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TITLE PAGE

Study Title: An Observational Study of Neutropenia in Subjects Being Treated for Relapsed or Relapsed/Refractory Multiple Myeloma

Product or Therapeutic Area:

Hematology/Oncology

Brief Description: This study was a multicenter, prospective observational study of neutropenia in subjects being treated with a regimen of lenalidomide with dexamethasone for relapsed or relapsed/refractory multiple myeloma

Study Sponsor: Amgen Inc., Uxbridge Business Park1 Sanderson RoadUxbridge, UB8 1DHUnited KingdomTelephone: +44 (0) 1895 525000Fax: +44 (0) 1895 525100

Study No.: 20090330

Study Initiation Date: 12 February 2011 (first subject enrolled)

Study Completion Date: 03 July 2013 (last subject completed observational period)

Principal Investigators: This study was conducted at 34 centers in Australia, Austria, Czech Republic, France, Germany, Greece, Ireland, Spain,and The United Kingdom. Study centers and investigators are listed in Appendix 3.

Contact Person: Helen SwannAmgen LtdUxbridge Business Park1 Sanderson RoadUxbridge, UB8 1DHUnited KingdomTelephone: +44 (0) 1895 525589Fax: +44 (0) 1895 435235

Good Clinical Practice: This study was conducted in accordance with key principlesof applicable International Conference on Harmonisation Good Clinical Practice. Essential documents will be retained in accordance with the guidelines.

Report Date: 14 January 2014


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Hematology/OncologyObservational Research Study Report: 20090330

14 January 2014 Page 1 of 2114

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BODY OF REPORTName of Sponsor: Amgen Inc.

Product or Therapeutic Area: Hematology/Oncology

Indication: No investigational product was evaluated in this study. Study subjects were patients with relapsed or relapsed and refractory multiple myeloma (RR-MM).

Title of Study: An Observational Study of Neutropenia in Subjects Being Treated for Relapsed or Relapsed/Refractory Multiple Myeloma

Investigators and Study Centers: This study was conducted at 34 centers in 9 countries (Australia, Austria, Czech Republic, France, Germany, Greece, Ireland, Spain and The United Kingdom). A list of investigators is provided in Appendix 3.

Publications: None at the time of this report

Study Period: 12 February 2011 (first subject enrolled) to 03 July 2013 (last subject completed observational period)

Development Phase: Observational

Introduction and Objectives: Multiple myeloma (MM) is a hematologic malignancy characterized by buildup of abnormal monoclonal plasma cells in the bone marrow; presence of monoclonal (M) protein in the serum or urine; evidence of end-organ damage (eg, renal failure due to the M protein build up); and frequently skeletal lesions leading to bone pain or fractures (Kyle and Rajkumar, 2009). Kyle and Rajkumar recommended criteria for diagnosis,staging and response assessment for MM, based on 2 commonly used systems: Durie and Salmon (Durie and Salmon 1975) and the International Staging System (Greipp et al, 2005). They also proposed the following definition of relapsed and refractory disease versus relapsed disease:

• relapsed and refractory diagnosis: relapse of disease while on salvage therapy, or progression within 60 days of most recent therapy

• relapsed diagnosis: ≥ 1 prior regimen, not meeting criteria for relapsed and refractory disease

For the purposes of this study, the diagnosis of relapsed and diagnosis of relapsed and refractory is referred to as “RR-MM”.

New therapies have demonstrated improvements in time to relapse and in overall survival of patients who relapse (Kumar et al, 2008). A combined therapy of lenalidomide plus dexamethasone has been approved for treatment of patients with RR-MM in Europe and the United States. This treatment regimen demonstrated a better toxicity profile than thalidomide treatment and also has shown significant improvement intime to progression and in overall survival as compared with dexamethasone alone (Wang et al, 2008; Weber et al, 200�; Dimopoulos et al, 2007). The hematologic toxicities neutropenia and thrombocytopenia are the most common dose-limiting toxicities in patients receiving lenalidomide regimens (Richardson et al, 2009; Wang et al, 2008; Weber et al, 200�; Richardson et al, 2006). Knop used a regimen of lenalidomide plus doxorubicin and dexamethasone in subjects with RR-MM and found that the maximum tolerated dose was not formally reached when pegfilgrastim 6 mg was administered (Knop et al, 2009) (Table 1). A secondary analysis of the two phase 3 registrational studies of lenalidomide (Dimopoulos et al, 2007; and Weber et al, 2007)


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suggested that being able to maintain the full dose of lenalidomide (25 mg daily [QD] for 21 days followed by 7 days of drug holiday) plus dexamethasone for 12 months, followed by ongoing maintenance doses of lenalidomide, significantly improvedprogression-free survival. Of the 35 subjects requiring dose reduction, the most common reason for reduction was neutropenia in 28 subjects (72%) (Dimopoulos et al, 2009).

Table 1. Dose Reductions or Interruptions and Grade 3/4 Neutropenia Observed in Trials With Lenalidomide

The rationale for the current prospective observational study was to characterize patients with RR-MM who were treated with lenalidomide plus dexamethasone in the setting of normal clinical practice and to describe the nature of the neutropenia observed in this population.

Observational research techniques can be an effective tool to gain understanding of the risk of neutropenia in standard clinical practice because of the variation of patient characteristics, types of assessments, and office visit frequency between clinical trials and standard clinical practice. Information gathered in this study was expected to provide physicians with a better understanding of the use of lenalidomide and risk of neutropenia in this setting.

The primary objective of this study was:

• to estimate the incidence of grade 3/4 neutropenia in subjects with RR-MM who were starting treatment with the regimen of lenalidomide plus dexamethasone during an observational period of 12 months


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The secondary objectives of the study were:

• to describe demography and baseline medical data of subjects in the study population

• to describe targeted medical history, including Eastern Cooperative Oncology Group (ECOG) performance status, comorbidities, and disease-specific medical history

• to describe how grade 3/4 neutropenic toxicities in this population were managed (eg, reductions, delays, or interruption of lenalidomide dose, or granulocyte-colony stimulating factor [G-CSF] use, and hospitalizations)

Study Hypothesis: No formal hypothesis was tested in this study.

Study Design/MethodologyThis was a multicentre, international, prospective, observational study of subjects with RR-MM who were starting a treatment regimen of lenalidomide with dexamethasone. The observational period for each subject was 12 months, beginning with the start of lenalidomide treatment and continuing until 12 months of treatment was completed, lenalidomide treatment was ended, or early withdrawal occurred, whichever occurredfirst. Reasons for early withdrawal included administrative decision, lost to follow-up, death, withdrawal of consent, and ineligibility. Part of the observational period was retrospective if subjects began the first cycle of treatment prior to enrolment in the study. The overall study design is shown in Figure 1.


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Figure 1. Study Design

a. Involved retrospective data collection. Subject was enrolled and then retrospective data collection from medical records up to the start of cycle 1 of lenalidomide treatment was begun.

b. Before enrolment, subjects were asked to provide informed consent where required by local regulations.c. The observational period for each subject was 12 months, beginning with the start of lenalidomide

treatment and continuing until 12 months of treatment had been completed, until lenalidomide treatment had ended, or early withdrawal, whichever was first. Part of the observational period was retrospective if subjects began the first cycle of treatment before enrolment in the study.

Eligible subjects were ≥ 18 years of age, diagnosed with RR-MM and were starting treatment with lenalidomide plus dexamethasone upon enrolment in the study, or werecurrently in cycle 1 of treatment with lenalidomide plus dexamethasone (ie, ≤ 4 weeks had elapsed since lenalidomide was first prescribed). Subject or subject’s legally acceptable representative must have provided informed consent where required. Subjects were excluded if they were receiving a concomitant cytotoxic chemotherapeutic agent in addition to the regimen of lenalidomide and dexamethasone, had participated in another investigational device or drug study, if less than 30 days had elapsed since ending another investigational device or drug study(s) or received other investigational agent(s), or if the subject had any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent.

A total of 150 to 200 subjects were planned for enrollment by 20 to 40 sites. Subject enrolment was planned to continue until either a maximum of 200 subjects was enrolled or 18 months had elapsed since enrolment of the first subject. Each site was asked to


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enroll approximately 20 subjects. More subjects could be enrolled if agreed upon with the sponsor (up to a maximum of 30 subjects for any single site).

Precision estimates were calculated based on the assumption that 200 subjects would be enrolled into the study. Based on an anticipated 40% incidence of grade 3/4 neutropenia, a sample size of 200 subjects allowed for the 95% confidence limits to be calculated to within ± 7 percentage points of this estimate. For example, if at the end of the study the incidence of neutropenia was estimated to be 40% then the expected 95% confidence interval (CI) for this estimate would lie within 33% to 47%.

A risk analysis showing the required sample sizes for a range of precision levels and incidences is presented in Table 2. The sample size goal of 200 subjects allowed for a 6% dropout rate (189 subjects) while still preserving the ± 7 percentage points precision for the 95% CI.

Table 2. Risk Analysis of Sample Size Calculationfor a Range of Incidences and Precision Levels

Incidence of Grade 3/4 Neutropenic Events

20% 30% 40% 50%

Precision for 95% CI

± 5% 246 323 369 385

± 7% 126 165 189 196

± 10% 62 81 93 97

CI = Confidence Interval.

Bias was considered at the study design stage and methods were employed to reduce potential selection or information bias. Details are presented in Section 9.4 of the Statistical analysis plan (SAP) (Appendix 8). Sensitivity analysis was carried out on incidence of febrile neutropenia (FN).

The process defined in Section 8.1 of the protocol (removal of subjects) was modified after 26 January 2012 (Note to file 2012-10-08). The modified process is summarized below:

• Upon identification of an eligibility deviation, a subject was immediately withdrawn from the study. The clinical monitor, site staff, clinical manager, Clinical Data Management department, and Biostatistics group took coordinated action to assure that data for the ineligible subjects were inactivated in the database, other than those data points required for reporting the eligibility deviation in the clinical study report, and that ineligible subjects were excluded from the study analysis.

Amgen’s Clinical Data Management department provided all data to be used in the planned analyses. This study used the RAVE data capture system. Data werescreened to assess the quantity, quality, and statistical characteristics of the data relative to the requirements of the planned analyses. Missing data were not imputed, with the exception of dates; missing data considered key as defined by Clinical Data Management, were queried but not imputed. Details regarding data handling are presented in Section 10.4 of the Protocol (Appendix 1).


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Study safety data (adverse drug reactions and serious adverse drug reactions) were managed and reported as described in Section 9 of the protocol (Appendix 1).

Number of Subjects Included in Study: Of the 218 subjects enrolled, 198 subjects were eligible. All eligible subjects were included in the primary analysis set (PAS).

Study Endpoints: The primary endpoint was grade 3/4 neutropenia. Incidence of grade 3/4 neutropenia was estimated as proportion of subjects with ≥ 1 event of grade 3/4 neutropenia; unadjusted and adjusted per person-time.

The secondary endpoints were:

• Subject population characteristics

• Targeted medical history as described in Section 10.4.2.1 of the protocol

• Prior treatment for MM as described in Section 10.4.2.1 of the protocol

• Characteristics of neutropenia events

- Grade 3 neutropenia

- Grade 4 neutropenia

- Elapsed time to first grade 3/4 neutropenia since initiation of lenalidomide treatment

- Febrile neutropenia (defined as absolute neutrophil; count [ANC] < 1.0 x 109/L and body temperature ≥ 38.2°C)

• Management of neutropenia toxicities

- Lenalidomide administration

� Prescribed lenalidomide regimen at initiation of therapy (dose, length of cycle, including dexamethasone use)

� Dose interruptions, and dose interruptions due to neutropenia

� Dose reductions, and dose reductions due to neutropenia

� Last dose of lenalidomide before observation of first grade 3/4 neutropenia

� Total dose of lenalidomide to be based on total dose received based on prescription accounting for known interruptions and dose reductions

� Completion of the 12-month the observational period

� Occurrence of hospitalizations and outpatient visits resulting from MM

- G-CSF use

� Granulocyte colony stimulating factor use and agent

� Prescribed G-CSF regimen by G-CSF treatment episode (dose, schedule, start day, length, type of agent [pegfilgrastim, daily G-CSF {eg, filgrastim, lenograstim, etc}, other]) across all episodes

� ANC at initiation of G-CSF

� Dose of lenalidomide at G-CSF initiation


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� Elapsed time to first dose of G-CSF since initiation of treatment with lenalidomide, overall and by agent

- Best clinical response (Kyle and Rajkumar, 2009) achieved over observational period (Appendix D of the protocol [Appendix 1])

Statistical Methods: The approach to the statistical analysis was descriptive in nature. Unless otherwise specified, analyses were based on the PAS. Categorical data weresummarized by the number and percentage of subjects in each category. Continuous data were summarized by mean, standard deviation, median, lower and upper quartiles, and minimum and maximum values.

In general, proportions and corresponding 95% CI were based on all subjects and not just those with non-missing responses. As required, 2-sided 95% CI (calculated using Wilson’s Method) were presented. It is recognized that including ‘missing’ in the denominator of proportions will slightly under-estimate the true sample proportion; however the relative number of missing responses was expected to be small.

Important Protocol Deviation (IPD) categories were defined by the study team before the first patient visit and updated during the IPD reviews throughout the study prior to database lock. These definitions of IPD categories, sub-category codes, and descriptions were used during the course of the study. The final IPD list was used to produce the summary of IPDs and the subject listing of IPDs.

Descriptive statistics were used to summarize the demographic and baseline characteristics. The baseline characteristics were further summarized by the lenalidomide schedule and the number of prior therapies subgroups. Detailed descriptions regarding methods of statistical analyses are presented in Section 10 of the SAP (Appendix 8).

Summary of Results:Subject Characteristics:Enrollment: Thirty-four centers in 9 countries across Europe and Australia enrolled subjects into this study (Table 14-1.3). A total of 218 subjects were screened andenrolled into the study. Subsequently, 20 subjects who were found to be ineligible for the study were withdrawn from the study and their data was not included in the study analysis (Listing 14-1.4).

Disposition: Of the 198 eligible subjects, all were included in the PAS. Of the eligible subjects, 35% (n = 69) completed the observational period and 65% (n = 129) were prematurely withdrawn from the study. The most common reasons for early withdrawal were disease progression in 21% of subjects (n = 42), tolerability issues with lenalidomide in 15% of subjects (n = 30), and death in 12% of subjects (n = 23). Withdrawals for all other reasons occurred in ≤ 10% of subjects (Table 3).


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Table 3. Subject Disposition with Discontinuation Reason(PAS)

PAS (N = 198)

Accounting - n (%) Subjects who were enrolled into study 198 (100.0) Subjects who completed the observation period 69 (34.8) Subjects who withdrew prematurely 129 (65.2)

Reason for withdrawal - n (%) Disease progression 42 (21.2) Tolerability issues with lenalidomide 30 (15.2) Death 23 (11.6) Other 20 (10.1) Administrative decision 10 (5.1) Lost to follow-up 3 (1.5) Consent withdrawn 1 (0.5) Missing 0 (0.0) Ineligibility determined 0 (0.0)

N=Number of subjects in the analysis set., n=number of subjects, PAS = primary analysis setNumber of subjects screened: 218.Created from Table 14-1.1.1 on 22 November 2013

Baseline Demographics: The PAS comprised 198 subjects. Of the subjects in the PAS 107, subjects (54%) were men and 91 subjects (46%) were women. The mean (standard deviation[SD]) age of subjects in the PAS was 69 (9.7) years with a range of 29 to 88 years (Table 4). Demographic and baseline characteristics are summarized in Table 14-2.1.1 through Table 14-2.2.4.

Additional baseline summaries are available for:

• bone and bone marrow parameters

- Table 14-2.5.1 (overall)

- Table 14-2.5.3 (by number of any prior therapies)

- Table 14-2.5.4 (by lenalidomide schedule)

• paraproteins

- Table 14-2.6.1 (overall),


- Table 14-2.6.4 (by lenalidomide schedule).

• other medical assessments

- Table 14-2.7.1 (overall)


- Table 14-2.7.4 (by lenalidomide schedule).


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Table 4. Baseline Demographics (PAS)PAS

(N = 198)Sex - n (%) Male 107 (54.0) Female 91 (46.0)Age (years) n 198 Mean 69.0 SD 9.7 Median 70.0 Q1, Q3 64.0, 76.0 Min, Max 29, 88Age group – n (%) < 65 years 55 (27.8) >= 65 years 143 (72.2) >= 75 years 56 (28.3)

Max=maximum; Min=minimum; N=Number of subjects; n=non-missing values; PAS=primary analysis set; SD=sample standard deviation; Q1=first quartile; Q3=third quartile.Created from Table 14-2.1.1 on 22 November 2013

The most common stages of MM at initial diagnosis by system were stage III (42%) according to the Durie and Salmon staging system and stage II (29%) according to the International Staging System (ISS) (Table 5). Summaries of initial diagnosis by number of any prior therapies and lenalidomide schedule are provided in Table 14-2.3.3 and Table 14-2.3.4, respectively.

Table 5. Summary of Initial Diagnosis (PAS)

PAS (N = 198)

Durie and Salmon staging at initial diagnosis - n (%) Stage I 30 (15.2) Stage II 50 (25.3) Stage III 84 (42.4) Missing 34 (17.2)International staging system at initial diagnosis - n (%) Stage I 43 (21.7) Stage II 58 (29.3) Stage III 50 (25.3) Missing 47 (23.7)

N=Number of subjects; n=non-missing values; PAS=primary analysis set; SD=sample standard deviation; Q1=first quartile; Q3=third quartile.Program: /userdata/stat/peggcsf/sd01/sd20090330/analysis/final/tables/t-diag1.sasOutput:��14-2�3�1-diag-initial-pas-l.rtf (Date Generated: 08OCT13:06:16:58) Source Data: crt.diag

The majority of subjects (83%) had a current diagnosis of relapsed MM. Thirty-seven percent of subjects had a current diagnosis of stage III MM based on the Durie and Salmon staging system, while 33% of subjects had a current diagnosis of stage II MM based on the ISS (Table 6). Summaries of current diagnosis by number of any prior


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therapies and lenalidomide schedule are provided in Table 14-2.4.3 and Table 14-2.4.4, respectively.

Table 6. Summary of Current Diagnosis (PAS)PAS

(N = 198)Current diagnosis - n (%) Relapsed 165 (83.3) Relapsed and refractory 33 (16.7) Missing 0 (0.0)Durie and Salmon staging at current diagnosis - n (%) Stage I 24 (12.1) Stage II 60 (30.3) Stage III 74 (37.4) Missing 40 (20.2)International staging system at current diagnosis - n (%) Stage I 38 (19.2) Stage II 65 (32.8) Stage III 42 (21.2) Missing 53 (26.8)Time (months) since initial MM diagnosis a

n 162 Mean 48.631 SD 38.108 Median 35.992 Q1, Q3 22.308, 62.817 Min, Max 2.23, 177.15Time (months) since initial MM diagnosis a

0 0 (0.0) >0 – 48 102 (51.5) >48 – 96 36 (18.2) >96 – 144 19 (9.6) >144 5 (2.5) Missing 36 (18.2)

Max=maximum; Min=minimum;, MM=multiple myeloma; N=Number of subjects; n=non-missing values; PAS=primary analysis set; SD=sample standard deviation; Q1=first quartile; Q3=third quartileNote: Current diagnosis refers to diagnosis at the time of enrolment.Time between the date of initial MM diagnosis and the date of current MM diagnosis.Created from Table 14-2.4.1 on 22 November 2013

Prior therapies for MM are presented in Table 7. The 3 most common agents in prior therapies were dexamethasone in 82%, melphalan in 74%, and bortezomib in 72% of subjects. Of note were 6% of subjects with prior lenalidomide therapy. Overall, most subjects had received 1 or 2 lines of prior therapy (31% and 29% of subjects, respectively). The most common reason for discontinuation of most recent treatment regimen prior to current lenalidomide treatment was Other (31% of subjects) followed by Remission and Progression (30% and 18% of subjects, respectively).


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Table 7. Summary of Prior Treatment for MM (PAS)PAS

(N = 198)Prior Therapy for MM Dexamethasone 163 (82.3) Melphalan 147 (74.2) Bortezomib 142 (71.7) Thalidomide 106 (53.5) Other Cytotoxic chemotherapy 94 (47.5) Stem cell transplantation 75 (37.9) Other 61 (30.8) Doxorubicin 57 (28.8) Radiotherapy 44 (22.2) Lenalidomide 11 (5.6) Experimental agent 5 (2.5)Total number of lines received 1 61 (30.8) 2 58 (29.3) 3 37 (18.7) 4 27 (13.6) >4 15 (7.6) Missing 0 (0.0)Reason for discontinuation of most recent treatment regimen prior to current lenalidomide treatment Toxicity 23 (11.6) Progression 35 (17.7) Remission 59 (29.8) Not Applicable 20 (10.1) Other 61 (30.8) Missing 0 (0.0)

MM=multiple myeloma; N=Number of subjects in the analysis set; PAS=primary analysis set.Categories under ‘Prior Therapy’ are not mutually exclusive. Subjects can be included in multiple categories.Progression within 60 days (i.e., 60 days or less) was "Unknown" if either date of progression or date of last administration of the most recent therapy was partial. It was "Missing" if both dates were missing.Time between the date of last relapse and cycle 1 start date. The date of last relapse was taken as the date of last administration of the most recent therapy recorded when progression was checked as a reason for discontinuation.Created from Table 14-2.10.1 on 22 November 2013

Eighty four percent of subjects had at least 1 comorbidity at baseline (Table 8). Themost common comorbidity was diseases of the circulatory system in 60% of subjects;hypertensive disease and ischemic heart disease were reported by 49% and 13% of subjects, respectively. The second most common comorbidity were endocrine, nutritional, and metabolic diseases in 31% of subjects; diabetes mellitus and disorders of lipoprotein metabolism and other lipidaemias were reported by 14% of subjects in each case. It is noteworthy that renal failure, observed in 8% of subjects is a hallmark of MMthat has an effect on lenalidomide dosing. The summary of baseline renal impairment by lenalidomide schedule is provided in Table 14-2.9.4.


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Table 8. Summary of Baseline Comorbidities (PAS)PAS

(N = 198) Number of subjects reporting at least one comorbidity - n (%) 166 (83.8) Certain infectious and parasitic diseases 9 (4.5) Neoplasms 20 (10.1) Diseases of blood and blood forming organs and disorders of immune

mechanism 24 (12.1)

Mental and behavioural disorders 13 (6.6) Diseases of the nervous system 38 (19.2) Diseases of the eye and adnexa 14 (7.1) Diseases of the ear and mastoid process 2 (1.0) Diseases of the digestive system 30 (15.2) Diseases of the skin and subcutaneous tissue 10 (5.1) Diseases of the musculoskeletal system and connective tissue 35 (17.7) Endocrine, nutritional and metabolic diseases 61 (30.8) Diabetes mellitus 28 (14.1) Obesity 9 (4.5) Disorders of lipoprotein metabolism and other lipidaemias 27 (13.6) Diseases of the circulatory system 118 (59.6) Hypertensive disease 96 (48.5) Ischemic heart disease 25 (12.6) Pulmonary embolism 9 (4.5) Other forms of heart disease 22 (11.1) Cerebrovascular disease 6 (3.0) Disease of arteries, arterioles and capillaries 20 (10.1) Diseases of the respiratory system 31 (15.7) Pneumonia 10 (5.1) Chronic lower respiratory diseases 17 (8.6) Other diseases affecting the interstitium 7 (3.5) Diseases of the genitourinary system 35 (17.7) Renal failure 16 (8.1)

N=Number of subjects in the analysis set; n (%) = numbers (percentages); PAS=primary analysis set.The subcategories within each category are not mutually exclusive. Subjects can be included in multiple subcategories.These comorbidities refer to earlier or ongoing events that may have an impact on the current health status of the subject.Created from Table 14-2.8.1 on 22 November 2013

Endpoint evaluations:Primary endpoint: Overall, 62 subjects (31%; 95% CI: 25%, 38%) had at least one grade 3/4 neutropenia event between the initiation of lenalidomide treatment and the end of the observational period (Table 9). The frequency of subjects with grade 3/4 neutropenia was 5 per 100 subject-months (95% CI: 3.9, 6.5). There were 14 (7%) subjects who experienced grade 3/4 neutropenia in cycle 1. Cycle 2 and cycle 6 had the largest percentages of subjects experiencing at least one grade 3/4 neutropenia event; with ≥12% of subjects in each cycle. A relatively high proportion of subjects experiencedgrade 3/4 neutropenia late in the treatment course. Incidences of grade 3/4 neutropenia


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by number of any prior therapies and by lenalidomide schedule are provided in Table 14-4.1.3 and Table 14-4.1.4, respectively.

Table 9. Incidence of Grade 3/4 Neutropenia (Primary Endpoint) (PAS)(N = 198)

n (%)a or n/month b 95% CI

Subjects with grade 3/4 neutropeniaProportion of subjects (method 1)a 62 (31.3) a [25.3, 38.1]

Frequency of subjects with grade 3/4 neutropeniaPer 100 subject-months (method 2)b 5 b [3.9, 6.5]

Subjects in Cycle 1 198Subjects with grade 3/4 neutropenia in Cycle 1 Proportion of subjects (method 1)a 14 (7.1) a [4.3, 11.5]





Page 1 of 2n=number of subjects; N = Number of subjects in the analysis set; CI for method 1=Wilson's 95% Confidence Interval. CI for method 2= Exact Poisson Confidence Interval; PAS=primary analysis set.a. Incidence of subjects with grade 3/4 neutropenia is calculated as a proportion of subjects with at least 1

event of grade 3/4 neutropenia.b. Incidence of subjects with grade 3/4 neutropenia is calculated as a frequency of subjects with grade 3/4

neutropenia per 100 subject-months (exposure adjusted subject incidence).Grade 3/4: ANC < 1.0 x 109/L.12 subjects had an event after the end of their last cycle.Created from Table 14 4.1.1 22 November 2013


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Table 9. Incidence of Grade 3/4 Neutropenia (Primary Endpoint) (PAS)PAS

(N = 198)n (%)a or n/month b

95% CI










Page 2 of 2n=number of subjects; N = Number of subjects in the analysis set; CI for method 1=Wilson's 95% Confidence Interval. CI for method 2= Exact Poisson Confidence Interval; PAS=primary analysis set.a. Incidence of subjects with grade 3/4 neutropenia is calculated as a proportion of subjects with at least 1

event of grade 3/4 neutropenia.b. Incidence of subjects with grade 3/4 neutropenia is calculated as a frequency of subjects with grade 3/4

neutropenia per 100 subject-months (exposure adjusted subject incidence).Grade 3/4: ANC < 1.0 x 109/L.12 subjects had an event after the end of their last cycle.Created from Table 14 4.1.1 22 November 2013


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Secondary endpoints: The separate incidences of grade 3 and grade 4 neutropenia are provided in Table 14-4.2.1. Between the initiation of lenalidomide treatment and the end of the observational period, 30% of subjects (95% CI: 24%, 37%) had at least one grade 3 neutropenic event and 10% of subjects (95% CI: 6%, 15%) had at least one grade 4 neutropenic event. The separate incidences of grade 3 and 4 neutropenia by number of any prior therapies and by lenalidomide schedule are provided in Table 14-4.2.3 and Table 14-4.2.4, respectively.

As shown in Table 10, the median (Q1, Q3) elapsed time to first grade 3/4 neutropenia event measured from the initiation of lenalidomide treatment was 8.8 (5.9, 17.3) weeks. The elapsed time to first event of grade 3/4 neutropenia by number of any prior therapies and by lenalidomide schedule is provided in Table 14-4.3.3 and Table 14-4.3.4, respectively. Of the 62 subjects who experienced a grade 3/4 neutropenic event, half (31 [15.7% of subjects in the PAS]) had 3 or more events (Table 14-4.29.1).

Table 10. Elapsed Time to First Event of Grade 3/4 Neutropenia (PAS)PAS

(N = 198)Elapsed time to grade 3/4 neutropenia (weeks) n 62 Mean 12.349 SD 9.692 Median 8.786 Q1, Q3 5.857, 17.286 Min, Max 0.07, 44.71

Max=maximum; Min=minimum; N=Number of subjects; n=non-missing values; PAS=primary analysis set; SD=sample standard deviation; Q1=first quartile; Q3=third quartile.Note: Time is measured from initiation of lenalidomide treatment.Elapsed time to first event of grade 3/4 neutropenia is set to 0.5 days when date of first event of grade 3/4 neutropenia is the same as date of initiation of lenalidomide treatment.Program: /userdata/stat/peggcsf/sd01/sd20090330/analysis/final/tables/t-etf34neut.sasOutput:��14-4�3�1-etf34neut-pas-p.rtf (Date Generated: 09OCT13:08:40:30) Source Data: crt.neut

Overall, 6 subjects (3%) each experienced 1 event of FN (Table 11). Cycle 9 was the only cycle in which more than 1 subject experienced FN (Table 14-4.4.1). The results of the sensitivity analysis of the incidence of FN (Table 14-4.5.1) were consistent with the results of the former analysis provided in Table 14-4.3.1. The incidence of FN by number of any prior therapies and by lenalidomide schedule is provided in Table 14-4.4.3 and Table 14-4.4.4, respectively. The number of FN events per subject is provided in Table 14-4.30.1.

The median (Q1, Q3) elapsed time to first event of FN from the initiation of lenalidomide treatment was 17.0 (10.0, 37.3) weeks (Table 14-4.6.1). The results of the sensitivity analysis of elapsed time to first event of FN (Table 14-4.7.1) were consistent with the results of the former analysis shown in Table 14-4.6.1. The elapsed time to first event of FN by number of any prior therapies and by lenalidomide schedule is provided in Table 14-4.6.3 and Table 14-4.6.4, respectively.


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Table 11. Incidence of Febrile Neutropenia (PAS)PAS

(N = 198)n (%)

95% CI

Subjects with FN events a 6 (3.0) [1.4, 6.5]FN=febrile neutropenia; n=number of subjects; N = Number of subjects in the analysis set. CI=Wilson's Confidence Interval; PAS=primary analysis set.Note: Where ANC and temperature values were taken within ±1 day but on different days, the first date was used for the FN date.1 subject had an event after the end of the last cycle.a. Incidence of subjects with FN was calculated as a proportion of subjects with at least 1 event of FN.Created from Table 14-4.4.1 on 22 November 2013

Chemotherapy Administration: At the initiation of therapy, 141 subjects (71%) were prescribed 25 mg of lenalidomide, while for the other subjects, prescribed lenalidomide dose was lower, with the “other” dose being 20 mg (Table 12, Listing 14-4.4). Therewere 183 subjects (92%) with standard lenalidomide schedule and 121 subjects (61%) with standard dexamethasone schedule. The original lenalidomide/dexamethasone prescription by number of any prior therapies is provided in Table 14-4.8.3.

Table 12. Original Lenalidomide/Dexamethasone Prescription (PAS)PAS

(N = 198)

Original lenalidomide dose - n (%) 5mg 4 (2.0) 10mg 26 (13.1) 15mg 25 (12.6) 25mg 141 (71.2) Other 2 (1.0)

Original lenalidomide schedule - n (%) Standard a 183 (92.4) Every other day, days 1-21 9 (4.5) Other 6 (3.0)

Dexamethasone schedule - n (%) Standard 121 (61.1) Lower dose than standard 71 (35.9) Other 5 (2.5) Missing 1 (0.5)

n= number of subjects; N = Number of subjects in the analysis set; PAS=primary analysis set.a. Standard: Daily administration on days 1-21, no administration days 22-28.Every other day: Every other day administration on days 1-21, no administration on days 22-28.Original prescription denotes the initial prescription in the first cycle of the study.Program: /userdata/stat/peggcsf/sd01/sd20090330/analysis/final/tables/t-oldpresc.sasOutput:��14-4�8�1-oldpresc-pas-p.rtf (Date Generated: 03OCT13:08:30:12) Source Data: crt.lendex

The total lenalidomide dose interruptions, reductions, and delays during the observational period are summarized in Table 14-4.9.1. A total of 88 subjects (44%) had at least 1 lenalidomide dose interruption, with neutropenia being the primary reason for


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dose interruptions in 5 subjects (3%). Forty-eight subjects (24%) had at least 1 dose reduction, with neutropenia being the primary reason for dose reductions in 4 subjects (2%). There were a total of 282 dose delays experienced by 127 subjects (64%).

The mean (SD) percentage of the last prescribed lenalidomide dose prior to neutropenic event was 98% (8.2%) of the original prescribed lenalidomide dose (Table 14-4.13.1). The mean (SD) total lenalidomide dose (mg planned and mg delivered) were 3837.7 (2337.4) and 2548.6 (1968.3), respectively (Table 14-4.14.1). Lenalidomide dose interruptions due to neutropenia and suspected neutropenia-related infections are provided in Table 14-4.10.1. The elapsed time to first events of lenalidomide dose interruption, reduction, and delay is provided in Table 14-4.11.1, while the reducedlenalidomide exposure, and the number of subjects who completed the 12 month treatment period on lenalidomide are provided in Table 14-4.12.1 and Table 14-4.15.1, respectively.

G-CSF use: Overall, 46 subjects (23%) received at least 1 administration of G-CSFbetween initiation of lenalidomide treatment and the end of the observational period. Pegfilgrastim was administered at least once to 16 subjects (8%) and G-CSFformulations designed for daily administration were given to 32 subjects (16%)(Table 13).

Table 13. G-CSF Use (PAS)PAS

(N = 198)Total administrations 289

Subjects with >= 1 administration of G-CSF - n(%) 46 (23.2)

Subjects with >= 1 administration by G-CSF type - n(%) Pegfilgrastim 16 (8.1) Daily G-CSF 32 (16.2) Filgrastim 27 (13.6) Biosimilar filgrastim 2 (1.0) Lenograstim 3 (1.5) Other growth factors 0 (0.0)

G-CSF=granulocyte colony stimulating factor; n=number of subjects; N = Number of subjects in the analysis set.Note: The subcategories within each category of G-CSF agent are not mutually exclusive. Subjects can be included in multiple subcategories.Program: /userdata/stat/peggcsf/sd01/sd20090330/analysis/final/tables/t-gcsfuse.sasOutput: ��14-4�16�1-gcsfuse-pas-p.rtf (Date Generated: 03OCT13:08:06:52) Source Data: crt.gcsfuse

The mean and median times to first G-CSF administration were 9.8 weeks and 8.0 weeks, respectively. The mean and median times to first G-CSF administrations are broken down by individual G-CSF in Table 14-4.20.1.

The mean values in days for the length of each course of G-CSF treatment for pegfilgrastim, filgrastim, biosimilar filgrastim, and lenograstim were 1.3, 6.9, 3.4, and 73.6 days, respectively (Table 14-4.17.1.1, Table 14-4.17.1.2, Table 14-4.17.1.3, and Table 14-4.17.1.4). Some subjects had maximum values that exceeded 140 days in length. The first subject (site number 65001, subject number 001, and G-CSF agent filgrastim) had a length of treatment of 141 days and the second subject (site number 25006, subject number 002, and G-CSF agent lenograstim) had a length of


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treatment of 356 days. For these 2 subjects, non-consecutive administration is likely but cannot be confirmed based on information in the database. Another subject with a long course of treatment was: site number 12004, subject number 004, and G-CSF agent filgrastim. This subject has corresponding database information that supports the conclusion that G-CSF was administered in an ongoing but non-consecutive dailymanner (Listing 14-5.4). These inconsistencies in G-CSF data collection cause the resulting summary data for average length of use to be difficult to interpret.

The absolute neutrophil count and the lenalidomide dose at initiation of G-CSF treatment are provided in Table 14-4.18.1 and Table 14-4.19.1, respectively.

Hospitalizations, Outpatient Visits and Response: A total of 88 (44%) subjects hadat least 1 unplanned hospitalization (Table 14-4.21.1). The most common primaryreason for hospitalization was other non-hematologic toxicity, which accounted for in 59 hospitalizations (45%). The median (Q1, Q3) length of unplanned hospitalizations was 7.0 (4.0, 12.0) nights.

A total of 190 subjects (96%) had at least 1 outpatient visit (Table 14-4.22.1). The median (Q1, Q3) number of outpatient visits per subject were 9.0 (5.0, 13.0) visits. The most common reason for outpatient visits was “part of normal clinical practice for lenalidomide and/or lenalidomide prescription” (81%).

The complete response to treatment as defined by Kyle and Rajkumar (2009) was achieved by 14 subjects (7%) as best response during the period of observation. Details of other levels of best response are provided in Table 14-4.23.1.

End of the observational period summary tables are provided for bone parameters (Table 14-4.25.1), paraproteins (Table 14-4.26.1), and other medical assessments (Table 14-4.27.1). Subjects with at least 1 event of grade 3 or grade 4 neutropenia were more likely to have dose interruptions, dose reductions, dose delays, G-CSF administrations, and unplanned hospitalizations than subjects without with no grade 3 or grade 4 neutropenic events. (Table 14-4.28.5)

Safety: There were no adverse or serious adverse drug reactions reported for any Amgen products (Table 14-6.2.1 and Table 14-6.3.1). During the study, 23 deaths were reported (Table 14-1.1.1).

Ten subjects (5%) had important protocol deviations and all were “Subject stopped treatment with lenalidomide but was not withdrawn from the study” (Table 14-3.1).

Bias/Limitations:Identification of Main Sources of Bias

There were 2 primary sources of potential selection bias: Subjects were not randomly selected for enrolment into the study and a low proportion of subjects completed the observational period. The results from the subjects who did not complete the study period could differ from the overall study population with respect to risk factors for the study endpoints.

Differing amounts of information collected for subjects in the study may reflect the varying levels of data entry or differences at the site or investigator level in the monitoring of neutropenia or the collecting and recording of baseline medical data in clinical practice.


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Potential Extent and Impact of Bias

Differing amounts of information collected for subjects in the study may cause information bias and potentially lead to an under-reporting of neutropenic events or baseline medical data for some sites and subjects. The variable lenalidomide exposure across subjects due to the different lengths of treatment may have affected the reporting of neutropenic events at later cycles (eg, subjects in the Czech Republic could only receive 10 cycles of lenalidomide due to reimbursement issues).

Subjects who remained in the study longer may differ in terms of risk factors from the overall study population, including exposure to the toxicity of lenalidomide, so observed event rates in later cycles may be biased and the events may have a different nature.

The potential selection bias caused by non-random enrolment may have resulted in the study population not being representative of the population of patients with RR-MM who are treated with lenalidomide plus dexamethasone. This may have resulted in biased estimates of the study endpoints.

Measures Taken to Minimize Bias at the Study Design or Analyses Stage

The subject eligibility criteria were designed to be broad and in alignment with the product information for lenalidomide to ensure that the study sample would represent the RR-MM population starting lenalidomide plus dexamethasone in current clinical practice.

For assessment of selection bias, investigators were expected to maintain a log of all potential study candidates and to provide reasons for eligible subjects not being enrolled.

Information bias was partly reduced by ensuring the same eCRF was used for all subjects and by not restricting the number of records that could be entered. Where sites anticipated data entry omissions, for example due to resource limitations, they were asked to enter all relevant data that met criteria for an event.

Subject time in the study was considered in the analysis with the presentation of the primary endpoint by cycle and adjustment for the total time of observation.

With regard to treatment of patients, no changes to routine practice were required for this study.

Impact on Generalizability of Findings

The rationale for this prospective observational study was to characterize subjects with RR- MM who were treated with lenalidomide plus dexamethasone in normal clinical practice, especially to better characterize the nature of the neutropenia observed in this population. The majority of subjects were initially prescribed standard schedules of lenalidomide and dexamethasone, which reflected the current clinical practice in the treatment of subjects with RR- MM. Therefore, the subjects enrolled into this study were considered to be a representative sample (in terms of countries, disease characteristics, and alignment with lenalidomide treatment recommended in the product information) to assess the objectives of the study. However, the low proportion of subjects completing the study and the likelihood that those subjects could have differed in risk factors for study endpoints when compared with those who completed the observation period may limit the generalizability of the findings to the RR-MM population and should be taken into account when applying these results.


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Discussion/Conclusions:The demography and baseline disease characteristics of the study population were consistent with the expected pattern of the general RR-MM population.

Thirty-one percent of subjects had grade 3/4 neutropenia in this study. This incidence was similar to the percentages of subjects treated with lenalidomide and dexamethasonein the registrational Phase 3 studies who had grade 3/4 neutropenia, as described byDimopoulos et al, 2007 (29.5%) and Weber et al 2007 (41.2%), even though the median age of the observational group (70 years) was considerably higher than the median age (63 and 64 years, respectively) in the registrational studies. The observed incidence of grade 3/4 neutropenia in this study was also similar to, but numerically lower than the 51% incidence rate reported in the smaller (n = 63) Spanish cohort of the lenalidomide expanded-access study (Alegre et al, 2010).

The median time to first grade 3/4 neutropenia (9 weeks) was much longer than the usually observed time (5-9 days) in the classical cytotoxic chemotherapy setting. The late occurrence of neutropenia (> 10% incidence in cycle 11) and the observed low overall incidence of FN (3%) altogether suggest that the neutropenia management strategy could be different with lenalidomide compared with the FN risk based primary prophylaxis recommendations reported in the international guidelines for the use of G-CSFs with chemotherapy. This is further supported by a specific recommendation published as a consensus statement of experts on management of neutropenia in MMstating that “Reactive G-CSF treatment is indicated when patients undergoing low-risk chemotherapy experience grade 3/4 neutropenia. If ANC restores to > 1000 cells/mL, therapy can be resumed with no dose modifications. In case of persistence of severe neutropenia, treatment should be delayed until ANC reaches > 1000 cells/mL, and dose reductions are necessary.” (Palumbo et al 2012).

Standard schedules of lenalidomide and dexamethasone were prescribed most commonly in the study. In alignment with the recommended starting dose for lenalidomide treatment of multiple myeloma as stated in the product information, the majority of subjects were initially prescribed treatment with 25 mg of lenalidomide. A total of 88 subjects (44%) experienced at least 1 lenalidomide dose interruption, with neutropenia being the primary reason for dose interruption in 5 (3%) subjects. Neutropenia was also found to be the primary reason for dose reductions in 4 (2%) subjects. There were 127 subjects (64%) who experienced at least 1 dose delay.

G-CSF was administered to 46 subjects (23%) during the 12-month observational period, with a median time to first G-CSF administration of 8.0 weeks. This result was similar to the results of the phase 3 study described in Dimopoulos et al, 2007 (21%).The maximum value of the length of daily G-CSF administration for filgrastim and lenograstim exceeded 140 days in some subjects. Variation in the recording of G-CSF use by site staff may have contributed to those values. For example: Some sites recorded each day of administration as a separate log line in the eCRF while other sites recorded only the start and end date of the administration. There was no defined place in the eCRF to add the description of whether G-CSF administration occurred every day or intermittently between start and end date. These inconsistencies in G-CSF data collection cause the resulting summary data for average length of use to be difficult to interpret. It is noteworthy that evidence is available to confirm long-term administration of daily G-CSFs in an ongoing, but not necessarily consecutive, daily format for most subjects.

No adverse drug reactions, serious adverse drug reactions, product complaints, or other safety events to any Amgen products were reported.


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Reference ListAlegre A, Oriol-Rocafiguera A, Garcia-Larana H, et al. Safety, efficacy, and quality-of-life study of lenalidomide plus dexamethasone in previously treated patients with multiple myeloma: The Spanish Experience. [abstract] Blood. 2010; Abstract 3045.

Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Eng J Med. 2007;357(21):2123-2132.

Dimopoulos MA, Hussein M, Swern AS, Weber D. Full dose of lenalidomide for 12 months followed by a lower maintenance dose improves progression-free survival in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2009;114(22):2874. Abstract 2874.

Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36:842-854.

Greipp PR, San Miguel JF, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412-3420.

Knop S, Gerecke C, Liebisch P, et al. Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood. 2009;113(18):4137-4143.

Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516-2520.

Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3-9.

Palumbo A, Blade JP, Boccadoro M, et al. How to manage neutropenia in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012;12(1):5-11.

Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108(10):3458-64.

Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol. 2009;27(34):5713-9.

Wang M, Dimopoulos MA, Chen C, et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood. 2008;112(12):4445-4451.

Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 200�;357(21):2133-2142.


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