Lenalidomide in multiple myeloma: an evidence-based review of its role in therapy

Abstract

Introduction: Multiple myeloma (MM) is a relatively common and incurable hematological malignancy. Currently, there is no single standard therapy, with choice of treatment dependent on individual patient factors. Lenalidomide is an immunomodulatory drug with potent antitumor, antiangiogenic, immunomodulatory, and proapoptotic activity in MM.

Aims: To evaluate the evidence for the use of lenalidomide in its current indication in relapsed or refractory MM, and additionally its investigational use for the treatment of newly diagnosed MM.

Evidence review: In patients with relapsed and refractory MM, adding lenalidomide to high-dose dexamethasone significantly improves response rates and time-to-progression, relative to high-dose dexamethasone alone. This translates into a significant extension of overall survival (with a median extension of 9.1 months in a pivotal phase III study). Outcome is independent of patient age, number of previous therapies, type of previous therapy (including thalidomide or autologous stem cell transplantation), renal impairment, and beta(2)-microglobulin level. Evidence suggests that combining lenalidomide with low-dose dexamethasone improves outcomes in patients with newly diagnosed disease and is superior to lenalidomide combined with high-dose dexamethasone. Myelosuppression is the predominant toxicity observed, although some studies have shown high incidences of venous thromboembolism in the absence of prophylactic antithrombotic anticoagulation therapy. There is currently only limited evidence regarding the health economics of lenalidomide. ROLE IN THERAPY: The encouraging results obtained with lenalidomide alone and in combination with dexamethasone in patients with relapsed or refractory MM have led to its adoption as a recommended therapy in patients who have received at least one prior treatment. Emerging evidence supports the ongoing investigation of lenalidomide in combination with low-dose dexamethasone, and in other combinations including bortezomib, for use both in relapsed, refractory, and newly diagnosed MM.

Keywords: evidence; lenalidomide; multiple myeloma; outcomes; treatment.

Figure 1

Treatment options in multiple myeloma. Abbreviations: Bort, bortezomib; Bort/Dex, bortezomib and dexamethasone; DCEP, dexamethasone, cyclophosphamide, etoposide, and cisplatin; Dex, dexamethasone; DT-PACE, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide; DVD, liposomal doxorubicin, vincristine, and dexamethasone; Len/Dex, lenalidomide plus dexamethasone; MP, melphalan and prednisone; MPT, melphalan, prednisone, and thalidomide; SCT, stem cell transplantation; RVD, lenalidomide, bortezomib and dexamethasone; VAD, vincristine, doxorubicin, and dexamethasone; Thal/Dex, thalidomide plus dexamethasone.

Figure 2

Pathogenesis of multiple myeloma. Copyright © 2007. Adapted with permission from Macmillan Publishers Ltd. Hideshima T, Mitsiades C, Tonon G, et al Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585–598. Abbreviations: BAD, BCL-X_L associated death promoter; BCL-X_L, basal cell lymphoma-extra large; bFGF, basic fibroblast growth factor; BMECs, bone marrow endothelial cells; CAMDR, cell adhesion-mediated drug resistance; DKK1, Dickkopf-1; FKHR, forkhead transcription factor; GSK3β, glycogen synthase kinase 3-beta; HGF, hepatocyte growth factor; IAP, inhibitor of apoptosis proteins; ICAM, intercellular adhesion molecule;IGF-1, insulin-like growth factor;IL, interleukin; JAK/STAT, janus kinases/signal transducers, and activators of transcription; LFA, lymphocyte function-associated antigen; MCL, myeloid cell leukemia; MEK/ERK, mitogen-activated protein kinase/extracellular regulated kinase; MIP1 α, macrophage inflammatory protein 1alpha; mTOR, mammalian target of rapamycin; MUC, mucin; NFκB, nuclear factor kappa B; OPG, osteoprotegerin; PKC, protein kinase C; RANKL, receptor activated NFκB ligand; RUNX, runt-related transcription factor; SDF1α, stromal cell derived factor 1-alpha; TGFβ, transforming growth factor beta; TNF-α, tumor necrosis factor-alpha; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; VLA4, very late antigen-4.

Figure 3

Caspase-mediated pathway. Copyright © 2007. Reproduced with permission by American Society of Hematology. Richardon P, Mitsiades C, Schlossman R, et al. The treatment of relapsed and refractory multiple myeloma. Hematology Am Soc Hematol Educ Program. 2007:317–323. Abbreviations: MM, multiple myeloma; PARP1, Poly(adenine diphosphate-ribose) polymerase 1; Smac, second mitochondria-derived activator of caspase; Caspase, cysteine-aspartic acid proteases.

Figure 4

Mechanism of action of lenalidomide in multiple myeloma. Copyright © 2009. Adapted with permission from Richardson P, Jagannanth S, Hussein M, et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009;114:772–778. Abbreviations: bFGF, basic fibroblast growth factor; CTL, cytotoxic T lymphocytes; NK, natural killer cells; VEGF, vascular endothelial growth factor.