HOVON 49 MM Version: 5 October 2005

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1 Randomized phase III study in elderly patients with a multiple myeloma on the value of Thalidomide added to Melphalan plus Prednisone. A phase III study PROTOCOL Study Coordinators : P.W. Wijermans M.R. Schaafsma Statistician : W.J. Graveland Datamanager : M.M.C. Steijaert Registration : HOVON Data Center University Hospital Rotterdam - Daniel P.O.Box AE ROTTERDAM The Netherlands tel fax First version : October 2000 Final version : 9 April 2002 Date of activation : 1 August 2002 Approved : CKTO , 25 June 2002 METC Ziekenhuis Leyenburg, 15 July 2002 Adjustment : 9 December 2002, not (yet) submitted for approval Page 1 of 51

2 1 Scheme of study Multiple Myeloma Salmon & Durie stage Ib, II or III age > 65 years Arm A 3 cycles Melphalan/Prednisone R Arm B 3 cycles Melphalan/Prednisone + Thalidomide NR evaluation evaluation NR 5 cycles Melphalan/Prednisone 5 cycles Melphalan/Prednisone + Thalidomide evaluation plateau phase evaluation still improvement of disease still improvement of disease continue treatment continue treatment evaluation every 2 nd cycle evaluation every 2 nd cycle plateau phase Arm A Arm B plateau phase Off protocol treatment Thalidomide until relapse/progression Off protocol treatment Follow up Follow up Page 2 of 51

3 2 Table of contents Page 1 Scheme of study Table of contents Synopsis Investigators and study administrative structure Cytogenetic review Introduction Multiple myeloma Melphalan and Prednisone Thalidomide Bisphosphonate therapy Study objectives Study design Study population Eligibility for registration Inclusion criteria Exclusion criteria Treatments Induction therapy with Melphalan and Prednisone Special management orders in conjunction with Melphalan and Prednisone Thalidomide therapy Special management orders in conjunction with Thalidomide Bisphosphonates Recommended treatment after progression End of protocol treatment Required clinical evaluations Time of clinical evaluations Medical history Physical examination Hematology Blood chemistry Immunochemistry Bone marrow Specific investigations Additional investigations Cytogenetic analysis Evaluation of response Quality of life assessement Toxicities Reporting serious adverse events Endpoints Page 3 of 51

4 15 Forms and procedures for collecting data CRF s and schedule for completion Registration and randomization Registration and randomization for induction treatment Statistical considerations Patient numbers and power considerations Statistical analysis Efficacy analysis Toxicity analysis Additional analyses Interim analysis and safety monitoring Data and safety monitoring board Statistical analysis of the quality of life assessement Ethics Independent ethics committee or Institutional review board Ethical conduct of the study Patient information and consent Trial insurance Publication policy Glossary of abbreviations References Appendices A. Diagnostic Criteria Multiple Myeloma according to Salmon & Durie B. Response Criteria for Multiple Myeloma C. Common Toxicity Criteria D. ZUBROD-ECOG-WHO Performance Status Scale E. NYHA* scoring list F. Patiënteninformatie G. Quality of life questionnaire Page 4 of 51

5 3 Synopsis Study phase Phase III Study objectives Evaluation of the effect of Thalidomide added to the standard induction therapy with Melphalan and Prednisone in myeloma patients. Patient population Patients with multiple myeloma, previously untreated, Salmon & Durie stage IB, II and III, age > 65 years Study design Prospective, multicenter, randomized Duration of treatment (minimum of) 8 cycles of Melphalan and Prednisone + / - Thalidomide until disease progression. Number of patients 420 Adverse events Adverse events will be documented if observed, mentioned during open questioning, or when spontaneously reported. Serious adverse events will be reported immediately Planned start and end of Start of recruitment: beginning of 2002 recruitment End of recruitment: Page 5 of 51

6 4 Investigators and study administrative structure Responsibility Name Affiliation/Address Study Coordinators P.W. Wijermans M.R. Schaafsma Leyenburg Hospital, The Hague Medical Spectrum Twente, Enschede Writing Committee A.J. Croockewit University Hospital St. Radboud, Nijmegen P.C. Huijgens VU medical center, Amsterdam J.C. Kluin-Nelemans University Hospital Groningen H.M. Lokhorst University Hospital Utrecht E.C.M. van Pampus University Hospital Maastricht M.H.J. van Oers Academic Medical Center, Amsterdam K.J. Roozendaal OLVG Amsterdam M.R. Schaafsma Medical Spectrum Twente, Enschede P. Sonneveld Erasmus Medical Center E. Vellenga University Hospital Groningen P.W. Wijermans Leyenburg Hospital, The Hague S. Wittebol Eemland Hospital, Amersfoort Statistician W.J. Graveland HOVON Data Center, Rotterdam Datamanagement M.M.C. Steijaert HOVON Data Center, Rotterdam Quality of life HOVON Data Center, Rotterdam Serious Adverse Events (SAE s) notification HOVON Data Center fax: Page 6 of 51

7 4.1 Cytogenetic review Each cytogeneticist, responsible for the cytogenetic analysis of the multiple myeloma patients in a hospital will be notified automatically by of the registration of a patient from that hospital in the study. A filled out cytogenetic form together with 2 representative karyotypes and a copy of the original cytogenetic report is requested to be sent within 3 months to the HOVON Data Center for central review. 5 Introduction 5.1 Multiple myeloma Multiple myeloma is a malignant proliferation with an incidence of about 7 per people per year 1,2 of which the majority of patients is older than 65 years at the time of diagnosis 1,3. In most patients the malignant plasmacell proliferation causes bone destruction, bone marrow suppression, impairment of normal immunoglobuline synthesis and sometimes renal failure. This leads to a characteristic clinical situation often with a rather high morbidity. For decades, Melphalan in combination with Prednisone has been the keystone of therapy. However the response duration is rather short and the median survival for elderly patients is about 3 years 4. Many trials with combination chemotherapy have been performed but in none of them any improved outcome as compared to the combination of Melphalan and Prednisone has been documented 5, Melphalan and Prednisone Melphalan and Prednisone are the most effective drugs in patients with multiple myeloma 5,6. In younger patients high-dose chemotherapy may lead to a better response rate and to a better overall survival 7,8, but this therapy can not be given to patients over the age of 65 years. In the HOVON 16 study good experience was obtained with Melphalan 0.25 mg per kg and Prednisone 1 mg/kg for 5 days every 4 weeks with a number of cycles of at least 8, or more when a response was still ongoing. In the HOVON 36 we studied if higher doses of Melphalan intravenously given together with Dexamethason was more active in this group of elderly patients. However this study had to be stopped due to toxicity seen in the intensive arm. Page 7 of 51

8 5.3 Thalidomide Thalidomide was originally prescribed for sleep disturbances and for morning sickness. It was withdrawn after it became clear that it had a major teratogenetic effect. However for some diseases like M. Behcet, GVHD en erythema nodosum leprosum it remained a valuable therapeutic option 9. Recently an antitumor activity was found and Thalidomide was tested in patients with multiple myeloma It is now clear that it has an antimyeloma effect in one third of therapy-refractory myeloma patients. In the initial study of Singhai et al 10 the starting dose was 200 mg/day, with dose escalation of 200 mg every 2 weeks to a maximum of 800 mg/day. In those patients 30% had mild to moderate side effects, such as constipation, somnolence, neuropathy, rash, weakness and fatigue, while 10% had severe side effects. The side effects were most frequently seen in the patients treated with the higher doses of Thalidomide. Most probably, doses up to 800 mg are not more effective than lower doses. In patients responding to Thalidomide the M-protein levels began to drop in the first weeks of therapy, while using 200 or 400 mg/day, suggesting that the higher doses were not necessary for inducing a response. Recent data confirm that lower doses of Thalidomide ( mg/day) are indeed effective 14,15. The exact mechanism of action of Thalidomide is unknown although originally anti-angiogenesis was considered 16, it seems that Thalidomide can stimulate the apoptosis of the pathologic plasma cell Bisphosphonate therapy It is clear that bisphosphonates do have an influence on myeloma bone disease. Both APD intravenously and Clodronate orally have shown improvement of pain and bone lesions. Bisphosphonates are at this moment considered standard treatment in multiple myeloma Study objectives To study the efficacy of the addition of low dose Thalidomide to the Melphalan + Prednisone therapy in previously untreated myeloma patients, as measured by the event free survival. Events are induction failure, disease progression and death from any cause To evaluate the response rate, overall survival and progression free survival To assess the safety and toxicity of the addition of Thalidomide to the combination therapy with Melphalan and Prednisone. To assess the effect of the addition of Thalidomide on quality of life. Page 8 of 51

9 7 Study design Details of all treatments (dose and schedule) are given in The study is a phase III, open labelled, multicenter study that compares the standard therapy of Melphalan + Prednisone (MP) with Melphalan + Prednisone + Thalidomide. Patients with multiple myeloma, meeting all eligibility criteria (see 8.1) will be randomized on entry between: Arm A: Melphalan + Prednisone Arm B: Melphalan + Prednisone + Thalidomide. 8 Study population 8.1 Eligibility for registration All eligible patients have to be registered and randomized before start of treatment (see 16.1) Inclusion criteria Patients with a confirmed diagnosis of multiple myeloma stage Ib, II or III according to the Salmon & Durie criteria (see appendix A); Age > 65 years; WHO performance status 0-3 (see appendix D); Measurable tumorparameter (M-protein or Bence Jones proteïnuria); Written informed consent Exclusion criteria Known intolerance to Thalidomide; Systemic AL amyloidosis; Polyneuropathy; Severe cardiac dysfunction (NYHA classification II-IV, see appendix E) ; Severe pulmonary dysfunction; Significant hepatic dysfunction (serum bilirubin 30 µmol/l or transaminases 2.5 times normal level), unless related to myeloma; Renal failure with dependency on dialysis; Patients with active, uncontrolled infections; Page 9 of 51

10 Pre-treatment with cytostatic drug or alpha interferon; Patients known to be HIV-positive; Patients with a history of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma; 9 Treatments 9.1 Induction therapy with Melphalan and Prednisone All patients will receive 8 cycles of Melphalan 0.25 mg/kg per day for 5 days and Prednisone 1 mg/kg per day for 5 days regardless of pre-existing cytopenia. Therapy cycles will be given every 4 weeks unless the bloodcell count does not allow this (see for dose modification or therapy delay). Agent Dose/day Route Days Melphalan 0.25 mg/kg p.o 5 days Prednisone 1 mg/kg p.o 5 days After cycle 3, 6 and 8 a response evaluation will take place. Non responders will be taken off protocol treatment after 3 cycles of therapy. If after 8 cycles a plateau-phase is reached therapy can be stopped. (Please note Thalidomide (50 mg/day) will be continued until disease progression). If after 8 cycles a patient still shows improvement of the disease, therapy will be continued until a plateau phase has been reached and this will be evaluated every second cycle. If progression occurs during Melphalan + Prednisone therapy the patient is taken off protocol treatment but will be followed until death Special management orders in conjunction with Melphalan and Prednisone During the first cycle Melphalan will always be given in a 100% dose, independently of the observed blood cell count. The therapy cycles will be given every 4 weeks unless the blood cell counts have not reached the preexisting values. The dose modification rules are as follows: If pre-existing values for leucocytes and platelets are reached or if leucocytes 3.0 x 10 9 /l and platelets 100 x 10 9 /l, the next cycle can be given without dose modification of Melphalan. If leukocytes and/or platelets < pre-existing values and leucocytes < 3.0 x 10 9 /l and/or platelets < 100 x 10 9 /l therapy will be postponed for one week. If after one week: Page 10 of 51

11 Leucocytes (x 10 9 /l) Platelets (x 10 9 /l) Melphalan pre-existing value or 3.0 and pre-existing value or % < pre-existing value and < 3.0 and/or < pre-existing value and <100 but both leucocytes 2.0 x 10 9 /l and platelets 50 x 10 9 /l < pre-existing value and < 2.0 and/or < pre-existing value and < 50 50% postpone and start at 50% when these values are reached If after a delay of 4 weeks no recovery is observed bone marrow investigation is necessary to look for progression, bone marrow hypoplasia or myelodysplasia. In case of progression or myelodysplasia the patient will go off protocol treatment In case of a hypoplastic bone marrow therapy should be continued without Melphalan. There will be no dose modification of Prednisone. Supportive care with G-CSF is allowed but the above rules for dose modification need to be followed. 9.2 Thalidomide therapy Patients randomized to receive Thalidomide (patients randomized to arm B) will receive this from day 1 onwards until disease progression. Thalidomide dose will start at 200 mg per day orally and will be continued during the chemotherapy phase. Maintenance therapy is started 4 weeks after the last cycle of Melphalan and Prednisone. In order to reduce the risk of Thalidomide-induced polyneuropathy, the dose of Thalidomide in the maintenance phase is reduced to 50 mg daily. Agent Dose/day Route Days Thalidomide (in combination with 200 mg p.o Until 4 weeks after the last cycle of Melphalan and Prednisone Melphalan and Prednisone) Thalidomide (maintenance therapy) 50 mg p.o. Until disease progression Page 11 of 51

12 9.2.1 Special management orders in conjunction with Thalidomide In case of side effects of Thalidomide dose modification will be tried starting with a decrease of Thalidomide towards 50% of the given dose. Thus when 200 mg is given the new dose will be 100 mg. No doses lower than 50 mg are given. Otherwise Thalidomide therapy will be stopped. In case of (the suspicion of ) polyneuropathy Thalidomide will be stopped until neurologic investigation has ruled out this diagnosis. When Thalidomide during maintenance is interrupted for more than 6 weeks, it is regarded as end of Thalidomide maintenance and the patient will go off protocol treatment. 9.3 Bisphosphonates It is to the physicians choice to give either APD 90 mg i.v. every 4 weeks or clodronate orally (2 x mg/day). Bisphosphonates have to be given throughout the study. 9.4 Recommended treatment after progression In case of progression of the disease in patients treated in arm A (without Thalidomide), Thalidomide can be given as second line therapy eventually followed by VAD or CVP as third line therapy In case of disease progression in patients already treated with Thalidomide VAD therapy is advised as second line therapy. When the general condition (comorbidity) does not allow VAD as second line therapy than monotherapy with dexamethason can be a therapeutic option. 10 End of protocol treatment Reasons for going off protocol treatment are: 1. no response after 3 cycles of Melphalan and Prednisone 2. completion of protocol treatment (i.e. plateau phase reached in arm A) 3. progression/relapse 4. myelodysplasia 5. excessive toxicity 6. death 7. no compliance of the patient 8. protocol violation Page 12 of 51

13 11 Required clinical evaluations Aim of the clinical evaluation at entry is to determine the stage of disease according to Salmon & Durie (see appendix A) and to determine the presence of adverse prognostic factors. Aim of the clinical evaluation during treatment and follow up is to determine response, toxicities and eligibility for further treatment. Evaluation of response is described in paragraph 11.2 and appendix B. Before start of each treatment cycle, routine investigations like blood cell count and renal function will be performed according to local policy Time of clinical evaluations At entry: before start of treatment After cycle 3 MP: approximately 3 weeks after start of cycle 3 After cycle 6 MP: approximately 3 weeks after start of cycle 6 After cycle 8 MP: approximately 3 weeks after start of cycle 8 After every 2 nd cycle MP thereafter: approximately 3 weeks after start cycle Maintenance and follow up: every 2 months until progression, thereafter every 6 months routine follow up evaluations Required investigations at entry, during treatment and during follow up: At entry after cycle 3 after cycle 6 after cycle 8 1) (end MP therapy) maintenance and follow up Medical history X X X X X Physical examination X X X X X Hematology X after each cycle X Blood chemistry X X X X X Immunochemistry X after each cycle X Bone marrow Bone marrow aspirate X after last cycle X 2) Bone marrow biopsy X after last cycle Specific investigations β 2-microglobulin X X X X X Creatinin clearance o.i. o.i. o.i. o.i. Skeletal survey X X X 3) X-thorax X ECG X Additional investigations o.i. o.i. o.i. o.i. Cytogenetic analysis X Quality of Life X X X X 4) o.i. on indication 1) at ongoing response after cycle 8 (see 9.1) evaluation after every 2 nd cycle, with the exception of QoL 2) once a year, twice a year if non-secretory myeloma 3) once a year 4) at 12, 18 and 24 months after randomization Page 13 of 51

14 Medical history Standard medical history, with special attention for: WHO performance status Bone pain Infections Bleeding tendency Obstipation Polyneuropathy Only at entry: Occupational history Prior and present other diseases Antecedent hematological or oncological diseases Previous chemotherapy or radiotherapy Physical examination Standard physical examination including body weight and height, with special attention for: Macroglossia Kyphoscoliosis Orthostatic hypotension Carpal tunnel syndrome Polyneuropathy or other neurologic symptoms Edema Infections Bleeding tendency Hematology Hemoglobin Leukocyte count, differential count Platelets Blood chemistry Creatinin Liver enzymes Total bilirubin Page 14 of 51

15 Alkaline phosphatase Total proteins Albumin LDH CRP Calcium Phosphate Sodium Potassium Uric acid Immunochemistry Quantitative serum M-protein, including immunofixation to confirm CR Quantitative urine M-protein in 24 hrs urine, including immunofixation to confirm CR Only at entry: Qualitative serum M-protein Qualitative urine M-protein (Bence Jones) Bone marrow Bone marrow biopsy Bone marrow aspirate at entry for:! Morphology! Cytogenetic analysis (see ) Bone marrow aspirate at end of induction treatment and during maintenance / follow up for:! Morphology Specific investigations Serum β 2 -microglobulin Creatinin clearance if increased serum creatinin Radiographic skeletal survey including skull, pelvis, vertebral column and long bones X-Thorax ECG Page 15 of 51

16 Additional investigations Only on clinical indication: Survey for exclusion of AL amyloidosis Cardiac ejection by scintigraphy or cardiac echo Bleeding time Cryoglobulins, cold agglutinins Serum viscosity, funduscopy Spirometry Cytogenetic analysis Conventional cytogenetic analysis should be performed in all patients at diagnosis. Additional FISH analysis for chromosome 13 deletions should also be performed. Conditions for FISH will be standardized by the HOVON Cytogenetic Working Party Evaluation of response Response will be evaluated according to EBMT, IBMTR and ABMT criteria (see appendix B). Time points are after the third, sixth and eight MP course and every 2 nd cycle thereafter if applicable. During maintenance and follow up disease status will be evaluated every 2 months until progression 11.3 Quality of life assessement Quality of life (QoL) will be assessed by means of the following questionnaires: EORTC QLQ-C30 questionnaire (see appendix G). The QLQ-C30 is a multidimensional, cancer-specific quality-of-life questionnaire developed by the European Organization for Research and Treatment of Cancer (EORTC) Study Group on Quality of Life for use in international clinical trial settings. The questionnaire is designed for use with a wide range of cancer patient populations, irrespective of specific diagnosis. The QLQ-C30 includes 5 functional scales (physical, role, emotional, social and cognitive functioning), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status/quality of life scale and a number of single items assessing additional symptoms (dyspnoea, sleep disturbance, constipation and diarrhea) and perceived financial impact. For the majority of the QLQ-C30 items a 4-point Likert-type response scale is used. Exceptions are the items for the global quality of life scale (where a 7-point scale is used). All subscale and Page 16 of 51

17 individual item responses are linearly converted to 0 to 100 scales. For the functional and global quality of life scales, a higher score represents a better level of functioning. For the symptom scales and items, a higher score reflects a greater degree of symptomatology. EORTC QLQ-MY24 This questionnaire measures specific aspects of multiple myeloma, i.e. specific pain complaints. Collection of the QoL questionnaires will be performed in the following manner: A QoL coordinator will be assigned in each particpating center. During informed consent the patient will be asked to participate in the quality of life part of this study. As soon as a patient is randomized at the HOVON Data Center (HDC), the QoL coordinator is notified by . Patient subject number, date of birth, date of randomization are mentioned in this . The baseline questionnaire, including a pre-stamped reply envelope and an address sheet, will be handed over to the patient by the QoL coordinator/local investigator. Name and address information will be sent together with this first questionnaire to HOVON Data Center, if the patient and the hospital consent with this. The following QoL questionnaire will be sent at the correct date to the patient by HDC. A prestamped reply envelope will be added to the questionnaire to facilitate returning the questionnaire by the patient. In this manner we foresee a minimum of questionnaires getting lost or not being filled in at all. Furthermore, questionnaires will only be sent if the previous one is received or if an explanation (other than death or refusal) for not received questionnaires is known. If any hospital and/or local investigator and/or local ethical committee refuses to transmit the patients address information to HOVON Data Center (based on privacy arguments, although the patient is informed about this procedure) then the QoL questionnaire collection is left to the responsibility of the QoL coordinator. The coordinator will be reminded in time to hand over the questionnaire at the correct date. If a QoL questionnaire has not been received by HOVON Data Center within 14 days of the expected date, a reminder/request will be sent to the local QoL coordinator to collect and send in the questionnaire. Quality of life will be measured:! at entry! after cycle 3, approx. at 3 months after start cycle 1! after cycle 8, approx. at 9 months after start cycle 1! at 12 months after start cycle 1! at 18 months after start cycle 1 Page 17 of 51

18 12 Toxicities All the chemotherapeutic agents used in the protocol cause pancytopenia and can induce septic or hemorrhagic complications. Side effects of Thalidomide are constipation, somnolence, neuropathy, rash, weakness and fatigue, which are more frequent with higher doses (400 mg and more). Thalidomide, especially when it is combined with Dexamethasone and Doxorubicin, may increase the risk on Deep Venous Thrombosis (DVT). DVT is considered a Serious Adverse Event (SAE), and accordingly any DVT must be reported to the HOVON Data Center within 48 hours of the initial observation of DVT (see paragraph 13). In case of DVT Thalidomide therapy should be stopped. Toxicities will be scored according to the NCI Common Toxicity Criteria, version 2.0 (Appendix C). 13 Reporting serious adverse events An Adverse Event (AE) is any untoward medical occurrence or experience in a patient or clinical investigation subject which occurs during or following treatment regardless of the causal relationship. This can include any unfavourable and unintended signs (such as rash or enlarged liver), or symptoms (such as nausea or chest pain), an abnormal laboratory finding (including blood tests, x-rays or scans) or a disease temporarily associated with the treatment. Serious Adverse Events (SAE) are defined as any undesirable experience occurring to a patient, whether or not considered related to the treatment. Adverse events which are considered as serious are those which result in: death a life-threatening event (i.e. the patient was at immediate risk of death at the time the reaction was observed) hospitalization or prolongation of hospitalization severe/permanent disability a congenital anomaly Note that any death, whether due to side effects of the treatment or due to progressive disease or due to other causes is considered as a serious adverse event. Unexpected Serious Adverse Events are those SAE s of which the nature or severity is not consistent with information in the relevant source documents. For a medicinal product not yet Page 18 of 51

19 approved for marketing in a country, a company s Investigator s Brochure will serve as a source document in that country. Reporting Serious Adverse Events During protocol treatment all deaths, all SAE s that are life threatening and any unexpected SAE must be reported to the HOVON Data Center by fax within 48 hours of the initial observation of the event. All details should be documented on the Serious Adverse Event and Death Report. In circumstances where it is not possible to submit a complete report an initial report may be made giving only the mandatory information. Initial reports must be followed-up by a complete report within a further 14 calendar days and sent to the HOVON Data Center. All SAE Reports must be dated and signed by the responsible investigator or one of his/her authorized staff members. At any time after the completion of protocol treatment, unexpected Serious Adverse Events that are considered to be possibly related to protocol treatment and ANY death (regardless the cause) must also be reported to the HOVON Data Center using the same procedure, within 48 hours after the SAE or death was known to the investigator. The investigator will decide whether the serious adverse event is related to the treatment (i.e. unrelated, unlikely, possible, probable, definitely and not assessable) and the decision will be recorded on the serious adverse event form. The assessment of causality is made by the investigator using the following : RELATIONSHIP UNRELATED UNLIKELY POSSIBLE PROBABLE DEFINITELY NOT ASSESSABLE DESCRIPTION There is no evidence of any causal relationship There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within a reasonable time after administration of the trial medication). There is another reasonable explanation for the event (e.g. the patient s clinical condition, other concomitant treatments). There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable time after administration of the trial medication). However, the influence of other factors may have contributed to the event (e.g. the patient s clinical condition, other concomitant treatments). There is evidence to suggest a causal relationship and the influence of other factors is unlikely. There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out. There is insufficient or incomplete evidence to make a clinical judgement of the causal relationship. Page 19 of 51

20 The HOVON Data Center will forward all reports within 24 hours of receipt to the study coordinator and the study central datamanager. The report of an SAE will be the signal for the central datamanager to ask the investigator or the responsible local datamanager to complete and send as soon as possible all relevant CRF s for the involved patient with details of treatment and outcome. It is of utmost importance that all SAE s (including all deaths due to any cause) are reported in a timely fashion. Patients without a report of an SAE are implicitly considered alive without SAE. This information will be used in monitoring the incidence of SAE s, the estimation of overall survival and monitoring of safety of experimental treatments 14 Endpoints Primary endpoint 1. Event free survival (i.e. time from registration to induction failure, death, progression or relapse whichever occurs first). 2. Response rate (CR or PR) Secondary endpoints 1. Quality of life 2. Toxicity of the combination therapy 3. Overall survival measured from time of registration. Patients still alive or lost to follow up are censored at the date they were last known to be alive. 4. Progression free survival measured from the time of achievement of PR (or CR) to date of relapse, progression or death from any cause (whichever occurs first). Page 20 of 51

21 15 Forms and procedures for collecting data 15.1 CRF s and schedule for completion LIST OF FORMS Form nr. Nr. of pages Title 1 1 Registration & Randomization Form 2 3 On Study Form 3 3 Cytogenetics Form 4 2 Melphalan/Prednisone Treatment Form 5 2 Melphalan/Prednisone response evaluation form 6 3 Thalidomide Maintenance Form 7 1 Off Treatment Form 8 3 Follow Up Form 9 1 Side Effects Form 10 1 Infection Report Form 11 1 General Comments Form Table for filling out forms Forms Registration & randomization X (X) On study X X (X) MP Treatment X X (X) (X) (X) Thalidomide Maintenance X (X) End of treatment X X (X) Follow up X (X) (x) fill out if necessary, see instructions Instructions for completion and sending in of the forms are specified in a separate document together with the forms. Page 21 of 51

22 In order to be able to closely monitor the occurrence of untoward events and detect a difference in failure rate between the two induction treatments (see 17.3) it is of utmost importance that the CRF s regarding induction treatment, especially for the first 100 patients, are sent in a timely fashion i.e. within one month of completion of the induction treatment. 16 Registration and randomization 16.1 Registration and randomization for induction treatment The patient should be registered immediately after diagnosis (on the basis of cytological examination of marrow and blood smears in the participating center), and before the start of chemotherapy. Patients need to be registered at the HOVON Data Center of the University Hospital Rotterdam - Daniel by phone call: or fax Monday through Friday, from 09:00 to 17:00 or via the Internet via TOP (Trial Online Process; A logon to TOP can be requested at the HOVON Data Center for participants. The following information will be requested at registration: 1. Protocol number 2. Institution name 3. Name of caller/responsible investigator 4. Patient s initials or code 5. Patient s hospital record number 6. Sex 7. Date of birth 8. Date of diagnosis of multiple myeloma 9. Planned date of start cycle Will the patient participate in the Quality of Life assessment? 11. Eligibility criteria All eligibility criteria will be checked with a checklist. Each patient will be given a unique patient study number. Patients will be randomized, stratified by center with a minimization procedure, ensuring balance within each stratum and overall balance. Patient study number and result of randomization will be given immediately by TOP or phone and confirmed by fax or . Page 22 of 51

23 17 Statistical considerations 17.1 Patient numbers and power considerations Based on previous studies we expect the following: Accrual rate: about 100 patients per year EFS at first five years from registration in the standard arm: 60%, 45%, 33%,25% and 15% For the calculation of the required number of patients to be entered in the study, the EFS from registration, as defined in paragraph 14, will be considered as primary endpoint. A relative hazard rate of 0.7 for arm B corresponds to an increase of EFS 1 from 60 % to 70 % and an increase of EFS 5 from 15 % to 27 %. For the detection of this difference with α = 0.05 (two-sided) and 80 % power, 252 events have to be observed. This number of events is expected to be reached after recruitment of 420 patients in about 4,5 years and an additional follow up after inclusion of the last patient of one year Statistical analysis All analyses will be according the intention to treat principle Efficacy analysis Main endpoint for the comparison of the two induction treatment arms will be EFS from registration as defined in paragraph 14. Secondary endpoints are response rate, overall survival from registration and progression free survival from PR / CR. Actuarial estimates of competing risks of failure (progression or death without progression) will be made for each treatment arm. Formal tests for the difference in EFS between the two treatment arms will be done with Cox regression analysis Toxicity analysis The analysis of treatment toxicity will be done primarily by tabulation of the incidence of side effects and infections with CTC grade 2 or more (Appendix C) by treatment arm and cycle. Actuarial competing risks estimates of probability of death will be split by cause of death where a difference will be made between death due to or after relapse or induction failure and death due to side effects of treatment, overall and separately by treatment arm and cycle. Page 23 of 51

24 Additional analyses Additional analyses involve the analysis of prognostic factors, especially β 2 -microglobulin and cytogenetic abnormalities especially chromosome 13 deletion with respect to response rate, EFS and OS from registration. Logistic and Cox regression analysis will be used for this purpose Interim analysis and safety monitoring One interim analysis is planned, primarily to guard against unfavourable results in the Thalidomide arm. Results of the interim analysis will be presented confidentially to an independent data and safety monitoring board (DSMB). Only if the DSMB recommends that the study should be stopped or modified the results will be made public to the principal investigators for further decisions. The main endpoint for the interim analysis is the failure rate. A patient counts as failure if the patient does not achieve a PR on protocol treatment, or if the patient progresses or dies during or after protocol treatment. This interim analysis is planned after 50 failures or 50 reported SAE s. This timepoint is expected to be reached after 19 months after the start of the study by an inclusion of 160 patients. In this interim analysis, a detailed report will be generated and presented to the DSMB. The report includes by treatment arm the number of entered patients and at that time evaluable patients, treatment given, the number of failures, failure types, actuarial estimates and incidence of SAE s and other side effects and infections (CTC grade). The DSMB is free in her public recommendations to the study coordinators and the confidential recommendations to the study statistician, but the following guidelines apply: 1. Primary purpose of the interim analyses is to guard against a higher failure rate in the Thalidomide arm compared to the control arm. A higher failure rate in the experimental arm with a P-value < 0.10 is a good reason to recommend the stopping of the trial or recommendations for modifications. 2. A benefit in terms of event free survival or overall survival in the experimental arm is in general no reason to recommend early stopping of the study, unless the associated P-value is very extreme (P < 0.001). The study will be closely and sequentially monitored before the interim analysis. That monitoring will be based on the reported SAE s which are not subjected to data delay. The difference in incidence of the number of patients with a SAE in both arms and the difference in incidence of the number of deaths in both arms are tested using the logrank test. We repeatedly test whether the incidence in the experimental arm is higher at a significance level of 0.10, adjusted for multiple Page 24 of 51

25 testing. If one of those incidences is significantly higher in the experimental arm an early report will be presented to the DSMB Data and safety monitoring board A Data and safety monitoring board will be installed before start of the study Statistical analysis of the quality of life assessement All patients with at least one follow-up QoL questionnaire will be included in the analysis. To evaluate the differences between the treatment groups with respect to the muli-item scales of the QLQ-C30, the repeated measures will be analysed using mixed ANOVA models. The single items in the QLQ-C30 will be analysed using (ordinal) logistic regression with random effects. The items concerning the diagnosis-specific symptoms will be summarized using the unweighted sumscore. The reliability and validity of this sumscore will be established using baseline data and, when sufficient, the effect of treatment on this sumscore will be evaluated using mixed ANOVA models. Special attention will be paid to the relation between response (i.e. serum M-protein level) and QoL. 18 Ethics 18.1 Independent ethics committee or Institutional review board The study protocol and any amendment that is not solely of an administrative nature will be approved by an Independent Ethics Committee or Institutional Review Board Ethical conduct of the study The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki (Edinburgh, Scotland, 2000) and the ICH-GCP Guidelines of 17 January Patient information and consent Written Informed consent of patients is required before randomization. The procedure, the risks and the opinions for post-induction therapy in multiple myeloma will be explained to the patient. Page 25 of 51

26 19 Trial insurance The HOVON insurance program covers all patients from participating centers in the Netherlands according to Dutch law (WMO). The WMO insurance statement can be viewed on the HOVON Web site Individual participating centers from outside the Netherlands have to inform the HOVON about the national laws regarding the risk insurance of patients participating in a study. If necessary HOVON will extend the insurance to cover these patients. Intergroup studies. The HOVON insurance program does not cover the risk insurance of patients from centers participating within another cooperative group taking part in an intergroup study. The other participating groups will cover the insurance of patients registered/randomized through their offices. 20 Publication policy The final publication of the trial results will be written by the Study Coordinator(s) on the basis of the statistical analysis performed at the HOVON Data Center. A draft manuscript will be submitted to the Data Center and all co-authors (and the sponsor, where applicable) for review. After revision by the Data Center, the other co-authors (and the sponsor), the manuscript will be sent to a peer reviewed scientific journal. Authors of the manuscript will include the study coordinator(s), the lead investigators of the major groups (in case of intergroup studies), investigators who have included more than 5% of the evaluable patients in the trial (by order of inclusion), the statistician(s), the HOVON datamanager in charge of the trial, and others who have made significant scientific contributions. Interim publications or presentations of the study may include demographic data, overall results and prognostic factor analyses, but no comparisons between randomized treatment arms may be made publicly available before the recruitment is discontinued. Any publication, abstract or presentation based on patients included in this study must be approved by the study coordinator(s). This is applicable to any individual patient randomized in the trial, or any subgroup of the trial patients. Such a publication cannot include any comparisons Page 26 of 51

27 between randomized treatment arms nor an analysis of any of the study endpoints unless the final results of the trial have already been published. Page 27 of 51

28 21 Glossary of abbreviations (in alphabetical order) AE AL APD BJ BM BUN Ca CKTO CR CRF CRP CTC DSMB DVT ECG ECOG EORTC EBMT EFS FISH GCP G-CSF GVHD HIV HOVON IBMTR ICH Ig IRB LDH LVEF METC MM MP M-protein MR NC NCI NYHA Adverse Event Amyloid Light-chain Pamidronaat Bence Jones Bone Marrow Blood Urea Nitrogen Calcium `Commissie voor Klinisch Toegepast Onderzoek (previously CKVO ) Complete Remission Case Report Form C-Reactive Protein Common Toxicity Criteria Data and Safety Monitoring Board Deep Venous Thrombosis Electrocardiogram Eastern Cooperative Oncology Group European Organisation for Research and treatment of Cancer European Group for Blood and Marrow Transplantation Event Free Survival Fluorescence In Situ Hybridisation Good Clinical Practice Granulocyte-Colony Stimulating Factor Graft Versus Host Disease Human Immunodeficiency Virus Dutch-Belgian Hematology-Oncology Cooperative Group International Bone Marrow Transplantation Registry International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use Immuun globulin Institutional Review Board Lactate Dehydrogenase Left Ventricular Ejection Fraction Medical Ethical review committee Multiple Myeloma Melphalan Prednisone Monoclonal protein Minimal Response No Change National Cancer Institute New York Heart Association Page 28 of 51

29 OS PD PO PR QOL QLQ SAE TOP VAD WHO WMO Overall Survival Progressive Disease Per Os Partial Response Quality of Life Quality of Life Questionnaire Serious Adverse Event Trial Online Process Vincristine, Doxorubicin (Adriamycin), Dexamethasone World Health Organization `Wet Medisch-Wetenschappelijk Onderzoek met mensen Page 29 of 51

30 22 References 1. Hjorht M. e.a. Impact of active and passive exclusions on the results of a clinical trial in multiple myeloma. Br. J. Haematol. 80: 55-61, Turesson I. Comparison of trends in the incidence of multiple myeloma on Malmo, Sweden, and other countries, New Eng. J. Med. 310: , Bergsagel D. The incidence and epidemiology of plasma cell neoplasms. Stem cells 1995; 13 suppl.2; Alexanian R, Dimopoulos M. The treatment of multiple myeloma. N. Engl. J. Med. 330: , Gregory W.M. e.a. Combination chemotherapy versus Melphalan and Prednisone in the treatment of multiple myeloma; an overview of published data. J. Clin. Oncol. 10: , Myeloma Trialists' Collaborative Group. Combination chemotherapy versus Melphalan plus Prednisone as treatment for multiple myeloma: an overview of 6633 patients from 27 randomized trials. J. Clin. Oncol. 126: , Attal M, Harousseau JL, Stoppa AM et al, for the the Intergroupe Francais du Myelome. A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 335: 91-97, Lokhorst HM, Sonneveld P, Verdonck LF. Intensive treatment for multiple myeloma: where do we stand? Br. J. Haematol. 106: 18-27, Sampaio EP, Kannen G, Miranda A, et al. The influence of Thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum. J. Infect. Dis. 168: , Singhai S, Mehta J, Desikan R, et al. Antitumor activity of Thalidomide in refractory multiple myeloma. New Engl. J. Med. 341: , Kneller A, Raanani P, Hardan I, et al. Therapy with Thalidomide in refractory multiple myeloma. The revival of an old drug. Br. J. Haematol. 108: , Juliusson G, Celsing F, Turesson I. et al. Frequent good partial remissions from Thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. Br J Haematol. 109(1):89-96, Rajkumar SV, Fonseca R, Dizpenzieri A, et al. Thalidomide in the treatment of relapsed multiple myeloma. Mayo Clinic Proc. 75: , Larkin M et al. Low-dose thalidomide seems to be effective in multiple myeloma. Lancet 354: 925, 1999 Page 30 of 51

31 15. Pini M, Baraldi A, Pietrasanta D, et al. Low-dose of Thalidomide in the treatment of refractory myeloma. Haematologica 85: , D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci 91: , Brooks PC et al. Intergrin αvß3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79: , Lahtinen R. et al. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet 340: , 1992 Page 31 of 51

32 Appendix A HOVON 49 MM Version: 5 October 2005 A. Diagnostic Criteria Multiple Myeloma according to Salmon & Durie DIAGNOSIS OF MULTIPLE MYELOMA Major criteria: 1. plasmacytoma (tissue biopsy) 2. > 30% plasma cells in bone marrow 3. monoclonal serum M-protein IgG > 35 g/l; IgA >20 g/l, or urine M-protein >1 g/24 hrs in the absence of amyloidosis Minor criteria: a. plasma cells in bone marrow > 10% but 30% b. monoclonal serum M-protein IgG 35 g/l, IgA 20 g/l, urine M-protein 1 g/24 hrs c. lytic bone lesions d. normal IgG <6 g/l or IgM <0.5 g/l or IgA <0.2 g/l Multiple Myeloma is diagnosed in case one of the following combinations of criteria is present: 1 + b or 1 + c or 1 + d 2 + b or 2 + c or 2 + d 3 + a or 3 + c or 3 + d a + b + c or a + b + d Page 32 of 51

33 Appendix A HOVON 49 MM Version: 5 October 2005 STAGING OF MULTPLE MYELOMA Stage I Low Tumor Mass all of the following: Hemoglobin > 6.2 mmol/l Ca 2+ < 2.65 mmol/l * IgG < 50 g/l IgA < 30 g/l Urine M-protein < 4 g/24 hrs Normal skeletal assessment or solitary plasmacytoma Stage II Intermediate Tumor Mass: Patients who qualify for neither Stage I nor III Stage III High Tumor Mass Any one of the following: Hemoglobin < 5.3 mmol/l Ca 2+ > 2.65 mmol/l * IgG > 70 g/l IgA > 50 g/l Urine M-protein > 12 g/24 hrs 3 lytic bone lesions on skeletal survey (bone scans are not acceptable) A B Normal renal function (creatinin < 177 µmol/l) Renal insufficiency (creatinin 177 µmol/l) * Correct the serum Ca 2+ by adding 0.02 mmol/l for every g/l albumin below 40 g/l Page 33 of 51

34 Appendix B HOVON 49 MM Version: 5 October 2005 B. Response Criteria for Multiple Myeloma Based on EBMT, IBMTR and ABMT criteria (British J. Haemat. 102: , 1998) Complete response (CR) requires all of the following: 1. Absence of the original monoclonal paraprotein (M-Protein) in serum and (10 x concentrated) urine by immunofixation, maintained for at least 6 weeks. 2. < 5% plasma cells in a representative bone marrow aspirate or otherwise in a bone marrow biopsy. Only in patients with non-secretory myeloma, bone marrow investigation must be repeated after an interval of 6 weeks to confirm CR. 3. No increase in size or number of lytic bone lesions (development of compression fractures does not exclude CR) 4. Disappearance of any soft tissue plasmacytoma. Patients in whom some, but not all, criteria for CR are fulfilled are classified as PR, providing the remaining criteria satisfy the requirements for PR. This includes patients in whom routine electrophoresis is negative but in whom immunofixation has not been performed. Partial response (PR) requires all of the following: 1. 50% reduction of serum M-protein concentration maintained for at least 6 weeks. 2. Reduction in 24 hrs urine M-protein either by 90% or to < 200 mg, maintained for at least 6 weeks. 3. In patients with non-secretory myeloma, 50% reduction in plasma cells in a representative bone marrow aspirate, or otherwise bone marrow biopsy, maintained for at least 6 weeks % reduction in size of soft tissue plasmacytoma. 5. No increase in size or number of lytic bone lesions (development of compression fractures does not exclude PR). Patients in whom some, but not all, criteria for PR are fulfilled are classified as MR, providing the remaining criteria satisfy the requirements for PR. Minimal response (MR) requires all of the following: 1. 25% reduction of serum M-protein concentration maintained for at least 6 weeks % reduction in 24 hrs urine M-protein, maintained for at least 6 weeks. 3. In patients with non-secretory myeloma, 25% reduction in plasma cells in a representative bone marrow aspirate, or otherwise bone marrow biopsy, maintained for at least 6 weeks. Page 34 of 51