Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma

Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients likely to benefit and obtain additional safety information. Relapsed/refractory MM patients received lenalidomide 25 mg/d (days 1–21) and dexamethasone 40 mg/d (days 1–4, 9–12, and 17–20 of cycles 1–4; days 1–4 only from cycle 5 onwards), in 4-week cycles until disease progression, study drug discontinuation, or lenalidomide approval. Of the 1438 patients enrolled, ∼60% were male, median age was 64 years, and 61·7% had Durie-Salmon stage III disease. Median time on study was 15·4 weeks (range: 0·1–49·1) and median dose was 25 mg. The most common adverse events (AEs) were haematological (49%), gastrointestinal (59%), and fatigue (55%). The most common grade ≥3 AEs were haematological (45%), fatigue (10%), and pneumonia (7%). The most common serious AEs were pneumonia (8%), pyrexia (4%), and deep-vein thrombosis (3%). Primary cause of death was disease progression (10%). Safety data confirmed known AEs of lenalidomide plus dexamethasone therapy in patients with relapsed/refractory MM.

Celgene Corporation, Summit, NJ, USA) is a more potent analogue of thalidomide that is effective (with a good safety profile) in the treatment of patients with relapsed or refractory MM (Corral et al, 1999;Hideshima et al, 2000;Richardson et al, 2002Richardson et al, , 2006Dimopoulos et al, 2007;Weber et al, 2007), and transfusion-dependent International Prognostic Scoring System (IPSS)-defined Low-and Int-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q [del(5q)] chromosomal abnormality (List et al, 2006). On 29 June 2006, the US Food and Drug Administration (FDA) approved lenalidomide given in combination with dexamethasone for the treatment of patients with MM who had received prior therapy, based on the results from two parallel, randomized, double-blind, placebo-controlled phase III trials (Dimopoulos et al, 2007;Weber et al, 2007). In June 2007, the European Medicines Agency approved lenalidomide for the same indication. In pre-planned interim analyses of these two trials, patients treated with the lenalidomide and dexamethasone combination had a significantly longer time to disease progression compared with patients treated with dexamethasone alone. Based on these results, an Independent Data Safety Monitoring Board recommended unblinding of the studies so that all enrolled patients could have access to lenalidomide.
In April 2005, over a year before FDA approval and while lenalidomide therapy for relapsed or refractory MM was under review, the Oncology Division of the FDA, along with myeloma patient advocacy groups, requested that the manufacturer of lenalidomide, Celgene Corporation, establish an 'expanded access programme'. This would make lenalidomide, in combination with dexamethasone, available to patients with relapsed or refractory MM with a high likelihood of benefit. On this basis, the safety study protocol MM-016 was initiated.
Here we provide the safety analysis of patients with relapsed or refractory MM who participated in this expanded access trial.

Patient eligibility and enrolment
The institutional review boards or ethics committees at each participating centre approved the study protocol and all patients provided written informed consent. The inclusion and exclusion criteria for the study were the same as for the pivotal phase III studies (MM-009 and MM-010) (Dimopoulos et al, 2007;Weber et al, 2007). Patients were eligible if they were aged ‡18 years, and had MM that had progressed after ‡2 cycles of anti-myeloma treatment or relapsed with progressive disease after treatment. Patients were required to have measurable levels of myeloma paraprotein in the serum ( ‡5AE0 g/l) or urine ( ‡0AE2 g secreted in a 24-h collection sample), and an Eastern Cooperative Oncology Group (ECOG) performance status score of £2. Prior thalidomide or radiation therapy was allowed. Radiation therapy initiated prior to or at baseline was permitted concurrent to study treatment, but all other anti-myeloma medication or other therapy had to be discontinued prior to the first study dose.
Women of childbearing potential had to have two negative pregnancy tests before starting the study treatment, and had to agree to use two reliable methods of contraception simultaneously or to practise complete abstinence from heterosexual intercourse from 28 d before the start of lenalidomide treatment until 28 d after treatment discontinuation. While participating in the study, and for at least 28 d after treatment discontinuation, men (including those who had undergone a successful vasectomy) had to agree to use a latex condom during sexual contact with women of childbearing potential. Participating men and women had to agree not to donate blood (and men also not to donate semen or sperm) during the study, and for at least 28 d after treatment discontinuation.
Patients were excluded from the study if they had: a prior history of malignancy other than MM, except for basal cell or squamous cell skin carcinoma or carcinoma in situ of the cervix or breast (unless the patient had been free of disease for at least 1 year); known hypersensitivity to thalidomide or dexamethasone; prior history of uncontrollable side-effects to dexamethasone treatment; development of desquamating rash while taking thalidomide; or neuropathy grade ‡2. Patients with any of the following laboratory abnormalities were also excluded from the study: those with an absolute neutrophil count of <1AE0 · 10 9 /l; those with a platelet count of <75 · 10 9 / l (for patients in whom <50% of bone marrow nucleated cells were plasma cells), or a platelet count of <30 · 10 9 /l (for patients in whom ‡50% of bone marrow nucleated cells were plasma cells); serum creatinine >221 lmol/l; serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >3· upper limit of normal; and serum total bilirubin >34AE2 lmol/l.
Patients were enrolled in the study starting September 2005. Accrual in the USA was terminated following FDA approval of the MM indication in June 2006. Enrolment is continuing in Canada and is planned to continue until the drug is approved by the Canadian regulatory authorities. This report is a summary of the trial results from initiation on 6 September 2005 to termination of the US involvement on 21 September 2006.

Treatment schedule and assessments
Patients were instructed to self-administer oral lenalidomide at a starting dose of 25 mg/d for 21 d, and dexamethasone 40 mg/d on days 1-4, 9-12, and 17-20. Each cycle was repeated every 28 d. Beginning with cycle 5, the dexamethasone schedule was reduced to 40 mg/d for days 1-4, every 28 d. Treatment was continued as tolerated, until disease progression or unacceptable adverse events as per the dose modification guidelines. After baseline evaluation at study entry, patients were seen at study visits every 2 weeks for the first three treatment cycles, and then every 4 weeks until documentation of disease progression or if treatment was discontinued for any reason.
Although the investigators assessed the patients for disease progression, there was no formal efficacy evaluation performed in this study. Safety evaluations included: vital signs; haematology; serum chemistries; serum thyroid-stimulating hormone; thyroid function (T 3 , T 4 ); electrocardiogram; serum and urine beta-human chorionic gonadotrophin (for female patients of childbearing potential only); and adverse events. The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (National Cancer Institute, 2006). An internal data monitoring committee reviewed ongoing safety data throughout the study. The members of the committee included representatives from regulatory affairs and drug safety, a lead product safety physician, a biostatistician, and three medical officers (one an oncologist).
Lenalidomide was supplied by the manufacturer in bottles containing 21 (25-mg or 5-mg) capsules. Commercial supplies of dexamethasone were used. Antithrombotic therapy, such as daily aspirin, was recommended as prophylaxis for deep-vein thrombosis (DVT); daily prophylaxis with antibiotics was recommended for all patients; and erythropoietin was recommended for chronic transfusion-dependent anaemia, but none of these was mandated. Other therapies considered necessary for the well-being of the patient (e.g. analgesics, antihistamines, growth factors, and transfusions of red blood cells, platelets, or fresh-frozen plasma) were allowed at the discretion of the investigator.

Dose modifications
Lenalidomide doses were interrupted for: grade 3 or 4 neutropenia; thrombocytopenia with a platelet count of <30 · 10 9 /l; grade 2 allergic reaction or hypersensitivity; hyperthyroidism or hypothyroidism of grade ‡2; grade 2 neuropathy; and other lenalidomide-related grade 3 or 4 adverse events. Treatment was resumed at a lower dose level after the adverse event improved to grade 2 or better. Lenalidomide treatment was discontinued for grade ‡3 rash/ desquamation, grade 3 or 4 allergic reaction or hypersensitivity, and grade 3 or 4 neuropathy. For patients with grade ‡3 venous thrombosis or embolism, the dose was interrupted and anticoagulation therapy was started. Lenalidomide treatment was to be restarted at the same dose level at the physician's discretion.
The protocol included four lenalidomide dose reduction levels. Level )1 included maintenance of the 25-mg starting dose, supplemented by granulocyte colony-stimulating factor according to the American Society of Clinical Oncology (ASCO) guidelines (Ozer et al, 2000). This level was recommended for patients with grade 3 or 4 neutropenia only. For all other adverse events requiring lenalidomide dose reduction, the dose reductions were Level )2 (15 mg), Level )3 (10 mg), and Level )4 (5 mg). Lenalidomide treatment was discontinued for patients who could not tolerate dose Level )4.
Dexamethasone doses were interrupted or reduced in response to dyspepsia, gastric or duodenal ulcers, gastritis, oedema, confusion or mood alterations, muscle weakness, hyperglycaemia, and acute pancreatitis. There were three dexamethasone dose reduction levels: 40 mg/d for 4 d every 2 weeks; 40 mg/d for 4 d every 4 weeks; and 20 mg/d for 4 d every 4 weeks.
For both lenalidomide and dexamethasone, dose escalation was not permitted after dose reduction.

Statistical design and analysis
The primary objective of this trial was to provide lenalidomide to patients with a high likelihood of benefit. The secondary objective was to obtain additional safety data. The study endpoint was safety, including assessment of type, frequency, severity, and relationship of side-effects to study treatment. Data from all patients who received at least one dose of lenalidomide were included in the safety analyses. Continuous demographic and baseline variables were summarized using descriptive statistics, whereas categorical variables were summarized in frequency tabulations. The median exposure to lenalidomide was calculated as the average dose over all the days between the first and last dose date, including the 7 d off-drug in each 28-d cycle and any interruption periods. Thus a dose exposure of 18AE75 mg/d was 100% of the scheduled daily dose of 25 mg for 21 d of every 28-d cycle with no interruption.

Results
Between 6 September 2005 and 21 September 2006, a total of 1438 patients from 69 centres in the USA and Canada were enrolled. Patient characteristics are summarized in Table I. The median age was 64 years (range: 29-91 years). Prior treatments included thalidomide, alkylators, bortezomib, high-dose chemotherapy/stem cell transplantation, and anthracycline. The median time on study was 15AE4 weeks (range: 0AE1-49AE1 weeks). The median exposure to lenalidomide was 18AE8 mg/d (range: 1AE7-28AE6 mg), over a median of 15AE1 weeks (range: 0AE1-49AE1 weeks). This was 100% of the scheduled daily dose of lenalidomide 25 mg for 21 d. A total of 424 (29AE5%) patients had at least one dose reduction (dose level )2 through )4), with 306 patients requiring one dose reduction, 89 patients requiring two dose reductions, 28 patients requiring three dose reductions, and one patient requiring four dose reductions (the first dose reduction level for this patient was 20 mg). The adverse events most commonly causing dose reduction were thrombocytopenia (1AE6%), neutropenia (1AE5%), and pneumonia (1AE3%).

Adverse events
The most common adverse events (all grades) were haematological, gastrointestinal, fatigue, and muscle cramps (Table II).

C. Chen et al ª 2009 The Authors
Haematological events (neutropenia, thrombocytopenia, leucopenia, and anaemia) were manageable with dose reductions and resulted in only 3AE75% of patients discontinuing lenalidomide treatment. Hypokalaemia, hyperglycaemia not otherwise specified (NOS), and blurred vision were noted in less than 10% of patients. The most common grade ‡3 adverse events were haematological, fatigue, and pneumonia (Table III). The most common grade 4 adverse events were thrombocytopenia (7AE1%), neutropenia (5AE2%), anaemia (1AE2%), and pneumonia (1AE0%). At least one grade 3 or 4 adverse event was reported in 69AE7% of patients. The most common serious adverse events were pneumonia, pyrexia, DVT, and thrombocytopenia (Table IV).
Neuropathic symptoms (neuropathy NOS, peripheral neuropathy NOS, peripheral sensory neuropathy, peripheral motor neuropathy, and polyneuropathy NOS) were reported by 18AE2% of patients on the study at some point during their treatment. The majority (224 of 263 [85AE2%] patients) had grade 1 or 2 events. Of the 18AE2% patients who experienced neuropathic symptoms, 73AE9% had a prior history. Two thirds (67%) of all patients on study had a prior history of neuropathy.

Incidence of dose reductions and discontinuations due to adverse events
Overall, 18AE5% of patients enrolled in the trial discontinued treatment with lenalidomide due to adverse events. The most common causes of lenalidomide discontinuation due to adverse events were thrombocytopenia, neutropenia, pneumonia, and sepsis (Table V). Other reasons for treatment discontinuation included commercial availability of the drug in the USA (46AE7%), disease progression (18AE5%), death (5AE1%), and withdrawal of consent (4AE4%). Neutropenia (17AE8%), thrombocytopenia (9AE2%), fatigue (8AE3%), pneumonia (3AE5%), pyrexia (3AE5%), and anaemia (3AE3%) were the most common adverse events that led to dose reductions, interruptions, or discontinuation. The median time to the first dose reduction, interruption, or discontinuation was 36 d (range: 1-282 d).

Deaths
Overall, 216 deaths (15%) were reported in the trial, with 125 deaths (8AE7%) occurring within 30 d from the last dose. The most frequent causes of death were disease progression (10AE2%) and adverse events (4AE3%); 1% of deaths were due to adverse events related to the study drug.

Discussion
Thalidomide emerged as an anticancer agent after investigators demonstrated its antineoplastic activity in haematological malignancies and, in particular, for the treatment of patients with MM (Singhal et al, 1999;Rajkumar et al, 2000Rajkumar et al, , 2002Rajkumar et al, , 2006Barlogie et al, 2001;Weber et al, 2003). Lenalidomide was developed to further enhance efficacy while avoiding the teratogenicity, sedation, peripheral neuropathy, and severe constipation associated with thalidomide therapy (Richardson et al, 2002(Richardson et al, , 2006Rajkumar et al, 2005;Dimopoulos et al, 2007;Weber et al, 2007). The expanded access trial permitted lenalidomide plus dexamethasone to be available to patients in the USA and Canada while the drug awaited FDA approval for use in patients with MM. During the course of this trial, the FDA approved the   use of the drug for transfusion-dependent IPSS Low-or Int-1risk MDS associated with a del(5q) chromosomal abnormality. This trial was continued as the daily dose of lenalidomide used for the treatment of MDS was 10 mg, and that for MM is 25 mg. This trial provides a model of how regulatory agencies, advocacy groups, healthcare providers, and industry can work together to quickly provide an effective treatment to a large number of patients in need, while a regimen with clearly demonstrated safety and activity awaits approval. The type and frequency of adverse events from over 1400 patients with MM enrolled in this trial are consistent with results from the phase III studies used to register the drug in the USA and Europe. Compared with the MM-009 study, a similar number of patients discontinued treatment due to adverse events (19AE8% vs. 18AE5%, respectively) (Weber et al, 2007).
The most commonly observed grade 3 or 4 adverse events in this study occurred at a similar frequency as those reported for the pivotal MM-009 and MM-010 studies (Dimopoulos et al, 2007;Weber et al, 2007). Among the MM-009 and MM-010 patients who were treated with lenalidomide and dexamethasone, thrombosis occurred in 23% of patients who received concomitant erythropoietic therapy, such as epoetin alfa or darbepoetin, compared to 5% who did not . The lower frequency of thromboembolic events that occurred in this trial may be attributed to the strong recommendation that daily aspirin or other thromboprophylactic therapy continued to be used, which has been shown to decrease the incidence of VTE without bleeding complications (Baz et al, 2005;Rajkumar et al, 2005Rajkumar et al, , 2006Zonder et al, 2006).
The majority of patients (67%) on this trial had a prior history of neuropathy. Most neuropathy observed in this trial was grade 1 or 2. Although 18AE2% of patients reported the occurrence of neuropathy, it is unclear if this represented residual neurological damage from prior therapies associated with neurological damage, such as thalidomide, vincristine, and bortezomib (Richardson et al, 2003(Richardson et al, , 2005Glasmacher et al, 2006).
As with other studies of lenalidomide, most adverse events that occurred were well managed by lenalidomide dose reductions or interruptions, and symptom-control medications (according to study protocol).
In conclusion, the safety profile of lenalidomide therapy in conjunction with dexamethasone for relapsed or refractory MM in an expanded access programme is consistent with the two randomized, placebo-controlled trials that were the basis for US and European approval.

Conflicts of interest
CC, DER, RVB and RV have received honoraria and research funding from Celgene Corporation. RN has been a consultant to Celgene Corporation and Millennium Pharmaceuticals, and has received honoraria and research funding from Celgene Corporation and Millennium Pharmaceuticals. EAS, JM and SEC have been consultants to Celgene Corporation and have received honoraria from Celgene Corporation. RA has been a consultant to Celgene Corporation and Millennium Pharmaceuticals, and has received honoraria from Celgene Corporation, Millennium Pharmaceuticals and Novartis. PR has received honoraria from Celgene Corporation, Millennium Pharmaceuticals and Johnson & Johnson. SK has received research funding from Celgene Corporation. NJB has been a consultant to Celgene Corporation and Ortho-Biotech, and has received honoraria from Celgene Corporation and Ortho-Biotech and research funding from Celgene Corporation. DP, RDK and JBZ are employees of Celgene Corporation. DS, MA and SVR have no conflicts to disclose.

Funding
Supported by Celgene Corporation, Summit, NJ, USA.