Management of relapsed or refractory multiple myeloma in French hospitals and estimation of associated direct costs: a multi-centre retrospective cohort study

What is known and background: For relapsed or refractory multiple myeloma (RRMM), a series of novel agents (thalidomide, bortezomib and lenalidomide) has emerged during the latest decade, but their use in routine clinical practice is not well documented as well as the cost of RRMM. Objective: Our aim is to review the therapeutic management of such patients in France and to estimate the associated costs. Methods: A retrospective cohort study, based on chart reviews, was conducted in French Haematology Departments over the period 2004–2007 and the associated direct costs estimated. Results: One hundred and two patients with a relapse after first‐line therapy were selected from five centres. The average follow‐up from diagnosis or the date of first relapse to death or to the latest news was respectively 56·25 and 23·53 months. Novel agents were used in 73% of all cases, and in all cases of first relapse. Thalidomide and bortezomib were respectively the most frequently used second‐line (57%) and third‐line treatments (44%). The average number of lines of treatment received per patient as from first relapse was 2·75 (min 1; max 8) and the mean direct cost per month was estimated at 3130 € after the first relapse. This cost was represented in greater part by the cost of chemotherapy drugs (66%). What is new and conclusion: The use of novel agents such as thalidomide, bortezomib and lenalidomide for RRMM is highly prevalent in France from the first relapse. The associated medical cost is substantial mainly due to the cost of the new agents.     

Optimizing the efficacy and safety of bortezomib in relapsed multiple myeloma

Bortezomib (Velcade, Millennium) is the first proteasome inhibitor to be used in clinical practice and is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Bortezomib inhibits the intracellular degradation of proteins necessary for normal cell cycling and function. This, in turn, results in cell-cycle arrest and apoptosis. Bortezomib has shown significant activity in trials of patients with relapsed or refractory multiple myeloma; approximately one third of patients have shown significant improvement with bortezomib monotherapy in phase II and III clinical trials. Early phase trials are also evaluating bortezomib in combination with other agents used in the treatment of multiple myeloma, including melphalan, prednisone, thalidomide, and lenalidomide. Preliminary data suggest that bortezomib may act synergistically with some agents, and improves response rates. Bortezomib is generally well tolerated, but common side effects include peripheral neuropathy and thrombocytopenia. Studies are underway to explore different dosing strategies as well as ways to maximize patient benefit while reducing toxicity. This review will discuss what is known thus far about the efficacy and safety profile of bortezomib, ways for optimizing treatment with bortezomib, and strategies for managing side effects and enhancing quality of life.     

Multiple myeloma and treatment-related thromboembolism: oncology nurses' role in prevention, assessment, and diagnosis

Immunomodulating agents such as thalidomide and its newly emerged derivative, lenalidomide, are becoming increasingly popular in the treatment of multiple myeloma because of their ability to combat drug resistance. Clinical trials suggest that thalidomide and lenalidomide are effective in all stages of multiple myeloma treatment-new diagnoses, stem cell transplantations, maintenance therapy, and relapsed or refractory disease. The drugs are most efficacious when combined with additional chemotherapeutic agents and/or corticosteroids. However, deep vein thrombosis and other thromboembolic events are associated with the treatment regimens. Oncology nurses must understand the pharmacologic properties of the drugs and the potentially life-threatening complications associated with them. To provide the highest standard of care, oncology nurses must play a vital role in the prevention, diagnosis, and management of thromboembolic events through awareness of the clinical problem, assessment tools, and thromboembolic prophylactic regimens.     

Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta‐analysis

Summary. Introduction: The incidence of venous thromboembolism (VTE) in patients with multiple myeloma (MM) treated with thalidomide‐ and lenalidomide‐based regimens is high. Recent observational studies have suggested that thromboprophylaxis might be efficacious in decreasing the risk of VTE in this population. Purpose: To determine the absolute rates of VTE with and without different thromboprophylactic agents in patients with newly diagnosed or previously treated MM receiving thalidomide‐ or lenalidomide‐based regimens. Results: Patients with newly diagnosed MM treated with thalidomide in combination with dexamethasone have a VTE risk of 4.1 (95% CI, 2.8–5.9) per 100 patient‐cycles. Therapeutic doses of anticoagulants seem to provide the largest absolute risk reduction of VTE. The rate of VTE in patients with previously treated MM receiving thalidomide in combination with dexamethasone is 0.8 (95% CI, 0.1–2.1) per 100 patient‐months. A combination of lenalidomide and dexamethasone is associated with of risk of VTE of 0.8 (95% CI, 0.07–2.0) per 100 patient‐cycles and 0.7 (95% CI, 0.4–0.9) per 100 patient‐cycles in patients with newly diagnosed and previously treated MM, respectively. Similarly, the rates of VTE in patients also receiving thromboprophylaxis with aspirin were 0.9 (95% CI, 0.5–1.5) and 0.6 (95% CI, 0.01–2.1), respectively. Conclusion: Patients with newly diagnosed or previously treated MM receiving thalidomide‐ or lenalidomide‐based regimens in combination with dexamethasone are at high risk of VTE. The benefit of various types of thromboprophylaxis is difficult to quantify in patients with MM receiving immunomodulatory therapy, especially in those receiving lenalidomide‐based therapy or who have previously treated MM. Randomized controlled trials are needed to address this important clinical need.     

Clinical roundtable monograph. Emerging treatment options for relapsed and refractory multiple myeloma

Multiple myeloma is a major hematologic malignancy, with an incidence of over 20,000 new diagnoses in the United States each year. Historically, a lack of effective therapies led to a poor patient prognosis. However, the introduction of new agents over the past decade has improved the treatment landscape for these patients, resulting in improved responses and prolonged progression-free and overall survival. Unfortunately, though, nearly all multiple myeloma patients go on to experience relapsed disease. The definition of this progression has also evolved with a growing understanding of the biology of multiple myeloma as well how the disease responds to these newer agents. While refractory multiple myeloma is considered to be a disease that does not respond to a particular therapy, the new definition of relapsed and refractory multiple myeloma includes patients who show disease progression within 60 days of discontinuing therapy. These new definitions are an important consideration when interpreting both previously reported and ongoing clinical trial data. Another major issue in the management of relapsed and refractory multiple myeloma is how to treat patients after they no longer respond to thalidomide, lenalidomide, and bortezomib. Regarding this issue, a number of novel agents are now in clinical trial development; many of them show indications of significant activity, even in heavily pretreated patients. Thus, the introduction of these newer agents has the potential to again make a major impact on multiple myeloma patient outcomes.     

Role of bortezomib in the treatment of multiple myeloma

The proteasome inhibitor bortezomib is approved for the treatment of patients with relapsed/refractory multiple myeloma. Botezomib represents a new generation of treatments for multiple myeloma that affects both specific intracellular signaling pathways and the tumor microenvironment. There is a growing body of clinical evidence showing its effectiveness alone and in combination not only in relapsed/refractory cases but also in the front line setting. Regimens incorporating bortezomib and other novel agents such as immunomodulatory derivatives of thalidomide together with commonly used conventional drugs show considerable high response rates including complete response that resulting in improving survival, with or without following stem cell transplantation. Thus these approaches represent a promising future direction in myeloma treatment.     

Diagnosis and management guideline for multiple myeloma

The prognosis of patients with multiple myeloma has been improved in the last decade due to the induction of autologous stem cell transplantation and novel drugs including thalidomide, lenalidomide, and bortezomib into the treatment. Recently, the UK Myeloma Forum and International Myeloma Foundation have successively proposed myeloma management guidelines. Because many novel drugs are not available in Japanese patients, we can not use the same treatment strategy in U.S.A. and Europe. In this chapter, the diagnosis and management guideline is proposed for Japanese patients with myeloma. For convenience, the recommendations are divided into: 1. Diagnostic criteria 2. Indications for starting therapy 3. Treatment(initial therapy, maintenance therapy, and therapy for refractory/relapsed patients) 4. Response criteria 5. Supportive care and management of specific complications.     

Targeted therapeutics for multiple myeloma: the arrival of a risk-stratified approach

Multiple myeloma (MM) remains an incurable hematologic malignancy characterized by frequent early responses, inevitably followed by treatment relapse. Until recently, few effective therapies existed. Indeed, the use of alkylating agents and corticosteroids had remained the treatment of choice for almost four decades. Several novel agents for MM have now become available, including the immunomodulatory drugs thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib. Each of these agents is undergoing extensive clinical evaluation in combination with other therapies to produce unprecedented response rates in newly diagnosed and relapsed MM. Nevertheless, relapse remains universal and further therapeutics with broad activity are required. Importantly, it has become clear that pivotal genetic events are the primary harbingers of clinical outcome and novel targeted therapy approaches using existing approved drugs or novel agents, which address that disrupted signaling pathways are now in various stages of clinical testing. It seems increasingly likely that novel drug combinations, which together turn off these critical Achilles heels, will become the standard of care and that treatment will become increasingly personalized and guided by genetic testing and prognostic factors.     

Proteasome inhibitor therapy in multiple myeloma

Multiple myeloma remains incurable despite available therapies, and novel therapies that target both tumor cell and bone marrow microenvironment are urgently needed. Preclinical in vitro and in vivo studies show remarkable anti-multiple myeloma activity of the proteasome inhibitor bortezomib/PS-341 even in multiple myeloma cells refractory to multiple prior therapies, including dexamethasone, melphalan, and thalidomide. Based on these findings, the U.S. Food and Drug Administration recently approved the first proteasome inhibitor bortezomib (Velcade), formerly known as PS-341, for the treatment of relapsed/refractory multiple myeloma. Bortezomib therapy has set an outstanding example of translational research in the field of oncology. Genomics and proteomic studies further provide rationale for combining bortezomib with conventional and novel agents to inhibit multiple myeloma growth, overcome drug resistance, reduce attendant toxicity, and improve patient outcome in multiple myeloma.     

Monoclonal antibodies currently in Phase II and III trials for multiple myeloma

Introduction: Despite the introduction of novel agents, such as thalidomide, lenalidomide and bortezomib, multiple myeloma (MM) remains an incurable disease and new therapies are needed. mAbs are a new promising anticancer treatment option.

Areas covered: This review will focus on mAbs that are currently under evaluation in Phase II and III clinical trials, as single agent and in combination with established treatment options.

Expert opinion: mAbs are a new strategy against MM, and they have demonstrated encouraging results in preclinical models. mAbs have a relatively benign side-effect profile and work synergistically with traditional chemotherapies and with immunomodulatory drugs and proteasome inhibitors.     

Chemotherapy for multiple myeloma

The combination of the melphalan and prednisolone (MP) can induce objective responses in about 50% of patients with multiple myeloma (MM) since its introduction in 1960. Since then many combination chemotherapy regimens have been used, but a large metaanalysis showed that the combination of oral MP is as effective as combination regimens including intravenous drugs. In recent years, many novel agents (including bortezomib, thalidomide, and liposomal doxorubicin) have been developed for the MM treatment. More recently, MP has been used in combination with these novel agents. The combination treatment of MP and thalidomide, overall survival was significantly better than seen in the MP treatment. In the near future, primary induction therapy will be changed.     

Advances in oral therapy in the treatment of multiple myeloma

Conventional IV chemotherapy regimens used for induction chemotherapy or salvage therapy in the treatment of multiple myeloma (MM) are cumbersome, with a negative impact on patient quality of life. A number of new oral drugs, including immunomodulatory agents such as thalidomide and lenalidomide, have demonstrated potent antimyeloma activity in relapsed and refractory as well as newly diagnosed MM. Clinically, response rates of 56%-72% have been reported with the combination of thalidomide and dexamethasone in patients with newly diagnosed disease; however, the combination is associated with a higher incidence of side effects, including constipation, somnolence, peripheral neuropathy, and thromboembolic complications. In contrast, preliminary safety and efficacy data from clinical studies of lenalidomide show promise. Response rates as high as 83% have been reported in patients with newly diagnosed MM, and the most common adverse event is manageable myelosuppression, which is reversible with dose reduction. Lenalidomide has different toxicities than thalidomide, exhibiting greater myelosuppression but virtually no constipation, somnolence, or peripheral neuropathy. Oncology nurses play a key role in monitoring patients for side effects and pain control and educating them about emerging treatment options. This article reviews the nursing experience with oral agents in the treatment of MM.     

Management of the adverse effects of lenalidomide in multiple myeloma

The introduction of new agents in the treatment of multiple myeloma, such as thalidomide, bortezomib, or lenalidomide, has represented an important step forward in the management of this disease, with improvement in both treatment response and patient survival. On the other hand, when new drugs are used it is very important to know their associated toxicity, since adequate management of the adverse effects can help to avoid unnecessary treatment interruptions - thereby undoubtedly contributing to improvement in the efficacy of therapy. The present study reviews the main hematological and nonhematological adverse effects potentially associated with the use of lenalidomide in its most common combinations used for the treatment of multiple myeloma, and the recommendations for dealing with such effects.     

硼替佐米联合地塞米松治疗多发性骨髓瘤的临床研究

本研究观察硼替佐米治疗多发性骨髓瘤的疗效及不良反应。7例初治患者均采用硼替佐米联合地塞米松治疗；另3例复发难治患者中2例采用硼替佐米联合地塞米松，1例同时加用米托蒽醌和沙利度胺治疗。结果显示，根据EMBT标准判定疗效，7例初治患者中1例完全缓解（CR），5例部分缓解（PR），1例轻微缓解（MR）；3例复发难治患者中2例部分缓解（PR），1例轻微缓解（MR）。总缓解率（CR＋PR）80％。3例患者在治疗过程中出现血小板减少，1例出现腹泻，1例足部麻木，经对症处理后均恢复。结论：硼替佐米治疗初发及复发难治多发性骨髓瘤均有较好的疗效，对治疗相关的副反应患者可耐受。     

多发性骨髓瘤的临床特征及疗效分析

目的 探讨多发性骨髓瘤的临床特征及不同方案的疗效.方法 回顾性分析2006年2月- 2010年8月110例多发性骨髓瘤的临床特征及治疗情况,对不同方案的疗效进行比较.结果 110例患者中Ⅲ期73例,40例伴发有基础疾病;24例接受MP方案,部分缓解10例,无变化1例,疾病进展8例,总有效率41.7%;其余86例接受...     

Lenalidomide treatment for patients with multiple myeloma: Diagnosis and management of most frequent adverse events

The introduction of novel antimyeloma therapies, including thalidomide, lenalidomide, and bortezomib, has expanded treatment options for patients with this disease. These compounds have altered the natural history of multiple myeloma, resulting in substantial improvements in patient outcomes. However, like with any other drug, their use is associated with a specific toxicity profile. The major adverse events (AEs) associated with lenalidomide include: hematological toxicities (myelosuppression), mainly neutropenia, venous thromboembolism, gastrointestinal disturbance, skin toxicity, atrial fibrillation, asthenia, and decreased peripheral blood stem cell yield during stem cell collection when lenalidomide is used after a long period of time. These AEs are predictable, consistent, and manageable with patient monitoring, supportive care, and dose adjustment. In this article, using three clinical cases as examples, we discuss the diagnoses and management of the most frequent AEs associated with lenalidomide treatment in patients with multiple myeloma.     

Lenalidomide treatment for patients with multiple myeloma: diagnosis and management of most frequent adverse events

The introduction of novel antimyeloma therapies, including thalidomide, lenalidomide, and bortezomib, has expanded treatment options for patients with this disease. These compounds have altered the natural history of multiple myeloma, resulting in substantial improvements in patient outcomes. However, like with any other drug, their use is associated with a specific toxicity profile. The major adverse events (AEs) associated with lenalidomide include: hematological toxicities (myelosuppression), mainly neutropenia, venous thromboembolism, gastrointestinal disturbance, skin toxicity, atrial fibrillation, asthenia, and decreased peripheral blood stem cell yield during stem cell collection when lenalidomide is used after a long period of time. These AEs are predictable, consistent, and manageable with patient monitoring, supportive care, and dose adjustment. In this article, using three clinical cases as examples, we discuss the diagnoses and management of the most frequent AEs associated with lenalidomide treatment in patients with multiple myeloma.     

Adenosine A2A and beta-2 adrenergic receptor agonists: novel selective and synergistic multiple myeloma targets discovered through systematic combination screening

The use of combination drug regimens has dramatically improved the clinical outcome for patients with multiple myeloma. However, to date, combination treatments have been limited to approved drugs and a small number of emerging agents. Using a systematic approach to identify synergistic drug combinations, combination high-throughput screening (cHTS) technology, adenosine A2A and β-2 adrenergic receptor (β2AR) agonists were shown to be highly synergistic, selective, and novel agents that enhance glucocorticoid activity in B-cell malignancies. Unexpectedly, A2A and β2AR agonists also synergize with melphalan, lenalidomide, bortezomib, and doxorubicin. An analysis of agonists, in combination with dexamethasone or melphalan in 83 cell lines, reveals substantial activity in multiple myeloma and diffuse large B-cell lymphoma cell lines. Combination effects are also observed with dexamethasone as well as bortezomib, using multiple myeloma patient samples and mouse multiple myeloma xenograft assays. Our results provide compelling evidence in support of development of A2A and β2AR agonists for use in multi-drug combination therapy for multiple myeloma. Furthermore, use of cHTS for the discovery and evaluation of new targets and combination therapies has the potential to improve cancer treatment paradigms and patient outcomes.     

硼替佐米联合化疗与常规化疗方案治疗多发性骨髓瘤的临床比较

目的 观察硼替佐米联合地塞米松及沙利度胺BDT(Velcade+ Daxamethasone+ Thalidomide)方案与改良VAD(Vinorebine+Pirarubicin+Daxamethasone)方案、MPT(Melphalan+ Prednisone+ Thalidomide)治疗初发或复发/难治性多发性骨髓瘤患者的疗效及不良反应.方法 52例多发性骨髓瘤(MM)患者均为Durie-Salmon分期Ⅲ期,其中初治45例,复发/难治7例.21例(16例初治,5例复发/难治)MM患者采用BDT方案治疗,19例(18例初治,1例复发/难治)MM患者采用改良VAD方案治疗,12例(11例初治,1例复发/难治)MM患者采用MPT方案治疗.临床疗效根据EBMT/IBMTR/ABMTR标准判定,不良反应按依据NCICTCAE标准判断.结果 BDT方案组患者骨痛症状明显消失,贫血及肾功能不全得到明显改善,甚至恢复正常,21例患者中14例(66.7%)完全缓解(CR),6例(28.6%)部分缓解(PR),1例(4.8%)无变化(NC),总有效率为95.2%;改良VAD方案组19例患者中5例(26.3%)CR,3例(15.8%)PR,5例(26.3%)微小缓解(MR),2例(10.5%)NC,4例(21.0%)疾病进展(PD),总有效率为68.4%;MPT方案组12例患者中1例(8.3%)CR,2例(16.7%)PR,2例(16.7%)MR,1例(8.3%)NC,6例(50.0%)PD,总有效率为50.0%;三组间疗效比较差异有统计学意义(P<0.05).出现的不良反应包括血液学毒性和非血液学毒性.BDT组所有不良反应均在对症处理或停药后缓解或减轻.结论硼替佐米联合地塞米松及沙利度胺是一种新的有效治疗多发性骨髓瘤的化疗方案,不良反应轻且大多可逆,患者具有较好的耐受性.     

Cost analysis of adding pregabalin or gabapentin to the management of community-treated patients with peripheral neuropathic pain

Objective To compare the cost of adding either pregabalin or gabapentin to the management of community‐treated patients with peripheral neuropathic pain (PNP). Methods A retrospective observational study was conducted using medical records from a Spanish health care provider claims database. Patients receiving health care for PNP, above 18 years and for which either pregabalin or gabapentin was initiated between 2006 and 2008 were included. Economic evaluation included health care resource utilization costs and costs due to sick leave. Results A total of 1163 patients with PNP were eligible for analysis: 764 were prescribed pregabalin and 399 gabapentin in addition to current pain therapy. Mean age was 59.2 years and 62.2% were female. Concomitant use of analgesics was higher in the gabapentin cohort (3.2 vs. 2.7; P = 0.003), mainly due to non‐steroidal anti‐inflammatory drugs (74.9% vs. 69.5%; P = 0.018) and opioids (27.7% vs. 17.9%; P = 0.031). Adjusted total costs per patient was lower in pregabalin‐treated patients (€2514 vs. €3241; P = 0.003), due to less sick leave (€1067 vs. €1633; P = 0.018) and lower health care costs (€1447 vs. €1609; P = 0.004). The higher acquisition cost of pregabalin (€351 vs. €191; P < 0.001) was largely compensated with lower costs in medical visits, physiotherapy, hospital stays and concomitant analgesics. Conclusions In community‐treated patients with PNP, total costs were considerably less for those patients initiated with pregabalin therapy than for those patients starting gabapentin add‐on therapy. The relatively higher treatment acquisition cost of pregabalin was largely compensated by the overall lower costs for the other components of health care resources and sick leave, thus reducing the economic impact on the health care provider's budget and society.