Lahuerta, et al DOI: DOI: /JCO

Transcription

1 The following protocol information is provided solely to describe how the authors conducted the research underlying the published report associated with the following article: Depth of response in multiple myeloma: a comprehensive analysis in patients enrolled in four consecutive PETHEMA/GEM clinical trials Lahuerta, et al DOI: DOI: /JCO The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Author Center ( manuscriptguidelines.xhtml#randomized_phase_one_and_two) only specific elements of the most recent version of the protocol are requested by JCO. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of these protocol materials or due to any errors or omissions. Individuals seeking additional information about the protocol are encouraged to consult with the corresponding author directly.

2 1 CLINICAL TRIAL PROTOCOL Drugs: Bortezomib/Velcade and Thalidomide Protocol code: GEM05MENOS65 Study title: A randomized, open-label, national, multicenter, comparative phase III trial studying VBMCP-VBAD/Velcade versus Thalidomide/Dexamethasone versus Velcade /Thalidomide/Dexamethasone as induction therapy followed by high-dose chemotherapy treatment with autologous hematopoietic stem cell transplant followed by maintenance treatment with INTERFERON-alfa 2b versus Thalidomide versus Thalidomide/Velcade in patients 65 years of age or under with newly-diagnosed, symptomatic multiple myeloma (MM). Development phase: III Date of final protocol: January 26, 2005 Date of version 3.0 of the protocol: September 1, 2011 EudraCT number: Sponsor: Fundación PETHEMA Trial coordinators: Dr. J. Bladé, Hospital Clínico de Barcelona* Dr. JJ Lahuerta, Hospital 12 de Octubre, Madrid* Dr. Jesús San Miguel, Hospital Universitario de Salamanca* *On behalf of the Spanish Myeloma Group (GEM): José García Laraña. Hospital Ramón y Cajal. Madrid; Adrián Alegre. Hospital La Princesa. Madrid; Joaquín Díaz Mediavilla. Hospital Clínico. Madrid; Anna Sureda. Hospital Sant Pau. Barcelona; Juan José Lahuerta. Hospital 12 de Octubre. Madrid; Javier de la Rubia. Hospital La Fe. Valencia; Joan Bargay. Hospital Son Llatzer. Palma de Mallorca; Felipe de Arriba. H. Morales Messeguer. Murcia; Felipe Prósper. Clínica Universitaria de Navarra. CONFIDENTIAL PROPERTY OF FUNDACIÓN PETHEMA USE, DISTRIBUTION, OR PUBLICATION OF THIS DOCUMENT IS PROHIBITED WITHOUT THE EXPRESS CONSENT OF FUNDACIÓN PETHEMA.

3 2 PROTOCOL SIGNATURE PAGE Protocol GEM05MENOS65 Bortezomib/VELCADE -Thalidomide I have read this protocol and I agree to lead this study in accordance with the protocol stipulations and the Declaration of Helsinki. Signature of Fundación PETHEMA staff Dr. J. Bladé (Trial coordinator) Signature Date Dr. JJ Lahuerta (Trial coordinator) Signature Date Dr. J.F. San Miguel (Trial coordinator) Signature Date Dr. J. Díaz Mediavilla (PETHEMA representative) Signature Date

4 3 PROTOCOL SIGNATURE PAGE Protocol GEM05MENOS65 Bortezomib/VELCADE -Thalidomide I have read this protocol and I agree to lead this study in accordance with the protocol stipulations and the Declaration of Helsinki. Principal Investigator: Name Signature Date Co-Investigator: Name Signature Date Co-Investigator: Name Signature Date

5 4 LIST OF ABBREVIATIONS Abbreviation C M 20S BM CAT Cm CR CREC CRF CTC dl DP EBMT G-CSF GEM ICH IV Kg LVEF m 2 Mg Min Ml MM mm 3 Mmol MP MR MUGA NC NCI Ng Nmol NMRI NYHA OS PBSC PFS PR SAE TTP ITT Definition Degree Celsius Micromole Proteasome 20S subunit Bone marrow Computerized axial tomography Centimeter Complete response Clinical Research Ethics Committee Case Report Form (NCI) Common Toxicity Criteria Deciliter Disease progression European Bone Marrow Transplantation Granulocyte-colony stimulating factor Spanish Myeloma Group International Conference on Harmonization Intravenous Kilogram Left ventricle ejection fraction Meters squared Milligram Minute Milliliter Multiple Myeloma Cubic millimeter Millimole Melphalan-Prednisone Minor response Multiparametric Gate No change National Cancer Institute Nanogram Nanomol Nuclear Magnetic Resonance Imaging New York Heart Association Overall survival Peripheral blood stem cells Progression-free survival Partial response Serious Adverse Effect Time to progression Intention to treat

6 5 1. SUMMARY 1.0. Type of Application Clinical trial following the first trial authorized with an IND Sponsor information Fundación PETHEMA Tax ID number: G Representative: Dr. Joaquín Díaz Mediavilla Servicio de Hematología, 2 ª Sur Hospital Clínico San Carlos C/ Profesor Martín Lagos s/n Madrid Tel Fax: pethema@pethema.es 1.2. Title A randomized, open-label, national, multicenter, comparative phase III trial studying VBMCP- VBAD/Velcade versus Thalidomide/Dexamethasone versus Velcade /Thalidomide/Dexamethasone as induction therapy followed by high-dose maintenance chemotherapy treatment with autologous hematopoietic stem cell transplant followed by maintenance treatment with INTERFERON-alfa 2b versus Thalidomide versus Thalidomide/Velcade in patients 65 years of age or under with newly-diagnosed, symptomatic multiple myeloma Protocol code GEM05MENOS Trial coordinators Dr. J Bladé* Servicio de Hematología (Hematology Division) Hospital Clínico y Provincial de Barcelona Villarroel, Barcelona. Spain Tel Dr. JJ. Lahuerta* Servicio de Hematología Hospital 12 de Octubre Ctra. Andalucia, km 5, Madrid Tel

7 6 Dr. J.F San Miguel* Servicio de Hematología Hospital Universitario de Salamanca Paseo de San Vicente Tel: *On behalf of the GEM Group 1.5. Anticipated trial sites See Appendix Clinical Research Ethics Committees See Appendix Name and qualifications of clinical monitors Clinical monitor: Clinical Trial Monitors with the CRO Trial Form Support (TFS). Project Manager: Project Manager with the CRO Trial Form Support (TFS). Address: C/ Arturo Soria, 336 7ª Pl Madrid 1.8. Experimental and control drugs: dosing, dosage form, route of administration, and therapeutic group Experimental drug: Bortezomib/ Velcade Dosage form: Vials of sterile lyophilized powder to be reconstituted Route of administration: Intravenous Therapeutic group: Proteasome inhibitor. Other antineoplastic agents. ATC CODE: L01XX32 Experimental drug: Dosage form: Capsules Route of administration: Oral Therapeutic group: Angiogenesis inhibitors- anti-inflammatories Immunosuppressant. ATC CODE (provisional): L04AX Clinical trial phase Phase III

8 Clinical trial objectives The efficacy objectives of this study are: To analyze the efficacy (in terms of response rates) of the three chemotherapy regimens proposed as induction treatments. To analyze the efficacy (in terms of duration of response) of the three chemotherapy regimens proposed as maintenance treatment. Evaluate patients overall health status using patient reported outcomes (PRO), via a questionnaire completed by the patients themselves (EORTC QLQ-C30 and QLQ-MY24). Questionnaire QLQ-MY24 is a module containing 24 questions added to the QLQ-C30 specifically for patients with MM. The safety objectives of this study are: To evaluate the safety and tolerability of the three proposed chemotherapy induction regimens, as measured by the incidence of clinical and laboratory toxicities. Evaluate the safety and tolerability of the three proposed chemotherapy maintenance regimens, as measured by the incidence of clinical and laboratory toxicities. Evaluate the peripheral blood stem cell mobilization capacity of the three proposed chemotherapy induction treatment regimens for subsequent autologous transplant Design This protocol is a randomized, open-label, national, multicenter, comparative phase III study designed to compare, in the first instance, the efficacy and safety (in terms of response rates) of three induction chemotherapy regimens: VBMCP-VBAD/Velcade versus Thalidomide/Dexamethasone versus Velcade /Thalidomide/Dexamethasone. The second objective of this study is to evaluate the peripheral blood stem cell mobilization capacity of the three proposed induction treatment regimens in order to carry out autologous transplant. Finally, this study is designed to compare the safety and efficacy (in terms of duration of response) of three maintenance chemotherapy regimens: Interferon alfa-2b versus Thalidomide versus Thalidomide/Velcade. One hundred thirty (130) patients will be included in each treatment arm. The evaluations and scheduled visits will be carried out over three periods: Pre-treatment, Treatment, and Follow-up. The Pre-treatment period includes the screening visit in which patients will provide informed consent in writing to participate in the study. Following this, during the screening period which will take place 14 days prior to the baseline visit (days -14 to -1), patients will be evaluated to determine their eligibility.

9 8 Eligible patients will be included in the study and will be randomized in a 1:1:1 ratio to receive VBMCP-VBAD/Velcade (induction treatment Group A) or Thalidomide/Dexamethasone (induction treatment Group B), or Velcade / Thalidomide/Dexamethasone (induction treatment Group C). Patients assigned to induction treatment Group A will receive four cycles of chemotherapy consisting of alternating cycles of VBMCP-VBAD followed by two, 3-week cycles of Velcade administered two times per week (days 1, 4, 8, and 11) with a rest period of 10 days (days 12 to 21). The cycles of VBMCP will last 5 weeks and the cycles of VBAD will last 4 weeks. Patients assigned to induction treatment Group B will receive six, 4-week cycles consisting of Thalidomide administered daily and Dexamethasone in pulses (days 1-4 and 9-12). Patients assigned to induction treatment Group C will receive six, 4-week cycles each of Thalidomide administered daily, and Dexamethasone in pulses (days 1 to 4 and 8-11), and Velcade administered two times per week (days 1, 4, 8, and 11) followed by a 17- day rest period (days 12 to 28). After the induction treatment period (a minimum of four weeks after the last cycle of induction chemotherapy is administered), and in the absence of disease progression or unacceptable toxicity, all patients will undergo peripheral blood stem cell mobilization and collection with G-CSF followed by autologous transplant using melphalan as the conditioning regimen. Three months after this and independently of the treatment arm to which they were assigned, patients will again be randomized in a 1:1:1 ratio to receive Interferon alfa 2b (maintenance treatment Group M1) three times per week (Monday, Wednesday, and Friday), or Thalidomide (maintenance treatment Group M2), or Velcade /Thalidomide (maintenance treatment Group M3). Maintenance treatment Group M1 will receive Interferon alfa 2b three times per week (Monday, Wednesday, and Friday) for a maximum of three years, in the absence of disease progression or unacceptable toxicity. Maintenance treatment group M2 will receive Thalidomide daily for a maximum period of three years in the absence of disease progression or unacceptable toxicity. Maintenance treatment Group M3 will receive Thalidomide daily and one pulse of Velcade (days 1, 4, 8 and 11) every three months for three years in the absence of disease progression or unacceptable toxicity. Patients should be evaluated during the treatment period: 1) on day 1 of each induction cycle and approximately 1 month after completing the period of induction treatment, 2) three months post-transplant and 3) during maintenance treatment, monthly for the first year and every two months for the following two years. During the follow-up period patients will be evaluated every three months.

10 9 Safety will be evaluated through monitoring of all adverse events, physical examinations, vital signs, as well as hematometry and biochemistry tests. Response to treatment will be assessed according to EBMT criteria on day 1 of cycles 2 through 6 of the induction period, pre-transplant, three months post-transplant, and during maintenance treatment monthly for the first year, and every two months for two years thereafter. During the follow-up period patients will be evaluated every three months Disease under study Multiple Myeloma (MM) Primary endpoints The primary efficacy endpoints are: Response rates (with a focus on Complete Response (CR)) in the three proposed induction treatment groups for patients under 65 with newly-diagnosed, symptomatic MM Complete response rates after transplant in the different treatment groups Duration of response in each of the assigned maintenance treatment groups The secondary efficacy endpoints are: Evaluate the safety and tolerability of the three proposed induction and maintenance treatment regimens in patients under 65 with newly-diagnosed, symptomatic MM, as measured by the incidence of clinical and laboratory toxicities. Evaluate the peripheral blood stem cell mobilization capacity of each of the three proposed maintenance treatment regimens Survival: Overall survival, duration of response and time to progression in each treatment arm. Changes in the scoring of PROs in the applied questionnaires Study population Population under study Patients 65 years of age with newly-diagnosed, symptomatic multiple myeloma, based on standard criteria (see Appendix 7), who require treatment and who have not previously been treated. Total enrollment A total of 390 patients will be included, 130 assigned to each treatment arm.

11 Duration of treatment Patients included in the trial will receive induction chemotherapy for 24 weeks. Following this, mobilization and collection of peripheral blood stem cells and autologous transplant will take place. Maintenance treatment will be initiated three months after this and, in the absence of disease progression or unacceptable toxicity, will continue for three years Schedule and anticipated completion date It is anticipated that the trial will begin in June of 2005 and finish by June of The enrolment period will be approximately three and half years. Patients will receive induction treatment for 24 weeks, after which autologous transplant of PBSCs will take place. Maintenance treatment will be initiated three months after transplant and will last a maximum of three years.

12 11 2. TABLE OF CONTENTS 1. SUMMARY TABLE OF CONTENTS GENERAL INFORMATION Trial identification Protocol code Study title Type of clinical trial Description of the study products Sponsor Information Technical Director of Biological Samples Management Clinical Monitor Information Investigator Information Anticipated trial sites Anticipated trial duration Anticipated enrolment LIST OF TABLES IN THE TEXT INTRODUCTION AND STUDY RATIONALE SCIENTIFIC BACKGROUND Overview of Multiple Myeloma Current treatment for multiple myeloma STUDY RATIONALE AND DOSE SELECTION CLINICAL TRIAL OBJECTIVES Efficacy objectives Safety objectives TYPE OF CLINICAL TRIAL AND DESIGN Overall design Treatment plan Study procedures 25 POPULATION UNDER STUDY Inclusion criteria Exclusion criteria Anticipated enrolment Termination of treatment and /or participation in the trial Duration of patient participation DESCRIPTION OF THE STUDY TREATMENT Clinical trial products Preparation, care, and storage of the study drugs Administration of the study drugs and dosing schedule Dose adjustments and delays Assignment to treatment Packaging and labeling Concomitant treatment Permitted medications and supportive therapies Prohibited medication Compliance with treatment 67

13 12 8 DEVELOPMENT OF THE TRIAL AND RESPONSE ASSESSMENT Primary and secondary endpoints Tests to be conducted Response assessment Efficacy and safety measures Assessments of patient-reported outcomes (PRO) 74 9 ADVERSE EVENTS Minimum information Adverse Events (AE) Serious Adverse Events (SAE) Qualification of an adverse event Procedures for expedited reporting of serious adverse events ETHICAL ASPECTS Good clinical practice Ethical considerations Patient information and informed consent Patient confidentiality Compliance with the protocol Premature end to the trial ` Liability and insurance PRACTICAL CONSIDERATIONS Responsibilities of all trial participants Investigator Clinical Monitor Sponsor Audit Drug accountability Custody of records Publication of the trial results and use of information General regulations PETHEMA group conditions of publication STATISICAL ANALYSIS Estimation of the sample size Population to be analyzed Procedures for handling non-existent, unused, or spurious data Statistical methods Efficacy analysis ` Baseline comparisons Safety analysis Procedures for reporting deviations from the original statistical plan Preliminary analysis REFERENCES 94 APPENDIX 1: CASE REPORT FORM 99 APPENDIX 2: INVESTIGATOR S BROCHURE 100 APPENDIX 3: STANDARD OPERATING PROCEDURES 101 APPENDIX 4: SCHEDULE OF VISITS 102 APPENDIX 5: ECOG PERFORMANCE STATUS SCALE 111 APPENDIX 6: CALCULATION OF BODY SURFACE AREA AND CORRECTED CALCIUM 112

14 13 APPENDIX 7: MULTIPLE MYELOMA DIAGNOSTIC CRITERIA 113 APPENDIX 8: DISEASE RESPONSE CRITERIA 114 APPENDIX 9: INSURANCE POLICY 116 APPENDIX 10: CENTRALIZATION OF BONE MARROW SAMPLES 117 APPENDIX 11: PATIENT INFORMATION AND INFORMED CONSENT 118 APPENDIX 12: DECLARATION OF HELSINKI 133 APPENDIX 13: LIST OF SITES AND INVESTIGAORS 137 APPENDIX 14: LIST OF CRECs 139 APPENDIX 15: COMMON TOXICITY CRITERIA (CTC) Version

15 14 3. GENERAL INFORMATION 3.1. Trial identification Protocol code GEM05MENOS Study title A randomized, open-label, national, multicenter, comparative phase III trial studying VBMCP- VBAD/Velcade versus Thalidomide/Dexamethasone versus Velcade /Thalidomide/Dexamethasone as induction therapy followed by high-dose maintenance chemotherapy treatment with autologous hematopoietic stem cell transplant followed by maintenance treatment with INTERFERON-alfa 2b versus Thalidomide versus Thalidomide/Velcade in patients 65 years of age or under with newly-diagnosed, symptomatic multiple myeloma Type of clinical trial Clinical trial following the first trial authorized with an IND Description of the study products Bortezomib (Velcade) Vials of lyophilized powder to be reconstituted Intravenous administration Johnson & Johnson Pharmaceutical Research & Development (J&JPR&D) 50 mg hard capsules Oral administration Celgene Europe LTD 3.4. Sponsor information: Fundación PETHEMA Tax ID Number: G Representative: Dr. Joaquín Díaz Mediavilla Servicio de Hematología, 2ª Sur Hospital Clínico San Carlos C/ Profesor Martín Lagos s/n Madrid Tel: Fax: pethema@pethema.es

16 Technical directors of biological samples management Fisher Clinical Services UK Limited and Penn Pharmaceutical Services Ltd Clinical Monitor information Clinical monitor: Clinical Trial Monitors from CRO Trial Form Support (TFS, Project Manager: CRO Trial Form Support (TFS) Project Manager. Address: C/ Arturo Soria, 336 7ªPl Madrid 3.7. Investigator information See Appendix Anticipated trial sites See Appendix Anticipated trial duration Until June Anticipated enrolment A total of up to 390 patients List of tables in the text Table 1: Group A induction treatment regimen: Table 2: Group B induction treatment regimen: Table 3: Group C induction treatment regimen: Table 4: Management of patients with Velcade-related sensory neuropathy or neuropathic pain Table 5: Management of patients with Thalidomide-related sensory neuropathy

17 16 4. INTRODUCTION AND STUDY RATIONALE 4.1. SCIENTIFIC BACKGROUND Overview of Multiple Myeloma Multiple myeloma (MM) is a malignant disorder characterized by the proliferation of a single clone of plasma cells derived from B cells. It is the second most common blood cancer after non-hodgkin lymphoma, with an incidence rate of approximately 4 cases per 100,000 1 inhabitants per year. Multiple myeloma continues to be an incurable disease. As the disease progresses, it weakens resistance to infections and causes significant skeletal destruction (including bone pain, pathological fractures, and hyperkalemia), anemia, renal failure and, less frequently, neurological complications and hyperviscosity, all of which lead to morbidity and subsequent mortality 2. The 5-year survival rate for patients with multiple myeloma who receive conventional chemotherapy treatment is 29% 3,4. There is, therefore, an urgent need for new agents to treat this disease Current treatment for Multiple Myeloma Before alkylating agents were available, the median survival rate of patients with multiple myeloma (MM) was less than one year 5. With conventional chemotherapy treatment, essentially intermittent cycles of melphalan and prednisone (MP), a response rate of between 50 and 60% is achieved, with the median survival at 2 to 3 years 6. When it has been compared in prospective randomized studies, the aforementioned association of MP with combination chemotherapies (VBMCP protocol M2- association of ABCM or alternating cycles of VCMP/VBAP) 7-11, it has been observed that, in general, a greater number of objective responses are achieved with combination chemotherapy. However, a significant prolongation of survival was only observed in two studies 7,10. It has also been found that the duration of response is around one and a half years, whether melphalan or any other combination chemotherapies are used. 11. The results of a meta-analysis were recently published in which data was analyzed from 6,633 patients enrolled in 27 studies in which MP was compared to combination chemotherapy. This study showed that there was a higher rate of response with combination chemotherapy, without this translating into a significant prolongation of survival. 12. The number and quality of response has increased with high-dose melphalan chemotherapy (140 mg/m 2 ) 13 or VAD 14, however the average duration of response is less than two years. 13,14 This reality has promoted the introduction of chemotherapy treatments that are even more dose-intensive, followed by salvage therapy with hematopoietic stem cells, either allogeneic or autologous, in the hope of improving results that, even in younger patients, have not changed in the last two decades 15.

18 17 With respect to transplant, the allogeneic type would be the most suitable, as healthy stem cells are infused into the body through an IV with a potential anti-myeloma effect 16. However, limiting factors such as age and donor availability make this type of transplant only applicable to a minority of patients. While it is true that this procedure achieves a high rate of complete response (CR), mortality directly related to this procedure sits at around 30 to 50% 17,18. On the other hand, the rate of relapse in patients who achieve CR is around 50% at five years of followup 17, a fact which makes the proportion of patients who can be considered cured just 10 to 20% in the published series to date 17,18. With the aim of improving these results, the role of reducedintensity transplants or so-called mini-transplants is being investigated. Mini-transplants have achieved not only a 20% reduction in procedure-related mortality, they allow the age limit to be increased to 65, whereas with conventional allogeneic transplant the age limit is 55. Allogeneic transplantation with reduced-intensity conditioning regimens appears most promising in the intensification of patients in which CR has not been obtained with autologous transplant. 19 Dose-intensive treatment followed by salvage therapy using peripheral blood stem cells (autologous transplant) achieves a complete response rate of between 30 and 40%. Yet, procedure-related mortality is less than 5% 20,21. Achieving CR is the critical factor that will determine progression-free survival (PFS) and overall survival (OS) There are two studies randomized to autologous transplant and conventional chemotherapy treatment regimens that show that the rate of response, PFS, and OS were significantly greater with autologous transplant 27. As well, various case-control studies exist in which autologous transplant was shown to be superior to conventional chemotherapy 24,25, A cause for uncertainty when interpreting the results of studies such as these is, despite careful statistical analysis, there may be an inevitable bias in favor of patients who, in the end, undergo more dose-intensive treatment 31. In fact, there are three randomized studies in which no significant prolongation in overall survival has been observed with autologous transplant versus conventional chemotherapy. That said, it has come to be accepted that autologous transplant is superior to chemotherapy, to the point that high-dose chemotherapy is already considered the standard treatment for MM. Furthermore, the Intergroup Français du Myélome has reported that in patients who do not achieve a reduction in monoclonal component greater than 90% with a first autologous transplant, they do benefit from a second dose-intensive procedure in terms of progression-free survival and overall survival. On the other hand, the best results for patients who are at first resistant to chemotherapy treatment appear to be obtained when high-dose treatment followed by salvage therapy with hematopoietic stem cells is used during the first year 32,33. Given that there is a close relationship between achieving CR post-transplant and PFS and OS, it is extremely important to know the parameters that will determine said CR. In the experience of the MD Anderson Cancer Center and the Hospital Clínic of Barcelona, sensitivity to initial chemotherapy treatment measured by

19 18 M-component pre-transplant is the critical factor in obtaining CR post-transplant. Thus, in patients in whom the M-component is less than 10 g/dl, the probability of obtaining CR post-transplant is 50-70%, whereas in patients with M component greater than 20 g/l, it is less than 10%. From this, it can be deduced that the efficacy of the pre-transplant chemotherapy regimen is of crucial importance in determining the final outcome. In this sense, the introduction of two new drugs of proven efficacy in patients with resistant myeloma, such as thalidomide and bortezomib, into the initial pre-transplant regimens is of particular interest. Thalidomide in combination with dexamethasone produces a partial response rate that varies between 35% and 58% in patients with refractory myelomas. 34,35 Thalidomide s high degree of efficacy has encouraged its use in newly-diagnosed patients. In phase II studies, the association of dexamethasone and thalidomide has achieved partial response rates of between 64 and 72%, with a 16% complete response rate in one study 36,37. These values are superior to those referred to previously using conventional chemotherapy. There are two international randomized studies that compare the effectiveness of dexamethasone combined with thalidomide to dexamethasone alone, and preliminary results from one of these studies show that, at least in terms of response, the association of these two drugs is superior. 38. In the US, combination Thalidomide- Dexamethasone has become one of the most widely-used pre-transplant regimens. Bortezomib is a proteasome inhibitor, which has been shown to be a highly effective, single-drug therapy in patients with refractory myeloma (response rate of 35% with 10% CR) 39,41. In the context of refractory disease, a group in Arkansas studied the efficacy and toxicity of combining these two new drugs (Bortezomib and Thalidomide) with Dexamethasone, and confirmed that this combination was highly effective (70% overall response and 22% CR/nCR) with acceptable toxicity 42. Once again, these results have led to the study of bortezomib in newly-diagnosed patients. Bortezomib combined with Dexamethasone produces a response rate of 80% with a CR rate of 25% 43. A pilot study conducted by the MD Anderson group tested Velcade (bortezomib) combined with Thalidomide and Dexamethasone and achieved an 80% response rate with just two cycles, and with very low toxicity 44. These results also highlight the fact that the collection of hematopoietic stems cells was performed without any problems. Therefore, the addition of bortezomib to the dexamethasone/thalidomide regimen is feasible, and could contribute to further increasing the response rate in induction treatment. Finally, although the combination chemotherapy regimen based on alternating cycles of VBMCP/VBAD used previously by the GEM group in the GEM2000 study produced a high number of partial responses and around 10% rate of complete response, the sequential addition of bortezomib to reduce residual disease could contribute to an increase in the degree of response pre-transplant and,

20 19 finally, the rate of CR post-transplant, which ultimately is what translates into greater progressionfree survival and overall survival. With respect to the conditioning regimen for autologous transplant, the consensus is that melphalan 200 mg/m 2 is optimal in terms of efficacy and toxicity. The best standard for mobilization of peripheral blood stem cells in MM consists of the association of high-dose cyclophosphamide and G-CSF 21,22,28, or high-dose G-CSF alone 45. In a randomized study comparing cyclophosphamide/g-csf versus high-dose G-CSF alone, it was demonstrated that with the latter it is possible to achieve sufficient cellularity in order to carry out salvage therapy for two dose-intensive treatments 45. In addition, mobilization time and morbidity are lower than with cyclophosphamide plus G-CSF 46. Various studies have shown that, in general, maintenance treatment with interferon significantly prolongs the duration of response, but with no significant influence on survival. On the other hand, a meta-analysis carried out using individual data from 1,524 patients included in 12 clinical trials studying the efficacy of maintenance treatment with interferon showed that said treatment was associated with a modest, yet significant, prolongation of the duration of response as well as survival. 46. It is quite probable that maintenance treatment with interferon represents an important benefit for a minority of MM patients (5-10%) who have responded to treatment, while for the vast majority it is of no benefit. 47 Unfortunately, there are no parameters that allow us to predict which patients will benefit from maintenance treatment with interferon and which will not 47. Some studies have shown that the administration of glucocorticoids is associated with a significant prolongation of duration of response and/or survival Thalidomide and bortezomib are drugs that act on plasma cells through the microenvironment of the bone marrow, and it is highly probable that they are effective in maintaining response. In fact, there are several international studies which are researching this possibility, and the preliminary results of the Intergroupe Francophone du Myélome are promising with respect to Thalidomide maintenance treatment compared to abstaining from therapy or administration of pamidronate. Despite efforts to develop new drugs for patients with MM, MM continues to be an incurable disease. The majority of patients relapse, becoming refractory to treatment, and die from their disease. For these reasons, it is necessary to use new treatments in these patients STUDY RATIONALE AND SELECTION OF DOSES

21 20 Current treatment for newly-diagnosed MM patients under 65 is based on the initial administration of a limited series of chemotherapy cycles, followed by autologous transplant of peripheral blood stem cells, and then maintenance treatment. However, this treatment does not cure the disease as, eventually, all patients relapse. Advances in treatment for patients with MM should be directed at improving both initial chemotherapy as well as maintenance treatment. It is known that the efficacy of initial chemotherapy treatment is a key factor in achieving an optimal response post-transplant; therefore, the first objective in the treatment of MM should be to increase the rate of response to initial chemotherapy treatment. The second objective should be to design an optimal post-transplant maintenance treatment to control, and if possible eradicate, residual disease and prolong the duration of response. Initial chemotherapy regimens in MM patients under 65 include high-dose dexamethasone, chemotherapy cycles such as VAD (vincristine, Adriamycin, and dexamethasone) or with alkylating agents such as VBMCP (vincristine, BCNU, melphalan, cyclophosphamide, prednisone) or alternating cycles of VBMCP/VBAD (vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, Adriamycin, dexamethasone). Although the rate of complete response with these regimens is higher than that observed with the classic MP regimen (melphalan, prednisone) 5-10% vs. <4%--this does not translate into a significant prolongation of survival. Therefore, the addition of new drugs to the classic chemotherapy regimens such as Thalidomide and Velcade, whose efficacy has been demonstrated in patients with relapsed or refractory MM, may contribute to an increase in response and, eventually, to survival of patients under 65 with newly diagnosed MM. Thalidomide`s proven efficacy in the treatment of patients with relapsed or refractory multiple myeloma has resulted in its use as first-line treatment, usually in combination with other drugs such as dexamethasone, or even melphalan and prednisone. A clinic trial conducted by the Mayo Clinic evaluated the efficacy of combination Thalidomide/Dexamethasone in 50 patients with newly-diagnosed multiple myeloma, and observed a response rate of 92% (64% partial response or better). These results have been confirmed in a separate clinical trial conducted by the MD Anderson Cancer Center, which compared the combination Thalidomide/Dexamethasone to Dexamethasone alone. The preliminary results show a higher rate of response in the Thalidomide/Dexamethasone treatment arm. These data, together with scarcely-reported myelotoxicity, makes induction treatment regimens with Thalidomide and Dexamethasone treatments of choice prior to the collection of peripheral blood stem cells (PBSC) and autologous transplant. Velcade is the first proteasome inhibitor to be used in clinical practice. Its safety and efficacy have been demonstrated in clinical trials conducted with patients with relapsed or refractory MM

22 21 (response rate of up to 35% with 10% complete response). There is current data on the use of Velcade in combination with Thalidomide and Dexamethasone from a pilot study conducted with patients with newly diagnosed MM, whose results look very promising, with a high response rate (80%, with 22% of complete response with positive/negative immunofixation). This induction treatment regimen could, therefore, increase the rate of response to initial chemotherapy treatment in patients with MM, and help to improve the situation at the time of transplant. The efficacy of alkylating agents in the treatment of MM has been clearly demonstrated. However, due to its myelotoxic effects on stems cells, its use should be restricted if transplant will be carried out later. Our group has recently reported that alkylating agents do not affect the collection of stem cells when they are administered over short periods of time (2-3 cycles). With the current use of alternating cycles of VBMCP/VBAD, the rate of complete response is greater than 10% and, the use of additional cycles of Velcade could contribute to lowering minimal residual disease. This hypothesis would succeed in improving the rate of response to induction treatments prior to transplant and would ultimately contribute to improving overall survival in these patients. The optimal conditioning regimen for autologous transplant is melphalan at a dose of 200 mg/m 2, since it is effective and minimally toxic in patients with MM. With respect to maintenance treatment, there is no optimal treatment option. Interferon and/or corticosteroids have been used as treatment options for many years, and interferon is known to produce a modest prolongation in the duration of response and overall survival (approximately 6 months). Thalidomide and Velcade are new maintenance treatment options since, in addition to acting on the plasma cell tumor, they also act on the bone marrow microenvironment; the action of these drugs on the latter is the basis for their use as maintenance treatment for the purpose of reducing stimuli that may favor the development of tumor clones. Preliminary data from the IFM (Francophone Myeloma Intergroup of France) suggest that Thalidomide may be one of the most effective maintenance treatment drugs. With respect to assessing patients overall health status, in the Summit trial, patient reported outcomes (PRO) were evaluated using questionnaires completed by patients themselves (EORTC QLQ-C30 and QLQ-MY24, as well as FACIT-F) during the screening visit, on day 1 of cycles 3, 5 and 7 and at the end of the study. In patients who achieved CR and PR, an improvement was seen in overall quality of life, disease symptoms, pain, fatigue, and physical function compared to the situation at baseline. Therefore, an assessment of PROs using validated questionnaires would be important in this study, since they are a direct reflection of

23 22 the patient s view of their disease and treatment, and would help in evaluating the beneficial effects of treatment CLINICAL TRIAL OBJECTIVES Efficacy objectives The efficacy objectives of this study are: Analyze the efficacy (in terms of response rates) of the three chemotherapy regimens proposed as induction treatment. Analyze the efficacy (in terms of duration of response) of the three chemotherapy regimens proposed as maintenance treatment). Evaluate patients overall health status using patient reported outcomes (PRO), through questionnaires completed by the patients themselves (EORTC QLQ-C30 and QLQ- MY24). Questionnaire QLQ-MY24 is a module containing 24 questions added to the QLQ- C30 specifically for patients with MM Safety objectives The safety objectives of this study are: Evaluate the safety and tolerability of the three proposed chemotherapy induction regimens, as measured by the incidence of clinical and laboratory toxicities. Evaluate the safety and tolerability of the three proposed chemotherapy maintenance regimens, as measured by the incidence of clinical and laboratory toxicities. Evaluate the capacity of the three proposed induction treatment regimens to mobilize peripheral blood stem cells for subsequent autologous transplant

24 23 5. TYPE OF CLINICAL TRIAL AND DESIGN 5.1. Overall design This protocol is a national, multicenter, comparative, open-label, randomized study, designed in the first instance to determine the safety and efficacy (in terms of rate of response rate) of three chemotherapy induction regimens: VBMCP-VBAD/Velcade versus Thalidomide/Dexamethasone versus Velcade /Thalidomide/Dexamethasone. The second objective of this study is to evaluate the capacity of the three proposed induction treatment regimens to mobilize peripheral blood stem cells, in order to carry out autologous transplant. Finally, this study is designed to compare the safety and efficacy (in terms of duration of response) of three maintenance treatment regimens Interferon-alfa 2b versus Thalidomide versus Thalidomide/Velcade. In addition, the status of patients overall health will be evaluated, as determined by PROs using a questionnaire completed by the patients themselves (EORTC QLQ-C30 and QLQ- MY24). One hundred thirty (130) patients will be included in each treatment arm from the Spanish treatment sites belonging to the GEM Treatment plan Patients will be evaluated over the course of three periods: Pre-treatment, Treatment and Follow-up. The Pre-treatment period includes the screening visit in which patients will complete the informed consent form in order to participate in the study. Following this, during the screening period which will take place 14 days before the baseline visit (days -14 to -1), (except serology and the skeletal survey, which can be performed up to one month prior to the baseline visit), patients will be evaluated to determine their eligibility. Eligible patients will be included in the study and will be randomized in a 1:1:1 ratio to receive, during the Treatment Period, VBMCP- VBAD/Velcade (induction treatment Group A) or Thalidomide/Dexamethasone (induction treatment Group B), or Velcade /Thalidomide/Dexamethasone (induction treatment Group C). Patients assigned to induction treatment Group A will receive four cycles of chemotherapy consisting of alternating cycles of VBMCP-VBAD followed by two, 3-week cycles each of Velcade administered two times per week (on days 1, 4, 8, and 11), with a rest period of 10 days (days 12 to 21). The interval between cycles of VBMCP and VBAD will be five weeks, and there will be a four-week interval between cycles of VBAD and VBMCP. Patients assigned to induction treatment Group B will receive six, 4-week cycles of each one which will consist of

25 24 Thalidomide administered daily and Dexamethasone in pulses (on days 1-4 and 9-12). Patients assigned to induction treatment Group C will receive six, 4-week cycles of each one which will consist of Thalidomide administered daily, Dexamethasone administered in pulses (days 1-4 and 8-11), and Velcade administered two times per week (on days 1, 4, 8, and 11), followed by a rest period of 17 days (days 12 to 28). Following the induction treatment period (a minimum of four weeks after the last cycle of induction chemotherapy is administered) and in the absence of disease progression or unacceptable toxicity, mobilization of peripheral blood stem cells will be carried out with G-CSF and then collected for autologous transplant using melphalan as the conditioning regimen. Three months after this, and independently of the induction treatment group to which they were assigned, patients will again be randomized in a 1:1:1 ratio to receive Interferon alfa 2b (maintenance treatment Group M1) three times per week (Monday, Wednesday, and Friday), or Thalidomide (maintenance treatment Group M2), or Velcade /Thalidomide (maintenance treatment Group M3). Maintenance treatment Group M1 will receive interferon- alfa-2b three times per week (Monday, Wednesday, and Friday) for three years in the absence of disease progression or unacceptable toxicity. Maintenance treatment Group M2 will receive Thalidomide for three years in the absence of disease progression or unacceptable toxicity. Maintenance treatment Group M3 will receive Thalidomide daily and one pulse of Velcade (on days 1, 4, 8, and 11) every three months for three years in the absence of disease progression or unacceptable toxicity. After autologous transplant, patients who have not achieved CR who have an HLAidentical donor and meet the appropriate conditions, can be withdrawn from the study at the principal investigator s discretion in order to undergo an allogeneic transplant; following transplant, the patient cannot be re-admitted to the study during the maintenance period. Patients should be evaluated during the treatment period: 1) on day one of each induction cycle and approximately one month after completing the induction treatment period, 2) three months post-transplant and 3) during the maintenance treatment period, monthly for one year and every two months for two months thereafter. Following this, the End-of-Study Visit will take place a minimum of 30 days after maintenance treatment is finished, to evaluate safety. All patients who end treatment prematurely must also complete an End-of-Study visit, at least 30 days after receiving the final dose of study medications (Velcade /Thalidomide), in order to evaluate safety.

26 25 Once the treatment period is complete, all patients must be evaluated during the Follow-up Period, in order to record all adverse events (e.g. disease progression, toxicity), as well as look at survival. Patients must visit the trial site every three months for this to be carried out. Patient-reported outcomes (PROs) will be analyzed in this study using the EORTC QLQ-C30 questionnaire along with module MY-24 which is a disease-specific module for MM patients. The questionnaires should be completed on day 1 of each induction cycle: 1, 3, and 6. During the maintenance period in each of the treatment arms, the questionnaires should be completed every 3 months which, in the case of maintenance treatment Group M3, will coincide with day 1 of Velcade administration, as well as during the End-of-Study Visit. Safety will be evaluated through monitoring of all adverse events, physical examinations, vital signs, complete blood counts and biochemistry. Response to treatment will be measured according to EBMT criteria 52 and will be evaluated during cycles 2 through 6 of the induction period, post induction which will coincide with the pretransplant evaluation, three months after transplant, and during maintenance treatment monthly for the first year, every two months for two years and, finally, every three months. All patients will receive bisphosphonates, in accordance with standard clinical practice, a minimum of every three or four weeks during the first two years of treatment, and subsequently at the discretion of each site (one possibility would be to receive one dose of bisphosphonates every three months). Patients who develop confirmed disease progression during the treatment period should be withdrawn from the trial. The details of each visit and its procedures are set out in Section 5.3 and a complete schedule of visits is included in Appendix 4. A data monitoring committee, made up of the study coordinators and the other members of the GEM group, will be formed to evaluate the preliminary efficacy and safety results. These data will be analyzed once 30 patients have been included in each of the proposed induction treatment arms Study procedures The evaluations to be carried out during the study are outlined below, with reference to the period, day, and cycle of the study. Appendix 4 includes a diagram of the schedule of study procedures.

27 26 Screening procedures Each patient must sign and date the informed consent form before any study procedure takes place. However, all procedures that are part of the routine diagnosis of MM and that were carried out before informed consent was signed are valid as long as they are carried out 14 days prior to initiation of treatment. The skeletal survey and serology may be performed up to one month prior to the initiation of treatment. The following procedures will be carried out during the screening visit. Patients must complete and sign their informed consent in order to participate in the study before any analysis or other exams are carried out. All evaluations during the screening period will be carried out before the study medication is administered. Informed consent given in writing Demographics Medical history, including concomitant diseases and medication, supportive therapy, and baseline medical conditions Complete physical exam Electrocardiogram Echocardiogram or MUGA scan to determine FEV1 (at the discretion of each site, this test can be performed after randomization if the patient has been assigned to VBMCP/VBAD/Velcade ). Pregnancy test in women of childbearing potential and the use of safe contraceptive methods, especially in patients who receive Thalidomide. Skeletal survey to determine the presence of bone lesions, as well as other diagnostic imagining tests (scans) or MRI needed to determine the presence of extramedullary plasmacytomas. [A skeletal survey may be carried out up to one month prior to initiation of treatment.] Vital signs Height and weight ECOG performance status Collection of blood samples for analysis: hematology tests, biochemistry, serology (serology can be performed up to a month prior to initiation of treatment), quantification of immunoglobulin, monoclonal component and immunofixation, C-reactive protein and B2- microglobulin. Blood collection to determine the presence of serum free light chains. This study will be carried out centrally in reference laboratories (see Appendix 10).