Thalidomide and lenalidomide in multiple myeloma

Multiple myeloma is a treatable but not necessarily a curable plasma-cell cancer. After decades of minimal progress, two new classes of drugs with novel mechanisms of action - immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) - have been introduced for the treatment of this disease. Thalidomide and lenalidomide have shown great activity as single agents and in combination with glucocorticoids for the treatment of chemotherapy-refractory myeloma. Thalidomide - and more recently lenalidomide - in combination with dexamethasone have shown promising results as induction therapy. These drugs can easily be combined with other chemotherapeutic agents to potentiate the anti-myeloma effect. The immunomodulatory function of these drugs can be successfully exploited to control residual disease during remission. Thus, both thalidomide and lenalidomide have ushered in a new era of optimism in the management of this incurable cancer.     

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.     

Multiple myeloma: chemotherapy or transplantation in the era of new drugs

Objective: To review the current results of studies incorporating novel agents in multiple myeloma (MM) and discuss the role of autologous stem‐cell transplantation (ASCT) in the era of new active drugs for the treatment of this disease. The outlook for patients with symptomatic MM is changing with the introduction of bortezomib, thalidomide, and lenalidomide into the repertoire of available chemotherapeutic agents. Compared with standard chemotherapy, a survival benefit has been reported for the first time in 30 yrs. Methods: Articles published in English between 1969 and 2008 were identified by searching PubMed for ‘myeloma’, ‘diagnosis’, ‘thalidomide’, ‘bortezomib’, ‘lenalidomide’, ‘dexamethasone’, ‘prednisone’, ‘doxorubicin’, ‘cyclophosphamide’, ‘melphalan’, ‘combination chemotherapy’, and ‘autologous transplantation’. Results: In randomized studies, bortezomib, thalidomide, and lenalidomide have each been combined with dexamethasone, alkylating agents, or doxorubicin, and such combinations resulted in significant improvement in progression‐free survival. Conclusions: The incorporation of new drugs as induction therapy along with ASCT appears to produce very good partial response rates, slightly superior to those achieved by conventional chemotherapy with new drugs. How to best optimize induction, consolidation, and maintenance therapy and how to best select and prepare patients for ASCT are still to be determined. Randomized trials are needed to directly compare the current best chemotherapeutic approach with best ASCT strategies and to guide clinical practice for patients with MM.     

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.     

Emerging combination treatment strategies containing novel agents in newly diagnosed multiple myeloma

Treatment strategies for multiple myeloma have changed substantially over the past 10 years following the introduction of bortezomib and the immunomodulatory drugs thalidomide and lenalidomide. In the front-line setting, combination regimens incorporating these novel agents are demonstrating substantial activity, which is translating into improved outcomes compared with previous standards of care. Response rates and depth of response that were previously only seen with high-dose therapy plus stem-cell transplantation (HDT–SCT) can now be achieved with new induction regimens utilizing these novel agents. This has raised the need for trials that will determine the clinical benefit of early SCT in patients that have already achieved a high quality of response. Here, we review the improvements in response and outcome that are seen with these novel-agent regimens, both as induction therapy prior to HDT–SCT and in non-transplant patients, and highlight the latest data from key studies of various novel combinations, including regimens featuring bortezomib plus thalidomide or lenalidomide. We also review data on response and outcomes in patients with poor prognostic characteristics that indicate that the adverse impact typically seen with these factors may be overcome using novel-agent 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.     

How best to use new therapies in multiple myeloma

Advances in the molecular understanding of myeloma have led to the development of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib). When used alone, these agents have significant activity against myeloma and responses increase significantly when they are combined with additional agents including glucocorticosteroids and chemotherapeutic agents such as alkylators. There is a drive to use these novel agents in patients with newly diagnosed myeloma, where they lead to impressive response rates with increasing duration of responses. In addition, novel agents are now the mainstays of therapy for relapsed disease. In the following paper, we summarize the key observations from recent completed and ongoing studies that determined the effect of these novel therapies both in the setting of newly diagnosed myeloma and for relapsed disease. We also discuss our approach to the use of these agents in specific myeloma settings.     

Management of multiple myeloma: the changing landscape

Many changes have been incorporated into the approach to multiple myeloma over the last few years, due to improvements in our understanding of the disease biology. New diagnostic and prognostic criteria from the International Myeloma Working Group have clarified the initial clinical approach to this disease. The prognostic impact of chromosomal abnormalities is now recognized, and the detection of specific abnormal cytogenetics is beginning to influence therapeutic decisions. The introduction of the novel agents thalidomide, bortezomib and lenalidomide has expanded treatment options at different points in the disease course; these agents are being evaluated in conjunction with conventional chemotherapy and stem cell transplantation. This report highlights some of the key recent findings in multiple myeloma, and describes areas for future research.     

Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib‐based treatment regimens

Toward our goal of personalized medicine, we comprehensively profiled pre‐treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib‐based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially‐regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of ‘universal response’ pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA‐damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib‐based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti‐myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly‐diagnosed myeloma.     

Outcomes of multiple myeloma patients receiving bortezomib,lenalidomide, and carfilzomib

New classes of drugs including the proteasome inhibitors (PI) bortezomib and, more recently, carfilzomib and the immunomodulatory agent lenalidomide have shown improved outcomes for multiple myeloma (MM) patients during the past decade. However, most of the studies reporting outcomes for patients receiving these drugs have relied on older data sets derived from large institutions that included patients not receiving their treatment at those facilities and represented only those eligible for clinical trials or were from sites where treatment options were limited. We have analyzed data from 258 MM patients who have received treatment with at least one of three agents: bortezomib, carfilzomib, and lenalidomide in a single clinic specializing in MM with respect to their responses and other outcomes to treatment regimens including these agents. Response rates were similar between these three drugs when used for the first time and again during subsequent treatment regimens. As expected, the clinical benefit rates (CBRs) were better for patients receiving their first treatment when compared to their use in subsequent treatment regimens. The CBRs were similar during their 2nd, 3rd, and 4th treatments containing these agents. Many patients refractory to these agents showed responses to regimens containing these same drugs when used in different combinations. In addition, patients refractory to one PI often responded to the other PI. The results of this study demonstrate that novel agents can be used repeatedly in novel combinations with significant clinical benefit for patients with MM.     

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.     

Future drug developments in multiple myeloma: an overview of novel lenalidomide-based combination therapies

The introduction of thalidomide, lenalidomide, and bortezomib has changed the way that multiple myeloma (MM) is treated and has greatly improved survival outcomes. These novel agents are often used in combination with conventional drugs, such as dexamethasone, to optimize clinical responses; however, they are also being evaluated as part of novel treatment combinations to build upon the success of available treatment regimens. Lenalidomide-based combinations are a focus of clinical research due to the high efficacy, good tolerability, and lack of cumulative toxicity associated with lenalidomide. Lenalidomide is an IMiDs? immunomodulatory compound with a dual mechanism of action - tumoricidal effects rapidly reduce MM burden while long-term immunomodulatory actions maintain tumor suppression. Several new agents with antimyeloma effects have been identified including: epigenetic agents (e.g. histone deacetylase inhibitors); novel proteasome inhibitors; novel immunomodulatory compounds; cyclin-dependent kinase inhibitors; interleukin-6 inhibitors; and other experimental agents such as heat-shock protein 90 inhibitors and monoclonal antibodies targeting MM cell surface receptors (e.g. anti-CS1 and anti-CD40). Many of these new agents, in combination with lenalidomide, are in early phases of clinical evaluation. Early clinical results are promising, indicating that the novel lenalidomide-based drug combinations are effective and generally well tolerated in patients with MM; future research will continue to evaluate these novel combinations and help to identify the optimal setting (e.g. induction, salvage, or maintenance) in which they may provide the greatest impact on the disease course.     

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多发性骨髓瘤仍是一种不可治愈的血液肿瘤,近10年的治疗突破很大程度上依赖新药的研发,主要包括蛋白酶体抑制剂硼替佐米、免疫调节剂如来那度胺和沙利度胺等。力求达到完全缓解(CR)是目前的治疗目标,因为CR意味着无进展生存期(PFS)甚至总生存期(OS)的延长。以新药为基础的不同诱导方案显著提高一线治疗缓解率。缓解后或移植后进行巩固和维持治疗显著延长PFS。文章主要对包含新药的诱导方案进行总结,并简要讨论难治复发骨髓瘤患者的治疗。     

Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium

The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called low-dose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.     

Management of myeloma-associated renal dysfunction in the era of novel therapies

Multiple myeloma (MM) is a plasma cell neoplasm often associated with renal impairment (RI), with myeloma cast nephropathy recognized as the most common cause. While RI is present in over 50% of MM patients at some point in their disease course, it is associated with higher tumor burden, more aggressive disease, diminished quality of life, development of complications and increased mortality. The introduction of novel therapies, including bortezomib, lenalidomide and thalidomide, has revolutionized the management of MM. They are now considered first-line therapies in induction, maintenance and salvage therapy for MM. In addition to their anti-MM effect, they can improve outcome in patients with RI, especially when combined, and bortezomib with dexamethasone may have a renal protective effect. This review focuses on the use of these agents in patients with MM and RI, and evaluates their efficacy, safety, need for dose adjustment and impact on RI.     

Management strategies for relapsed/refractory multiple myeloma: current clinical perspectives

In the last decade, the introduction of novel agents including the immunomodulatory drugs thalidomide and lenalidomide, and the first-in-class proteasome inhibitor bortezomib, has dramatically improved clinical outcome in patients with relapsed/refractory multiple myeloma (MM) compared to conventional chemotherapy alone. Although combination treatment approaches with traditional cytotoxic agents and novel agents have led to response rates as high as 85% in patients with relapsed/refractory disease, not all patients will respond to established novel agents, and even those who do respond will ultimately relapse or become refractory to currently available regimens. There is no generally accepted standard treatment for patients with relapsed/refractory disease; however, both disease-related (eg, quality and duration of response to previous therapies and the aggressiveness of the relapse) and patient-related (eg, preexisting toxicities, comorbid conditions, quality of life, age, and performance status) factors should be considered when selecting the best treatment option. This article will review up-to-date approaches for managing patients with relapsed/refractory MM, including the efficacy and safety of established novel agents, the use of adjunctive/supportive care, and strategies for tailored treatment.     

Novel therapeutics in multiple myeloma

Most myeloma patients still experience recurrent relapse and eventually become resistant and/or intolerant of effective agents such as corticosteroids, alkylating agents, immune modulators (lenalidomide and thalidomide) or proteasome inhibitors such as bortezomib. Once this happens average survivals are less than one year. Progress has been made for such patients, however, with the demonstration of clinical benefit of novel proteasome inhibitors (carfilzomib) and immune modulators (pomalidomide). Pomalidomide when used with dexamethasone has activity in 30-60% of patients depending on disease stage. Carfilzomib is an irreversible proteasome inhibitor with favorable toxicity profile (minimal neuropathy) and response rates of 17-54% depending on the disease stage treated. Novel targets are also being explored. Histone deacetylase inhibitors such as vorinostat and panobinostat are in phase II testing although results from a randomized trial combining vorinostat with bortezomib were disappointing. Other small molecules or monoclonal antibodies with novel targets such as kinase inhibitors(AKT, CDK5) and cell surface receptors (e.g. elotuzumab) are undergoing active investigation.     

Current approaches for the treatment of multiple myeloma

The development of novel therapeutic agents over the past decade, including the proteasome inhibitor, bortezomib, and the immunomodulatory drugs, lenalidomide and thalidomide, has resulted in improved outcomes for patients with multiple myeloma. However, there is still considerable controversy as to which regimen should be used as first-line therapy, which patients should be considered for autologous or allogeneic transplantation, and how consolidation or maintenance therapy is used in patients that have a good response to first-line therapy. The present paper will review clinical evidence from previous and ongoing studies to explore issues related to these questions.     

Suitable drug combination with bortezomib for multiple myeloma under stroma-free conditions and in contact with fibronectin or bone marrow stromal cells

Several clinical trials have demonstrated the effectiveness of bortezomib in combination with various anti-myeloma agents; however, no definitive information is available regarding drugs best suited for use in combination with bortezomib. Using isobologram analysis, we investigated the combined effects of bortezomib with four key anti-myeloma drugs (melphalan, cyclophosphamide, doxorubicin and lenalidomide), which represent components of major bortezomib-based regimens with corticosteroids, in three myeloma cell lines (U266, RPMI8226 and KMS-12BM) under various conditions. Melphalan showed the best performance with bortezomib under all culture conditions tested (liquid culture, on fibronectin-coated plates, and co-culture with bone marrow stromal cells), whereas cyclophosphamide was antagonistic with bortezomib especially in the presence of stromal cells. Doxorubicin showed additive effects under stroma-free conditions and in contact with fibronectin, but was rather antagonistic in the presence of stromal cells. In contrast, lenalidomide exerted the most favorable effect with bortezomib in contact with stromal cells. Consistent with these results, caspase-3 was activated more strongly by melphalan than by other agents in combination with bortezomib. Moreover, bortezomib-induced up-regulation of CHOP was readily enhanced by lenalidomide in contact with stromal cells. The present findings may provide fundamental information for the selection of bortezomib-based regimens for myeloma patients.     

Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management

DISEASE OVERVIEW: Multiple myeloma is malignant plasma-cell disorder that accounts for ～10% of all hematologic malignancies. DIAGNOSIS: The diagnosis requires (1) 10% or more clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma plus (2) evidence of end-organ damage felt to be related to the underlying plasma cell disorder. RISK STRATIFICATION: Patients with 17p deletion, t(4;14), t(14;16), t(14;20), and karyotypic deletion 13 or hypodiploidy are considered to have high-risk myeloma. All others are considered to have standard-risk disease. RISK-ADAPTED THERAPY: Standard-risk patients are treated with nonalkylator-based therapy such as lenalidomide plus low-dose dexamethasone (Rd) followed by autologous stem-cell transplantation (ASCT). If patients are tolerating the induction regimen treatment well, an alternative strategy is to continue initial therapy after stem-cell collection, reserving ASCT for first relapse. High-risk patients are treated with a bortezomib-based induction followed by ASCT and then bortezomib-based maintenance. Patients not eligible for ASCT can be treated with Rd for standard risk disease or a bortezomib-based regimen if high-risk features are present. To reduce toxicity, when using bortezomib, the once-weekly dose is preferred; similarly, when using dexamethasone, the low-dose approach (40 mg once a week) is preferred, unless there is a need for rapid disease control. MANAGEMENT OF REFRACTORY DISEASE: Patients with indolent relapse can be treated first with lenalidomide, bortezomib, or alkylators plus low-dose corticosteroids. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. The most promising new agents in development are pomalidomide and carfilizomib.