Use of Thalidomide, Lenalidomide, Carfilzomib, Bortezomib and Vorinostat in the Initial Treatment of Newly Diagnosed Multiple Myeloma Patients

Study Overview
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Brief Summary
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The purpose of this study is to compare a standard chemotherapy regimen of cyclophosphamide, dexamethasone plus thalidomide with a newer regimen of cyclophosphamide, dexamethasone plus lenalidomide with or without carfilzomib. Patients who do not have the best response to their initial treatment may then also be given a combination of cyclophosphamide, dexamethasone plus bortezomib. Patients who are relatively fit may, on their doctor's advice, go on to receive more intensive chemotherapy, supported with a transplant of their own blood cells. This is standard treatment which patients may be offered anyway even if they didn't take part in this study. After maximal response has been achieved with the treatment described above, and as long as the myeloma has not got worse, patients will be treated with either long-term lenalidomide, lenalidomide with vorinostat, or receive no further treatment, with close observation.

Detailed Description
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The last ten years has seen the introduction of a number of effective new anti-myeloma agents into the clinical arena. These agents have been shown to be highly effective in the relapse setting and now are being introduced as treatment earlier in the disease course. This study aims to address in the randomised setting some of the key questions concerning the use of thalidomide, bortezomib, lenalidomide, carfilzomib and vorinostat in the initial treatment of multiple myeloma patients. Newly diagnosed patients of all ages with symptomatic myeloma requiring treatment are eligible. For initial treatment, thalidomide in combination with cyclophosphamide and dexamethasone, the UK gold standard, will be compared with the newer combination of lenalidomide, cyclophosphamide and dexamethasone with or without carfilzomib. For patients with a sub-optimal response to initial therapy, the response to the proteasome inhibitor bortezomib will be assessed, as previous studies have demonstrated that it is able to induce responses and improve progression-free and overall survival in patients resistant to standard chemotherapy. Patients young and fit enough to tolerate an autologous transplant will then proceed to high dose melphalan with peripheral blood stem cell rescue and then on to maintenance randomisation. Older or less fit patients will go directly to a maintenance randomisation. The value of lenalidomide and lenalidomide combined with vorinostat maintenance will then be assessed by randomising eligible patients to receive either lenalidomide, lenalidomide combined with vorinostat maintenance therapy, or close observation. The primary end points of the study are overall and progression-free survival (OS and PFS). Secondary end points include response and toxicity. A number of laboratory based studies will also be performed in order to determine patient specific factors predicting overall and progression-free survival and response to treatment.

Official Title
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Randomised Comparisons, in Myeloma Patients of All Ages, of Thalidomide, Lenalidomide, Carfilzomib and Bortezomib Induction Combinations, and of Lenalidomide and Combination Lenalidomide Vorinostat as Maintenance (Myeloma XI)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Induction (intensive pathway) - cyclophosphamide, lenalidomide, & dexamethasone (CRD) regimen
* Drug: Induction (intensive pathway) - cyclophosphamide, thalidomide, & dexamethasone (CTD) regimen
* Drug: Induction (intensive pathway) - carfilzomib, cyclophosphamide, lenalidomide, & dexamethasone (CCRD) regimen
* Drug: Induction (non-intensive pathway) - cyclophosphamide, lenalidomide, & dexamethasone attenuated (CRDa) regimen
* Drug: Induction (non-intensive pathway) - cyclophosphamide, thalidomide, & dexamethasone attenuated (CTDa) regimen
* Drug: Consolidation (intensive & non-intensive pathways) - bortezomib, cyclophosphamide, & dexamethasone (VCD) regimen
* Drug: Maintenance (intensive & non-intensive pathways) - lenalidomide maintenance
* Drug: Maintenance (intensive & non-intensive pathways - protocol v5.0 only) - lenalidomide plus vorinostat maintenance
* Drug: High dose melphalan therapy and autologous stem cell transplant (intensive pathway only)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or greater Newly diagnosed as having symptomatic multiple myeloma or non-secretory multiple myeloma Provide written informed consent Women of childbearing potential and male patients whose partner is a woman of child bearing potential must be prepared to use contraception in accordance with (and consent to) the Celgene-approved process for thalidomide and lenalidomide Risk Management and Pregnancy Prevention, or commit to absolute and continuous abstinence Women of child bearing potential must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene-approved process for thalidomide and lenalidomide Risk Management and Pregnancy Prevention Exclusion Criteria: Asymptomatic myeloma Solitary plasmacytoma of bone. (Patients with previous solitary plasmacytoma now progressed to symptomatic or non-secretory myeloma are eligible) Extramedullary plasmacytoma (without evidence of myeloma) Previous (<5 years since diagnosis) or concurrent active malignancies, except surgically-removed basal or squamous cell carcinoma of the skin, treated carcinoma in situ of the breast or cervix, or incidental histologic finding of prostate cancer (TMN stage of T1a or 1b). Patients with remote histories (>5 years) of other cured malignancies may be entered. Documented diagnosis of Myelodysplastic Syndrome (MDS) that meets International Prognostic Scoring System (IPSS) criteria for high-risk disease Previous treatment for myeloma, except the following: local radiotherapy to relieve bone pain or spinal cord compression; or prior bisphosphonate treatment; or corticosteroids within the last 3 months Known history of allergy contributable to compounds containing boron or mannitol Grade 2 or greater (NCI criteria) peripheral neuropathy Acute renal failure (unresponsive to up to 72 hours of rehydration, characterised by creatinine >500µmol/L or urine output <400 mL/day or requirement for dialysis) Lactating or breastfeeding Patient has active or prior hepatitis C Caution is advised in patients with a past history of ischaemic heart disease, pericardial disease, acute diffuse infiltrative pulmonary disease or psychiatric disorders, evidence of impaired marrow function or elevated liver function tests, but exclusion is essentially to be at the discretion of the treating clinician

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intensive pathway<br>The intensive pathway is aimed at younger and fitter patients who will receive the standard dose of chemotherapy. The initial treatments will be followed by high-dose chemotherapy with a stem cell transplant which is generally standard practice. Participants receive one treatment from each following stage in intensive pathway, depending on what they are randomised to (Protocol v6.0): Induction treatment: CRD regimen - cyclophosphamide, lenalidomide, dexamethasone CTD regimen - cyclophosphamide, thalidomide, dexamethasone CCRD regimen - carfilzomib, cyclophosphamide, lenalidomide, dexamethasone Consolidation treatment (depending on response to induction treatment): VCD regimen - bortezomib, cyclosphosphamide, dexamethasone No consolidation treatment High-dose therapy and stem cell transplant Maintenance treatment: Lenalidomide maintenance No maintenance Lenalidomide plus vorinostat maintenance (Protocol v5.0 only) | Drug: Induction (intensive pathway) - cyclophosphamide, lenalidomide, & dexamethasone (CRD) regimen<br>* Days 1 & 8 - cyclophosphamide 500 mg PO Days 1-21 - lenalidomide 25 mg daily PO Days 1-4 & 12-15 - dexamethasone 40 mg daily PO This cycle is repeated every 28 days<br>* Other names: Revlimid (lenalidomide);Drug: Induction (intensive pathway) - cyclophosphamide, thalidomide, & dexamethasone (CTD) regimen<br>* Days 1,8,15 (i.e. weekly) - cyclophosphamide 500 mg PO Continuously - thalidomide 50 mg hard capsules. Initially 100 mg daily PO for 3 weeks, increasing to 200 mg daily PO Days 1-4 and 12-15 - dexamethasone 40 mg daily PO The cycle is repeated every 21 days<br>Drug: Induction (intensive pathway) - carfilzomib, cyclophosphamide, lenalidomide, & dexamethasone (CCRD) regimen<br>* Days 1 & 8 - cyclophosphamide 500 mg PO Days 1 & 2, 8 & 9, 15 & 16 - carfilzomib 20*/36 mg/m2** IV (*carfilzomib 20 mg/m2 is only administered on days 1 and 2 of cycle 1; **carfilzomib will be dose capped at a body surface area of 2.2 m2) Days 1-21 - lenalidomide 25 mg daily PO Days 1-4, 8, 9 & 15, 16 - dexamethasone 40 mg daily PO This cycle is repeated every 28 days<br>* Other names: Revlimid (lenalidomide);Drug: Consolidation (intensive & non-intensive pathways) - bortezomib, cyclophosphamide, & dexamethasone (VCD) regimen<br>* Days 1, 4, 8 & 11 - bortezomib 1.3 mg/m2 SC or IV Days 1, 8, 15 - cyclophosphamide 500 mg PO Days 1-2, 4-5, 8-9 & 11-12 - dexamethasone 20 mg daily PO This cycle is repeated every 21 days<br>* Other names: Velcade (bortezomib);Drug: Maintenance (intensive & non-intensive pathways) - lenalidomide maintenance<br>* Days 1-21 - lenalidomide 10 mg daily PO This cycle is repeated every 28 days<br>* Other names: Revlimid (lenalidomide);Drug: Maintenance (intensive & non-intensive pathways - protocol v5.0 only) - lenalidomide plus vorinostat maintenance<br>* Days 1-21 - lenalidomide 10 mg daily PO Days 1-7 & 15-21 - vorinostat 300mg PO This cycle is repeated every 28 days<br>* Other names: Zolinza (vorinostat);Drug: High dose melphalan therapy and autologous stem cell transplant (intensive pathway only)<br>* High dose melphalan therapy and autologous stem cell transplant to be given as per local practice<br>|
| Active Comparator: Non-intensive pathway<br>The non-intensive pathway is aimed at participants who are not deemed suitable for the stem cell transplant, and will receive lower doses of some of the drugs. Interventions in each stage of non-intensive pathway (depending on what the participant has been randomised to) - from Protocol v6.0: Induction treatment CRDa regimen - cyclophosphamide, lenalidomide, dexamethasone attenuated CTDa regimen - cyclophosphamide, thalidomide, dexamethasone attenuated Consolidation treatment (depending on participant's response to induction treatment): VCD regimen - bortezomib, cyclosphosphamide, dexamethasone No consolidation treatment Maintenance treatment Lenalidomide maintenance No maintenance Lenalidomide plus vorinostat maintenance (*for participants recruited under Protocol v5.0 only*) | Drug: Induction (non-intensive pathway) - cyclophosphamide, lenalidomide, & dexamethasone attenuated (CRDa) regimen<br>* Days 1 & 8 - cyclophosphamide 500 mg PO Days 1-21 - lenalidomide 25 mg daily PO Days 1-4 & 15-18 - dexamethasone 20 mg daily PO This cycle is repeated every 28 days<br>* Other names: Revlimid (lenalidomide);Drug: Induction (non-intensive pathway) - cyclophosphamide, thalidomide, & dexamethasone attenuated (CTDa) regimen<br>* Days 1, 8, 15, 22 (weekly) - cyclophosphamide 500 mg PO Continuously - thalidomide 50 mg hard capsules; initially 50 mg daily PO for 4 weeks, increasing every 4 weeks by 50 mg increments to 200 mg daily PO Days 1-4 & 15-18 - dexamethasone 20 mg daily PO This cycle is repeated every 28 days<br>Drug: Consolidation (intensive & non-intensive pathways) - bortezomib, cyclophosphamide, & dexamethasone (VCD) regimen<br>* Days 1, 4, 8 & 11 - bortezomib 1.3 mg/m2 SC or IV Days 1, 8, 15 - cyclophosphamide 500 mg PO Days 1-2, 4-5, 8-9 & 11-12 - dexamethasone 20 mg daily PO This cycle is repeated every 21 days<br>* Other names: Velcade (bortezomib);Drug: Maintenance (intensive & non-intensive pathways) - lenalidomide maintenance<br>* Days 1-21 - lenalidomide 10 mg daily PO This cycle is repeated every 28 days<br>* Other names: Revlimid (lenalidomide);Drug: Maintenance (intensive & non-intensive pathways - protocol v5.0 only) - lenalidomide plus vorinostat maintenance<br>* Days 1-21 - lenalidomide 10 mg daily PO Days 1-7 & 15-21 - vorinostat 300mg PO This cycle is repeated every 28 days<br>* Other names: Zolinza (vorinostat);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival for induction chemotherapy comparisons is defined as the time from initial randomisation to the trial to death from any cause or last follow-up. Overall survival for maintenance therapy comparisons is defined from the time of maintenance randomisation. | Time from initial randomisation to the trial death from any cause or last follow-up | 
| Progression-free survival | Progression-free survival for induction chemotherapy comparisons is defined as the time from initial randomisation to the trial to progression or death from any cause. Patients who do not progress will be censored at the last date they were known to be alive and progression-free. Progression-free survival for maintenance therapy comparisons is defined from the time of maintenance randomisation | time from initial randomisation to the trial to progression or death from any cause | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response | Disease progression and response rates will be determined according to the modified International uniform response criteria for multiple myeloma | Response will be determined according to the modified international uniform response criteria for multiple myeloma | 
| Toxicity | Toxicity will be reported based on adverse events, as graded by CTCAE V4.0 and determined by routine clinical assessments at each centre | will be based on adverse events as graded by CTCAE v4.0 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myeloma, lenalidomide, Revlimid, cyclophosphamide, dexamethasone, bortezomib, Velcade, vorinostat, Zolinza, stem cell, carfilzomib, Kyprolis