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Lenalidomide: A new therapy for multiple myeloma

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Summary

The last decade has seen rapid evolution in the management of multiple myeloma. Cytogenetic, molecular, and proteomic techniques have led to a better understanding of the pathophysiology and prognostic markers of this heterogeneous malignancy. New immunomodulatory drugs, such as lenalidomide, which interrupt myeloma growth and survival pathways have entered into clinical usage. Combined with dexamethasone, oral lenalidomide has proved to be highly effective in patients whose disease has become resistant to conventional therapy. Currently, several clinical trials are ongoing in order to define the optimal use of this new agent and its combinations across the spectrum of patients with myeloma. Whether the ultimate outcome of future research will be a single-treatment solution for all patients, or whether treatments will become better-tailored to the individual (based on prognostic markers and pre-existing co-morbidities) has yet to be determined.

Introduction

Multiple myeloma (MM) is a haematological malignancy characterised by proliferating plasma cells in the bone marrow, with subsequent over-production of a monoclonal protein in most patients.1, 2 MM accounts for 1.5–2% of all cancer deaths and approximately 20% of deaths from haematological malignancies.3 Although MM is initially sensitive to conventional chemotherapy, it remains incurable with almost all patients eventually relapsing. The median overall survival achieved with conventional approaches is approximately 33 months.4, 5 High-dose melphalan and autologous stem-cell transplantation (ASCT) increase the rate of complete remission, and extend event-free survival and overall survival in selected patients. However, relapse rates are high and, until recently, there were few salvage therapies. With the advent of biologically-based treatment strategies such as bortezomib, thalidomide, and lenalidomide, treatments are now available which specifically target myeloma cell interactions within the bone marrow microenvironment. These interactions are key to the growth and survival of malignant cells, and have proved to be powerful tools in overcoming drug resistance and prolonging the duration of response in patients with MM.6, 7

Lenalidomide (Revlimid®; Celgene, NJ, USA) is an oral immunomodulatory derivative of thalidomide with potent activity, but a different toxicity profile to the parent compound. It possesses pleoyotropic (immunomodulatory, anti-angiogenic, and antineoplastic) activities, as well as anti-inflammatory effects.7, 8 Lenalidomide induces apoptosis, decreases the binding of MM cells to bone marrow stromal cells, and inhibits the production of cytokines (e.g. interleukin-6, vascular endothelial growth factor, tumour necrosis factor alpha) in the bone marrow milieu, which mediate angiogenesis and the growth and survival of resistant MM cells (Fig. 1).9 It also enhances dexamethasone cytotoxicity, stimulates host anti-MM natural killer cell immunity, and inhibits osteoclast differentiation.10, 11 Recently, lenalidomide has been found to have a direct antiproliferative effect on MM cell lines (via p21WAF-1 up-regulation), while protecting normal B-cells from apoptosis, suggesting a potential role in bone marrow regeneration.12

This paper reviews the recent clinical findings with lenalidomide, an agent which has demonstrated remarkable activity against resistant MM cells.6, 7 Lenalidomide has been approved by the Food and Drug Administration (FDA) in the USA, and the European Medicines Agency for use in combination with dexamethasone in patients with MM who have received at least one prior therapy.

Section snippets

Lenalidomide as a single agent

Two phase I dose-escalation trials of oral lenalidomide in advanced MM defined 25 mg/day as the maximum tolerated dose.10, 13 These studies revealed the favourable pharmacokinetic profile and the acceptable toxicity profile of lenalidomide in patients with relapsed/refractory disease. In a subsequent phase II study, 25% of patients with relapsed/refractory MM responded to lenalidomide (complete response [CR], partial response [PR], or minor response). In patients who failed to respond to

Adverse events

While the phase III studies found that combining lenalidomide with high-dose dexamethasone was associated with more side effects than dexamethasone alone (19.8% vs 10.2%, respectively, of patients dropped out of the study because of side effects), this has to be considered in the context of the improved overall response rate. Only 38.4% of patients in the lenalidomide plus dexamethasone group withdrew from the study because of disease progression, compared with 71.6% of those taking

Lenalidomide plus dexamethasone

A phase II trial was conducted to evaluate the efficacy and safety of lenalidomide plus dexamethasone as initial therapy for MM (Table 2). A total of 34 patients were enrolled and were treated with oral daily doses of lenalidomide (25 mg on Days 1–21 of each 28-day cycle) and dexamethasone (40 mg/day on Days 1–4, 9–12, and 17–20).46, 47 For patients who continued therapy beyond 4 months, the dose of dexamethasone was reduced to 40 mg/day on Days 1–4 of each cycle only. Patients also received

Amyloidosis

Based on the encouraging results seen with lenalidomide in MM patients, a phase II trial was conducted in order to evaluate the haematological response rate and toxicity of lenalidomide monotherapy and lenalidomide plus dexamethasone combination, in patients with primary systemic amyloidosis.52 Overall, the experience in 23 patients found that lenalidomide monotherapy had limited activity in patients with primary systemic amyloidosis. Only 1 out of 22 patients achieved a haematological response

Conclusions

Current evidence confirms that once-daily oral treatment with lenalidomide when combined with high-dose dexamethasone is an effective new treatment option for patients with recurrent/refractory MM, with a manageable adverse events profile.15, 16 Regardless of whether patients had been previously treated with thalidomide, the lenalidomide plus dexamethasone combined regimen was more effective at stalling the progression of the disease than dexamethasone alone.18 In addition, it has been shown in

Conflict of interest statement

A.P. is a speaker and advisory board member for both Celgene and Pharmion, and has received a research grant from Celgene. J.S.M. is an advisory board member for Celgene, Pharmion and Janssen-Cilag. P.S. and P.M. are speakers and advisory board members for Celgene. G.M. is an advisory board member for Celgene, Johnson & Johnson, Millennium and Novartis. H.E. is a speaker for Celgene and has received a research grant from Celgene.

Acknowledgements

The authors received editorial support from Excerpta Medica in the preparation of this manuscript, funded by Celgene. The authors, however, were fully responsible for content and editorial decisions for this manuscript.

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