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