research paper

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

Christine Chen,1 Donna E. Reece,1 David Siegel,2 Ruben Niesvizky,3 Ralph V. Boccia,4 Edward A. Stadtmauer,5 Rafat Abonour,6 Paul Richardson,7 Jeffrey Matous,8 Shaji Kumar,9 Nizar J. Bahlis,10 Melissa Alsina,11 Robert Vescio,12 Steven E. Coutre,13 Dennis Pietronigro,14 Robert D. Knight,14 Jerome B. Zeldis14 and Vincent Rajkumar9
1

Summary 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 61Æ7% had Durie-Salmon stage III disease. Median time on study was 15Æ4 weeks (range: 0Æ1–49Æ1) 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. Keywords: multiple myeloma, relapsed/refractory, lenalidomide plus dexamethasone, combination therapy.

Princess Margaret Hospital, Toronto, ON,

Canada, 2The Cancer Center at Hackensack University Medical Center, Hackensack, NJ,
3 4

Weill Cornell Medical College, New York, NY, Center for Cancer and Blood Disorders, Bethesda,

MD, 5University of Pennsylvania Abramson Cancer Center, Philadelphia, PA, 6Indiana University Simon Cancer Center, Indianapolis, IN, 7Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 8Rocky Mountain Cancer Centers, Denver, CO, 9Mayo Clinic, Rochester, MN, USA, 10University of Calgary, Calgary, AB, Canada, 11H. Lee Mofﬁtt Cancer Center and Research Institute, Tampa, FL,
12

University of California Los Angeles School of
13

Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, CA, Stanford University
14

School of Medicine, Stanford, CA, and Corporation, Summit, NJ, USA

Celgene

Received 4 February 2009; accepted for publication 15 April 2009 Correspondence: S. V. Rajkumar, MD, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: rajkumar.vincent@mayo.edu This study was presented as a poster at the Annual Meeting of the American Society of Hematology, 9–12 December 2006, Orlando, FL, USA. Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

The outcomes for many patients with multiple myeloma (MM) have been improved in the past few years with the introduction of the immunomodulatory drugs thalidomide

and lenalidomide, and the proteasome inhibitor bortezomib, though the disease is usually still incurable (Kyle & Rajkumar, 2004; Anderson et al, 2007). Lenalidomide (RevlimidÒ;

First published online 26 May 2009 ª 2009 The Authors doi:10.1111/j.1365-2141.2009.07728.x Journal Compilation ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 146, 164–170

Expanded Access Programme of Len + Dex in 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, 2002, 2006; Dimopoulos 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. 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 <1Æ0 · 109/l; those with a platelet count of <75 · 109/ l (for patients in whom <50% of bone marrow nucleated cells were plasma cells), or a platelet count of <30 · 109/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 >34Æ2 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.

Patients and methods 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 (‡5Æ0 g/l) or urine (‡0Æ2 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

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 165

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C. Chen et al 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 (T3, T4); 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. 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 18Æ75 mg/d was 100% of the scheduled daily dose of 25 mg for 21 d of every 28-d cycle with no interruption.

Results Dose modiﬁcations
Lenalidomide doses were interrupted for: grade 3 or 4 neutropenia; thrombocytopenia with a platelet count of <30 · 109/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), 166 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 15Æ4 weeks (range: 0Æ1–49Æ1 weeks). The median exposure to lenalidomide was 18Æ8 mg/d (range: 1Æ7–28Æ6 mg), over a median of 15Æ1 weeks (range: 0Æ1– 49Æ1 weeks). This was 100% of the scheduled daily dose of lenalidomide 25 mg for 21 d. A total of 424 (29Æ5%) 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 (1Æ6%), neutropenia (1Æ5%), and pneumonia (1Æ3%).

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

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Expanded Access Programme of Len + Dex in MM
Table I. Patient demographics and disease characteristics (N = 1438). Patients Patients Characteristic Age, years Median Range Sex Male Female Race* White Black Hispanic Asian/Paciﬁc Islander American Indian/Alaska native Other Stage of disease (Durie-Salmon) I II III Missing Prior multiple myeloma therapy Alkylators Anthracycline High-dose chemotherapy/ stem cell transplantation Bortezomib Vinca alkaloid Thalidomide Other Medical history Neuropathy Venous thromboembolism n % Adverse event 64 29–91 863 575 1191 154 47 26 2 18 176 358 887 17 846 566 758 824 548 1094 865 958 227 60 40 82Æ8 10Æ7 3Æ3 1Æ8 0Æ1 1Æ3 12Æ2 24Æ9 61Æ7 1Æ2 58Æ8 39Æ4 52Æ7 57Æ3 38Æ1 76Æ1 60Æ2 66Æ6 15Æ8 Patients with ‡1 adverse event General Fatigue Asthenia Pyrexia Peripheral oedema Gastrointestinal Constipation Diarrhoea NOS Nausea Musculoskeletal Muscle cramp Back pain Arthralgia Nervous system Dizziness Neuropathy NOS Haematological Neutropenia Anaemia NOS Thrombocytopenia Respiratory Dyspnoea NOS Cough Infections Pneumonia NOS Upper respiratory tract infection NOS Psychiatric Insomnia Skin Rash NOS Metabolic Anorexia NOS, not otherwise speciﬁed. n 1404 796 220 215 202 341 297 272 338 190 145 170 145 425 340 306 235 223 155 144 286 186 147 % 97Æ6 55Æ4 15Æ3 15Æ0 14Æ0 23Æ7 20Æ7 18Æ9 23Æ5 13Æ2 10Æ1 11Æ8 10Æ1 29Æ6 23Æ6 21Æ3 16Æ3 15Æ5 10Æ8 10Æ0 19Æ9 12Æ9 10Æ2 Table II. Most common grade 1–4 adverse events due to any cause reported in ‡10Æ0% of patients (N = 1438).

*Percentages may add up to more than 100% as patients were allowed to select more than one race. Percentages may add up to more than 100% as more than one response was allowed.

Haematological events (neutropenia, thrombocytopenia, leucopenia, and anaemia) were manageable with dose reductions and resulted in only 3Æ75% 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 (7Æ1%), neutropenia (5Æ2%), anaemia (1Æ2%), and pneumonia (1Æ0%). At least one grade 3 or 4 adverse event was reported in 69Æ7% 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 18Æ2% of patients on the study at some point during their

treatment. The majority (224 of 263 [85Æ2%] patients) had grade 1 or 2 events. Of the 18Æ2% patients who experienced neuropathic symptoms, 73Æ9% had a prior history. Two thirds (67%) of all patients on study had a prior history of neuropathy. Venous thromboembolic events (VTEs) of all grades occurred in 8Æ3% of patients with a median duration of 12 d (range: 1–113 d). VTEs included DVT (6Æ1%), pulmonary embolism (1Æ5%), thrombosis (0Æ8%), jugular vein thrombosis (0Æ1%); thrombosis (0Æ9%; thrombosis, phlebothrombosis), unspeciﬁed phlebitis (0Æ3%), and unspeciﬁed embolism (0Æ2%). Grades 3/4/5 VTEs occurred in 5Æ8% of patients. Arterial thromboembolic events (ATEs) occurred in 2Æ9% of patients. ATEs included myocardial infarction (0Æ5%), transient ischaemic attack (0Æ4%), cerebrovascular accident (0Æ4%), and thrombotic stroke (0Æ1%). Only 1Æ8% of these patients had 167

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C. Chen et al
Table III. Most common grade 3 or 4 adverse events due to any cause reported in >2Æ0% of patients (N = 1438). Patients Adverse event Patients with ‡1 grade 3 or 4 adverse event Haematological Neutropenia Thrombocytopenia Anaemia NOS Febrile neutropenia General Fatigue Asthenia Infections Pneumonia NOS Metabolic Hyperglycaemia NOS Dehydration Musculoskeletal Back pain Muscle weakness NOS Investigations Neutrophil count decreased Respiratory Dyspnoea NOS Venous thromboembolism Deep-vein thrombosis NOS, not otherwise speciﬁed. n 1002 315 195 111 35 149 53 102 61 38 39 37 31 57 65 % 69Æ7 21Æ9 13Æ6 7Æ7 2Æ4 10Æ4 3Æ7 7Æ1 4Æ2 2Æ6 2Æ7 2Æ6 2Æ2 4Æ0 4Æ5 Adverse event Patients with ‡1 adverse event leading to discontinuation of study drug Thrombocytopenia Neutropenia Pneumonia NOS Sepsis NOS Fatigue Pancytopenia Anaemia NOS Asthenia Multiple myeloma Rash NOS Acute renal failure Dyspnoea NOS Pyrexia NOS, not otherwise speciﬁed. Table V. Most common adverse events leading to treatment discontinuation due to any cause reported in >0Æ5% of patients (N = 1438). Patients n 266 23 21 19 14 11 11 10 10 9 9 9 8 8 % 18Æ5 1Æ6 1Æ5 1Æ3 1Æ0 0Æ8 0Æ8 0Æ7 0Æ7 0Æ6 0Æ6 0Æ6 0Æ6 0Æ6

Table IV. Most common serious adverse events (N = 1438). Patients Serious adverse event Pneumonia Pyrexia Deep-vein thrombosis Thrombocytopenia Dehydration Febrile neutropenia Anaemia Dyspnoea n 117 54 43 42 36 36 35 29 % 8Æ1 3Æ8 3Æ0 2Æ9 2Æ5 2Æ5 2Æ4 2Æ0

included commercial availability of the drug in the USA (46Æ7%), disease progression (18Æ5%), death (5Æ1%), and withdrawal of consent (4Æ4%). Neutropenia (17Æ8%), thrombocytopenia (9Æ2%), fatigue (8Æ3%), pneumonia (3Æ5%), pyrexia (3Æ5%), and anaemia (3Æ3%) 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 (8Æ7%) occurring within 30 d from the last dose. The most frequent causes of death were disease progression (10Æ2%) and adverse events (4Æ3%); 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, 2000, 2002, 2006; Barlogie 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, 2006; Rajkumar 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

an grade ‡3, although 6 (0Æ4%) patients experienced grade 5 ATEs.

Incidence of dose reductions and discontinuations due to adverse events
Overall, 18Æ5% 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 168

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Expanded Access Programme of Len + Dex in MM 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 (19Æ8% vs. 18Æ5%, 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 (Knight et al, 2006). 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, 2005, 2006; Zonder 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 18Æ2% 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, 2005; Glasmacher 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. 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 OrthoBiotech 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.

Acknowledgements
In addition to the authors, the expanded access programme study investigators were Dr Brian Abbott, Dr Mary Audrey Ackerman, Dr Ashraf Badros, Dr Michael Bar, Dr Olcay Batuman, Dr Archie Brown, Dr Vikas Bhushan, Dr Craig Cole, Dr Ajit Divgi, Dr Louis Fehrenbacher, Dr George Geils, Jr, Dr Teresa Gentile, Dr Martha Glenn, Dr Stephanie Gregory, Dr Scott Hall, Dr W. Graydon Harker, Dr Leona Holmberg, Dr David Hurd, Dr David B. Johnson, Dr Richard Just, Dr Delva Deauna-Limayo, Dr Henry Kaplan, Dr Kelvin Lee, Dr Steven Limentani, Dr Sagar Lonial, Dr Jose Lutzky, Dr Joseph Mace, Dr John McCarty, Dr Kelly McCaul, Dr Kenneth Meehan, Dr Timothy Moore, Dr Jonathan Polikoff, Dr Craig Reeder, Dr Tony Reiman, Dr David G. Roodman, Dr Edward Samuel, Dr Roger Santala, Dr Kaushik Sen, Dr Stuart Seropian, Dr Richard Shadduck, Dr Grace Shumaker, Dr Chaim Shustik, Dr Seema Singhal, Dr Kevin Song, Dr Daniel Spitz, Dr Robert Stuart, Dr Stefano Tarantolo, Dr Nagendra Tirumali, Dr Ravi Vij, Dr Donna Weber, Dr Matthias Weiss, Dr Darrell White, Dr Ann Wierman, and Dr Peter H. Wiernik.

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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

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