The start of a new wave: Developments in proteasome inhibition in multiple myeloma

Multiple myeloma (MM) accounts for 10% of hematological cancers. Stem cell transplantation remains the cornerstone of first‐line treatment for eligible patients, but historically, pharmaceutical treatment options for MM have been limited. The proteasome was identified as a target for MM therapy in the early 2000s and, in 2004, the boronic acid proteasome inhibitor bortezomib gained European approval. Bortezomib now plays a major role in MM treatment, but the duration of its use can be limited by toxicities such as peripheral neuropathy and the development of resistance. A new generation of proteasome inhibitors has since entered the treatment landscape: carfilzomib, an epoxyketone‐based agent with a distinct mode of action, high clinical efficacy, and lower levels of peripheral neuropathy compared with bortezomib, received approval in 2015 for use in patients with relapsed and/or refractory MM (RRMM). Ixazomib, a second‐generation, orally administered, boronic acid proteasome inhibitor, has also been approved for use in patients with RRMM. In just over a decade, proteasome inhibitor‐based regimens have become an integral component of MM treatment; with more proteasome inhibitors in development, this remains a vibrant research area with potential to improve the lives of patients with MM in the years to come.     

Bortezomib-induced rhabdomyolysis in multiple myeloma

Although multiple myeloma (MM) remains an incurable disease, its treatment has improved over the past decade. This improvement has been at least in part due to the introduction of novel antimyeloma agents with new mechanisms of action, including those that target both myeloma cells and the tumor microenvironment, with antiangiogenic and immunomodulatory properties. Among these drugs, bortezomib (Velcade), a selective proteasome inhibitor, has been approved for the treatment of relapsed and refractory MM patients after one line of therapy. The toxicity profile of bortezomib includes gastrointestinal symptoms, fatigue, thrombocytopenia, peripheral neuropathy, postural hypotension, as well as some uncommon events. A patient with relapsed MM who developed recurrent bortezomib-induced rhabdomyolysis is reported. To our knowledge, this adverse event has not been previously described is this context.     

Therapie des multiplen Myeloms

The multiple myeloma (MM) has an incidence of 3-4/100,000 in the Caucasian population. MM has to be distinguished from smouldering MM and monoclonal gammopathy of uncertain significance (MGUS). In younger patients (<65 years) a good long-term remission is the aim of therapy, while in the elderly patients with comorbidities the aim is a good partial remission with good quality of life. In the elderly this can be achieved with a combination of melphalan and prednisone. High-dose chemotherapy, often as a tandem transplantation, is part of standard therapy of MM patients <65 years. However, allogeneic stem cell transplantation is the only curative approach. New substances approved for treatment of relapsed MM include bortezomib, thalidomide, and lenalidomide.     

Aktuelle Therapiestrategien beim Mantelzelllymphom

Mantle cell lymphoma is a subtype of B?cell lymphoma with a mostly aggressive behavior and poor long-term prognosis. The choice of therapy depends on the age, performance status and risk profile of the patient. Randomized trials have confirmed the superiority of a dose-intensified induction therapy containing cytarabine followed by autologous stem cell transplantation in the first-line treatment of younger patients with a good general condition. Elderly patients benefit from a rituximab maintenance therapy after immunochemotherapy. Novel targeted therapies of the B?cell receptor pathway with the Bruton’s tyrosine kinase inhibitor ibrutinib and the mechanistic target of rapamycin (mTOR) antagonist temsirolimus as well as immunomodulatory drugs (lenalidomide) have shown promising results in relapsed disease. The proteasome inhibitor bortezomib has been approved for first-line treatment in combination with conventional chemotherapy.     

Transplantation strategies for patients with follicular lymphoma

PURPOSE OF REVIEW: This review summarizes the current status and new developments in autologous and allogeneic transplantation strategies for patients with follicular lymphoma including novel concepts of myeloablative radioimmunotherapy, allogeneic transplantation with dose-reduced conditioning, and in-vivo purging strategies using B-cell-specific antibodies. RECENT FINDINGS: Substantial progress has been made in the clinical management of follicular lymphoma. Besides immunochemotherapeutic approaches combining the B-cell antibody rituximab with conventional chemotherapy regimens, myeloablative chemotherapy or radiochemotherapy supported by autologous peripheral blood stem cell transplantation has been shown to be a highly effective treatment for advanced-stage disease. Dose-reduced conditioning regimens followed by allogeneic transplantation have substantially reduced treatment-related mortality of this approach and ongoing studies are evaluating whether the therapeutic benefit outweighs morbidity and mortality of this potentially curative treatment. Emerging concepts include the use of rituximab for in-vivo purging before reinfusion of autologous stem cells or the application of myeloablative radioimmunotherapy as part of myeloablative consolidation. SUMMARY: The data on myeloablative therapy followed by autologous stem cell transplantation or allogeneic transplantation are encouraging. Allogeneic transplantation with dose-reduced conditioning should be further evaluated within clinical trials, however, in particular for patients with relapsed or refractory lymphoma. Future prospective randomized clinical trials should reevaluate the role of autologous stem cell transplantation in the era of antibody-based therapy and define the role of radioimmunotherapy and of reduced-intensity allogeneic transplantation.     

International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation

The role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients.     

自体外周造血干细胞移植治疗21例多发性骨髓瘤的临床疗效及预后因素评价

目的:评价自体外周造血干细胞移植(APBSCT)治疗21例多发性骨髓瘤(MM)患者的临床疗效以及影响预后的相关因素.方法:21例MM患者中有2例患者复发后行2次APBSCT,因此共行APBSCT 23例次.5例患者在诱导治疗时采用硼替佐米(万坷)联合方案,其他患者多数采用长春新碱、阿霉素加地塞米松(VAD)方案诱导治疗...     

Treatment of newly diagnosed advanced stage Hodgkin lymphoma

ABVD continues to be the standard of care for patients with advanced stage Hodgkin Lymphoma (HL) although escalated BEACOPP has improved survival in one randomized controlled trial (RCT). More intensive regimens have higher rates of acute and late toxicities and this poses significant issues for patients. Consolidation strategies such as radiation or autologous stem cell transplantation (ASCT) have not demonstrated an improvement in overall survival in RCTs. Novel technology and therapeutics are leading us to investigate new questions. Interim FDG-PET scanning is now being tested in prospective studies. Small, typically retrospective trials suggest that interim PET scans are independent markers of outcome and current trials are piloting the use of PET-adapted therapy. Targeted therapeutics have been evaluated in the relapsed and refractory setting and now show promising single agent activity. Agents including brentuximab vedotin (a conjugated anti-CD30 monoclonal antibody) and the histone deacetylase inhibitor panabinostat have reported encouraging single agent activity and a large study of brentuximab vedotin maintenance post ASCT is underway. Combination and maintenance trials are planned or ongoing in the primary treatment setting that will hopefully improve on the treatment standards of the past decade. This review will discuss the current standard of care in advanced stage HL, summarize some of the current data regarding interim FDG-PET scans and will conclude with some issues related to the development of new agents that are likely to be involved in the future standard of therapy.     

Therapeutic approaches for newly diagnosed multiple myeloma patients in the era of novel drugs

The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new effective drugs with novel mechanisms of action, such as thalidomide, lenalidomide and bortezomib in the last decade, has resulted in a new scenario expected to impact favorably on the outcome of patients with MM. The introduction of new drugs in the treatment of patients eligible for autologous stem cell transplantation (ASCT) has allowed for a significant increase of complete response rate with a positive impact on progression‐free survival. In patients not eligible for ASCT, randomized trials have shown that both thalidomide and bortezomib when combined with melphalan and prednisone (MP) are superior to MP and are now considered the standard of care. Ongoing trials are assessing whether MP plus lenalidomide or the combination of lenalidomide plus dexamethasone should be considered an attractive treatment option, while additional studies are needed to determine the role of routine maintenance or consolidation therapy with these new drugs. This new therapeutic armamentarium in light of adequate prophylaxis and supportive care allows clinicians to greatly improve the survival perspectives for both young and elderly patients. In this review, we report updated data for the front‐line therapy of MM, examining the role of new drugs either when administered as induction therapy before ASCT in younger patients or when combined with alkylating agents for the treatment of older patients. The most relevant articles on therapy of MM published from November 1982 to January 2010 (selected through PubMed), and recent meeting abstracts were used as sources for this review.     

Targeted treatments to improve stem cell outcome: old and new drugs

Thalidomide, lenalidomide and bortezomib have been approved for the treatment of relapsed or refractory multiple myeloma in the recent years. These agents are now being increasingly integrated into therapeutic regimens for newly diagnosed patients. First data are available on the promising activity of these novel agents in induction therapy, as well as maintenance treatment to improve outcome after stem cell transplantation. Whether these early results will lead to prolonged overall survival and thereby ultimately redefine the role of stem cell transplantation in first-line treatment of multiple myeloma will be one of the most important questions to be answered in the coming years.Bone Marrow Transplantation (2007) 40, 1129-1137; doi:10.1038/sj.bmt.1705829; published online 3 September 2007.     

Bortezomib for previously untreated multiple myeloma

The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new effective drugs with novel mechanisms of action, such as bortezomib, in the last decade have resulted in a new scenario expected to impact favorably on the outcome of MM patients. In the transplant and nontransplant setting, several randomized trials have shown that front-line treatment with bortezomib-based combinations are superior to conventional treatment and have allowed for a significant increase of complete response rate, with a positive impact on progression-free survival. Furthermore, this drug appears to be active in patients with high-risk disease and comorbidities. Thus, bortezomib-containing regimens are now considered as a new standard of care for newly diagnosed myeloma patients. In this article, we will attempt to overview the results of bortezomib when administered as a standard component of front-line therapy for MM patients.     

Changing paradigms in the treatment of multiple myeloma

The outcome of patients with multiple myeloma treated with conventional approaches has been unsatisfactory. In this perspective article, Drs. Bladé and Rosiñol examine the novel therapeutic options and their impact on the survival of these patients. See related paper on page 270.The outcome of patients with multiple myeloma (MM) treated with conventional approaches, mainly alkylating agents and glucocorticoids with or without high-dose therapy/autologous stem cell transplant (HDT/ASCT), has been unsatisfactory with a median survival of 2–3 years and 5–6 years for older and younger patients respectively.¹ Moreover, the number of long-term survivors has been disappointingly small. The introduction of the so-called dose-reduced intensity conditioning allogeneic transplantation (Allo-RIC) and the availability of new effective drugs with novel mechanisms of action such as thalidomide, lenalidomide and bortezomib in the last decade have resulted in a new scenario in which there is an expectation for real improvement in long-term outcome for patients with MM. This improvement can come from a better initial therapy for patients eligible and not eligible for HDT/SCT, from more effective rescue regimens for patients with relapsed/refractory disease and finally from better supportive measures and general management.     

Recent Developments in Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Multiple myeloma (MM) is often successfully controlled with conventional chemotherapy; however, complete remissions are uncommon, and cure is rare. High-dose therapy followed by administration of autologous or allogeneic stem cells, used for the treatment of MM in the past 15 years, is promising as a means of increasing remission rates and improving survival. Autologous transplantation has not always demonstrated survival benefits in randomized studies because most of the patients receiving transplants have relapses, whereas patients given conventional therapy can receive salvage transplants when relapse occurs. Efforts to improve the results of autologous transplantation include targeted radiation, tandem transplantation, and posttransplantation immunotherapy. Only allogeneic hematopoietic stem cell transplantation is potentially curative, owing to a graft-versus-myeloma effect. Although patients who receive either allogeneic or autologous stem cell transplants for MM have similar 3- to 5-year survival rates, only allograft recipients appear to enjoy long-term disease-free survival. High transplantation-related mortality associated with allogeneic stem cell transplantation is currently the major limitation to wider use of this potentially curative modality. Strategies designed to improve the therapeutic index of allografts include the use of nonablative conditioning regimens, peripheral blood cells rather than bone marrow, graft engineering, and targeted conditioning therapies, such as bone-seeking radioisotopes.     

Successful mobilization of peripheral blood stem cells with bortezomib + high-dose cyclophosphamide + G-CSF in a light chain myeloma patient after failure with Total Therapy 2

Autologous stem cell transplantation is considered the best post-induction therapy for multiple myeloma (MM). Therefore, therapy for myeloma should be chosen not only on the basis of efficacy, but also taking into account their impact on the hematopoietic stem cell compartment. We describe the case of a MM patient in which a successful mobilization of peripheral stem cells was obtained with bortezomib, cyclophosphamide and G-CSF, after two failed attempts in the framework of Total Therapy 2. The patient underwent an autologous transplantation, showing a rapid and complete post-transplant hematological recovery. Our experience suggests that bortezomib is an effective anti-myeloma agent without negative impact on stem cell mobilization, even in patients with a previous history of failed harvest.     

Thalidomide, lenalidomide and bortezomib in the management of newly diagnosed multiple myeloma

The field of multiple myeloma therapeutics has been an active one for many years, but perhaps no more so than in the past decade. The introduction of thalidomide, lenalidomide and bortezomib in the treatment of this disease highlights clinical advances made during this period. While these agents were initially utilized in the setting of relapsed and refactory disease, they are now part of the therapeutic armamentarium for transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma. The principles of management applied in the care of newly diagnosed multiple myeloma are reviewed in this article, along with the clinical studies supporting the use of thalidomide, lenalidomide and bortezomib in newly diagnosed multiple myeloma. Management of treatment-related side effects is also discussed, since it constitutes a critical element in the successful management of patients with this disease. Combination regimens utilizing thalidomide, lenalidomide and bortezomib are also highlighted, as these regimens are likely to play an increasingly important role in myeloma therapy in the future.     

Autologous stem cell transplantation in the elderly including pre- and post-treatment options

Multiple myeloma (MM) is a disease of the elderly with a median age at diagnosis of 67 years in a referral population. High-dose chemotherapy (HDT) and autologous stem cell transplantation has been shown to improve survival in patients with MM in randomized trials and remains the preferred option for eligible patients. However, the randomized clinical trials demonstrating an advantage for HDT included only patients younger than 65 years and evidence supporting its role for the elderly patients has been based on retrospective reviews. The introduction of thalidomide, lenalidomide and bortezomib has changed the paradigm for treatment of myeloma and improved the outcome for these patients. Several ongoing clinical trials are evaluating the role of these novel agents in this population, specifically comparing these to HDT-based approaches. Other trials are examining the role of maintenance therapy post-HDT with these novel drugs with or without steroids. The role of HDT will be further redefined in the coming years with improvements in other therapies.     

Conventional therapy and approach to management

The treatment of multiple myeloma (MM) has undergone major changes in the last decade. There is now an array of therapeutic options, including autologous stem-cell transplantation, non-myeloablative (mini) allogeneic transplantation, and new drugs such as thalidomide and bortezomib. There is also an awareness that there are subsets of patients with MM who have not gained much from the recent advances, including patients with certain adverse prognostic factors (high-risk MM). In this article, we outline our approach to the diagnosis, risk stratification and treatment of MM with a focus on conventional therapy. We incorporate a risk-based strategy for the treatment of MM that also takes into account the eligibility of the patient to undergo stem-cell transplantation. We also outline the role and current indications for the use of new active agents in this disease.     

Bendamustine in multiple myeloma

The advent of high‐dose melphalan with autologous stem‐cell transplantation (ASCT), the availability of novel agents such as thalidomide, lenalidomide (immunomodulatory drugs or IMiDs) and bortezomib (proteasome inhibitor) and improvements in supportive care have allowed to increase overall survival in multiple myeloma (MM) patients; nevertheless, MM remains an incurable pathology. For this reason, newer agents are required for continued disease control. Bendamustine is an old drug rediscovered in the last decade. In fact, its unique mechanism of action with structural similarities to both alkylating agents and antimetabolities, but which is not cross‐resistant to alkylating agents, has reawakened interest in the use of this drug in the treatment of MM. Studies have proven the safety and efficacy of bendamustine administered alone or in combination with new drugs in both upfront and relapse/refractory settings of MM patients, including those with renal impairment. Moreover, bendamustine has been successfully used as conditioning for autologous stem‐cell transplantation. Finally, the use of bendamustine does not compromise peripheral blood stem‐cell collection. This drug is generally well tolerated, with the majority of adverse events being due to myelosuppression. Non‐haematological adverse events are infrequent and usually mild.     

Bortezomib plus dexamethasone treatment followed by reduced-intensity allogeneic stem cell transplantation for multiple myeloma refractory to high-dose chemotherapy with autologous transplantation

We present two long-term survivors after allogeneic transplantation with reduced-intensity conditioning regimen following relapse after autologous stem cell transplantation (ASCT) for multiple myeloma (MM). The first case was a 47-year-old male with IgG MM treated with 2 courses of high-dose melphalan along with ASCT and thalidomide, resulting in a minimal response. He then received 2 courses of bortezomib plus dexamethasone (BD) regimen, which was discontinued due to peripheral neuropathy. Allogeneic peripheral stem cell transplantation (PBSCT) from a sibling donor was performed after pretreatment with fludarabin (125 mg/m(2)) and melphalan (100 mg/m(2)). Engraftment was observed on day 11 and monoclonal IgG had disappeared 5 months after transplantation. The patient has been in complete remission for more than two and a half years with moderate chronic graft-versus-host disease (GVHD). The second case was a 51-year-old male who relapsed after ASCT for IgA MM. After 3 courses of BD treatment, irradiation to lumbar plasmacytoma, and thalidomide therapy, he received allogeneic PBSCT from a related donor after the same reduced intensity conditioning as performed in case 1. A complete response was observed 6 months after PBSCT. The patient has remained relapse-free for two years without GVHD. BD treatment followed by allogeneic stem cell transplantation with reduced intensity conditioning is supposed to be one of the most powerful strategies for patients showing relapse after ASCT.     

Bortezomib in multiple myeloma

Multiple myeloma (MM) remains an incurable disease, and novel agents are therefore needed to improve outcome. Bortezomib is the first proteasome inhibitor to be approved by the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products for the treatment of refractory/relapsed MM. Bortezomib has demonstrated significant anti-myeloma activity as a single agent in refractory/relapsed MM. When used in combination with other agents, responses have suggested the possibility of chemosensitization and synergy. All these facts have been the rationale for the use of bortezomib-based regimens as upfront treatment in young and elderly newly diagnosed MM patients. Furthermore, bortezomib does not appear to have an adverse effect on subsequent stem-cell collection. Bortezomib is well tolerated; most side-effects are only mild to moderate and manageable. Practical management of these side-effects is given so that they can be recognized and minimized by dose modification or concomitant therapy.