Evolving paradigms in the treatment of newly diagnosed multiple myeloma

The treatment of multiple myeloma has undergone significant changes in the past few years. The introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, has dramatically improved the outcome of this disease and considerably increased the treatment options available. Several trials have shown the advantages linked to the use of novel agents both in young patients, who are considered eligible for transplantation, and elderly patients, for whom a conventional therapy should be considered. These novel agents may increase the efficacy of autologous stem cell transplantation with deeper and long-lasting response. In the transplant setting, different novel agent combinations have proved to be superior to the traditional vincristine-doxorubicin-dexamethasone. Similarly, novel agents have also changed the treatment paradigm of patients not eligible for transplantation, thus replacing the traditional melphalan-prednisone approach. Preliminary data also support the role of consolidation and maintenance therapy to further improve outcomes. This article provides an overview of the latest strategies, including novel agents used to treat patients with multiple myeloma, both in the transplant and nontransplant settings.     

Latest advances and current challenges in the treatment of multiple myeloma

Effectively treating patients with multiple myeloma is challenging. The development of therapeutic regimens over the past decade that incorporate the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has been the cornerstone of improving the outcome of patients with myeloma. Although these treatment regimens have improved patient survival, nearly all patients eventually relapse. Our improved understanding of the biology of the disease and the importance of the microenvironment has translated into ongoing work to help overcome the challenge of relapse. Several classes of agents including next-generation proteasome inhibitors, immunomodulatory agents, selective histone-deacetylase inhibitors, antibody and antitumor immunotherapy approaches are currently undergoing preclinical and clinical evaluation. This Review provides an update on the latest advances in the treatment of multiple myeloma. In particular, we focus on novel therapies including modulating protein homeostasis, kinases inhibitors, targeting accessory cells and cytokines, and immunomodulatory agents. A discussion of the challenges associated with these therapeutic approaches is also presented.     

多发性骨髓瘤靶向药物治疗进展:第56届美国血液学会年会报道

随着对多发性骨髓瘤(MM)分子发病机制研究的深入,许多新的靶向治疗药物进入临床试验,使MM患者的缓解率和生存质量得到进一步提高.2014年第56届美国血液学会(ASH)年会针对MM的靶向治疗最新进展进行了专题报道,这些药物临床试验结果均明显提高了MM的疗效,或许将给MM的治疗策略带来重大改变.现将会议上报道的针对MM的分子靶向治疗药物研究新进展进行介绍.     

Targeted therapy in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is an incurable malignancy. Recent insights into its biology has allowed the use of novel therapies targeting not only the deregulated intracellular signaling in MM cells but also its interaction with the bone marrow microenvironment that confers drug resistance, growth, and survival advantage to the malignant cells. METHODS: We review and summarize the recent advances in our knowledge of myeloma biology as well as the mechanism of action and clinical efficacy for novel therapeutic agents in clinical trials. RESULTS: Several novel therapeutic agents are currently in clinical trials. Thalidomide is already established for both initial and salvage treatment. Bortezomib is being tested alone and in combination with conventional chemotherapy in various settings. Other agents are less effective in producing response but have been able to stabilize disease in patients with relapsed and/or refractory disease, such as arsenic trioxide, farnesyltransferase inhibitors, 2-methoxyestradiol, and vascular endothelial growth factor receptor inhibitors. Insights into drug resistance mechanism have also led to the development of novel agents that sensitize myeloma cells to chemotherapy (Bcl-2 antisense). Gene expression studies have in many instances identified pathways other than the intended target of the drug and have provided insights into the therapeutic mechanisms. CONCLUSIONS: In the future, patients with MM will have more therapeutic options available than ever before. The challenge will be to identify patient subgroups that will benefit most from the different therapies and then determine how these biologically based therapies could be combined and incorporated into the overall management of patients.     

New drugs for myeloma

Although multiple myeloma remains incurable with conventional treatments, management of the disease has recently been transformed with the introduction of three novel agents, bortezomib, thalidomide, and lenalidomide. The proteasome inhibitor bortezomib is approved for the treatment of patients who have received one prior therapy; there is a growing body of clinical evidence showing its effectiveness alone and in combination in the frontline setting, with high response rates and consistently high rates of complete response. Thalidomide plus dexamethasone is approved as frontline treatment of multiple myeloma. Other combination regimens including thalidomide have demonstrated substantial activity in both relapsed and frontline settings. Recently, the thalidomide analogue lenalidomide has been approved, in combination with dexamethasone, for the treatment of patients who have received one prior therapy; this regimen has shown promising results in the frontline setting. These agents represent a new generation of treatments for multiple myeloma that affect both specific intracellular signaling pathways and the tumor microenvironment. Other novel, targeted therapies are also being evaluated in preclinical and clinical studies. Regimens incorporating bortezomib, thalidomide, lenalidomide, and other novel agents, together with commonly used conventional drugs, represent a promising future direction in myeloma treatment. At present, further investigation is required to assess the safety and activity of combinations integrating these other novel agents. However, bortezomib, thalidomide, and lenalidomide are now in widespread clinical use. This review therefore focuses on the extensive clinical data available from studies of these drugs in the treatment of newly diagnosed and advanced multiple myeloma.     

多发性骨髓瘤生物靶向治疗研究进展

近年来,多发性骨髓瘤（MM）新药研发迅速,新的靶向治疗药物的临床应用进一步提高了MM患者的疗效。2016年第58届美国血液学会（ASH）年会上,多项关于MM的生物靶向治疗研究有了令人鼓舞的进展,尤其是各种新药的联合应用更是本届年会的一大亮点,同时还有很多新药的Ⅰ、Ⅱ期临床试验研究报道。对该届ASH年会上报道的关于MM的分子靶向治疗药物研究新进展进行介绍。     

Management of Double-Refractory Multiple Myeloma

Widespread use of the novel agents bortezomib and lenalidomide has improved outcomes in multiple myeloma (MM). Despite remarkable progress, patients will eventually relapse after exhausting treatment with these drugs. Management of myeloma that is refractory to both bortezomib and lenalidomide (double-refractory MM, DRMM) is complicated due to disease, patient, and treatment-related factors and new therapies for these patients are required. A review of the unique challenges of treating DRMM, recently FDA-approved therapeutic agents, and selected novel drugs under active clinical investigation, is presented below.     

多发性骨髓瘤的临床治疗:第56届美国血液学会年会报道

近十年来,多发性骨髓瘤(MM)治疗的主要进展之一就是对适合大剂量化疗(HDT)及自体干细胞移植(ASCT)的年轻患者引入新药(如沙利度胺、硼替佐米、来那度胺)作为一线治疗.这些药物在没有增加不良反应的基础上明显提高了ASCT前后的完全缓解率.实现“最佳治疗”包括新药基础上的诱导治疗、HDT以及在巩固和维持治疗阶段使用新药,使MM患者5年生存率达到80％,对于初诊时确定为良好预后分型的患者可能达到治愈.然而,新药的高效性促使一些研究机构研究在不进行ASCT的情况下其作用如何.2014年末,初步的随机数据提示早期ASCT加新药疗效优于单独使用新药.因此,对于适合HDT的年轻MM患者,最佳治疗方案依然包括ASCT.文章介绍2014年第56届美国血液学会(ASH)年会关于临床治疗多发性骨髓瘤的研究进展.     

Pathogenic signaling in multiple myeloma

Multiple myeloma is a common hematological malignancy of plasma cells, the terminally differentiated B cells that secrete antibodies as part of the adaptive immune response. Significant progress has been made in treating multiple myeloma, but this disease remains largely incurable, and most patients will eventually suffer a relapse of disease that becomes refractory to further therapies. Moreover, a portion of patients with multiple myeloma present with disease that is refractory to all treatments from the initial diagnosis, and no current therapeutic approaches can help. Therefore, the task remains to advance new therapeutic strategies to help these vulnerable patients. One strategy to meet this challenge is to unravel the complex web of pathogenic signaling pathways in malignant plasma cells and use this information to design novel precision medicine strategies to assist these patients most at risk.     

The adverse prognostic impact of advanced age in multiple myeloma

The adverse prognostic impact of advanced age in multiple myeloma is multi-factorial. In this review we explore the various contributory factors to this phenomenon. These include general biological and psychosocial factors, which impact on cancer in the elderly population such as the presence of multiple co morbidities and poor performance status at diagnosis and variation in patient's expectations of treatment. Factors specific to myeloma include the ability to deliver optimum therapy in older patients and the impact of this on disease response, possible biological differences of myeloma in older patients, and how these various factors impact on the efficacy of conventional-dose, high-dose (HDT) and newer disease modifying therapies. Selected elderly patients can gain equal benefit to younger patients from effective therapies such as HDT. However, the use of specific assessment tools for the elderly, apart from chronological age, should be used to select elderly patients who will benefit. Future testing of newer therapies in patients with myeloma must include older patients, who will make up an increasing proportion of the myeloma population in the future and should incorporate assessment of effect of these therapies on quality of life.     

New horizons in multiple myeloma therapy

Recent advances in the understanding of the molecular and biological aspects of multiple myeloma have opened new horizons in the management and treatment of this hitherto incurable disease. With better understanding of the pathobiological ‘web’ responsible for triggering plasma cells to develop into myeloma, scientists have been able to develop therapeutic strategies that target not only the myeloma cell, but its microenvironment as well. This article will review novel agents commonly used to treat multiple myeloma, either alone or in combination. The role of these agents as induction therapy in newly diagnosed, relapsed and/or refractory disease will also be evaluated. Finally, an overview of novel therapies moving from the bench to the bedside will be provided.     

New horizons in multiple myeloma therapy

Recent advances in the understanding of the molecular and biological aspects of multiple myeloma have opened new horizons in the management and treatment of this hitherto incurable disease. With better understanding of the pathobiological 'web' responsible for triggering plasma cells to develop into myeloma, scientists have been able to develop therapeutic strategies that target not only the myeloma cell, but its microenvironment as well. This article will review novel agents commonly used to treat multiple myeloma, either alone or in combination. The role of these agents as induction therapy in newly diagnosed, relapsed and/or refractory disease will also be evaluated. Finally, an overview of novel therapies moving from the bench to the bedside will be provided.     

High-risk multiple myeloma: does it still exist?

Major improvement milestones in the treatment of patients with multiple myeloma (MM) include the introduction of the melphalan/prednisone combination in the 1960s, high-dose chemotherapy supported by autologous stem cell transplant in the 1980s, and the more recent introduction of the novel agents thalidomide, lenalidomide, and bortezomib. Historically, age and eligibility for autologous stem cell transplantation were the primary basis for treatment selection, but, from a biologic standpoint, MM therapy was "one size fits all," in that therapy was not tailored based on molecular or other features that define subtypes of MM. Recently, novel therapies have extended overall survival for the broad spectrum of patients with myeloma. Moreover, newer data demonstrate that novel therapies may ameliorate the prognostic impact of predictors of high risk and poor outcome in MM, which suggests that patients with MM and with high-risk disease should receive novel agents. Such approaches may constitute nascent steps toward individualized therapy, ie, the selection of highly effective therapies based on specific features exhibited by an individual patient's MM. However, prospective data that demonstrate the validity of these approaches are lacking. Definitive, multi-institutional clinical trials are required before redefining standards of myeloma care based on this approach.     

Role of Proteasome Inhibitors in Relapsed and/or Refractory Multiple Myeloma

Proteasome inhibition is an established treatment strategy for patients with multiple myeloma as proteasome inhibitors (PIs) selectively target and disrupt the protein metabolism of aberrant plasma cells. Since the introduction of the first-in-class PIs bortezomib, the therapeutic landscape for multiple myeloma has shifted with the development of next-generation PIs (carfilzomib and ixazomib) and new classes of agents. Treatment with modern combination therapies has been shown to result in deep responses and improved outcomes, and these potent regimens are increasingly used as frontline therapy. As patients continue to live longer with modern frontline therapy, there will be an increased need for effective regimens after initial treatment failure. Several recent studies have shown that treatment with combination therapy incorporating PIs induces deep and durable responses in patients with relapsed and/or refractory multiple myeloma. In this review, we review pivotal data and discuss the role of PIs-based doublet and triplet regimens for the management of relapsed/refractory multiple myeloma in the era of modern combination therapy.     

Society of Hematologic Oncology State of the Art Update and Next Questions: Multiple Myeloma

During the past decade, the survival outcomes of patients with multiple myeloma (MM) have dramatically improved, not only owing to the advent of a number of novel therapies, but also to the deepening insight regarding how to best use these options. Triplet-based induction regimens can yield overall response rates of ≤ 100%. In the relapsed and refractory setting, we have a multitude of doublet and triplet options available with high and durable response rates. The addition of monoclonal antibodies has provided a new class of agents to augment our standard approach with novel therapies. Minimal residual disease status testing has worked its way into the lexicon of the myeloma-treating physician and provides both prognostic and potentially therapeutic insight into management. Despite the influx of novel therapies, high-dose melphalan with autologous stem cell rescue remains a vital tenet of induction therapy for our younger and more fit patients. The current generation of clinical trials using immunologic approaches such as bifunctional antibodies and chimeric antigen receptor T cells is extremely promising and will likely become the future standard of care. Although the disease remains, on the whole, incurable, we now possess therapeutic modalities that can provide deep and durable remissions and, potentially, cure for some.     

CAR T-cell therapy in multiple myeloma: more room for improvement

The emergence of various novel therapies over the last decade has changed the therapeutic landscape for multiple myeloma. While the clinical outcomes have improved significantly, the disease remains incurable, typically in patients with relapsed and refractory disease. Chimeric antigen receptor (CAR) T-cell therapies have achieved remarkable clinical success in B-cell malignancies. This scope of research has more recently been extended to the field of myeloma. While B-cell maturation antigen (BCMA) is currently the most well-studied CAR T antigen target in this disease, many other antigens are also undergoing intensive investigations. Some studies have shown encouraging results, whereas some others have demonstrated unfavorable results due to reasons such as toxicity and lack of clinical efficacy. Herein, we provide an overview of CAR T-cell therapies in myeloma, highlighted what has been achieved over the past decade, including the latest updates from ASH 2020 and discussed some of the challenges faced. Considering the current hits and misses of CAR T therapies, we provide a comprehensive analysis on the current manufacturing technologies, and deliberate on the future of CAR T-cell domain in MM.Subject terms: Cancer immunotherapy, Translational research, Myeloma     

Chimeric antigen receptor T-cell therapy in multiple myeloma: A comprehensive review of current data and implications for clinical practice

Multiple myeloma (MM) is a hematologic malignancy defined by the clonal proliferation of transformed plasma cells. Despite tremendous advances in the treatment paradigm of MM, a cure remains elusive for most patients. Although long-term disease control can be achieved in a very large number of patients, the acquisition of tumor resistance leads to disease relapse, especially in patients with triple-class refractory MM (defined as resistance to immunomodulatory agents, proteosome inhibitors, and monoclonal antibodies). There is an unmet need for effective treatment options in these patients. Chimeric antigen receptor (CAR) T-cell therapy is a novel approach that has demonstrated promising efficacy in the treatment of relapsed, refractory MM (RRMM). These genetically modified cellular therapies have demonstrated deep and durable remissions in other B-cell malignancies, and current efforts aim to achieve similar results in patients with RRMM. Early studies have demonstrated remarkable response rates with CAR T-cell therapy in RRMM; however, durable responses with CAR T-cell therapies in myeloma have yet to be realized. In this comprehensive review, the authors describe the development of CAR T-cell therapies in myeloma, the outcomes of notable clinical trials, the toxicities and limitations of CAR T-cell therapies, and the strategies to overcome therapeutic challenges of CAR T cells in the hope of achieving a cure for multiple myeloma.     

Treatment Options for Patients With Heavily Pretreated Relapsed and Refractory Multiple Myeloma

Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for patients with late-stage, highly refractory disease. In this review, we discuss currently approved treatment options for heavily pretreated patients with relapsed and refractory multiple myeloma, with a focus on the optimal management of patients with MM refractory to lenalidomide, bortezomib, and in some cases, daratumumab or an anti-CD38 monoclonal antibody. Data from recent clinical trials of immunomodulatory agents (pomalidomide), proteasome inhibitors (PIs; carfilzomib and ixazomib), monoclonal antibodies (elotuzumab, daratumumab, and isatuximab), and other novel therapies (including panobinostat-based therapy) are summarized. We also provide potential therapeutic strategies for patients according to different treatment histories, and include case studies to illustrate the practical use of various treatment options in a clinical setting. Regimens containing pomalidomide, elotuzumab, next-generation PIs, panobinostat, or selinexor may provide effective treatment options in patients with triple-refractory disease. The choice of agents used, and combinations thereof should be individualized as well as strategically planned from early- to late-stage relapse.     

Improving Induction Therapy in Multiple Myeloma

Significant improvements in induction therapy for multiple myeloma have been seen over the past decade for both transplant-eligible patients and transplant-ineligible patients. The emergence of novel agents in managing myeloma has revealed new directions for clinicians to approach the disease. The first determinant is transplant eligibility. With the recognition of the prognostic impact of postinduction response on overall outcomes, the importance of the choice of optimal regimen has become more important than ever. The preference of induction therapy for transplant-eligible patients has progressively changed from the alkylator-based therapies to doublet therapies to triplet therapies incorporating immunomodulatory drugs (IMiDs) and proteasome inhibitors. The role of quadruplet therapies remains unclear, but with appropriate dosage modifications, these regimens were efficacious and had an acceptable toxicity profile. Similar treatment approaches for transplant-ineligible patients resulted in superior outcomes with the triplet therapies. Many challenges remain however, such as achieving greater depth of responses with molecular remissions and more effective use of risk stratification in induction therapy. These are still to be explored.     

多发性骨髓瘤的免疫治疗研究进展

多发性骨髓瘤是血液系统恶性肿瘤,该病的复发及难治一直是一项难题。越来越多的研究发现免疫失调是骨髓瘤细胞逃避免疫监视、导致疾病发生发展的关键因素,因此免疫治疗为多发性骨髓瘤的治疗带来了很大的前景。其中一些免疫疗法已在临床应用中取得较好的治疗效果,一些仍在试验研究中的疗法也显示出巨大的治疗潜力。本文结合相关文献对免疫治疗中的免疫调节剂、靶向B细胞成熟抗原疗法的研究进展进行综述。