Drug Profile
Lenalidomide in multiple myeloma Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15 For personal use only.
Expert Rev. Anticancer Ther. 15(5), 491–497 (2015)
Young Kim and Ingo GH Schmidt-Wolf* Medizinische Klinik III, Center for Integrated Oncology (CIO), University of Bonn, Bonn, Germany *Author for correspondence: Tel.: +49 228 2871 7050 Fax: +49 22 828 7908 0059 [email protected]
In the last couple of years major progress has been made in the treatment of multiple myeloma (MM) through the introduction of novel agents like thalidomide, lenalidomide, bortezomib and pomalidomide, mostly in combination with autologous stem cell transplantation. Lenalidomide, a second-generation immunomodulatory agent with antitumor and immunomodulatory effects against MM, in combination with dexamethasone was proven to show significant clinical benefits (overall survival and progression-free survival) in Phase III trials either as induction or as maintenance therapy. With a manageable toxicity profile, lenalidomide seems to be an attractive agent in the treatment of MM. Here, we discuss the present data and research on lenalidomide in the treatment of MM. KEYWORDS: adverse effects . drug profile . immunomodulation . immunotherapy . lenalidomide . myeloma .
pharmacokinetics
Multiple myeloma (MM), a malignant disease being considered treatable but still incurable, is a well-known hematological neoplasm derived from plasma cells with the presence of monoclonal paraproteins which can cause bone lesions and kidney dysfunction [1,2]. The degree of the tumor cell proliferation can vary greatly, ranging from a slowly progressing disease with few clinical symptoms to a highly malignant course of disease, which will be fatal without treatment in a very short time. MM was considered to be a disease of the elderly patient, but now the average age at diagnosis is in the early 60s with more and more patients being diagnosed much younger. While MM is still considered to be an incurable disease, it is close to becoming identified as a chronic disease [1,2]. Major progress has been achieved in the treatment of MM through the introduction of novel agents like lenalidomide, bortezomib and pomalidomide, and hence, pure chemotherapy could be replaced as the only therapeutic option [3,4]. Other novel agents like sorafenib, carfilzomib or daratumumab showed a significant antitumor efficacy in MM but are not yet approved for clinical application. Even new therapeutic approaches have been developed (e.g., inhibition of the Wnt-Pathway) in a murine myeloma model [5–9]. Improved progression-free and overall survival in MM patients could only be achieved by autologous stem cell transplantation informahealthcare.com
10.1586/14737140.2015.1033407
(ASCT), if eligible. Nevertheless, allogeneic stem cell transplantation (allo-SCT) has shown to be the only potentially curative therapy concept; thus for most of the patients, being nonASCT/allo-SCT-eligible myeloma still remains an incurable disease [10–13]. While in 2000 the average life expectancy of MM patient was 3–4 years, MM patients can now survive 10 years or more with a good quality of life due to the development of novel agents and modern treatment regimens [10,11]. Lenalidomide, one of the promising novel agents, has already shown promising results in the treatment of MM, especially in combination with other drugs, for example, dexamethasone. The main goal of an effective treatment regimen is to transform this incurable disease into a chronic disease in patients that are not eligible for ASCT [14–16]. Here we discuss the current impact of lenalidomide on the course of disease of MM. Lenalidomide: a novel agent
Lenalidomide (FIGURE 1) is a derivative of thalidomide (FIGURE 2) and a member of a class of compounds called immunomodulatory drugs introduced in 2004. Lenalidomide serves as a second-generation drug with immunomodulatory and anti-inflammatory effects against hematologic malignancies and showed significant improvement in overall and progression-free survival in combination with dexamethasone [17–19].
2015 Informa UK Ltd
ISSN 1473-7140
491
Drug Profile
Kim & Schmidt-Wolf
O
O
N NH O
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15 For personal use only.
NH2
Figure 1. Structural formula of lenalidomide as derivative of thalidomide.
Lenalidomide-based combination therapies have been approved for the treatment of relapsed and/or refractory MM and even showed great benefits as initial treatment in patients with newly diagnosed MM with an acceptable toxicity profile allowing long-term administration, especially when compared to its parent agent thalidomide [19,20]. Due to a long-term follow-up on overall survival from Phase III trials (MM-009 and MM-010) of lenalidomide in combination with dexamethasone in relapsed or refractory MM patients, lenalidomide has been approved by the US FDA and the EMA [20,21]. In the context of ASCT, lenalidomide has been proven to show effect as maintenance therapy after ASCT (ASCT, CALGB 100104) or as potent therapy regimen for ASCTineligible patients (MM-015) [10,11,22]. Even new combination regimens that include lenalidomide are tested in order to improve the therapy outcome of MM patients. Apart from MM, lenalidomide showed significant efficacy in the class of other hematological malignancies such as myelodysplastic syndrome (MDS), non-Hodgkin lymphoma and chronic lymphocytic leukemia [23–25]. Immunomodulation
In recent studies, lenalidomide displayed both immunomodulatory and tumoricidal effects (FIGURE 3), which finally resulted in a significant decrease of the tumor load and a stabilized disease. Through activation of the tumor-suppressor genes EGR1, EGR2, EGR3, p15, p21 and p27 in MM cells, lenalidomide in combination with dexamethasone induces an arrest of the MM cell cycle followed by apoptosis due to activation of the caspase cascade. Additionally, the synthesis of IFN-g via NK cells and IL-2 via T-lymphocytes is induced [26–28]. During treatment of MM by a lenalidomide-based therapy regimen, the primary tumoricidal effect of lenalidomide results in reduced tumor load. Secondary, the immunomodulatory effect of lenalidomide takes place by suppression of the residual tumor’s proliferation [28–30]. Through stimulation of T cells, O
N
O NH
O
O
Figure 2. Structural formula of thalidomide.
492
NK cells and dendritic cells and by improving IL-2 and IFN-g secretion, lenalidomide increases cellular immunity and response. The suppression of Tregs may be the reason why lenolidomide is able to show significant antitumor efficacy in MM [31,32]. Another anti-proliferative mechanism of lenalidomide is the inhibition of the production of cytokines and growth factors (IL-6, TNF alpha, VEGF) and the down-regulation of CCAAT/enhancer-binding proteins, a family of transcription factors, which promote gene expression through interaction with their promoters and can be found in the tissues of different internal organs. Lenalidomide has been proven to show inhibition of angiogenesis induced by growth factor, especially with bone marrow endothelial cells [33,34]. In a recent study, it was shown that lenalidomide affected the regulation and expression of cereblon, a protein which is involved in maintaining the function and activity of MM cells and is encoded by the CRBN gene [35,36]. An increased response of a lenalidomide-based therapy regimen in combination with dexamethasone could be associated with high cereblon levels [37]. Nevertheless, further studies are needed to understand the exact role of cereblon in MM [38]. Pharmacokinetics
Lenalidomide is usually administered orally at a dose of 25 mg once daily on days 1–21 of repeated 28-day cycles and is quickly absorbed with high plasma concentrations occurring after 0.5–4 h after administration in MM patients [1,10,15]. With linear pharmacokinetics, identical in healthy subjects as well in MM patients, plasma concentrations increase proportionally to the administered dose. With main substance clearance via the kidneys and a half-life of 3–5 h, about 70% of lenalidomide is eliminated, unchanged, in urine by tubular secretion and glomerular filtration [39,40]. Thus, renal insufficiency results in reduced clearance, an increased plasma exposure and a prolonged half-life of lenalidomide of up to 6–12 h without affecting oral absorption, protein binding and non-renal elimination. It has been shown that the level of lenalidomide exposure was increased with the degree of renal insufficiency; thus, dosage adjustments are recommended for MM patients with moderate/severe renal impairment or a creatinine clearance below 60 ml/min to ensure safe exposure levels [39–41]. Adverse effects
Due to its manifold immunomodulatory and myelosuppressive effects, the administration of lenalidomide can lead to several adverse events, with hematologic toxicities and venous thromboembolic complications being the most common [14,42,43]. Other side effects are increased infection rate, fatigue, muscle weakness, peripheral neuropathy and altered electrolyte composition. Secondary primary malignancies can occur in combination with or after treatment with melphalan [43,44]. The myelosuppressive effects of lenalidomide result in hematologic toxicities such as neutropenia with increased infections rates and thrombocytopenia with bleeding complications. Data Expert Rev. Anticancer Ther. 15(5), (2015)
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15 For personal use only.
Lenalidomide in MM
of the MM-009 and MM-010 trials confirmed the following incidences of grade ‡3 neutropenia, anemia and thrombocytopenia with 35, 11 and 13%, respectively [45,46]. While severe neutropenia was observed in most patients during the first 6 months of treatment, febrile neutropenia occurred in only 3% of the MM patients over the whole treatment cycles. Discontinuation of treatment due to neutropenia was necessary in only 3%, while dose reduction was performed in only 14% of the neutropenic patients [43,45–47]. In case of a treatment-related hematologic adverse event, an interruption of treatment and/or a dose reduction were the method of choice; thus, blood counts on a regular basis of 2 weeks during the first 3 months of treatment were recommended [44,48,46]. With severe neutropenia, the administration of granulocyte colony-stimulating factor should be suggested to boost neutrophil count according to a recent published consensus statement from the European Myeloma Network. With an absolute neutrophil count above 1000/l, treatment can be continued at the same dosage during the next therapy cycle, otherwise the dosage should be reduced [45–47]. In MM, peripheral neuropathy has been considered as mainly secondary to the plasma cell dyscrasia itself, particularly in POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy or edema, M-protein and skin abnormalities). The neuropathy was also considered to be caused by a direct nerval compression (radicular or medullar), by light chain deposits (e.g., amyloidosis) or an autoimmune mechanism. Lenalidomide is known to cause peripheral neuropathy; however, a Phase III study of treatment with lenalidomide/dexamethasone showed that neurological side effects are generally mild [44,47,49,50]. Thus, only 3% of patients in the study developed grade 3/4 neuropathy. Nevertheless, the symptoms of peripheral neuropathy should be monitored carefully, and treatment options should be discussed with the patient [50,51]. The adverse event of venous thromboembolism (VTE) is not increased when lenalidomide is administered as monotherapy; however, in combination with dexamethasone the incidence of VTE (grade 3 or higher) rises up to 25% in MM patients without thromboprophylaxis. The VTE rate was shown to be significantly influenced by the dexamethasone dosage with a significantly reduced VTE incidence when dexamethasone is administered at low dosages. However, the thromboprophylaxis with heparin or low-dose aspirin was shown to eliminate the increased VTE incidence by dexamethasone in combination with lenalidomide. Lacorra et al. (2012) showed that pulmonary embolism was observed in
Lenalidomide in multiple myeloma Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15 For personal use only.
Expert Rev. Anticancer Ther. 15(5), 491–497 (2015)
Young Kim and Ingo GH Schmidt-Wolf* Medizinische Klinik III, Center for Integrated Oncology (CIO), University of Bonn, Bonn, Germany *Author for correspondence: Tel.: +49 228 2871 7050 Fax: +49 22 828 7908 0059 [email protected]
In the last couple of years major progress has been made in the treatment of multiple myeloma (MM) through the introduction of novel agents like thalidomide, lenalidomide, bortezomib and pomalidomide, mostly in combination with autologous stem cell transplantation. Lenalidomide, a second-generation immunomodulatory agent with antitumor and immunomodulatory effects against MM, in combination with dexamethasone was proven to show significant clinical benefits (overall survival and progression-free survival) in Phase III trials either as induction or as maintenance therapy. With a manageable toxicity profile, lenalidomide seems to be an attractive agent in the treatment of MM. Here, we discuss the present data and research on lenalidomide in the treatment of MM. KEYWORDS: adverse effects . drug profile . immunomodulation . immunotherapy . lenalidomide . myeloma .
pharmacokinetics
Multiple myeloma (MM), a malignant disease being considered treatable but still incurable, is a well-known hematological neoplasm derived from plasma cells with the presence of monoclonal paraproteins which can cause bone lesions and kidney dysfunction [1,2]. The degree of the tumor cell proliferation can vary greatly, ranging from a slowly progressing disease with few clinical symptoms to a highly malignant course of disease, which will be fatal without treatment in a very short time. MM was considered to be a disease of the elderly patient, but now the average age at diagnosis is in the early 60s with more and more patients being diagnosed much younger. While MM is still considered to be an incurable disease, it is close to becoming identified as a chronic disease [1,2]. Major progress has been achieved in the treatment of MM through the introduction of novel agents like lenalidomide, bortezomib and pomalidomide, and hence, pure chemotherapy could be replaced as the only therapeutic option [3,4]. Other novel agents like sorafenib, carfilzomib or daratumumab showed a significant antitumor efficacy in MM but are not yet approved for clinical application. Even new therapeutic approaches have been developed (e.g., inhibition of the Wnt-Pathway) in a murine myeloma model [5–9]. Improved progression-free and overall survival in MM patients could only be achieved by autologous stem cell transplantation informahealthcare.com
10.1586/14737140.2015.1033407
(ASCT), if eligible. Nevertheless, allogeneic stem cell transplantation (allo-SCT) has shown to be the only potentially curative therapy concept; thus for most of the patients, being nonASCT/allo-SCT-eligible myeloma still remains an incurable disease [10–13]. While in 2000 the average life expectancy of MM patient was 3–4 years, MM patients can now survive 10 years or more with a good quality of life due to the development of novel agents and modern treatment regimens [10,11]. Lenalidomide, one of the promising novel agents, has already shown promising results in the treatment of MM, especially in combination with other drugs, for example, dexamethasone. The main goal of an effective treatment regimen is to transform this incurable disease into a chronic disease in patients that are not eligible for ASCT [14–16]. Here we discuss the current impact of lenalidomide on the course of disease of MM. Lenalidomide: a novel agent
Lenalidomide (FIGURE 1) is a derivative of thalidomide (FIGURE 2) and a member of a class of compounds called immunomodulatory drugs introduced in 2004. Lenalidomide serves as a second-generation drug with immunomodulatory and anti-inflammatory effects against hematologic malignancies and showed significant improvement in overall and progression-free survival in combination with dexamethasone [17–19].
2015 Informa UK Ltd
ISSN 1473-7140
491
Drug Profile
Kim & Schmidt-Wolf
O
O
N NH O
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15 For personal use only.
NH2
Figure 1. Structural formula of lenalidomide as derivative of thalidomide.
Lenalidomide-based combination therapies have been approved for the treatment of relapsed and/or refractory MM and even showed great benefits as initial treatment in patients with newly diagnosed MM with an acceptable toxicity profile allowing long-term administration, especially when compared to its parent agent thalidomide [19,20]. Due to a long-term follow-up on overall survival from Phase III trials (MM-009 and MM-010) of lenalidomide in combination with dexamethasone in relapsed or refractory MM patients, lenalidomide has been approved by the US FDA and the EMA [20,21]. In the context of ASCT, lenalidomide has been proven to show effect as maintenance therapy after ASCT (ASCT, CALGB 100104) or as potent therapy regimen for ASCTineligible patients (MM-015) [10,11,22]. Even new combination regimens that include lenalidomide are tested in order to improve the therapy outcome of MM patients. Apart from MM, lenalidomide showed significant efficacy in the class of other hematological malignancies such as myelodysplastic syndrome (MDS), non-Hodgkin lymphoma and chronic lymphocytic leukemia [23–25]. Immunomodulation
In recent studies, lenalidomide displayed both immunomodulatory and tumoricidal effects (FIGURE 3), which finally resulted in a significant decrease of the tumor load and a stabilized disease. Through activation of the tumor-suppressor genes EGR1, EGR2, EGR3, p15, p21 and p27 in MM cells, lenalidomide in combination with dexamethasone induces an arrest of the MM cell cycle followed by apoptosis due to activation of the caspase cascade. Additionally, the synthesis of IFN-g via NK cells and IL-2 via T-lymphocytes is induced [26–28]. During treatment of MM by a lenalidomide-based therapy regimen, the primary tumoricidal effect of lenalidomide results in reduced tumor load. Secondary, the immunomodulatory effect of lenalidomide takes place by suppression of the residual tumor’s proliferation [28–30]. Through stimulation of T cells, O
N
O NH
O
O
Figure 2. Structural formula of thalidomide.
492
NK cells and dendritic cells and by improving IL-2 and IFN-g secretion, lenalidomide increases cellular immunity and response. The suppression of Tregs may be the reason why lenolidomide is able to show significant antitumor efficacy in MM [31,32]. Another anti-proliferative mechanism of lenalidomide is the inhibition of the production of cytokines and growth factors (IL-6, TNF alpha, VEGF) and the down-regulation of CCAAT/enhancer-binding proteins, a family of transcription factors, which promote gene expression through interaction with their promoters and can be found in the tissues of different internal organs. Lenalidomide has been proven to show inhibition of angiogenesis induced by growth factor, especially with bone marrow endothelial cells [33,34]. In a recent study, it was shown that lenalidomide affected the regulation and expression of cereblon, a protein which is involved in maintaining the function and activity of MM cells and is encoded by the CRBN gene [35,36]. An increased response of a lenalidomide-based therapy regimen in combination with dexamethasone could be associated with high cereblon levels [37]. Nevertheless, further studies are needed to understand the exact role of cereblon in MM [38]. Pharmacokinetics
Lenalidomide is usually administered orally at a dose of 25 mg once daily on days 1–21 of repeated 28-day cycles and is quickly absorbed with high plasma concentrations occurring after 0.5–4 h after administration in MM patients [1,10,15]. With linear pharmacokinetics, identical in healthy subjects as well in MM patients, plasma concentrations increase proportionally to the administered dose. With main substance clearance via the kidneys and a half-life of 3–5 h, about 70% of lenalidomide is eliminated, unchanged, in urine by tubular secretion and glomerular filtration [39,40]. Thus, renal insufficiency results in reduced clearance, an increased plasma exposure and a prolonged half-life of lenalidomide of up to 6–12 h without affecting oral absorption, protein binding and non-renal elimination. It has been shown that the level of lenalidomide exposure was increased with the degree of renal insufficiency; thus, dosage adjustments are recommended for MM patients with moderate/severe renal impairment or a creatinine clearance below 60 ml/min to ensure safe exposure levels [39–41]. Adverse effects
Due to its manifold immunomodulatory and myelosuppressive effects, the administration of lenalidomide can lead to several adverse events, with hematologic toxicities and venous thromboembolic complications being the most common [14,42,43]. Other side effects are increased infection rate, fatigue, muscle weakness, peripheral neuropathy and altered electrolyte composition. Secondary primary malignancies can occur in combination with or after treatment with melphalan [43,44]. The myelosuppressive effects of lenalidomide result in hematologic toxicities such as neutropenia with increased infections rates and thrombocytopenia with bleeding complications. Data Expert Rev. Anticancer Ther. 15(5), (2015)
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15 For personal use only.
Lenalidomide in MM
of the MM-009 and MM-010 trials confirmed the following incidences of grade ‡3 neutropenia, anemia and thrombocytopenia with 35, 11 and 13%, respectively [45,46]. While severe neutropenia was observed in most patients during the first 6 months of treatment, febrile neutropenia occurred in only 3% of the MM patients over the whole treatment cycles. Discontinuation of treatment due to neutropenia was necessary in only 3%, while dose reduction was performed in only 14% of the neutropenic patients [43,45–47]. In case of a treatment-related hematologic adverse event, an interruption of treatment and/or a dose reduction were the method of choice; thus, blood counts on a regular basis of 2 weeks during the first 3 months of treatment were recommended [44,48,46]. With severe neutropenia, the administration of granulocyte colony-stimulating factor should be suggested to boost neutrophil count according to a recent published consensus statement from the European Myeloma Network. With an absolute neutrophil count above 1000/l, treatment can be continued at the same dosage during the next therapy cycle, otherwise the dosage should be reduced [45–47]. In MM, peripheral neuropathy has been considered as mainly secondary to the plasma cell dyscrasia itself, particularly in POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy or edema, M-protein and skin abnormalities). The neuropathy was also considered to be caused by a direct nerval compression (radicular or medullar), by light chain deposits (e.g., amyloidosis) or an autoimmune mechanism. Lenalidomide is known to cause peripheral neuropathy; however, a Phase III study of treatment with lenalidomide/dexamethasone showed that neurological side effects are generally mild [44,47,49,50]. Thus, only 3% of patients in the study developed grade 3/4 neuropathy. Nevertheless, the symptoms of peripheral neuropathy should be monitored carefully, and treatment options should be discussed with the patient [50,51]. The adverse event of venous thromboembolism (VTE) is not increased when lenalidomide is administered as monotherapy; however, in combination with dexamethasone the incidence of VTE (grade 3 or higher) rises up to 25% in MM patients without thromboprophylaxis. The VTE rate was shown to be significantly influenced by the dexamethasone dosage with a significantly reduced VTE incidence when dexamethasone is administered at low dosages. However, the thromboprophylaxis with heparin or low-dose aspirin was shown to eliminate the increased VTE incidence by dexamethasone in combination with lenalidomide. Lacorra et al. (2012) showed that pulmonary embolism was observed in
