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Front-line lenalidomide therapy in patients with newly diagnosed multiple myeloma
María J Cejalvo1 & Javier de la Rubia*,1,2
Abstract The availability of novel drugs with different and innovative mechanisms of action such as proteasome inhibitors such as bortezomib and immunomdulatory agents as thalidomide and lenalidomide have changed the landscape of the treatment of patients with newly diagnosed multiple myeloma, allowing the development of several new therapeutic regimens both for transplant-eligible and -ineligible patients. Among these new agents, lenalidomide has become one of the most commonly used in these patients. In this article, we review the current state-of-the-art of different induction and maintenance lenalidomidecontaining regimens administered in transplant-eligible and -ineligible patients with newly diagnosed multiple myeloma. We also discuss the safety profile and potential long-term side effects of this drug and analyze its utility in certain subgroups of patients like those with high-risk disease or different degrees of renal impairment. Multiple myeloma (MM) is a malignant B-cell disorder characterized by the clonal proliferation of plasma cells in the bone marrow [1] and, usually, the presence of a monoclonal immunoglobulin (M-protein) in blood and/or urine [2] . It is associated with a constellation of disease manifestations, including osteolytic lesions, anemia, immunosuppression due to loss of normal hematopoietic stem cell function and increased risk of infection and end-organ damage especially renal impairment due to monoclonal immunoglobulin secretion [3] . It accounts for 1% of all malignant diseases and for slightly more than 10% of all hematologic cancers [4] . The mean age of affected individuals is 62 years for men (75% >70 years) and 61 years for women (79% >70 years) [5] . Although the etiology of MM is unknown [6] , a series of genetic changes and mutational alterations are known to occur in the complex microenvironment, involving the clonal plasma cell. MM angiogenesis is a hallmark of disease progression with prognostic potential, since it correlates with tumor growth, relapse and drug resistance [7] . MM is still considered an incurable disease. However, the availability of many novel drugs with different and complementary mechanisms of action has allowed the development of several new regimens that have widely broadened the spectrum of therapeutic alternatives for these patients. Overall, these new alternatives have been associated in the last decades with significant improvements in the overall response rate and survival of MM patients [5] . Lenalidomide is a second-generation immunomodulatory drug a chemical analog of thalidomide [8] but with enhanced immunomodulatory and antiangiogenic properties and without most of the typical thalidomide-associated adverse events. It is a synthetic derivate of glutamic acid that differs from thalidomide by the addition of an amino group (NH2) and the removal of the carbonyl group (C=O) from the fourth position of phthaloyl ring (Table 1) .
Hematology Service, University Hospital Doctor Peset, Avda Gaspar Aguilar 90, 46017 Valencia, Spain Universidad Católica de Valencia ‘San Vicente Mártir’, Valencia, Spain *Author for correspondence: Tel.: +34 961 622 536; Fax: +34 961 622 312; [email protected]
Keywords
• front-line therapy • immunomodulatory drugs • lenalidomide • multiple
myeloma
1 2
10.2217/FON.15.51 © 2015 Future Medicine Ltd
Future Oncol. (Epub ahead of print)
part of
ISSN 1479-6694-0794
Drug Evaluation Cejalvo & de la Rubia Table 1. Characteristics of thalidomide and lenalidomide. Structure
Thalidomide (Thalomid®)
Lenalidomide (Revlimid®)
O O
O O NH
N
NH
O
N
O
MW Formula
O
NH2
258.23 C13H10N2O4 2-(2,6-dioxopiperidin-3-yl)-1Hisoindole-1,3(2H)-dione
259.26 C13H13N3O3 3-(4’aminoisoindoline-1’-one)-1piperidine-2,6-dione
MW: Molecular weight in g/mol.
Mechanism of action The mechanism of action of lenalidomide is only partially understood. It has been suggested that its antitumoral action is mediated by a double tumoricidal and immunomodulatory effect present [9,10] even in thalidomiderefractory patients [11] . Additionally, this drug displays a much more favorable toxicity profile than thalidomide [9,10] . In order to have a better knowledge of the dual therapeutic mechanism of lenalidomide it is of special interest to understand the complex microenvironment of bone marrow in MM patients that includes a storm of cytokines and growth factors interacting with BMSCs and the extracellular matrix glycoproteins [12,13] . IMiD® compounds are known to suppress the production of pro-inflammatory cytokines TNF-α, IL-12, IL-6 and IL-1β [14] , while increase the yield of anti-inflammatory cytokines IL-2, IFN-γ, and IL-10 in peripheral blood mononuclear cells (PBMCs) [15] . Recently, cereblon (CRBN) has been identified as a possible target of IMiD compounds teratogenecity [16] , and its reduced expression has been suggested to be associated with lenalidomide-resistance patients [17,18] . Pharmacodynamics properties The antitumor properties of lenalidomide are well known and have been extensively reported both in vitro and in vivo [19] . Lenalidomide exerts a direct disrupt on BMSCs inhibiting growth and survival of myeloma tumor cells by reducing the over expression of IL-6 and its positive feedback in VEGF and bFGF [20] . Inhibition of VEGF and bFGF reduce Akt phosphorylation [21] providing a potential mechanism for the antimigratory and antiangiogenic effects of lenalidomide. In addition, lenalidomide induces G0/G1 growth arrest via a novel epigenetic mechanism mediated by lysine-specific demethylase 1 [22] , associated with
10.2217/FON.15.51
Future Oncol. (Epub ahead of print)
tumor suppression genes (e.g., p21) and upregulation [19] of the transcriptional factors Egr1 and Erg2 [22] . Also, lenalidomide combined with dexamethasone (LEN/DEX) induces cell apoptosis through caspase-9 cascade and activation of caspase-8 [23] . Additionally, lenalidomide blocks the antiapoptotic pathway NF-κB by the suppression of DNA binding activity of the p50/p65 NF-κB triggered by TNFα and IL-1β in Jurkat cell line [24] and in PBMCs [25] . In vitro studies, have also shown that lenalidomide inhibits COX-2 [26] and reduces prostaglandin E2 exerting a potent anti-inflammatory action that might contribute to its antitumor activity. Recent studies have also observed that two transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) are intermediaries in the binding of lenalidomide to CRBN [27,28] , promoting additional inhibition of the autoubiquitlating process by altering the function of the E3 ubiquitin ligase complex [16] . Besides, lenalidomide produces transcriptional downregulation of Aiolos inducing ribosomal stress with the suppression of RNA-polymerase I activity [29] , interferon regulatory factor 4 and MYC responsible for MM cytotoxicity [30] . Additionally, the immunomodulatory actions of lenalidomide are also exerted by regulating T-cell co-stimulation and increasing NK-T- and CD8 + T-cell cytotoxicity [31] . Finally, lenalidomide also co-stimulates proliferation of CD3 + T cells induced by immature and dendritic cells [32] , and enhances humoral vaccine responses (Figure 1) [33] . Pharmacokinetics properties Pharmacokinetics of lenalidomide has been investigated in healthy volunteers, in subjects with various degrees of renal impairment [34] and in patients with relapsed/refractory MM [35] . Lenalidomide is a small racemic molecule orally administered with a rapid absorption
future science group
Front-line lenalidomide therapy in patients with newly diagnosed multiple myeloma and bioavailability greater than 80% in healthy individuals [36] and moderate solubility at physiological pH where it is not ionized [37] . The volume distribution is extensive into tissues. The linear pharmacokinetics characteristics are proportional to the administered dose [35] . The mean protein binding in plasma is low, 22.7 and 29.2% in MM patients and healthy volunteers,
Drug Evaluation
respectively [38] . Approximately 90% of lenalidomide clearance occurs primarily by renal excretion (unchanged form) and a portion of this is believed to be transporter mediated [34,39] . The elimination half-life is 3 h after a 5-mg dose, increasing to 9 h after a 400 mg dose. In healthy volunteers decreased renal function resulted in an increase in the maximum plasma concentration
CRBN
Tumoricidal Reduces MM cell burden
IgA
Cell cycle arrest M
Immunomodulatory Improves immune function and tumor killing
+ Dexamethasone
G0/G1
arrest arrest G2
Enhancement of humoral and vaccine responses
B Caspase activation (apoptosis)
G1 S CD4 Bone marrow stroma cell
IL-2
CD8
NK
Cytokine receptor
MM cell Integrin
IFN-γ
Activated immune cells target and trigger MM cell apoptosis
CD4 IL-6 VEGF TNF-α
MIP-1α IL-6
VEGF
CD8 IL-6 VEGF
NK CD4
NK
CD8
Neoangiogenesis Osteoclast Inhibition of MM cell survival, angiogenic migration and growth
Activated immune cells release cytokines and proliferate
Figure 1. Mechanism of action of lenalidomide. CD4: Helper T cell; CD8: Cytotoxic T cell; CRBN: Cereblon; MM: Multiple myeloma; NK: Natural killer.
future science group
www.futuremedicine.com
10.2217/FON.15.51
Drug Evaluation Cejalvo & de la Rubia Table 2. Summary of pharmacokinetic parameters of lenalidomide. Renal Function (ml/min)
Normal CLCR >80
Mild 50 ≤ CLCR ≤80
Moderate 30 ≤ CLCR ≤ 50
Severe CLCR
Front-line lenalidomide therapy in patients with newly diagnosed multiple myeloma
María J Cejalvo1 & Javier de la Rubia*,1,2
Abstract The availability of novel drugs with different and innovative mechanisms of action such as proteasome inhibitors such as bortezomib and immunomdulatory agents as thalidomide and lenalidomide have changed the landscape of the treatment of patients with newly diagnosed multiple myeloma, allowing the development of several new therapeutic regimens both for transplant-eligible and -ineligible patients. Among these new agents, lenalidomide has become one of the most commonly used in these patients. In this article, we review the current state-of-the-art of different induction and maintenance lenalidomidecontaining regimens administered in transplant-eligible and -ineligible patients with newly diagnosed multiple myeloma. We also discuss the safety profile and potential long-term side effects of this drug and analyze its utility in certain subgroups of patients like those with high-risk disease or different degrees of renal impairment. Multiple myeloma (MM) is a malignant B-cell disorder characterized by the clonal proliferation of plasma cells in the bone marrow [1] and, usually, the presence of a monoclonal immunoglobulin (M-protein) in blood and/or urine [2] . It is associated with a constellation of disease manifestations, including osteolytic lesions, anemia, immunosuppression due to loss of normal hematopoietic stem cell function and increased risk of infection and end-organ damage especially renal impairment due to monoclonal immunoglobulin secretion [3] . It accounts for 1% of all malignant diseases and for slightly more than 10% of all hematologic cancers [4] . The mean age of affected individuals is 62 years for men (75% >70 years) and 61 years for women (79% >70 years) [5] . Although the etiology of MM is unknown [6] , a series of genetic changes and mutational alterations are known to occur in the complex microenvironment, involving the clonal plasma cell. MM angiogenesis is a hallmark of disease progression with prognostic potential, since it correlates with tumor growth, relapse and drug resistance [7] . MM is still considered an incurable disease. However, the availability of many novel drugs with different and complementary mechanisms of action has allowed the development of several new regimens that have widely broadened the spectrum of therapeutic alternatives for these patients. Overall, these new alternatives have been associated in the last decades with significant improvements in the overall response rate and survival of MM patients [5] . Lenalidomide is a second-generation immunomodulatory drug a chemical analog of thalidomide [8] but with enhanced immunomodulatory and antiangiogenic properties and without most of the typical thalidomide-associated adverse events. It is a synthetic derivate of glutamic acid that differs from thalidomide by the addition of an amino group (NH2) and the removal of the carbonyl group (C=O) from the fourth position of phthaloyl ring (Table 1) .
Hematology Service, University Hospital Doctor Peset, Avda Gaspar Aguilar 90, 46017 Valencia, Spain Universidad Católica de Valencia ‘San Vicente Mártir’, Valencia, Spain *Author for correspondence: Tel.: +34 961 622 536; Fax: +34 961 622 312; [email protected]
Keywords
• front-line therapy • immunomodulatory drugs • lenalidomide • multiple
myeloma
1 2
10.2217/FON.15.51 © 2015 Future Medicine Ltd
Future Oncol. (Epub ahead of print)
part of
ISSN 1479-6694-0794
Drug Evaluation Cejalvo & de la Rubia Table 1. Characteristics of thalidomide and lenalidomide. Structure
Thalidomide (Thalomid®)
Lenalidomide (Revlimid®)
O O
O O NH
N
NH
O
N
O
MW Formula
O
NH2
258.23 C13H10N2O4 2-(2,6-dioxopiperidin-3-yl)-1Hisoindole-1,3(2H)-dione
259.26 C13H13N3O3 3-(4’aminoisoindoline-1’-one)-1piperidine-2,6-dione
MW: Molecular weight in g/mol.
Mechanism of action The mechanism of action of lenalidomide is only partially understood. It has been suggested that its antitumoral action is mediated by a double tumoricidal and immunomodulatory effect present [9,10] even in thalidomiderefractory patients [11] . Additionally, this drug displays a much more favorable toxicity profile than thalidomide [9,10] . In order to have a better knowledge of the dual therapeutic mechanism of lenalidomide it is of special interest to understand the complex microenvironment of bone marrow in MM patients that includes a storm of cytokines and growth factors interacting with BMSCs and the extracellular matrix glycoproteins [12,13] . IMiD® compounds are known to suppress the production of pro-inflammatory cytokines TNF-α, IL-12, IL-6 and IL-1β [14] , while increase the yield of anti-inflammatory cytokines IL-2, IFN-γ, and IL-10 in peripheral blood mononuclear cells (PBMCs) [15] . Recently, cereblon (CRBN) has been identified as a possible target of IMiD compounds teratogenecity [16] , and its reduced expression has been suggested to be associated with lenalidomide-resistance patients [17,18] . Pharmacodynamics properties The antitumor properties of lenalidomide are well known and have been extensively reported both in vitro and in vivo [19] . Lenalidomide exerts a direct disrupt on BMSCs inhibiting growth and survival of myeloma tumor cells by reducing the over expression of IL-6 and its positive feedback in VEGF and bFGF [20] . Inhibition of VEGF and bFGF reduce Akt phosphorylation [21] providing a potential mechanism for the antimigratory and antiangiogenic effects of lenalidomide. In addition, lenalidomide induces G0/G1 growth arrest via a novel epigenetic mechanism mediated by lysine-specific demethylase 1 [22] , associated with
10.2217/FON.15.51
Future Oncol. (Epub ahead of print)
tumor suppression genes (e.g., p21) and upregulation [19] of the transcriptional factors Egr1 and Erg2 [22] . Also, lenalidomide combined with dexamethasone (LEN/DEX) induces cell apoptosis through caspase-9 cascade and activation of caspase-8 [23] . Additionally, lenalidomide blocks the antiapoptotic pathway NF-κB by the suppression of DNA binding activity of the p50/p65 NF-κB triggered by TNFα and IL-1β in Jurkat cell line [24] and in PBMCs [25] . In vitro studies, have also shown that lenalidomide inhibits COX-2 [26] and reduces prostaglandin E2 exerting a potent anti-inflammatory action that might contribute to its antitumor activity. Recent studies have also observed that two transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) are intermediaries in the binding of lenalidomide to CRBN [27,28] , promoting additional inhibition of the autoubiquitlating process by altering the function of the E3 ubiquitin ligase complex [16] . Besides, lenalidomide produces transcriptional downregulation of Aiolos inducing ribosomal stress with the suppression of RNA-polymerase I activity [29] , interferon regulatory factor 4 and MYC responsible for MM cytotoxicity [30] . Additionally, the immunomodulatory actions of lenalidomide are also exerted by regulating T-cell co-stimulation and increasing NK-T- and CD8 + T-cell cytotoxicity [31] . Finally, lenalidomide also co-stimulates proliferation of CD3 + T cells induced by immature and dendritic cells [32] , and enhances humoral vaccine responses (Figure 1) [33] . Pharmacokinetics properties Pharmacokinetics of lenalidomide has been investigated in healthy volunteers, in subjects with various degrees of renal impairment [34] and in patients with relapsed/refractory MM [35] . Lenalidomide is a small racemic molecule orally administered with a rapid absorption
future science group
Front-line lenalidomide therapy in patients with newly diagnosed multiple myeloma and bioavailability greater than 80% in healthy individuals [36] and moderate solubility at physiological pH where it is not ionized [37] . The volume distribution is extensive into tissues. The linear pharmacokinetics characteristics are proportional to the administered dose [35] . The mean protein binding in plasma is low, 22.7 and 29.2% in MM patients and healthy volunteers,
Drug Evaluation
respectively [38] . Approximately 90% of lenalidomide clearance occurs primarily by renal excretion (unchanged form) and a portion of this is believed to be transporter mediated [34,39] . The elimination half-life is 3 h after a 5-mg dose, increasing to 9 h after a 400 mg dose. In healthy volunteers decreased renal function resulted in an increase in the maximum plasma concentration
CRBN
Tumoricidal Reduces MM cell burden
IgA
Cell cycle arrest M
Immunomodulatory Improves immune function and tumor killing
+ Dexamethasone
G0/G1
arrest arrest G2
Enhancement of humoral and vaccine responses
B Caspase activation (apoptosis)
G1 S CD4 Bone marrow stroma cell
IL-2
CD8
NK
Cytokine receptor
MM cell Integrin
IFN-γ
Activated immune cells target and trigger MM cell apoptosis
CD4 IL-6 VEGF TNF-α
MIP-1α IL-6
VEGF
CD8 IL-6 VEGF
NK CD4
NK
CD8
Neoangiogenesis Osteoclast Inhibition of MM cell survival, angiogenic migration and growth
Activated immune cells release cytokines and proliferate
Figure 1. Mechanism of action of lenalidomide. CD4: Helper T cell; CD8: Cytotoxic T cell; CRBN: Cereblon; MM: Multiple myeloma; NK: Natural killer.
future science group
www.futuremedicine.com
10.2217/FON.15.51
Drug Evaluation Cejalvo & de la Rubia Table 2. Summary of pharmacokinetic parameters of lenalidomide. Renal Function (ml/min)
Normal CLCR >80
Mild 50 ≤ CLCR ≤80
Moderate 30 ≤ CLCR ≤ 50
Severe CLCR
