug, which was recently introduced for the treatment of multiple myeloma (MM). It has been used for the treatment of newly diagnosed and relapsed MM patients, as both maintenance and preventive therapy. Available data show a progression-free survival and overall survival improvement associated with this drug. Areas covered: Efficacy results of lenalidomide in Phase I, II, and III trials in MM are reported herein. The recent use of lenalidomide as maintenance and preventive therapy is described. An overview of the most important adverse events is also presented, such as myelosuppression, thromboembolic events, fatigue, dermatologic toxicity, infections, teratogenic potential, and second primary malignancies. The literature reviewed consists of clinical trials published from 2001 to 2012. Expert opinion: Lenalidomide is one of the most important therapeutic agents for MM treatment. Various trials have confirmed its remarkable anticancer activity, alone or combined with high- or low-dose dexamethasone, or other drugs. Lenalidomide-related adverse events can be controlled with dose reductions, supportive therapy, and appropriate prophylaxis.     

New Therapeutic Approaches for Waldenstrom Macroglobulinemia

Waldenstrom Macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow (BM) with lymphoplasmacytic cells, as well as detection of an IgM monoclonal gammopathy in the serum. WM is an incurable disease, with an overall medial survival of only 5-6 years. First-line therapy of WM has been based on single-agent or combination therapy with alkylator agents (e.g. chlorambucil or cyclophasphamide), nucleoside analogues (cladribine or fludarabine), and the monoclonal antibody rituximab. Novel therapeutic agents that have demonstrated efficacy in WM include thalidomide, lenalidomide, bortezomib, everolimus, Atacicept, and perifosine. The range of the ORR to these agents is between 25-80%. Ongoing and planned future clinical trials include those using PKC inhibitors such as enzastaurin, new proteasome inhibitors such as carfilzomib, histone deacetylase inhibitors such as panobinostat, humanized CD20 antibodies such as Ofatumumab, and additional alkylating agents such as bendamustine. These agents, when compared to traditional chemotherapeutic agents, may lead in the future to higher responses, longer remissions and better quality of life for patients with WM.     

Current treatment options for myeloma

In most cases multiple myeloma is an incurable plasma cell malignancy. Despite the use of conventional therapy or high-dose chemotherapy with autologous stem cell transplantation (ASCT), patients continue to relapse at a constant rate. A small minority of patients are cured by allogeneic transplantation. Novel drugs targeting not only the myeloma cell but also its interactions with the malignant microenvironment have recently been used in patients with relapsed/refractory disease. So far, ASCT has been the treatment of choice for eligible myeloma patients. However, many questions regarding the management of myeloma patients remain unanswered. How safe is ASCT in elderly patients? Is there a role for non-myeloablative allogeneic transplantation in multiple myeloma? What is the role of novel agents, such as thalidomide, its analogues and bortezomib, in the treatment of newly diagnosed patients or as maintenance post-ASCT? This review summarises all available data for the current treatment options for myeloma providing a useful algorithm for its management.     

Stroke after treatment with bortezomib and dexamethasone in a Chinese patient with extramedullary relapse of multiple myeloma

Thromboembolic complications commonly occur in patients with multiple myeloma (MM). The risk of such complications may be elevated by the use of immunomodulatory agents such as thalidomide and lenalidomide as initial therapy for MM. However, arterial thrombosis after treatment with bortezomib is rare. Herein we report a case of a 70-year-old Chinese male patient with extramedullary relapse of MM. After treatment with bortezomib and dexamethasone he developed a nonfatal thrombotic stroke. Administration of bortezomib and dexamethasone was then discontinued and he obtained partial remission.     

Novel targets and derived small molecule inhibitors in multiple myeloma

Recent research advances have defined a key role of the bone marrow (BM) in multiple myeloma (MM) pathogenesis thereby leading to new treatment paradigms, which aim to target both the tumor cell as well as its BM microenvironment. The incorporation of thalidomide, bortezomib, and lenalidomide into conventional cytotoxic and transplantation regimens in relapsed and refractory, but also in newly diagnosed MM has changed treatment options during the last decade. However, MM remains still incurable. Ongoing translational research aims to identify additional therapeutic targets and to design derived agents, predominantly small molecule inhibitors, with higher potency and less toxicity to further improve MM patient outcome and to overcome drug resistance.