Pomalidomide: a new hope for relapsed and refractory multiple myeloma

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1 4 Pomalidomide: a new hope for relapsed and refractory multiple myeloma C. Doyen, MD 1 Relapsed and refractory multiple myeloma patients have a particularly poor prognosis and the development of new drugs is urgently needed. Pomalidomide, a third-generation immunomodulatory drug with a pleiotropic activity, was approved in 2013 by the Food and Drug Administration and the European Medicines Agency, in association with low dose dexamethasone in relapsed and refractory multiple myeloma, in patients who received at least two prior therapies, including bortezomib and lenalidomide and demonstrated progression on the last therapy. In the phase III MM-003 study, pomalidomide associated with low dose dexamethasone was superior to high dose dexamethasone in these patients, with a manageable safety and tolerability profile. This paper will review the available data concerning the mechanisms of action, the efficacy in clinical studies and the safety of this very promising new drug. (Belg J Hematol 2014;5(4):137-42) Introduction The introduction of the novel agents, proteasome inhibitors and immunomodulatory drugs (IMiDs) represents a major advance in the treatment of multiple myeloma (MM) and resulted in a 50% improvement in median overall survival (OS). 1 However MM remains an incurable disease and virtually all patients ultimately acquire resistance and relapse. 2 The prognosis of MM patients who are refractory to both bortezomib and lenalidomide (dual refractory) is particularly poor: in the retrospective study of Kumar, median OS is nine months and event-free survival (EFS) is five months. 3 Pomalidomide, a third-generation IMiD has shown significant activity and efficacy in relapsed and refractory multiple myeloma (RRMM). A phase III study recently demonstrated the superiority of pomalidomide associated to low dose dexamethasone as compared to high dose dexamethasone in terms of progression-free survival (PFS), overall response rate (ORR) and OS in RRMM. 4 Pomalidomide received approval from the Food and Drug Administration (FDA) in February 2013 and from the European Medicines Agency (EMA) in September In Europe pomalidomide is approved for use in combination with dexamethasone in patients with RRMM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy. 5 In this paper we will review the mechanisms of action, the results of clinical studies, the efficacy and the safety of this very promising new drug. Pharmacodynamic properties Pomalidomide is derived from thalidomide and differs from lenalidomide with two, rather than one, oxo groups substituted in the phthaloyl ring (Figure 1). In vitro pomalidomide is ten times more potent than lenalidomide at inhibiting TNF-α. 6 Oral pomalidomide is rapidly absorbed and has a good bioavailability. 6 It is a substrate of cytochrome P450 1 Department of Haematology, CHU Dinant Godinne UCL Namur, Yvoir, Belgium. Please send all correspondence to: C. Doyen, MD, CHU Dinant Godinne UCL Namur, Department of Haematology, Avenue G. Thérasse 1, 5530 Yvoir, Belgium, tel: , chantal.doyen@uclouvain.be. Conflict of interest: C. Doyen received honoraria of Celgene, as a member of the Celgene Advisory Board (Belgium). Keywords: immunomodulatory drugs, pomalidomide, relapsed and refractory multiple myeloma. 137

2 Thalidomide Lenalidomide Pomalidomide Figure 1. With permission from M. Delforge, (CYP3A4 and CYP1A2) and of Pgp. There are few concerns about drug to drug interactions. 6-8 Excretion is primarily via urine, predominantly as metabolites with only 2% of unchanged drug. Mechanisms of action The exact mechanism of action of pomalidomide is not yet fully understood and like other IMiDs, pomalidomide has a pleiotropic activity. Direct antiproliferative effect on MM cells In vitro, like lenalidomide but unlike thalidomide, pomalidomide upregulates the expression of p21 waf1 tumour suppressor gene (independent of p53) correlating with inhibition of the cyclin-dependent pathway leading to cell-cycle arrest in Go-G1 and apoptosis. 9,10,18 Pomalidomide also has proapoptotic effect via a caspase-8 dependent mechanism and enhances MM sensitivity to Fas-induced and TRAIL/Apo 2L-induced apoptosis. 2 Effects on BM microenvironment Pomalidomide inhibits the binding of MM cells to bone marrow stromal cells (BMSC) by downregulating the secretion of cell adhesion molecules that facilitate the MM- and BMSC cells adhesion. This results in a reduction of secretion of growth promoting cytokines such as IL-6, bfgf, and VEGF and promotes the death of MM cells. The downregulation of cell adhesion molecules is probably due to the potent inhibition of TNF-α. By reducing the secretion of VEGF and IL-6, pomalidomide also inhibits the angiogenesis. The decreased production of key pro-survival cytokines such as IL-6, TNF-α, bfgf and VEGF is likely to have many other effects, since these molecules are involved in multiple signalling pathways. 2,6 Effects on bone metabolism In vitro pomalidomide downregulates the transcription factor PU1 and prevents bone resorption. 2 This effect may also involve regulation of Rho GTPases and requires further study. Pomalidomide also normalises the RANKLosteoprotegerin ratio in vitro. 6 Immunomodulatory effects In preclinical studies, pomalidomide improves cellular immunity via a costimulatory effect on T-cells. It increases secretion of IL-2 and Interferon-γ, which activate NK cells and dendritic cells and enhances antibody-dependent NK-cell mediated activity. It also potentiates the activity of transcription factor AP1, key driver of IL-2 secretion. Pomalidomide inhibits the proliferation of regulatory T-cells and their suppressor function. 18 Increased number of T-cells and NK cells were observed in patients treated by pomalidomide, indicating an increased type1 helper-t-cell immune response. 2 Cereblon is a highly conserved E3 ligase protein and is a binding target for IMiDs. It plays an important role in lenalidomide and pomalidomide activity. 11,2 A recent study showed a positive association between cereblon levels and survival in 53 RRMM treated by pomalidomide. 13 The effect of dexamethasone on immunomodulatory effects of pomalidomide is not known. It was demonstrated recently that the combination of pomalidomide and dexamethasone has a strong synergistic activity on MM cells. 13 Clinical studies Phase I studies Schey and Streetly conducted phase I dose-escalation studies of pomalidomide in RRMM and reported Maximal Tolerated Dose (MTD) of 2 mg daily and 5 mg on alternate days, respectively. 14,15 The overall response rate (ORR) was around 50%. These two studies were conducted before the wide availability of bortezomib and lenalidomide, probably explaining the high response rates. 138

3 4 MM-002 is a phase I/II open-label dose escalation study, conducted by Richardson, in patients pretreated by bortezomib and lenalidomide, where 62% of patients were refractory to both drugs. 16 This first part of the study established a MTD of 4 mg per day, 21 days of 28 days, in combination with dexamethasone 40 mg weekly in patients <75 years and dexamethasone 20 mg weekly for patients >75 years. Thirty-eight patients (21%) achieved at least a partial remission (PR). Phase II studies Lacy conducted three phase II trials of pomalidomide 2 mg per day in 28-day cycles, compared to pomalidomide 4 mg daily in the third study, in combination to dexamethasone In lenalidomide refractory patients, ORR was 40% and 47%. 17,18 In dual refractory patients ORR reached 49% in the 2 mg group and 43% in the 4 mg group, thus without additional benefit of the dose of 4 mg dose in this non-randomised trial. 19 In the MM-002 phase II trial, Richardson reported 221 patients randomised to pomalidomide 4 mg daily 21 days of 28 in association with lodex (dexamethasone 40 mg weekly) or given alone. 20 All patients received at least two prior anti MM therapies, including at least two cycles of bortezomib and lenalidomide. Sixty-two percent of patients were refractory to both lenalidomide and bortezomib. This study confirmed the synergistic effect of pomalidomide associated with lodex. Median PFS was 4,2 months and 2,7 months respectively. ORR (at least PR) was 33% and 18%, median OS was 16,5 months and 13,6 months. In a randomised trial, IFM , Leleu compared two different schedules of pomalidomide administration (4 mg for either 21 or 28 days of a 28 day cycle) in association with lodex, in patients who were refractory or never achieved a response to bortezomib and lenalidomide. 21 The ORR was 34,5%, similar in both arms and the PFS and OS for the total population was 4,6 months and 14,9 months respectively. The efficacy and safety data suggest an advantage for the 21 of 28 days regimen, but the study was not powered to make any formal comparison between the two arms. Phase III studies San Miguel reported the results of the MM-003, an open-label randomised phase III study also called the Nimbus study, comparing in a 2:1 ratio pomalidomide 4 mg 21 of 28 days, in association with lodex (40 mg weekly, 20 mg weekly if >75 years) to high dose dexamethasone (40 mg per day, day 1-4, 9-12,17-20; 20 mg/day if patients >75 years) given orally in 455 patients refractory or relapse and refractory who had failed two previous treatments of bortezomib and lenalidomide. 4 Patients progressing in the arm highdose dexamethasone could receive pomalidomide alone in a companion trial, MM-003c. At the interim analysis, the independent data monitoring committee recommend that patients randomised to the dexamethasone arm should have access to pomalidomide, because the primary endpoint for PFS was met with a superior OS in patients receiving pomalidomide-lodex. After a median follow-up of ten months, median PFS with pomalidomide-lodex was 4 months versus 1,9 months. ORR was 31% versus 10%. Stable disease was seen in 43% of patients receiving pomalidomide-lodex versus 46%. OS was 12,7 months versus 8,1 months, median DOR was 7 months versus 6,1 months. Results for PFS, OS and DOR were similar regardless of age. The most common grade 3-4 toxicities in the pomalidomide arm were neutropenia (48%), anaemia (33%), thrombocytopenia (22%), pneumonia (13%), fatigue (5%) and bone pain (7%). VTE events were rare. Ongoing studies More than twenty studies are ongoing, exploring the role of pomalidomide with low dose dexamethasone in association with other antimyeloma agents such as bortezomib, carfilzomib, and cyclophosphamide or in special populations. 22,23 MM-010 (Stratus) is an international phase III study, exploring safety of pomalidomide-lodex. IFM includes only patients with high risk cytogenetics. 24 MM-008 and MM-013 include patients with moderate to severe renal insufficiency. 8 Safety and management of adverse events The most common toxicity of pomalidomide is myelosuppression, similar to lenalidomide. In clinical trials, the incidence of grade 3-4 neutropenia, thrombocytopenia and anaemia ranged from 41 to 62%, from 22 to 36% and from 19 to 27% respectively. Infections, most often bacterial and not associated with neutropenia, occurred in roughly 20 to 30% in the phase II and III trials. The incidence of grade 3-4 peripheral neuropathy is very low but patients with severe neuropathy were excluded from pomalidomide trials. Thromboprophylaxis was mandatory and severe VTE events were rarely seen. Recently Dimopoulos et al. reported very useful guidelines on the optimal use of pomalidomide in RRMM

4 Table 1. Clinical efficacy of pomalidomide in patients with multiple myeloma. Trial Phase N Median age (years) Median prior Tx Regimen Dose Schedule/ MTD ORR (%) PFS-OS (months) Schey et al. 14 I Pom dose escalation MTD=2mg/day 54 9,7-22,5 Streetly et al. 15 I Pom+/-Dex MTD=5mg q.o.d 50 10,5-33 Richardson I/II Pom-Dex MTD=4mg;40mg 33 4,9-16,5 et al. 16, Pom 4mg 18 2,7-13,6 Lacy et al. 17 II 60 66,5 2 Pom-Dex 2mg; 40mg 63 11,6-76% at 2 years Lacy et al. 18a II Pom-Dex 2mg; 40mg 47 4,8-13,9 Leleu et al. 21 Arm A II Pom-Dex 4mg; 40mg 35 Arm B Pom-Dex 4mg; 40mg 34 4,6-14,9 Lacy et al. 19b Cohort A II Pom-Dex 2mg; 40mg 49 6,5-78% at 6 months Cohort B Pom-Dex 4mg; 40mg 43 3,2-67% at 6 months San Miguel 4 Cohort A III Pom-Dex 4mg; 40mg ,7 Cohort B Dex 40mg 10 1,9-8,1 Abbreviations: dex : dexamethasone; Median prior Tx : Median number of prior treatments; MTD : maximum-tolerated dose; ORR : overall response rate; OS : overall survival; Pom : pomalidomide; PFS : progression-free survival; study was conducted in lenalidomide-refractory patients. a Study was conducted in lenalidomide and bortezomib-refractory patients. b Neutropenia Neutropenia is very common: in the MM-003 trial, neutropenia grade 3 occurred in 26% of the patients and grade 4 in 22%, mainly in the first cycles of treatment. Febrile neutropenia, however, is rare (less than 10%). Neutropenia with pomalidomide is usually short-lived and can be managed by close monitoring, dose interruption, dose reduction and growth factors. 8 Infection Infections, particularly bacterial infections, and pneumonia are very frequent in MM patients. RRMM and older patients are particularly at risk. 8,25 In the MM-003 trial, grade 3-4 infections occurred in 30 and 24% of patients receiving pomalidomide and high dose dexamethasone respectively. Most infections were not associated with neutropenia. 4 Dimopoulos among others recommends routine vaccinations but also antibiotic prophylaxis, for a minimum of the first three months of therapy with pomalidomide. 8 There is no consensus, however, about the optimal regimen and in Belgium, to the author s knowledge, antibiotic prophylaxis is not routine practice. The quinolones ciprofloxacine and enoxacin strongly inhibit the activity of CYP1A2 and therefore increase exposure to pomalidomide. Close monitoring is needed 140

5 4 Key messages for clinical practice 1. Mechanisms of action Direct antitumor effects: antiproliferative and proapoptotic effects. Modulation of microenvironment: anti angiogenesis, decrease of IL-6,bGFG,VEGF and TNF-α. Immunomodulation: increase of activity of T-cells and NK cells. Effects on bone metabolism. Role of cereblon. 2. How to administer pomalidomide? Starting dose : 4 mg daily, 21 days of each 28 day cycle. In combination with low dose dexamethasone (40 mg weekly if <75 years, 20 mg weekly if 75 years). Until progression or unacceptable toxicity. Consider reducing dexamethasone dose in plateau phase. 3. How to minimise toxicity? As for lenalidomide. 5,8 Close monitoring of complete blood count (every 1-2 weeks for the first two cycles, monthly thereafter). Interrupt pomalidomide if grade 3-4 toxicity, consider reduction dose level when toxicity resolves. For secondary prophylaxis of neutropenia: consider G-CSF (day or twice a week). when using these two drugs. 6,8 When infection develops in a patient treated by pomalidomide, treatment should be interrupted regardless of the presence of neutropenia and can be restarted when the infection subsides. 8 Venous thromboembolism VTE is a common complication of IMiDs and stimulated the use of thromboprophylaxis which was mandatory in all trials with pomalidomide. 8 In MM-002 and MM-003, incidence of VTE was 2% and it was 4% in IFM , in patients receiving low dose aspirine. 4,20 Thromboprophylaxis has to be given to all patients receiving IMiDs, including pomalidomide. In case of a VTE event, pomalidomide should be interrupted and anticoagulant therapy started. Pomalidomide can be resumed a few weeks later. 8 Polyneuropathy Polyneuropathy (PN) is uncommon with pomalidomide, and following the expert panel there is no concern related to peripheral neuropathy with pomalidomide. 8 Other adverse events They include fatigue, gastrointestinal disorders, muscle cramps and rash, the latter two appearing less frequently with pomalidomide than with lenalidomide. These side effects are most often grade 1-2 and can be managed by standard intervention (low dose prednisone and antihistamines for rash grade 1-2). 8 For grade 3 toxicity, pomalidomide is interrupted and resumed to a lower dose when toxicity resolves to grade 2. For grade 4 toxicity pomalidomide is discontinued. 8 Conclusion Pomalidomide is the newest of the IMiD molecules and is more potent than lenalidomide in vitro. In association with low dose dexamethasone, pomalidomide is superior to high dose dexamethasone in RRMM, after at least two cycles of bortezomib and lenalidomide and progression on the last therapy and was recently approved in this setting by the EMA. 4,5 Benefit of pomalidomide was seen in all subgroups, including patients with advanced age and with high-risk cytogenetics. Toxicity is mainly haematological, predictable and manageable. 2,4,6,7 Ongoing studies will help to predict the role of pomalidomide in patients with renal failure (MM-003, MM-008) and in patients with unfavourable cytogenetics (IFM , MM-010). Preliminary results of phases I/II studies exploring the association of pomalidomide with other antimyeloma agents are very encouraging, with an increase of the depth of response. Hopefully Belgian RRMM patients will have access to this very important new treatment option in the near future. 141

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