Clinical trial NCT01554852: Use of Thalidomide, Lenalidomide, Carfilzomib, Bortezomib and Vorinostat in the Initial Treatment of Newly Diagnosed Multiple Myeloma Patients
Official title: 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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: myeloma
lenalidomide
Revlimid
cyclophosphamide
dexamethasone
bortezomib
Velcade
vorinostat
Zolinza
stem cell
carfilzomib
Kyprolis
Lead sponsor: University of Leeds
Sponsor class: OTHER
Collaborators: name: Celgene
name: Merck Sharp & Dohme LLC
name: Amgen
First posted: 2012-03-15
Enrollment: 4420
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall survival
timeFrame: Time from initial randomisation to the trial death from any cause or last follow-up
measure: Progression-free survival
timeFrame: time from initial randomisation to the trial to progression or death from any cause
Secondary outcomes:
measure: Response
timeFrame: Response will be determined according to the modified international uniform response criteria for multiple myeloma
measure: Toxicity
timeFrame: will be based on adverse events as graded by CTCAE v4.0
Other outcomes:
Locations:
city: United Kingdom
country: United Kingdom
facility: 112 sites UK wide
Study officials:
affiliation: Freeman Health System
name: Graham Jackson
role: PRINCIPAL_INVESTIGATOR
References:
citation: Agbuduwe C, Iqbal G, Cairns D, Menzies T, Dunn J, Gregory W, Kaiser M, Owen R, Pawlyn C, Child JA, Davies F, Morgan GJ, Jackson GH, Drayson MT, Basu S. Clinical characteristics and outcomes of IgD myeloma: experience across UK national trials. Blood Adv. 2022 Sep 13;6(17):5113-5123. doi: 10.1182/bloodadvances.2022007608.
citation: de Tute RM, Pawlyn C, Cairns DA, Davies FE, Menzies T, Rawstron A, Jones JR, Hockaday A, Henderson R, Cook G, Drayson MT, Jenner MW, Kaiser MF, Gregory WM, Morgan GJ, Jackson GH, Owen RG. Minimal Residual Disease After Autologous Stem-Cell Transplant for Patients With Myeloma: Prognostic Significance and the Impact of Lenalidomide Maintenance and Molecular Risk. J Clin Oncol. 2022 Sep 1;40(25):2889-2900. doi: 10.1200/JCO.21.02228. Epub 2022 Apr 4.
citation: Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM, Proszek PZ, Johnson DC, Kaiser MF, Melchor L, Aronson LI, Scales M, Pawlyn C, Mirabella F, Jones JR, Brioli A, Mikulasova A, Cairns DA, Gregory WM, Quartilho A, Drayson MT, Russell N, Cook G, Jackson GH, Leleu X, Davies FE, Morgan GJ. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin Oncol. 2015 Nov 20;33(33):3911-20. doi: 10.1200/JCO.2014.59.1503. Epub 2015 Aug 17.