HOVON 50 MM Version: 12 August 2003

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1 A randomized phase III study on the effect of Thalidomide combined with Adriamycin, Dexamethasone (AD) and High Dose Melphalan in patients with multiple myeloma PROTOCOL Study Coordinators : H.M. Lokhorst P. Sonneveld Statistician : B. van der Holt Datamanagers : P.H.M. Westveer E.J. van Stein Registration : HOVON Data Center University Hospital Rotterdam - Daniel P.O.Box AE ROTTERDAM The Netherlands tel fax First version : 15 September 2000 Final version : 19 June 2001 Date of activation : 27 November 2001 Approved : CKVO , 9 July 2001 METC UMCU 01/080, 30 July 2001 Amendment 1 : 18 September approved METC UMCU, 21 November 2001 Amendment 2 : 8 January approved METC UMCU, 5 February 2002 Amendment 3 : 12 August approved METC UMCU, 7 October 2003 Page 1 of 71

2 1 Scheme of study Multiple Myeloma Salmon & Durie stage II or III age years inclusive Arm A R Arm B 3 x VAD rapid infusion 3 x AD rapid infusion + Thalidomide 200 mg 1) CAD + G-CSF + stem cell collection 1) CAD + G-CSF + stem cell collection 1) 1) 2) 2) HDM + stem cell reinfusion HDM + stem cell reinfusion (second HDM optional) (second HDM optional) Inclusion in HOVON 54 trial α-interferon until relapse/progression Thalidomide 50 mg until relapse/progression Off protocol treatment Follow up 1) Patients who do not meet the inclusion criteria for CAD or HDM but with a CR, PR or MR, may proceed with 3 more cycles of VAD (arm A) or AD with Thalidomide (arm B), followed by IFN maintenance (arm A) or Thalidomide maintenance (arm B) until progression 2) Patients with an HLA-identical family donor who meet the eligibility criteria may be included in the HOVON 54 trial to proceed with non myeloablative allogeneic stem cell transplantation after the first course of HDM Page 2 of 71

3 2 Table of contents Page 1 Scheme of study Table of contents Synopsis Investigators and study administrative structure Cytogenetic review Introduction Conventional therapy Intensive treatment Double transplantation Thalidomide Maintenance therapy with α-interferon Prognostic factors Rationale of the study Study objectives Study design Induction chemotherapy with Vincristine, Adriamycin and Dexamethasone (VAD) or with Adriamycin and Dexamethasone (AD) Stem cell mobilization and collection High Dose Melphalan Thalidomide Maintenance therapy with α-interferon Treatment of patients in CR, PR or MR who do not meet the inclusion criteria for stem cell mobilization or intensification Non-myeloablative allogeneic transplantation (HOVON 54) Study population Eligibility for registration Inclusion criteria Exclusion criteria Treatments Thalidomide Special management orders in conjunction with Thalidomide Treatment of Deep Venous Thrombosis Induction therapy Special management orders in conjunction with (V)AD Stem cell mobilization and collection Inclusion criteria for CAD and stem cell collection Stem cell mobilization with CAD Special management orders in conjunction with CAD Stem cell collection Intensification Inclusion criteria for intensification High Dose Melphalan followed by stem cell reinfusion Special management orders in conjunction with Melphalan 200 mg/m² (100 mg/m²) and stem cell reinfusion...22 Page 3 of 71

4 9.4.4 Supportive care during Melphalan 200 mg/m² (100 mg/m²) aplasia Second course of Melphalan 200 mg/m 2 followed by stem cell reinfusion Maintenance therapy with α-interferon Inclusion criteria for α-interferon maintenance Administration of α-interferon Dose adjustment of α-interferon Maintenance therapy with Thalidomide Non-myeloablative allogeneic stem cell transplantation (HOVON 54) Bisphosphonates End of protocol treatment Required clinical evaluations Time of clinical evaluations Required investigations at entry, during treatment and during follow up Medical history Physical examination Hematology Blood chemistry Immunochemistry Bone marrow Specific investigations Additional investigations Cytogenetic analysis Evaluation of response Toxicities Reporting serious adverse events Endpoints 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 analyses and safety monitoring Data and safety monitoring board Ethics Independent ethics committee or Institutional review board Ethical conduct of the study Patient information and consent Trial insurance Publication policy Glossary of abbreviations Page 4 of 71

5 22 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. Factor VIII and von Willebrand factor as a risk factor for Thalidomide induced Deep Venous Thrombosis in Multiple Myeloma Page 5 of 71

6 3 Synopsis Study phase Study objectives Patient population Study design Duration of treatment Number of patients Adverse events Planned start and end of recruitment Phase III Evaluation of the effect of Thalidomide in addition to AD and High Dose Melphalan Patients with multiple myeloma, previously untreated, Salmon & Durie stage II or III, age years inclusive Prospective, multicenter, randomized Expected duration of induction, stem cell collection and intensification (with or without Thalidomide) is 5-7 months. Thalidomide will be continued as maintenance until relapse or progression; however it will be discontinued early when the patient has not at least a PR 3 months after Melphalan. In patients not randomized to Thalidomide, maintenance therapy with α-interferon will be given until relapse or progression 450 patients registered and randomized Adverse events will be documented if observed, mentioned during open questioning, or when spontaneously reported. Start of recruitment: III 2001 End of recruitment: III 2005 Page 6 of 71

7 4 Investigators and study administrative structure Responsibility Name Affiliation/Address Study Coordinators H.M. Lokhorst P. Sonneveld Writing Committee J.W. Baars A. van Leeuwenhoek Hospital, Amsterdam R. Barge University Medical Center, Leiden G.M.J. Bos University Hospital Maastricht J.J. Cornelissen University Hospital Rotterdam-Daniel A.J. Croockewit University Hospital St. Radboud, Nijmegen P.C. Huijgens University Hospital Free University, Amsterdam P. Joosten Medical Center, Leeuwarden H.M. Lokhorst University Hospital Utrecht M. van Marwijk Kooy Isala Clinic - Sophia, Zwolle M.H.J. van Oers Academic Medical Center, Amsterdam M.R. Schaafsma Medical Spectrum Twente, Enschede C.M. Segeren, P. Sonneveld University Hospital Rotterdam-Dijkzigt H.A.M. Sinnige Bosch Medicentrum, Den Bosch E. Vellenga University Hospital Groningen G.E.G. Verhoef University Hospital Leuven O. de Weerd St. Antonius Hospital, Nieuwegein P.W. Wijermans Leyenburg Hospital, The Hague S. Wittebol Hospital Eemland, Amersfoort Cytogenetics review E. van den Berg Dept. Medical Genetics, University of Groningen Statistician B. van der Holt HOVON Data Center, Rotterdam Datamanagement P.H.M. Westveer E.J. van Stein HOVON Data Center, Rotterdam HOVON Data Center, Rotterdam Serious Adverse Events (SAEs) notification HOVON Data Center fax: Page 7 of 71

8 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 Conventional therapy Multiple myeloma is a hematological malignancy characterized by a proliferation of monoclonal plasma cells, which produce a homogeneous immunoglobulin (M-protein) which can be detected in the serum and/or the urine. It accounts for approximately 1% of all malignancies and 10% of hematological cancers. 1 For several decades intermittent Melphalan and prednisone has been the treatment of choice. Many trials with combination chemotherapy have been performed, but these did not result in an improved outcome as compared to Melphalan and prednisone. 2,3 Fifty to sixty percent of patients respond to conventional chemotherapy and only a minority (< 5%) of patients achieve a complete response. 4 Virtually all patients succumb to refractory disease and the median overall survival is less than 3 years. Even after having achieved a response, patients may remain symptomatic due to a considerable residual tumorload. 5.2 Intensive treatment High dose chemotherapy for myeloma was introduced in 1983 showing for the first time that in a substantial percentage of patients complete remissions could be induced. 5 Morbidity and mortality however was high, but was strongly reduced later by the application of autologous stem cell rescue. Bone marrow was the source of stem cells in the first studies, peripheral blood stem cells (PBSC) are now routinely applied as autologous rescue. 6 So far one randomized study has been published which showed that autologous transplantation was superior to conventional treatment regarding response rate, event-free and overall survival. In this study patients under 65 years were randomized at diagnosis to receive VBAP/VMCP or High Dose Melphalan 140 mg/m 2 and TBI 8 Gy supported with autologous bone marrow collected after 2 courses of VBAP/VMCP. 7 In 1994 the Nordic Myeloma Study Group (NMSG) started a study with high-dose chemotherapy in newly diagnosed patients under 60 years. 8 After induction therapy with VAD followed by stem cell collection after Cyclophosphamide 4 g/m 2 and G-CSF, patients received Page 8 of 71

9 Melphalan 200 mg/m 2 with stem cell rescue. Survival in the intensive group was significantly prolonged as compared to the control group. The control patients were selected from a historic population of 313 patients identified from 5 previous population-based Nordic studies. Of these, 274 fulfilled the eligibility criteria for the high dose therapy in the NMSG group. 5.3 Double transplantation Attempts have been made to improve the outcome of myeloma by performing double transplants. The rationale of this approach was based on the observation that the achievement of CR after intensive therapy was a favourable prognostic factor for EFS and OS. The largest series of double transplants has been performed by the group led by Barlogie. 9 In previously untreated patients the CR rate increased from 26% after the first transplant to 41% after the second. Median OS and EFS durations were 68 months and 43 months, respectively. On multivariate analysis, superior EFS and OS were observed in the absence of unfavourable karyotypes (11q breakpoint abnormalities, -13, or 13-q) and with a low β 2 -microglobulin at diagnosis. Using case-matched registry data as controls double transplants improved response rate, EFS and OS as compared to conventional treatment. In a recent update of results of tandem transplants in 1000 patients the adverse impact of chromosome 13 deletion was established. In a recently completed randomized study by the Intergroup Français de Myelom (IFM), single versus double stem cell transplantation was compared in previously untreated patients. The results show that patients with a low β 2 -microglobulin at diagnosis had a slightly better OS after double transplants. 10 However no improvement of outcome was found in patients with unfavourable prognostic factors like a high β 2 -microglobulin and/or deletion of chromosome A retrospective EBMT registry study showed that double transplants, planned or unplanned at the time of the first transplant may be superior to single transplants. Cavo et al found in a small series of patients significantly improved CR rate and EFS in patients following double transplant. 12 In 1996 HOVON initiated a phase III study in which single intensive therapy without stem cell rescue was compared with double high-dose chemoradiotherapy including stem cell rescue. After induction therapy with VAD patients were randomized between arm A: High Dose Melphalan divided into 2 courses of i.v. Intermediate Dose Melphalan (IDM, Melphalan 70 mg/m 2 ) followed by maintenance therapy with α-interferon and arm B: High Dose Melphalan divided into 2 courses of IDM followed by myelo-ablative treatment (Cyclophosphamide,120 mg/m 2 and TBI 8 Gy) with PBSCT followed by maintenance with α-interferon. Stem cells were mobilized after VAD with Cyclophosphamide 4 g/m 2 and G-CSF. The study was closed April 1, 2000, after the inclusion of 453 patients. An interim analysis performed in January 2001 showed that there is an ongoing improvement of the response rate with every treatment step. However overall survival and event Page 9 of 71

10 free survival were not different between the two treatment arms. For definite firm conclusions about the effectiveness of tandem transplants further follow-up of the French randomized study seems warranted. 5.4 Thalidomide Thalidomide prescribed in the early sixties as sleep inducing drug was withdrawn after the appearance of reports of teratogenecity and phocomelia. Because of its broad spectrum of pharmacological and immunological effects it has returned in modern medicine today and is now used in a wide spectrum of diseases like erythema nodosum leprosum and refractory Becet s disease. 13,14 Recently it was discovered that Thalidomide has substantial antitumor activity in patients with advanced myeloma. 15 Eighty-four previously treated patients, including 76 with a relapse after high dose chemotherapy, received oral Thalidomide as a single agent for a median of 80 days. The starting dose was 200 mg/day and dose escalation with 200 mg was performed every 2 weeks until a maximum of 800 mg/day. Total response was 32%. In 80% of responding patients M-protein levels began to drop within two months from start of therapy. Responses also included reduced bone marrow plasma cell infiltration and improved general status. After 12 months of follow-up EFS and OS for all patients was 22% and 58% respectively. At least 30% of patients had mild to moderate side effects - constipation, somnolence, neuropathy, rash, weakness and fatigue- while 10% of patients had severe adverse effects. Side effects were most frequent in the group with the higher Thalidomide dosis. The promising results of Thalidomide in refractory myeloma have been confirmed by several other groups. Juliussen et al observed frequent (43%) good partial remissions from Thalidomide including best response ever in 23 patients with advanced and refractory myeloma. 16 In other studies comparable response rates were achieved The mechanisms of action of Thalidomide are still not clear. Bone marrow vascularization is strongly increased in myeloma and it may be that Thalidomide inhibits angiogenesis thereby inducing apoptosis of myeloma plasma cells. 17,21,22 The microvascular density of bone marrow however did not change in responding patients. Other possible mechanisms of action may include a direct apoptosis inducing effect on myeloma cells, or indirectly influencing the growth and survival of myeloma cells by modulating adhesion molecules or the secretion of cytokines. The optimal dose of Thalidomide is not known. The maximum tolerated dose varies substantially among patients. However very few patients tolerate the higher doses of mg. The observation that in most responding patients M-protein levels begin to drop within the first weeks of treatment suggests that dose escalation may not be necessary to induce responses in myeloma and in that way unnecessary side effects can be avoided. The efficacy of low dose Thalidomide Page 10 of 71

11 has already been confirmed in clinical studies. 23 A recent analysis in 138 patients indicates that the duration of disease remissions increases with the achieved cumulative dose of Thalidomide (B. Barlogie, personal communication). Recently the outcome of several studies with Thalidomide alone or combined with Dexamethasone or Doxorubicin were presented at the VIII th Myeloma Workshop (May 2001, Banff, Alberta, Canada). Important is that Thalidomide, especially when it is combined with Dexamethasone and Doxorubicin, may increase the risk on Deep Venous Thrombosis (DVT). The mechanism sofar is unknown. Since then two reports were published describing the increased incidence of DVT when combined with VAD. Osman et al described symptomatic DVT in 4 of the 15 patients (27%) receiving VAD in previously untreated patients. 36 Zangari and Barlogie et al described that in patients included in the Total Therapy II study, DVT developed in 14 of 50 patients (28%) who were randomly assigned to receive Thalidomide but in only 2 of 50 patients (4%) not given the agent. 37 All DVT s occurred during the first 3 months of induction therapy when the patients received multi-agent treatment including Doxorubicin and Dexamethasone. Thalidomide was resumed in 75% of patients receiving anticoagulation therapy. In the Total Therapy II study anticoagulation prophylaxis with low dose coumarines is now given to all patients randomized to Thalidomide in combination with multi-agent therapy during the first 3 months of induction therapy. 5.5 Maintenance therapy with α-interferon A meta-analysis of 30 randomized trials in multiple myeloma including more than 3000 patients, with α-interferon either as combined IFN-chemotherapy or as maintenance, was recently published. 24 Interferon maintenance therapy as compared to no maintenance, lead to a 4.4 months (P<0.01) and 7 months (P<0.01) prolongation of relapse-free and overall survival, respectively. In this meta-analysis no differentiation was made between IFN given after high dose or after conventional treatment. The Royal Marsden Group evaluated α-interferon given as maintenance in patients with a response to High Dose Melphalan in a randomized fashion. 25 At a median follow up of 52 months the progression-free survival from HDM was 46 months in the α-interferon arm versus 27 months in the control group (P<0.025), and overall survival was also significantly better for the α-interferon arm (P=0.006). At a median follow up of 77 months, most of the patients had succumbed to their disease and the survival advantage which was noted at the 4½ year follow up had ceased to exist. The European Bone Marrow Transplantation group found in a multivariate analysis that patients who received IFN had a significant prolonged survival. 26 Page 11 of 71

12 5.6 Prognostic factors Recently, similar to what has been found in acute leukemia, data have been published indicating that specific chromosomal abnormalities have prognostic significance in multiple myeloma. Using conventional cytogenetics, Tricot et al found that partial or complete deletion of chromosome 13 and abnormalities of chromosome 11, present in 10-15% of untreated myeloma, were strong adverse prognostic factors in patients treated with tandem transplantation. 27 Using interphase FISH with specific probes for the retinoblastoma gene (rb-1) the frequency of chromosome 13 deletions was much higher than found with metaphase analysis and varied between 33% and 42% in different studies. 13,28-30 Despite the fact that this technique revealed 13q14 deletions in a much higher frequency as did metaphase analysis, the presence of abnormal chromosome 13 remained the single most significant adverse prognostic factor in patients treated with conventional-dose or high-dose chemotherapy. 31,32 It is obvious that in every prospective myeloma trial classic metaphase analysis and interphase FISH to detect abnormal chromosomes 11 and 13 should be part of the pretreatment staging of patients. 5.7 Rationale of the study This is a phase III study to test the efficacy and feasibility of Thalidomide combined with intensive treatment as compared to intensive treatment only in younger patients with multiple myeloma in relation to established MM prognostic factors. The rationale for combining Thalidomide with chemotherapy is based on the different mechanisms of actions and the potential synergism of Thalidomide and cytostatics and/or Dexamethasone. These assumptions were confirmed in an animal breast cancer model which showed that angiotherapy with Thalidomide combined with doxorubicin and cyclophosphamide had greater antitumor activity than chemotherapy alone. 33 The feasibility and efficacy of Thalidomide combined with chemotherapy was also found in human myeloma as demonstrated by the induction of CR in patients with plasma cell leukemia and relapsed refractory disease by the combination of Thalidomide with the DCEP regimen. 34 The rationale for low dose Thalidomide is based on the observation that refractory myeloma patients may be sensitive to low doses given over a prolonged period of time and the lack of evidence for a dose-response relation. In addition, the higher doses of Thalidomide are associated with severe side effects, which makes high dose Thalidomide unacceptable for induction and maintenance therapy. Novel data on the strong prognostic impact of chromosomal aberrations in patients with multiple myeloma make it possible to divide these patients into different prognostic groups. Therefore the potential benefit of Thalidomide can be evaluated in standard-risk patients (serum β 2 -microglobulin 3 µg/l and normal chromosome 13 as determined by FISH) and high-risk patients (β 2 -microglobulin > 3 µg/l and/or abnormal chromosome 13 as determined by FISH). Page 12 of 71

13 The protocol allows to apply two courses of intensified treatment with stem cell rescue, either immediately or with the second course given at relapse or progression. As has been described above, the final analysis of different studies (IFM 94, HOVON 24 MM) has to be awaited for definite conclusions about the impact of double intensification. 6 Study objectives To assess the efficacy of Thalidomide combined with intensive chemotherapy in comparison with intensive therapy alone in patients with previously untreated multiple myeloma, as measured by the event free survival. Events are induction failure, disease progression and death from any cause. To evaluate the response rate, complete response rate, overall survival and progression free survival. To assess the safety and toxicity of Thalidomide combined with intensive chemotherapy. To assess the value of risk factors at diagnosis, including β 2 -microglobulin and abnormalities of chromosomes 11 and 13 as analyzed in bone marrow plasma cells by karyotyping and FISH, for individual patients with myeloma who are treated with Thalidomide. 7 Study design Details of all treatments (dose and schedule) are given in Patients with multiple myeloma, meeting all eligibility criteria (see 8.1) will be randomized on entry between: Arm A: intensive chemotherapy alone followed by maintenance therapy with α-interferon (Roferon ) or Arm B: intensive chemotherapy with Thalidomide followed by maintenance with Thalidomide Patients may proceed to non myeloablative AlloSCT, therefore HLA typing of the patient and family should be performed within three months after inclusion in this trial. Page 13 of 71

14 7.1 Induction chemotherapy with Vincristine, Adriamycin and Dexamethasone (VAD) or with Adriamycin and Dexamethasone (AD) All patients will be given 3 cycles of induction chemotherapy. Dosages of (Vincristine), Adriamycin and Dexamethasone are according to the original VAD scheme (Vincristine, Adriamycin, Dexamethasone), with the exception that the dosage of Dexamethasone is the same in all three cycles. Vincristine is omitted in the Thalidomide arm because of the high risk of polyneuropathy when it is combined with Thalidomide. Patients will be evaluated for response after cycle 3. Patients who meet the inclusion criteria for CAD and stem cell collection (see 9.3.1), will continue with CAD. Patients who do not meet these inclusion criteria but who are in CR, PR or MR are strongly recommended to be treated as described in paragraph 7.6. Otherwise they go off protocol treatment. 7.2 Stem cell mobilization and collection In all eligible patients (see 9.3.1) stem cell collection will be performed after CAD (Cyclophosphamide, Adriamycin, Dexamethasone) chemotherapy and G-CSF (Neupogen SingleJect ). Patients will be evaluated for response after stem cell collection. 7.3 High Dose Melphalan All patients who meet the inclusion criteria for intensification (see 9.4.1) will be treated with High Dose Melphalan 200 mg/m² followed by autologous stem cell reinfusion. In patients with renal insufficiency (creatinin 40 ml/min) the Melphalan dose should be reduced to 100 mg/m². Patients in a hospital with a policy of double intensification will receive the second course of High Dose Melphalan between 2 and 3 months after the first course. Patients will be evaluated for response after each course of High Dose Melphalan. 7.4 Thalidomide Patients randomized to arm B (with Thalidomide) will be given Thalidomide 200 mg daily from day 1 throughout the 3 AD cycles. Thalidomide dose may be escalated to maximally 400 mg in case of good tolerability. Thalidomide is stopped 2 weeks before CAD. Page 14 of 71

15 Thalidomide maintenance, 50 mg daily, will start immediately after the first course of HDM. Thalidomide is then continued until progression. Thalidomide is also stopped when a patient has not achieved at least a PR 3 months after the last course of High Dose Melphalan. 7.5 Maintenance therapy with α-interferon In patients randomized to arm A (standard arm) who meet the inclusion criteria for α-interferon (Roferon ) maintenance (see 9.5.1), maintenance will start between 2 and 3 months after the last course of High Dose Melphalan. α-interferon is continued until progression. It is also stopped when a patient has not achieved at least a PR 3 months after start of IFN maintenance. 7.6 Treatment of patients in CR, PR or MR who do not meet the inclusion criteria for stem cell mobilization or intensification For patients who do not meet the inclusion criteria for either stem cell mobilization (see 9.3.1) or intensification (see 9.4.1) but who achieved a CR, PR or MR, it is strongly recommended to continue the treatment with 3 more cycles of (V)AD (see 9.2) with or without Thalidomide according to their randomization arm, followed by maintenance with IFN (arm A) or Thalidomide (arm B) until progression. Maintenance therapy with IFN or Thalidomide will also be stopped when a patient has not achieved at least a PR 3 months after start of maintenance. 7.7 Non-myeloablative allogeneic transplantation (HOVON 54) Patients with an HLA-identical family donor may be included in the HOVON 54 trial Non myeloablative allogeneic stem cell transplantation following high dose therapy as part of first line therapy to induce graft versus myeloma for patients 65 years participating in the HOVON 50 study. Eligibility criteria can be found in the HOVON 54 protocol. Since inclusion in the HOVON 50 trial is an eligibility criterium for the HOVON 54 trial, all patients who are planned for inclusion in the HOVON 54 trial must be entered into the HOVON 50 trial first. Patients will be treated according to their allocated treatment arm until 1 HDM course has been completed and evaluated. Eligible patients may then be included in the HOVON 54 trial. A patient will go off protocol treatment at the time of transplant in the HOVON 54 trial (see 9.7 for details). Page 15 of 71

16 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 II or III according to the Salmon & Durie criteria (see appendix A); Age years inclusive; WHO performance status 0-3 (see appendix D); Negative pregnancy test at inclusion if applicable; Written informed consent Exclusion criteria Known intolerance of Thalidomide; Systemic AL amyloidosis; Previous chemotherapy or radiotherapy except 2 cycles of Melphalan/Prednisone or local radiotherapy in case of local myeloma progression; Severe cardiac dysfunction (NYHA classification II-IV, see appendix E) ; Significant hepatic dysfunction (serum bilirubin 30 µmol/l or transaminases 2.5 times normal level), unless related to myeloma; Patients known to be HIV-positive; Patients with active, uncontrolled infections; 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; Patients who are not willing or capable to use adequate contraception during the therapy (all men, all pre-menopausal women); Patients 55 years with an HLA-identical sibling who will undergo myeloablative AlloSCT. Page 16 of 71

17 9 Treatments All men and pre-menopausal women should use adequate contraception during the study. Sperm should be frozen from men with child wish before start of treatment. 9.1 Thalidomide Thalidomide will be administered only to patients randomized to arm B. Agent Dose/day Route Days Thalidomide 200 mg Dose escalation to maximally p.o. Start day 1 of first AD Stop 2 weeks before start CAD 400 mg optional Thalidomide 50 mg p.o. Start immediately after the first course of HDM. Stop after progression, or when not at least in PR 3 months after last course HDM The starting dose will be 200 mg/day. The daily Thalidomide dose may be escalated to maximally 400 mg in case of good tolerability (optional). Thalidomide will be administered daily from day 1 throughout the 3 AD cycles. It will then be stopped 2 weeks before the start of CAD to facilitate optimal stem cell collection. Thalidomide will not be resumed between stem cell collection and the first course of HDM. Thalidomide maintenance 50 mg/day will start immediately after the first course of HDM. Thalidomide will be stopped after progression and also in patients who have not achieved at least a PR 3 months after the last course of HDM. When Thalidomide maintenance after HDM is interrupted for more than 6 weeks, it is regarded as end of Thalidomide maintenance and the patient will go off protocol treatment. Assessment of response during Thalidomide maintenance is described in paragraph 11 and appendix B. Page 17 of 71

18 9.1.1 Special management orders in conjunction with Thalidomide Due to increased risk on Deep Venous Thrombosis (DVT) during treatment with Thalidomide, especially when it is combined with anthracyclines and dexamethasone, patients should receive thrombosis prophylaxis with low molecular heparine during induction therapy with AD + Thalidomide: Fraxiparine 2850 IE anti-xa = 0.3 ml, sc. (> 90 kg: 5700 IE anti-xa = 0.6 ml) 1 dd. Start day 1 of first AD until 1 week before start of CAD. Thrombosis prophylaxis should also be given when a patient is treated with additional AD + Thalidomide cycles (see 7.6). In patients who do not tolerate Thalidomide 200 mg the dose may be adjusted to 100 or 50 mg/day eventually after interruption Treatment of Deep Venous Thrombosis When a DVT occurs during Thalidomide treatment, Thalidomide should be interrupted until the DVT has been resolved. Treatment of DVT is according to local protocol. As soon as the DVT has been resolved, Thalidomide can be resumed according to protocol. DVT during induction therapy is no contra-indication for low dose Thalidomide maintenance therapy (9.6). Also, it is no indication for thrombosis prophylaxis during Thalidomide maintenance unless additional DVT risk factors like FV Leiden are present. 9.2 Induction therapy All patients will receive 3 cycles of VAD (arm A) or AD (arm B) by rapid infusion. Patients randomized to arm B will also receive Thalidomide daily, see 9.1. Agent Dose/day Route Days Vincristine (only arm A) 0.4 mg i.v. rapid infusion 1, 2, 3, 4 Doxorubicin 9 mg/m 2 i.v. rapid infusion 1, 2, 3, 4 Dexamethasone 40 mg p.o. All cycles: 1, 2, 3, 4, 9, 10, 11, 12, 17, 18, 19, 20 Cycle 2 will start at day 29, cycle 3 will start at day 57. In case a patient receives additional (V)AD cycles these are considered as treatment according to protocol, so the corresponding data will be recorded on the appropriate CRF s. Page 18 of 71

19 Assessment of response after cycle 3 is described in paragraph 11 and appendix B. All patients who meet the inclusion criteria for CAD and stem cell collection (see 9.3.1) will continue with CAD (see 9.3). This also holds for patients with no response or progressive disease after (V)AD. Patients who do not meet the inclusion criteria for mobilization but with a CR, PR or MR are strongly recommended to be treated as described in paragraph 7.6. Patients who do not meet the inclusion criteria for mobilization and with no response or with progressive disease will go off protocol treatment. It should be noted that no response or progressive disease after (V)AD by itself is not a reason to go off protocol treatment Special management orders in conjunction with (V)AD. It is strongly recommended to give prophylactic treatment for pneumococcus infections and anti-fungal prophylaxis according to local protocols. 9.3 Stem cell mobilization and collection All eligible patients will be given CAD chemotherapy followed by G-CSF (Neupogen ) for stem cell collection. Patients randomized to arm B will discontinue Thalidomide two weeks before the start of CAD. CAD will start 4-6 weeks after start of the third (V)AD cycle Inclusion criteria for CAD and stem cell collection WHO performance 0-3 Absence of severe pulmonary, neurologic, or psychiatric disease Bilirubin and transaminases of less than 2.5 times the upper limit of normal values Page 19 of 71

20 9.3.2 Stem cell mobilization with CAD Agent Dose/day Route Days Cyclophosphamide 1000 mg/m 2 i.v. 1 Doxorubicin 15 mg/m 2 i.v. rapid infusion 1, 2, 3, 4 Dexamethasone 40 mg p.o. 1, 2, 3, 4 G-CSF (Neupogen SingleJect ) 10 µg/kg (divided in 2 gifts daily, according to local rules) s.c. day 5 until last pheresis Special management orders in conjunction with CAD. Selective gut decontamination should be performed according to local protocols Stem cell collection Stem cell collection will be performed as soon as CD34 + cells are present in peripheral blood, which is usually between 9-14 days after first day of CAD. In case double intensification is planned (immediately or a second course at relapse) a minimum of 5 x 10 6 CD34 + cells/kg is required. Otherwise 2.5 x 10 6 CD34 + cells/kg are sufficient. In case insufficient stem cells are collected the procedure may be repeated (possibly after the use of cyclophosphamide priming (4000 mg/m 2 )) or alternatively bone marrow stem cell collection may be performed. Assessment of response after stem cell collection is described in paragraph 11 and appendix B. All patients who meet the inclusion criteria for intensification (see 9.4.1) will continue with High Dose Melphalan. This also holds for patients with no response or progressive disease after stem cell collection. Patients who do not meet the inclusion criteria for intensification but with a CR, PR or MR are strongly recommended to be treated as described in paragraph 7.6. Patients who do not meet the inclusion criteria for intensification and with no response or with progressive disease will go off protocol treatment. It should be noted that no response or progressive disease by itself is not a reason to go off protocol treatment. Page 20 of 71

21 9.4 Intensification All eligible patients will be given High Dose Melphalan between 6 and 8 weeks after stem cell collection Inclusion criteria for intensification WHO performance 0-2 Absence of severe pulmonary, neurologic, or psychiatric disease Bilirubin and transaminases of less than 2.5 times the upper limit of normal values A suitable stem cell graft containing at least 2.5 x 10 6 CD34 + cells/kg High Dose Melphalan followed by stem cell reinfusion Agent Dose/day Route Days Melphalan 100 mg/m² i.v. rapid infusion -3, -2* Stem cell infusion 2.5 x 10 6 CD34 + cells/kg 0 * Melphalan 100 mg/m² in patients with renal insufficiency Although Melphalan pharmacokinetics are not adversely affected by impaired renal function, the general toxicity of Melphalan 200 mg/m 2 may be increased in patients with a creatinin clearance 40 ml/min. For patients with a creatinin clearance 40 ml/min, Melphalan dose should be reduced to 100 mg/m 2, given only at day -3. Assessment of response after each course of High Dose Melphalan is described in paragraph 11 and appendix B. Patients randomized to arm A will continue with α-interferon maintenance after the last course of HDM (see 9.5), provided they meet the inclusion criteria for IFN maintenance. Otherwise they go off protocol treatment. Patients randomized to arm B will continue with Thalidomide maintenance 50 mg/day after the first course of HDM (see 9.1). Patients with an HLA-identical family donor may be included in the HOVON 54 trial after the first course of HDM (see 7.7 and 9.7). Page 21 of 71

22 9.4.3 Special management orders in conjunction with Melphalan 200 mg/m² (100 mg/m²) and stem cell reinfusion A hydration regimen will be started 30 minutes before administration of Melphalan and consists of 500 ml NaCl 0.9 % and 40 mmol KCl over 1 hour. Diuretics must be administered when needed. On day 0 the stem cells are thawed at the bedside and infused without washing steps. The procedure will be performed according to the local standard protocols Supportive care during Melphalan 200 mg/m² (100 mg/m²) aplasia Placement of an indwelling central venous catheter; Anovulatory drugs for menstruating females; Antibacterial and antifungal prophylaxis; Antistreptococcus prophylaxis is recommended from day +4 until day Second course of Melphalan 200 mg/m 2 followed by stem cell reinfusion In institutions with a policy of double intensification, the second course of High Dose Melphalan will be administered between 2 and 3 months after the first course. Patients have to meet the criteria as described under before starting the second course. The policy of each center should be made clear to the HOVON Data Center before or at the time of registration of the first patient. It is prohibited to follow both policies for different patients in one individual participating center. Patients that are included in the HOVON 54 trial (see 9.7) wil not receive a second course of HDM, regardless of the center policy. Patients will go off protocol treatment at the time of transplant in the HOVON 54 trial. 9.5 Maintenance therapy with α-interferon Patients randomized to arm A who are eligible for maintenance with α-interferon (Roferon ) will start with IFN maintenance between 2 and 3 months after the last course of HDM. If α-interferon (Roferon ) has not started within 6 months after HDM, the patient will go off protocol treatment Inclusion criteria for α-interferon maintenance WHO performance 0-2 No progressive disease Page 22 of 71

23 Platelets 100 x 10 9 /l WBC 3 x 10 9 /l Absence of active infections Absence of severe metabolic or psychiatric disease Administration of α-interferon Agent Dose/day Route Days α-interferon (Roferon, preferentially Roferon -Pen containing 18 x 10 6 IU) 3 x 10 6 IU s.c. 3 times weekly Stop after progression, or when not at least in PR 3 months after start maintenance The dose will be 3 x 10 6 IU/day given subcutaneously three times a week. IFN is continued until progression. IFN is also stopped when a patient has not achieved at least a PR 3 months after start maintenance. When Interferon administration is interrupted for more than 6 weeks, it is regarded as end of maintenance and the patient will go off protocol treatment. Assessment of response during IFN maintenance is described in paragraph 11 and appendix B Dose adjustment of α-interferon Non-hematological toxicity CTC grade 4 and/or leukocytopenia (WBC < 2 x 10 9 /l) and/or thrombocytopenia (platelets < 50 x 10 9 /l): interrupt IFN. After disappearance of side effects, IFN may be started again at reduced dose levels according to the table below; Non-hematological toxicity CTC grade 2 or 3: reduce dose IFN according to the table below. Dose Reduction Level Dose/day Days Level 1 2 x 10 6 IU 3 times weekly Level 2 1 x 10 6 IU 3 times weekly Level 3 1 x 10 6 IU 1 time weekly When reducing the dose of IFN, start at Dose Reduction Level 1. In case that dose level is still associated with unacceptable side effects, reduce the dose further according to Level 2. If this is insufficient, reduce further to Level 3. In case Level 3 is not tolerated, maintenance therapy is ended and the patient will go off protocol treatment. Page 23 of 71

24 9.6 Maintenance therapy with Thalidomide Patients randomized to arm B will continue with Thalidomide after the first course of HDM. The dose of maintenance Thalidomide is 50 mg daily. For details see paragraph 9.1. Patients scheduled for inclusion in the HOVON 54 trial, however, should not continue with Thalidomide after the first course of HDM (see 9.7). 9.7 Non-myeloablative allogeneic stem cell transplantation (HOVON 54) Patients that are scheduled for inclusion in the HOVON 54 trial will be treated according to their allocated treatment arm until 1 HDM course is completed and evaluated. Arm A: 3 courses of VAD (see 9.2), CAD and stem cell collection (see 9.3), 1 course of HDM and stem cell reinfusion (see 9.4); Arm B: 3 courses of AD (see 9.2), CAD and stem cell collection (see 9.3), 1 course of HDM and stem cell reinfusion (see 9.4) and Thalidomide (see 9.1); Patients initially randomized to arm B (Thalidomide) will receive their Thalidomide according to protocol until 2 weeks before CAD. For patients scheduled for inclusion in the HOVON 54 trial, no maintenance therapy (IFN or Thalidomide) will be applied after HDM. If such a patient (for some reason other than disease progression) is not actually included in the HOVON 54 trial, the patient will remain on HOVON 50 protocol treatment. This means maintenance therapy can be started according to the criteria in 9.1 or Bisphosphonates It is strongly recommended to start treatment with bisphosphonates at diagnosis and to continue this treatment for at least 2 years. A commonly used regimen consists of pamidronate (APD) 90 mg i.v. once every 4-6 weeks. Page 24 of 71

25 10 End of protocol treatment Reasons for going off protocol treatment are: 1. Not eligible for CAD and stem cell collection, and no further treatment with (V)AD 2. Not eligible for intensification with HDM, and no further treatment with (V)AD 3. Not eligible for IFN maintenance 4. Not at least PR 3 months after start IFN maintenance (arm A) 5. Not at least PR 3 months after last course of HDM (arm B) 6. Excessive toxicity (including toxic death) 7. Progression / relapse (not after (V)AD I-III or stem cell collection) 8. Intercurrent death 9. No compliance of the patient (especially refusal to continue treatment) 10. Major protocol violation 11. Completion of protocol treatment (in case of AlloSCT) Page 25 of 71

26 11 Required clinical evaluations Aim of the clinical evaluation at entry is to know in which stage of disease according to Salmon & Durie (see appendix A) the patients are classified 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 11.3 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 (V)AD III: approximately 3 weeks after start of the third (V)AD cycle After (V)AD VI if applicable: approximately 3 weeks after start of the sixth (V)AD cycle After stem cell collection: approximately 4 weeks after start CAD After each HDM: approximately 6-8 weeks after each course of HDM Maintenance and follow up: every 2 months 11.2 Required investigations at entry, during treatment and during follow up At entry After (V)AD III / VI After stem cell collection After each HDM Maintenance and follow up Medical history X X X X X Physical examination X X X X X Hematology X X X X X Blood chemistry X X X X X Immunochemistry X X X X X Bone marrow Bone marrow aspirate X X X X 2) Bone marrow biopsy X BM cryopreservation 3) X X X X 1) Specific investigations β 2-microglobulin X X Creatinin clearance o.i. o.i. o.i. o.i. Skeletal survey X o.i. o.i. X X 1) X-thorax X ECG X X Cardiac ejection o.i. o.i. o.i. o.i. Additional investigations o.i. o.i. o.i. o.i. o.i. Cytogenetic analysis X o.i. on indication 1) once a year 2) once a year, twice a year if non-secretory myeloma 3) only in institutions that plan to perform molecular analysis Page 26 of 71

27 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 HLA typing of patient and family 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 Only after each HDM: Recovery of peripheral blood cells Page 27 of 71

28 Blood chemistry BUN Creatinin Liver enzymes Total bilirubin 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 ay entry: Qualitative serum M-protein Qualitative urine M-protein (Bence Jones) Bone marrow Bone marrow biopsy Bone marrow aspirate at entry for: Morphology, immunophenotyping Labeling Index (by BRDU) or KI-67 Cytogenetic analysis (see ) Molecular analysis (cryopreservation, only in institutions that plan to perform molecular analysis like measurement of tumorload with semi-quantitative ASO-PCR) Page 28 of 71

29 Bone marrow aspirate during treatment and follow up for: Morphology Molecular analysis (cryopreservation, only in institutions that plan to perform molecular analysis like measurement of tumorload with semi-quantitative ASO-PCR) 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 Cardiac ejection by scintigraphy or cardiac echo (only on idication) Additional investigations Only on clinical indication: Survey for exclusion of AL amyloidosis Bleeding time Cryoglobulins, cold agglutins 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 (V)AD course, after the sixth (V)AD course if applicable, after stem cell collection, and after each course of HDM. During maintenance, disease status will be evaluated every 2 months. According to the response criteria a response should be confirmed after 6 weeks. However, in general this can not be applied to the response measurements after (V)AD III, stem cell collection and between the 2 courses of HDM as the treatment intervals are too short. Page 29 of 71

30 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). 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. Page 30 of 71