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

University of Leeds

Status and phase: Unknown; Phase 3

Conditions: Multiple Myeloma

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

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT01554852

EudraCT number: 2009-010956-93

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 4,420 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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4,420 participants in 2 patient groups

Intensive pathway

Active Comparator group

Description:

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): 1. Induction treatment: 1. CRD regimen - cyclophosphamide, lenalidomide, dexamethasone 2. CTD regimen - cyclophosphamide, thalidomide, dexamethasone 3. CCRD regimen - carfilzomib, cyclophosphamide, lenalidomide, dexamethasone 2. Consolidation treatment (depending on response to induction treatment): 1. VCD regimen - bortezomib, cyclosphosphamide, dexamethasone 2. No consolidation treatment 3. High-dose therapy and stem cell transplant 4. Maintenance treatment: 1. Lenalidomide maintenance 2. No maintenance 3. Lenalidomide plus vorinostat maintenance (Protocol v5.0 only)

Treatment:

Drug: High dose melphalan therapy and autologous stem cell transplant (intensive pathway only)

Drug: Induction (intensive pathway) - carfilzomib, cyclophosphamide, lenalidomide, & dexamethasone (CCRD) regimen

Drug: Maintenance (intensive & non-intensive pathways) - lenalidomide maintenance

Drug: Induction (intensive pathway) - cyclophosphamide, lenalidomide, & dexamethasone (CRD) regimen

Drug: Consolidation (intensive & non-intensive pathways) - bortezomib, cyclophosphamide, & dexamethasone (VCD) regimen

Drug: Induction (intensive pathway) - cyclophosphamide, thalidomide, & dexamethasone (CTD) regimen

Drug: Maintenance (intensive & non-intensive pathways - protocol v5.0 only) - lenalidomide plus vorinostat maintenance

Non-intensive pathway

Active Comparator group

Description:

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: 1. Induction treatment 1. CRDa regimen - cyclophosphamide, lenalidomide, dexamethasone attenuated 2. CTDa regimen - cyclophosphamide, thalidomide, dexamethasone attenuated 2. Consolidation treatment (depending on participant's response to induction treatment): 1. VCD regimen - bortezomib, cyclosphosphamide, dexamethasone 2. No consolidation treatment 3. Maintenance treatment 1. Lenalidomide maintenance 2. No maintenance 3. Lenalidomide plus vorinostat maintenance (\*for participants recruited under Protocol v5.0 only\*)

Treatment:

Drug: Maintenance (intensive & non-intensive pathways) - lenalidomide maintenance

Drug: Induction (non-intensive pathway) - cyclophosphamide, thalidomide, & dexamethasone attenuated (CTDa) regimen

Drug: Induction (non-intensive pathway) - cyclophosphamide, lenalidomide, & dexamethasone attenuated (CRDa) regimen

Drug: Consolidation (intensive & non-intensive pathways) - bortezomib, cyclophosphamide, & dexamethasone (VCD) regimen

Drug: Maintenance (intensive & non-intensive pathways - protocol v5.0 only) - lenalidomide plus vorinostat maintenance